Patent Publication Number: US-8541201-B2

Title: Thrombopoietic compounds

Description:
The present application is a divisional of U.S. patent application Ser. No. 11/820,463, which was filed Jun. 18, 2007, which claims benefit under 35 U.S.C. §119 of U.S. Patent Application No. 60/814,490, which was filed Jun. 19, 2006, and U.S. Patent Application No. 60/844,301, which was filed Sep. 13, 2006, each of which is incorporated herein by reference in its entirety. 
    
    
     REFERENCE TO SEQUENCE LISTING 
     The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled A-1182-US-DIV_SeqList.txt, created Dec. 15, 2008, which is 288 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety. 
     FIELD OF THE INVENTION 
     Generally, the invention relates to the field of compounds, especially peptides and polypeptides that have thrombopoietic activity. The compounds of the invention may be used to increase of production platelets or platelet precursors (e.g., megakaryocytes) in a mammal 
     BACKGROUND OF THE INVENTION 
     The cloning of endogenous thrombopoietin (TPO) (Lok et al., Nature 369:568-571 (1994); Bartley et al., Cell 77:1117-1124 (1994); Kuter et al., Proc. Natl. Acad. Sci. USA 91:11104-11108 (1994); de Sauvage et al., Nature 369:533-538 (1994); Kato et al., Journal of Biochemistry 119:229-236 (1995); Chang et al., Journal of Biological Chemistry 270:511-514 (1995)) has rapidly increased our understanding of megakaryopoiesis (megakaryocyte production) and thrombopoiesis (platelet production). 
     Endogenous human TPO, a 60 to 70 kDa glycosylated protein primarily produced in the liver and kidney, consists of 332 amino acids (Bartley et al., Cell 77:1117-1124 (1994); Chang et al., Journal of Biological Chemistry 270:511-514 (1995)). The protein is highly conserved between different species, and has 23% homology with human erythropoietin (Gurney et al., Blood 85:981-988 (1995)) in the amino terminus (amino acids 1 to 172) (Bartley et al., Cell 77:1117-1124 (1994)). Endogenous TPO has been shown to possess all of the characteristics of the key biological regulator of thrombopoiesis. Its in vitro actions include specific induction of megakaryocyte colonies from both purified murine hematopoietic stem cells (Zeigler et al., Blood 84:4045-4052 (1994)) and human CD34 +  cells (Lok et al., Nature 369:568-571 (1994); Rasko et al., Stem Cells 15:33-42 (1997)), the generation of megakaryocytes with increased ploidy (Broudy et al., Blood 85:402-413 (1995)), and the induction of terminal megakaryocyte maturation and platelet production (Zeigler et al., Blood 84:4045-4052 (1994); Choi et al., Blood 85:402-413 (1995)). Conversely, synthetic antisense oligodeoxynucleotides to the TPO receptor (c-Mpl) significantly inhibit the colony-forming ability of megakaryocyte progenitors (Methia et al., Blood 82:1395-1401 (1993)). Moreover, c-Mpl knock-out mice are severely thrombocytopenic and deficient in megakaryocytes (Alexander et al., Blood 87:2162-2170 (1996)). 
     Recombinant human MGDF (rHuMGDF, Amgen Inc., Thousand Oaks, Calif.) is another thrombopoietic polypeptide related to TPO. It is produced using  E. coli  transformed with a plasmid containing cDNA encoding a truncated protein encompassing the amino-terminal receptor-binding domain of human TPO (Ulich et al., Blood 86:971-976 (1995)). The polypeptide is extracted, refolded, and purified, and a poly[ethylene glycol] (PEG) moiety is covalently attached to the amino terminus. The resulting molecule is referred to herein as PEG-rHuMGDF or MGDF for short. 
     Various studies using animal models (Ulich, T. R. et al., Blood 86:971-976 (1995); Hokom, M. M. et al., Blood 86:4486-4492 (1995)) have clearly demonstrated the therapeutic efficacies of TPO and MGDF in bone marrow transplantation and in the treatment of thrombocytopenia, a condition that often results from chemotherapy or radiation therapy. Preliminary data in humans have confirmed the utility of MGDF in elevating platelet counts in various settings. (Basser et al., Lancet 348:1279-81 (1996); Kato et al., Journal of Biochemistry 119:229-236 (1995); Ulich et al., Blood 86:971-976 (1995)). MGDF might be used to enhance the platelet donation process, since administration of MGDF increases circulating platelet counts to about three-fold the original value in healthy platelet donors. 
     TPO and MGDF exert their action through binding to the c-Mpl receptor which is expressed primarily on the surface of certain hematopoietic cells, such as megakaryocytes, platelets, CD34 +  cells and primitive progenitor cells (Debili, N. et al., Blood 85:391-401 (1995); de Sauvage, F. J. et al, Nature 369:533-538 (1994); Bartley, T. D., et al., Cell 77:1117-1124 (1994); Lok, S. et al., Nature 369: 565-8 (1994)). Like most receptors for interleukins and protein hormones, c-Mpl belongs to the class I cytokine receptor superfamily (Vigon, I. et al., Proc. Natl. Acad. Sci. USA 89:5640-5644 (1992)). Activation of this class of receptors involves ligand-binding induced receptor homodimerization which in turn triggers the cascade of signal transducing events. 
     In general, the interaction of a protein ligand with its receptor often takes place at a relatively large interface. However, as demonstrated in the case of human growth hormone bound to its receptor, only a few key residues at the interface actually contribute to most of the binding energy (Clackson, T. et al., Science 267:383-386 (1995)). This and the fact that the bulk of the remaining protein ligand serves only to display the binding epitopes in the right topology makes it possible to find active ligands of much smaller size. 
     In an effort toward this, the phage peptide library display system has emerged as a powerful technique in identifying small peptide mimetics of large protein ligands (Scott, J. K. et al., Science 249:386 (1990); Devlin, J. J. et al., Science 249:404 (1990)). 
     Further, in an effort to seek small structures as lead compounds in the development of therapeutic agents with more desirable properties, a different type of dimer of TMP and related structures were designed in which the C-terminus of one TMP peptide was linked to the N-terminus of a second TMP peptide, either directly or via a linker and the effects of this dimerization strategy on the bioactivity of the resulting dimeric molecules were then investigated (U.S. Pat. No. 6,835,809, Liu et al.; incorporated herein by reference in its entirety). In some cases, these so-called tandem dimers (C-N link) were designed to have linkers between the two monomers, the linkers being preferably composed of natural amino acids, therefore rendering their synthesis accessible to recombinant technologies (U.S. Pat. No. 6,835,809, supra). In addition, the tandem dimers may be further attached to one or more moieties that are derived from immunoglobulin proteins, referred to generally as the Fc region of such immunoglobulins. The resulting compounds are referred to as Fc fusions of TMP tandem dimers (U.S. Pat. No. 6,835,809, supra). 
     Antibodies comprise two functionally independent parts, a variable domain known as “Fab”, which binds antigen, and a constant domain, known as “Fc” which provides the link to effector functions such as complement fixation or phagocytosis. The Fc portion of an immunoglobulin has a long plasma half-life, whereas the Fab is short-lived. (Capon, et al., Nature 337:525-531 (1989)). 
     Therapeutic protein products have been constructed using the Fc domain to attempt to provide longer half-life or to incorporate functions such as Fc receptor binding, protein A binding, complement fixation, and placental transfer which all reside in the Fc region of immunoglobulins (Capon, et al., Nature 337:525-531 (1989)). For example, the Fc region of an IgG1 antibody has been fused to CD30-L, a molecule which binds CD30 receptors expressed on Hodgkin&#39;s Disease tumor cells, anaplastic lymphoma cells, T-cell leukemia cells and other malignant cell types. See, U.S. Pat. No. 5,480,981. IL-10, an anti-inflammatory and antirejection agent has been fused to murine Fcγ2a in order to increase the cytokine&#39;s short circulating half-life (Zheng, X. et al., Journal of Immunology, 154: 5590-5600 (1995)). Studies have also evaluated the use of tumor necrosis factor receptor linked with the Fc protein of human IgG1 to treat patients with septic shock (Fisher, C. et al., N. Engl. J. Med., 334: 1697-1702 (1996); Van Zee, K. et al., The Journal of Immunology, 156: 2221-2230 (1996)). Fc has also been fused with CD4 receptor to produce a therapeutic protein for treatment of AIDS. See, Capon et al., Nature, 337:525-531 (1989). In addition, interleukin 2 has been fused to the Fc portion of IgG1 or IgG3 to overcome the short half life of interleukin 2 and its systemic toxicity. See, Harvill et al., Immunotechnology, 1: 95-105 (1995). 
     The development of therapeutic agents can also be achieved by the use of peptide library screening. The interaction of a protein ligand with its receptor often takes place at a relatively large interface. However, as demonstrated for human growth hormone and its receptor, only a few key residues at the interface contribute to most of the binding energy. Clackson et al.,  Science  267: 383-6 (1995). The bulk of the protein ligand merely displays the binding epitopes in the right topology or serves functions unrelated to binding. Thus, molecules of only “peptide” length (2 to 40 amino acids and even 2 to 80 amino acids) can bind to the receptor protein of a given large protein ligand. Such peptides may mimic the bioactivity of the large protein ligand (“peptide agonists”) or, through competitive binding, inhibit the bioactivity of the large protein ligand (“peptide antagonists”). 
     Phage display peptide libraries have emerged as a powerful method in identifying such peptide agonists and antagonists. See, for example, Scott et al.,  Science  249: 386 (1990); Devlin et al.,  Science  249: 404 (1990); U.S. Pat. No. 5,223,409, issued Jun. 29, 1993; U.S. Pat. No. 5,733,731, issued Mar. 31, 1998; U.S. Pat. No. 5,498,530, issued Mar. 12, 1996; U.S. Pat. No. 5,432,018, issued Jul. 11, 1995; U.S. Pat. No. 5,338,665, issued Aug. 16, 1994; U.S. Pat. No. 5,922,545, issued Jul. 13, 1999; WO 96/40987, published Dec. 19, 1996; and WO 98/15833, published Apr. 16, 1998 (each of which is incorporated herein by reference). In such libraries, random peptide sequences are displayed by fusion with coat proteins of filamentous phage. Typically, the displayed peptides are affinity-eluted against an antibody-immobilized extracellular domain of a receptor. The retained phages may be enriched by successive rounds of affinity purification and repropagation. The best binding peptides may be sequenced to identify key residues within one or more structurally related families of peptides. See, e.g., Cwirla et al.,  Science  276: 1696-9 (1997), in which two distinct families were identified. The peptide sequences may also suggest which residues may be safely replaced by alanine scanning or by mutagenesis at the DNA level. Mutagenesis libraries may be created and screened to further optimize the sequence of the best binders. Lowman,  Ann. Rev. Biophys. Biomol. Struct.  26: 401-24 (1997). 
     Other methods compete with phage display in peptide research. A peptide library can be fused to the carboxyl terminus of the lac repressor and expressed in  E. coli . Another  E. coli -based method allows display on the cell&#39;s outer membrane by fusion with a peptidoglycan-associated lipoprotein (PAL). Hereinafter, these and related methods are collectively referred to as “ E. coli  display.” Another biological approach to screening soluble peptide mixtures uses yeast for expression and secretion. See Smith et al.,  Mol. Pharmacol.  43: 741-8 (1993). Hereinafter, the method of Smith et al. and related methods are referred to as “yeast-based screening.” In another method, translation of random RNA is halted prior to ribosome release, resulting in a library of polypeptides with their associated RNA still attached. Hereinafter, this and related methods are collectively referred to as “ribosome display.” Other methods employ chemical linkage of peptides to RNA; see, for example, Roberts &amp; Szostak,  Proc. Natl. Acad. Sci. USA,  94: 12297-12303 (1997). Hereinafter, this and related methods are collectively referred to as “RNA-peptide screening.” Chemically derived peptide libraries have been developed in which peptides are immobilized on stable, non-biological materials, such as polyethylene rods or solvent-permeable resins. Another chemically derived peptide library uses photolithography to scan peptides immobilized on glass slides. Hereinafter, these and related methods are collectively referred to as “chemical-peptide screening.” Chemical-peptide screening may be advantageous in that it allows use of D-amino acids and other unnatural analogues, as well as non-peptide elements. Both biological and chemical methods are reviewed in Wells &amp; Lowman,  Curr. Opin. Biotechnol.  3: 355-362 (1992). 
     In the case of known bioactive peptides, rational design of peptide ligands with favorable therapeutic properties can be completed. In such an approach, one makes stepwise changes to a peptide sequence and determines the effect of the substitution upon bioactivity or a predictive biophysical property of the peptide (e.g., solution structure). Hereinafter, these techniques are collectively referred to as “rational design.” In one such technique, one makes a series of peptides in which one replaces a single residue at a time with alanine This technique is commonly referred to as an “alanine walk” or an “alanine scan.” When two residues (contiguous or spaced apart) are replaced, it is referred to as a “double alanine walk.” The resultant amino acid substitutions can be used alone or in combination to result in a new peptide entity with favorable therapeutic properties. 
     Structural analysis of protein-protein interaction may also be used to suggest peptides that mimic the binding activity of large protein ligands. In such an analysis, the crystal structure may suggest the identity and relative orientation of critical residues of the large protein ligand, from which a peptide may be designed. See, e.g., Takasaki et al.,  Nature Biotech.  15: 1266-1270 (1997). Hereinafter, these and related methods are referred to as “protein structural analysis.” These analytical methods may also be used to investigate the interaction between a receptor protein and peptides selected by phage display, which may suggest further modification of the peptides to increase binding affinity. 
     Conceptually, one may discover peptide mimetics of any protein using phage display and the other methods mentioned above. These methods have been used for epitope mapping, for identification of critical amino acids in protein-protein interactions, and as leads for the discovery of new therapeutic agents. E.g., Cortese et al.,  Curr. Opin. Biotech.  7: 616-621 (1996). Peptide libraries are now being used most often in immunological studies, such as epitope mapping. Kreeger,  The Scientist  10(13): 19-20 (1996). 
     Of particular interest here is use of peptide libraries and other techniques in the discovery of pharmacologically active peptides. Some of these peptides have been modified (e.g., to form C-terminally cross-linked dimers). Typically, peptide libraries were screened for binding to a receptor for a pharmacologically active protein (e.g., EPO receptor). In at least one instance (CTLA4), the peptide library was screened for binding to a monoclonal antibody. 
     Peptides identified by peptide library screening were for a long time regarded simply as “leads” in development of therapeutic agents rather than as therapeutic agents themselves. Like other proteins and peptides, they would be rapidly removed in vivo either by renal filtration, cellular clearance mechanisms in the reticuloendothelial system, or proteolytic degradation. Francis,  Focus on Growth Factors  3: 4-11 (1992). As a result, the art used the identified peptides to validate drug targets or as scaffolds for design of organic compounds that might not have been as easily or as quickly identified through chemical library screening. Lowman,  Ann. Rev. Biophvs. Biomol. Struct.  26: 401-424 (1997); Kay et al.,  Drug Disc. Today  3: 370-378 (1998). 
     A more recent development is fusion of randomly generated peptides with the Fc domain. See U.S. Pat. No. 6,660,843, issued Dec. 9, 2003 to Feige et al. (incorporated herein by reference in its entirety). Such molecules have come to be known as “peptibodies.” They include one or more peptides linked to the N-terminus, C-terminus, amino acid sidechains, or to more than one of these sites. Peptibody technology enables design of therapeutic agents that incorporate peptides that target one or more ligands or receptors, tumor-homing peptides, membrane-transporting peptides, and the like. Peptibody technology has proven useful in design of a number of such molecules, including linear and disulfide-constrained peptides, “tandem peptide multimers” (i.e., more than one peptide on a single chain of an Fc domain). See, for example, U.S. Pat. No. 6,660,843; U.S. Pat. App. No. 2003/0195156, published Oct. 16, 2003 (corresponding to WO 02/092620, published Nov. 21, 2002); U.S. Pat. App. No. 2003/0176352, published Sep. 18, 2003 (corresponding to WO 03/031589, published Apr. 17, 2003); U.S. Ser. No. 09/422,838, filed Oct. 22, 1999 (corresponding to WO 00/24770, published May 4, 2000); U.S. Pat. App. No. 2003/0229023, published Dec. 11, 2003; WO 03/057134, published Jul. 17, 2003; U.S. Pat. App. No. 2003/0236193, published Dec. 25, 2003 (corresponding to PCT/US04/010989, filed Apr. 8, 2004); U.S. Ser. No. 10/666,480, filed Sep. 18, 2003 (corresponding to WO 04/026329, published Apr. 1, 2004), each of which is hereby incorporated by reference in its entirety. 
     The art would benefit from further technology enabling such rational design of polypeptide therapeutic agents, because there remains a need in the art for additional compounds that have a biological activity of stimulating the production of platelets (thrombopoietic activity) and/or platelet precursor cells, especially megakaryocytes (megakaryopoietic activity). 
     SUMMARY OF THE INVENTION 
     Provided herein is a group of compounds that are capable of binding to and triggering a transmembrane signal through, i.e., activating, the c-Mpl receptor, which is the same receptor that mediates the activity of endogenous thrombopoietin (TPO). Thus, the compounds have thrombopoietic activity, i.e., the ability to stimulate, in vivo and in vitro, the production of platelets, and/or megakaryocytopoietic activity, i.e., the ability to stimulate, in vivo and in vitro, the production of platelet precursors. 
     The compounds comprise polypeptides or peptides modified to include at least one antibody Fc region and, optionally, one or more water soluble polymers. 
     In one aspect, a substantially homogenous compound is provided comprising a structure set out in Formula I,
 
[(X 1 ) a -(F 1 ) z -(X 2 ) b ]-(L 1 ) c -WSP d    Formula I:
 
and multimers thereof, wherein:
         F 1  is a vehicle;   X 1  is independently selected from:
           P 1 -(L 2 ) e -   P 2 -(L 3 ) f -P 1 -(L 2 ) e -   P 3 -(L 4 ) g -P 2 -(L 3 ) f -P 1 -(L 2 ) e - and   P 4 -(L 5 ) h -P 3 -(L 4 ) g -P 2 -(L 3 ) f -P 1 -(L 2 ) e -   
           X 2  is independently selected from:
           -(L 2 ) e -P 1 ,   -(L 2 ) e -P 1 -(L 3 ) f -P 2 ,   -(L 2 ) e -P 1 -(L 3 ) f -P 2 -(L 4 ) g -P 3 ,and   -(L 2 ) e P 1 -(L 3 ) f -P 2 -(L 4 ) g -P 3 -(L 5 ) h -P 4      
           wherein P 1 , P 2 , P 3 , and P 4  are each independently sequences of pharmacologically active peptides;   L 1 , L 2 , L 3 , L 4 , and L 5  are each independently linkers;   a, b, c, d, e, f, g, and h are each independently 0 or 1;   z is 0, 1, 2, or more; and   WSP is a water soluble polymer, the attachment of which is effected at any reactive moiety in F 1 ;       

     said compound having a property of improved bioefficacy when administered in a multidose regimen. In one aspect, the compound is a multimer, and in another aspect, the compound is a dimer. 
     In one embodiment, the invention provides a compound of Formula I comprising a structure set out in Formula II
 
[X 1 -(F 1 ) z ]-(L 1 ) c -WSP d   Formula II:
 
wherein F 1  is an Fc domain and is attached at the C-terminus of X 1 , and zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Compounds having this structure are provided as a multimer in one aspect and a dimer in another aspect.
 
     In another embodiment, the invention provides a compound of Formula I comprising a structure set out in Formula III
 
[(F 1 ) z -X 2 ]-(L 1 ) c -WSP d   Formula III:
 
wherein F 1  is an Fc domain and is attached at the N-terminus of X 2 , and zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Multimers and dimers of a compound having this structure are also provided.
 
     The invention also provides a compound of Formula I comprising a structure set out in Formula IV
 
[(F 1 ) z -(L 1 ) e -P 1 ]-(L 1 ) c -WSP d   Formula IV:
 
wherein F 1  is an Fc domain and is attached at the N-terminus of -(L 1 ) c -P 1  and, zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Multimers and dimers of a compound having this structure are also provided.
 
     The invention further contemplates a compound of Formula I comprising a structure set out in Formula V
 
[(F 1 ) z -(L 1 ) e -P 1 -(L 2 ) f -P 2 ]-(L 1 ) c -WSP d   Formula V:
 
wherein F 1  is an Fc domain and is attached at the N-terminus of -L 1 -P 1 -L 2 -P 2  and, zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Multimers and dimers of a compound having this structure are also provided.
 
     In one aspect, a compound is provided as described above wherein P 1  and/or P 2  are independently selected from a TPO mimetic set out in any of Tables 1-6 and 8 (see Examples herein). In one aspect, P 1  and/or P 2  have the same amino acid sequence. 
     In another aspect, a compound is provided as described above wherein L 1  is a linker group which is optional and, if present, is independently selected from the linker groups consisting of 
     Y n , wherein Y is a naturally-occurring amino acid or a stereoisomer thereof and n is 1 through 20; 
     (Gly) n , wherein n is 1 through 20, and when n is greater than 1, up to half of the Gly residues may be substituted by another amino acid selected from the remaining 19 natural amino acids or a stereoisomer thereof; 
     
       
         
           
               
               
               
            
               
                   
                 (Gly) 3 Lys(Gly) 4 ; 
                 (SEQ ID NO: 4) 
               
               
                   
                   
               
               
                   
                 (Gly) 3 AsnGlySer(Gly) 2 ; 
                 (SEQ ID NO: 5) 
               
               
                   
                   
               
               
                   
                 (Gly) 3 Cys(Gly) 4 ; 
                 (SEQ ID NO: 6) 
               
               
                   
                   
               
               
                   
                 GlyProAsnGly; 
                 (SEQ ID NO: 7) 
               
            
           
         
       
     
     a Cys residue; and 
     (CH 2 ) n , wherein n is 1 through 20. 
     In one aspect, L is selected from the group consisting of Y n , wherein Y is selected a naturally-occurring amino acid or a stereoisomer thereof and n is 1 through 20. In another aspect, L comprises (Gly) n , wherein n is 1 through 20, and when n is greater than 1, up to half of the Gly residues may be substituted by another amino acid selected from the remaining 19 natural amino acids or a stereoisomer thereof. In yet another aspect, L is selected from the group consisting of 
     
       
         
           
               
               
               
            
               
                   
                 (Gly) 3 Lys(Gly) 4 ; 
                 (SEQ ID NO: 4) 
               
               
                   
               
               
                   
                 (Gly) 3 AsnGlySer(Gly) 2 ; 
                 (SEQ ID NO: 5) 
               
               
                   
               
               
                   
                 (Gly) 3 Cys(Gly) 4 ; 
                 (SEQ ID NO: 6) 
               
               
                   
                 and 
                   
               
               
                   
               
               
                   
                 GlyProAsnGly. 
                 (SEQ ID NO: 7) 
               
            
           
         
       
     
     In a further aspect of the invention, L comprises a Cys residue. In another aspect, the invention includes a compound wherein L comprises (CH 2 ) n , wherein n is 1 through 20. 
     In another aspect, a compound of the invention is provided as described herein wherein F 1  is an Fc domain. In another aspect, a compound is provided wherein WSP is PEG. In yet another aspect, a compound as described above is provided wherein F 1  is an Fc domain and WSP is PEG. 
     In one aspect, the PEG component of a compound described herein has a molecular weight of between about 2 kDa and 100 kDa. In another aspect, the PEG component of a compound described herein has a molecular weight of between about 6 kDa and 25 kDa. 
     The invention further provides a composition comprising a compound described herein wherein the composition comprises at least 50% PEGylated compound. In another aspect, the composition comprises at least 75% PEGylated compound, at least 85% PEGylated compound, at least 90% PEGylated compound, at least 95% PEGylated compound, and at least 99% PEGylated compound. 
     The invention also provides a method of treating a hematopoietic disorder comprising administering a compound or composition described herein in a regimen effective to treat said disorder. 
     In one embodiment, P comprises the following general structure: 
     U 1 -Y 1 (Cys, Leu, Met, Pro, Gln, Val, or X 1 )-Y 2 (Phe, Lys, Leu, Asn, Gln, Arg, Ser, Thr, Val, or X 2 )-Y 3 (Cys, Phe, Ile, Leu, Met, Arg, Ser, Val, Trp, or X 3 )-Y 4 -Y 5 (Ala, Asp, Glu, Gly, Lys, Met, Gln, Arg, Ser, Thr, Val, Tyr, or X 5 )-Y 6 (Cys, Phe, Gly, Leu, Met, Ser, Val, Trp, Tyr, or X 6 )-Y 7 (Cys, Gly, Ile, Lys, Leu, Met, Asn, Arg, Val, or X 7 )-U 2 , 
     wherein at least one of Y 1 -Y 3  and Y 5 -Y 7  corresponds to a respective X 1 -X 3  and X 5 -X 7 ; 
     wherein U 1  or U 2  is any amino acid or peptide, 
     wherein when Y 1  is not an amino acid selected from the group consisting of Cys, Leu, Met, Pro, Gln, and Val, then X 1  is selected from the group consisting of Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Asn, Arg, Ser, Thr, Trp, and Tyr; 
     wherein when Y 2  is not an amino acid selected from the group consisting of Phe, Lys, Leu, Asn, Gln, Arg, Ser, Thr, and Val, then X 2  is selected from the group consisting of Ala, Cys, Asp, Glu, Gly, His, Ile, Met, Pro, Trp, and Tyr; 
     wherein when Y 3  is not an amino acid selected from the group consisting of Cys, Phe, Ile, Leu, Met, Arg, Ser, Val, and Trp, then X 3  is selected from the group consisting of Ala, Asp, Glu, Gly, His, Lys, Asn, Pro, Gln, Thr, and Tyr; 
     wherein Y 4  is any amino acid; 
     wherein when Y 5  is not an amino acid selected from the group consisting of Ala, Asp, Glu, Gly, Lys, Met, Gln, Arg, Ser, Thr, Val, and Tyr, then X 5  is selected from the group consisting of Cys, Phe, His, Ile, Leu, Asn, Pro, and Trp; 
     wherein when Y 6  is not an amino acid selected from the group consisting of Cys, Phe, Gly, Leu, Met, Ser, Val, Trp, and Tyr, then X 6  is selected from the group consisting of Ala, Asp, Glu, His, Ile, Lys, Asn, Pro, Gln, Arg, and Thr; and 
     wherein Y 7  is not an amino acid selected from the group consisting of Cys, Gly, Ile, Lys, Leu, Met, Asn, Arg, and Val, then X 7  is selected from the group consisting of Ala, Asp, Glu, Phe, His, Pro, Gln, Ser, Thr, Trp, and Tyr; 
     and physiologically acceptable salts thereof. 
     In another aspect, the invention contemplates compounds, wherein at least two of Y 1 -Y 7  corresponds to two of X 1 -X 7 , respectively; at least three of Y 1 -Y 7  corresponds to three of X 1 -X 7 , respectively; at least four of Y 1 -Y 7  corresponds to four of X 1 -X 7 , respectively; at least five of Y 1 -Y 7  corresponds to five of X 1 -X 7 , respectively; at least six of Y 1 -Y 7  corresponds to six of X 1 -X 7 , respectively; and only one of Y 1 -Y 7  corresponds to one of X 1 -X 7 , respectively. 
     In one embodiment, the invention includes a compound of a structure set out in Formula I wherein at least a or b is 1. 
     In another embodiment, the invention includes a compound of a structure set out in Formula I wherein b, c, d, e, f, g, and h are 0. 
     In a further embodiment, the invention includes a compound that binds to an mpl receptor consisting essentially of a structure set out in Formula I. 
     In another embodiment, the invention includes a compound of a structure set out in Formula I wherein 
     F 1  is an Fc domain modified so that it comprises at least one X 3  in a loop region; 
     X 3  is independently selected from
         -(L 6 ) i -P 5 -(L 7 ) j ,   -(L 6 ) i -P 5 -(L 7 ) j -P 6 -(L 8 ) k ,   -(L 6 ) i -P 5 -(L 7 ) j -P 6 -(L 8 ) k -P 7 -(L 9 ) l , and   -(L 6 ) i -P 5 -(L 7 ) j -P 6 -(L 8 ) k -P 7 -(L 9 ) l -P 8 -(L 10 ) m ;       

     P 5 , P 6 , P 7 , and P 8  are each independently sequences of pharmacologically active peptides; 
     L 6 , L 7 , L 8 , L 9 , and L 10  are each independently linkers; 
     i, j, k, l, and m are each independently 0 or 1; and 
     z is 1, 2, or more. 
     The invention includes a compound of the aforementioned structure wherein a and b are each 0. 
     In one embodiment, the invention includes a compound wherein the Fc domain comprises an IgG Fc domain. In one aspect, this IgG Fc domain is an IgG1 Fc domain. 
     In another embodiment, the Fc domain comprises a sequence selected from any of SEQ ID NOS: 3 and 344-352. In a further aspect, the IgG1 Fc domain comprises SEQ ID NO: 3 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 428, 429, 431, 432, 434, 435, 437, 439, 441, and 443. In yet another aspect, X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 430, 433, 436, 438, 440, 442, and 444. In a more particular aspect, X 3  is inserted at Leu 139 /Thr 140 . 
     In yet another embodiment, the IgG1 Fc domain comprises SEQ ID NO: 347 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 428, 429, 431, 432, 434, 435, 437, 439, 441, and 443. In one aspect, X 3  is inserted at H 53 /E 54 , Y 81 /N 82 , N 110 /K 111 , L 143 /T 144 , Q 171 /P 172 , E 173 /N 174 , S 186 /D 187 , G 188 /S 189 , or G 205 /N 206 . 
     In a further embodiment, the IgG1 Fc domain comprises SEQ ID NO: 348 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 428, 429, 431, 432, 434, 435, 439, 441, 443, and 451. In one aspect, X 3  is inserted at H 53 /E 54 , Y 81 /N 82 , N 110 /K 111 , L 143 /T 144 , Q 171 /P 172 , E 173 /N 174 , S 186 /D 187 , G 188 /S 189 , or G 205 /N 206 . 
     The invention also includes a compound wherein the Fc domain comprises an IgG3 Fc domain. In one aspect, the IgG3 Fc domain comprises SEQ ID NO: 349 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 426, 428, 429, 431, 434, 446, 448, 451, 452, and 453. In another aspect, X 3  is inserted at H 100 /E 101 , F 128 /N 129 , N 157 /K 158 , M 190 /T 191 , Q 218 /P 219 , E 220 /N 221 , S 232 /D 233 , G 234 /S 235 , or G 252 /N 253 . 
     In yet another embodiment, the invention includes a compound wherein the Fc domain comprises an IgG2 Fc domain. In one aspect, the Fc domain comprises SEQ ID NO: 350 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 428, 429, 431, 439, 443, 446, 447, 449, 451, and 453. In another aspect, X 3  is inserted at H 49 /E 50 , F 77 /N 78 , N 106 /K 107 , M 139 /T 140 , Q 167 /P 168 , E 169 /N 170 , S 181 /D 182 , G 183 /S 184 , or G 201 /N 202 . 
     In another embodiment, the invention includes a compound wherein the Fc domain comprises an IgG4 Fc domain. In one aspect, the Fc domain comprises SEQ ID NO: 351 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 427, 428, 431, 434, 439, 441, 445, 446, 450, and 451. In another aspect, X 3  is inserted at Q 50 /E 51 , F 78 /N 79 , N 107 /K 108 , M 140 /T 141 , Q 168 /P 169 , E 170 /N 171 , S 182 /D 183 , G 184 /S 185 , or G 202 /N 203 . 
     In a further embodiment, the invention includes a compound wherein the Fc domain comprises SEQ ID NO: 352 and X 3  is inserted into or replaces all or part of a sequence selected from SEQ ID NOS: 428, 429, 435, 431, 434, 439, 443, 446, 451, and 453. In one aspect, X 3  is inserted at H 112 /E 113 , F 140 /N 141 , N 169 /K 170 , M 204 /T 205 , Q 232 /P 233 , E 234 /N 235 , S 246 /D 247 , G 248 /S 249 , or G 268 /N 269 . 
     In yet another embodiment, the invention includes compounds wherein at least two, or at least three, or at least four, or at least five, or at least six of Y 1 -Y 7  corresponds to two of X 1 -X 7 , respectively. However, the invention also includes compounds wherein only one of Y 1 -Y 7  corresponds to one of X 1 -X 7 , respectively. 
     Exemplary compounds of the general structure are shown below. Single letter amino acid abbreviations are used for these peptides. 
     
       
         
           
               
               
               
            
               
                   
                 QGCSSGGPTQREWLQCRRMQHS 
                 (SEQ ID NO: 8) 
               
               
                   
                   
               
               
                   
                 QGCSSGGPTLREWQQCRRMQHS 
                 (SEQ ID NO: 9) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKIWLQCVRAKHS 
                 (SEQ ID NO: 10) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKNWLQCVRAKHS 
                 (SEQ ID NO: 11) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKLWLQCVRAKHS 
                 (SEQ ID NO: 12) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKHWLQCVRAKHS 
                 (SEQ ID NO: 13) 
               
               
                   
                   
               
               
                   
                 QGGCRSGPTNREWLACREVQHS 
                 (SEQ ID NO: 14) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRQWPLCRQGRHS 
                 (SEQ ID NO: 15) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRLWLLCRQGRHS 
                 (SEQ ID NO: 16) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRIWLLCRQGRHS 
                 (SEQ ID NO: 17) 
               
            
           
         
       
     
     Further exemplary compounds comprising one or more Fc regions linked to a peptide are provided below. Single letter amino acid abbreviations for the peptide are used. 
     
       
         
           
               
               
               
            
               
                   
                 Fc-QGCSSGGPTQREWLQCRRMQHS 
                 (SEQ. ID NO: 18) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSSGGPTLREWQQCRRMQHS 
                 (SEQ. ID NO: 19) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSWGGPTLKIWLQCVRAKHS 
                 (SEQ ID NO: 20) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSWGGPTLKNWLQCVRAKHS 
                 (SEQ ID NO: 21), 
               
               
                   
                   
               
               
                   
                 Fc-QGCSWGGPTLKLWLQCVRAKHS 
                 (SEQ ID NO: 22), 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKIWLQCVRAKHS-Fc 
                 (SEQ ID NO: 23) 
               
               
                   
                   
               
               
                   
                 Fc 2 -QGGCRSGPTNREWLACREVQHS 
                 (SEQ ID NO: 24) 
               
               
                   
                   
               
               
                   
                 Fc 2 -QGCSWGGPTLKLWLQCVRAKHS 
                 (SEQ ID NO: 25) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRQWPLCRQGRHS-Fc 
                 (SEQ ID NO: 26) 
               
               
                   
                   
               
               
                   
                 Fc-QGTCEQGPTLRQWPLCRQGRHS 
                 (SEQ ID NO: 27) 
               
            
           
         
       
     
     Further exemplary compounds (Y 1 -Y 7 ) are provided below. Single letter amino acid abbreviations for the peptide are used. Y 4  may comprise any of the 20 naturally-occurring amino acids or non-naturally occurring amino acids well known in the art. 
     
       
         
           
               
               
               
            
               
                   
                 ETLY 4 QWL 
                 (SEQ ID NO: 28) 
               
               
                   
                   
               
               
                   
                 HTLY 4 QWL 
                 (SEQ ID NO: 29) 
               
               
                   
                   
               
               
                   
                 KTLY 4 QWL 
                 (SEQ ID NO: 30) 
               
               
                   
                   
               
               
                   
                 GTGY 4 QWL 
                 (SEQ ID NO: 31) 
               
               
                   
                   
               
               
                   
                 PTLY 4 IWL 
                 (SEQ ID NO: 32) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 33) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWF 
                 (SEQ ID NO: 34) 
               
               
                   
                   
               
               
                   
                 PTLY 4 HWL 
                 (SEQ ID NO: 35) 
               
               
                   
                   
               
               
                   
                 PILY 4 EWL 
                 (SEQ ID NO: 36) 
               
               
                   
                   
               
               
                   
                 KTLY 4 EWL 
                 (SEQ ID NO: 37) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 38) 
               
               
                   
                   
               
               
                   
                 PMLY 4 EWL 
                 (SEQ ID NO: 39) 
               
               
                   
                   
               
               
                   
                 PTLY 4 NWL 
                 (SEQ ID NO: 40) 
               
               
                   
                   
               
               
                   
                 PPLY 4 EWL 
                 (SEQ ID NO: 41) 
               
               
                   
                   
               
               
                   
                 PTQY 4 EWQ 
                 (SEQ ID NO: 42) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWS 
                 (SEQ ID NO: 43) 
               
               
                   
                   
               
               
                   
                 PTYY 4 EWL 
                 (SEQ ID NO: 44) 
               
               
                   
                   
               
               
                   
                 PTAY 4 QWL 
                 (SEQ ID NO: 45) 
               
               
                   
                   
               
               
                   
                 PCLY 4 QWL 
                 (SEQ ID NO: 46) 
               
               
                   
                   
               
               
                   
                 PTLY 4 FWL 
                 (SEQ ID NO: 47) 
               
               
                   
                   
               
               
                   
                 PTGY 4 QWL 
                 (SEQ ID NO: 48) 
               
               
                   
                   
               
               
                   
                 PTLY 4 HWL 
                 (SEQ ID NO: 49) 
               
               
                   
                   
               
               
                   
                 PILY 4 IWL 
                 (SEQ ID NO: 50) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 51) 
               
               
                   
                   
               
               
                   
                 PMLY 4 QWL 
                 (SEQ ID NO: 52) 
               
               
                   
                   
               
               
                   
                 PTLY 4 NWL 
                 (SEQ ID NO: 53) 
               
               
                   
                   
               
               
                   
                 PTPY 4 QWL 
                 (SEQ ID NO: 54) 
               
               
                   
                   
               
               
                   
                 PTLY 4 QWQ 
                 (SEQ ID NO: 55) 
               
               
                   
                   
               
               
                   
                 PTLY 4 QWS 
                 (SEQ ID NO: 56) 
               
               
                   
                   
               
               
                   
                 PTTY 4 QWT 
                 (SEQ ID NO: 57) 
               
               
                   
                   
               
               
                   
                 PTLY 4 WWL 
                 (SEQ ID NO: 58) 
               
               
                   
                   
               
               
                   
                 PTYY 4 QWL 
                 (SEQ ID NO: 59) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWF 
                 (SEQ ID NO: 60) 
               
               
                   
                   
               
               
                   
                 GTLY 4 EWL 
                 (SEQ ID NO: 61) 
               
               
                   
                   
               
               
                   
                 PTLY 4 HWL 
                 (SEQ ID NO: 62) 
               
               
                   
                   
               
               
                   
                 PILY 4 EWL 
                 (SEQ ID NO: 63) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 64) 
               
               
                   
                   
               
               
                   
                 PTQY 4 EWL 
                 (SEQ ID NO: 65) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWS 
                 (SEQ ID NO: 66) 
               
               
                   
                   
               
               
                   
                 PTLY 4 FWF 
                 (SEQ ID NO: 67) 
               
               
                   
                   
               
               
                   
                 GTLY 4 QWL 
                 (SEQ ID NO: 68) 
               
               
                   
                   
               
               
                   
                 PTLY 4 IWL 
                 (SEQ ID NO: 69) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 70) 
               
               
                   
                   
               
               
                   
                 PTLY 4 NWL 
                 (SEQ ID NO: 71) 
               
               
                   
                   
               
               
                   
                 PTLY 4 QWP 
                 (SEQ ID NO: 72) 
               
               
                   
                   
               
               
                   
                 PTLY 4 WWL 
                 (SEQ ID NO: 73) 
               
               
                   
                   
               
               
                   
                 PTYY 4 QWL 
                 (SEQ ID NO: 74) 
               
            
           
         
       
     
     Further exemplary compounds are provided below. Single letter amino acid abbreviations for the peptide are used. 
     
       
         
           
               
               
               
            
               
                   
                 KDTEVTAPRLWMVASVDE 
                 (SEQ ID NO: 75) 
               
               
                   
                   
               
               
                   
                 REMEGPTMRQWLAYRAVL 
                 (SEQ ID NO: 76) 
               
               
                   
                   
               
               
                   
                 CQNAGPTLRCWLAGRAYM 
                 (SEQ ID NO: 77) 
               
               
                   
                   
               
               
                   
                 CEREGPTLRCWLATREGS 
                 (SEQ ID NO: 78) 
               
               
                   
                   
               
               
                   
                 WRIEGPTLRHWLAARAWD 
                 (SEQ ID NO: 79) 
               
               
                   
                   
               
               
                   
                 ANMEGPTLRHWLAMRARV 
                 (SEQ ID NO: 80) 
               
               
                   
                   
               
               
                   
                 LDMEGPTLRHWLAARANG 
                 (SEQ ID NO: 81) 
               
               
                   
                   
               
               
                   
                 WRMEGPTLRHWLAARAWG 
                 (SEQ ID NO: 82) 
               
               
                   
                   
               
               
                   
                 WAMEGPTLRHWLAARAVL 
                 (SEQ ID NO: 83) 
               
               
                   
                   
               
               
                   
                 KSMEGPSLRQWLAARAQL 
                 (SEQ ID NO: 84) 
               
               
                   
                   
               
               
                   
                 TKIEGPTLRHWLAARAEL 
                 (SEQ ID NO: 85) 
               
               
                   
                   
               
               
                   
                 PRIEGPTLRLWLVTRALS 
                 (SEQ ID NO: 86) 
               
               
                   
                   
               
               
                   
                 IYMEGPTLRHWLANRAAK 
                 (SEQ ID NO: 87) 
               
               
                   
                   
               
               
                   
                 WPIEGATLRQWLKIRAGY 
                 (SEQ ID NO: 88) 
               
               
                   
                   
               
               
                   
                 RNMEGPTLRNWLAARAQH 
                 (SEQ ID NO: 89) 
               
               
                   
                   
               
               
                   
                 NGIEGPTLRLWLSERAKK 
                 (SEQ ID NO: 90) 
               
               
                   
                   
               
               
                   
                 MWMEGPTLRHWLEARARY 
                 (SEQ ID NO: 91) 
               
               
                   
                   
               
               
                   
                 YGIDGPTLRHWLAARARY 
                 (SEQ ID NO: 92) 
               
               
                   
                   
               
               
                   
                 RIIDGQTLRHWLAAGADP 
                 (SEQ ID NO: 93) 
               
               
                   
                   
               
               
                   
                 NGRDGPTVRHRLAGRAQK 
                 (SEQ ID NO: 94) 
               
               
                   
                   
               
               
                   
                 THIEGPTLRIWLASRAKA 
                 (SEQ ID NO: 95) 
               
               
                   
                   
               
               
                   
                 KGMEGPTLRHWLAARAHL 
                 (SEQ ID NO: 96) 
               
               
                   
                   
               
               
                   
                 QRIEGPTLRHWLAARASH 
                 (SEQ ID NO: 97) 
               
               
                   
                   
               
               
                   
                 KDTEVTAPRLWMVASVDE 
                 (SEQ ID NO: 98) 
               
            
           
         
       
     
     Further exemplary compounds are provided below. Single letter amino acid abbreviations for the peptide are used. 
     
       
         
           
               
               
               
            
               
                   
                 ENMEGPTLRHWLAARAHE 
                 (SEQ ID NO: 99) 
               
               
                   
                   
               
               
                   
                 SWMEGPTLRHWLMNRATY 
                 (SEQ ID NO: 100) 
               
               
                   
                   
               
               
                   
                 SMMEGPTLRHWLAARAKD 
                 (SEQ ID NO: 101) 
               
               
                   
                   
               
               
                   
                 QGIEGPTLRLWLAARTHP 
                 (SEQ ID NO: 102) 
               
               
                   
                   
               
               
                   
                 YMMEGPTLRHWLATRAGR 
                 (SEQ ID NO: 103) 
               
               
                   
                   
               
               
                   
                 GNMEGPTLRHWLAANERD 
                 (SEQ ID NO: 104) 
               
               
                   
                   
               
               
                   
                 NRMEGPTLRHWLAERAGS 
                 (SEQ ID NO: 105) 
               
               
                   
                   
               
               
                   
                 NMMEGPTLRHWLAARVAA 
                 (SEQ ID NO: 106) 
               
               
                   
                   
               
               
                   
                 SPIEGPTLRQQLCARAVK 
                 (SEQ ID NO: 107) 
               
               
                   
                   
               
               
                   
                 VQMEGTTLRQWLAERALD 
                 (SEQ ID NO: 108) 
               
               
                   
                   
               
               
                   
                 KRKDGHRPRQWLAPLACK 
                 (SEQ ID NO: 109) 
               
               
                   
                   
               
               
                   
                 EMMEGPTLRHWLAARAEK 
                 (SEQ ID NO: 110) 
               
               
                   
                   
               
               
                   
                 NMIEGPTLRHWLAERASQ 
                 (SEQ ID NO: 111) 
               
               
                   
                   
               
               
                   
                 KLMEGPTLRHWLAYRAGL 
                 (SEQ ID NO: 112) 
               
               
                   
                   
               
               
                   
                 YMMEGPTLRHWLAARALV 
                 (SEQ ID NO: 113) 
               
               
                   
                   
               
               
                   
                 GNMEGPTLRHWLAARALL 
                 (SEQ ID NO: 114) 
               
               
                   
                   
               
               
                   
                 WMMEGPTLRHWLAARARY 
                 (SEQ ID NO: 115) 
               
               
                   
                   
               
               
                   
                 TDRGGYTLRQWLAARAVL 
                 (SEQ ID NO: 116) 
               
               
                   
                   
               
               
                   
                 SAIEGPTLRHWLAWRAML 
                 (SEQ ID NO: 117) 
               
               
                   
                   
               
               
                   
                 RAIEGPTLRHCLAAGAGL 
                 (SEQ ID NO: 118) 
               
               
                   
                   
               
               
                   
                 VKRKGPTLRHWLAAWAFP 
                 (SEQ ID NO: 119) 
               
               
                   
                   
               
               
                   
                 TCMEGPTLRHWLAARAEG 
                 (SEQ ID NO: 120) 
               
               
                   
                   
               
               
                   
                 WFMEGPTLRHWLAARAYR 
                 (SEQ ID NO: 121) 
               
               
                   
                   
               
               
                   
                 ADIEGPTLRHWLAARALV 
                 (SEQ ID NO: 122) 
               
               
                   
                   
               
               
                   
                 WVMEGPTLRHWLAARASL 
                 (SEQ ID NO: 123) 
               
               
                   
                   
               
               
                   
                 PPGDGPTLRHWLAARARM 
                 (SEQ ID NO: 124) 
               
               
                   
                   
               
               
                   
                 DFMEGPTLRQRVDARAHY 
                 (SEQ ID NO: 125) 
               
               
                   
                   
               
               
                   
                 RWIEGPTQRQWLAARAYF 
                 (SEQ ID NO: 126) 
               
               
                   
                   
               
               
                   
                 IRMEGPTLRHWLASRAEI 
                 (SEQ ID NO: 127) 
               
               
                   
                   
               
               
                   
                 YYLEGPTLRHWLAARAYL 
                 (SEQ ID NO: 128) 
               
               
                   
                   
               
               
                   
                 GVIEGPTLRHWLAARAAQ 
                 (SEQ ID NO: 129) 
               
               
                   
                   
               
               
                   
                 GAMEGPTLRCWLAASDEK 
                 (SEQ ID NO: 130) 
               
               
                   
                   
               
               
                   
                 SVIDGPTLRQRLAARARY 
                 (SEQ ID NO: 131) 
               
               
                   
                   
               
               
                   
                 GGIERPTLRHCLAARPTS 
                 (SEQ ID NO: 132) 
               
               
                   
                   
               
               
                   
                 TKMEGPTLRHWLAWRAAY 
                 (SEQ ID NO: 133) 
               
               
                   
                   
               
               
                   
                 LKMEGPTLRNWLAWRAFQ 
                 (SEQ ID NO: 134) 
               
               
                   
                   
               
               
                   
                 GLVEGPTLRFWLAARAAE 
                 (SEQ ID NO: 135) 
               
               
                   
                   
               
               
                   
                 GLTDGPNLRHCLAARAPI 
                 (SEQ ID NO: 136) 
               
               
                   
                   
               
               
                   
                 DRNKGPTLRHWLAARAHA 
                 (SEQ ID NO: 137) 
               
               
                   
                   
               
               
                   
                 ASMVGPKLRHGLAAVAKK 
                 (SEQ ID NO: 138) 
               
               
                   
                   
               
               
                   
                 DAIEGPTLRLWLEARRKQ 
                 (SEQ ID NO: 139) 
               
               
                   
                   
               
               
                   
                 NIIKRATDREWLDARTAL 
                 (SEQ ID NO: 140) 
               
               
                   
                   
               
               
                   
                 GDNEGPSPRVCLAARAVL 
                 (SEQ ID NO: 141) 
               
               
                   
                   
               
               
                   
                 EFMEGPTLRHWLASRARV 
                 (SEQ ID NO: 142) 
               
               
                   
                   
               
               
                   
                 WGMEGPTLRHWLAARGKR 
                 (SEQ ID NO: 143) 
               
               
                   
                   
               
               
                   
                 RWMEGPTLRHWLAERAML 
                 (SEQ ID NO: 144) 
               
               
                   
                   
               
               
                   
                 LMVEGPTLRHWLAARWRM 
                 (SEQ ID NO: 145) 
               
               
                   
                   
               
               
                   
                 NYIEGPTLRHWLAARAKL 
                 (SEQ ID NO: 146) 
               
               
                   
                   
               
               
                   
                 TWMEGPTLRLWLMARALY 
                 (SEQ ID NO: 147) 
               
               
                   
                   
               
               
                   
                 QYMEGPTLRHWLAARAAL 
                 (SEQ ID NO: 148) 
               
               
                   
                   
               
               
                   
                 AWMEGPTLRHWLAARAAY 
                 (SEQ ID NO: 149) 
               
               
                   
                   
               
               
                   
                 KQFEGPPMRRSLAGVNTP 
                 (SEQ ID NO: 150) 
               
               
                   
                   
               
               
                   
                 ALMEGPTLRQRLAARAAQ 
                 (SEQ ID NO: 151) 
               
               
                   
                   
               
               
                   
                 ARMKGTTLRQWVAARAFV 
                 (SEQ ID NO: 152) 
               
               
                   
                   
               
               
                   
                 DKIEIPTVQLRRAAYACQ 
                 (SEQ ID NO: 153) 
               
               
                   
                   
               
               
                   
                 YRMEGPTLRHWLAARAGV 
                 (SEQ ID NO: 154) 
               
               
                   
                   
               
               
                   
                 ALMEGPTLRHWLAARALM 
                 (SEQ ID NO: 155) 
               
               
                   
                   
               
               
                   
                 IWAGGPTLRHWLAARAAL 
                 (SEQ ID NO: 156) 
               
               
                   
                   
               
               
                   
                 GWVDGPTLRHWLAARARM 
                 (SEQ ID NO: 157) 
               
               
                   
                   
               
               
                   
                 ARMEGPTLRHWLAARAKM 
                 (SEQ ID NO: 158) 
               
               
                   
                   
               
               
                   
                 ESMEGASQRHCMAARAGG 
                 (SEQ ID NO: 159) 
               
               
                   
                   
               
               
                   
                 MPVDGPVLRTWHAAQAIE 
                 (SEQ ID NO: 160) 
               
               
                   
                   
               
               
                   
                 LEHNRPLTNPIPKPRTPIRP 
                 (SEQ ID NO: 161) 
               
               
                   
                   
               
               
                   
                 TTMEDPTLRHWLATGAPT 
                 (SEQ ID NO: 162) 
               
               
                   
                   
               
               
                   
                 HPIEGPTLRLWLAARARA 
                 (SEQ ID NO: 163) 
               
               
                   
                   
               
               
                   
                 FPMEGTTLRHWLAARVQM 
                 (SEQ ID NO: 164) 
               
               
                   
                   
               
               
                   
                 RGMNGPTLRHWLEESAKD 
                 (SEQ ID NO: 165) 
               
               
                   
                   
               
               
                   
                 DQMEGSMVHQWLARHVWG 
                 (SEQ ID NO: 166) 
               
               
                   
                   
               
               
                   
                 RNMEGPTLRHWLAARATY 
                 (SEQ ID NO: 167) 
               
               
                   
                   
               
               
                   
                 DGMEGPTLRLWMAARAGE 
                 (SEQ ID NO: 168) 
               
               
                   
                   
               
               
                   
                 ASMYGPTVSQRLAARTRG 
                 (SEQ ID NO: 169) 
               
               
                   
                   
               
               
                   
                 PMMEGPTLRHWLAARALR 
                 (SEQ ID NO: 170) 
               
               
                   
                   
               
               
                   
                 WPMEGPTLRHWLAARAAR 
                 (SEQ ID NO: 171) 
               
               
                   
                   
               
               
                   
                 VQMEGPTLRHWLAGRAPN 
                 (SEQ ID NO: 172) 
               
               
                   
                   
               
               
                   
                 HGIEGPTHRQWLAARADI 
                 (SEQ ID NO: 173) 
               
               
                   
                   
               
               
                   
                 GMMEGPTLRHWLAARAML 
                 (SEQ ID NO: 174) 
               
               
                   
                   
               
               
                   
                 HDMEGPTLRHWLALRATG 
                 (SEQ ID NO: 175) 
               
               
                   
                   
               
               
                   
                 DNMERTRRRHSLAAHFML 
                 (SEQ ID NO: 176) 
               
               
                   
                   
               
               
                   
                 RNMEGPTLRHWLAARADR 
                 (SEQ ID NO: 177) 
               
               
                   
                   
               
               
                   
                 WKFEGFTLRQWLTARAFG 
                 (SEQ ID NO: 178) 
               
               
                   
                   
               
               
                   
                 RGMEGPTLRQRLVERAQM 
                 (SEQ ID NO: 179) 
               
               
                   
                   
               
               
                   
                 DVMEGTTLRQWLACRALM 
                 (SEQ ID NO: 180) 
               
               
                   
                   
               
               
                   
                 RKMERATLRQWLTARANM 
                 (SEQ ID NO: 181) 
               
               
                   
                   
               
               
                   
                 GTKEGPTLRQWPAARANE 
                 (SEQ ID NO: 182) 
               
               
                   
                   
               
               
                   
                 CAIEGPTLRHWLAARAAT 
                 (SEQ ID NO: 183) 
               
               
                   
                   
               
               
                   
                 LTMEGPTLRHWLRARAYA 
                 (SEQ ID NO: 184) 
               
               
                   
                   
               
               
                   
                 MTMEGPTLRQWFAARADT 
                 (SEQ ID NO: 185) 
               
               
                   
                   
               
               
                   
                 SPMEGPTLRHSAAGRPWG 
                 (SEQ ID NO: 186) 
               
               
                   
                   
               
               
                   
                 VHMEDPTLRHGNAARAAE 
                 (SEQ ID NO: 187) 
               
               
                   
                   
               
               
                   
                 YPMEGPTLRHWLAARARH 
                 (SEQ ID NO: 188) 
               
               
                   
                   
               
               
                   
                 GKTQGPKQLKWQVGSSLP 
                 (SEQ ID NO: 189) 
               
               
                   
                   
               
               
                   
                 GEMEGPTLLHWRAARAMQ 
                 (SEQ ID NO: 190) 
               
               
                   
                   
               
               
                   
                 INMEGPTLRLWLAARAAA 
                 (SEQ ID NO: 191) 
               
               
                   
                   
               
               
                   
                 FRIEGPTLRNWLAARAAK 
                 (SEQ ID NO: 192) 
               
               
                   
                   
               
               
                   
                 GRMEGPTLRHWLAARAHP 
                 (SEQ ID NO: 193) 
               
               
                   
                   
               
               
                   
                 VLIQGHTVRNCMVARVDA 
                 (SEQ ID NO: 194) 
               
               
                   
                   
               
               
                   
                 DWIEGPTLRHWLAARALY 
                 (SEQ ID NO: 195) 
               
               
                   
                   
               
               
                   
                 SWTEGPTLRHWLAARARN 
                 (SEQ ID NO: 196) 
               
               
                   
                   
               
               
                   
                 RELEGPTLRLWLVERARM 
                 (SEQ ID NO: 197) 
               
               
                   
                   
               
               
                   
                 VSMEGPTLRNWLAARARM 
                 (SEQ ID NO: 198) 
               
               
                   
                   
               
               
                   
                 TTMEGPTLRHWLATRAVD 
                 (SEQ ID NO: 199) 
               
               
                   
                   
               
               
                   
                 AKLEGPTLRLWLAERAGR 
                 (SEQ ID NO: 200) 
               
               
                   
                   
               
               
                   
                 ARMEGPTLRHWLAARARY 
                 (SEQ ID NO: 201) 
               
               
                   
                   
               
               
                   
                 NIMDGPALRHWLPARAIQ 
                 (SEQ ID NO: 202) 
               
               
                   
                   
               
               
                   
                 NMIGGPTLGHRLADPAIQ 
                 (SEQ ID NO: 203) 
               
               
                   
                   
               
               
                   
                 VWMEGATLRQWLAARALI 
                 (SEQ ID NO: 204) 
               
               
                   
                   
               
               
                   
                 RVMEGPTLLQRLAARARS 
                 (SEQ ID NO: 205) 
               
               
                   
                   
               
               
                   
                 QPMDEPARRQWLSARAGL 
                 (SEQ ID NO: 206) 
               
               
                   
                   
               
               
                   
                 AWTEGPTLRHWLAARGRS 
                 (SEQ ID NO: 207) 
               
               
                   
                   
               
               
                   
                 ATMEGPTLRHWLAARAAL 
                 (SEQ ID NO: 208) 
               
               
                   
                   
               
               
                   
                 GRMEGPTLRHWLAARALF 
                 (SEQ ID NO: 209) 
               
               
                   
                   
               
               
                   
                 ENMQGRTLRHWLAARDYF 
                 (SEQ ID NO: 210) 
               
               
                   
                   
               
               
                   
                 KGVEGPTLRLWLAARALM 
                 (SEQ ID NO: 211) 
               
               
                   
                   
               
               
                   
                 VEMEGPTLRHWLAARASV 
                 (SEQ ID NO: 212) 
               
               
                   
                   
               
               
                   
                 AFIEGPTLKNWLAARAIM 
                 (SEQ ID NO: 213) 
               
               
                   
                   
               
               
                   
                 TVMEGPTLRHWLAARSRS 
                 (SEQ ID NO: 214) 
               
               
                   
                   
               
               
                   
                 AHMEGPTLRHWLATRAKM 
                 (SEQ ID NO: 215) 
               
               
                   
                   
               
               
                   
                 KDIEGPTLRHWLAARANY 
                 (SEQ ID NO: 216) 
               
               
                   
                   
               
               
                   
                 RIHDGRKLRQWLTVRDTM 
                 (SEQ ID NO: 217) 
               
               
                   
                   
               
               
                   
                 KPIEGPTLKLWLAERMAA 
                 (SEQ ID NO: 218) 
               
               
                   
                   
               
               
                   
                 AKDVGTRLRQWLAAGARA 
                 (SEQ ID NO: 219) 
               
               
                   
                   
               
               
                   
                 QSQEGPTLRLWLAERAKW 
                 (SEQ ID NO: 220) 
               
               
                   
                   
               
               
                   
                 MYTEGATLRQWLAARARI 
                 (SEQ ID NO: 221) 
               
               
                   
                   
               
               
                   
                 PKMEGPTRRTRLADRSTS 
                 (SEQ ID NO: 222) 
               
               
                   
                   
               
               
                   
                 NVMEGPTLRHWLAYRARM 
                 (SEQ ID NO: 223) 
               
               
                   
                   
               
               
                   
                 TWMEGPTLRHWLAARALG 
                 (SEQ ID NO: 224) 
               
               
                   
                   
               
               
                   
                 LTMEGPTLRHWLAARATR 
                 (SEQ ID NO: 225) 
               
               
                   
                   
               
               
                   
                 YTMEGPTLRHWLAARALH 
                 (SEQ ID NO: 226) 
               
               
                   
                   
               
               
                   
                 NEMEGATLRQWLAARAKW 
                 (SEQ ID NO: 227) 
               
               
                   
                   
               
               
                   
                 FSKEGATLRQWLAARALD 
                 (SEQ ID NO: 228) 
               
               
                   
                   
               
               
                   
                 SNGVCRTLRQWLAARAEE 
                 (SEQ ID NO: 229) 
               
               
                   
                   
               
               
                   
                 KGMEGPTLRNWLAERAML 
                 (SEQ ID NO: 230) 
               
               
                   
                   
               
               
                   
                 QDMVGPTLRHWLAARARL 
                 (SEQ ID NO: 231) 
               
               
                   
                   
               
               
                   
                 YSHEGPTLRHWLAARALL 
                 (SEQ ID NO: 232) 
               
               
                   
                   
               
               
                   
                 GVIEGPTLRHWLAARMKV 
                 (SEQ ID NO: 233) 
               
               
                   
                   
               
               
                   
                 MHMEGPTLRHWLATRALI 
                 (SEQ ID NO: 234) 
               
               
                   
                   
               
               
                   
                 CRSEGPTLRCWLAARAGY 
                 (SEQ ID NO: 235) 
               
               
                   
                   
               
               
                   
                 MCIEGPTLRQWQVCRVGL 
                 (SEQ ID NO: 236) 
               
               
                   
                   
               
               
                   
                 CRVEGPSQRQCLAARACW 
                 (SEQ ID NO: 237) 
               
               
                   
                   
               
               
                   
                 CTMEGPTLRHWLAARACI 
                 (SEQ ID NO: 238) 
               
               
                   
                   
               
               
                   
                 CQVDGPTVRHCRAARAGL 
                 (SEQ ID NO: 239) 
               
               
                   
                   
               
               
                   
                 CDMAGATLRQWLACRSGT 
                 (SEQ ID NO: 240) 
               
               
                   
                   
               
               
                   
                 ICTEGCTLRLWLAERSRV 
                 (SEQ ID NO: 241) 
               
               
                   
                   
               
               
                   
                 CGMEGPALRQWLACRAVD 
                 (SEQ ID NO: 242) 
               
            
           
         
       
     
     In yet another embodiment, further exemplary compounds are provided below. Single letter amino acid abbreviations for the peptide are used. 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 QGCSSGGPTLREWQQCVRMQHS 
                 (SEQ ID NO: 243) 
               
               
                   
               
               
                 QGCSSGGPTLREWQQCRRAQHS 
                 (SEQ ID NO: 244) 
               
               
                   
               
               
                 QGCSSGGPTLREWQQCVRAQHS 
                 (SEQ ID NO: 245) 
               
               
                   
               
               
                 IEGQSWEFENDRVPAHSLERVLLLRRVPTEP 
                 (SEQ ID NO: 246) 
               
               
                 SGPSICAQIEGPTFKQWQECINGHS; 
                   
               
               
                   
               
               
                 IEGPTFKQWQKCRNMHS; 
                 (SEQ ID NO: 247) 
               
               
                   
               
               
                 IEGPTFKQWQKLRRVHS; 
                 (SEQ ID NO: 248) 
               
               
                   
               
               
                 IEGEPVSDGKRRPRVHSLERVDAVHAKVGPS 
                 (SEQ ID NO: 249) 
               
               
                 ICAQIEGPTFKQWQKCKRAHS; 
                   
               
               
                   
               
               
                 IEGRWPPPQFPVTQQHSLERVGRPPPSVELP 
                 (SEQ ID NO: 250) 
               
               
                 RPTFVCAQIEGPTFKQWQRCLREHS; 
                   
               
               
                   
               
               
                 IEGPTFKQWQRWRLLHS; 
                 (SEQ ID NO: 251) 
               
               
                   
               
               
                 IEGPTFKQWQAWRKKHS; 
                 (SEQ ID NO: 252) 
               
               
                   
               
               
                 IEGPTFKQWQRWRKMHS; 
                 (SEQ ID NO: 253) 
               
               
                   
               
               
                 IEGRWPPPQFPVTEHHSLERVGRRPPNAQMP 
                 (SEQ ID NO: 254) 
               
               
                 QSIFICGQNEGPTFQYCQRCLREHS; 
                   
               
               
                   
               
               
                 IEGWWWQFYFHAKEDHS; 
                 (SEQ ID NO: 255) 
               
               
                   
               
               
                 PSICAQIEGPTFKQWQTCMRAHS; 
                 (SEQ ID NO: 256) 
               
               
                   
               
               
                 IEGYVGGPYEQTNSLERVPPTLAWKYGPRTP 
                 (SEQ ID NO: 257) 
               
               
                 SICAQIEGPTFKQWQQCLSDHS; 
                   
               
               
                   
               
               
                 IEGPTFKQWQGRSKRHS; 
                 (SEQ ID NO: 258) 
               
               
                   
               
               
                 IEGWPWQLYVHPEGEHS; 
                 (SEQ ID NO: 259) 
               
               
                   
               
               
                 IEGWWWQLYFHAKDDHS; 
                 (SEQ ID NO: 260) 
               
               
                   
               
               
                 IEGPTFKQWQKLRRSHS; 
                 (SEQ ID NO: 261) 
               
               
                   
               
               
                 IEGWWWQFYFHPKEDHS; 
                 (SEQ ID NO: 262) 
               
               
                   
               
               
                 IEGPTFKQWQKSRTKHS; 
                 (SEQ ID NO: 263) 
               
               
                   
               
               
                 IEGWTWQFYVHPKGDHS; 
                 (SEQ ID NO: 264) 
               
               
                   
               
               
                 IEGPTFKQWQAARMHHS; 
                 (SEQ ID NO: 265) 
               
               
                   
               
               
                 IEGPTFKQWQACLHSHS; 
                 (SEQ ID NO: 266) 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS; 
                 (SEQ ID NO: 267) 
               
               
                   
               
               
                 IEGPSFTPWFHERRSHS; 
                 (SEQ ID NO: 268) 
               
               
                   
               
               
                 IEGPTFKQWQWLRRHHS; 
                 (SEQ ID NO: 269) 
               
               
                   
               
               
                 IEGWWWQFYVHAKGDHS; 
                 (SEQ ID NO: 270) 
               
               
                   
               
               
                 IEGPTFKQWQVWRNRHS; 
                 (SEQ ID NO: 271) 
               
               
                   
               
               
                 IEGQSWLRRLHWKEEHS; 
                 (SEQ ID NO: 272) 
               
               
                   
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRS 
                 (SEQ ID NO: 273) 
               
               
                 CAQIEGPTFKQWQICKDQHS; 
                   
               
               
                   
               
               
                 IEGPTFKQWQKWRKTHS; 
                 (SEQ ID NO: 274) 
               
               
                   
               
               
                 IEGPTFKQWQYWRAKHS; 
                 (SEQ ID NO: 275) 
               
               
                   
               
               
                 IEGPTFKQWQVRQKTHS; 
                 (SEQ ID NO: 276) 
               
               
                   
               
               
                 IEGWSWQFYFHAKGDHS; 
                 (SEQ ID NO: 277) 
               
               
                   
               
               
                 IEGRTWQLYFHAKEEHS; 
                 (SEQ ID NO: 278) 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS; 
                 (SEQ ID NO: 279) 
               
               
                   
               
               
                 IEGWPRQLYAHAKEDHS; 
                 (SEQ ID NO: 280) 
               
               
                   
               
               
                 IEGWWWQFYAHPQGDHS; 
                 (SEQ ID NO: 281) 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS; 
                 (SEQ ID NO: 282) 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS; 
                 (SEQ ID NO: 283) 
               
               
                   
               
               
                 IEGHGSQKPTAARALESTSSLTTRTRTTSIC 
                 (SEQ ID NO: 284) 
               
               
                 AQQDMVGPTIRQWLAARACI 
                   
               
               
                   
               
               
                 IEGPTFEQWQHWRRGHS; 
                 (SEQ ID NO: 285) 
               
               
                   
               
               
                 IEGWIWRQWLAARA; 
                 (SEQ ID NO: 286) 
               
               
                   
               
               
                 IEGWIWRPWLAARA; 
                 (SEQ ID NO: 287) 
               
               
                   
               
               
                 IEGYWWYASWAARA; 
                 (SEQ ID NO: 288) 
               
               
                   
               
               
                 IEGWPWQFYAHPQGDHS; 
                 (SEQ ID NO: 289) 
               
               
                   
               
               
                 IEGWVWCQWLAARA; 
                 (SEQ ID NO: 290) 
               
               
                   
               
               
                 IEGPTLHEWLRWLRQHS; 
                 (SEQ ID NO: 291) 
               
               
                   
               
               
                 IEGWVWRPWLAARA; 
                 (SEQ ID NO: 292) 
               
               
                   
               
               
                 IEGWVWCPWLAARA; 
                 (SEQ ID NO: 293) 
               
               
                   
               
               
                 IEGEALVFWWRVRGGHS; 
                 (SEQ ID NO: 294) 
               
               
                   
               
               
                 IEGWVWCPWLAARA; 
                 (SEQ ID NO: 295) 
               
               
                   
               
               
                 IEGWVWWPWLAARA; 
                 (SEQ ID NO: 296) 
               
               
                   
               
               
                 IEGWTWQFYALPRGDHS; 
                 (SEQ ID NO: 297) 
               
               
                   
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRS 
                 (SEQ ID NO: 298)  
               
               
                 CAQIEGPTFKQWQICKDQHS; 
                   
               
               
                   
               
               
                 IEGPTLRQRLAARA; 
                 (SEQ ID NO: 299) 
               
               
                   
               
               
                 IEGWSWQFYAHPKGDHS; 
                 (SEQ ID NO: 300) 
               
               
                   
               
               
                 IEGWVWRQWLAARA; 
                 (SEQ ID NO: 301) 
               
               
                   
               
               
                 IEGRHYQKWPARRLGHS; 
                 (SEQ ID NO: 302) 
               
               
                   
               
               
                 IEGFVGTVDWRQGRPHS; 
                 (SEQ ID NO: 303) 
               
               
                   
               
               
                 IEGQEPTRLRLqMDRHS; 
                 (SEQ ID NO: 304) 
               
               
                   
               
               
                 IAQVRMLGRFTLLVLSRARAASTQLSFQHSI 
                 (SEQ ID NO: 305) 
               
               
                 CAQIEGGAQTQWDAARA; 
                   
               
               
                   
               
               
                 IEGEIWAGPGAARA; 
                 (SEQ ID NO: 306) 
               
               
                   
               
               
                 IEGEALVFWWAARA; 
                 (SEQ ID NO: 307) 
               
               
                   
               
               
                 IEGSYRERQQAARA; 
                 (SEQ ID NO: 308) 
               
               
                   
               
               
                 IEGWVWRPWLAARA; 
                 (SEQ ID NO: 309) 
               
               
                   
               
               
                 IEGWNPWRGAASRV; 
                 (SEQ ID NO: 310) 
               
               
                   
               
               
                 IEGWTRRQWLAARA; 
                 (SEQ ID NO: 311) 
               
               
                   
               
               
                 IEGWVWRPWLAARA; 
                 (SEQ ID NO: 312) 
               
               
                   
               
               
                 IEGPTFKQWQAMRRHS; 
                 (SEQ ID NO: 313) 
               
               
                   
               
               
                 IEGMVKLGVIRLLVL; 
                 (SEQ ID NO: 314) 
               
               
                   
               
               
                 IEGPTFKQWQAWRRWHS; 
                 (SEQ ID NO: 315) 
               
               
                   
               
               
                 IEVWQSHWYQAARALESTSSRLLPMRPPPSI 
                 (SEQ ID NO: 316)  
               
               
                 CAQIEGPTLPQRMAARA; 
                   
               
               
                   
               
               
                 IEGWTWQFYAHPQGDHS; 
                 (SEQ ID NO: 317) 
               
               
                   
               
               
                 IEGPTFKQWQALRKRHS; 
                 (SEQ ID NO: 318) 
               
               
                   
               
               
                 IEGPTFKQWQKLRLGHS; 
                 (SEQ ID NO: 319) 
               
               
                   
               
               
                 IEGPTFKQWQLMGFPHS; 
                 (SEQ ID NO: 320) 
               
               
                   
               
               
                 IEGWIWRQWLMQTLWHS; 
                 (SEQ ID NO: 321) 
               
               
                   
               
               
                 IEGPTFKQWQAMRKNHS; 
                 (SEQ ID NO: 322) 
               
               
                   
               
               
                 IEGPTFKQWQKWRLSHS; 
                 (SEQ ID NO: 323) 
               
               
                   
               
               
                 IEGWQEGRQSAARA; 
                 (SEQ ID NO: 324) 
               
               
                   
               
               
                 IEGPTFKQWQRWLKYHS; 
                 (SEQ ID NO: 325) 
               
               
                   
               
               
                 IEGNYWFWQQVGQENTLSREWIQTLGQKYWY 
                 (SEQ ID NO: 326) 
               
               
                 RPPSICAQIEGWSRHQHYSAMSGHS; 
                   
               
               
                   
               
               
                 IEGPTFKQWQLWRLQHS; 
                 (SEQ ID NO: 327) 
               
               
                   
               
               
                 IEGPTFKQWQMLRRHHS; 
                 (SEQ ID NO: 328) 
               
               
                   
               
               
                 IEGPTFKQWQRLRKNHS; 
                 (SEQ ID NO: 329) 
               
               
                   
               
               
                 IEGLLSQLWQAARA; 
                 (SEQ ID NO: 330) 
               
               
                   
               
               
                 IEGPSLPEWLHVWRHHS; 
                 (SEQ ID NO: 331) 
               
               
                   
               
               
                 IEGPTLHEWLAERRKHS; 
                 (SEQ ID NO: 332) 
               
               
                   
               
               
                 IEGPTLHEWLALLRSHS; 
                 (SEQ ID NO: 333) 
               
               
                   
               
               
                 IEGPTLHEWLAQRREHS; 
                 (SEQ ID NO: 334) 
               
               
                   
               
               
                 IEGPTLHEWLLYRRAHS; 
                 (SEQ ID NO: 335) 
               
               
                   
               
               
                 IEGPTLHEWLRQRRQHS; 
                 (SEQ ID NO: 336) 
               
               
                   
               
               
                 CSSGGPTLREWQQCSRAQ; 
                 (SEQ ID NO: 454) 
               
               
                   
               
               
                 CSSGGPTLREWQQCQRAQ; 
                 (SEQ ID NO: 455) 
               
               
                 and 
                   
               
               
                   
               
               
                 CSSGGPTLREWQQCGRAQ. 
                 (SEQ ID NO: 456) 
               
               
                   
               
            
           
         
       
     
     In another embodiment, any of the exemplary compounds comprising a TPO-mimetic peptide may be fused to either an Fc region or inserted into an Fc-Loop, a modified Fc molecule. Fc-Loops are described herein and in U.S. Patent Application Publication No. US2006/0140934 incorporated herein by reference in its entirety. The invention includes such molecules comprising an Fc domain modified to comprise a peptide as an internal sequence (preferably in a loop region) of the Fc domain. The Fc internal peptide molecules may include more than one peptide sequence in tandem in a particular internal region, and they may include further peptides in other internal regions. While the putative loop regions are exemplified, insertions in any other non-terminal domains of the Fc are also considered part of this invention. 
     In a further embodiment, the invention contemplates a compound comprising a peptide inserted into an Fc amino acid sequence. In one aspect, the peptide is inserted into a loop region of the Fc amino acid sequence. In a further aspect, the Fc amino acid sequence is SEQ ID NO: 3. In still another aspect, the peptide is inserted into the loop region of the Fc amino acid sequence of SEQ ID NO: 3 between amino acids 139 (Leu) and 140 (Thr). Such peptide may be inserted into the loop region of the Fc using one or more linkers. In one aspect, the linker comprises four glycine residues at the N-terminus of the peptide. In another aspect, the linker comprises two glycine residues at the N-terminus of the peptide and two glycine residues at the C-terminus of the peptide. Other linkers, as discussed in U.S. Patent Application Publication No. US2006/0140934, are also contemplated for use modifying Fc molecules in the invention. Exemplary TPO-mimetic fusion proteins comprise a peptide comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 243. 
     Exemplary compounds of the invention include a compound which is selected from the group consisting of SEQ ID NOS: 353-422. 
     Derivatives of any of the above compounds are also provided in the invention. The compounds provided may be derivatized as set forth in one or more of the following: 
     one or more of the peptidyl [—C(O)NR—] linkages (bonds) have been replaced by a non-peptidyl linkage such as a —CH 2 -carbamate linkage [—CH 2 —OC(O)NR—]; a phosphonate linkage; a —CH 2 -sulfonamide [—CH 2 —S(O) 2 NR—] linkage; a urea [—NHC(O)NH—] linkage; a —CH 2 -secondary amine linkage; or an alkylated peptidyl linkage [—C(O)NR 6 — where R 6  is lower alkyl]; 
     the N-terminus is a —NRR 1  group; to a —NRC(O)R group; to a —NRC(O)OR group; to a —NRS(O) 2 R group; to a —NHC(O)NHR group where R and R 1  are hydrogen and lower alkyl with the proviso that R and R 1  are not both hydrogen; to a succinimide group; to a benzyloxycarbonyl-NH— (CBZ—NH—) group; or to a benzyloxycarbonyl-NH— group having from 1 to 3 substituents on the phenyl ring selected from the group consisting of lower alkyl, lower alkoxy, chloro, and bromo; 
     the C terminus is —C(O)R 2  where R 2  is selected from the group consisting of lower alkoxy and —NR 3 R 4  where R 3  and R 4  are independently selected from the group consisting of hydrogen and lower alkyl. By “lower” is meant a group having from 1 to 6 carbon atoms. 
     In another aspect, compounds are provided wherein all of the amino acids have a D configuration, or at least one of the amino acids has a D configuration. In a further aspect, the compounds may be cyclic. In yet a further aspect, P is constrained through a disulfide bond between cysteine residues such that P is cyclic. In another aspect, P comprises four glycine residues at its N-terminus. The invention also includes a compound wherein P comprises two glycine residues at the N-terminus of P and two glycine residues at the C-terminus of P. 
     The compounds in one aspect are peptides, and they may be prepared by standard synthetic methods, by phage library, or by any other methods of preparing peptides. The compounds that encompass non-peptide portions may be synthesized by standard organic chemistry reactions, in addition to standard peptide chemistry reactions when applicable. 
     The compounds provided may be used for therapeutic or prophylactic purposes by incorporating them with appropriate pharmaceutical carrier materials and administering an effective amount to a subject, such as a human (or other mammal). 
     Also provided are methods of increasing megakaryocytes or platelets in a patient in need thereof, which comprise administering to said patient an effective amount of the compounds of the invention. In one aspect, the amount is from 1 μg/kg to 100 mg/kg. 
     The invention further provides pharmaceutical compositions comprising any of the compounds of the invention in admixture with a pharmaceutically acceptable carrier thereof. 
     In another embodiment, the invention provides polynucleotides that encode the compounds of the invention, vectors that comprise the polynucleotides, and host cells that comprise such vectors. 
     In a further embodiment, the invention provides methods of producing the compounds of the invention which comprise growing such host cells in a suitable nutrient medium and isolating said compound from said cell or nutrient medium. 
     Other related aspects are also provided in the instant invention. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       Numerous other aspects and advantages of the present invention will be apparent upon consideration of the following detailed description thereof, reference being made to the drawings wherein: 
       FIG. 1 shows exemplary Fc polynucleotide and protein sequences (SEQ ID NO: 1 is the coding strand reading 5′63; SEQ ID NO: 2 is the complementary strand reading 3′65; and SEQ ID NO:  3  is the encoded amino acids sequence) of human IgG1 that may be used in the Fc fusion compounds of this invention. 
       FIG. 2 shows exemplary platelet values of mice given positive control or a TPO-mimetic compound of the invention (100 μg/kg). 
       FIG. 3 shows exemplary platelet values of mice given positive control or a TPO-mimetic compound of the invention (100 μg/kg) six days post-injection. 
       FIG. 4 shows exemplary platelet values of mice given positive control or a TPO-mimetic compound of the invention (at dosages from 3-200 μg/kg) six days post-injection. 
     
    
    
     DETAILED DESCRIPTION OF THE EMBODIMENTS 
     Definitions 
     The term “comprising” means that a compound may include additional amino acids on either or both of the N- or C-termini of the given sequence. Of course, these additional amino acids should not significantly interfere with the activity of the compound. 
     The term “vehicle” refers to a molecule that prevents degradation and/or increases half-life, reduces toxicity, reduces immunogenicity, or increases biological activity of a therapeutic protein. Exemplary vehicles include an Fc domain as well as a linear polymer; a branched-chain polymer (see, for example, U.S. Pat. No. 4,289,872 to Denkenwalter et al., issued Sep. 15, 1981; U.S. Pat. No. 5,229,490 to Tam, issued Jul. 20, 1993; WO 93/21259 by Frechet et al., published 28 Oct. 1993); a lipid; a cholesterol group; a carbohydrate or oligosaccharide; or any natural or synthetic protein, polypeptide or peptide that binds to a salvage receptor. Vehicles are further described hereinafter. 
     The term “native Fc” refers to molecule or sequence comprising the sequence of a non-antigen-binding fragment resulting from digestion of whole antibody, whether in monomeric or multimeric form. The original immunoglobulin source of the native Fc is in one aspect of human origin and may be any of the immunoglobulins. A native Fc is a monomeric polypeptide that may be linked into dimeric or multimeric forms by covalent association (i.e., disulfide bonds), non-covalent association or a combination of both. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from one to four depending on class (e.g., IgG, IgA, IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2). One example of a native Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. Ellison et al. (1982), Nucleic Acids Res. 10: 4071-9. The term “native Fc” as used herein is generic to the monomeric, dimeric, and multimeric forms. 
     The term “Fc variant” refers to a molecule or sequence that is modified from a native Fc, but preferably still comprises a binding site for the salvage receptor, FcRn. International applications WO 97/34631 (published 25 Sep. 1997) and WO 96/32478 describe exemplary Fc variants, as well as interaction with the salvage receptor, and are hereby incorporated by reference. In one aspect, the term “Fc variant” comprises a molecule or sequence that is humanized from a non-human native Fc. In another aspect, a native Fc comprises sites that may be removed because they provide structural features or biological activity that are not required for the fusion molecules of the present invention. Thus, the term “Fc variant” comprises a molecule or sequence that lacks one or more native Fc sites or residues that affect or are involved in (1) disulfide bond formation, (2) incompatibility with a selected host cell (3) N-terminal heterogeneity upon expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than a salvage receptor, (7) binding to the FcRn salvage receptor in cases where a shorter half-life is desired, or (8) antibody-dependent cellular cytotoxicity (ADCC). Fc variants are described in further detail hereinafter. 
     The term “Fc domain” encompasses native Fc and Fc variant molecules and sequences as defined above. As with Fc variants and native Fcs, the term “Fc domain” includes molecules in monomeric or multimeric form, whether digested from whole antibody or produced by other means. In one embodiment, for example, the Fc domain or the Fc region can comprise: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 3) 
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS 
               
               
                   
               
               
                 HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 
               
               
                   
               
               
                 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV 
               
               
                   
               
               
                 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT 
               
               
                   
               
               
                 VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK. 
               
            
           
         
       
     
     In another embodiment, other exemplary amino acid sequences (SEQ ID NOS: 344 to 352) of human Fc regions from IgA, IgM and IgG subtypes are also used in the invention. 
     The term “multimer” as applied to Fc domains or molecules comprising Fc domains refers to molecules having two or more polypeptide chains associated covalently, noncovalently, or by both covalent and non-covalent interactions. IgG molecules typically form dimers; IgM, pentamers; IgD, dimers; and IgA, monomers, dimers, trimers, or tetramers. Multimers may be formed by exploiting the sequence and resulting activity of the native Ig source of the Fc or by derivatizing (as defined below) such a native Fc. 
     The term “dimer” as applied to Fc domains or molecules comprising Fc domains refers to molecules having two polypeptide chains associated covalently or non-covalently. 
     The terms “derivatizing,” “derivative” or “derivatized” comprise processes and resulting compounds in which, for example and without limitation, (1) the compound has a cyclic portion; for example, cross-linking between cysteinyl residues within the compound; (2) the compound is cross-linked or has a cross-linking site; for example, the compound has a cysteinyl residue and thus forms cross-linked dimers in culture or in vivo; (3) one or more peptidyl linkage is replaced by a non-peptidyl linkage; (4) the N-terminus is replaced by —NRR 1 , NRC(O)R 1 , —NRC(O)OR 1 , —NRS(O) 2 R 1 , —NHC(O)NHR, a succinimide group, or substituted or unsubstituted benzyloxycarbonyl-NH—, wherein R and R 1  and the ring substituents are as defined hereinafter; (5) the C-terminus is replaced by —C(O)R 2  or —NR 3 R 4  wherein R 2 , R 3  and R 4  are as defined hereinafter; and (6) compounds in which individual amino acid moieties are modified through treatment with agents capable of reacting with selected side chains or terminal residues. Derivatives are further described hereinafter. 
     The term “peptide” refers to molecules of approximately 2 to 80 amino acids, molecules of 2 to 40 amino acids, molecules of 3 to 20 amino acids, and those of 6 to 15 amino acids. For example, peptides having a size selected from no greater than 75, no greater than 70, no greater than 65, no greater than 60, no greater than 55, no greater than 50, no greater than 45, no greater than 40, no greater than 35, no greater than 30, no greater than 25, no greater than 20 amino acids and/or no greater than 15 amino acids, are contemplated herein. Exemplary peptides may be randomly generated by any of the methods cited described herein, carried in a peptide library (e.g., a phage display library), derived by digestion of proteins, or chemically synthesized and the like. Peptides include D and L form, either purified or in a mixture of the two forms. Exemplary peptides are the “biologically active” moieties of the compounds provided herein, i.e., provide the compound with Mpl-binding capacity. 
     The term “randomized” as used to refer to peptide sequences refers to fully random sequences (e.g., selected by phage display methods) and sequences in which one or more residues of a naturally occurring molecule is replaced by an amino acid residue not appearing in that position in the naturally occurring molecule. Exemplary methods for identifying peptide sequences include phage display,  E. coli  display, ribosome display, yeast-based screening, RNA-peptide screening, chemical screening, rational design, protein structural analysis, and the like. 
     The term “pharmacologically active” means that a substance so described is determined to have activity that affects a medical parameter (e.g., blood pressure, blood cell count, cholesterol level) or disease state (e.g., cancer, autoimmune disorders). Thus, pharmacologically active peptides comprise agonistic or mimetic and antagonistic peptides as defined below. 
     The terms “-mimetic peptide” and “-agonist peptide” refer to a peptide having biological activity comparable to a protein (e.g., TPO) that interacts with a protein of interest. These terms further include peptides that indirectly mimic the activity of a protein of interest, such as by potentiating the effects of the natural ligand of the protein of interest. Those of ordinary skill in the art appreciate that each of these references enables one to select different peptides than actually disclosed therein by following the disclosed procedures with different peptide libraries. Such peptides may mimic the bioactitivy of the large protein ligand or, through competitive binding, inhibit the bioactivity of the large protein ligand, and are commonly referred to as “peptide mimetics” or “mimetic peptides.” 
     The term “TPO-mimetic peptide” or “TMP” comprises peptides that can be identified or derived as described in International application WO 00/24770, published May 4, 2000, and U.S. Pat. No. 6,835,809, hereby incorporated by reference in their entirety, and any other reference identified as having TPO-mimetic subject matter. Those of ordinary skill in the art appreciate that each of these references enables one to select different peptides than actually disclosed therein by following the disclosed procedures with different peptide libraries. 
     The term “physiologically acceptable salts” comprises any salts that are known or later discovered to be pharmaceutically acceptable. Some specific examples are: acetate; trifluoroacetate; hydrohalides, such as hydrochloride and hydrobromide; sulfate; citrate; tartrate; glycolate; and oxalate. 
     The term “WSP” refers to a water soluble polymer which prevents a peptide, protein or other compound to which it is attached from precipitating in an aqueous environment, such as, by way of example, a physiological environment. 
     The term “PEG” refers to polyethylene glycol, and as used herein is meant to include various forms described in detail infra. 
     “Substantially homogenous” as used herein with reference to a preparation of the invention means that the preparation includes a single species of a therapeutic compound detectable in the preparation of total therapeutic molecules in the preparation, unless otherwise stated at a specific percentage of total therapeutic molecules. In general, a substantially homogenous preparation is homogenous enough to display the advantages of a homogenous preparation, e.g., ease in clinical application in predictability of lot to lot pharmacokinetics. 
     “Bioefficacy” refers to the capacity to produce a desired biological effect. Bioefficacy of different compounds, or different dosages of the same compound, or different administrations of the same compound are generally normalized to the amount of compound(s) to permit appropriate comparison. 
     Structure of Compounds 
     Provided herein is a group of compounds that are capable of binding to and triggering a transmembrane signal through, i.e., activating, the c-Mpl receptor, which is the same receptor that mediates the activity of endogenous thrombopoietin (TPO). Thus, the compounds have thrombopoietic activity, i.e., the ability to stimulate, in vivo and in vitro, the production of platelets, and/or megakaryocytopoietic activity, i.e., the ability to stimulate, in vivo and in vitro, the production of platelet precursors. 
     The compounds comprise polypeptides or peptides modified to include at least one vehicle (i.e., Fc region) attached to the peptide at either the N- or C-terminus and, optionally, one or more WSP covalently attached to the vehicle-peptide molecule at any reactive moiety in the vehicle-peptide molecule. 
     In one aspect, a substantially homogenous compound is provided comprising a structure set out in Formula I,
 
[(X 1 ) n -(F 1 ) z -(X 2 ) b ]-(L 1 ) c -WSP d   Formula I:
 
and multimers thereof, wherein:
         F 1  is a vehicle;   X 1  is independently selected from:
           P 1 -(L 2 ) e -   P 2 -(L 3 ) f -P 1 -(L 2 ) e -   P 3 -(L 4 ) g -P 2 -(L 3 ) f -P 1 -(L 2 ) e - and   P 4 -(L 5 ) h -P 3 -(L 4 ) g -P 2 -(L 3 ) f -P 1 -(L 2 ) e -   
           X 2  is independently selected from:
           -(L 2 ) e -P 1 ,   -(L 2 ) e -P 1 -(L 3 ) f -P 2 ,   -(L 2 ) e -P 1 -(L 3 ) f -P 2 -(L 4 ) g -P 3 , and   -(L 2 ) e -P 1 -(L 3 ) f -P 2 -(L 4 ) g -P 3 -(L 5 ) h -P 4      
           wherein P 1 , P 2 , P 3 , and P 4  are each independently sequences of pharmacologically active peptides;   L 1 , L 2 , L 3 , L 4 , and L 5  are each independently linkers;   a, b, c, d, e, f, g, and h are each independently 0 or 1;   z is 0, 1, 2, or more; and   WSP is a water soluble polymer, the attachment of which is effected at any reactive moiety in F 1 ;       

     said compound having a property of improved bioefficacy when administered in a multidose regimen. In one aspect, the compound a multimer, and in another aspect, the compound is a dimer. 
     The invention also provides a compound of Formula I comprising a structure set out in Formula II
 
[X 1 -(F 1 ) z ]-(L 1 ) c -WSP d   Formula II:
 
     wherein F 1  is an Fc domain and is attached at the C-terminus of X 1 , and zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Compounds having this structure are provided as a multimer in one aspect and a dimer in another aspect. 
     The invention also provides a compound of Formula I comprising a structure set out in Formula III
 
[(F 1 ) z -X 2 ]-(L 1 ) c -WSP d   Formula III:
 
     wherein F 1  is an Fc domain and is attached at the N-terminus of X 2 , and zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Multimers and dimers of a compound having this structure are also provided. 
     The invention also provides a compound of Formula I comprising a structure set out in Formula IV
 
[(F 1 ) z -(L 1 ) e -P 1 ]-(L 1 ) c -WSP d   Formula IV:
 
     wherein F 1  is an Fc domain and is attached at the N-terminus of -(L 1 ) c -P 1  and, zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Multimers and dimers of a compound having this structure are also provided. 
     The invention further provides a compound of Formula I comprising a structure set out in Formula V)
 
[(F 1 ) z -(L 1 ) e -P 1 -(L 2 ) f -P 2 ]-(L 1 ) c -WSP d   Formula V:
 
     wherein F 1  is an Fc domain and is attached at the N-terminus of -L 1 -P 1 -L 2 -P 2  and, zero, one, or more WSP is attached to the Fc domain, optionally through linker L 1 . Multimers and dimers of a compound having this structure are also provided. 
     Provided herein are compounds, as described above, wherein P 1  and/or P 2  are independently selected from a TPO-mimetic set out in any of Tables 1-6 and 8 herein. In one aspect, P 1  and/or P 2  have the same amino acid sequence. 
     The term “P” is used in the formula to mean a moiety made up of, i.e., comprising, at least 7 subunits (Y 1 -Y 7 ) wherein Y 1 -Y 7  comprises the core structure. U 1  and U 2  comprise any amino acid or peptide on either side of the Y 1 -Y 7  core structure. The Y 1 -Y 7  subunits are preferably amino acids independently selected from among the 20 naturally-occurring amino acids, however, the invention embraces compounds where Y 1 -Y 7  are independently selected from the group of atypical, non-naturally occurring amino acids well known in the art. In certain embodiments, specific amino acids are identified for each position. For example, Y 1  is Cys, Leu, Met, Pro, Gln, Val, or X 1 ; Y 2  is Phe, Lys, Leu, Asn, Gln, Arg, Ser, Thr, Val, or X 2 ; Y 3  is Cys, Phe, Ile, Leu, Met, Arg, Ser, Val, Trp, or X 3 ; Y 4  is any amino acid; Y 5  is Ala, Asp, Glu, Gly, Lys, Met, Gln, Arg, Ser, Thr, Val, Tyr, or X 5 ; Y 6  is Cys, Phe, Gly, Leu, Met, Ser, Val, Trp, Tyr, or X 6 ; and Y 7  is Cys, Gly, Ile, Lys, Leu, Met, Asn, Arg, Val, or X 7 . X 1 -X 7  subunits are preferably amino acids independently selected from among the 20 naturally-occurring amino acids, however, the invention embraces compounds where X 1 -X 7  are independently selected from the group of atypical, non-naturally occurring amino acids known in the art. Wherein it is stated that Y 1 -Y 7  corresponds to a respective X 1 -X 7 , it is understood that Y 1  corresponds to X 1 , Y 2  corresponds to X 2 , Y 3  corresponds to X 3 , Y 5  corresponds to X 5 , Y 6  corresponds to X 6 ; Y 7  corresponds to X 7 ; and Y 4  does not have a corresponding X 4  per se because X 4  may be any amino acid or non-naturally occurring amino acid known in the art. 
     In one embodiment, P comprises the following general structure: 
     U 1 -Y 1 (Cys, Leu, Met, Pro, Gln, Val, or X 1 )-Y 2 (Phe, Lys, Leu, Asn, Gln, Arg, Ser, Thr, Val, or X 2 )-Y 3 (Cys, Phe, Ile, Leu, Met, Arg, Ser, Val, Trp, or X 3 )-Y 4 -Y 5 (Ala, Asp, Glu, Gly, Lys, Met, Gln, Arg, Ser, Thr, Val, Tyr, or X 5 )-Y 6 (Cys, Phe, Gly, Leu, Met, Ser, Val, Trp, Tyr, or X 6 )-Y 7 (Cys, Gly, Ile, Lys, Leu, Met, Asn, Arg, Val, or X 7 )-U 2 ,
         wherein at least one of Y 1 -Y 3  and Y 5 -Y 7  corresponds to a respective X 1 -X 3  and X 5 -X 7 ;   wherein U 1  or U 2  is any amino acid or peptide,   wherein when Y 1  is not an amino acid selected from the group consisting of Cys, Leu, Met, Pro, Gln, and Val, then X 1  is selected from the group consisting of Ala, Asp, Glu, Phe, Gly, His, Ile, Lys, Asn, Arg, Ser, Thr, Trp, and Tyr;   wherein when Y 2  is not an amino acid selected from the group consisting of Phe, Lys, Leu, Asn, Gln, Arg, Ser, Thr, and Val, then X 2  is selected from the group consisting of Ala, Cys, Asp, Glu, Gly, His, Ile, Met, Pro, Trp, and Tyr;   wherein when Y 3  is not an amino acid selected from the group consisting of Cys, Phe, Ile, Leu, Met, Arg, Ser, Val, and Trp, then X 3  is selected from the group consisting of Ala, Asp, Glu, Gly, His, Lys, Asn, Pro, Gln, Thr, and Tyr;   wherein when Y 4  is any amino acid;   wherein when Y 5  is not an amino acid selected from the group consisting of Ala, Asp, Glu, Gly, Lys, Met, Gln, Arg, Ser, Thr, Val, and Tyr, then X 5  is selected from the group consisting of Cys, Phe, His, Ile, Leu, Asn, Pro, and Trp;   wherein when Y 6  is not an amino acid selected from the group consisting of Cys, Phe, Gly, Leu, Met, Ser, Val, Tip, and Tyr, then X 6  is selected from the group consisting of Ala, Asp, Glu, His, Ile, Lys, Asn, Pro, Gln, Arg, and Thr; and   wherein when Y 7  is not an amino acid selected from the group consisting of Cys, Gly, Ile, Lys, Leu, Met, Asn, Arg, and Val, then X 7  is selected from the group consisting of Ala, Asp, Glu, Phe, His, Pro, Gln, Ser, Thr, Trp, and Tyr;   and physiologically acceptable salts thereof.       

     In another aspect, the invention contemplates compounds, wherein at least two of Y 1 -Y 7  corresponds to two of X 1 -X 7 , respectively; at least three of Y 1 -Y 7  corresponds to three of X 1 -X 7 , respectively; at least four of Y 1 -Y 7  corresponds to four of X 1 -X 7 , respectively; at least five of Y 1 -Y 7  corresponds to five of X 1 -X 7 , respectively; at least six of Y 1 -Y 7  corresponds to six of X 1 -X 7 , respectively; and only one of Y 1 -Y 7  corresponds to one of X 1 -X 7 , respectively. 
     In one embodiment, the invention includes a compound of a structure set out in Formula I wherein at least a or b is 1. 
     In another embodiment, the invention includes a compound of a structure set out in Formula I wherein b, c, d, e, f, g, and h are 0. 
     In a further embodiment, the invention includes a compound that binds to an mpl receptor consisting essentially of a structure set out in Formula I. 
     In another embodiment, the invention includes a compound of a structure set out in Formula I wherein 
     F 1  is an Fc domain modified so that it comprises at least one X 3  in a loop region;
         X 3  is independently selected from
           -(L 6 ) i -P 5 -(L 7 ) j ,   -(L 6 ) i -P 5 -(L 7 ) j -P 6 -(L 8 ) k ,   -(L 6 ) i -P 5 -(L 7 ) j -P 6 -(L 8 ) k -P 7 -(L 9 ) l , and   -(L 6 ) i -P 5 -(L 7 ) j -P 6 -(L 8 ) k -P 7 -(L 9 ) l -P 8 -(L 10 ) m ;   
           P 5 , P 6 , P 7 , and P 8  are each independently sequences of pharmacologically active peptides;   L 6 , L 7 , L 8 , L 9 , and L 10  are each independently linkers;   j, k, l, and m are each independently 0 or 1; and   z is 1, 2, or more.       

     The invention includes a compound of the aforementioned structure wherein a and b are each 0. 
     Both three-letter and single letter abbreviations for amino acids are used herein; in each case, the abbreviations are the standard ones used for the 20 naturally-occurring amino acids or well-known variations thereof. These amino acids may have either L or D stereochemistry (except for Gly, which is neither L nor D), and P 1  may comprise a combination of stereochemistries. However, the L stereochemistry is preferred for all of the amino acids in the P 1  chain. The invention also provides reverse P 1  molecules wherein the amino terminal to carboxy terminal sequence of the amino acids is reversed. For example, the reverse of a molecule having the normal sequence Y 1 -Y 7  would be Y 7 -Y 1 . The invention also provides retro-reverse P 1  molecules wherein, like a reverse P 1 , the amino terminal to carboxy terminal sequence of amino acids is reversed and residues that are normally “L” enatiomers in P 1  are altered to the “D” stereoisomer form. 
     In addition to the core structure set forth above, Y 1 -Y 7 (X 1 -X 7 ), other structures that are specifically contemplated are those in which one or more additional Y groups are attached to the core structure. Thus, one or more Y groups make up the structures U 1  and U 2 . Thus, U 1  and or U 2  may be attached to the core structure. 
     Exemplary compounds of the general structure are shown below. Single letter amino acid abbreviations are used for these peptides. 
     
       
         
           
               
               
               
            
               
                   
                 QGCSSGGPTQREWLQCRRMQHS 
                 (SEQ ID NO: 8) 
               
               
                   
                   
               
               
                   
                 QGCSSGGPTLREWQQCRRMQHS 
                 (SEQ ID NO: 9) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKIWLQCVRAKHS 
                 (SEQ ID NO: 10) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKNWLQCVRAKHS 
                 (SEQ ID NO: 11) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKLWLQCVRAKHS 
                 (SEQ ID NO: 12) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKHWLQCVRAKHS 
                 (SEQ ID NO: 13) 
               
               
                   
                   
               
               
                   
                 QGGCRSGPTNREWLACREVQHS 
                 (SEQ ID NO: 14) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRQWPLCRQGRHS 
                 (SEQ ID NO: 15) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRLWLLCRQGRHS 
                 (SEQ ID NO: 16) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRIWLLCRQGRHS 
                 (SEQ ID NO: 17) 
               
            
           
         
       
         
         
           
             Further exemplary compounds comprising one or more Fc regions linked to a peptide are provided below. Single letter amino acid abbreviations for the peptide are used. 
           
         
       
    
     
       
         
           
               
               
               
            
               
                   
                 Fc-QGCSSGGPTQREWLQCRRMQHS 
                 (SEQ. ID NO: 18) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSSGGPTLREWQQCRRMQHS 
                 (SEQ. ID NO: 19) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSWGGPTLKIWLQCVRAKHS 
                 (SEQ ID NO: 20) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSWGGPTLKNWLQCVRAKHS 
                 (SEQ ID NO: 21) 
               
               
                   
                   
               
               
                   
                 Fc-QGCSWGGPTLKLWLQCVRAKHS 
                 (SEQ ID NO: 22) 
               
               
                   
                   
               
               
                   
                 QGCSWGGPTLKIWLQCVRAKHS-Fc 
                 (SEQ ID NO: 23) 
               
               
                   
                   
               
               
                   
                 Fc 2 -QGGCRSGPTNREWLACREVQHS 
                 (SEQ ID NO: 24) 
               
               
                   
                   
               
               
                   
                 Fc 2 -QGCSWGGPTLKLWLQCVRAKHS 
                 (SEQ ID NO: 25) 
               
               
                   
                   
               
               
                   
                 QGTCEQGPTLRQWPLCRQGRHS-Fc 
                 (SEQ ID NO: 26) 
               
               
                   
                   
               
               
                   
                 Fc-QGTCEQGPTLRQWPLCRQGRHS 
                 (SEQ ID NO: 27) 
               
               
                   
                   
               
               
                   
                 ETLY 4 QWL 
                 (SEQ ID NO: 28) 
               
               
                   
                   
               
               
                   
                 HTLY 4 QWL 
                 (SEQ ID NO: 29) 
               
               
                   
                   
               
               
                   
                 KTLY 4 QWL 
                 (SEQ ID NO: 30) 
               
               
                   
                   
               
               
                   
                 GTGY 4 QWL 
                 (SEQ ID NO: 31) 
               
               
                   
                   
               
               
                   
                 PTLY 4 IWL 
                 (SEQ ID NO: 32) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 33) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWF 
                 (SEQ ID NO: 34) 
               
               
                   
                   
               
               
                   
                 PTLY 4 HWL 
                 (SEQ ID NO: 35) 
               
               
                   
                   
               
               
                   
                 PILY 4 EWL 
                 (SEQ ID NO: 36) 
               
               
                   
                   
               
               
                   
                 KTLY 4 EWL 
                 (SEQ ID NO: 37) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 38) 
               
               
                   
                   
               
               
                   
                 PMLY 4 EWL 
                 (SEQ ID NO: 39) 
               
               
                   
                   
               
               
                   
                 PTLY 4 NWL 
                 (SEQ ID NO: 40) 
               
               
                   
                   
               
               
                   
                 PPLY 4 EWL 
                 (SEQ ID NO: 41) 
               
               
                   
                   
               
               
                   
                 PTQY 4 EWQ 
                 (SEQ ID NO: 42) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWS 
                 (SEQ ID NO: 43) 
               
               
                   
                   
               
               
                   
                 PTYY 4 EWL 
                 (SEQ ID NO: 44) 
               
               
                   
                   
               
               
                   
                 PTAY 4 QWL 
                 (SEQ ID NO: 45) 
               
               
                   
                   
               
               
                   
                 PCLY 4 QWL 
                 (SEQ ID NO: 46) 
               
               
                   
                   
               
               
                   
                 PTLY 4 FWL 
                 (SEQ ID NO: 47) 
               
               
                   
                   
               
               
                   
                 PTGY 4 QWL 
                 (SEQ ID NO: 48) 
               
               
                   
                   
               
               
                   
                 PTLY 4 HWL 
                 (SEQ ID NO: 49) 
               
               
                   
                   
               
               
                   
                 PILY 4 IWL 
                 (SEQ ID NO: 50) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 51) 
               
               
                   
                   
               
               
                   
                 PMLY 4 QWL 
                 (SEQ ID NO: 52) 
               
               
                   
                   
               
               
                   
                 PTLY 4 NWL 
                 (SEQ ID NO: 53) 
               
               
                   
                   
               
               
                   
                 PTPY 4 QWL 
                 (SEQ ID NO: 54) 
               
               
                   
                   
               
               
                   
                 PTLY 4 QWQ 
                 (SEQ ID NO: 55) 
               
               
                   
                   
               
               
                   
                 PTLY 4 QWS 
                 (SEQ ID NO: 56) 
               
               
                   
                   
               
               
                   
                 PTTY 4 QWT 
                 (SEQ ID NO: 57) 
               
               
                   
                   
               
               
                   
                 PTLY 4 WWL 
                 (SEQ ID NO: 58) 
               
               
                   
                   
               
               
                   
                 PTYY 4 QWL 
                 (SEQ ID NO: 59) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWF 
                 (SEQ ID NO: 60) 
               
               
                   
                   
               
               
                   
                 GTLY 4 EWL 
                 (SEQ ID NO: 61) 
               
               
                   
                   
               
               
                   
                 PTLY 4 HWL 
                 (SEQ ID NO: 62) 
               
               
                   
                   
               
               
                   
                 PILY 4 EWL 
                 (SEQ ID NO: 63) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 64) 
               
               
                   
                   
               
               
                   
                 PTQY 4 EWL 
                 (SEQ ID NO: 65) 
               
               
                   
                   
               
               
                   
                 PTLY 4 EWS 
                 (SEQ ID NO: 66) 
               
               
                   
                   
               
               
                   
                 PTLY 4 FWF 
                 (SEQ ID NO: 67) 
               
               
                   
                   
               
               
                   
                 GTLY 4 QWL 
                 (SEQ ID NO: 68) 
               
               
                   
                   
               
               
                   
                 PTLY 4 IWL 
                 (SEQ ID NO: 69) 
               
               
                   
                   
               
               
                   
                 PTLY 4 LWL 
                 (SEQ ID NO: 70) 
               
               
                   
                   
               
               
                   
                 PTLY 4 NWL 
                 (SEQ ID NO: 71) 
               
               
                   
                   
               
               
                   
                 PTLY 4 QWP 
                 (SEQ ID NO: 72) 
               
               
                   
                   
               
               
                   
                 PTLY 4 WWL 
                 (SEQ ID NO: 73) 
               
               
                   
                   
               
               
                   
                 PTTY 4 QWL 
                 (SEQ ID NO: 74) 
               
            
           
         
       
     
     Further exemplary compounds are provided below. Single letter amino acid abbreviations for the peptide are used. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 75) 
               
               
                 KDTEVTAPRLWMVASVDE 
               
               
                   
               
               
                 (SEQ ID NO: 76) 
               
               
                 REMEGPTMRQWLAYRAVL 
               
               
                   
               
               
                 (SEQ ID NO: 77) 
               
               
                 CQNAGPTLRCWLAGRAYM 
               
               
                   
               
               
                 (SEQ ID NO: 78) 
               
               
                 CEREGPTLRCWLATREGS 
               
               
                   
               
               
                 (SEQ ID NO: 79) 
               
               
                 WRIEGPTLRHWLAARAWD 
               
               
                   
               
               
                 (SEQ ID NO: 80) 
               
               
                 ANMEGPTLRHWLAMRARV 
               
               
                   
               
               
                 (SEQ ID NO: 81) 
               
               
                 LDMEGPTLRHWLAARANG 
               
               
                   
               
               
                 (SEQ ID NO: 82) 
               
               
                 WRMEGPTLRHWLAARAWG 
               
               
                   
               
               
                 (SEQ ID NO: 83) 
               
               
                 WAMEGPTLRHWLAARAVL 
               
               
                   
               
               
                 (SEQ ID NO: 84) 
               
               
                 KSMEGPSLRQWLAARAQL 
               
               
                   
               
               
                 (SEQ ID NO: 85) 
               
               
                 TKIEGPTLRHWLAARAEL 
               
               
                   
               
               
                 (SEQ ID NO: 86) 
               
               
                 PRIEGPTLRLWLVTRALS 
               
               
                   
               
               
                 (SEQ ID NO: 87) 
               
               
                 IYMEGPTLRHWLANRAAK 
               
               
                   
               
               
                 (SEQ ID NO: 88) 
               
               
                 WPIEGATLRQWLKIRAGY 
               
               
                   
               
               
                 (SEQ ID NO: 89) 
               
               
                 RNMEGPTLRNWLAARAQH 
               
               
                   
               
               
                 (SEQ ID NO: 90) 
               
               
                 NGIEGPTLRLWLSERAKK 
               
               
                   
               
               
                 (SEQ ID NO: 91) 
               
               
                 MWMEGPTLRHWLEARARY 
               
               
                   
               
               
                 (SEQ ID NO: 92) 
               
               
                 YGIDGPTLRHWLAARARY 
               
               
                   
               
               
                 (SEQ ID NO: 93) 
               
               
                 RIIDGQTLRHWLAAGADP 
               
               
                   
               
               
                 (SEQ ID NO: 94) 
               
               
                 NGRDGPTVRHRLAGRAQK 
               
               
                   
               
               
                 (SEQ ID NO: 95) 
               
               
                 THIEGPTLRIWLASRAKA 
               
               
                   
               
               
                 (SEQ ID NO: 96) 
               
               
                 KGMEGPTLRHWLAARAHL 
               
               
                   
               
               
                 (SEQ ID NO: 97) 
               
               
                 QRIEGPTLRHWLAARASH 
               
               
                   
               
               
                 (SEQ ID NO: 98) 
               
               
                 KDTEVTAPRLWMVASVDE 
               
               
                   
               
               
                 (SEQ ID NO: 99) 
               
               
                 ENMEGPTLRHWLAARAHE 
               
               
                   
               
               
                 (SEQ ID NO: 100) 
               
               
                 SWMEGPTLRHWLMNRATY 
               
               
                   
               
               
                 (SEQ ID NO: 101) 
               
               
                 SMMEGPTLRHWLAARAKD 
               
               
                   
               
               
                 (SEQ ID NO: 102) 
               
               
                 QGIEGPTLRLWLAARTHP 
               
               
                   
               
               
                 (SEQ ID NO: 103) 
               
               
                 YMMEGPTLRHWLATRAGR 
               
               
                   
               
               
                 (SEQ ID NO: 104) 
               
               
                 GNMEGPTLRHWLAANERD 
               
               
                   
               
               
                 (SEQ ID NO: 105) 
               
               
                 NRMEGPTLRHWLAERAGS 
               
               
                   
               
               
                 (SEQ ID NO: 106) 
               
               
                 NMMEGPTLRHWLAARVAA 
               
               
                   
               
               
                 (SEQ ID NO: 107) 
               
               
                 SPIEGPTLRQQLCARAVK 
               
               
                   
               
               
                 (SEQ ID NO: 108) 
               
               
                 VQMEGTTLRQWLAERALD 
               
               
                   
               
               
                 (SEQ ID NO: 109) 
               
               
                 KRKDGHRPRQWLAPLACK 
               
               
                   
               
               
                 (SEQ ID NO: 110) 
               
               
                 EMMEGPTLRHWLAARAEK 
               
               
                   
               
               
                 (SEQ ID NO: 111) 
               
               
                 NMIEGPTLRHWLAERASQ 
               
               
                   
               
               
                 (SEQ ID NO: 112) 
               
               
                 KLMEGPTLRHWLAYRAGL 
               
               
                   
               
               
                 (SEQ ID NO: 113) 
               
               
                 YMMEGPTLRHWLAARALV 
               
               
                   
               
               
                 (SEQ ID NO: 114) 
               
               
                 GNMEGPTLRHWLAARALL 
               
               
                   
               
               
                 (SEQ ID NO: 115) 
               
               
                 WMMEGPTLRHWLAARARY 
               
               
                   
               
               
                 (SEQ ID NO: 116) 
               
               
                 TDRGGYTLRQWLAARAVL 
               
               
                   
               
               
                 (SEQ ID NO: 117) 
               
               
                 SAIEGPTLRHWLAWRAML 
               
               
                   
               
               
                 (SEQ ID NO: 118) 
               
               
                 RAIEGPTLRHCLAAGAGL 
               
               
                   
               
               
                 (SEQ ID NO: 119) 
               
               
                 VKRKGPTLRHWLAAWAFP 
               
               
                   
               
               
                 (SEQ ID NO: 120) 
               
               
                 TCMEGPTLRHWLAARAEG 
               
               
                   
               
               
                 (SEQ ID NO: 121) 
               
               
                 WFMEGPTLRHWLAARAYR 
               
               
                   
               
               
                 (SEQ ID NO: 122) 
               
               
                 ADIEGPTLRHWLAARALV 
               
               
                   
               
               
                 (SEQ ID NO: 123) 
               
               
                 WVMEGPTLRHWLAARASL 
               
               
                   
               
               
                 (SEQ ID NO: 124) 
               
               
                 PPGDGPTLRHWLAARARM 
               
               
                   
               
               
                 (SEQ ID NO: 125) 
               
               
                 DFMEGPTLRQRVDARAHY 
               
               
                   
               
               
                 (SEQ ID NO: 126) 
               
               
                 RWIEGPTQRQWLAARAYF 
               
               
                   
               
               
                 SEQ ID NO: 127) 
               
               
                 IRMEGPTLRHWLASRAEI 
               
               
                   
               
               
                 (SEQ ID NO: 128) 
               
               
                 YYLEGPTLRHWLAARAYL 
               
               
                   
               
               
                 (SEQ ID NO: 129) 
               
               
                 GVIEGPTLRHWLAARAAQ 
               
               
                   
               
               
                 (SEQ ID NO: 130) 
               
               
                 GAMEGPTLRCWLAASDEK 
               
               
                   
               
               
                 (SEQ ID NO: 131) 
               
               
                 SVIDGPTLRQRLAARARY 
               
               
                   
               
               
                 (SEQ ID NO: 132) 
               
               
                 GGIERPTLRHCLAARPTS 
               
               
                   
               
               
                 (SEQ ID NO: 133) 
               
               
                 TKMEGPTLRHWLAWRAAY 
               
               
                   
               
               
                 (SEQ ID NO: 134) 
               
               
                 LKMEGPTLRNWLAWRAFQ 
               
               
                   
               
               
                 (SEQ ID NO: 135) 
               
               
                 GLVEGPTLRFWLAARAAE 
               
               
                   
               
               
                 (SEQ ID NO: 136) 
               
               
                 GLTDGPNLRHCLAARAPI 
               
               
                   
               
               
                 (SEQ ID NO: 137) 
               
               
                 DRNKGPTLRHWLAARAHA 
               
               
                   
               
               
                 (SEQ ID NO: 138) 
               
               
                 ASMVGPKLRHGLAAVAKK 
               
               
                   
               
               
                 (SEQ ID NO: 139) 
               
               
                 DAIEGPTLRLWLEARRKQ 
               
               
                   
               
               
                 (SEQ ID NO: 140) 
               
               
                 NIIKRATDREWLDARTAL 
               
               
                   
               
               
                 (SEQ ID NO: 141) 
               
               
                 GDNEGPSPRVCLAARAVL 
               
               
                   
               
               
                 (SEQ ID NO: 142) 
               
               
                 EFMEGPTLRHWLASRARV 
               
               
                   
               
               
                 (SEQ ID NO: 143) 
               
               
                 WGMEGPTLRHWLAARGKR 
               
               
                   
               
               
                 (SEQ ID NO: 144) 
               
               
                 RWMEGPTLRHWLAERAML 
               
               
                   
               
               
                 (SEQ ID NO: 145) 
               
               
                 LMVEGPTLRHWLAARWRM 
               
               
                   
               
               
                 (SEQ ID NO: 146) 
               
               
                 NYIEGPTLRHWLAARAKL 
               
               
                   
               
               
                 (SEQ ID NO: 147) 
               
               
                 TWMEGPTLRLWLMARALY 
               
               
                   
               
               
                 (SEQ ID NO: 148) 
               
               
                 QYMEGPTLRHWLAARAAL 
               
               
                   
               
               
                 (SEQ ID NO: 149) 
               
               
                 AWMEGPTLRHWLAARAAY 
               
               
                   
               
               
                 (SEQ ID NO: 150) 
               
               
                 KQFEGPPMRRSLAGVNTP 
               
               
                   
               
               
                 (SEQ ID NO: 151) 
               
               
                 ALMEGPTLRQRLAARAAQ 
               
               
                   
               
               
                 (SEQ ID NO: 152) 
               
               
                 ARMKGTTLRQWVAARAFV 
               
               
                   
               
               
                 (SEQ ID NO: 153) 
               
               
                 DKIEIPTVQLRRAAYACQ 
               
               
                   
               
               
                 (SEQ ID NO: 154) 
               
               
                 YRMEGPTLRHWLAARAGV 
               
               
                   
               
               
                 (SEQ ID NO: 155) 
               
               
                 ALMEGPTLRHWLAARALM 
               
               
                   
               
               
                 (SEQ ID NO: 156) 
               
               
                 IWAGGPTLRHWLAARAAL 
               
               
                   
               
               
                 (SEQ ID NO: 157) 
               
               
                 GWVDGPTLRHWLAARARM 
               
               
                   
               
               
                 (SEQ ID NO: 158) 
               
               
                 ARMEGPTLRHWLAARAKM 
               
               
                   
               
               
                 (SEQ ID NO: 159) 
               
               
                 ESMEGASQRHCMAARAGG 
               
               
                   
               
               
                 (SEQ ID NO: 160) 
               
               
                 MPVDGPVLRTWHAAQAIE 
               
               
                   
               
               
                 (SEQ ID NO: 161) 
               
               
                 LEHNRPLTNPIPKPRTPIRP 
               
               
                   
               
               
                 (SEQ ID NO: 162) 
               
               
                 TTMEDPTLRHWLATGAPT 
               
               
                   
               
               
                 (SEQ ID NO: 163) 
               
               
                 HPIEGPTLRLWLAARARA 
               
               
                   
               
               
                 (SEQ ID NO: 164) 
               
               
                 FPMEGTTLRHWLAARVQM 
               
               
                   
               
               
                 (SEQ ID NO: 165) 
               
               
                 RGMNGPTLRHWLEESAKD 
               
               
                   
               
               
                 (SEQ ID NO: 166) 
               
               
                 DQMEGSMVHQWLARHVWG 
               
               
                   
               
               
                 (SEQ ID NO: 167) 
               
               
                 RNMEGPTLRHWLAARATY 
               
               
                   
               
               
                 (SEQ ID NO: 168) 
               
               
                 DGMEGPTLRLWMAARAGE 
               
               
                   
               
               
                 (SEQ ID NO: 169) 
               
               
                 ASMYGPTVSQRLAARTRG 
               
               
                   
               
               
                 (SEQ ID NO: 170) 
               
               
                 PMMEGPTLRHWLAARALR 
               
               
                   
               
               
                 (SEQ ID NO: 171) 
               
               
                 WPMEGPTLRHWLAARAAR 
               
               
                   
               
               
                 (SEQ ID NO: 172) 
               
               
                 VQMEGPTLRHWLAGRAPN 
               
               
                   
               
               
                 (SEQ ID NO: 173) 
               
               
                 HGIEGPTHRQWLAARADI 
               
               
                   
               
               
                 (SEQ ID NO: 174) 
               
               
                 GMMEGPTLRHWLAARAML 
               
               
                   
               
               
                 (SEQ ID NO: 175) 
               
               
                 HDMEGPTLRHWLALRATG 
               
               
                   
               
               
                 (SEQ ID NO: 176) 
               
               
                 DNMERTRRRHSLAAHFML 
               
               
                   
               
               
                 (SEQ ID NO: 177) 
               
               
                 RNMEGPTLRHWLAARADR 
               
               
                   
               
               
                 (SEQ ID NO: 178) 
               
               
                 WKFEGFTLRQWLTARAFG 
               
               
                   
               
               
                 (SEQ ID NO: 179) 
               
               
                 RGMEGPTLRQRLVERAQM 
               
               
                   
               
               
                 (SEQ ID NO: 180) 
               
               
                 DVMEGTTLRQWLACRALM 
               
               
                   
               
               
                 (SEQ ID NO: 181) 
               
               
                 RKMERATLRQWLTARANM 
               
               
                   
               
               
                 (SEQ ID NO: 182) 
               
               
                 GTKEGPTLRQWPAARANE 
               
               
                   
               
               
                 (SEQ ID NO: 183) 
               
               
                 CAIEGPTLRHWLAARAAT 
               
               
                   
               
               
                 (SEQ ID NO: 184) 
               
               
                 LTMEGPTLRHWLRARAYA 
               
               
                   
               
               
                 (SEQ ID NO: 185) 
               
               
                 MTMEGPTLRQWFAARADT 
               
               
                   
               
               
                 (SEQ ID NO: 186) 
               
               
                 SPMEGPTLRHSAAGRPWG 
               
               
                   
               
               
                 (SEQ ID NO: 187) 
               
               
                 VHMEDPTLRHGNAARAAE 
               
               
                   
               
               
                 (SEQ ID NO: 188) 
               
               
                 YPMEGPTLRHWLAARARH 
               
               
                   
               
               
                 (SEQ ID NO: 189) 
               
               
                 GKTQGPKQLKWQVGSSLP 
               
               
                   
               
               
                 (SEQ ID NO: 190) 
               
               
                 GEMEGPTLLHWRAARAMQ 
               
               
                   
               
               
                 (SEQ ID NO: 191) 
               
               
                 INMEGPTLRLWLAARAAA 
               
               
                   
               
               
                 (SEQ ID NO: 192) 
               
               
                 FRIEGPTLRNWLAARAAK 
               
               
                   
               
               
                 (SEQ ID NO: 193) 
               
               
                 GRMEGPTLRHWLAARAHP 
               
               
                   
               
               
                 (SEQ ID NO: 194) 
               
               
                 VLIQGHTVRNCMVARVDA 
               
               
                   
               
               
                 (SEQ ID NO: 195) 
               
               
                 DWIEGPTLRHWLAARALY 
               
               
                   
               
               
                 (SEQ ID NO: 196) 
               
               
                 SWTEGPTLRHWLAARARN 
               
               
                   
               
               
                 (SEQ ID NO: 197) 
               
               
                 RELEGPTLRLWLVERARM 
               
               
                   
               
               
                 (SEQ ID NO: 198) 
               
               
                 VSMEGPTLRNWLAARARM 
               
               
                   
               
               
                 (SEQ ID NO: 199) 
               
               
                 TTMEGPTLRHWLATRAVD 
               
               
                   
               
               
                 (SEQ ID NO: 200) 
               
               
                 AKLEGPTLRLWLAERAGR 
               
               
                   
               
               
                 (SEQ ID NO: 201) 
               
               
                 ARMEGPTLRHWLAARARY 
               
               
                   
               
               
                 (SEQ ID NO: 202) 
               
               
                 NIMDGPALRHWLPARAIQ 
               
               
                   
               
               
                 (SEQ ID NO: 203) 
               
               
                 NMIGGPTLGHRLADPAIQ 
               
               
                   
               
               
                 (SEQ ID NO: 204) 
               
               
                 VWMEGATLRQWLAARALI 
               
               
                   
               
               
                 (SEQ ID NO: 205) 
               
               
                 RVMEGPTLLQRLAARARS 
               
               
                   
               
               
                 (SEQ ID NO: 206) 
               
               
                 QPMDEPARRQWLSARAGL 
               
               
                   
               
               
                 (SEQ ID NO: 207) 
               
               
                 AWTEGPTLRHWLAARGRS 
               
               
                   
               
               
                 (SEQ ID NO: 208) 
               
               
                 ATMEGPTLRHWLAARAAL 
               
               
                   
               
               
                 (SEQ ID NO: 209) 
               
               
                 GRMEGPTLRHWLAARALF 
               
               
                   
               
               
                 (SEQ ID NO: 210) 
               
               
                 ENMQGRTLRHWLAARDYF 
               
               
                   
               
               
                 (SEQ ID NO: 211) 
               
               
                 KGVEGPTLRLWLAARALM 
               
               
                   
               
               
                 (SEQ ID NO: 212) 
               
               
                 VEMEGPTLRHWLAARASV 
               
               
                   
               
               
                 (SEQ ID NO: 213) 
               
               
                 AFIEGPTLKNWLAARAIM 
               
               
                   
               
               
                 (SEQ ID NO: 214) 
               
               
                 TVMEGPTLRHWLAARSRS 
               
               
                   
               
               
                 (SEQ ID NO: 215) 
               
               
                 AHMEGPTLRHWLATRAKM 
               
               
                   
               
               
                 (SEQ ID NO: 216) 
               
               
                 KDIEGPTLRHWLAARANY 
               
               
                   
               
               
                 (SEQ ID NO: 217) 
               
               
                 RIHDGRKLRQWLTVRDTM 
               
               
                   
               
               
                 (SEQ ID NO: 218) 
               
               
                 KPIEGPTLKLWLAERMAA 
               
               
                   
               
               
                 (SEQ ID NO: 219) 
               
               
                 AKDVGTRLRQWLAAGARA 
               
               
                   
               
               
                 (SEQ ID NO: 220) 
               
               
                 QSQEGPTLRLWLAERAKW 
               
               
                   
               
               
                 (SEQ ID NO: 221) 
               
               
                 MYTEGATLRQWLAARARI 
               
               
                   
               
               
                 (SEQ ID NO: 222) 
               
               
                 PKMEGPTRRTRLADRSTS 
               
               
                   
               
               
                 (SEQ ID NO: 223) 
               
               
                 NVMEGPTLRHWLAYRARM 
               
               
                   
               
               
                 (SEQ ID NO: 224) 
               
               
                 TWMEGPTLRHWLAARALG 
               
               
                   
               
               
                 (SEQ ID NO: 225) 
               
               
                 LTMEGPTLRHWLAARATR 
               
               
                   
               
               
                 (SEQ ID NO: 226) 
               
               
                 YTMEGPTLRHWLAARALH 
               
               
                   
               
               
                 (SEQ ID NO: 227) 
               
               
                 NEMEGATLRQWLAARAKW 
               
               
                   
               
               
                 (SEQ ID NO: 228) 
               
               
                 FSKEGATLRQWLAARALD 
               
               
                   
               
               
                 (SEQ ID NO: 229) 
               
               
                 SNGVCRTLRQWLAARAEE 
               
               
                   
               
               
                 (SEQ ID NO: 230) 
               
               
                 KGMEGPTLRNWLAERAML 
               
               
                   
               
               
                 (SEQ ID NO: 231) 
               
               
                 QDMVGPTLRHWLAARARL 
               
               
                   
               
               
                 (SEQ ID NO: 232) 
               
               
                 YSHEGPTLRHWLAARALL 
               
               
                   
               
               
                 (SEQ ID NO: 233) 
               
               
                 GVIEGPTLRHWLAARMKV 
               
               
                   
               
               
                 (SEQ ID NO: 234) 
               
               
                 MHMEGPTLRHWLATRALI 
               
               
                   
               
               
                 (SEQ ID NO: 235) 
               
               
                 CRSEGPTLRCWLAARAGY 
               
               
                   
               
               
                 (SEQ ID NO: 236) 
               
               
                 MCIEGPTLRQWQVCRVGL 
               
               
                   
               
               
                 (SEQ ID NO: 237) 
               
               
                 CRVEGPSQRQCLAARACW 
               
               
                   
               
               
                 (SEQ ID NO: 238) 
               
               
                 CTMEGPTLRHWLAARACI 
               
               
                   
               
               
                 (SEQ ID NO: 239) 
               
               
                 CQVDGPTVRHCRAARAGL 
               
               
                   
               
               
                 (SEQ ID NO: 240) 
               
               
                 CDMAGATLRQWLACRSGT 
               
               
                   
               
               
                 (SEQ ID NO: 241) 
               
               
                 ICTEGCTLRLWLAERSRV 
               
               
                   
               
               
                 (SEQ ID NO: 242) 
               
               
                 CGMEGPALRQWLACRAVD 
               
               
                   
               
               
                 (SEQ ID NO: 243) 
               
               
                 QGCSSGGPTLREWQQCVRMQHS 
               
               
                   
               
               
                 (SEQ ID NO: 244) 
               
               
                 QGCSSGGPTLREWQQCRRAQHS 
               
               
                   
               
               
                 (SEQ ID NO: 245) 
               
               
                 QGCSSGGPTLREWQQCVRAQHS 
               
               
                   
               
               
                 (SEQ ID NO: 246) 
               
               
                 IEGQSWEFENDRVPAHSLERVLLLRRVPTEPSGPSICAQIEGPTFKQW 
               
               
                   
               
               
                 QECINGHS; 
               
               
                   
               
               
                 (SEQ ID NO: 247) 
               
               
                 IEGPTFKQWQKCRNMHS; 
               
               
                   
               
               
                 (SEQ ID NO: 248) 
               
               
                 IEGPTFKQWQKLRRVHS; 
               
               
                   
               
               
                 (SEQ ID NO: 249) 
               
               
                 IEGEPVSDGKRRPRVHSLERVDAVHAKVGPSICAQIEGPTFKQWQKCKR 
               
               
                   
               
               
                 AHS; 
               
               
                   
               
               
                 (SEQ ID NO: 250) 
               
               
                 IEGRWPPPQFPVTQQHSLERVGRPPPSVELPRPTFVCAQIEGPTFKQWQ 
               
               
                   
               
               
                 RCLREHS; 
               
               
                   
               
               
                 (SEQ ID NO: 251) 
               
               
                 IEGPTFKQWQRWRLLHS; 
               
               
                   
               
               
                 (SEQ ID NO: 252) 
               
               
                 IEGPTFKQWQAWRKMHS; 
               
               
                   
               
               
                 (SEQ ID NO: 253) 
               
               
                 IEGPTFKQWQRWRKMHS; 
               
               
                   
               
               
                 (SEQ ID NO: 254) 
               
               
                 IEGRWPPPQFPVTEHHSLERVGRRPPNAQMPQSIFICGQNEGPTFQYCQ 
               
               
                   
               
               
                 RCLREHS; 
               
               
                   
               
               
                 (SEQ ID NO: 255) 
               
               
                 IEGWWWQFYFHAKEDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 256) 
               
               
                 PSICAQIEGPTFKQWQTCMRAHS; 
               
               
                   
               
               
                 (SEQ ID NO: 257) 
               
               
                 IEGYVGGPYEQTNSLERVPPTLAWKYGPRTPSICAQIEGPTFKQWQQCL 
               
               
                   
               
               
                 SDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 258) 
               
               
                 IEGPTFKQWQGRSKRHS; 
               
               
                   
               
               
                 (SEQ ID NO: 259) 
               
               
                 IEGWPWQLYVHPEGEHS; 
               
               
                   
               
               
                 (SEQ ID NO: 260) 
               
               
                 IEGWWWQLYFHAKDDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 261) 
               
               
                 IEGPTFKQWQKLRRSHS; 
               
               
                   
               
               
                 (SEQ ID NO: 262) 
               
               
                 IEGWWWQFYFHPKEDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 263) 
               
               
                 IEGPTFKQWQKSRTKHS; 
               
               
                   
               
               
                 (SEQ ID NO: 264) 
               
               
                 IEGWTWQFYVHPKGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 265) 
               
               
                 IEGPTFKQWQAARMHHS; 
               
               
                   
               
               
                 (SEQ ID NO: 266) 
               
               
                 IEGPTFKQWQACLHSHS; 
               
               
                   
               
               
                 (SEQ ID NO: 267) 
               
               
                 IEGWSWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 268) 
               
               
                 IEGPSFTPWFHERRSHS; 
               
               
                   
               
               
                 (SEQ ID NO: 269) 
               
               
                 IEGPTFKQWQWLRRHHS; 
               
               
                   
               
               
                 (SEQ ID NO: 270) 
               
               
                 IEGWWWQFYVHAKGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 271) 
               
               
                 IEGPTFKQWQVWRNRHS; 
               
               
                   
               
               
                 (SEQ ID NO: 272) 
               
               
                 IEGQSWLRRLHWKEEHS; 
               
               
                   
               
               
                 (SEQ ID NO: 273) 
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRSCAQIEGPTFKQWQICKDQ 
               
               
                   
               
               
                 HS; 
               
               
                   
               
               
                 (SEQ ID NO: 274) 
               
               
                 IEGPTFKQWQKWRKTHS; 
               
               
                   
               
               
                 (SEQ ID NO: 275) 
               
               
                 IEGPTFKQWQYWRAKHS; 
               
               
                   
               
               
                 (SEQ ID NO: 276) 
               
               
                 IEGPTFKQWQVRQKTHS; 
               
               
                   
               
               
                 (SEQ ID NO: 277) 
               
               
                 IEGWSWQFYFHAKGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 278) 
               
               
                 IEGRTWQLYFHAKEEHS; 
               
               
                   
               
               
                 (SEQ ID NO: 279) 
               
               
                 IEGWSWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 280) 
               
               
                 IEGWPRQLYAHAKEDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 281) 
               
               
                 IEGWWWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 282) 
               
               
                 IEGWSWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 283) 
               
               
                 IEGWSWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 284) 
               
               
                 IHGHGSQKPTAARALESTSSLTTRTRTTSICAQQDMVGPTIRQWLAARA 
               
               
                   
               
               
                 CI; 
               
               
                   
               
               
                 (SEQ ID NO: 285) 
               
               
                 IEGPTFEQWQHWRRGHS; 
               
               
                   
               
               
                 (SEQ ID NO: 286) 
               
               
                 IEGWIWRQWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 287) 
               
               
                 IEGWIWRPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 288) 
               
               
                 IEGYWWYASWAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 289) 
               
               
                 IEGWPWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 290) 
               
               
                 IEGWVWCQWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 291) 
               
               
                 IEGPTLHEWLRWLRQHS; 
               
               
                   
               
               
                 (SEQ ID NO: 292) 
               
               
                 IEGWVWRPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 293) 
               
               
                 IEGWVWCPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 294) 
               
               
                 IEGEALVFWWRVRGGHS; 
               
               
                   
               
               
                 (SEQ ID NO: 295) 
               
               
                 IEGWVWCPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 296) 
               
               
                 IEGWVWWPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 297) 
               
               
                 IEGWTWQFYALPRGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 298) 
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRSCAQIEGPTFKQWQICKDQ 
               
               
                   
               
               
                 HS; 
               
               
                   
               
               
                 (SEQ ID NO: 299) 
               
               
                 IEGPTLRQRLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 300) 
               
               
                 IEGWSWQFYAHPKGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 301) 
               
               
                 IEGWVWRQWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 302) 
               
               
                 IEGRHYQKWPARRLGHS; 
               
               
                   
               
               
                 (SEQ ID NO: 303) 
               
               
                 IEGFVGTVDWRQGRPHS; 
               
               
                   
               
               
                 (SEQ ID NO: 304) 
               
               
                 IEGQEPTRLRLqMDRHS; 
               
               
                   
               
               
                 (SEQ ID NO: 305) 
               
               
                 IAQVRMLGRFTLLVLSRARAASTQLSFQHSICAQIEGGAQTQWDAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 306) 
               
               
                 IEGEIWAGPGAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 307) 
               
               
                 IEGEALVFWWAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 308) 
               
               
                 IEGSYRERQQAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 309) 
               
               
                 IEGWVWRPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 310) 
               
               
                 IEGWNPWRGAASRV; 
               
               
                   
               
               
                 (SEQ ID NO: 311) 
               
               
                 IEGWTRRQWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 312) 
               
               
                 IEGWVWRPWLAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 313) 
               
               
                 IEGPTFKQWQAMRRHS; 
               
               
                   
               
               
                 (SEQ ID NO: 314) 
               
               
                 IEGMVKLGVIRLLVL; 
               
               
                   
               
               
                 (SEQ ID NO: 315) 
               
               
                 IEGPTFKQWQAWRRWHS; 
               
               
                   
               
               
                 (SEQ ID NO: 316) 
               
               
                 IEVWQSHWYQAARALESTSSRLLPMRPPPSICAQIEGPTLPQRMAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 317) 
               
               
                 IEGWTWQFYAHPQGDHS; 
               
               
                   
               
               
                 (SEQ ID NO: 318) 
               
               
                 IEGPTFKQWQALRKRHS; 
               
               
                   
               
               
                 (SEQ ID NO: 319) 
               
               
                 IEGPTFKQWQKLRLGHS; 
               
               
                   
               
               
                 (SEQ ID NO: 320) 
               
               
                 IEGPTFKQWQLMGFPHS; 
               
               
                   
               
               
                 (SEQ ID NO: 321) 
               
               
                 IEGWIWRQWLMQTLWHS; 
               
               
                   
               
               
                 (SEQ ID NO: 322) 
               
               
                 IEGPTFKQWQAMRKNHS; 
               
               
                   
               
               
                 (SEQ ID NO: 323) 
               
               
                 IEGPTFKQWQKAVRLSHS; 
               
               
                   
               
               
                 (SEQ ID NO: 324) 
               
               
                 IEGWQEGRQSAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 325) 
               
               
                 IEGPTFKQWQRWLKYHS; 
               
               
                   
               
               
                 (SEQ ID NO: 326) 
               
               
                 IEGNYWFWQQVGQENTLSREWIQTLGQKYWYRPPSICAQIEGWSRHQH 
               
               
                   
               
               
                 YSAMSGHS; 
               
               
                   
               
               
                 (SEQ ID NO: 327) 
               
               
                 IEGPTFKQWQLWRLQHS; 
               
               
                   
               
               
                 (SEQ ID NO: 328) 
               
               
                 IEGPTFKQWQMLRRHHS; 
               
               
                   
               
               
                 (SEQ ID NO: 329) 
               
               
                 IEGPTFKQWQRLRKNHS; 
               
               
                   
               
               
                 (SEQ ID NO: 330) 
               
               
                 IEGLLSQLWQAARA; 
               
               
                   
               
               
                 (SEQ ID NO: 331) 
               
               
                 IEGPSLPEWLHVWRHHS; 
               
               
                   
               
               
                 (SEQ ID NO: 332) 
               
               
                 IEGPTLHEWLAERRKHS; 
               
               
                   
               
               
                 (SEQ ID NO: 333) 
               
               
                 IEGPTLHEWLALLRSHS; 
               
               
                   
               
               
                 (SEQ ID NO: 334) 
               
               
                 IEGPTLHEWLAQRREHS; 
               
               
                   
               
               
                 (SEQ ID NO: 335) 
               
               
                 IEGPTLHEWLLYRRAHS; 
               
               
                   
               
               
                 (SEQ ID NO: 336) 
               
               
                 IEGPTLHEWLRQRRQHS; 
               
               
                   
               
               
                 (SEQ ID NO: 454) 
               
               
                 CSSGGPTLREWQQCSRAQ; 
               
               
                   
               
               
                 (SEQ ID NO: 455) 
               
               
                 CSSGGPTLREWQQCQRAQ; 
               
               
                 and 
               
               
                   
               
               
                 (SEQ ID NO: 456) 
               
               
                 CSSGGPTLREWQQCGRAQ. 
               
            
           
         
       
     
     Some exemplary compounds of this invention, as set out above, are also shown in Tables 1-6, 8, and 12, and are set out in the Examples herein. Single letter amino acid abbreviations are used, and the linker is shown separated by dashes for clarity. Additional exemplary compounds of the invention are set out in Table 10 herein. 
     Linkers 
     Any “linker” group (L 1 , L 2 , L 3 , L 4 , and L 5 ) is optional. When present, its chemical structure is not critical, since it serves primarily as a spacer. Thus, the terms “linker” and “spacer” may be used interchangeably herein. In one aspect, the linker is made up of amino acids linked together by peptide bonds. Thus, in some embodiments, the linker is made up of from 1 to 20 amino acids linked by peptide bonds, wherein the amino acids are selected from the 20 naturally occurring amino acids. Some of these amino acids may be glycosylated, as is well understood by those in the art. In another embodiment, the 1 to 20 amino acids are selected from glycine, alanine, proline, asparagine, glutamine, and lysine. In a further aspect, a linker is made up of a majority of amino acids that are sterically unhindered, such as glycine and alanine Thus, linkers are polyglycines (particularly (Gly)4, (Gly)5), poly(Gly-Ala), and polyalanines. Other specific examples of linkers are: 
     
       
         
           
               
               
               
            
               
                   
                 (Gly) 3 Lys(Gly) 4 ; 
                 (SEQ ID NO: 4) 
               
               
                   
                   
               
               
                   
                 (Gly) 3 AsnGlySer(Gly) 2   
                 (SEQ ID NO: 5) 
               
            
           
         
       
     
     (this structure provides a site for glycosylation, when it is produced recombinantly in a mammalian cell system that is capable of glycosylating such sites); 
     
       
         
           
               
               
               
            
               
                   
                 (Gly) 3 Cys(Gly) 4 ; 
                 (SEQ ID NO: 6) 
               
               
                   
                 and 
                   
               
               
                   
                   
               
               
                   
                 GlyProAsnGly. 
                 (SEQ ID NO: 7) 
               
            
           
         
       
     
     To explain the above nomenclature, for example, (Gly) 3 Lys(Gly) 4  means Gly-Gly-Gly-Lys-Gly-Gly-Gly-Gly. Combinations of Gly and Ala are also contemplated. The linkers shown here are exemplary; linkers within the scope of this invention may be much longer and may include other residues. 
     In another embodiment, glycine linkers (or spacers) are used in inserting the TPO-mimetic compounds of the invention into Fc-Loops. These linkers (or spacers) may be symmetric or asymmetric. When linkers (or spacers) are used to connect tandem or multiple peptide sequences, the linkers may be the same or different. Moreover, to the extent where peptides are inserted into other sequences, the linkers at the N- and C-termini may be the same or different. 
     Non-peptide linkers are also possible. For example, alkyl linkers such as —NH—(CH 2 )s—C(O)—, wherein s=2-20 could be used. These alkyl linkers may further be substituted by any non-sterically hindering group such as lower alkyl (e.g., C1-C6) lower acyl, halogen (e.g., Cl, Br), CN, NH 2 , phenyl, etc. An exemplary non-peptide linker is a PEG linker, which has a molecular weight of 100 to 5000 kD, or 100 to 500 kD. The peptide linkers may be altered to form derivatives as described herein below. 
     Derivatives 
     It is also contemplated that “derivatives” of a TMP (peptide and/or vehicle portion of the TMP) may be substituted for a TMP described above. Such derivatives may improve the solubility, absorption, biological half life, and the like of the compounds. The moieties may alternatively eliminate or attenuate any undesirable side-effect of the compounds and the like. 
     Such derivative TMPs include compounds in which: 
     1. The compound or some portion thereof is cyclic. For example, the peptide portion may be modified to contain two or more Cys residues (e.g., in the linker), which could cyclize by disulfide bond formation. 
     2. The compound is cross-linked or is rendered capable of cross-linking between molecules. For example, the peptide portion may be modified to contain one Cys residue and thereby be able to form an intermolecular disulfide bond with a like molecule. The compound may also be cross-linked through its C-terminus. 
     3. One or more peptidyl [—C(O)NR—] linkages (bonds) is replaced by a non-peptidyl linkage. Exemplary non-peptidyl linkages are —CH2-carbamate [—CH2-OC(O)NR—], phosphonate, —CH2-sulfonamide [—CH2-S(O)2NR—], urea [—NHC(O)NH—], —CH2-secondary amine, and alkylated peptide [—C(O)NR6- wherein R6 is lower alkyl]. 
     4. The N-terminus is derivatized. Typically, the N-terminus may be acylated or modified to a substituted amine. Exemplary N-terminal derivative groups include —NRR1 (other than —NH2), —NRC(O)R1,
         —NRC(O)OR1, —NRS(O)2R1, —NHC(O)NHR1, succinimide, or benzyloxycarbonyl-NH— (CBZ—NH—), wherein R and R1 are each independently hydrogen or lower alkyl with the proviso that R and R1 are not both hydrogen and wherein the phenyl ring may be substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, chloro, and bromo; to a succinimide group; to a benzyloxycarbonyl-NH— (CBZ—NH—) group; and peptides wherein the free C terminus is derivatized to —C(O)R2 where R2 is selected from the group consisting of lower alkoxy and —NR3R4 where R3 and R4 are independently selected from the group consisting of hydrogen and lower alkyl. By “lower” is meant a group having from 1 to 6 carbon atoms.       

     5. The free C-terminus is derivatized. Typically, the C-terminus is esterified or amidated. For example, one may use methods described in the art to add (NH—CH2-CH2-NH2)2 to compounds of this invention at the C-terminus. Likewise, one may use methods described in the art to add —NH2 to compounds of this invention at the C-terminus. Exemplary C-terminal derivative groups include, for example, —C(O)R2 wherein R2 is lower alkoxy or —NR3R4 wherein R3 and R4 are independently hydrogen or C1-C8 alkyl (preferably C1-C4 alkyl). 
     6. A disulfide bond is replaced with another, preferably more stable, cross-linking moiety (e.g., an alkylene). See, e.g., Bhatnagar et al. (1996), J. Med. Chem. 39: 3814-9; Alberts et al. (1993) Thirteenth Am. Pep. Symp., 357-9. 
     7. One or more individual amino acid residues is modified. Various derivatizing agents are known to react specifically with selected side chains or terminal residues, as described in detail below. 
     Additionally, modifications of individual amino acids may be introduced into the TMP sequence by reacting targeted amino acid residues of the peptide with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues. The following are exemplary. 
     Lysinyl and amino terminal residues may be reacted with succinic or other carboxylic acid anhydrides. Derivatization with these agents has the effect of reversing the charge of the lysinyl residues. Other suitable reagents for derivatizing alpha-amino-containing residues include imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4 pentanedione; and transaminase-catalyzed reaction with glyoxylate. 
     Arginyl residues may be modified by reaction with one or several conventional reagents, among them phenylglyoxal, 2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residues requires that the reaction be performed in alkaline conditions because of the high pKa of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine guanidino group. 
     The specific modification of tyrosyl residues per se has been studied extensively, with particular interest in introducing spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane. Most commonly, N-acetylimidizole and tetranitromethane may be used to form O-acetyl tyrosyl species and 3-nitro derivatives, respectively. 
     Carboxyl side groups (aspartyl or glutamyl) may be selectively modified by reaction with carbodiimides (R′—N═C═N—R′) such as 1-cyclohexyl-3-(2-morpholinyl-(4-ethyl)carbodiimide or 1-ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide. Furthermore, aspartyl and glutamyl residues may be converted to asparaginyl and glutaminyl residues by reaction with ammonium ions. 
     Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues may be deamidated under mildly acidic conditions. Either form of these residues falls within the scope of this invention. 
     Cysteinyl residues can be replaced by amino acid residues or other moieties either to eliminate disulfide bonding or, conversely, to stabilize cross-linking See, e.g., Bhatnagar et al. (1996), J. Med. Chem. 39: 3814-9. 
     Derivatization with bifunctional agents is useful for cross-linking the peptides or their functional derivatives to a water-insoluble support matrix or to other macromolecular carriers. Commonly used cross-linking agents include, e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3′-dithiobis (succinimidylpropionate), and bifunctional maleimides such as bis-N-maleimido-1,8-octane. Derivatizing agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate yield photoactivatable intermediates that are capable of forming crosslinks in the presence of light. Alternatively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and the reactive substrates described in U.S. Pat. Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and 4,330,440 may be employed for protein immobilization. 
     Other possible modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, oxidation of the sulfur atom in Cys, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (Creighton, T. E., Proteins: Structure and Molecule Properties, W.H. Freeman &amp; Co., San Francisco, pp. 79-86 (1983)), acetylation of the N-terminal amine, and, in some instances, amidation of the C-terminal carboxyl groups. 
     Such derivatized moieties preferably improve one or more characteristics including thrombopoietic activity, solubility, absorption, biological half life, and the like of the inventive compounds. Alternatively, derivatized moieties result in compounds that have the same, or essentially the same, characteristics and/or properties of the compound that is not derivatized. The moieties may alternatively eliminate or attenuate any undesirable side effect of the compounds and the like. 
     As ascertained by peptide mapping and N-terminal sequencing, a preparation is provided which is at least 50% dipolymer/peptide conjugate and at most 50% unreacted peptide and/or monopolymer/peptide conjugate. In other embodiments, preparations are provided which are at least 75% dipolymer/peptide conjugate and at most 25% unreacted peptide and/or monopolymer/peptide conjugate; at least 85% dipolymer/peptide conjugate and at most 15% unreacted peptide and/or monopolymer/peptide conjugate; at least 90% dipolymer/peptide conjugate and at most 10% unreacted peptide and/or monopolymer/peptide conjugate; at least 95% dipolymer/peptide conjugate and at most 5% unreacted peptide and/or monopolymer/peptide conjugate; and at least 99% dipolymerpeptide conjugate and at most 1% unreacted peptide and/or monopolymer/peptide conjugate. 
     Carbohydrate (oligosaccharide) groups may conveniently be attached to sites that are known to be glycosylation sites in proteins. Generally, O-linked oligosaccharides are attached to serine (Ser) or threonine (Thr) residues while N-linked oligosaccharides are attached to asparagine (Asn) residues when they are part of the sequence Asn-X-Ser/Thr, where X can be any amino acid except proline. X is preferably one of the 19 naturally occurring amino acids other than proline. The structures of N-linked and O-linked oligosaccharides and the sugar residues found in each type are different. One type of sugar that is commonly found on both is N-acetylneuraminic acid (referred to as sialic acid). Sialic acid is usually the terminal residue of both N-linked and O-linked oligosaccharides and, by virtue of its negative charge, may confer acidic properties to the glycosylated compound. Such site(s) may be incorporated in the linker of the compounds of this invention and are preferably glycosylated by a cell during recombinant production of the polypeptide compounds (e.g., in mammalian cells such as CHO, BHK, COS). However, such sites may further be glycosylated by synthetic or semi-synthetic procedures known in the art. 
     Compounds of the present invention may be changed at the DNA level, as well. The DNA sequence of any portion of the compound may be changed to codons more compatible with the chosen host cell. For  E. coli , which is the host cell in one aspect, optimized codons are known in the art. Codons may be substituted to eliminate restriction sites or to include silent restriction sites, which may aid in processing of the DNA in the selected host cell. The vehicle, linker and peptide DNA sequences may be modified to include any of the foregoing sequence changes. 
     Isotope- and toxin-conjugated derivatives. Another set of useful derivatives are the above-described molecules conjugated to toxins, tracers, or radioisotopes. Such conjugation is especially useful for molecules comprising peptide sequences that bind to tumor cells or pathogens. Such molecules may be used as therapeutic agents or as an aid to surgery (e.g., radioimmunoguided surgery or RIGS) or as diagnostic agents (e.g., radioimmunodiagnostics or RID). 
     As therapeutic agents, these conjugated derivatives possess a number of advantages. They facilitate use of toxins and radioisotopes that would be toxic if administered without the specific binding provided by the peptide sequence. They also can reduce the side-effects that attend the use of radiation and chemotherapy by facilitating lower effective doses of the conjugation partner. 
     Useful conjugation partners include:
         radioisotopes, such as  90 Yttrium,  131 Iodine,  225 Actinium, and  213 Bismuth;   ricin A toxin, microbially derived toxins such as  Pseudomonas  endotoxin (e.g., PE38, PE40), and the like;   partner molecules in capture systems (see below);   biotin, streptavidin (useful as either partner molecules in capture systems or as tracers, especially for diagnostic use); and   cytotoxic agents (e.g., doxorubicin).       

     One useful adaptation of these conjugated derivatives is use in a capture system. In such a system, the molecule of the present invention would comprise a benign capture molecule. This capture molecule would be able to specifically bind to a separate effector molecule comprising, for example, a toxin or radioisotope. Both the vehicle-conjugated molecule and the effector molecule would be administered to the patient. In such a system, the effector molecule would have a short half-life except when bound to the vehicle-conjugated capture molecule, thus minimizing any toxic side-effects. The vehicle-conjugated molecule would have a relatively long half-life but would be benign and non-toxic. The specific binding portions of both molecules can be part of a known specific binding pair (e.g., biotin, streptavidin) or can result from peptide generation methods such as those described herein. 
     Such conjugated derivatives may be prepared by methods known in the art. In the case of protein effector molecules (e.g.,  Pseudomonas  endotoxin), such molecules can be expressed as fusion proteins from correlative DNA constructs. Radioisotope conjugated derivatives may be prepared, for example, as described for the BEXA antibody (Coulter). Derivatives comprising cytotoxic agents or microbial toxins may be prepared, for example, as described for the BR96 antibody (Bristol-Myers Squibb). Molecules employed in capture systems may be prepared, for example, as described by the patents, patent applications, and publications from NeoRx. Molecules employed for RIGS and RID may be prepared, for example, by the patents, patent applications, and publications from NeoProbe. 
     The compounds of the invention may also be covalently or noncovalently associated with a carrier molecule, such as a linear polymer (e.g., polyethylene glycol, polylysine, dextran, etc.), a branched-chain polymer (see, for example, U.S. Pat. No. 4,289,872 to Denkenwalter et al., issued Sep. 15, 1981; U.S. Pat. No. 5,229,490 to Tam, issued Jul. 20, 1993; WO 93/21259 by Frechet et al., published 28 Oct. 1993); a lipid; a cholesterol group (such as a steroid); or a carbohydrate or oligosaccharide. Other possible carriers include one or more water soluble polymer attachments such as polyoxyethylene glycol, or polypropylene glycol as described U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. Still other useful polymers known in the art include monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of these polymers. 
     In one aspect, the carrier is polyethylene glycol (PEG). The PEG group may be of any convenient molecular weight and may be straight chain or branched. The average molecular weight of the PEG will range from about 2 kDa to about 100 kDa, or from about 5 kDa to about 50 kDa, or from about 5 kDa to about 10 kDa. 
     The PEG groups will generally be attached to the compounds of the invention via acylation, reductive alkylation, Michael addition, thiol alkylation or other chemoselective conjugation/ligation methods through a reactive group on the PEG moiety (e.g., an aldehyde, amino, ester, thiol, α-haloacetyl, maleimido or hydrazino group) to a reactive group on the target compound (e.g., an aldehyde, amino, ester, thiol, α-haloacetyl, maleimido or hydrazino group). 
     Vehicles 
     This invention requires the presence of at least one vehicle (F 1 , F 2 ) attached to a peptide through the N-terminus, C-terminus or a side chain of one of the amino acid residues. An Fc domain is a vehicle provided herein. Thus, an Fc domain may be fused to the N or C termini of the peptides or at both the N and C termini. Multiple vehicles may also be used; e.g., Fc&#39;s at each terminus or an Fc at a terminus and a PEG group at the other terminus or a side chain. 
     In various embodiments, the Fc component is either a native Fc or an Fc variant. By way of example and without limitation, the Fc component is preferably the Fc region of the human immunoglobulin IgG1 heavy chain or a biologically active fragment, derivative, or dimer thereof, see Ellison, J. W. et al., Nucleic Acids Res. 10:4071-4079 (1982). Native Fc domains are made up of monomeric polypeptides that may be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and/or non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2). One example of a native Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG (see Ellison et al. (1982), Nucleic Acids Res. 10: 4071-9). 
     In one aspect, the Fc sequence shown in SEQ ID NO: 3 is an Fc sequence for the compounds provided herein. Also provided are compounds in which the Fc is a dimeric form of the sequence of SEQ ID NO: 3 and each Fc chain is attached to a TMP tandem dimer. Additional Fc sequences are known in the art and are contemplated for use in the invention. For example, Fc IgG1 (GenBank Accession No. P01857), Fc IgG2 (GenBank Accession No. P01859), Fc IgG3 (GenBank Accession No. P01860), Fc IgG4 (GenBank Accession No. P01861), Fc IgA1 (GenBank Accession No. P01876), Fc IgA2 (GenBank Accession No. P01877), Fc IgD (GenBank Accession No. P01880), Fc IgM (GenBank Accession No. P01871), and Fc IgE (GenBank Accession No. P01854) are some additional Fc sequences contemplated for use herein. 
     Variants, analogs or derivatives of the Fc portion may be constructed by, for example, making various substitutions of residues or sequences. In one aspect, an Fc variant is incorporated which comprises a molecule or sequence that is humanized from a non-human native Fc. Alternately, an Fc variant comprises a molecule or sequence that lacks one or more native Fc sites or residues that affect or are involved in (1) disulfide bond formation, (2) incompatibility with a selected host cell (3) N-terminal heterogeneity upon expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than a salvage receptor, or (7) antibody-dependent cellular cytotoxicity (ADCC), each of which is described in detail in U.S. Patent Application No. 20040087778, the disclosure of which is incorporated by reference in its entirety. 
     Variant (or analog) polypeptides include insertion variants, wherein one or more amino acid residues supplement an Fc amino acid sequence. Insertions may be located at either or both termini of the protein, or may be positioned within internal regions of the Fc amino acid sequence. Insertion variants, with additional residues at either or both termini, can include for example, fusion proteins and proteins including amino acid tags or labels. For example, the Fc molecule may optionally contain an N-terminal Met, especially when the molecule is expressed recombinantly in a bacterial cell such as  E. coli.    
     In Fc deletion variants, one or more amino acid residues in an Fc polypeptide are removed. Deletions can be effected at one or both termini of the Fc polypeptide, or with removal of one or more residues within the Fc amino acid sequence. Deletion variants, therefore, include all fragments of an Fc polypeptide sequence. 
     In Fc substitution variants, one or more amino acid residues of an Fc polypeptide are removed and replaced with alternative residues. In one aspect, the substitutions are conservative in nature and conservative substitutions of this type are well known in the art. Alternatively, the invention embraces substitutions that are also non-conservative. 
     For example, cysteine residues can be deleted or replaced with other amino acids to prevent formation of some or all disulfide crosslinks of the Fc sequences. Each cysteine residue can be removed and/or substituted with other amino acids, such as Ala or Ser. As another example, modifications may also be made to introduce amino acid substitutions to (1) ablate the Fc receptor binding site; (2) ablate the complement (C1q) binding site; and/or to (3) ablate the antibody dependent cell-mediated cytotoxicity (ADCC) site. Such sites are known in the art, and any known substitutions are within the scope of Fc as used herein. For example, see Molecular Immunology, Vol. 29, No. 5, 633-639 (1992) with regard to ADCC sites in IgG1. 
     Likewise, one or more tyrosine residues can be replaced by phenylalanine residues. In addition, other variant amino acid insertions, deletions and/or substitutions are also contemplated and are within the scope of the present invention. Conservative amino acid substitutions will generally be preferred. Furthermore, alterations may be in the form of altered amino acids, such as peptidomimetics or D-amino acids. 
     As noted above, both native Fcs and Fc variants are suitable Fc domains for use within the scope of this invention. A native Fc may be extensively modified to form an Fc variant provided binding to the salvage receptor is maintained; see, for example WO 97/34631 and WO 96/32478. In such Fc variants, one may remove one or more sites of a native Fc that provide structural features or functional activity not required by the fusion molecules of this invention. One may remove these sites by, for example, substituting or deleting residues, inserting residues into the site, or truncating portions containing the site. The inserted or substituted residues may also be altered amino acids, such as peptidomimetics or D-amino acids. Fc variants may be desirable for a number of reasons, several of which are described below. Exemplary Fc variants include molecules and sequences in which: 
     Sites involved in disulfide bond formation are removed. Such removal may avoid reaction with other cysteine-containing proteins present in the host cell used to produce the molecules of the invention. For this purpose, the cysteine-containing segment at the N-terminus may be truncated or cysteine residues may be deleted or substituted with other amino acids (e.g., alanyl, seryl). In particular, one may truncate the N-terminal 20-amino acid segment of SEQ ID NO: 3 or delete or substitute the cysteine residues at positions 7 and 10 of SEQ ID NO: 3. Even when cysteine residues are removed, the single chain Fc domains can still form a dimeric Fc domain that is held together non-covalently. 
     A native Fc is modified to make it more compatible with a selected host cell. For example, one may remove the PA sequence near the N-terminus of a typical native Fc, which may be recognized by a digestive enzyme in  E. coli  such as proline iminopeptidase. One may also add an N-terminal methionine residue, especially when the molecule is expressed recombinantly in a bacterial cell such as  E. coli . The Fc domain of SEQ ID NO: 3 is one such Fc variant. 
     A portion of the N-terminus of a native Fc is removed to prevent N-terminal heterogeneity when expressed in a selected host cell. For this purpose, one may delete any of the first 20 amino acid residues at the N-terminus, particularly those at positions 1, 2, 3, 4 and 5. 
     One or more glycosylation sites are removed. Residues that are typically glycosylated (e.g., asparagine) may confer cytolytic response. Such residues may be deleted or substituted with unglycosylated residues (e.g., alanine) 
     Sites involved in interaction with complement, such as the C1q binding site, are removed. For example, one may delete or substitute the EKK sequence of human IgG1. Complement recruitment may not be advantageous for the molecules of this invention and so may be avoided with such an Fc variant. 
     Sites are removed that affect binding to Fc receptors other than a salvage receptor. A native Fc may have sites for interaction with certain white blood cells that are not required for the fusion molecules of the present invention and so may be removed. 
     The ADCC site is removed. ADCC sites are known in the art; see, for example,  Molec. Immunol.  29 (5): 633-9 (1992) with regard to ADCC sites in IgG1. These sites, as well, are not required for the fusion molecules of the present invention and so may be removed. 
     When the native Fc is derived from a non-human antibody, the native Fc may be humanized. Typically, to humanize a native Fc, one will substitute selected residues in the non-human native Fc with residues that are normally found in human native Fc. Techniques for antibody humanization are well known in the art. 
     Preferred Fc variants include the following. In SEQ ID NO: 3, the leucine at position 15 may be substituted with glutamate; the glutamate at position 99, with alanine; and the lysines at positions 101 and 103, with alanines In addition, one or more tyrosine residues can be replaced by phenylalanine residues. 
     It should be noted that Fc monomers will spontaneously dimerize when the appropriate cysteine residues are present, unless particular conditions are present that prevent dimerization through disulfide bond formation. Even if the cysteine residues that normally form disulfide bonds in the Fc dimer are removed or replaced by other residues, the monomeric chains will generally form a dimer through non-covalent interactions. The term “Fc” herein is used to mean any of these forms: the native monomer, the native dimer (disulfide bond linked), modified dimers (disulfide and/or non-covalently linked), and modified monomers (i.e., derivatives). 
     Fc sequences may also be derivatized, i.e., bearing modifications other than insertion, deletion, or substitution of amino acid residues. In one aspect, the modifications are covalent in nature, and include for example, chemical bonding with polymers, lipids, other organic, and inorganic moieties. However, non-covalent modifications are also contemplated. Derivatives of the invention may be prepared to increase circulating half-life, or may be designed to improve targeting capacity for the polypeptide to desired cells, tissues, or organs. 
     It is also possible to use the salvage receptor binding domain of the intact Fc molecule as the Fc part of a compound of the invention, such as described in WO 96/32478, entitled “Altered Polypeptides with Increased Half-Life.” Additional members of the class of molecules designated as Fc herein are those that are described in WO 97/34631, entitled “Immunoglobulin-Like Domains with Increased Half-Lives.” Both of the published PCT applications cited in this paragraph are hereby incorporated by reference. 
     As discussed herein, the Fc fusions may be at the N or C terminus of a TMP of the invention, or at both the N and C termini of the TMP. It has been previously been shown that peptides in which an Fc moiety is ligated to the N terminus of the TMP group is more bioactive than the other possibilities. When the Fc is fused at the N-terminus of the TMP or linker, such fusion will generally occur at the C-terminus of the Fc chain, and vice versa. 
     An alternative vehicle would be a protein, polypeptide, peptide, antibody, antibody fragment, or small molecule (e.g., a peptidomimetic compound) capable of binding to a salvage receptor. For example, one could use as a vehicle a polypeptide as described in U.S. Pat. No. 5,739,277, issued Apr. 14, 1998 to Presta et al. Peptides could also be selected by phage display for binding to the FcRn salvage receptor. Such salvage receptor-binding compounds are also included within the meaning of “vehicle” and are within the scope of this invention. Such vehicles should be selected for increased half-life (e.g., by avoiding sequences recognized by proteases) and decreased immunogenicity (e.g., by favoring non-immunogenic sequences, as discovered in antibody humanization). 
     As noted above, polymer vehicles may also be used for F 1  and F 2 . Various means for attaching chemical moieties useful as vehicles are currently available, see, e.g., Patent Cooperation Treaty (“PCT”) International Publication No. WO 96/11953, entitled “N-Terminally Chemically Modified Protein Compositions and Methods,” herein incorporated by reference in its entirety. This PCT publication discloses, among other things, the selective attachment of water soluble polymers to the N-terminus of proteins. 
     Water-Soluble Polymers 
     This invention contemplates compounds comprising a water-soluble polymer (WSP). Suitable, clinically acceptable, WSP include without limitation, PEG, polyethylene glycol propionaldehyde, copolymers of ethylene glycol/propylene glycol, monomethoxy-polyethylene glycol, carboxymethylcellulose, polyacetals, polyvinyl alcohol (PVA), polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, poly (.beta.-amino acids) (either homopolymers or random copolymers), poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers (PPG) and other polyakylene oxides, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (POG) (e.g., glycerol) and other polyoxyethylated polyols, polyoxyethylated sorbitol, or polyoxyethylated glucose, colonic acids or other carbohydrate polymers, Ficoll or dextran and mixtures thereof. In fact, any of the forms of PEG that have been used to derivatize other proteins, such as and without limitation mono-(C1-C10) alkoxy- or aryloxy-polyethylene glycol, are provided. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. 
     The PEG group may be of any convenient molecular weight and may be linear or branched. The average molecular weight of PEG contemplated for use in the invention ranges from about 2 kDa to about 100 kDa, from about 5 kDa to about 50 kDa, from about 5 kDa to about 10 kDa. In another aspect, the PEG moiety has a molecular weight from about 6 kDa to about 25 kDa. PEG groups generally are attached to peptides or proteins via acylation or reductive alkylation through a reactive group on the PEG moiety (e.g., an aldehyde, amino, thiol, or ester group) to a reactive group on the target peptide or protein (e.g., an aldehyde, amino, or ester group). Using methods described herein, a mixture of polymer/peptide conjugate molecules can be prepared, and the advantage provided herein is the ability to select the proportion of polymer/peptide conjugate to include in the mixture. Thus, if desired, a mixture of peptides with various numbers of polymer moieties attached (i.e., zero, one or two) can be prepared with a predetermined proportion of polymer/protein conjugate. 
     A useful strategy for the PEGylation of synthetic peptides consists of combining, through forming a conjugate linkage in solution, a peptide and a WSP (PEG) moiety, each bearing a special functionality that is mutually reactive toward the other. The peptides can be easily prepared with conventional solid phase synthesis. The peptides are “preactivated” with an appropriate functional group at a specific site. The precursors are purified and fully characterized prior to reacting with the PEG moiety. Ligation of the peptide with PEG usually takes place in aqueous phase and can be easily monitored by reverse phase analytical HPLC. The PEGylated peptides can be easily purified by preparative HPLC and characterized by analytical HPLC, amino acid analysis and laser desorption mass spectrometry. 
     Polysaccharide polymers are another type of WSP which may be used for protein modification. Dextrans are polysaccharide polymers comprised of individual subunits of glucose predominantly linked by α1-6 linkages. The dextran itself is available in many molecular weight ranges, and is readily available in molecular weights from about 1 kD to about 70 kD. Dextran is a suitable water soluble polymer for use in the present invention as a vehicle by itself or in combination with another vehicle (e.g., Fc). See, for example, WO 96/11953 and WO 96/05309. The use of dextran conjugated to therapeutic or diagnostic immunoglobulins has been reported; see, for example, European Patent Publication No. 0 315 456, which is hereby incorporated by reference. Dextran of about 1 kD to about 20 kD is preferred when dextran is used as a vehicle in accordance with the present invention. 
     The WSP moiety of the molecule may be branched or unbranched. For therapeutic use of the end-product preparation, the polymer is pharmaceutically acceptable. In general, a desired polymer is selected based on such considerations as whether the polymer conjugate will be used therapeutically, and if so, the desired dosage, circulation time, resistance to proteolysis, and other considerations. In various aspects, the average molecular weight of each WSP is between about 2 kDa and about 100 kDa, between about 5 kDa and about 50 kDa, between about 12 kDa and about 40 kDa and between about 20 kDa and about 35 kDa. In yet another aspect the molecular weight of each polymer is between about 6 kDa and about 25 kDa. The term “about” as used herein and throughout, indicates that in preparations of a water soluble polymer, some molecules will weigh more, some less, than the stated molecular weight. Generally, the higher the molecular weight or the more branches, the higher the polymer/protein ratio. Other sizes may be used, depending on the desired therapeutic profile including for example, the duration of sustained release; the effects, if any, on biological activity; the ease in handling; the degree or lack of antigenicity and other known effects of a water soluble polymer on a therapeutic protein. 
     The WSP should be attached to a peptide or protein with consideration given to effects on functional or antigenic domains of the peptide or protein. In general, chemical derivatization may be performed under any suitable condition used to react a protein with an activated polymer molecule. Activating groups which can be used to link the water soluble polymer to one or more proteins include without limitation sulfone, maleimide, sulfhydryl, thiol, triflate, tresylate, azidirine, oxirane and 5-pyridyl. If attached to the peptide by reductive alkylation, the polymer selected should have a single reactive aldehyde so that the degree of polymerization is controlled. 
     Production of Compounds/Methods of Making 
     The compounds described herein largely may be made in transformed host cells using recombinant DNA techniques. To do so, a recombinant DNA molecule coding for the peptide is prepared. Methods of preparing such DNA molecules are well known in the art. For instance, sequences coding for the peptides could be excised from DNA using suitable restriction enzymes. Alternatively, the DNA molecule could be synthesized using chemical synthesis techniques, such as the phosphoramidate method. Also, a combination of these techniques could be used. 
     The invention also includes a vector capable of expressing the peptides in an appropriate host. The vector comprises the DNA molecule that codes for the peptides operatively linked to appropriate expression control sequences. Methods of effecting this operative linking, either before or after the DNA molecule is inserted into the vector, are well known. Expression control sequences include promoters, activators, enhancers, operators, ribosomal binding sites, start signals, stop signals, cap signals, polyadenylation signals, and other signals involved with the control of transcription or translation. 
     The resulting vector having the DNA molecule thereon is used to transform an appropriate host. This transformation may be performed using methods well known in the art. 
     Any of a large number of available and well-known host cells may be used in the practice of this invention. The selection of a particular host is dependent upon a number of factors recognized by the art. These include, for example, compatibility with the chosen expression vector, toxicity of the peptides encoded by the DNA molecule, rate of transformation, ease of recovery of the peptides, expression characteristics, bio-safety and costs. A balance of these factors must be struck with the understanding that not all hosts may be equally effective for the expression of a particular DNA sequence. Within these general guidelines, useful microbial hosts include bacteria (such as  E. coli  sp.), yeast (such as  Saccharomyces  sp.) and other fungi, insects, plants, mammalian (including human) cells in culture, or other hosts known in the art. 
     Next, the transformed host is cultured and purified. Host cells may be cultured under conventional fermentation conditions so that the desired compounds are expressed. Such fermentation conditions are well known in the art. Finally, the peptides are purified from culture by methods well known in the art. 
     The compounds may also be made by synthetic methods. For example, solid phase synthesis techniques may be used. Suitable techniques are well known in the art, and include those described in Merrifield (1973), Chem. Polypeptides, pp. 335-61 (Katsoyannis and Panayotis eds.); Merrifield (1963), J. Am. Chem. Soc. 85: 2149; Davis et al. (1985), Biochem. Intl. 10: 394-414; Stewart and Young (1969), Solid Phase Peptide Synthesis; U.S. Pat. No. 3,941,763; Finn et al. (1976), The Proteins (3rd ed.) 2: 105-253; and Erickson et al. (1976), The Proteins (3rd ed.) 2: 257-527. Solid phase synthesis is a preferred technique of making individual peptides since it is the most cost-effective method of making small peptides. 
     The compounds in one aspect are peptides, and they may be prepared by standard synthetic methods or any other methods of preparing peptides. The compounds that encompass non-peptide portions may be synthesized by standard organic chemistry reactions, in addition to standard peptide chemistry reactions when applicable. 
     Phage display, in particular, is useful in generating peptides for use in the present invention. It has been stated that affinity selection from libraries of random peptides can be used to identify peptide ligands for any site of any gene product. Dedman et al. (1993), J. Biol. Chem. 268: 23025-30. Phage display is particularly well suited for identifying peptides that bind to such proteins of interest as cell surface receptors or any proteins having linear epitopes. Wilson et al. (1998), Can. J. Microbiol. 44: 313-29; Kay et al. (1998), Drug Disc. Today 3: 370-8. Such proteins are extensively reviewed in Herz et al. (1997), J. Receptor &amp; Signal Transduction Res. 17(5): 671-776, which is hereby incorporated by reference. Such proteins of interest are contemplated for use in this invention. 
     Peptide compounds are contemplated wherein all of the amino acids have a D configuration, or at least one of the amino acids has a D configuration. It is also contemplated that the peptide compounds may be cyclic. 
     Compounds that contain derivatized peptides or which contain non-peptide groups may be synthesized by well-known organic chemistry techniques. 
     A TMP of a preparation of the invention can be prepared using recombinant DNA techniques. Alternatively, a polynucleotide encoding a TMP is prepared using chemical synthesis techniques known in the art, such as the phosphoramidate method. In yet another alternative, a combination of these techniques is used. 
     Vectors 
     For recombinant protein expression, the invention provides a vector encoding a TMP polypeptide which can be expressed in an appropriate host. Such a vector comprises a polynucleotide that encodes a TMP in monomeric or multimer (generally in a tandem structure) arrangement, with or without an Fc domain modification, operatively linked to appropriate expression control sequences. Methods of effecting operative linking, either before or after the DNA molecule is inserted into the vector, are well known in the art. Expression control sequences include promoters, activators, enhancers, operators, ribosomal binding sites, start signals, stop signals, cap signals, polyadenylation signals, and/or other signals involved with the control of transcription or translation. The worker of skill in the art will appreciate that various combinations of these control sequences can be utilized, depending on, for example, the choice of host cell in which the TMP is to be expressed. The resulting vector is transformed into an appropriate host using methods well known in the art. 
     Host Cells 
     Any of a large number of available and well-known host cells is used to express a TMP polypeptide. Selection of a host is dependent upon a number of factors including, for example and without limitation, compatibility with the chosen expression vector, toxicity of the expressed TMP encoded by a transformed polynucleotide, rate of transformation, ease of recovery of the expressed TMP, expression characteristics, degree and type of glycosylation, if desired, bio-safety and costs. A balance of these factors must be struck with the understanding that not all host cells may be equally effective for the expression of a particular TMP. Depending upon the host cell employed, the TMP expression product may be glycosylated with mammalian or other eukaryotic carbohydrates, or it may be non-glycosylated. The TMP expression product may also include an initial methionine amino acid residue (at amino acid residue position −1) if expressed in, for example, a bacterial host cell. Within these general guidelines, useful host cells include bacteria, yeast and other fungi, insects, plants, mammalian (including human) cells in culture, or other host cells known in the art. Host cells are cultured under conventional fermentation conditions well known in the art to permit expression of the desired compounds and the TMP expression product is purified using techniques also known in the art. 
     Depending on the host cell utilized to express a TMP, carbohydrate (oligosaccharide) groups may conveniently be attached to sites that are known to be glycosylation sites in proteins. Generally, O-linked oligosaccharides are attached to serine (Ser) or threonine (Thr) residues while N-linked oligosaccharides are attached to asparagine (Asn) residues when they are part of the sequence Asn-X-Ser/Thr, where X can be any amino acid except proline. X is preferably one of the 19 naturally occurring amino acids not counting proline. The structures of N-linked and O-linked oligosaccharides and the sugar residues found in each type are different. One type of sugar that is commonly found on both is N-acetylneuraminic acid (referred to as sialic acid). Sialic acid is usually the terminal residue of both N-linked and O-linked oligosaccharides and, by virtue of its negative charge, may confer acidic properties to the glycosylated compound. Such site(s) may be incorporated in the linker of the compounds of this invention and are preferably glycosylated by a cell during recombinant production of the polypeptide compounds (e.g., in mammalian cells such as CHO, BHK, COS). However, such sites may further be glycosylated by synthetic or semi-synthetic procedures known in the art. 
     WSP Modification of a Compound 
     A process for preparing conjugation derivatives is also contemplated. Tumor cells, for example, exhibit epitopes not found on their normal counterparts. Such epitopes include, for example, different post-translational modifications resulting from their rapid proliferation. Thus, one aspect of this invention is a process comprising: a) selecting at least one randomized peptide that specifically binds to a target epitope; and b) preparing a pharmacologic agent comprising (i) at least one vehicle (Fc domain preferred), (ii) at least one amino acid sequence of the selected peptide or peptides, and (iii) an effector molecule. 
     In one aspect, the target epitope is a tumor-specific epitope or an epitope specific to a pathogenic organism. The effector molecule may be any of the above-noted conjugation partners and is preferably a radioisotope. 
     For obtaining a compound, with or without an Fc modification and/or linker(s), modified to include a covalently attached to WSP, any method described herein or otherwise known in the art is employed. By way of example and without limitation, a reductive alkylation chemical modification procedure method may be utilized. An alternative method for WSP modification is described in Francis et al., In: Stability of protein pharmaceuticals: in vivo pathways of degradation and strategies for protein stabilization (Eds. Ahern., T. and Manning, M. C.) Plenum, N. Y., 1991, is used. In still another aspect, the method described in Delgado et al., “Coupling of PEG to Protein By Activation With Tresyl Chloride, Applications In Immunoaffinity Cell Preparation”, In: Fisher et al., eds., Separations Using Aqueous Phase Systems, Applications In Cell Biology and Biotechnology, Plenum Press, N.Y. N.Y., 1989 pp. 211-213, which involves the use of tresyl chloride, which results in no linkage group between the WSP moiety and the TMP polypeptide moiety. This alternative method, however, may be difficult to use to produce therapeutic products as the use of tresyl chloride may produce toxic by-products. In other aspects, attachment of a WSP is effected through use of N-hydroxy succinimidyl esters of carboxymethyl methoxy polyethylene glycol, as well known in the art. 
     Depending on the method of WSP attachment chosen, the proportion of WSP molecules attached to the target peptide or protein molecule will vary, as will their concentrations in the reaction mixture. In general, the optimum ratio (in terms of efficiency of reaction in that there is no excess unreacted protein or polymer) is determined by the molecular weight of the WSP selected. In addition, when using methods that involve non-specific attachment and later purification of a desired species, the ratio may depend on the number of reactive groups (typically amino groups) available. 
     Reductive Alkylation 
     In one aspect, covalent attachment of a WSP to a TMP, with or without Fc modification and with or without a linker, is carried out by reductive alkylation chemical modification procedures as provided herein to selectively modify the N-terminal α-amino group, and testing the resultant product for the desired biological characteristic, such as the biological activity assays provided herein. 
     Reductive alkylation for attachment of a WSP to a protein or peptide exploits differential reactivity of different types of primary amino groups (e.g., lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved. 
     Using reductive alkylation, the reducing agent should be stable in aqueous solution and preferably be able to reduce only the Schiff base formed in the initial process of reductive alkylation. Reducing agents are selected from, and without limitation, sodium borohydride, sodium cyanoborohydride, dimethylamine borate, timethylamine borate and pyridine borate. 
     The reaction pH affects the ratio of polymer to protein to be used. In general, if the reaction pH is lower than the pKa of a target reactive group, a larger excess of polymer to protein will be desired. If the pH is higher than the target pKa, the polymer:protein ratio need not be as large (i.e., more reactive groups are available, so fewer polymer molecules are needed). 
     Accordingly, the reaction is performed in one aspect at a pH which allows one to take advantage of the pKa differences between the ε-amino groups of the lysine residues and that of the α-amino group of the N-terminal residue of the protein. By such selective derivatization, attachment of a water soluble polymer to a protein is controlled; the conjugation with the polymer takes place predominantly at the N-terminus of the protein and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs. 
     In one aspect, therefore, methods are provided for covalent attachment of a WSP to a target TMP and which provide a substantially homogenous preparation of WSP/protein conjugate molecules, in the absence of further extensive purification as is required using other chemical modification chemistries. More specifically, if polyethylene glycol is used, methods described allow for production of an N-terminally PEGylated protein lacking possibly antigenic linkage groups, i.e., the polyethylene glycol moiety is directly coupled to the protein moiety without potentially toxic by-products. 
     Purification of a WSP-Modified Compound 
     The method of obtaining a substantially homogeneous WSP-TMP preparation is, in one aspect, by purification of a predominantly single species of modified TMP from a mixture of TMP species. By way of example, a substantially homogeneous TMP species is first separated by ion exchange chromatography to obtain material having a charge characteristic of a single species (even though other species having the same apparent charge may be present), and then the desired species is separated using size exclusion chromatography. Other methods are reported and contemplated by the invention, includes for example, PCT WO 90/04606, published May 3, 1990, which describes a process for fractionating a mixture of PEG-protein adducts comprising partitioning the PEG/protein adducts in a PEG-containing aqueous biphasic system. 
     Thus, one aspect of the present invention is a method for preparing a WSP-TMP conjugate comprised of (a) reacting a TMP having more than one amino group with a water soluble polymer moiety under reducing alkylation conditions, at a pH suitable to selectively activate the α-amino group at the amino terminus of the protein moiety so that said water soluble polymer selectively attaches to said α-amino group; and (b) obtaining the reaction product. Optionally, and particularly for a therapeutic product, the reaction products are separated from unreacted moieties. 
     Bioassays 
     For assessing biological activity for a preparation of the invention, standard assays are contemplated, such as, for example and without limitation, those described in WO95/26746 entitled “Compositions and Methods for Stimulating Megakaryocyte Growth and Differentiation” and in U.S. Pat. No. 6,835,809, incorporated herein in its entirety. 
     In one such assay, normal mice of similar age are administered a preparation of the invention either with a bolus treatment or continuous delivery. Compounds administered include any preparation, whether in pharmaceutical composition for or not, with appropriate control(s). 
     Mice are bled at specified time points, generally with a minimum number of bleeds per week. At a set end time point, blood parameters, for example, white blood cells, red blood cells, hematocrit, hemoglobin, platelets, neutrophils are measured. 
     Pharmaceutical Compositions 
     The present invention also provides methods of using pharmaceutical compositions of the inventive compounds. Such pharmaceutical compositions may be for administration for injection, or for oral, pulmonary, nasal, transdermal or other forms of administration. In general, the invention encompasses pharmaceutical compositions comprising effective amounts of a compound of the invention together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronic acid may also be used, and this may have the effect of promoting sustained duration in the circulation. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the present proteins and derivatives. See, e.g., Remington&#39;s Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference. The compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form. Implantable sustained release formulations are also contemplated, as are transdermal formulations. 
     Oral Dosage Forms 
     Contemplated for use herein are oral solid dosage forms, which are described generally in Chapter 89 of Remington&#39;s Pharmaceutical Sciences (1990), 18th Ed., Mack Publishing Co. Easton Pa. 18042, which is herein incorporated by reference. Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets. Also, liposomal or proteinoid encapsulation may be used to formulate the present compositions (as, for example, proteinoid microspheres reported in U.S. Pat. No. 4,925,673). Liposomal encapsulation may be used and the liposomes may be derivatized with various polymers (e.g., U.S. Pat. No. 5,013,556). A description of possible solid dosage forms for the therapeutic is given in Chapter 10 of Marshall, K., Modern Pharmaceutics (1979), edited by G. S. Banker and C. T. Rhodes, herein incorporated by reference. In general, the formulation will include the inventive compound, and inert ingredients which allow for protection against the stomach environment, and release of the biologically active material in the intestine. 
     If necessary, the compounds may be chemically modified so that oral delivery is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the compound molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the compound and increase in circulation time in the body. Moieties useful as covalently attached vehicles in this invention may also be used for this purpose. Examples of such moieties include: PEG, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. See, for example, Abuchowski and Davis, Soluble Polymer-Enzyme Adducts, Enzymes as Drugs (1981), Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp 367-83; Newmark, et al. (1982), J. Appl. Biochem. 4:185-9. Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. In one aspect, PEG moieties are provided for pharmaceutical usage, as indicated above. 
     For oral delivery dosage forms, it is also possible to use a salt of a modified aliphatic amino acid, such as sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC), as a carrier to enhance absorption of the therapeutic compounds of this invention. The clinical efficacy of a heparin formulation using SNAC has been demonstrated in a Phase II trial conducted by Emisphere Technologies. See U.S. Pat. No. 5,792,451, “Oral drug delivery composition and methods”. 
     The compounds of this invention can be included in the formulation as fine multiparticulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression. 
     Colorants and flavoring agents may all be included. For example, the protein (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. 
     One may dilute or increase the volume of the compound of the invention with an inert material. These diluents could include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell. 
     Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrants include but are not limited to starch including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. 
     Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic. 
     An antifrictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. 
     Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. 
     To aid dissolution of the compound of this invention into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could include benzalkonium chloride or benzethonium chloride. The list of potential nonionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the protein or derivative either alone or as a mixture in different ratios. 
     Additives may also be included in the formulation to enhance uptake of the compound. Additives potentially having this property are for instance the fatty acids oleic acid, linoleic acid and linolenic acid. 
     Controlled release formulation may be desirable. The compound of this invention could be incorporated into an inert matrix which permits release by either diffusion or leaching mechanisms e.g., gums. Slowly degenerating matrices may also be incorporated into the formulation, e.g., alginates, polysaccharides. Another form of a controlled release of the compounds of this invention is by a method based on the Oros therapeutic system (Alza Corp.), i.e., the drug is enclosed in a semipermeable membrane which allows water to enter and push drug out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect. 
     Other coatings may be used for the formulation. These include a variety of sugars which could be applied in a coating pan. The therapeutic agent could also be given in a film coated tablet and the materials used in this instance are divided into 2 groups. The first are the nonenteric materials and include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxy-ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, sodium carboxy-methyl cellulose, providone and the polyethylene glycols. The second group consists of the enteric materials that are commonly esters of phthalic acid. 
     A mix of materials might be used to provide the optimum film coating. Film coating may be carried out in a pan coater or in a fluidized bed or by compression coating. 
     Pulmonary Delivery Forms 
     Also contemplated herein is pulmonary delivery of the present protein (or derivatives thereof). The protein (or derivative) is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. (Other reports of this include Adjei et al., Pharma. Res. (1990) 7: 565-9; Adjei et al. (1990), Internatl. J. Pharmaceutics 63: 135-44 (leuprolide acetate); Braquet et al. (1989), J. Cardiovasc. Pharmacol. 13 (suppl.5): s.143-146 (endothelin-1); Hubbard et al. (1989), Annals Int. Med. 3: 206-12 (α1-antitrypsin); Smith et al. (1989), J. Clin. Invest. 84: 1145-6 (α1-proteinase); Oswein et al. (March 1990), “Aerosolization of Proteins”, Proc. Symp. Resp. Drug Delivery II, Keystone, Colo. (recombinant human growth hormone); Debs et al. (1988), J. Immunol. 140: 3482-8 (interferon-γ and tumor necrosis factor α) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor). 
     Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, N.C.; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass. 
     All such devices require the use of formulations suitable for the dispensing of the inventive compound. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to diluents, adjuvants and/or carriers useful in therapy. 
     The inventive compound should most advantageously be prepared in particulate form with an average particle size of less than 10 μm (or microns), most preferably 0.5 to 5 μm, for most effective delivery to the distal lung. 
     Pharmaceutically acceptable carriers include carbohydrates such as trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol. Other ingredients for use in formulations may include DPPC, DOPE, DSPC and DOPC. Natural or synthetic surfactants may be used. PEG may be used (even apart from its use in derivatizing the protein or analog). Dextrans, such as cyclodextran, may be used. Bile salts and other related enhancers may be used. Cellulose and cellulose derivatives may be used. Amino acids may be used, such as use in a buffer formulation. 
     Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. 
     Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise the inventive compound dissolved in water at a concentration of about 0.1 to 25 mg of biologically active protein per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for protein stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the protein caused by atomization of the solution in forming the aerosol. 
     Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the inventive compound suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant. 
     Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing the inventive compound and may also include a bulking agent, such as lactose, sorbitol, sucrose, mannitol, trehalose, or xylitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. 
     Nasal Delivery Forms 
     Nasal delivery of the inventive compound is also contemplated. Nasal delivery allows the passage of the protein to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. Delivery via transport across other mucous membranes is also contemplated. 
     Buccal Delivery Forms 
     Buccal delivery of the inventive compound is also contemplated. Buccal delivery formulations are known in the art for use with peptides. 
     Dosages 
     The dosage regimen involved in a method for treating the above-described conditions will be determined by the attending physician, considering various factors which modify the action of drugs, e.g. the age, condition, body weight, sex and diet of the patient, the severity of any infection, time of administration and other clinical factors. Generally, the daily regimen should be in the range of 0.1-1000 micrograms of the inventive compound per kilogram of body weight, preferably 0.1-150 micrograms per kilogram. 
     Provided herein are pharmaceutical compositions comprising preparations of the invention. Such pharmaceutical compositions may be for administration for injection, or for oral, nasal, transdermal or other forms of administration, including, e.g., by intravenous, intradermal, intramuscular, intramammary, intraperitoneal, intrathecal, intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) or subcutaneous injection (including depot administration for long term release); by sublingual, anal, vaginal, or by surgical implantation, e.g., embedded under the splenic capsule, brain, or in the cornea. The treatment may consist of a single dose or a plurality of doses over a period of time. In general, comprehended by the invention are pharmaceutical compositions comprising effective amounts of a compound of the invention together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronic acid may also be used, and this may have the effect of promoting sustained duration in the circulation. The pharmaceutical compositions optionally may include still other pharmaceutically acceptable liquid, semisolid, or solid diluents that serve as pharmaceutical vehicles, excipients, or media, including but are not limited to, polyoxyethylene sorbitan monolaurate, magnesium stearate, methyl- and propylhydroxybenzoate, starches, sucrose, dextrose, gum acacia, calcium phosphate, mineral oil, cocoa butter, and oil of theobroma. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the present proteins and derivatives. See, e.g., Remington&#39;s Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference. The compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form. Implantable sustained release formulations are also contemplated, as are transdermal formulations. 
     The therapeutic methods, compositions and compounds of the present invention may also be employed, alone or in combination with other cytokines, soluble c-Mpl receptor, hematopoietic factors, interleukins, growth factors or antibodies in the treatment of disease states characterized by other symptoms as well as platelet deficiencies. It is anticipated that the preparations of the invention will prove useful in treating some forms of thrombocytopenia in combination with general stimulators of hematopoiesis, such as IL-3 or GM-CSF. Other megakaryocytic stimulatory factors, i.e., meg-CSF, stem cell factor (SCF), leukemia inhibitory factor (LIF), oncostatin M (OSM), or other molecules with megakaryocyte stimulating activity may also be employed with Mpl ligand. 
     Additional exemplary cytokines or hematopoietic factors for such co-administration include IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, colony stimulating factor-1 (CSF-1), M-CSF, SCF, GM-CSF, granulocyte colony stimulating factor (G-CSF), EPO, interferon-alpha (IFN-alpha), consensus interferon, IFN-beta, IFN-gamma, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, thrombopoietin (TPO), angiopoietins, for example Ang-1, Ang-2, Ang-4, Ang-Y, the human angiopoietin-like polypeptide, vascular endothelial growth factor (VEGF), angiogenin, bone morphogenic protein-1, bone morphogenic protein-2, bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenic protein-5, bone morphogenic protein-6, bone morphogenic protein-7, bone morphogenic protein-8, bone morphogenic protein-9, bone morphogenic protein-10, bone morphogenic protein-11, bone morphogenic protein-12, bone morphogenic protein-13, bone morphogenic protein-14, bone morphogenic protein-15, bone morphogenic protein receptor IA, bone morphogenic protein receptor IB, brain derived neurotrophic factor, ciliary neutrophic factor, ciliary neutrophic factor receptor, cytokine-induced neutrophil chemotactic factor 1, cytokine-induced neutrophil, chemotactic factor 2α, cytokine-induced neutrophil chemotactic factor 2β, β endothelial cell growth factor, endothelin 1, epidermal growth factor, epithelial-derived neutrophil attractant, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7, fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblast growth factor acidic, fibroblast growth factor basic, glial cell line-derived neutrophic factor receptor α1, glial cell line-derived neutrophic factor receptor α2, growth related protein, growth related protein α, growth related protein β, growth related protein γ, heparin binding epidermal growth factor, hepatocyte growth factor, hepatocyte growth factor receptor, insulin-like growth factor I, insulin-like growth factor receptor, insulin-like growth factor II, insulin-like growth factor binding protein, keratinocyte growth factor, leukemia inhibitory factor, leukemia inhibitory factor receptor α, nerve growth factor nerve growth factor receptor, neurotrophin-3, neurotrophin-4, placenta growth factor, placenta growth factor 2, platelet-derived endothelial cell growth factor, platelet derived growth factor, platelet derived growth factor A chain, platelet derived growth factor AA, platelet derived growth factor AB, platelet derived growth factor B chain, platelet derived growth factor BB, platelet derived growth factor receptor α, platelet derived growth factor receptor β, pre-B cell growth stimulating factor, stem cell factor receptor, TNF, including TNF0, TNF1, TNF2, transforming growth factor a, transforming growth factor β, transforming growth factor β1, transforming growth factor β1.2, transforming growth factor β2, transforming growth factor β3, transforming growth factor β5, latent transforming growth factor β1, transforming growth factor β binding protein I, transforming growth factor β binding protein II, transforming growth factor β binding protein III, tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, urokinase-type plasminogen activator receptor, vascular endothelial growth factor, and chimeric proteins and biologically or immunologically active fragments thereof. 
     It may further be useful to administer, either simultaneously or sequentially, an effective amount of a soluble mammalian c-Mpl, which appears to have an effect of causing megakaryocytes to fragment into platelets once the megakaryocytes have reached mature form. Thus, administration of a preparation of the invention (to enhance the number of mature megakaryocytes) followed by administration of the soluble c-Mpl (to inactivate the ligand and allow the mature megakaryocytes to produce platelets) is expected to be a particularly effective means of stimulating platelet production. The dosage recited above would be adjusted to compensate for such additional components in the therapeutic composition. Progress of the treated patient can be monitored by conventional methods. 
     Therapeutic Uses 
     For the compounds herein, one can utilize such standard assays as those described in WO95/26746 entitled “Compositions and Methods for Stimulating Megakaryocyte Growth and Differentiation”. In vivo assays also appear in the Examples hereinafter. 
     The conditions to be treated are generally those that involve an existing megakaryocyte/platelet deficiency or an expected megakaryocyte/platelet deficiency (e.g., because of planned surgery or platelet donation). Such conditions will usually be the result of a deficiency (temporary or permanent) of active thrombopoietin in vivo. The generic term for platelet deficiency is thrombocytopenia, and the methods and compositions of the present invention are generally available for treating thrombocytopenia in patients in need thereof. 
     Thrombocytopenia (platelet deficiencies) may be present for various reasons, including chemotherapy and other therapy with a variety of drugs, radiation therapy, surgery, accidental blood loss, and other specific disease conditions. Exemplary specific disease conditions that involve thrombocytopenia and may be treated in accordance with this invention are: aplastic anemia; idiopathic or immune thrombocytopenia (ITP), including idiopathic thrombocytopenic purpura associated with breast cancer; HIV associated ITP and HIV-related thrombotic thrombocytopenic purpura; metastatic tumors which result in thrombocytopenia; systemic lupus erythematosus; including neonatal lupus syndrome splenomegaly; Fanconi&#39;s syndrome; vitamin B12 deficiency; folic acid deficiency; May-Hegglin anomaly; Wiskott-Aldrich syndrome; chronic liver disease; myelodysplastic syndrome associated with thrombocytopenia; paroxysmal nocturnal hemoglobinuria; acute profound thrombocytopenia following C7E3 Fab (Abciximab) therapy; alloimmune thrombocytopenia, including maternal alloimmune thrombocytopenia; thrombocytopenia associated with antiphospholipid antibodies and thrombosis; autoimmune thrombocytopenia; drug-induced immune thrombocytopenia, including carboplatin-induced thrombocytopenia, heparin-induced thrombocytopenia; fetal thrombocytopenia; gestational thrombocytopenia; Hughes&#39; syndrome; lupoid thrombocytopenia; accidental and/or massive blood loss; myeloproliferative disorders; thrombocytopenia in patients with malignancies; thrombotic thrombocytopenia purpura, including thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in cancer patients; autoimmune hemolytic anemia; occult jejunal diverticulum perforation; pure red cell aplasia; autoimmune thrombocytopenia; nephropathia epidemica; rifampicin-associated acute renal failure; Paris-Trousseau thrombocytopenia; neonatal alloimmune thrombocytopenia; paroxysmal nocturnal hemoglobinuria; hematologic changes in stomach cancer; hemolytic uremic syndromes in childhood; hematologic manifestations related to viral infection including hepatitis A virus and CMV-associated thrombocytopenia. Other hepatic diseases or conditions that involve thrombocytopenia and may be treated in accordance with this invention, in addition to viral hepatitis A (HAV) include, but are not limited to, alcoholic hepatitis, autoimmune hepatitis, drug-induced hepatitis, epidemic hepatitis, infectious hepatitis, long-incubation hepatitis, noninfectious hepatitis, serum hepatitis, short-incubation hepatitis, toxic hepatitis, transfusion hepatitis, viral hepatitis B (HBV), viral hepatitis C (HCV), viral hepatitis D (HDV), delta hepatitis, viral hepatitis E (HEV), viral hepatitis F (HFV), viral hepatitis G (HGV), liver disease, inflammation of the liver, hepatic failure, and other hepatic disease. Also, certain treatments for AIDS result in thrombocytopenia (e.g., AZT). Certain wound healing disorders might also benefit from an increase in platelet numbers. 
     With regard to anticipated platelet deficiencies, e.g., due to future surgery, a compound of the present invention could be administered several days to several hours prior to the need for platelets. With regard to acute situations, e.g., accidental and massive blood loss, a compound of this invention could be administered along with blood or purified platelets. 
     The compounds of this invention may also be useful in stimulating certain cell types other than megakaryocytes if such cells are found to express Mpl receptor. Conditions associated with such cells that express the Mpl receptor, which are responsive to stimulation by the Mpl ligand, are also within the scope of this invention. 
     In addition, the compounds of this invention may be used in any situation in which production of platelets or platelet precursor cells is desired, or in which stimulation of the c-Mpl receptor is desired. Thus, for example, the compounds of this invention may be used to treat any condition in a mammal wherein there is a need of platelets, megakaryocytes, and the like. Such conditions are described in detail in the following exemplary sources: WO95/26746; WO95/21919; WO95/18858; WO95/21920 and are incorporated herein. 
     The compounds of this invention may also be useful in maintaining the viability or storage life of platelets and/or megakaryocytes and related cells. Accordingly, it could be useful to include an effective amount of one or more such compounds in a composition containing such cells. 
     The therapeutic methods, compositions and compounds of the present invention may also be employed, alone or in combination with other cytokines, soluble Mpl receptor, hematopoietic factors, interleukins, growth factors or antibodies in the treatment of disease states characterized by other symptoms as well as platelet deficiencies. It is anticipated that the inventive compound will prove useful in treating some forms of thrombocytopenia in combination with general stimulators of hematopoiesis, such as IL-3 or GM-CSF. Other megakaryocytic stimulatory factors, i.e., meg-CSF, stem cell factor (SCF), leukemia inhibitory factor (LIF), oncostatin M (OSM), or other molecules with megakaryocyte stimulating activity may also be employed with Mpl ligand. Additional exemplary cytokines or hematopoietic factors for such co-administration include IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, colony stimulating factor-1 (CSF-1), SCF, GM-CSF, granulocyte colony stimulating factor (G-CSF), EPO, interferon-alpha (IFN-alpha), consensus interferon, IFN-beta, or IFN-gamma. It may further be useful to administer, either simultaneously or sequentially, an effective amount of a soluble mammalian Mpl receptor, which appears to have an effect of causing megakaryocytes to fragment into platelets once the megakaryocytes have reached mature form. Thus, administration of an inventive compound (to enhance the number of mature megakaryocytes) followed by administration of the soluble Mpl receptor (to inactivate the ligand and allow the mature megakaryocytes to produce platelets) is expected to be a particularly effective means of stimulating platelet production. The dosage recited above would be adjusted to compensate for such additional components in the therapeutic composition. Progress of the treated patient can be monitored by conventional methods. 
     In cases where the inventive compounds are added to compositions of platelets and/or megakaryocytes and related cells, the amount to be included will generally be ascertained experimentally by techniques and assays known in the art. An exemplary range of amounts is 0.1 μg-1 mg inventive compound per 10 6  cells. 
     In addition to therapeutic uses, the compounds of the present invention are useful in diagnosing diseases characterized by dysfunction of their associated protein of interest. In one embodiment, a method of detecting in a biological sample a protein of interest (e.g., a receptor) that is capable of being activated comprising the steps of: (a) contacting the sample with a compound of this invention; and (b) detecting activation of the protein of interest by the compound. The biological samples include tissue specimens, intact cells, or extracts thereof. The compounds of this invention may be used as part of a diagnostic kit to detect the presence of their associated proteins of interest in a biological sample. Such kits employ the compounds of the invention having an attached label to allow for detection. The compounds are useful for identifying normal or abnormal proteins of interest. 
     It is understood that the application of the teachings of the present invention to a specific problem or situation will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein. Examples of the products of the present invention and representative processes for their isolation, use, and manufacture appear below. 
     EXAMPLES 
     The following sets forth exemplary methods for making some of the compounds of the first group disclosed herein. 
     Materials and Methods 
     All amino acid derivatives (all of L-configurations) and resins used in peptide synthesis may be purchased from Novabiochem. Peptide synthesis reagents (DCC, HOBt, etc.) may be purchased in the solution forms from Applied Biosystems, Inc. The two PEG derivatives are from Shearwater Polymers, Inc. All solvents (dichloromethane, N-methylpyrrolidinone, methanol, acetonitrile) are from EM Sciences. Analytical HPLC is run on a Beckman system with a Vydac column (0.46 cm×25 cm, C18 reversed phase, 5 mm), at a flow rate of 1 ml/min and with dual UV detection at 220 and 280 nm. Linear gradients are used for all HPLC operations with two mobile phases: Buffer A—H 2 O (0.1% TFA) and Buffer B—acetonitrile (0.1% TFA). The TPO mimetics referred to herein are provided in Tables 1-6, 8, 10, and 12, and some of them are further illustrated in FIGS. 2 through 4. 
     Peptide Synthesis 
     Peptides are prepared using a variety of methods known in the art, including the well established stepwise solid phase synthesis method. Solid-phase synthesis with Fmoc chemistry is carried out using an ABI Peptide Synthesizer. Typically, peptide synthesis begins with a preloaded Wang resin on a 0.1 mmol scale. Fmoc deprotection is carried out with the standard piperidine protocol. The coupling is effected using DCC/HOBt. Side-chain protecting groups were: Glu(O-t-Bu), Thr(t-Bu), Arg(Pbf), Gln(Trt), Trp(t-Boc) and Cys(Trt). For the first peptide precursor for pegylation, Dde is used for side chain protection of the Lys on the linker and Boc-Ile-OH is used for the last coupling. Dde is removed by using anhydrous hydrazine (2% in NMP, 3×2 min), followed by coupling with bromoacetic anhydride preformed by the action of DCC. For peptide 18, the cysteine side chain in the linker is protected by a trityl group. The final deprotection and cleavage of all peptidyl-resins is effected at RT for 4 hr, using trifluoroacetic acid (TFA) containing 2.5% H 2 O, 5% phenol, 2.5% triisopropylsilane and 2.5% thioanisole. After removal of TFA, the cleaved peptide is precipitated with cold anhydrous ether. Disulfide formation of the cyclic peptide is performed directly on the crude material by using 15% DMSO in H 2 O (pH 7.5). All crude peptides are purified by preparative reverse phase HPLC and the structures are confirmed by ESI-MS and amino acid analysis. 
     Peptides are also prepared by phage library generation. The details on library generation methods and phage panning methods were described previously (see PCT/US02/32657 and US/2003/0176352). Phage panning methods are also performed using biotinylated MPL in the range of 10-0.01 μg per 100 μL of Streptavidin Dynabeads (Dynal, Lake Success, N.Y.). After phage are bound to the beads, they are washed 20-50 times before they are eluted. Phage ELISA for TPO-like activity and sequencing analysis are performed as described previously (PCT/US02/32657 and US/2003/0176352). 
     Alternatively, all peptides described in the application could also be prepared by using the t-Boc chemistry. In this case, the starting resins would be the classic Merrifield or Pam resin, and side chain protecting groups would be: Glu(OBzl), Thr(Bzl), Arg(Tos), Trp(CHO), Cys(p-MeBzl). Hydrogen fluoride (HF) would be used for the final cleavage of the peptidyl resins. 
     All peptides and tandem dimeric peptides described in herein that have linkers composed of natural amino acids can also be prepared by recombinant DNA technology. 
     PEGylation 
     A novel, convergent strategy for the pegylation of synthetic peptides was developed which consists of combining, through forming a conjugate linkage in solution, a peptide and a PEG moiety, each bearing a special functionality that is mutually reactive toward the other. The precursor peptides can be easily prepared with the conventional solid phase synthesis as described above. As described below, these peptides are “preactivated” with an appropriate functional group at a specific site. The precursors are purified and fully characterized prior to reacting with the PEG moiety. Ligation of the peptide with PEG usually takes place in aqueous phase and can be easily monitored by reverse phase analytical HPLC. The pegylated peptides can be easily purified by preparative HPLC and characterized by analytical HPLC, amino acid analysis and laser desorption mass spectrometry. 
     Bioactivity Assay 
     The TPO in vitro bioassay is a mitogenic assay utilizing an IL-3 dependent clone of murine 32D cells that have been transfected with human mpl receptor. This assay is described in greater detail in WO 95/26746. Cells are maintained in MEM medium containing 10% Fetal Clone II and 1 ng/ml mIL-3. Prior to sample addition, cells are prepared by rinsing twice with growth medium lacking mIL-3. An extended twelve point TPO standard curve is prepared, ranging from 3333 to 39 pg/ml. Four dilutions, estimated to fall within the linear portion of the standard curve, (1000 to 125 pg/ml), are prepared for each sample and run in triplicate. A volume of 100 Φl of each dilution of sample or standard is added to appropriate wells of a 96 well microtiter plate containing 10,000 cells/well. After forty-four hours at 37EC and 10% CO 2 , MTS (a tetrazolium compound which is bioreduced by cells to a formazan) is added to each well. Approximately six hours later, the optical density is read on a plate reader at 490 nm. A dose response curve (log TPO concentration vs. O.D.—Background) is generated and linear regression analysis of points which fall in the linear portion of the standard curve is performed. Concentrations of unknown test samples are determined using the resulting linear equation and a correction for the dilution factor. The TPO in vivo bioassay tests for platelet production in mice after administration of the compounds of the invention. 
     Abbreviations 
     HPLC: high performance liquid chromatography; ESI-MS: Electron spray ionization mass spectrometry; MALDI-MS: Matrix-assisted laser desorption ionization mass spectrometry; PEG: Poly(ethylene glycol). All amino acids are represented in the standard three-letter or single-letter codes. t-Boc: tert-Butoxycarbonyl; tBu: tert-Butyl; Bzl: Benzyl; DCC: Dicylcohexylcarbodiimide; HOBt: 1-Hydroxybenzotriazole; NMP: N-methyl-2-pyrrolidinone; Pbf: 2,2,4,6,7-pendamethyldihydro-benzofuran-5-sulfonyl; Trt: trityl; Dde: 1-(4,4-dimethyl-2,6-dioxo-cyclohexylidene)ethyl. 
     Results 
     TMP Monomers, Multimers and Fc-TMP Fusion Proteins 
     A series of TPO-mimetic peptides and TPO-mimetic fusion proteins were synthesized. TPO-mimetic peptides are readily synthesized by conventional solid phase peptide synthesis methods (Merrifiled, R. B., Journal of the American Chemical Society 85:2149 (1963)) with either Fmoc or t-Boc chemistry, by phage peptide library synthesis, or any other method known in the art. In such libraries, random peptide sequences are displayed by fusion with coat proteins of filamentous phage. Typically, the displayed peptides are affinity-eluted against an antibody-immobilized extracellular domain of a receptor. The retained phages may be enriched by successive rounds of affinity purification and repropagation. The best binding peptides may be sequenced to identify key residues within one or more structurally related families of peptides. 
     The synthetic peptides are tested directly for biological activity (platelet number: 10 9  cells/L) in vivo in mice (see FIGS. 2 and 3) or for relative activity in vitro (see Table 2 and Table 7). As the test results showed (see FIGS. 2 and 3), some TPO-mimetic peptides and TPO-mimetic fusion proteins are more effective than others in stimulating platelet production in mice. 
     Tables 1-10 and 12 set out some of the TPO-mimetic peptides of the invention. Bolded amino acids indicate Y 1 -Y 7  amino acids. The string of N-terminal amino acids at the N-terminus of the bolded amino acids are part of the U 1  subgroup. The string of C-terminal amino acids at the C-terminus of the bolded amino acids are part of the U 2  subgroup. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                 TPO-Mimetic 
                 AMINO ACID SEQUENCE 
                 SEQ ID NO: 
               
               
                   
               
            
           
           
               
               
               
            
               
                 8 
                 QGCSSGGPTQREWLQCRRMQHS 
                 8 
               
               
                   
               
               
                 9 
                 QGCSSGGPTLREWQQCRRMQHS 
                 9 
               
               
                   
               
               
                 10 
                 QGCSWGGPTLKIWLQCVRAKHS 
                 10 
               
               
                   
               
               
                 11 
                 QGCSWGGPTLKNWLQCVRAKHS 
                 11 
               
               
                   
               
               
                 12 
                 QGCSWGGPTLKLWLQCVRAKHS 
                 12 
               
               
                   
               
               
                 13 
                 QGCSWGGPTLKHWLQCVRAKHS 
                 13 
               
               
                   
               
               
                 14 
                 QGGCRSGPTNREWLACREVQHS 
                 14 
               
               
                   
               
               
                 15 
                 QGTCEQGPTLRQWPLCRQGRHS 
                 15 
               
               
                   
               
               
                 16 
                 QGTCEQGPTLRLWLLCRQGRHS 
                 16 
               
               
                   
               
               
                 17 
                 QGTCEQGPTLRIWLLCRQGRHS 
                 17 
               
               
                   
               
            
           
         
       
     
     Table 2 summarizes relative activities (% control activity) of some of the TPO-mimetic fusion proteins of the invention in terms of relative potencies based on in vitro assays as described above. An Fc molecule is fused at either the N-terminus or the C-terminus of the peptide. Some TPO-mimetics comprise an Fc molecule connected at the N-terminus of a dimer of the peptide (see, e.g., Fc-2-(SEQ ID NO: 9)). “Fc-2-peptide” and “Fc-2X-peptide” are used interchangeably to indicate that an Fc molecule is fused at the N-terminus of two copies of a peptide connected in tandem. As with all of the TPO-mimetic compounds, the peptide may be attached at the C-terminus of the Fc molecule with a linker/spacer or inserted into an Fc-Loop, optionally with the use of symmetric or asymmetric linkers/spacers. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 TPO-Mimetic Fusion Proteins 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 % CONTROL 
                   
               
               
                   
                 TPO-Mimetic 
                 ACTIVITY 
                 % ERROR 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Fc-(SEQ ID NO: 9) 
                 88.5 
                 24.9 
               
               
                   
                   
               
               
                   
                 Fc-2-(SEQ ID NO: 9) 
                 80.5 
                 14.9 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 11) 
                 78.6 
                 19.1 
               
               
                   
                   
               
               
                   
                 Fc-2-(SEQ ID NO: 8) 
                 74.8 
                 11.4 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 12) 
                 67.4 
                 16.0 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 13) 
                 60.9 
                 7.7 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 10)-Fc 
                 45.7 
                 11.2 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 10) 
                 40.5 
                 9.8 
               
               
                   
                   
               
               
                   
                 Fc-2-(SEQ ID NO: 12) 
                 37.7 
                 8.7 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 15) 
                 26.2 
                 6.1 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 8) 
                 25.8 
                 6.1 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 15)-Fc 
                 24.6 
                 6.1 
               
               
                   
                   
               
               
                   
                 Fc-(SEQ ID NO: 13) 
                 23.2 
                 2.5 
               
               
                   
                   
               
               
                   
                 Fc-2-(SEQ ID NO: 14) 
                 22.0 
                 8.5 
               
               
                   
                   
               
            
           
         
       
     
     Table 3 sets out some further TPO-mimetic peptides (Y 1 -Y 7 ) of the invention. Y 4  is designated Y 4  in the amino acid sequence because it may comprise any amino acid and the like as set out infra. These peptides were tested and were found to have c-mpl receptor binding activity. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides (Y 1 -Y 7 ) 
               
            
           
           
               
               
               
            
               
                   
                 AMINO ACID 
                   
               
               
                 TPO-Mimetic 
                 SEQUENCE   
                 SEQ ID NO: 
               
               
                   
               
               
                 28 
                 ETLY 4 QWL 
                 28 
               
               
                   
               
               
                 29 
                 HTLY 4 QWL 
                 29 
               
               
                   
               
               
                 30 
                 KTLY 4 QWL 
                 30 
               
               
                   
               
               
                 31 
                 GTGY 4 QWL 
                 31 
               
               
                   
               
               
                 32 
                 PTLY 4 IWL 
                 32 
               
               
                   
               
               
                 33 
                 PTLY 4 LWL 
                 33 
               
               
                   
               
               
                 34 
                 PTLY 4 EWF 
                 34 
               
               
                   
               
               
                 35 
                 PTLY 4 HWL 
                 35 
               
               
                   
               
               
                 36 
                 PILY 4 EWL 
                 36 
               
               
                   
               
               
                 37 
                 KTLY 4 EWL 
                 37 
               
               
                   
               
               
                 38 
                 PTLY 4 LWL 
                 38 
               
               
                   
               
               
                 39 
                 PMLY 4 EWL 
                 39 
               
               
                   
               
               
                 40 
                 PTLY 4 NWL 
                 40 
               
               
                   
               
               
                 41 
                 PPLY 4 EWL 
                 41 
               
               
                   
               
               
                 42 
                 PTQY 4 EWQ 
                 42 
               
               
                   
               
               
                 43 
                 PTLY 4 EWS 
                 43 
               
               
                   
               
               
                 44 
                 PTYY 4 EWL 
                 44 
               
               
                   
               
               
                 45 
                 PTAY 4 QWL 
                 45 
               
               
                   
               
               
                 46 
                 PCLY 4 QWL 
                 46 
               
               
                   
               
               
                 47 
                 PTLY 4 FWL 
                 47 
               
               
                   
               
               
                 48 
                 PTGY 4 QWL 
                 48 
               
               
                   
               
               
                 49 
                 PTLY 4 HWL 
                 49 
               
               
                   
               
               
                 50 
                 PILY 4 IWL 
                 50 
               
               
                   
               
               
                 51 
                 PTLY 4 LWL 
                 51 
               
               
                   
               
               
                 52 
                 PMLY 4 QWL 
                 52 
               
               
                   
               
               
                 53 
                 PTLY 4 NWL 
                 53 
               
               
                   
               
               
                 54 
                 PTPY 4 QWL 
                 54 
               
               
                   
               
               
                 55 
                 PTLY 4 QWQ 
                 55 
               
               
                   
               
               
                 56 
                 PTLY 4 QWS 
                 56 
               
               
                   
               
               
                 57 
                 PTTY 4 QWT 
                 57 
               
               
                   
               
               
                 58 
                 PTLY 4 WWL 
                 58 
               
               
                   
               
               
                 59 
                 PTYY 4 QWL 
                 59 
               
               
                   
               
               
                 60 
                 PTLY 4 EWF 
                 60 
               
               
                   
               
               
                 61 
                 GTLY 4 EWL 
                 61 
               
               
                   
               
               
                 62 
                 PTLY 4 HWL 
                 62 
               
               
                   
               
               
                 63 
                 PILY 4 EWL 
                 63 
               
               
                   
               
               
                 64 
                 PTLY 4 LWL 
                 64 
               
               
                   
               
               
                 65 
                 PTQY 4 EWL 
                 65 
               
               
                   
               
               
                 66 
                 PTLY 4 EWS 
                 66 
               
               
                   
               
               
                 67 
                 PTLY 4 FWF 
                 67 
               
               
                   
               
               
                 68 
                 GTLY 4 QWL 
                 68 
               
               
                   
               
               
                 69 
                 PTLY 4 IWL 
                 69 
               
               
                   
               
               
                 70 
                 PTLY 4 LWL 
                 70 
               
               
                   
               
               
                 71 
                 PTLY 4 NWL 
                 71 
               
               
                   
               
               
                 72 
                 PTLY 4 QWP 
                 72 
               
               
                   
               
               
                 73 
                 PTLY 4 WWL 
                 73 
               
               
                   
               
               
                 74 
                 PTYY 4 QWL 
                 74 
               
               
                   
               
            
           
         
       
     
     Table 4 sets out additional TPO-mimetic peptides contemplated and found to have c-mpl receptor binding activity. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                   
                 AMINO ACID SEQUENCE 
                 SEQ ID NO: 
               
               
                   
                   
               
               
                   
                 KDTEVTAPRLWMVASVDE 
                 75 
               
               
                   
                   
               
               
                   
                 REMEGPTMRQWLAYRAVL 
                 76 
               
               
                   
                   
               
               
                   
                 CQNAGPTLRCWLAGRAYM 
                 77 
               
               
                   
                   
               
               
                   
                 CEREGPTLRCWLATREGS 
                 78 
               
               
                   
                   
               
               
                   
                 WRIEGPTLRHWLAARAWD 
                 79 
               
               
                   
                   
               
               
                   
                 ANMEGPTLRHWLAMRARV 
                 80 
               
               
                   
                   
               
               
                   
                 LDMEGPTLRHWLAARANG 
                 81 
               
               
                   
                   
               
               
                   
                 WRMEGPTLRHWLAARAWG 
                 82 
               
               
                   
                   
               
               
                   
                 WAMEGPTLRHWLAARAVL 
                 83 
               
               
                   
                   
               
               
                   
                 KSMEGPSLRQWLAARAQL 
                 84 
               
               
                   
                   
               
               
                   
                 TKIEGPTLRHWLAARAEL 
                 85 
               
               
                   
                   
               
               
                   
                 PRIEGPTLRLWLVTRALS 
                 86 
               
               
                   
                   
               
               
                   
                 IYMEGPTLRHWLANRAAK 
                 87 
               
               
                   
                   
               
               
                   
                 WPIEGATLRQWLKIRAGY 
                 88 
               
               
                   
                   
               
               
                   
                 RNMEGPTLRNWLAARAQH 
                 89 
               
               
                   
                   
               
               
                   
                 NGIEGPTLRLWLSERAKK 
                 90 
               
               
                   
                   
               
               
                   
                 MWMEGPTLRHWLEARARY 
                 91 
               
               
                   
                   
               
               
                   
                 YGIDGPTLRHWLAARARY 
                 92 
               
               
                   
                   
               
               
                   
                 RIIDGQTLRHWLAAGADP 
                 93 
               
               
                   
                   
               
               
                   
                 NGRDGPTVRHRLAGRAQK 
                 94 
               
               
                   
                   
               
               
                   
                 THIEGPTLRIWLASRAKA 
                 95 
               
               
                   
                   
               
               
                   
                 KGMEGPTLRHWLAARAHL 
                 96 
               
               
                   
                   
               
               
                   
                 QRIEGPTLRHWLAARASH 
                 97 
               
               
                   
                   
               
               
                   
                 KDTEVTAPRLWMVASVDE 
                 98 
               
               
                   
                   
               
            
           
         
       
     
     Table 5 sets out still other TPO-mimetic peptides contemplated and found to have c-mpl receptor binding activity. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                   
                 AMINO ACID SEQUENCE 
                 SEQ ID NO: 
               
               
                   
                   
               
               
                   
                 ENMEGPTLRHWLAARAHE 
                  99 
               
               
                   
                   
               
               
                   
                 SWMEGPTLRHWLMNRATY 
                 100 
               
               
                   
                   
               
               
                   
                 SMMEGPTLRHWLAARAKD 
                 101 
               
               
                   
                   
               
               
                   
                 QGIEGPTLRLWLAARTHP 
                 102 
               
               
                   
                   
               
               
                   
                 YMMEGPTLRHWLATRAGR 
                 103 
               
               
                   
                   
               
               
                   
                 GNMEGPTLRHWLAANERD 
                 104 
               
               
                   
                   
               
               
                   
                 NRMEGPTLRHWLAERAGS 
                 105 
               
               
                   
                   
               
               
                   
                 NMMEGPTLRHWLAARVAA 
                 106 
               
               
                   
                   
               
               
                   
                 SPIEGPTLRQQLCARAVK 
                 107 
               
               
                   
                   
               
               
                   
                 VQMEGTTLRQWLAERALD 
                 108 
               
               
                   
                   
               
               
                   
                 KRKDGHRPRQWLAPLACK 
                 109 
               
               
                   
                   
               
               
                   
                 EMMEGPTLRHWLAARAEK 
                 110 
               
               
                   
                   
               
               
                   
                 NMIEGPTLRHWLAERASQ 
                 111 
               
               
                   
                   
               
               
                   
                 KLMEGPTLRHWLAYRAGL 
                 112 
               
               
                   
                   
               
               
                   
                 YMMEGPTLRHWLAARALV 
                 113 
               
               
                   
                   
               
               
                   
                 GNMEGPTLRHWLAARALL 
                 114 
               
               
                   
                   
               
               
                   
                 WMMEGPTLRHWLAARARY 
                 115 
               
               
                   
                   
               
               
                   
                 TDRGGYTLRQWLAARAVL 
                 116 
               
               
                   
                   
               
               
                   
                 SAIEGPTLRHWLAWRAML 
                 117 
               
               
                   
                   
               
               
                   
                 RAIEGPTLRHCLAAGAGL 
                 118 
               
               
                   
                   
               
               
                   
                 VKRKGPTLRHWLAAWAFP 
                 119 
               
               
                   
                   
               
               
                   
                 TCMEGPTLRHWLAARAEG 
                 120 
               
               
                   
                   
               
               
                   
                 WFMEGPTLRHWLAARAYR 
                 121 
               
               
                   
                   
               
               
                   
                 ADIEGPTLRHWLAARALV 
                 122 
               
               
                   
                   
               
               
                   
                 WVMEGPTLRHWLAARASL 
                 123 
               
               
                   
                   
               
               
                   
                 PPGDGPTLRHWLAARARM 
                 124 
               
               
                   
                   
               
               
                   
                 DFMEGPTLRQRVDARAHY 
                 125 
               
               
                   
                   
               
               
                   
                 RWIEGPTQRQWLAARAYF 
                 126 
               
               
                   
                   
               
               
                   
                 IRMEGPTLRHWLASRAEI 
                 127 
               
               
                   
                   
               
               
                   
                 YYLEGPTLRHWLAARAYL 
                 128 
               
               
                   
                   
               
               
                   
                 GVIEGPTLRHWLAARAAQ 
                 129 
               
               
                   
                   
               
               
                   
                 GAMEGPTLRCWLAASDEK 
                 130 
               
               
                   
                   
               
               
                   
                 SVIDGPTLRQRLAARARY 
                 131 
               
               
                   
                   
               
               
                   
                 GGIERPTLRHCLAARPTS 
                 132 
               
               
                   
                   
               
               
                   
                 TKMEGPTLRHWLAWRAAY 
                 133 
               
               
                   
                   
               
               
                   
                 LKMEGPTLRNWLAWRAFQ 
                 134 
               
               
                   
                   
               
               
                   
                 GLVEGPTLRFWLAARAAE 
                 135 
               
               
                   
                   
               
               
                   
                 GLTDGPNLRHCLAARAPI 
                 136 
               
               
                   
                   
               
               
                   
                 DRNKGPTLRHWLAARAHA 
                 137 
               
               
                   
                   
               
               
                   
                 ASMVGPKLRHGLAAVAKK 
                 138 
               
               
                   
                   
               
               
                   
                 DAIEGPTLRLWLEARRKQ 
                 139 
               
               
                   
                   
               
               
                   
                 NIIKRATDREWLDARTAL 
                 140 
               
               
                   
                   
               
               
                   
                 GDNEGPSPRVCLAARAVL 
                 141 
               
               
                   
                   
               
               
                   
                 EFMEGPTLRHWLASRARV 
                 142 
               
               
                   
                   
               
               
                   
                 WGMEGPTLRHWLAARGKR 
                 143 
               
               
                   
                   
               
               
                   
                 RWMEGPTLRHWLAERAML 
                 144 
               
               
                   
                   
               
               
                   
                 LMVEGPTLRHWLAARWRM 
                 145 
               
               
                   
                   
               
               
                   
                 NYIEGPTLRHWLAARAKL 
                 146 
               
               
                   
                   
               
               
                   
                 TWMEGPTLRLWLMARALY 
                 147 
               
               
                   
                   
               
               
                   
                 QYMEGPTLRHWLAARAAL 
                 148 
               
               
                   
                   
               
               
                   
                 AWMEGPTLRHWLAARAAY 
                 149 
               
               
                   
                   
               
               
                   
                 KQFEGPPMRRSLAGVNTP 
                 150 
               
               
                   
                   
               
               
                   
                 ALMEGPTLRQRLAARAAQ 
                 151 
               
               
                   
                   
               
               
                   
                 ARMKGTTLRQWVAARAFV 
                 152 
               
               
                   
                   
               
               
                   
                 DKIEIPTVQLRRAAYACQ 
                 153 
               
               
                   
                   
               
               
                   
                 YRMEGPTLRHWLAARAGV 
                 154 
               
               
                   
                   
               
               
                   
                 ALMEGPTLRHWLAARALM 
                 155 
               
               
                   
                   
               
               
                   
                 IWAGGPTLRHWLAARAAL 
                 156 
               
               
                   
                   
               
               
                   
                 GWVDGPTLRHWLAARARM 
                 157 
               
               
                   
                   
               
               
                   
                 ARMEGPTLRHWLAARAKM 
                 158 
               
               
                   
                   
               
               
                   
                 ESMEGASQRHCMAARAGG 
                 159 
               
               
                   
                   
               
               
                   
                 MPVDGPVLRTWHAAQAIE 
                 160 
               
               
                   
                   
               
               
                   
                 LEHNRPLTNPIPKPRTPIRP 
                 161 
               
               
                   
                   
               
               
                   
                 TTMEDPTLRHWLATGAPT 
                 162 
               
               
                   
                   
               
               
                   
                 HPIEGPTLRLWLAARARA 
                 163 
               
               
                   
                   
               
               
                   
                 FPMEGTTLRHWLAARVQM 
                 164 
               
               
                   
                   
               
               
                   
                 RGMNGPTLRHWLEESAKD 
                 165 
               
               
                   
                   
               
               
                   
                 DQMEGSMVHQWLARHVWG 
                 166 
               
               
                   
                   
               
               
                   
                 RNMEGPTLRHWLAARATY 
                 167 
               
               
                   
                   
               
               
                   
                 DGMEGPTLRLWMAARAGE 
                 168 
               
               
                   
                   
               
               
                   
                 ASMYGPTVSQRLAARTRG 
                 169 
               
               
                   
                   
               
               
                   
                 PMMEGPTLRHWLAARALR 
                 170 
               
               
                   
                   
               
               
                   
                 WPMEGPTLRHWLAARAAR 
                 171 
               
               
                   
                   
               
               
                   
                 VQMEGPTLRHWLAGRAPN 
                 172 
               
               
                   
                   
               
               
                   
                 HGIEGPTHRQWLAARADI 
                 173 
               
               
                   
                   
               
               
                   
                 GMMEGPTLRHWLAARAML 
                 174 
               
               
                   
                   
               
               
                   
                 HDMEGPTLRHWLALRATG 
                 175 
               
               
                   
                   
               
               
                   
                 DNMERTRRRHSLAAHFML 
                 176 
               
               
                   
                   
               
               
                   
                 RNMEGPTLRHWLAARADR 
                 177 
               
               
                   
                   
               
               
                   
                 WKFEGFTLRQWLTARAFG 
                 178 
               
               
                   
                   
               
               
                   
                 RGMEGPTLRQRLVERAQM 
                 179 
               
               
                   
                   
               
               
                   
                 DVMEGTTLRQWLACRALM 
                 180 
               
               
                   
                   
               
               
                   
                 RKMERATLRQWLTARANM 
                 181 
               
               
                   
                   
               
               
                   
                 GTKEGPTLRQWPAARANE 
                 182 
               
               
                   
                   
               
               
                   
                 CAIEGPTLRHWLAARAAT 
                 183 
               
               
                   
                   
               
               
                   
                 LTMEGPTLRHWLRARAYA 
                 184 
               
               
                   
                   
               
               
                   
                 MTMEGPTLRQWFAARADT 
                 185 
               
               
                   
                   
               
               
                   
                 SPMEGPTLRHSAAGRPWG 
                 186 
               
               
                   
                   
               
               
                   
                 VHMEDPTLRHGNAARAAE 
                 187 
               
               
                   
                   
               
               
                   
                 YPMEGPTLRHWLAARARH 
                 188 
               
               
                   
                   
               
               
                   
                 GKTQGPKQLKWQVGSSLP 
                 189 
               
               
                   
                   
               
               
                   
                 GEMEGPTLLHWRAARAMQ 
                 190 
               
               
                   
                   
               
               
                   
                 INMEGPTLRLWLAARAAA 
                 191 
               
               
                   
                   
               
               
                   
                 FRIEGPTLRNWLAARAAK 
                 192 
               
               
                   
                   
               
               
                   
                 GRMEGPTLRHWLAARAHP 
                 193 
               
               
                   
                   
               
               
                   
                 VLIQGHTVRNCMVARVDA 
                 194 
               
               
                   
                   
               
               
                   
                 DWIEGPTLRHWLAARALY 
                 195 
               
               
                   
                   
               
               
                   
                 SWTEGPTLRHWLAARARN 
                 196 
               
               
                   
                   
               
               
                   
                 RELEGPTLRLWLVERARM 
                 197 
               
               
                   
                   
               
               
                   
                 VSMEGPTLRNWLAARARM 
                 198 
               
               
                   
                   
               
               
                   
                 TTMEGPTLRHWLATRAVD 
                 199 
               
               
                   
                   
               
               
                   
                 AKLEGPTLRLWLAERAGR 
                 200 
               
               
                   
                   
               
               
                   
                 ARMEGPTLRHWLAARARY 
                 201 
               
               
                   
                   
               
               
                   
                 NIMDGPALRHWLPARAIQ 
                 202 
               
               
                   
                   
               
               
                   
                 NMIGGPTLGHRLADPAIQ 
                 203 
               
               
                   
                   
               
               
                   
                 VWMEGATLRQWLAARALI 
                 204 
               
               
                   
                   
               
               
                   
                 RVMEGPTLLQRLAARARS 
                 205 
               
               
                   
                   
               
               
                   
                 QPMDEPARRQWLSARAGL 
                 206 
               
               
                   
                   
               
               
                   
                 AWTEGPTLRHWLAARGRS 
                 207 
               
               
                   
                   
               
               
                   
                 ATMEGPTLRHWLAARAAL 
                 208 
               
               
                   
                   
               
               
                   
                 GRMEGPTLRHWLAARALF 
                 209 
               
               
                   
                   
               
               
                   
                 ENMQGRTLRHWLAARDYF 
                 210 
               
               
                   
                   
               
               
                   
                 KGVEGPTLRLWLAARALM 
                 211 
               
               
                   
                   
               
               
                   
                 VEMEGPTLRHWLAARASV 
                 212 
               
               
                   
                   
               
               
                   
                 AFIEGPTLKNWLAARAIM 
                 213 
               
               
                   
                   
               
               
                   
                 TVMEGPTLRHWLAARSRS 
                 214 
               
               
                   
                   
               
               
                   
                 AHMEGPTLRHWLATRAKM 
                 215 
               
               
                   
                   
               
               
                   
                 KDIEGPTLRHWLAARANY 
                 216 
               
               
                   
                   
               
               
                   
                 RIHDGRKLRQWLTVRDTM 
                 217 
               
               
                   
                   
               
               
                   
                 KPIEGPTLKLWLAERMAA 
                 218 
               
               
                   
                   
               
               
                   
                 AKDVGTRLRQWLAAGARA 
                 219 
               
               
                   
                   
               
               
                   
                 QSQEGPTLRLWLAERAKW 
                 220 
               
               
                   
                   
               
               
                   
                 MYTEGATLRQWLAARARI 
                 221 
               
               
                   
                   
               
               
                   
                 PKMEGPTRRTRLADRSTS 
                 222 
               
               
                   
                   
               
               
                   
                 NVMEGPTLRHWLAYRARM 
                 223 
               
               
                   
                   
               
               
                   
                 TWMEGPTLRHWLAARALG 
                 224 
               
               
                   
                   
               
               
                   
                 LTMEGPTLRHWLAARATR 
                 225 
               
               
                   
                   
               
               
                   
                 YTMEGPTLRHWLAARALH 
                 226 
               
               
                   
                   
               
               
                   
                 NEMEGATLRQWLAARAKW 
                 227 
               
               
                   
                   
               
               
                   
                 FSKEGATLRQWLAARALD 
                 228 
               
               
                   
                   
               
               
                   
                 SNGVCRTLRQWLAARAEE 
                 229 
               
               
                   
                   
               
               
                   
                 KGMEGPTLRNWLAERAML 
                 230 
               
               
                   
                   
               
               
                   
                 QDMVGPTLRHWLAARARL 
                 231 
               
               
                   
                   
               
               
                   
                 YSHEGPTLRHWLAARALL 
                 232 
               
               
                   
                   
               
               
                   
                 GVIEGPTLRHWLAARMKV 
                 233 
               
               
                   
                   
               
               
                   
                 MHMEGPTLRHWLATRALI 
                 234 
               
               
                   
                   
               
               
                   
                 CRSEGPTLRCWLAARAGY 
                 235 
               
               
                   
                   
               
               
                   
                 MCIEGPTLRQWQVCRVGL 
                 236 
               
               
                   
                   
               
               
                   
                 CRVEGPSQRQCLAARACW 
                 237 
               
               
                   
                   
               
               
                   
                 CTMEGPTLRHWLAARACI 
                 238 
               
               
                   
                   
               
               
                   
                 CQVDGPTVRHCRAARAGL 
                 239 
               
               
                   
                   
               
               
                   
                 CDMAGATLRQWLACRSGT 
                 240 
               
               
                   
                   
               
               
                   
                 ICTEGCTLRLWLAERSRV 
                 241 
               
               
                   
                   
               
               
                   
                 CGMEGPALRQWLACRAVD 
                 242 
               
               
                   
                   
               
            
           
         
       
     
     Table 6 sets out still other TPO-mimetic peptides having c-mpl receptor binding activity. These peptides are contemplated for use alone or as TPO-mimetic fusion proteins, wherein the TPO-mimetic peptide is fused to either an N-terminus of an Fc region or within an Fc-Loop, a modified Fc molecule. Fc-Loops are described herein and in U.S. Patent Application Publication No. US2006/0140934 incorporated herein by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides 
               
            
           
           
               
               
            
               
                   
                 SEQ 
               
               
                   
                 ID 
               
               
                 AMINO ACID SEQUENCE 
                 NO: 
               
               
                   
               
               
                 QGCSSGGPTLREWQQCRRMQHS 
                   9 
               
               
                   
               
               
                 QGCSSGGPTLREWQQCVRMQHS 
                 243 
               
               
                   
               
               
                 QGCSSGGPTLREWQQCRRAQHS 
                 244 
               
               
                   
               
               
                 QGCSSGGPTLREWQQCVRAQHS 
                 245 
               
               
                   
               
               
                 IEGQSWEFENDRVPAHSLERVLLLRRVPTEPSGPSICAQIEGP 
                 246 
               
               
                 TFKQWQECINGHS 
                   
               
               
                   
               
               
                 IEGPTFKQWQKCRNMHS 
                 247 
               
               
                   
               
               
                 IEGPTFKQWQKLRRVHS 
                 248 
               
               
                   
               
               
                 IEGEPVSDGKRRPRVHSLERVDAVHAKVGPSICAQIEGPTFKQ 
                 249 
               
               
                 WQKCKRAHS 
                   
               
               
                   
               
               
                 IEGRWPPPQFPVTQQHSLERVGRPPPSVELPRPTFVCAQIEGP 
                 250 
               
               
                 TFKQWQRCLREHS 
                   
               
               
                   
               
               
                 IEGPTFKQWQRWRLLHS 
                 251 
               
               
                   
               
               
                 IEGPTFKQWQAWRKKHS 
                 252 
               
               
                   
               
               
                 IEGPTFKQWQRWRKMHS 
                 253 
               
               
                   
               
               
                 IEGRWPPPQFPVTEHHSLERVGRRPPNAQMPQSIFICGQNEGP 
                 254 
               
               
                 TFQYCQRCLREHS 
                   
               
               
                   
               
               
                 IEGWWWQFYFHAKEDHS 
                 255 
               
               
                   
               
               
                 PSICAQIEGPTFKQWQTCMRAHS 
                 256 
               
               
                   
               
               
                 IEGYVGGPYEQTNSLERVPPTLAWKYGPRTPSICAQIEGPTFK 
                 257 
               
               
                 QWQQCLSDHS 
                   
               
               
                   
               
               
                 IEGPTFKQWQGRSKRHS 
                 258 
               
               
                   
               
               
                 IEGWPWQLYVHPEGEHS 
                 259 
               
               
                   
               
               
                 IEGWWWQLYFHAKDDHS 
                 260 
               
               
                   
               
               
                 IEGPTFKQWQKLRRSHS 
                 261 
               
               
                   
               
               
                 IEGWWWQFYFHPKEDHS 
                 262 
               
               
                   
               
               
                 IEGPTFKQWQKSRTKHS 
                 263 
               
               
                   
               
               
                 IEGWTWQFYVHPKGDHS 
                 264 
               
               
                   
               
               
                 IEGPTFKQWQAARMHHS 
                 265 
               
               
                   
               
               
                 IEGPTFKQWQACLHSHS 
                 266 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 267 
               
               
                   
               
               
                 IEGPSFTPWFHERRSHS 
                 268 
               
               
                   
               
               
                 IEGPTFKQWQWLRRHHS 
                 269 
               
               
                   
               
               
                 IEGWWWQFYVHAKGDHS 
                 270 
               
               
                   
               
               
                 IEGPTFKQWQVWRNRHS 
                 271 
               
               
                   
               
               
                 IEGQSWLRRLHWKEEHS 
                 272 
               
               
                   
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRSCAQIEGPTFKQW 
                 273 
               
               
                 QICKDQHS 
                   
               
               
                   
               
               
                 IEGPTFKQWQKWRKTHS 
                 274 
               
               
                   
               
               
                 IEGPTFKQWQYWRAKHS 
                 275 
               
               
                   
               
               
                 IEGPTFKQWQVRQKTHS 
                 276 
               
               
                   
               
               
                 IEGWSWQFYFHAKGDHS 
                 277 
               
               
                   
               
               
                 IEGRTWQLYFHAKEEHS 
                 278 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 279 
               
               
                   
               
               
                 IEGWPRQLYAHAKEDHS 
                 280 
               
               
                   
               
               
                 IEGWWWQFYAHPQGDHS 
                 281 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 282 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 283 
               
               
                   
               
               
                 IEGHGSQKPTAARALESTSSLTTRTRTTSICAQQDMVGPTIRQ 
                 284 
               
               
                 WLAARACI 
                   
               
               
                   
               
               
                 IEGPTFEQWQHWRRGHS 
                 285 
               
               
                   
               
               
                 IEGWIWRQWLAARA 
                 286 
               
               
                   
               
               
                 IEGWIWRPWLAARA 
                 287 
               
               
                   
               
               
                 IEGYWWYASWAARA 
                 288 
               
               
                   
               
               
                 IEGWPWQFYAHPQGDHS 
                 289 
               
               
                   
               
               
                 IEGWVWCQWLAARA 
                 290 
               
               
                   
               
               
                 IEGPTLHEWLRWLRQHS 
                 291 
               
               
                   
               
               
                 IEGWVWRPWLAARA 
                 292 
               
               
                   
               
               
                 IEGWVWCPWLAARA 
                 293 
               
               
                   
               
               
                 IEGEALVFWWRVRGGHS 
                 294 
               
               
                   
               
               
                 IEGWVWCPWLAARA 
                 295 
               
               
                   
               
               
                 IEGWVWWPWLAARA 
                 296 
               
               
                   
               
               
                 IEGWTWQFYALPRGDHS 
                 297 
               
               
                   
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRSCAQIEGPTFKQW 
                 298 
               
               
                 QICKDQHS 
                   
               
               
                   
               
               
                 IEGPTLRQRLAARA 
                 299 
               
               
                   
               
               
                 IEGWSWQFYAHPKGDHS 
                 300 
               
               
                   
               
               
                 IEGWVWRQWLAARA 
                 301 
               
               
                   
               
               
                 IEGRHYQKWPARRLGHS 
                 302 
               
               
                   
               
               
                 IEGFVGTVDWRQGRPHS 
                 303 
               
               
                   
               
               
                 IEGQEPTRLRLqMDRHS 
                 304 
               
               
                   
               
               
                 IAQVRMLGRFTLLVLSRARAASTQLSFQHSICAQIEGGAQTQW 
                 305 
               
               
                 DAARA 
                   
               
               
                   
               
               
                 IEGEIWAGPGAARA 
                 306 
               
               
                   
               
               
                 IEGEALVFWWAARA 
                 307 
               
               
                   
               
               
                 IEGSYRERQQAARA 
                 308 
               
               
                   
               
               
                 IEGWVWRPWLAARA 
                 309 
               
               
                   
               
               
                 IEGWNPWRGAASRV 
                 310 
               
               
                   
               
               
                 IEGWTRRQWLAARA 
                 311 
               
               
                   
               
               
                 IEGWVWRPWLAARA 
                 312 
               
               
                   
               
               
                 IEGPTFKQWQAMRRHS 
                 313 
               
               
                   
               
               
                 IEGMVKLGVIRLLVL 
                 314 
               
               
                   
               
               
                 IEGPTFKQWQAWRRWHS 
                 315 
               
               
                   
               
               
                 IEVWQSHWYQAARALESTSSRLLPMRPPPSICAQIEGPTLPQR 
                 316 
               
               
                 MAARA 
                   
               
               
                   
               
               
                 IEGWTWQFYAHPQGDHS 
                 317 
               
               
                   
               
               
                 IEGPTFKQWQALRKRHS 
                 318 
               
               
                   
               
               
                 IEGPTFKQWQKLRLGHS 
                 319 
               
               
                   
               
               
                 IEGPTFKQWQLMGFPHS 
                 320 
               
               
                   
               
               
                 IEGWIWRQWLMQTLWHS 
                 321 
               
               
                   
               
               
                 IEGPTFKQWQAMRKNHS 
                 322 
               
               
                   
               
               
                 IEGPTFKQWQKWRLSHS 
                 323 
               
               
                   
               
               
                 IEGWQEGRQSAARA 
                 324 
               
               
                   
               
               
                 IEGPTFKQWQRWLKYHS 
                 325 
               
               
                   
               
               
                 IEGNYWFWQQVGQENTLSREWIQTLGQKYWYRPPSICAQIEGW 
                 326 
               
               
                 SRHQHYSAMSGHS 
                   
               
               
                   
               
               
                 IEGPTFKQWQLWRLQHS 
                 327 
               
               
                   
               
               
                 IEGPTFKQWQMLRRHHS 
                 328 
               
               
                   
               
               
                 IEGPTFKQWQRLRKNHS 
                 329 
               
               
                   
               
               
                 IEGLLSQLWQAARA 
                 330 
               
               
                   
               
               
                 IEGPSLPEWLHVWRHHS 
                 331 
               
               
                   
               
               
                 IEGPTLHEWLAERRKHS 
                 332 
               
               
                   
               
               
                 IEGPTLHEWLALLRSHS 
                 333 
               
               
                   
               
               
                 IEGPTLHEWLAQRREHS 
                 334 
               
               
                   
               
               
                 IEGPTLHEWLLYRRAHS 
                 335 
               
               
                   
               
               
                 IEGPTLHEWLRQRRQHS 
                 336 
               
               
                   
               
            
           
         
       
     
     Fc-Loops 
     As set out above, all of the peptides discussed herein are contemplated for use alone or as TPO-mimetic fusion proteins, wherein the TPO-mimetic peptide is fused to either an N-terminus of an Fc region or within an Fc-Loop, a modified Fc molecule. 
     Fc-Loops comprising a TPO-mimetic peptide are prepared in a process in which at least one biologically active peptide is incorporated as an internal sequence into an Fc domain. Such an internal sequence may be added by insertion (i.e., between amino acids in the previously existing Fc domain) or by replacement of amino acids in the previously existing Fc domain (i.e., removing amino acids in the previously existing Fc domain and adding peptide amino acids). In the latter case, the number of peptide amino acids added need not correspond to the number of amino acids removed from the previously existing Fc domain. For example, in one aspect, a molecule in which 10 amino acids are removed and 15 amino acids are added is provided. Pharmacologically active compounds provided are prepared by a process comprising: a) selecting at least one peptide that modulates the activity of a protein of interest; and b) preparing a pharmacologic agent comprising an amino acid sequence of the selected peptide as an internal sequence of an Fc domain. This process may be employed to modify an Fc domain that is already linked through an N- or C-terminus or sidechain to a peptide, e.g., as described in U.S. Pat. App. Nos. 2003/0195156, 2003/0176352, 2003/0229023, and 2003/0236193, and international publication numbers WO 00/24770 and WO 04/026329. The process described in U.S. Patent Application Publication No. US2006/0140934 may also be employed to modify an Fc domain that is part of an antibody. In this way, different molecules can be produced that have additional functionalities, such as a binding domain to a different epitope or an additional binding domain to the precursor molecule&#39;s existing epitope. Molecules comprising an internal peptide sequence are also referred to as “Fc internal peptibodies” or “Fc internal peptide molecules.” 
     The Fc internal peptide molecules may include more than one peptide sequence in tandem in a particular internal region, and they may include further peptides in other internal regions. While the putative loop regions are preferred, insertions in any other non-terminal domains of the Fc are also considered part of this invention. Variants and derivatives of the above compounds (described below) are also encompassed by this invention. 
     The compounds of this invention may be prepared by standard synthetic methods, recombinant DNA techniques, or any other methods of preparing peptides and fusion proteins. 
     A use contemplated for Fc internal peptide molecules is as a therapeutic or a prophylactic agent. A selected peptide may have activity comparable to—or even greater than—the natural ligand mimicked by the peptide. In addition, certain natural ligand-based therapeutic agents might induce antibodies against the patient&#39;s own endogenous ligand. In contrast, the unique sequence of the vehicle-linked peptide avoids this pitfall by having little or typically no sequence identity with the natural ligand. Furthermore, the Fc internal peptibodies may have advantages in refolding and purification over N- or C-terminally linked Fc molecules. Further still, Fc internal peptibodies may be more stable in both thermodynamically, due to the stabilization of chimeric domains, and chemically, due to increased resistance to proteolytic degradation from amino- and carboxy-peptidases. Fc internal peptibodies may also exhibit improved pharmacokinetic properties. 
     In one embodiment, the invention includes Fc-Loop-QGCSSGGPTLREWQQCRRMQHS (SEQ ID NO: 9) wherein the peptide sequence of SEQ ID NO: 9 is inserted in the Fc molecule (SEQ ID NO: 3) in the loop region between amino acids 139 (Leu) and 140 (Thr) using a linker. In one aspect, the linker comprises four glycine residues at the N-terminus of the amino acid sequence of SEQ ID NO: 9. In another aspect, the linker comprises two glycine residues at the N-terminus and two glycine residues at the C-terminus of SEQ ID NO: 9. 
     In another embodiment, the invention includes Fc-Loop-QGCSSGGPTLREWQQCVRMQHS (SEQ ID NO: 243) wherein the peptide sequence of SEQ ID NO: 9 is inserted in the Fc molecule (SEQ ID NO: 3) in the loop region between amino acids 139 (L) and 140 (Thr) using a linker In one aspect, the linker comprises four glycine residues at the N-terminus of the amino acid sequence of SEQ ID NO: 243. In another aspect, the linker comprises two glycine residues at the N-terminus and two glycine residues at the C-terminus of SEQ ID NO: 243. 
     Other linkers, as discussed in U.S. Patent Application Publication No. US2006/0140934, are also contemplated for use in modifying Fc-Loop molecules in this embodiment. 
     Table 7 sets out still other TPO-mimetic peptides having c-mpl receptor binding activity. Like all of the peptides discussed herein, these peptides are contemplated for use alone or as TPO-mimetic fusion proteins, wherein the TPO-mimetic peptide is fused to either an N-terminus of an Fc region or within an Fc-Loop, a modified Fc molecule. Fc-Loops are described in U.S. Patent Application Publication No. US2006/0140934, incorporated herein by reference in its entirety. 
     The compounds of the invention are screened in dose response assays in hematologically normal mice (BDF1). Platelet numbers are measured every other day until platelets returned to baseline, usually less than three weeks. 
     The compounds of the invention are also screened using a phage-ELISA. Phage-ELISA methods are described in US 2003/0176352. Phage-ELISA TPO activity of the some of the peptides set out in Table 6 are shown below in Table 7. All ELISA activity values have error values less than 10%. TPO-mimetic peptides with various levels of activity are useful as therapeutics. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Phage-ELISA Activity of Some TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                   
                 SEQ 
                   
               
               
                   
                 ID 
                 Relative 
               
               
                 AMINO ACID SEQUENCE 
                 NO: 
                 activity 
               
               
                   
               
            
           
           
               
               
               
            
               
                 IEGPTLRQWLAARA (positive control) 
                 337 
                 150 
               
               
                   
               
               
                 Sequence unknown (negative control) 
                   
                 &lt;2.0 
               
               
                   
               
               
                 IEGQSWEFENDRVPAHSLERVLLLRRVPTEPSGPS 
                 246 
                 173.43 
               
               
                 ICAQIEGPTFKQWQECINGHS 
                   
                   
               
               
                   
               
               
                 IEGPTFKQWQKCRNMHS 
                 247 
                 164.21 
               
               
                   
               
               
                 IEGPTFKQWQKLRRVHS 
                 248 
                 154.55 
               
               
                   
               
               
                 IEGEPVSDGKRRPRVHSLERVDAVHAKVGPSICAQ 
                 249 
                 150.03 
               
               
                 IEGPTFKQWQKCKRAHS 
                   
                   
               
               
                   
               
               
                 IEGRWPPPQFPVTQQHSLERVGRPPPSVELPRPTF 
                 250 
                 149.48 
               
               
                 VCAQIEGPTFKQWQRCLREHS 
                   
                   
               
               
                   
               
               
                 IEGPTFKQWQRWRLLHS 
                 251 
                 149.28 
               
               
                   
               
               
                 IEGPTFKQWQAWRKKHS 
                 252 
                 145.97 
               
               
                   
               
               
                 IEGPTFKQWQRWRKMHS 
                 253 
                 143.61 
               
               
                   
               
               
                 IEGRWPPPQFPVTEHHSLERVGRPPNAQMPQSIFI 
                 254 
                 137.49 
               
               
                 CGQNEGPTFQYCQRCLREHS 
                   
                   
               
               
                   
               
               
                 IEGWWWQFYFHAKEDHS 
                 255 
                 135.88 
               
               
                   
               
               
                 PSICAQIEGPTFKQWQTCMRAHS 
                 256 
                 133.12 
               
               
                   
               
               
                 IEGYVGGPYEQTNSLERVPPTLAWKYGPRTPSICA 
                 257 
                 131.28 
               
               
                 QIEGPTFKQWQQCLSDHS 
                   
                   
               
               
                   
               
               
                 IEGPTFKQWQGRSKRHS 
                 258 
                 130.94 
               
               
                   
               
               
                 IEGWPWQLYVHPEGEHS 
                 259 
                 129.31 
               
               
                   
               
               
                 IEGWWWQLYFHAKDDHS 
                 260 
                 126.15 
               
               
                   
               
               
                 IEGPTFKQWQKLRRSHS 
                 261 
                 124.92 
               
               
                   
               
               
                 IEGWWWQFYFHPKEDHS 
                 262 
                 124.27 
               
               
                   
               
               
                 IEGPTFKQWQKSRTKHS 
                 263 
                 123.60 
               
               
                   
               
               
                 IEGWTWQFYVHPKGDHS 
                 264 
                 122.24 
               
               
                   
               
               
                 IEGPTFKQWQAARMHHS 
                 265 
                 121.50 
               
               
                   
               
               
                 IEGPTFKQWQACLHSHS 
                 266 
                 114.00 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 267 
                 112.55 
               
               
                   
               
               
                 IEGPSFTPWFHERRSHS 
                 268 
                 109.80 
               
               
                   
               
               
                 IEGPTFKQWQWLRRHHS 
                 269 
                 109.46 
               
               
                   
               
               
                 IEGWWWQFYVHAKGDHS 
                 270 
                 108.67 
               
               
                   
               
               
                 IEGPTFKQWQVWRNRHS 
                 271 
                 108.23 
               
               
                   
               
               
                 IEGQSWLRRLHWKEEHS 
                 272 
                 108.03 
               
               
                   
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRSCAQI 
                 273 
                 105.68 
               
               
                 EGPTFKQWQICKDQHS 
                   
                   
               
               
                   
               
               
                 IEGPTFKQWQKWRKRKTHS 
                 274 
                 105.28 
               
               
                   
               
               
                 IEGPTFKQWQYWRAKHS 
                 275 
                 105.24 
               
               
                   
               
               
                 IEGPTFKQWQVRQKTHS 
                 276 
                 105.18 
               
               
                   
               
               
                 IEGWSWQFYFHAKGDHS 
                 277 
                 103.56 
               
               
                   
               
               
                 IEGRTWQLYFHAKEEHS 
                 278 
                 101.72 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 279 
                 98.46 
               
               
                   
               
               
                 IEGWPRQLYAHAKEDHS 
                 280 
                 95.57 
               
               
                   
               
               
                 IEGWWWQFYAHPQGDHS 
                 281 
                 94.99 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 282 
                 93.70 
               
               
                   
               
               
                 IEGWSWQFYAHPQGDHS 
                 283 
                 93.70 
               
               
                   
               
               
                 IEGHGSQKPTAARALESTSSLTTRTRTTSICAQQD 
                 284 
                 92.11 
               
               
                 MVGPTIRQWLAARACI 
                   
                   
               
               
                   
               
               
                 IEGPTFEQWQHWRRGHS 
                 285 
                 91.49 
               
               
                   
               
               
                 IEGWIWRQWLAARA 
                 286 
                 91.41 
               
               
                   
               
               
                 IEGWIWRPWLAARA 
                 287 
                 83.33 
               
               
                   
               
               
                 IEGYWWYASWAARA 
                 288 
                 80.41 
               
               
                   
               
               
                 IEGWPWQFYAHPQGDHS 
                 289 
                 80.26 
               
               
                   
               
               
                 IEGWVWCQWLAARA 
                 290 
                 79.14 
               
               
                   
               
               
                 IEGPTLHEWLRWLRQHS 
                 291 
                 78.29 
               
               
                   
               
               
                 IEGWVWRPWLAARA 
                 292 
                 76.04 
               
               
                   
               
               
                 IEGWVWCPWLAARA 
                 293 
                 74.05 
               
               
                   
               
               
                 IEGEALVFWWRVRGGHS 
                 294 
                 73.91 
               
               
                   
               
               
                 IEGWVWCPWLAARA 
                 295 
                 73.05 
               
               
                   
               
               
                 IEGWVWWPWLAARA 
                 296 
                 63.46 
               
               
                   
               
               
                 IEGWTWQFYALPRGDHS 
                 297 
                 63.25 
               
               
                   
               
               
                 IEGWPWQFYALSRESGTSPSSAARTSSYLRSCAQI 
                 298 
                 62.08 
               
               
                 EGPTFKQWQICKDQHS 
                   
                   
               
               
                   
               
               
                 IEGPTLRQRLAARA 
                 299 
                 57.27 
               
               
                   
               
               
                 IEGWSWQFYAHPKGDHS 
                 300 
                 52.59 
               
               
                   
               
               
                 IEGWVWRQWLAARA 
                 301 
                 52.14 
               
               
                   
               
               
                 IEGRHYQKWPARRLGHS 
                 302 
                 51.98 
               
               
                   
               
               
                 IEGFVGTVDWRQGRPHS 
                 303 
                 49.81 
               
               
                   
               
               
                 IEGQEPTRLRLQMDRHS 
                 304 
                 48.29 
               
               
                   
               
               
                 IAQVRMLGRFTLLVLSRARAASTQLSFQHSICAQI 
                 305 
                 47.37 
               
               
                 EGGAQTQWDAARA 
                   
                   
               
               
                   
               
               
                 IEGEIWAGPGAARA 
                 306 
                 46.50 
               
               
                   
               
               
                 IEGEALVFWWAARA 
                 307 
                 40.33 
               
               
                   
               
               
                 IEGSYRERQQAARA 
                 308 
                 35.23 
               
               
                   
               
               
                 IEGWVWRPWLAARA 
                 309 
                 33.96 
               
               
                   
               
               
                 IEGWNPWRGAASRV 
                 310 
                 33.90 
               
               
                   
               
               
                 IEGWTRRQWLAARA 
                 311 
                 33.29 
               
               
                   
               
               
                 IEGWVWRPWLAARA 
                 312 
                 28.88 
               
               
                   
               
               
                 IEGPTFKQWQAMRRHS 
                 313 
                 28.41 
               
               
                   
               
               
                 IEGMVKLGVIRLLVL 
                 314 
                 28.30 
               
               
                   
               
               
                 IEGPTFKQWQAWRRWHS 
                 315 
                 28.15 
               
               
                   
               
               
                 IEVWQSHWYQAARALESTSSRLLPMRPPPSICAQI 
                 316 
                 24.91 
               
               
                 EGPTLPQRMAARA 
                   
                   
               
               
                   
               
               
                 IEGWTWQFYAHPQGDHS 
                 317 
                 24.20 
               
               
                   
               
               
                 IEGPTFKQWQALRKRHS 
                 318 
                 21.63 
               
               
                   
               
               
                 IEGPTFKQWQKLRLGHS 
                 319 
                 17.86 
               
               
                   
               
               
                 IEGPTFKQWQLMGFPHS 
                 320 
                 17.79 
               
               
                   
               
               
                 IEGWIWRQWLMQTLWHS 
                 321 
                 16.43 
               
               
                   
               
               
                 IEGPTFKQWQAMRKNHS 
                 322 
                 16.35 
               
               
                   
               
               
                 IEGPTFKQWQKWRLSHS 
                 323 
                 14.65 
               
               
                   
               
               
                 IEGWQEGRQSAARA 
                 324 
                 13.75 
               
               
                   
               
               
                 IEGPTFKQWQRWLKYHS 
                 325 
                 13.51 
               
               
                   
               
               
                 IEGNYWFWQQVGQENTLSREWIQTLGQKYWYRPPS 
                 326 
                 13.21 
               
               
                 ICAQIEGWSRHQHYSAMSGHS 
                   
                   
               
               
                   
               
               
                 IEGPTFKQWQLWRLQHS 
                 327 
                 12.61 
               
               
                   
               
               
                 IEGPTFKQWQMLRRHHS 
                 328 
                 12.49 
               
               
                   
               
               
                 IEGPTFKQWQRLRKNHS 
                 329 
                 12.14 
               
               
                   
               
               
                 IEGLLSQLWQAARA 
                 330 
                 7.11 
               
               
                   
               
               
                 IEGPSLPEWLHVWRHHS 
                 331 
                 117.03 
               
               
                   
               
               
                 IEGPTLHEWLAERRKHS 
                 332 
                 88.36 
               
               
                   
               
               
                 IEGPTLHEWLALLRSHS 
                 333 
                 80.68 
               
               
                   
               
               
                 IEGPTLHEWLAQRREHS 
                 334 
                 75.86 
               
               
                   
               
               
                 IEGPTLHEWLLYRRAHS 
                 335 
                 73.66 
               
               
                   
               
               
                 IEGPTLHEWLRQRRQHS 
                 336 
                 64.53 
               
               
                   
               
            
           
         
       
     
     Table 8 sets out still other TPO-mimetic peptides having c-mpl receptor binding activity, which were used in the invention. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                   
                   
                 SEQ 
               
               
                   
                   
                 ID 
               
               
                   
                 AMINO ACID SEQUENCE 
                 NO: 
               
               
                   
                   
               
               
                   
                 YSHCAQGAVPQGPTLKQWLLWRRCAHSLETVES 
                 338 
               
               
                   
                   
               
               
                   
                 YSHCAQGYCDEGPTLKQWLVCLGLQHSLETVES 
                 339 
               
               
                   
                   
               
               
                   
                 YSHCAQGCSSGGPTLREWLQCRRMQHSLETVES 
                 340 
               
               
                   
                   
               
               
                   
                 YSHCAQGCSWGGPTLKQWLQCVRAKHSLETVES 
                 341 
               
               
                   
                   
               
               
                   
                 YSHCAQGGCRSGPTLREWLACREVQHSLETVES 
                 342 
               
               
                   
                   
               
               
                   
                 YSHCAQGTCEQGPTLRQWLLCRQGRHSLETVES 
                 343 
               
               
                   
                   
               
            
           
         
       
     
     Fc-Loop Insertion Sites 
     As set out above, all of the peptides discussed herein are contemplated for use alone or as TPO-mimetic fusion proteins, wherein the TPO-mimetic peptide is fused to either an N-terminus of an Fc region or within an Fc-Loop, a modified Fc molecule. Fc-Loops are described in U.S. Patent Application Publication No. US2006/0140934 incorporated herein by reference in its entirety. Preferred internal sites for peptide addition into an Fc-Loop are shown in boldface below: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 3) 
               
            
           
           
               
               
            
               
                 1 
                 MDKTHTCPPC PAPELLGGPS VFLF PP KPKD TLMISRTPEV 
               
               
                   
                 TCVVV DV     SHE     
               
               
                   
               
               
                 51 
                   DPE VKFNWYV DGVE VHNA KT KPR EEQ     YNS     T  YRVVSVLT VL   
               
               
                   
                   HQDWLNGKE Y 
               
               
                   
               
               
                 101 
                 KCKVS NKA LP APIEKTISKA KGQPREPQVY TLPPSRDE LT   
               
               
                   
                 KNQVSLTCLV 
               
               
                   
               
               
                 151 
                 KGFYPSDIAV EWES NGQP     EN N   YK TTPP     VLD       SD     GS FFLYSK 
               
               
                   
                 LTVD KSRWQ     Q     
               
               
                   
               
               
                 201 
                     GN     V FSCSVMH EALHNHYTQK SLSLSPGK. 
               
            
           
         
       
     
     Particularly preferred sites are the insertion sites (H49/E50), (Y77/N78), (K107/A108), (L139/T140), (E169/N170), (S181/S182), and (G201/N202) of SEQ ID NO: 3. Most preferable are the insertion site (L139/T140) of SEQ ID NO: 3 and two additional loops in the CH2 domain (H49/E50) and (Y77/N78). 
     In one embodiment, a TPO-mimetic peptide is inserted into the human IgG1 Fc-Loop domain between Leu139 and Thr140 of SEQ ID NO: 3 and includes 2 Gly residues as linkers flanking either side of the inserted peptide. 
     Other exemplary amino acid sequences of human Fc regions from IgA, IgM and IgG subtypes (SEQ ID NOS: 344 to 351), as set out in Table 9 below, may also be used in the invention in addition to the Fc region set out in SEQ ID NO: 3. A consensus sequence is set out in (SEQ ID NO: 352). 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Amino Acid Sequences of Additional Human Fc Regions 
               
            
           
           
               
               
            
               
                   
                 SEQ 
               
               
                   
                 ID 
               
               
                 AMINO ACID SEQUENCE 
                 NO: 
               
               
                   
               
               
                 Ala Gly Lys Ser Val Thr Cys His Val Lys His Tyr Thr Asn Pro Ser Gln Asp Val Thr 
                 344 
               
               
                 Val Pro Cys Pro Val Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro 
                   
               
               
                 Ser Pro Ser Cys Cys His Pro Arg Leu Ser Leu His Arg Pro Ala Leu Glu Asp Leu Leu 
                   
               
               
                 Leu Gly Ser Glu Ala Asn Leu Thr Cys Thr Leu Thr Gly Leu Arg Asp Ala Ser Gly Val 
                   
               
               
                 Thr Phe Thr Trp Thr Pro Ser Ser Gly Lys Ser Ala Val Gln Gly Pro Pro Glu Arg Asp 
                   
               
               
                 Leu Cys Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly Cys Ala Glu Pro Trp Asn His 
                   
               
               
                 Gly Lys Thr Phe Thr Cys Thr Ala Ala Tyr Pro Glu Ser Lys Thr Pro Leu Thr Ala Thr 
                   
               
               
                 Leu Ser Lys Ser Gly Asn Thr Phe Arg Pro Glu Val His Leu Leu Pro Pro Pro Ser Glu 
                   
               
               
                 Glu Leu Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser Pro Lys 
                   
               
               
                 Asp Val Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu Pro Arg Glu Lys Tyr Leu Thr 
                   
               
               
                 Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr Phe Ala Val Thr Ser Ile Leu 
                   
               
               
                 Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe Ser Cys Met Val Gly His Glu 
                   
               
               
                 Ala Leu Pro Leu Ala Phe Thr Gln Lys Thr Ile Asp Arg Leu Ala Gly Lys Pro Thr His 
                   
               
               
                 Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr Cys Tyr 
                   
               
               
                   
               
               
                 Asp Gly Lys Ser Val Thr Cys His Val Lys His Tyr Thr Asn Pro Ser Gln Asp Val Thr 
                 345 
               
               
                 Val Pro Cys Pro Val Pro Pro Pro Pro Pro Cys Cys His Pro Arg Leu Ser Leu His Arg 
                   
               
               
                 Pro Ala Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn Leu Thr Cys Thr Leu Thr Gly 
                   
               
               
                 Leu Arg Asp Ala Ser Gly Ala Thr Phe Thr Trp Thr Pro Ser Ser Gly Lys Ser Ala Val 
                   
               
               
                 Gln Gly Pro Pro Glu Arg Asp Leu Cys Gly Cys Tyr Ser Val Ser Ser Val Leu Pro Gly 
                   
               
               
                 Cys Ala Gln Pro Trp Asn His Gly Glu Thr Phe Thr Cys Thr Ala Ala His Pro Glu Leu 
                   
               
               
                 Lys Thr Pro Leu Thr Ala Asn Ile Thr Lys Ser Gly Asn Thr Phe Arg Pro Glu Val His 
                   
               
               
                 Leu Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu Thr Cys Leu 
                   
               
               
                 Ala Arg Gly Phe Ser Pro Lys Asp Val Leu Val Arg Trp Leu Gln Gly Ser Gln Glu Leu 
                   
               
               
                 Pro Arg Glu Lys Tyr Leu Thr Trp Ala Ser Arg Gln Glu Pro Ser Gln Gly Thr Thr Thr 
                   
               
               
                 Phe Ala Val Thr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Asp Thr Phe 
                   
               
               
                 Ser Cys Met Val Gly His Glu Ala Leu Pro Leu Ala Phe Thr Gln Lys Thr Ile Asp Arg 
                   
               
               
                 Leu Ala Gly Lys Pro Thr His Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr 
                   
               
               
                 Cys Tyr 
                   
               
               
                   
               
               
                 Glu Gly Lys Gln Val Gly Ser Gly Val Thr Thr Asp Gln Val Gln Ala Glu Ala Lys Glu 
                 346 
               
               
                 Ser Gly Pro Thr Thr Tyr Lys Val Thr Ser Thr Leu Thr Ile Lys Glu Asp His Arg Gly 
                   
               
               
                 Leu Thr Phe Gln Gln Asn Ala Ser Ser Met Cys Val Pro Asp Gln Asp Thr Ala Ile Arg 
                   
               
               
                 Val Phe Ala Ile Pro Pro Ser Phe Ala Ser Ile Phe Leu Thr Lys Ser Thr Lys Leu Thr 
                   
               
               
                 Cys Leu Val Thr Asp Leu Thr Thr Tyr Asp Ser Val Thr Ile Ser Trp Asn Ser Gly Glu 
                   
               
               
                 Arg Phe Thr Cys Thr Val Thr His Thr Asp Leu Pro Ser Pro Leu Lys Gln Thr Ile Ser 
                   
               
               
                 Arg Pro Lys Gly Val Ala Leu His Arg Pro Asp Val Tyr Leu Leu Pro Pro Ala Arg Glu 
                   
               
               
                 Gln Leu Asn Leu Arg Glu Ser Ala Thr Ile Thr Cys Leu Val Thr Gly Phe Ser Pro Ala 
                   
               
               
                 Asp Val Phe Val Gln Trp Met Gln Arg Gly Gln Pro Leu Ser Pro Glu Lys Tyr Val Thr 
                   
               
               
                 Ser Ala Pro Met Pro Glu Pro Gln Ala Pro Gly Arg Tyr Phe Ala His Ser Ile Leu Thr 
                   
               
               
                 Val Ser Glu Glu Glu Trp Asn Thr Gly Glu Thr Tyr Thr Cys Val Ala His Asp Ala Leu 
                   
               
               
                 Pro Asn Arg Val Thr Glu Arg Thr Val Asp Lys Ser Thr Gly Lys Pro Thr Leu Tyr Asn 
                   
               
               
                 Val Ser Leu Val Met Ser Asp Thr Ala Gly Thr Cys Tyr 
                   
               
               
                   
               
               
                 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 
                 347 
               
               
                 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                   
               
               
                 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 
                   
               
               
                 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 
                   
               
               
                 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 
                   
               
               
                 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                   
               
               
                 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 
                   
               
               
                 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 
                   
               
               
                 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 
                   
               
               
                 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                   
               
               
                 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 
                   
               
               
                 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                   
               
               
                   
               
               
                 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 
                 348 
               
               
                 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 
                   
               
               
                 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 
                   
               
               
                 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 
                   
               
               
                 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 
                   
               
               
                 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 
                   
               
               
                 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 
                   
               
               
                 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 
                   
               
               
                 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 
                   
               
               
                 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                   
               
               
                 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 
                   
               
               
                 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                   
               
               
                   
               
               
                 Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro Arg Cys Pro Glu Pro Lys 
                 349 
               
               
                 Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro 
                   
               
               
                 Pro Pro Cys Pro Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg 
                   
               
               
                 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 
                   
               
               
                 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 
                   
               
               
                 Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 
                   
               
               
                 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val 
                   
               
               
                 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 
                   
               
               
                 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val 
                   
               
               
                 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 
                   
               
               
                 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu 
                   
               
               
                 Asn Asn Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 
                   
               
               
                 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile Phe Ser Cys Ser Val Met 
                   
               
               
                 His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 
                   
               
               
                   
               
               
                 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 
                 350 
               
               
                 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 
                   
               
               
                 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val 
                   
               
               
                 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 
                   
               
               
                 Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 
                   
               
               
                 Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 
                   
               
               
                 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 
                   
               
               
                 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 
                   
               
               
                 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp 
                   
               
               
                 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 
                   
               
               
                 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 
                   
               
               
                 Ser Leu Ser Leu Ser Pro Gly Lys 
                   
               
               
                   
               
               
                 Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 
                 351 
               
               
                 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 
                   
               
               
                 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 
                   
               
               
                 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 
                   
               
               
                 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 
                   
               
               
                 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 
                   
               
               
                 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 
                   
               
               
                 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 
                   
               
               
                 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 
                   
               
               
                 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 
                   
               
               
                 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 
                   
               
               
                 Lys Ser Leu Ser Leu Ser Leu Gly Lys 
                   
               
               
                   
               
               
                 Glu Xaa Lys Ser Xaa Asp Xaa Thr Val Pro Cys Pro Xaa Cys Pro Ala Pro Glu Leu Leu 
                 352 
               
               
                 Gly Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Pro Ser Val Phe Leu 
                   
               
               
                 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 
                   
               
               
                 Val Val Asp Val Ser His Glu Asp Pro Glu Val Xaa Phe Asn Trp Tyr Val Asp Gly Val 
                   
               
               
                 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 
                   
               
               
                 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 
                   
               
               
                 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Xaa Gly 
                   
               
               
                 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Xaa Ser Arg Glu Glu Met Thr Lys 
                   
               
               
                 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 
                   
               
               
                 Trp Glu Ser Asn Gly Gln Xaa Xaa Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 
                   
               
               
                 Asp Ser Asp Gly Xaa Xaa Xaa Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 
                   
               
               
                 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 
                   
               
               
                 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Xaa Xaa 
               
               
                   
               
            
           
         
       
     
     An Fc-Loop TPO-mimetic clone is transformed into  E. coli  by conventional methods known to those in the art. The isolated inclusion body fraction (1 g) is solubilized in 6 M guanidine-HCl, 50 mM Tris, 8 mM DTT, pH 9 (10 ml) at room temperature with mixing, for 1 hour. The denatured and reduced peptibody is refolded from the solubilized inclusion body fraction by a 1:25 (v/v) dilution into 2 M urea, 50 mM Tris, 4 mM cysteine, 1 mM cystamine, pH 8.5. The solubilized peptibody is added drop wise to the refold buffer at 4° C. with stirring. The refold reactions are allowed to stir for 48 hours, and then aliquots are evaluated by SDS-PAGE and reversed-phase HPLC. 
     Purification is achieved using a 2-column process. First a recombinant Protein-A column is equilibrated in 2 M urea, 50 mM Tris, pH 8.5 and loaded with the filtered peptibody refold reaction. The column is then washed with 2 column volumes of equilibration buffer, followed by 2 column volumes of PBS. The peptibody fraction is eluted with 50 mM NaOAc, pH3 and quickly neutralized by a 1:4 dilution into 10 mM NaOAc, 50 mM NaCl, pH 5. The diluted Protein-A eluate is again filtered and loaded to an SP Sepharose HP cation exchange column (Pharmacia) equilibrated in 10 mM NaOAc, 50 mM NaCl, pH 5. The peptibody fractions are then eluted with a linear 50-500 mM NaCl gradient, pooled and concentrated to about 2 mg/ml. The final pools of Fc-Loop TPO-mimetics are evaluated by SDS-PAGE and RP-HPLC. The final preparation of Fc-Loop TPO-mimetics are tested in an in vivo mouse bioassay. 
     Table 10 sets out the amino acid sequences of some TPO-mimetic peptides inserted into an Fc-Loop of SEQ ID NO: 3. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides in an Fc-Loop 
               
            
           
           
               
               
            
               
                   
                 SEQ 
               
               
                   
                 ID 
               
               
                 AMINO ACID SEQUENCE 
                 NO: 
               
               
                   
               
               
                 Fc-Loop H49/E50 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 353 
               
               
                 VVDVSH GG     QGCSSGGPTLREWQQCRRMQHS     GG EDPEVK 
                   
               
               
                 FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
                   
               
               
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 354 
               
               
                 VVDVSH GG     QGCSSGGPTLREWQQCVRMQHS     GG EDPEVK 
                   
               
               
                 FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
                   
               
               
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 355 
               
               
                 VVDVSH GG     QGCSSGGPTLREWQQCRRAQHS     GG EDPEVK 
                   
               
               
                 FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
                   
               
               
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 356 
               
               
                 VVDVSH GG     QGCSSGGPTLREWQQCVRAQHS     GG EDPEVK 
                   
               
               
                 FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL 
                   
               
               
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 357 
               
               
                 VVDVSH GG     LDMEGPTLRHWLAARANG     GG EDPEVKFNWY 
                   
               
               
                 VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
                   
               
               
                 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 358 
               
               
                 VVDVSH GG     YMMEGPTLRHWLATRAGR     GG EDPEVKFNW 
                   
               
               
                 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
                   
               
               
                 EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 359 
               
               
                 VVDVSH GG     THIEGPTLRIWLASRAKA     GG EDPEVKFNWYV 
                   
               
               
                 DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY 
                   
               
               
                 KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 
                   
               
               
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
                   
               
               
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS 
                   
               
               
                 PGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 360 
               
               
                 VVDVSH GG     SAIEGPTLRHWLAWRAML     GG EDPEVKFNWY 
                   
               
               
                 VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 
                   
               
               
                 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 361 
               
               
                 VVDVSH GG     WMMEGPTLRHWLAARARY     GG EDPEVKFNW 
                   
               
               
                 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
                   
               
               
                 EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 362 
               
               
                 VVDVSH GG     AWMEGPTLRHWLAARAAY     GG EDPEVKFNW 
                   
               
               
                 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK 
                   
               
               
                 EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 Fc-Loop Y77/N78 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 363 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     QGC     
                   
               
               
                     SSGGPTLREWQQCRRMQHS     GG NSTYRVVSVLTVLHQDW 
                   
               
               
                 LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 
                   
               
               
                 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 
                   
               
               
                 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
                   
               
               
                 QKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 364 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     QGC     
                   
               
               
                     SSGGPTLREWQQCVRMQHS     GG NSTYRVVSVLTVLHQDW 
                   
               
               
                 LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 
                   
               
               
                 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 
                   
               
               
                 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
                   
               
               
                 QKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 365 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     QGC     
                   
               
               
                     SSGGPTLREWQQCRRAQHS     GG NSTYRVVSVLTVLHQDWL 
                   
               
               
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 366 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     QGC     
                   
               
               
                     SSGGPTLREWQQCVRAQHS     GG NSTYRVVSVLTVLHQDWL 
                   
               
               
                 NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 367 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     LDM     
                   
               
               
                     EGPTLRHWLAARANG     GG NSTYRVVSVLTVLHQDWLNGKE 
                   
               
               
                 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 368 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     YMM     
                   
               
               
                     EGPTLRHWLATRAGR     GG NSTYRVVSVLTVLHQDWLNGKE 
                   
               
               
                 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 369 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     THIE     
                   
               
               
                     GPTLRIWLASRAKA     GG NSTYRVVSVLTVLHQDWLNGKEY 
                   
               
               
                 KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN 
                   
               
               
                 QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 
                   
               
               
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS 
                   
               
               
                 PGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 370 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     SAIE     
                   
               
               
                     GPTLRHWLAWRAML     GG NSTYRVVSVLTVLHQDWLNGKE 
                   
               
               
                 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 371 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     WM     
                   
               
               
                     MEGPTLRHWLAARARY     GG NSTYRVVSVLTVLHQDWLNG 
                   
               
               
                 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT 
                   
               
               
                 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
                   
               
               
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
                   
               
               
                 LSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 372 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY GG     AW     
                   
               
               
                     MEGPTLRHWLAARAAY     GG NSTYRVVSVLTVLHQDWLNG 
                   
               
               
                 KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT 
                   
               
               
                 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
                   
               
               
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
                   
               
               
                 LSLSPGK 
                   
               
               
                   
               
               
                 Fc-Loop K107/A108 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 373 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     QGCSSGGPTLREW     
                   
               
               
                     QQCRRMQHS     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 374 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     QGCSSGGPTLREW     
                   
               
               
                     QQCVRMQHS     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRD 
                   
               
               
                 ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 375 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     QGCSSGGPTLREW     
                   
               
               
                     QQCRRAQHS     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDE 
                   
               
               
                 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
                   
               
               
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
                   
               
               
                 LSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 376 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     QGCSSGGPTLREW     
                   
               
               
                     QQCVRAQHS     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDE 
                   
               
               
                 LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 
                   
               
               
                 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
                   
               
               
                 LSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 377 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     LDMEGPTLRHWL     
                   
               
               
                     AARANG     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 378 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     YMMEGPTLRHWL     
                   
               
               
                     ATRAGR     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 379 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     THIEGPTLRIWLAS     
                   
               
               
                     RAKA     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ 
                   
               
               
                 VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF 
                   
               
               
                 FLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 
                   
               
               
                 GK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 380 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     SAIEGPTLRHWLA     
                   
               
               
                     WRAML     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 381 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     WMMEGPTLRHW     
                   
               
               
                     LAARARY     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDELT 
                   
               
               
                 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS 
                   
               
               
                 DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 
                   
               
               
                 LSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 382 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNK GG     AWMEGPTLRHWL     
                   
               
               
                     AARAAY     GG ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK 
                   
               
               
                 NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 Fc-Loop L139/T140 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 383 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     QGCSSGGPTLREWQQCRRMQHS     GG TKNQV 
                   
               
               
                 SLTCLVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 384 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     QGCSSGGPTLREWQQCVRMQHS     GG TKNQV 
                   
               
               
                 SLTCLVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 385 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     QGCSSGGPTLREWQQCRRAQHS     GG TKNQV 
                   
               
               
                 SLTCLVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 386 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     QGCSSGGPTLREWQQCVRAQHS     GG TKNQV 
                   
               
               
                 SLTCLVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 387 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     LDMEGPTLRHWLAARANG     GG TKNQVSLTC 
                   
               
               
                 LVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 388 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     YMMEGPTLRHWLATRAGR     GG TKNQVSLTC 
                   
               
               
                 LVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 389 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     THIEGPTLRIWLASRAKA     GG TKNQVSLTCLV 
                   
               
               
                 KGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 390 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     SAIEGPTLRHWLAWRAML     GG TKNQVSLTCL 
                   
               
               
                 VKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 391 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     WMMEGPTLRHWLAARARY     GG TKNQVSLT 
                   
               
               
                 CLVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 392 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVL 
                   
               
               
                 HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT 
                   
               
               
                 LPPSRDEL GG     AWMEGPTLRHWLAARAAY     GG TKNQVSLTC 
                   
               
               
                 LVKGFY 
                   
               
               
                 PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 
                   
               
               
                 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 
                   
               
               
                   
               
               
                 Fc-Loop E169/N170 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 393 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     QGCSSGGPTLREWQQCRRMQHS     GG NNYKTTPPV 
                   
               
               
                 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
                   
               
               
                 QKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 394 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     QGCSSGGPTLREWQQCVRMQHS     GG NNYKTTPPV 
                   
               
               
                 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT 
                   
               
               
                 QKSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 395 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     QGCSSGGPTLREWQQCRRAQHS     GG NNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 396 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     QGCSSGGPTLREWQQCVRAQHS     GG NNYKTTPPVL 
                   
               
               
                 DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 397 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     LDMEGPTLRHWLAARANG     GG NNYKTTPPVLDSDG 
                   
               
               
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL 
                   
               
               
                 SPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 398 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     YMMEGPTLRHWLATRAGR     GG NNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 399 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     THIEGPTLRIWLASRAKA     GG NNYKTTPPVLDSDGS 
                   
               
               
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS 
                   
               
               
                 PGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 400 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     SAIEGPTLRHWLAWRAML     GG NNYKTTPPVLDSDG 
                   
               
               
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL 
                   
               
               
                 SPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 401 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     WMMEGPTLRHWLAARARY     GG NNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 402 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPE GG     AWMEGPTLRHWLAARAAY     GG NNYKTTPPVLDSD 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 Fc-Loop S181/D182 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 403 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     QGCSSGGPTLREWQQCRRMQHS     
                   
               
               
                   GG DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 404 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     QGCSSGGPTLREWQQCVRMQHS     
                   
               
               
                   GG DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 405 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     QGCSSGGPTLREWQQCRRAQHS     
                   
               
               
                   GG DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 406 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     QGCSSGGPTLREWQQCVRAQHS     
                   
               
               
                   GG DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 407 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     LDMEGPTLRHWLAARANG     GG DG 
                   
               
               
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL 
                   
               
               
                 SPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 408 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     YMMEGPTLRHWLATRAGR     GG D 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 409 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     THIEGPTLRIWLASRAKA     GG DGS 
                   
               
               
                 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS 
                   
               
               
                 PGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 410 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     SAIEGPTLRHWLAWRAML     GG DG 
                   
               
               
                 SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL 
                   
               
               
                 SPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 411 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     WMMEGPTLRHWLAARARY     GG D 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 412 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDS GG     AWMEGPTLRHWLAARAAY     GG D 
                   
               
               
                 GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 Fc-Loop G201/N202 
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 413 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     QGCS     
                   
               
               
                     SGGPTLREWQQCRRMQHS     GG NVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 414 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     QGCS     
                   
               
               
                     SGGPTLREWQQCVRMQHS     GG NVFSCSVMHEALHNHYTQ 
                   
               
               
                 KSLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 415 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     QGCS     
                   
               
               
                     SGGPTLREWQQCRRAQHS     GG NVFSCSVMHEALHNHYTQK 
                   
               
               
                 SLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 416 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     QGCS     
                   
               
               
                     SGGPTLREWQQCVRAQHS     GG NVFSCSVMHEALHNHYTQK 
                   
               
               
                 SLSLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 417 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     LDM     
                   
               
               
                     EGPTLRHWLAARANG     GG NVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 418 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     YMM     
                   
               
               
                     EGPTLRHWLATRAGR     GG NVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 419 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     THIE     
                   
               
               
                     GPTLRIWLASRAKA     GG NVFSCSVMHEALHNHYTQKSLSLS 
                   
               
               
                 PGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 420 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     SAIE     
                   
               
               
                     GPTLRHWLAWRAML     GG NVFSCSVMHEALHNHYTQKSLSL 
                   
               
               
                 SPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 421 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     WM     
                   
               
               
                     MEGPTLRHWLAARARY     GG NVFSCSVMHEALHNHYTQKSL 
                   
               
               
                 SLSPGK 
                   
               
               
                   
               
               
                 MDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 
                 422 
               
               
                 VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV 
                   
               
               
                 VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP 
                   
               
               
                 REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 
                   
               
               
                 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG GG     AWM     
                   
               
               
                     EGPTLRHWLAARAAY     GG NVFSCSVMHEALHNHYTQKSLS 
                   
               
               
                 LSPGK 
               
               
                   
               
            
           
         
       
     
     There is a high degree of homology in the secondary and tertiary structural conformations within the Fc domains of different IgG subtypes and between species. The x-ray crystal structure coordinates for these structures can be found in the RCSB Protein Data Bank (http://www.rcsb.org/pdb/). 
     In the human IgG1 Fc sequence (SEQ ID NO: 3) used for peptibody fusions, predicted Fc-Loop regions are found in SEQ ID NOS: 428, 429, 431, 432, 434, 435, 437, 439, 441, and 443. Any, or all of these sites may be suitable for full or partial replacement by or insertion of peptide sequences and are considered part of this invention. Specifically preferred internal sites are SEQ ID NOS: 430, 433, 436, 438, 440, 442, and 444. One preferred site is SEQ ID NO: 438, between Leu 139  and Thr 140  in the DELTK (SEQ ID NO: 437) loop. Potential loop sites in other Ig subtypes are understood in the art. 
     Exemplary amino acid sequences of human Fc regions from IgA, IgM and IgG subtypes are SEQ ID NOS: 344 to 351). A consensus sequence is provided in SEQ ID NO: 352. 
     Preferred internal sites for peptide addition that correspond to those of the Fc sequence in SEQ ID NO: 3 are set out as follows:
         SEQ ID NO: 428 within SEQ ID NOS: 347 to 352;   SEQ ID NO: 429 within SEQ ID NOS: 347 to 350 and 352;   SEQ ID NO: 445 within SEQ ID NO: 351;   SEQ ID NO: 431 within SEQ ID NO: 347 to 352;   SEQ ID NO: 432 within SEQ ID NOS: 347 and 348;   SEQ ID NO: 446 within SEQ ID NOS: 349 to 352;   SEQ ID NO: 434 within SEQ ID NOS: 347 to 349, 351, and 352;   SEQ ID NO: 447 within SEQ ID NO: 350;   SEQ ID NO: 435 within SEQ ID NOS: 347, 348, and 352;   SEQ ID NO: 448 within SEQ ID NO: 349;   SEQ ID NO: 449 within SEQ ID NO: 350;   SEQ ID NO: 450 within SEQ ID NO: 351;   SEQ ID NO: 437 within SEQ ID NO: 347;   SEQ ID NO: 451 within SEQ ID NOS: 348 to 352;   SEQ ID NO: 439 within SEQ ID NOS: 347, 348, 350, 351, and 352;   SEQ ID NO: 452 within SEQ ID NO: 349;   SEQ ID NO: 441 within SEQ ID NOS: 347, 348, and 351;   SEQ ID NO: 453 within SEQ ID NOS: 349, 350 and 352;   SEQ ID NO: 443 within SEQ ID NOS: 347, 348, 350, and 352;   SEQ ID NO: 426 within SEQ ID NO: 349; and   SEQ ID NO: 427 within SEQ ID NO: 351.       

     Sequence alignments suggest two more potential insertion sites at Q 167 /P 168  and/or G 183 /S 184  (using the numbering of SEQ ID NO: 3). These positions correspond to gaps in the IgG sequences where there are two and three residue insertions found in the aligned IgA and IgM sequences. Some preferred insertion sites are set out as follows: 
     H 53 /E 54  in SEQ ID NOS: 347 and 348; 
     H 100 /E 101  in SEQ ID NO: 349; 
     H 49 /E 50  in SEQ ID NO: 350; 
     Q 50 /E 51  in SEQ ID NO: 351; 
     H 112 /E 113  in SEQ ID NO: 352; 
     Y 81 /N 82  in SEQ ID NOS: 347 and 348; 
     F 128 /N 129  in SEQ ID NO: 349; 
     F 77 /N 78  in SEQ ID NO: 350; 
     F 78 /N 79  in SEQ ID NO: 351; 
     F 140 /N 141  in SEQ ID NO: 352; 
     N 110 /K 111  in SEQ ID NOS: 347 and 348; 
     N 157 /K 158  in SEQ ID NO: 349; 
     N 106 /K 107  in SEQ ID NO: 350; 
     N 107 /K 108  in SEQ ID NO: 351; 
     N 169 /K 170  in SEQ ID NO: 352; 
     L 143 /T 144  in SEQ ID NOS: 347 and 348; 
     M 190 /T 191  in SEQ ID NO: 349; 
     M 139 /T 140  in SEQ ID NO: 350; 
     M 140 /T 141  in SEQ ID NO: 351; 
     M 204 /T 205  in SEQ ID NO: 352; 
     Q 171 P 172  in SEQ ID NOS: 347 and 348; 
     Q 218 /P 219  in SEQ ID NO: 349; 
     Q 167 /P 168  in SEQ ID NO: 350; 
     Q 168 /P 169  in SEQ ID NO: 351; 
     Q 232 /P 233  in SEQ ID NO: 352; 
     E 173 N 174  in SEQ ID NOS: 347 and 348; 
     E 220 /N 221  in SEQ ID NO: 349; 
     E 169 /N 170  in SEQ ID NO: 350; 
     E 170 /N 171  in SEQ ID NO: 351; 
     E 234 /N 235  in SEQ ID NO: 352; 
     S 186 /D 187  in SEQ ID NOS: 347 and 348; 
     S 232 /D 233  in SEQ ID NO: 349; 
     S 181 /D 182  in SEQ ID NO: 350; 
     S 182 /D 183  in SEQ ID NO: 351; 
     S 246 /D 247  in SEQ ID NO: 352; 
     G 188 /S 189  in SEQ ID NOS: 347 and 348; 
     G 234 /S 235  in SEQ ID NO: 349; 
     G 183 /S 184  in SEQ ID NO: 350; 
     G 184 /S 185  in SEQ ID NO: 351; 
     G 248 /S 249  in SEQ ID NO: 352; 
     G 205 /N 206  in SEQ ID NOS: 347 and 348; 
     G 252 /N 253  in SEQ ID NO: 349; 
     G 201 /N 202  in SEQ ID NO: 350; 
     G 202 /N 203  in SEQ ID NO: 351; and 
     G 268 /N 269  in SEQ ID NO: 352. 
     An alignment of human IgG1 Fc domain (SEQ ID NO: 423) used for the peptibody platform with rat IgG2A from crystal structure of FcRn/Fc complex (SEQ ID NO: 424) provided a consensus sequence (SEQ ID NO: 425). 
     Table 11 sets out amino acid sequences of some of the Fc sequences for use in the present invention and some of the internal sites for peptide addition/insertion. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Amino Acid Sequences of IgG sequences and Insertion Sites 
               
            
           
           
               
               
            
               
                 AMINO ACID SEQUENCE 
                 SEQ ID NO: 
               
               
                   
               
               
                 Glu Gly Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 
                 423 
               
               
                 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 
                   
               
               
                 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 
                   
               
               
                 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 
                   
               
               
                 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 
                   
               
               
                 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 
                   
               
               
                 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 
                   
               
               
                 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 
                   
               
               
                 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 
                   
               
               
                 Leu Thr Lys Asn Gln Val Ser Ser Arg Trp Gln Gln Gly Asn Val Phe 
                   
               
               
                 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 
                   
               
               
                 Ser Leu Ser Leu Ser Pro Gly Lys 
                   
               
               
                   
               
               
                 Ser Val Phe Ile Phe Pro Pro Lys Thr Lys Asp Val Leu Thr Ile Thr 
                 424 
               
               
                 Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Gln Asn Asp 
                   
               
               
                 Pro Glu Val Arg Phe Ser Trp Phe Ile Asp Asp Val Glu Val His Thr 
                   
               
               
                 Ala Gln Thr His Ala Pro Glu Lys Gln Ser Asn Ser Thr Leu Arg Ser 
                   
               
               
                 Val Ser Glu Leu Pro Ile Val His Arg Asp Trp Leu Asn Gly Lys Thr 
                   
               
               
                 Phe Lys Cys Lys Val Asn Ser Gly Ala Phe Pro Ala Pro Ile Glu Lys 
                   
               
               
                 Ser Ile Ser Lys Pro Glu Gly Thr Pro Arg Gly Pro Gln Val Tyr Thr 
                   
               
               
                 Met Ala Pro Pro Lys Glu Glu Met Thr Gln Ser Gln Val Ser Ile Thr 
                   
               
               
                 Cys Met Val Lys Gly Phe Tyr Pro Pro Asp Ile Tyr Thr Glu Trp Lys 
                   
               
               
                 Met Asn Gly Gln Pro Gln Glu Asn Tyr Lys Asn Thr Pro Pro Thr 
                   
               
               
                 Met Asp Thr Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Asn Val 
                   
               
               
                 Lys Lys Glu Thr Trp Gln Gln Gly Asn Thr Phe Thr Cys Ser Val Leu 
                   
               
               
                 His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His 
                   
               
               
                   
               
               
                 Ser Val Phe Ile Phe Pro Pro Lys Xaa Lys Asp Xaa Leu Xaa Ile Ser 
                 425 
               
               
                 Xaa Thr Pro Xaa Val Thr Cys Val Val Val Asp Ile Ser Xaa Xaa Asp 
                   
               
               
                 Pro Glu Val Lys Phe Xaa Trp Phe Ile Asp Xaa Val Glu Val His Xaa 
                   
               
               
                 Ala Xaa Thr Xaa Xaa Xaa Glu Xaa Gln Xaa Asn Ser Thr Xaa Arg 
                   
               
               
                 Xaa Val Ser Xaa Leu Ile Leu His Xaa Asp Trp Leu Asn Gly Lys 
                   
               
               
                 Xaa Phe Lys Cys Lys Val Xaa Xaa Xaa Ala Xaa Pro Ala Pro Ile Glu 
                   
               
               
                 Lys Ser Ile Ser Lys Xaa Xaa Gly Xaa Pro Arg Xaa Pro Gln Val Tyr 
                   
               
               
                 Thr Leu Xaa Pro Xaa Lys Asp Glu Leu Thr Xaa Xaa Gln Val Ser Ile 
                   
               
               
                 Thr Cys Leu Val Lys Gly Phe Tyr Pro Xaa Asp Ile Xaa Xaa Glu Trp 
                   
               
               
                 Xaa Xaa Asn Gly Gln Pro Xaa Xaa Asn Tyr Lys Xaa Thr Pro Pro 
                   
               
               
                 Xaa Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Xaa 
                   
               
               
                 Val Xaa Lys Xaa Xaa Trp Gln Gln Gly Asn Xaa Phe Ser Cys Ser 
                   
               
               
                 Val Leu His Glu Ala Leu His Asn His His Thr Xaa Lys Ser Leu Ser 
                   
               
               
                 Xaa 
                   
               
               
                   
               
               
                 Lys Ser Arg Trp Gln Gln Gly Asn Ile 
                 426 
               
               
                   
               
               
                 Lys Ser Arg Trp Gln Glu Gly Asn Val 
                 427 
               
               
                   
               
               
                 Pro Pro 
                 428 
               
               
                   
               
               
                 Asp Val Ser His Glu Asp Pro Glu 
                 429 
               
               
                   
               
               
                 Ser His Glu 
                 430 
               
               
                   
               
               
                 Val His Asn Ala 
                 431 
               
               
                   
               
               
                 Glu Glu Gln Tyr Asn Ser Thr 
                 432 
               
               
                   
               
               
                 Tyr Asn Ser 
                 433 
               
               
                   
               
               
                 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 
                 434 
               
               
                   
               
               
                 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 
                 435 
               
               
                   
               
               
                 Asn Lys Ala 
                 436 
               
               
                   
               
               
                 Asp Glu Leu Thr Lys 
                 437 
               
               
                   
               
               
                 Leu Thr Lys 
                 438 
               
               
                   
               
               
                 Asn Gly Gln Pro Glu Asn Asn 
                 439 
               
               
                   
               
               
                 Glu Asn Asn 
                 440 
               
               
                   
               
               
                 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 
                 441 
               
               
                   
               
               
                 Val Leu Asp Ser Asp 
                 442 
               
               
                   
               
               
                 Lys Ser Arg Trp Gln Gln Gly Asn Val 
                 443 
               
               
                   
               
               
                 Gln Gly Asn 
                 444 
               
               
                   
               
               
                 Asp Val Ser Gln Glu Asp Pro Glu 
                 445 
               
               
                   
               
               
                 Glu Glu Gln Phe Asn Ser Thr 
                 446 
               
               
                   
               
               
                 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu 
                 447 
               
               
                   
               
               
                 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 
                 448 
               
               
                 Gly Gln Pro Arg Glu Pro 
                   
               
               
                   
               
               
                 Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 
                 449 
               
               
                 Gly Gln Pro Arg Glu Pro 
                   
               
               
                   
               
               
                 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Ala Lys Gly Gln Pro Arg 
                 450 
               
               
                 Glu Pro 
                   
               
               
                   
               
               
                 Glu Glu Met Thr Lys 
                 451 
               
               
                   
               
               
                 Ser Gly Gln Pro Glu Asn Asn 
                 452 
               
               
                   
               
               
                 Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 
                 453 
               
               
                   
               
            
           
         
       
     
     Table 12 sets out still other TPO-mimetic peptides having c-mpl receptor binding activity. These peptides are contemplated for use alone or as TPO-mimetic fusion proteins, wherein the TPO-mimetic peptide is fused to either an N-terminus of an Fc region or within an Fc-Loop, a modified Fc molecule. Fc-Loops are described herein and in U.S. Patent Application Publication No. US2006/0140934 incorporated herein by reference in its entirety. 
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                   
                 AMINO ACID SEQUENCE 
                 SEQ ID NO: 
               
               
                   
                   
               
               
                   
                 cssggptlrewqqcsraq 
                 454 
               
               
                   
                   
               
               
                   
                 cssggptlrewqqcqraq 
                 455 
               
               
                   
                   
               
               
                   
                 cssggptlrewqqcgraq 
                 456 
               
               
                   
                   
               
            
           
         
       
     
     Table 13 reports the effective concentration (Pb EC50 in ng/ml) at which some of the TPO-mimetic fusion proteins of the invention demonstrate peptibody activity based on an in vitro activity assay using murine 32D cells expressing human MPL in a reporter assay format as described herein above. This TPO in vitro bioassay is a mitogenic assay utilizing an IL-3 dependent clone of murine 32D cells that have been transfected with human mpl receptor. This assay is described in greater detail in WO 95/26746. An Fc molecule is fused at either the N-terminus or the C-terminus of the peptide. Some TPO-mimetics in this table were inserted into an Fc-Loop (see, e.g., Fc-Loop-(SEQ ID NO: X)), comprise an Fc molecule connected at the N-terminus of two different peptide sequences connected in tandem (see, e.g., Fc-(SEQ ID NO: 91)-(SEQ ID NO: 81), or comprise an Fc molecule connected at the N-terminus of two tandem copies of the same peptide (see, e.g., Fc-2X-(SEQ ID NO: 81)). 
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Activity of Some TPO-Mimetic Peptides 
               
            
           
           
               
               
               
            
               
                   
                   
                 Pb EC50 
               
               
                 TPO-Mimetic 
                 Peptide Sequences Used in the TPO-Mimetic 
                 (ng/ml) 
               
               
                   
               
               
                 Fc-Loop-(SEQ ID NO: 454) 
                 cssggptlrewqqcsraq (SEQ ID NO: 454) 
                 0.28 
               
               
                   
               
               
                 Fc-Loop-(SEQ ID NO: 455) 
                 cssggptlrewqqcqraq (SEQ ID NO: 455) 
                 0.27 
               
               
                   
               
               
                 Fc-Loop-(SEQ ID NO: 456) 
                 cssggptlrewqqcgraq (SEQ ID NO: 456) 
                 2.31 
               
               
                   
               
               
                 SEQ ID NO: 9 
                 cssggptlrewqqcrrmq (SEQ ID NO: 9) 
                 0.44 
               
               
                   
               
               
                 SEQ ID NO: 11 
                 cswggptlknwlqcvrak (SEQ ID NO: 11) 
                 4.01 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 91)- 
                 MWMEGPTLRHWLEARARY (SEQ ID NO: 91)- 
                 0.65 
               
               
                 (SEQ ID NO: 81) 
                 LDMEGPTLRHWLAARANG (SEQ ID NO: 81) 
                   
               
               
                   
               
               
                 SEQ ID NO: 103 
                 YMMEGPTLRHWLATRAGR (SEQ ID NO: 103) 
                 0.79 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 95) 
                 THIEGPTLRIWLASRAKA (SEQ ID NO: 95) 
                 1.04 
               
               
                   
               
               
                 SEQ ID NO: 117 
                 SAIEGPTLRHWLAWRAML (SEQ ID NO: 117) 
                 1.09 
               
               
                   
               
               
                 SEQ ID NO: 115 
                 WMMEGPTLRHWLAARARY (SEQ ID NO: 115) 
                 1.43 
               
               
                   
               
               
                 SEQ ID NO: 115 
                 WMMEGPTLRHWLAARARY (SEQ ID NO: 115) 
                 1.81 
               
               
                   
               
               
                 SEQ ID NO: 149 
                 AWMEGPTLRHWLAARAAY (SEQ ID NO: 149) 
                 1.84 
               
               
                   
               
               
                 SEQ ID NO: 171 
                 WPMEGPTLRHWLAARAAR (SEQ ID NO: 171) 
                 1.56 
               
               
                   
               
               
                 SEQ ID NO: 241 
                 ICTEGCTLRLWLAERSRV (SEQ ID NO: 241) 
                 1.83 
               
               
                   
               
               
                 SEQ ID NO: 139 
                 DAIEGPTLRLWLEARRKQ (SEQ ID NO: 139) 
                 1.89 
               
               
                   
               
               
                 SEQ ID NO: 128 
                 YYLEGPTLRHWLAARAYL (SEQ ID NO: 128) 
                 1.82 
               
               
                   
               
               
                 Fc-2x-(SEQ ID NO: 81) 
                 LDMEGPTLRHWLAARANG (SEQ ID NO: 81) 
                 2.56 
               
               
                   
               
               
                 SEQ ID NO: 123 
                 WVMEGPTLRHWLAARASL (SEQ ID NO: 123) 
                 2.08 
               
               
                   
               
               
                 SEQ ID NO: 225 
                 LTMEGPTLRHWLAARATR (SEQ ID NO: 225) 
                 3.10 
               
               
                   
               
               
                 SEQ ID NO: 163 
                 HPIEGPTLRLWLAARARA (SEQ ID NO: 163) 
                 2.80 
               
               
                   
               
            
           
         
       
     
     Table 14 reports the in vitro and in vivo activity of some TPO-mimetic compounds of the invention. The constructs set out in Table 14 were assessed for in vitro activity using murine 32D cells expressing human MPL in a reporter assay format as described herein above. This TPO in vitro bioassay is a mitogenic assay utilizing an IL-3 dependent clone of murine 32D cells that have been transfected with human mpl receptor. This assay is described in greater detail in WO 95/26746. The activity of the constructs was determined to be comparable when considering reasonable assay variance. 
     The constructs were also subjected to an in vivo activity study by by injecting mice with 3, 5, 50, 100, or 200 μg/kg of the noted construct and then observing the change in platelet number over a 17-day period. An in vivo activity of “++++” indicates high activity, while an in vivo activity of “+” denotes low activity. Using this in vivo assay system, all eight TPO-mimetic compounds shown in Table 14 appeared to be indistinguishable. 
     Fc-(SEQ ID NO: 9) (M19A) indicates that the M at amino acid position 19 in SEQ ID NO: 9 is replaced with an A. Fc-(SEQ ID NO: 9) (R17V) indicates that the R at amino acid position 17 is replaced with a V. Accordingly, Fc-(SEQ ID NO: 9) (R17V/M19A) denotes that there are two substitutions in SEQ ID NO: 9; the R at position 17 is replaced with a V and the M at position 19 is replaced with an A. Fc-Loop (Asym) (SEQ ID NO: 9) in Table 14 denotes that SEQ ID NO: 9 is inserted into the loop region of the Fc at position L139/T140 using four glycine spacers at the N-terminus and two glycine spacers at the C-terminus. Fc-Loop (Sym) (SEQ ID NO: 9) in Table 14 denotes that SEQ ID NO: 9 is inserted into the loop region of the Fc at position L139/T140 using two glycine spacers at both the N- and C-termini. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 TPO-Mimetic Fusion Protein Activity In Vitro and 
               
               
                 In Vivo 
               
            
           
           
               
               
               
               
            
               
                   
                 In vitro 
                 In vitro 
                   
               
               
                   
                 EC 50   
                 EC 50   
                 In 
               
               
                 Construct 
                 (pM) 
                 (95% CI) 
                 vivo 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Fc-(SEQ ID NO: 9) 
                 14.6 
                  8.9-24.0 
                 ++++ 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9) 
                 10.4 
                  8.0-13.6 
                 ++++ 
               
               
                 (M19A) 
                   
                   
                   
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9) 
                 25.1 
                 14.0-45.2 
                 ++++ 
               
               
                 (R17V) 
                   
                   
                   
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9) 
                 5.5 
                 3.6-8.4 
                 ++++ 
               
               
                 (R17V/M19A) 
                   
                   
                   
               
               
                   
               
               
                 Fc-Loop(Asym) 
                 12.7 
                  9.1-17.7 
                 ++++ 
               
               
                 (SEQ ID NO: 9) 
                   
                   
                   
               
               
                   
               
               
                 Fc-Loop(Sym) 
                 13.7 
                 10.1-18.5 
                 ++++ 
               
               
                 (SEQ ID NO: 9) 
                   
                   
                   
               
               
                   
               
               
                 Fc-Loop(Asym- 
                 5.7 
                 4.2-7.7 
                 ++++ 
               
               
                 R17V) 
                   
                   
                   
               
               
                   
               
               
                 Fc-Loop(Sym-R17V) 
                 9.9 
                  6.9-14.0 
                 ++++ 
               
               
                   
               
            
           
         
       
     
     Table 15 further reports the in vitro activity of some TPO-mimetic compounds of the invention. Fc-Loop (Asym) (SEQ ID NO: 9) in Table 15 denotes that SEQ ID NO: 9 was inserted into the loop region of the Fc at position L139/T140 using four glycine spacers at the N-terminus. Fc-Loop (Asym) (SEQ ID NO: 243) in Table 15 denotes that SEQ ID NO: 243 was inserted into the loop region of the Fc at position L139/T140 using four glycine spacers at the N-terminus and two glycine spacers at the C-terminus. The appended “-C” at the end of the construct name in Table 15 denotes that the purified cyclic form (the cysteines in SEQ ID NO: 9 form an intrachain disulfide bond). The appended “XL” at the end of the construct name in Table 15 denotes that the purified cross-linked form (the cysteines in SEQ ID NO: 9 form an interchain disulfide bond). The appended “-Mixed” at the end of the construct name in Table 15 denotes that there is a mixture of the cyclic and cross-linked forms. Fc-Loop (Sym) (SEQ ID NO: 9 or 243 or 244) in Table 15 denotes that SEQ ID NO: 9, 243, or 244 was inserted into the loop region of the Fc at position L139/T140 using two glycine spacers at the N-terminus and two glycine spacers at the C-terminus. 
     TPO-dependent proliferation of 32Dcl23/Mpl cells and differentiation of primary human CD34+ progenitors were used to measure the in vitro potency of TPO-mimetic compounds. In the latter assay, the percentage of cells expressing the CD61 surface marker was chosen as the key parameter to measure megakaryocytic differentiation. For both assays, measurements were expressed as POC relative to the peak value (cell proliferation or differentiation) measured for a well-characterized positive control, Fc-2X-(SEQ ID NO: 337). At least three determinations for each molecule were performed in the 32Dcl23/Mpl proliferation assay, and at least three determinations on two separate donors were performed for each molecule in the CD34+ differentiation assay. 
     CD34+ Liquid Culture Assay 
     StemPro-34 Serum-Free Media supplemented with 100 ng/mL recombinant human Stem Cell Factor (rhSCF, Amgen, Inc.) was used as the growth medium. CD34+ cells were obtained from normal, G-CSF mobilized donors, provided by All Cells, Inc. All experiments were performed in 96-well plates using 5-20×10 3  CD34+ cells/well. 
     Two solutions of each TPO-mimetic compound (or peptibody) were prepared at a concentration of 2 μg/mL and 0.6 μg/mL, respectively. From each of these solutions, 1:10 serial dilutions were made into a 96-well tissue culture plate containing a volume of 180 μl/well (20 μl of sample into 200 μl final) of growth medium to obtain a concentration curve of 200, 60, 20, 6, 2, 0.6, and 0.2 ng/mL. Next, 100 μl from each well was transferred into another 96-well plate and 100 μl (5-20,000 CD34+ cells) of cells resuspended in SP34 media (supplemented with 100 ng/mL SCF) were added. The final concentration of the test molecules was 100, 30, 10, 3, 1.0, 0.3 and 0.1 ng/mL. 
     The tissue culture plate was cultured in 5% CO 2  in 100% humidified air at 37° C. for 7 days. Next, the cells were stained in the 96-well plate (per BD Biosciences protocol) with 2 μl (0.1 μg)/well FITC-CD15 or 0.5 μl (0.1 μg)/well APC-CD61 along with the appropriate isotype controls. Just before analysis, 1 μl (0.05 μg) of propidium iodide was added to each well, to stain dead cells. Live cells were identified by appropriate FSC/SSC gating and propidium iodide exclusion. Data were acquired on a FACSCalibur flow cytometer (Beckton Dickinson). 
     32Dcl23/Mpl Cell Proliferation Assay 
     32Dcl23/Mpl cells were cultured at 37° C. in 5% CO 2 , in MEM containing 10% FBS, PGS (100 units/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, 292 μg/mL L-glutamine), and 5 ng/mL murine IL-3. Cell viability greater than 80% was confirmed by the Beckman Coulter Vi-Cell XR instrument (Beckman Coulter Inc., Fullerton, Calif.). 
     For each experiment, 32Dcl23/Mpl cells were washed twice in growth medium, and the cells pellet was resuspended in 1×10 6  cells per mL. Cells were plated in 96-well Costar round bottom plates at a cell density of 60,000 cells per well (60 μL per well). 
     Test molecules were serially diluted 1:3 in growth medium, to obtain a dose range from 40 ng/mL to 0.01 ng/mL. Sixty microliters of the diluted peptibody were added to the cell plate containing 60 μL of 60,000 cells per well. The treated cells were incubated for 24 hours in 5% CO 2  humidifier incubator. Cellular ATP was then measured as surrogate marker for cell proliferation with the Promega CellTiter-Glo reagent (Cat #G7572), according to the manufacturer&#39;s specifications. Luminescence signal was measured with Molecular Devices LMax 384  instrument (Molecular Devices Inc., Sunnyvale, Calif.). 
     Data Analysis 
     Percentages of cells expressing CD61 were calculated with the FCS Express v3.0 software, gating for live cells based on forward scatter/side scatter and propidium iodide exclusion. Dose responses were plotted with Spotfire DecisionSite v8.2.1. 
     Statistical Analysis 
     Data were plotted as mean ±SD. For relevant candidates, EC 50 s were calculated with the GraphPad Prism v4.01 software package using the following sigmoidal dose-response equation:
 
 Y =min+(max−min)/(1+10^((Log EC50− X )))
 
     where X is the logarithm of concentration, and Y the response. 
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 TPO-Mimetic Fusion Protein Activity 
               
            
           
           
               
               
               
            
               
                   
                 EC 50  on 
                 EC 50   
               
               
                   
                 32Dc123/ 
                 on 
               
               
                   
                 Mpl 
                 CD34 + 
               
               
                 Construct Sequence 
                 (pM) 
                 (pM) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Fc-Loop(Asym)(SEQ ID NO: 9) 
                 13 
                 0.1 
               
               
                   
               
               
                 Fc-Loop(Sym)(SEQ ID NO: 9) 
                 15 
                 2 
               
               
                   
               
               
                 Fc-Loop(Asym)(SEQ ID NO: 243) 
                 6 
                 5 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9)(M19A) 
                 10 
                 6 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9)(R17V/M19A)-C 
                 5 
                 6 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9)(R17V/M19A)-XL 
                 9 
                 5 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9)(R17V)-XL 
                 15 
                 5 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9)(R17V)-Mixed 
                 11 
                 0.01 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9)(R17V) 
                 25 
                 3 
               
               
                   
               
               
                 Fc-(SEQ ID NO: 9) 
                 15 
                 5 
               
               
                   
               
               
                 Fc-Loop (Sym)(SEQ ID NO: 243) 
                 10 
                 5 
               
               
                   
               
               
                 Fc-Loop (Sym)(SEQ ID NO: 244) 
                 12 
                 0.6 
               
               
                   
               
               
                 Fc-2X-(SEQ ID NO: 337) 
                 15 
                 4.5 
               
               
                 (positive control) 
               
               
                   
               
            
           
         
       
     
     Some of the TPO-mimetics set out above also have been tested directly for biological activity in vivo in mice (see FIG. 4). Platelet values in FIG. 4 were expressed as the area under the curve (AUC), or the integral of the curve. GraphPad Prism 4.1 statistical software (GraphPad Software, Inc., San Diego, Calif.) was used to calculate platelet values. This program uses the trapezoidal rule with the following equation: ResultY(i)=ResultY(i−1)+0.5 [Y(i−1)+Y(i)] [X(i)−X(i−1)]. The positive control (Fc-2X-(SEQ ID NO: 337)) was the same positive control for experiments shown in Table 15. Some TPO-mimetic peptides and TPO-mimetic fusion proteins are more effective than others in stimulating platelet production in mice. 
     The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto, without departing from the spirit and scope of the invention as set forth herein.