CONJUGATES TARGETED TO TARGET RECEPTORS

Abstract: A conjugate for intracellular delivery of a chemical agent into a target receptor such as an interleukin-2-receptor-bearing cell, <i>e.g.</i>, an activated T cell and cancer cell, includes a chemical agent, at least one copy of target-receptor binding and endocytosis-inducing ligand coupled to a water soluble polymer. The ligand binds to a target receptor such as an IL-2 receptor on the target receptor bearing cell and elicits endocytosis of the conjugate. The conjugate also optionally includes a biodegradable spacer for coupling the chemical agent and the ligand to the polymer. Chemical agents can include cytotoxins, transforming nucleic acids, gene regulators, labels, antigens, drugs, and the like. A preferred water soluble polymer is polyalkylene oxide, such as polyethylene glycol and polyethylene oxide, and activated derivatives thereof. Methods of using these compositions for delivering a chemical agent <i>in vivo</i>or <i>in vitro</i> are also disclosed. Methods of detecting a disease, such as cancer, T-cell lymphocytic leukemia, T-cell acute lymphoblastic leukemia, peripheral T-cell lymphoma, Hodgkin's disease, and non-Hodgkin's lymphoma, associated with elevated levels of soluble target receptor and/or IL-2 receptor also are disclosed.

Description: CONJUGATESTARGETED TO TARGETRECEPTORS CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. Patent Application Serial No. 09/128,572, filed August 4, 1998; which is a continuation-in-part of U.S. Application Serial No. 08/914,042, filed August 5, 1997; and a continuation in part of PCT US99/17648, filed August 4, 1999, the disclosures of each of which are hereby incorporated herein in their entirety. BACKGROUND OF THE INVENTION Toxins that target cell surface receptors or antigens on tumor cells have attracted considerable attention for treatment of cancer. See, e.g., Pastan and FitzGerald, Recombinant Toxins for Cancer Treatment, 254 Science 1173 (1991); Anderson et al, U.S. Patent Nos. 5,169,933 and 5,135,736; Thorpe et al, U.S. Patent No. 5,165,923; Jansen et ah, U.S. Patent No. 4,906,469; Frankel, U.S. Patent No. 4,962,188; Uhr et al., U.S. Patent No. 4,792,447; and Masuho et al., U.S. Patent Nos. 4,450,154 and 4,350,626. These agents include a cell-targeting moiety, such as a growth factor or an antigen-binding protein, linked to a plant or bacterial toxin. They kill cells by mechanisms different from conventional chemotherapy, thus potentially reducing or eliminating cross resistance to conventional chemotherapeutic agents. Copending PCT Patent Application Serial No. PCT/US95/11515 (WO 96/08263) filed September 12, 1995, describes compositions and methods for specific intracellular delivery of a chemical agent into a CR2-receptor-bearing cell, e.g., B lymphocytes. The compositions comprise a CR2-receptor-binding and endocytosis-inducing ligand (CBEL) coupled to the chemical agent. The CBEL binds to the CR2 receptor on the surface of B lymphocytes and elicits endocytosis of the composition such that the composition is transported to lysosomes. In the lysosomes, the chemical agent is preferably separated from the remainder of the composition such that the chemical agent can be transported or diffuse into the cytoplasm or nucleus. Optionally, the composition can include a spacer, which can be either biodegradable (in the lysosome) or non-biodegradable, for coupling the CBEL to the chemical agent. Chemical agents can include cytotoxins, transforming nucleic acids, gene regulators, labels, antigens, drugs, and the like. The composition can further comprise a carrier such as another water soluble polymer, liposome, or particulate. Copending PCT Patent Applications, Serial No. PCT/US97/03832, filed March 12, 1997, and Serial No. PCT/US98/09057, filed May 4, 1997, describe compositions and methods for specific intracellular delivery of a chemical agent into T lymphocytes. The compositions are represented by the formula [L-S] a -C-[S-A] b wherein L is a ligand configured for binding to a receptor on a T lymphocyte and stimulating receptor-mediated endocytosis of the composition, A is a chemical agent, S is a spacer moiety, C is a water soluble polymer having functional groups compatible with forming covalent bonds with the ligand, chemical agent, and spacer, and a and b are positive integers. These compositions are also designed to be transported to lysosomes, where the chemical agent is separated from the remainder of the composition for diffusion or transport to other locations in the cell. Preferred water soluble polymers include poly(ethylene glycol). Preferred chemical agents include cytotoxins, transforming nucleic acids, gene regulators, labels, antigens, drugs, and the like. The composition can further comprise a carrier such as other water soluble polymers, liposomes, or particulates. It would also be advantageous to develop additional compositions that are specifically targeted to other receptors on T lymphocytes or cancer cells. For example, targeting of T lymphocytes would enable therapeutic applications for T-cell-associated diseases and tissue graft rejection. Such T-cell-associated diseases include arthritis, T-cell lymphoma, skin cancers, psoriasis, and diseases resulting from HIV infection. In view of the foregoing, it will be appreciated that compositions for intracellular delivery of chemical agents to cancer cells and/or T cells and methods of use thereof would be significant advancements in the art. The uptake of drugs by cells is modulated by absorptive endocytosis at concentrations of drugs clinically achievable in the vicinity of cancer cells. The effectiveness of this pathway depends first of all on the affinity of the polymer-drug conjugate to the cell surface. Driving forces for interactions of the polymer-anticancer drug conjugates based on biologically inert polymers with the cell surface are interactions of anticancer drugs with the lipid matrix of the plasma membrane. Such interactions could be cancer cell-specific for some particular drug. For example, a differential interaction of doxorubicin with cardiolipin-containing membranes may confer specificity for the drug towards malignant cells (Duarte-Karim et al. (1976) Biochem. Biophys. Res. Commun., 71:658:663.; Tritton et al. (1978), Biochem. Biophys. Res. Commun. 84:802-808). Cardiolipin, present in the mitochondrial membrane in normal cells, occurs in the plasma membrane of malignant cells (Wallach, D.F.H. (1975) Membrane Molecules Biology of Neoplastic Cells, Elsevier, New York, NY). A low content of cholesterol increases interactions of doxorubicin with the lipid matrix (Hernandez et al. (1991) Bioconjug. Chem. 2:398-402; Gaber et al. (1998) Biophys. Chem.70:223-9). On the other hand it was found that most cancer cells have a lower content of cholesterol than normal cells (Wallach, D.F.H. (1975) Membrane Molecules Biology ofNeoplastic Cells, Elsevier, New York, NY). Kopecek et al., U.S. Patent No. 5,258,453 discloses compositions for the treatment of cancer tissues comprising a copolymeric carrier and anticancer drug attached by a degradable side chain. See also Putnam and Kopecek, Adv. Polymer Sci, 122:550123 (1995). HPMA (N-(2-hydroxypropyl)methacrylamide) copolymer-adriamycin conjugates comprising a degradable GFLG spacer have been shown to have anticancer activity. Omelyanenko et ah, Int. J. Cancer, 75:600-608 (1998); and Vasey et al, Clinical Cancer Research, 5:83-94 (1999). It would be advantageous to provide compositions comprising therapeutic agents that could undergo effective and specific delivery via endocytosis into target cells, such as cancer cells. SUMMARY OF THE INVENTION Provided are compositions for intracellular delivery of selected chemical agents to a specific cell type, such as cancer cells or IL-2-receptor-bearing cells. Also provided are methods of making and methods of using compositions for intracellular delivery of selected chemical agents to cells such as cancer cells and/or IL-2-receptor-bearing cells. There are also provided compositions and methods for delivering selected chemical agents to cells such as cancer cells and/or IL-2-receptor-bearing cells using water soluble polymers that are inexpensive, biocompatible, and resistant to development of an antibody response. Compositions and methods of use thereof for intracellular delivery of selected chemical agents to activated T cells also are provided. Further provided are conjugates of a peptide and a pendant PEG and the equivalent thereof and a methods of making thereof. In one embodiment, there is provided a composition for intracellular delivery of a chemical agent into a targeted cell type such as an IL-2-receptor bearing cell, the composition comprising (a) a water-soluble, biocompatible polymer, (b) the chemical agent covalently, releasably coupled to the polymer, and (c) a ligand comprising an targeted receptor-binding peptide covalently coupled to the polymer. In a preferred embodiment of the invention, the composition further comprises a biodegradable peptide. Preferably, the biocompatible polymer is a polyalkylene oxide. Polyalkylene oxides include alpha-substituted polyalkylene oxide derivatives, polyethylene glycol homopolymers and derivatives thereof, polypropylene glycol homopolymers and derivatives thereof, alkyl-capped polyethylene oxides, bis-polyethylene oxides, copolymers of poly(alkylene oxides), branched polyethylene glycols, star polyethylene glycols, pendant polyethylene glycols, block copolymers of poly(alkylene oxides) and the activated derivatives thereof. The polyalkylene oxide can have, for example, a number average molecular weight of about 200 to about 50,000, for example, about 2,000 to about 20,000, or about 5,000. Embodiments of polyalkylene oxides include polyethylene glycol and polyethylene oxide. The target receptor-binding peptide in one embodiment comprises a sequence selected from the group consisting of SEQ ID NO: 1 and biologically functional equivalents thereof. For example, the target-receptor-binding peptide can be selected from the group consisting of SEQ ID NO:l through SEQ ID NO:l 1, and SEQ ID NO:21 through SEQ ID NO:47. For example, the target-receptor-binding peptide may be SEQ ID NO:22, SEQ ID NO:31, or SEQ ID NO:46. Chemical agents includes cytotoxins, transforming nucleic acids, gene regulators, labels, antigens, and drugs. In one embodiment, the target receptor binding peptide comprises a biodegradable portion, such as Gly-Phe-Leu-Gly (SEQ ID NO:21). In another embodiment the Gly-Phe- Leu-Gly sequence further acts as the target receptor binding peptide that binds to some component of the cell, in addition to acting as the biodegradable portion. In one embodiment, the conjugate is provided in a composition further comprising a carrier selected from the group consisting of other water soluble polymers, liposomes, and particulates. Exemplary water soluble polymers include dextran, inulin, poly(L-lysine) with modified epsilon amino groups, poly(L-glutamic acid), and N-substituted methacrylamide-containing polymers. In one embodiment, there is provided a method of delivering a chemical agent in vitro or in vivo into a target cell, such as an IL-2-receptor-bearing cell, or a cancer cell bearing the targeting receptor, in a population of cells, comprising: (a) providing a composition comprising (i) a water-soluble, biocompatible polymer, (ii) the chemical agent covalently, releasably coupled to the polymer, and (iii) a ligand comprising an target-receptor-binding peptide covalently coupled to the polymer; and (b) contacting the population of cells with an effective amount of the composition under conditions wherein the ligand binds to an target receptor on the target- receptor-bearing cell and elicits internalization, for example by endocytosis, of the composition. In one embodiment, a method of delivering a chemical agent into an target-receptor- bearing cell in a warm-blooded animal, is provided that comprises: (a) providing a composition comprising (i) a water-soluble, biocompatible polymer, (ii) the chemical agent covalently, releasably coupled to the polymer, and (iii) a ligand comprising an target-receptor-binding peptide covalently coupled to the polymer; and (b) administering to the warm-blooded animal an effective amount of the composition under conditions wherein the ligand contacts and binds to an target receptor on the target-receptor-bearing cell and elicits internalization, for example, by endocytosis, of the composition. The composition of the present invention can be administered, for example, systemically or locally, depending on the individual's need. Another aspect of the invention relates to a composition comprising peptides disclosed herein including SEQ ID NO:3, SEQ ID NO:7 through SEQ ID NO:l 1 and SEQ ID NO:21 through SEQ ID NO:47, amides and chemically modified equivalents thereof. In another embodiment, there is provided a method for detecting a disease associated with elevated levels of soluble target receptor in circulation comprising the steps of: (a) providing a composition comprising a target receptor binding peptide; (b) mixing the composition with a body fluid to be tested under conditions suitable for binding of the composition to said soluble target receptor in the body fluid to form a complex; and (c) detecting the complex and determining whether the complex is present at elevated levels as compared to normal individuals. Diseases that can be detected according to this method include cancer, T-cell lymphocytic leukemia, T-cell acute lymphoblastic leukemia, peripheral T-cell lymphoma, Hodgkin's disease, and non-Hodgkin's lymphoma. "Body fluid", refers to any secretion or liquid composition carried on a warm blooded animal, such as blood serum, sweat, saliva, tear, urea, etc. Preferably, the body fluid that is tested is serum. Detection of the complex of peptide and soluble target receptor, such as the interleukin-2 receptor, preferably comprises an enzymatic or radioactive-label sorbent assay. Target receptor binding peptides that are suitable for this invention include SEQ ID NO:l through SEQ ID NO:l 1 and SEQ ID NO:21 through SEQ ID NO:47, amides or other chemical modifications that result in biologically functional equivalents thereof. Preferred peptides are SEQ ID NO:22, SEQ ID NO:31 , SEQ ID NO:46, amides and other biologically functional equivalents thereof. As is well known in the art, such an amide is generally formed by reaction of an acid chloride of the peptide with ammonia, resulting in replacement of -OH group of the C-terminal carboxylic acid with -NH 2 . In a further embodiment, there is provided a conjugate comprising (a) a water- soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target- receptor-binding peptide; wherein the ligand comprises the sequence: Xj-X z -leUj-gluj-tøSj-leu^leU s -leUβ-Xj-X^X s -X e ;, wherein: X l5 if present, is thr, ser or gly; X 2 if present, is thr, gly, or ser; X 3 if present, is thr, gly or ala; and X 4 -X 5 -X 6 , if present, is phe-leu-gly or leu-phe-gly; and wherein, in the leu-glu-his-leu-leu-leu sequence, at least one amino acid is substituted as follows: leu, is optionally substituted with met, ile, or val; glu, is optionally substituted with gin, asp, or asn; his 3 is optionally substituted with arg, lys, leu, or ile; leu 4 is optionally substituted with ile, met or val; leug is optionally substituted with ile, val, met or phe; and leu 6 is optionally substituted with ile, val, met or trp. In one embodiment, in the ligand sequence: X 2 is gly; gl^ is substituted with asn; and his 3 is substituted with arg, and optionally X ! and X 4 . 6 are not present. In another embodiment, gluj is substituted with gin or asn. In yet another embodiment, glu 2 is substituted with asn or gin. For example, the ligand may comprise gly-phe-leu-gly. In one embodiment, the polymer is a polyalkylene oxide, such as an alkyl blocked pendant polyethylene glycol, such as mono-methyl or dimethyl blocked pendant polyethylene glycol. In another embodiment, there is provided a conjugate comprising (a) a water- soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target- receptor-binding peptide, wherein said target-receptor binding peptide comprises at least one sequence other than SEQ ID NO 1 , that is capable of binding to the target receptor. The conjugate can include multiple copies of the ligand, for example, 2, 3, 4, 5, 6, 7 or 8 copies of the ligand. In another embodiment, there is provided a conjugate comprising (a) a water- soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target- receptor-binding peptide, wherein the side chains of the target-receptor binding peptide are free of carboxyl groups, such as peptides disclosed herein. One advantage of a target- receptor binding peptide free of carboxyl groups in the side chains is that it is more readily able to be chemically modified, for example at the carboxy terminus, without interfering side reactions of carboxyl groups on the side chains. In a further embodiment, there is provided a conjugate comprising (a) a water- soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target- receptor-binding peptide, wherein said target-receptor binding peptide comprises the sequence Gly-Phe-Leu-Gly or Gly-Leu-Phe-Gly. There is further provided a conjugate comprising: a water-soluble, biocompatible alkyl blocked pendant polyalkylene glycol; at least one molecule of a chemical agent covalently, releasably coupled to the polymer; and at least one copy of a ligand comprising a target-receptor-binding peptide. The alkyl blocked pendant polyalkylene glycol is, for example, an alkyl blocked pendant polyethylene glycol, such as a mono-methyl blocked pendant polyethylene glycol or dimethyl blocked pendant polyethylene glycol. The conjugate can comprise, for example, at least 3 molecules of the chemical agent, or, for example, at least 5 molecules of the chemical agent. Any of a variety of target receptor and target receptor binding peptides can be selected in the art and as disclosed herein. Any of a variety of polymers may be used available in the art and as disclosed herein. Methods of delivering a chemical agent into a target-receptor-bearing cell in a population of cells are provided comprising: contacting the population of cells with an effective amount of a conjugate or peptide as disclosed herein under conditions wherein the ligand binds to a target receptor on the target-receptor-bearing cells and elicits entry of the conjugate or peptide into the cells, for example by endocytosis. Methods of detecting a disease associated with elevated levels of soluble target receptor in circulation also are provided comprising combining a conjugate or peptide as disclosed herein with a body fluid to be tested under conditions suitable for binding of said conjugate or peptide to the soluble target receptor on the target-receptor in said body fluid to form a complex; and detecting said complex and determining whether said complex is present at elevated levels as compared to normal individuals. Also provided are pharmaceutically acceptable compositions comprising the conjugates in a form suitable for administration to a human, for example, orally, by inhalation, or systemically, optionally in combination with a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the in vitro cytotoxic activity of a composition according to the present invention and control compositions against mouse CTLL-2 T cells: (□) PEG-TT23- ADR (SEQ ID NO:22); (Δ) PEG-GFLG-ADR (SEQ ID NO:21); and (o) unconjugated adriamycin. Figure 2 shows the in vitro inhibition of IL-2-induced proliferation of murine splenocytes using (o) PEG-TT23 (SEQ ID NO:22) and (Δ) unconjugated TT23 (SEQ ID NO:22). Figure 3 shows the in vitro cytotoxic dose response curves of a composition according to the present invention (Doxorubicin conjugated 20KD PEG-8PA-TT30 (SEQ ID NO:46) against human cells: Human B-cell lymphoma cell line: Raji (IC50=1.19mcM).; Human T-cell lymphoma cell line: HuT78 (IC50=7.80mcM).; and Human B-cell lymphoma cell line: Daudi (IC50=2.08mcM). Figure 4 shows the in vitro cytotoxic activity of unconjugated Doxorubicin against human cells: Human T-cell lymphoma cell line: HuT78 (IC50=4.36mcM).; Human B-cell lymphoma cell line: Daudi (IC50=0.19mcM).; and Human B-cell lymphoma cell line: Raji (IC50=0.18mcM). Figure 5 is a graph of tumor weight after treatment with doxorubicin conjugates over time in a Daudi human lymphoma tumor xenograft model. Figure 6 is a table showing dosages, tumor weight change, response numbers, and toxic deaths in a Daudi human lymphoma tumor xenograft model in which mice were treated with free doxorubicin or PEG-peptide-doxorubicin conjugates. Figure 7 is a graph of percent change in body weight over time for animals treated with doxorubicin. Figure 8 is a graph of percent change in body weight over time for animals treated with Doxil. Figure 9 is a graph of percent change in body weight over time for animals treated with doxorubicin PEG conjugates containing TT23 (SEQ ID NO 22). Figure 10 is a graph of percent change in body weight over time for animals treated with doxorubicin TT23 conjugate and unconjugated doxorubicin. Figure 11 is a graph of in vitro cytotoxicity for 20KD mpPEG-8PA-GFLG and unconjugated doxorubicin against HuT 78 cells. Figure 12 is a graph of in vitro cytotoxicity for 20KD mpPEG-8PA-GFLG and unconjugated doxorubicin against Daudi cells. Figure 13 is a graph of in vitro cytotoxicity for 20KD mpPEG-8PA-GFLG and unconjugated doxorubicin against Raji cells. Figure 14 is a graph of in vitro cytotoxicity for 20KD mpPEG-8PA-GFLG and unconjugated doxorubicin against HEP G2 cells. Figure 15 is a graph of in vitro cytotoxicity for 20KD mpPEG-8PA-GFLG and unconjugated doxorubicin against SK Br-3 cells. Figure 16 is a graph of progression of tumor growth in mice injected with HuT 78 Cutaneous T-Cell lymphoma, then treated with 20KD mpPEG-8PA-TT45-DXR, 20KD mpPEG-8PA-GFLG-DXR, 20KD mpPEG-8PA-TT30-DXR, or unconjugated doxorubicin (Free DXR), or left without treatment. Figure 17 is a graph of inhibition of tumor growth in mice injected with HuT 78 Cutaneous T-Cell lymphoma, then treated with 20KD mpPEG-8PA-TT45-DXR, 20KD mρPEG-8PA-GFLG-DXR, 20KD mpPEG-8PA-TT30-DXR, or unconjugated doxorubicin (Free DXR). Figures 18a, b and c show Table 2 which lists amino acid sequences and corresponding SEQ ID NOS. DETAILED DESCRIPTION In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a ligand" includes reference to two or more ligands, reference to "a chemical agent" includes reference to one or more of such chemical agents that may be the same or different chemical agents, and reference to "a spacer" includes reference to two or more spacers. As used herein, "peptide" means peptides of any length and includes proteins. The terms "polypeptide" and "oligopeptide" are used herein without any particular intended size limitation, unless a particular size is otherwise stated. As used herein, "target-receptor-binding peptide" refers to a peptide capable of binding to a target receptor on a cell to promote internalization thereof into the cell. The "target receptor" can be any moiety on the cell surface to which the target receptor binding peptide binds to promote internalization thereof into the cell. Internalization into the cell can occur by any mechanism including passive diffusion and endocytosis. Thus, in one embodiment, the target receptor is a receptor that promotes endocytosis of the target receptor binding peptide upon binding of the target receptor binding peptide to the target receptor. The term "IL-2- receptor-binding peptide" refers a peptide configured for binding to IL-2 receptor, for example, to promote receptor-mediated endocytosis. The target receptor is in one embodiment a receptor which is specifically or dominantly expressed in a cancer cell, which can be a receptor other an IL-2 receptor, or an IL-2 receptor. Ligands comprising such target-receptor binding peptides or IL-2-receptor- binding peptides are coupled to various functional molecules so that, upon endocytosis or other internalization mechanism, of the ligands, the various functional molecules coupled thereto are also internalized by the cells. Target-receptor-binding peptides include the peptide having the amino acid sequence identified as SEQ ID NO:l and biologically functional equivalents thereof. Such functional equivalents retain functionality in binding the target receptor such as an IL-2 receptor and eliciting internalization, for example via receptor-mediated endocytosis, although they may be truncations, deletion variants, chemically modified, substitution variants of SEQ ID NO:l or include additional amino acid residues attached thereto. The target-receptor-binding peptides can have any size, for example, 1000-2000 amino acids or more, oriabout 1-100 amino acids, or about 6-20 amino acid residues, or about 6-12 amino acid residues, or, for example, about 6-8 amino acid residues. Preferred target receptor binding peptides include SEQ ID NO:l through SEQ ID NO:l 1 and SEQ ID NO:21 through SEQ ID NO:47 and amides thereof. Preferred peptides include SEQ ID NO 21, SEQ ID NO:22, SEQ ID NO:31 and SEQ ID NO:46, amides thereof and functional equivalents thereof. As mentioned above, changes may be made in the structure of the target receptor- binding peptide while maintaining the desirable receptor-binding characteristics. For example, certain amino acid residues may be substituted for other amino acid residues in a protein structure without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites of ligands such as an IL-2 receptor-binding peptide. Since it is the interactive capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid sequence substitutions can be made in a protein sequence and nevertheless obtain a protein with like properties. It is thus contemplated that various changes may be made in the sequence of an target receptor-binding peptide without appreciable loss of its biological utility or activity. It is also well understood by the skilled artisan that inherent in the definition of a biologically functional equivalent protein or peptide is the concept that there is a limit to the number of changes that may be made within a defined portion of the molecule and still result in a molecule with an still remains acceptable level of equivalent biological activity. It is also well understood that where certain residues are shown to be particularly important to the biological or structural properties of a protein or peptide, e.g., residues in active sites, such residues may not generally be exchanged. By "biologically functional equivalents" or "chemically modified equivalents", it means that one or more of the amino acids of the peptides of the present invention can be chemically modified, or substituted by its analogues without a significant loss of its target receptor binding activity. Various types of chemically modified amino acid analogues are commercially available and are well known to one skilled in the art. Amino acid substitutions are generally based on the relative similarity of the amino acid side-chains relative to, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. An analysis of the size, shape, and type of the amino acid side-chains reveals, for example, that arginine, lysine, and histidine are all positively charged residues; that alanine, glycine, and serine are all a similar size; and that phenylalanine, tryptophan, and tyrosine all have a generally similar shape. Therefore, based upon these considerations, the following conservative substitution groups or biologically functional equivalents have been defined:(a) Cys; (b) Phe, Trp, Tyr; (c) Gin, Glu, Asn, Asp; (d) His, Lys, Arg; (e) Ala, Gly, Pro, Ser, Thr; and (f) Met, Ile, Leu, Val. M. Dayhoff et al., Atlas of Protein Sequence and Structure (Nat'l Biomed. Res. Found., Washington, D.C., 1978), hereby incorporated by reference. To effect more quantitative changes, the hydropathic index of amino acids may be considered. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics, which are as follows: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5). The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is generally understood in the art. J. Kyte & R. Doolittle, 157 J Mol. Biol. 105-132 (1982), incorporated herein by reference. It is known that certain amino acids may be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based on the hydropathic index, the substitution of amino acids whose hydropathic indices are within ± 2 is preferred, within ± 1 is particularly preferred, and within ± 0.5 is even more particularly preferred. It is also understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent protein. As detailed in U.S. Patent No. 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0); glutamate (+3.0 ± 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ± 1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4). In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ± 2 is preferred, within ± 1 is particularly preferred, and within ± 0.5 is even more particularly preferred. A hexapeptide believed to be a part of IL-2 that binds to the IL-2 receptor has been identified (SEQ ID NO:l), D.A. Weigent et al, 139 Biochem. Biophys. Res. Commun. 367- 74 (1986). Moreover, regions of homology between this IL-2 hexapeptide and env proteins of immunosuppressive retroviruses have been discovered. D.A. Weigent et al., supra; W.E. Reiher III et al, 83 Proc. Nat'lAcad. Sci. USA 9188-92 (1986). Thus, amino acid substitutions in these regions of homology as compared to the IL-2 hexapeptide are also considered to be biologically functional equivalents. Therefore, illustrative biologically functional equivalents of SEQ ID NO:l include the following: SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6. Other illustrative biologically functional equivalents have also been discovered, including: SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:ll, SEQ ID NO:26, and SEQ ID NO:27. Additional biologically functional equivalents can be discovered by a person of ordinary skill in the art according to the guidance and principles disclosed herein without undue experimentation. In a further embodiment, the target receptor binding peptide comprises the sequence Gly-Phe-Leu-Gly or Gly-Leu-Phe-Gly. This sequence surprisingly can serve as both a targeting ligand and a biodegradable linker in the conjugates. Additionally, truncations, deletion variants, chemically modified forms, and substitution variants can be used. Thus, biologically functional equivalents or chemically modified equivalents can be made, for example by amino acid substitutions, as disclosed herein. As used herein, "macromolecule" means a composition comprising a water soluble polymer with a ligand and a chemical agent releasably coupled thereto. Preferably the polymer is a polyalkylene oxide and the ligand is an oligopeptide. The chemical agent can be from many different classes of molecules, as explained in more detail herein. As used herein, "releasably coupled" or "releasable, covalent bond" or "covalently, releasably coupled", refers to covalent bonds of the ligand, the chemical agent and the biocompatible polymer that are biodegradable. In particular, a conjugate comprising a chemical agent "covalently, releasably coupled to the polymer" refers to the embodiment wherein the chemical agent is covalently bonded to a component of the conjugate, but is releasable after internalization of the conjugate, for example, by receptor-mediated endocytosis, of the conjugate into the target cell. The chemical agent may be releasable, for example, by being attached to a portion of the conjugate, such as the polymer, via a degradable linkage, such as a peptide linkage that degrades in the presence of a protease. As used herein, "prodrug" means a chemical agent that is chemically modified to overcome a biological barrier. When a chemical agent is converted into its prodrug form, its biological activity is eliminated or substantially reduced, but the biological barrier that inhibited its effectiveness is no longer problematic. The chemical group that is attached to the chemical agent to form the prodrug, i.e. the "pro-moiety", is removed from the prodrug by enzymatic or nonenzymatic means to release the active form of the chemical agent. See A. Albert, Chemical Aspects of Selective Toxicity, 182 Nature 421 (1958). The instant compositions are prodrugs because the chemical agent that has the selected effect when internalized in IL-2-receptor-bearing cells is modified with a ligand, water soluble polymer, and, optionally, spacers such that the composition is delivered into the target receptor and/or IL-2-receptor-bearing cells, thus penetrating the cell membrane thereof. The biological effect of the chemical agent is greatly reduced or eliminated until the composition is delivered intracellularly and the chemical agent is released from the remainder of the composition by biodegradation of the spacer. As used herein, "chemical agent" means and includes any substance that has a selected effect when internalized into a target cell such as a cancer cell and/or an IL-2- receptor-bearing cell. Certain chemical agents have a physiological effect, such as a cytotoxic effect or an effect on gene regulation, when internalized into the cell. A "transforming nucleic acid" (RNA or DNA), when internalized into a cell, can be replicated and/or expressed within the cell. Other nucleic acids can interact with regulatory sequences or regulatory factors within the cell to influence gene expression within the cell in a selected manner. A detectable "label" delivered intracellularly can permit identification of cells that have internalized the compositions of the present invention by detection of the label. "Drugs" or "pharmacologically active compounds" can be used to ameliorate pathogenic effects or other types of disorders. Particularly useful chemical agents include polypeptides, and some such chemical agents are active fragments of biologically active proteins, or are specific antigenic fragments (e.g., epitopes) of antigenic proteins. Thus, chemical agents include cytotoxins, gene regulators, transforming nucleic acids, labels, antigens, drugs, and the like. As used herein, "drug" or "pharmacologically active agent" means any chemical material or compound suitable for intracellular administration in a target cell such as a cancer cell or an IL-2 receptor bearing cell, e.g., an activated T lymphocyte, and /or a cancer, that stimulates a desired biological or pharmacological effect in such cell. Preferred drugs are cytotoxins and immunosuppressant drugs. Preferred cytotoxins include adriamycin™ (doxorubicin), taxol, cisplatin, methotrexate, cyclophosphamide and derivatives thereof. Adriamycin is a trademark name for doxorubicin, which is available commercially, for example from Sigma, St. Louis, MO. The names adriamycin and doxorubicin are used herein interchangeably. Other drugs include Daunorubicin, Epirubicin, Idarubicin, Mitoxantrone, Novantrone, Actinomycin D and Amsacrine. Preferred immunosuppressants include cyclosporin, rapamycin, FK506 and derivatives thereof. Other anticancer drugs are described in Cancer Medicine, edited by James F. Holland et al, 1997, hereby incorporated herein by reference. Other drugs include aminopterin, folic acid, 10-ethyldeazaaminopterin, trimetrexate, piritrexim, tomudex, Daraprim, lemotrexol, fluorouracil, 5-azacytidine, 2',2'-difluoro-2'deoxycytidine, brequinar, pyrazofurin, 6-azauridine, 5-ethynyluracil, allopurinol, acivicin, leucovorin, acyclovir, and ganciclovir. As used herein, "carrier" means any carrier, such as water soluble polymers, particulates, or liposomes to which a conjugate according to the instant invention can be combined or coupled. Such carriers can, for example, increase the molecular size of the compositions and may provide added selectivity, biodistribution, and/or stability. Such selectivity can arise because carrier-containing compositions are too large to enter cells by passive diffusion, and thus are limited to entering cells through receptor-mediated endocytosis. The potential for use of such carriers for targeted drug delivery has been established. See, e.g., J. Kopecek, 5 Biomaterials 19 (1984); E. Schacht et al, Polysaccharides as Drug Carriers, in Controlled-Release Technology 188 (P.I. Lee & W.R. Good, eds., 1987); F. Hudecz et al, 19 J. Controlled Release 231 (1992); Z. Brich et al, 19 J. Controlled Release 245 (1992). Illustrative water soluble polymers include dextran, inulin, poly(L-lysine) with modified epsilon-amino groups, poly(L-glutamic acid), N-substituted methacrylamide-containing synthetic polymers and copolymers, and the like. As used herein, "effective amount" is an amount sufficient to produce a selected effect. For example, a selected effect of a composition containing a cytotoxin as the chemical agent could be to kill a selected proportion of IL-2-receptor-bearing cells, e.g., activated T cells, within a selected time period. An effective amount of the composition would be the amount that achieves this selected result, and such an amount could be determined as a matter of routine by a person skilled in the art. The compositions of the present invention provide intracellular delivery of a chemical agent capable of eliciting a selected effect when delivered into a target-receptor- bearing cell. For example, the conjugate comprises a ligand configured for binding to an target receptor, such as an IL-2 receptor, on the target-receptor-bearing cells and stimulating internalization into the cell, for example, by receptor-mediated endocytosis. The conjugate may include a chemical agent and a water soluble polymer having functional groups compatible with forming a releasable, covalent bonds with the ligand. The binding ligands are peptides which preferably comprise a biodegradable, spacer such that the chemical agent is detached from the composition by hydrolysis and/or enzymatic cleavage inside the target cells, such as IL-2-receptor-bearing cells, cancer cells or T cells, especially in lysosomes. Once detached, the chemical agent diffuses or is transported to other locations in the cell where it can exert its functional effect in the cell. Illustrative of such spacers is the peptide Gly-Phe-Leu-Gly (SEQ ID NO:21). Equivalent peptide spacers are well known in the art. The water soluble polymer is preferably a poly(alkylene oxide). Within this group of substances are alpha-substituted polyalkylene oxide derivatives, such as methoxypolyethylene glycols or other suitable alkyl-substituted derivatives, such as those containing -C 4 alkyl groups. Preferably the polymer is a monomethyl-substituted pendant PEG homopolymer. Other poly(alkylene oxides) are also useful, including other polyethylene glycol (PEG) homopolymers and derivatives thereof, polypropylene glycol homopolymers and derivatives thereof, other alkyl-capped polyethylene oxides, bis- poly ethylene oxides, copolymers of poly (alky lene oxides), and block copolymers of poly(alkylene oxides) or activated derivatives thereof. Other preferred PEGs include branched, pendant and star PEGs, such as are commercially available from Shearwater Polymers, Inc. (Huntsville, AL). Y. Gnanou et ah, 189 Makromol. Chem. 2885 (1988); D.Rein et al, 44 Acta Polymer, 225 (1993); E.W. Merrill, U.S.Patent 5,171,264; Poly(Ethylene Glycol) Chemistry in Biotechnical and Biomedical Application, J. Milton Harris, 1992, hereby incorporated by reference. In those embodiments of the invention where PEG-based polymers are used, in one embodiment, they have number average molecular weights of from about 200 to about 50,000, or 2,000 to about 20,000, or about 20,000. PEG is preferred because it is inexpensive, approved by the FDA for administration to humans, and is resistant to eliciting an antibody response. Poly(ethylene oxide) (PEO) is another preferred water soluble polymer represented by P. The coupling of a ligand to a chemical agent can be, without limitation, by covalent bond, electrostatic interaction, hydrophobic interaction, physical encapsulation, and the like. One preferred polymer for the invention is a pendant PEG, or a star shaped PEG. It is another novel aspect of the present invention to provide a peptide conjugated to a pendant PEG or a star shaped PEG and a method of preparing thereof. In one preferred embodiment, the polymer is a blocked pendant polyalkylene glycol, such as an alkyl blocked pendant polyalkylene glycol. The polymer may be, in one preferred embodiment, an alkyl blocked pendant polyethylene glycol. For example, the alkyl blocked pendant polyethylene glycol may be a mono-methyl blocked pendant polyethylene glycol, or a dimethyl blocked pendant polyethylene glycol. Alternatively, the pendant polyethylene glycol hydroxyl moieties can be blocked with an acyl group (via an ester bond from reaction with a mono or dicarboxylic acid or derivative), for example, an acetyl or hemisuccinyl or other diacyl compound. In the case of hemisuccinyl and other diacyl compounds additional reactive groups (carboxyl groups) are introduced, which can be used for further derivatization. The term "pendant" polyalkylene glycol or "pendant" polyethylene glycol refers to a polyalkylene glycol or polyethylene glycol polymer, wherein the polymer that includes a plurality of pendant functional groups, dispersed along the polymer chain, that typically comprise reactive groups, or can be modified to comprise reactive groups, that permit further modification and covalent attachment of other molecules to the polymer. The number of pendant groups on a single polymer molecule can vary and can be, for example, 2, 3, 4, 5, 6, 7, 8 or more, and provide attachment points for targeting ligands and/or chemical agents. For example, in one embodiment, the polymer molecule includes at least 2, at least 3, at least 4, at least 5, or at least 6, 7 or 8 or more pendant groups for attachment ligands and/or chemical agents. In a further embodiment, in a composition comprising plural molecules of the polymer, the average number of pendant groups on the polymer molecules is at least 2, 3, 4, or 5, or at least 6, 7, 8 or more. The pendant polymer is in one preferred embodiment a linear polymer, and includes terminal hydroxyl groups. Preferably at least one of the terminal hydroxyl groups is capped with a nonreactive functional group such as an alkyl group. Thus, the term "alkyl blocked" or "alkyl capped" polyalkylene glycol or polyethylene glycol refers to the form of the polymer when one or more of the terminal hydroxyl groups are capped with an alkyl group, such as a methyl group. The polymer can, for example, be mono-methyl blocked, i.e., include one terminal hydroxyl capped with a methyl group, or may be dimethyl blocked with a methyl capping group on each of the terminal hydroxyls. In the case of a mono-alkyl blocked polyalkylene glycol, the remaining free hydroxyl group can be further blocked by an acyl group (via an ester bond from reaction with a mono or dicarboxylic acid or derivative) such as acetyl or hemisuccinyl. In the case of hemisuccinyl or other diacyl compound, additional reactive groups (carboxyl groups) are introduced, which can be used for further derivatization. Alternatively, the un-alkylated pendant polymer containing two terminal hydroxyl groups can be capped with two acyl or diacyl compounds such as acyl or hemisuccinyl to yield a bi-substituted (bis-) blocked polymer. In the case of bis-hemisuccinyl or other bis-diacyl compound, two additional reactive groups (carboxyl groups) are introduced at the ends of each polymer chain, which can be used for further derivatization. Blocked pendant polyalkylene glycols can be made using synthetic methods available in the art. Pendant PEGs are commercially available, for example, from Innophase Corporation (Westbrook, CT) using methods available in the art. Alkyl-blocked pendant polyalkylene glycols are generally prepared by alkoxylation of monoalkylalkylene glycols using alkylene oxide and pendant groups attached by methods available in the art. The monomethyl PEGs are also commercially available. Dialkyl blocked pendant polyalkylene glycols are generally prepared from monoalkyl PEGs by reaction with dialkyl sulfate and a strong base or via the tosylate ester by reaction with alkoxide and subsequent attchment of pendant groups by methods available in the art (see, for example, Advanced Organic Chemistry, J. March, Wiley: New York, Fourth Editon, 1992, pp. 386-387). Acyl and diacyl blocked pendant PEGs can be prepared, for example by reaction of activated carboxyl derivatives such as acyl or cyclic anhydrides with the pendant polyalkylene glycols or monoalkyl blocked pendant polyalkylene glycols (See Advanced Organic Chemistry, J. March, Wiley: New York, Fourth Edition, 1992, pp. 392-396). The use of alkyl blocked pendant polyalkylene glycol, such as an alkyl blocked pendant polyethylene glycol is advantageous. The multiple pendant groups on the polymer permit the attachment of plural chemical agents to the conjugate, to improve efficacy of the conjugate. For example, the polymer may include 2, 3, 4, 5, 6, 7, 8, or 9 or more molecules of the chemical agent. Preferably, the polymer includes at least 3, at least 4, at least 5 or at least 6 molecules of the chemical agent. Additionally, although the use of acyl blocked pendant polyalkylene glycols has similar advantages to the use of alkyl blocked pendant polyalkylene glycols, the use of a diacyl blocked pendant polyalkylene glycol, such as bis-hemisuccinyl pendant polyethylene glycol or monomethyl-hemisuccinyl pendant polyethylene glycol offers the advantage that additional reactive carboxyl group(s) are introduced which can be further derivatized. This is a particular advantage when the pendant groups contain carboxyl moieties, since the possibility of differential reactivity between the hemisuccinyl carboxyl groups and the pendant carboxyl groups is created. Thus, according to the invention, the composition permits preferential binding to a target receptor such as IL-2 receptor, on activated T cells, thus triggering internalization of the composition, for example, by endocytosis. The chemical agent permits a selected effect in the target-receptor bearing cells. Accordingly, for example, chemical agents comprise cytotoxins, including radionuclides, for selective killing or disabling of cells; nucleic acids for genetically transforming or regulating gene expression in cells; drugs or other pharmacologically active agents including immunosuppressant, for achieving a selected therapeutic effect; labels, including fluorescent, radioactive, and magnetic labels, for permitting detection of cells that have taken up the compositions; and the like. IL-2 is a lymphocyte growth factor produced by T cells that is essential for a normal immune response. Binding of IL-2 to the IL-2 receptor precedes internalization by receptor-mediated endocytosis. The human IL-2 gene has been sequenced, T. Taniguchi et al, 302 Nature 305-10 (1983), hereby incorporated by reference, as has the gene for the human IL-2 receptor, W. J. Leonard et al, 311 Nature 626-31 (1984); T. Nikaido et al, 311 Nature 631-35 (1984); D. Cosman et al, 312 Nature 768-71 (1984). The IL-2 receptor is a heterotrimeric glycoprotein complex on the cell membrane with a 55 kDa α subunit, a 75 kDa β subunit, and a 64 kDa γ subunit. The only normal human tissues expressing the α and β subunits are activated T cells, B cells, LGL cells, and monocytes and some liver Kupffer cells, macrophages, and skin Langerhans' cells. A.E. Frankel et al, 11 Leukemia 22-30 (1997). A variety of hematologic neoplasms may show high affinity IL-2 receptor expression including hairy cell leukemia, adult T cell leukemia, and a fraction of cutaneous T cell lymphomas and B cell chronic lymphocytic leukemias. Recombinant toxins targeted to the IL-2 receptor have been described wherein the ligand is IL-2. A.E. Frankel et al, supra; U.S. Patent No. 4,675,382; J. VanderSpek et al, 268 J. Biol Chem. 12077-82 (1993); and I. Pastan & D. Fitzgerald, supra. In some embodiments of the present invention, the compositions are constructed by chemically conjugating the ligand and chemical agent to the water soluble polymer. "Chemically conjugating" the ligand and the chemical agent to the water soluble polymer, as that term is used herein, means covalently bonding the ligand and chemical agent to each other, preferably by way of a spacer mojety, and conjugating the resulting ligand/agent conjugate to the water soluble polymer. In particular embodiments, a biodegradable spacer moiety is used to form a linkage between the ligand and the chemical agent. Peptide portions of the compositions can be produced in a genetically engineered organism, such as E. coli, as a "fusion protein." That is, a hybrid gene containing a sequence of nucleotides encoding a ligand, spacer, or peptide chemical agent can be constructed by recombinant DNA technology. This hybrid gene can be inserted into an organism such that the "fusion protein" encoded by the hybrid gene is expressed. The fusion protein can then be purified by standard methods, including affinity chromatography. Peptides containing a ligand, spacer, or peptide chemical agent can also be constructed by chemical synthesis. Short peptide ligands are generally preferred, both because short peptides can be manipulated more readily and because the presence of additional amino acids residues, and particularly of substantial numbers of additional amino acids residues, may interfere with the function of the peptide ligand in stimulating internalization of the chemical agent, for example, by endocytosis. Compositions according to the present invention preferably also further include a protease digestion site, such that once the composition is within the cell, such as in a lysosome, the chemical agent can be separated from the remainder of the composition by proteolysis of the digestion site. Such a protease susceptible biodegradable peptide portion can be added regardless of whether the peptide portions of the composition are synthesized chemically or as expression peptides in a genetically engineered organism. In the latter case, nucleotides encoding the protease susceptible spacer can be inserted into the hybrid gene encoding the ligand and or a peptide chemical agent by techniques well known in the art. In one illustrative embodiment, the protease-susceptible peptide portion is designed to be cleaved by proteolysis in the lysosome of the target cell. The composition that is internalized, for example by endocytosis, is packaged in an endocytic vesicle, which is transported to a lysosome. Once in the lysosome, the protease-susceptible portion is cleaved, and the chemical agent is then available to be transported to the cytoplasm. Another aspect of the present invention features a method for specifically effecting a desired activity in target receptor, such as IL-2-receptor-bearing cell, e.g., a cancer cell or activated T lymphocyte, contained in a heterogeneous population of cells, by the step of contacting the population of cells with a composition, prepared according to the present invention, that directs such activity into the cells. The compositions of the invention are selectively bound to cancer cells bearing a target receptor or IL-2-receptor-bearing T cells in the mixed population, whereupon endocytosis of the composition into such cells is stimulated, and the chemical agent effects its activity within such cells. This application employs, except where otherwise indicated, standard techniques for manipulation of peptides and for manipulation of nucleic acids for expression of peptides. Techniques for conjugation of oligopeptides and oligonucleotides are known in the art, and are described for example in T. Zhu et al, 3 Antisense Res. Dev. 265 (1993); T. Zhu et al, 89 Proc. Nat'lAcad. Sci. USA 7934 (1992); P. Rigaudy et al, 49 Cancer Res. 1836 (1989), which are hereby incorporated by reference. As is noted above, the invention features peptides, employed as ligands, spacers, and/or chemical agents. The peptides according to the invention can be made by any of a variety of techniques, including organic synthesis and recombinant DNA methods. Techniques for chemical synthesis of peptides are described, for example, in B. Merrifield et al, 21 Biochemistry 5020 (1982); Houghten, 82 Proc. Nat'lAcad. Sci. USA 5131 (1985); M. Bodanszky & A. Bodanszky, The Practice of Peptide Synthesis (Springer- Verlag 2d ed., 1994), incorporated herein by reference. Techniques for chemical conjugation of peptides with other molecules are known in the art. A fusion protein according to the invention can be made by expression in a suitable host cell of a nucleic acid containing an oligonucleotide encoding a ligand and/or spacer and/or chemical agent. Such techniques for producing recombinant fusion proteins are well-known in the art, and are described generally in, e.g., J. Sambrook et al, Molecular Cloning: A Laboratory Manual (2d ed., 1989), the pertinent parts of which are hereby incorporated herein by reference. Reagents useful in applying such techniques, such as restriction endonucleases and the like, are widely known in the art and commercially available from any of several vendors. The polymeric drug delivery systems disclosed herein are useful in a wide variety of therapeutic applications including enhancing the usefulness of cancer chemotherapeutic agents. The covalent binding of low molecular weight drugs to water-soluble polymer carriers permits enhancement of the specificity of drug action, for example, wherein endocytosis is the mode of cell entry of the drug-polymer conjugates, thus offering a highly cell-specific mechanism. Examples include compositions wherein a peptide ligand and a cytotoxic chemical agent, adriamycin or doxorubicin, are coupled to a branched PEG or a pendant PEG. The compositions and conjugates according to the present invention can be used for targeted delivery of a chemical agent to target cells such as IL-2-receptor-bearing cells, e.g., activated T cells, generally by contacting the cells with the composition under conditions in which binding of the ligand to a receptor stimulates internalization, for example, by endocytosis, of the composition into the cells. The chemical agent then acts on or within the targeted cell into which the composition is internalized, and the desired effect of the active agent can be defined to those cells having the receptor. For example, a conjugate can be used as an effective antitumor agent in vivo for killing cancer cells and/or activated T cells. The conjugate also can be used for treating cancer and/or T-cell-associated diseases and tissue graft rejection. Such diseases include cancer, arthritis, cutaneous T-cell lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancers, psoriasis, graft rejection disease, multiple sclerosis, Type II diabetes mellitus, and disease resulting from HIV infection. The composition can be administered locally or systemically. Preferably, the composition is administered to the subject by systemic administration, typically by subcutaneous, intramuscular, or intravenous injection, or intraperitoneal administration, which are methods well known in the art. Injectable preparations for such use can be made in conventional forms, either as a liquid solution or suspension or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion. Suitable excipients include j for example, water, saline, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances such as wetting or emulsifying agents, buffers, and the like may be added. Effective amounts of such compositions can be determined by those skilled in the art without undue experimentation according to the guidelines provided herein. The composition can be contacted with the cells in vitro or in vivo. The cells, such as T cells can constitute a sub-population of a mixed population of cell types; the ligand according to the invention can provide for internalization, for example, by endocytosis of the conjugate into target cells such as T cells and possibly into a small proportion of other cells having a closely related receptor. The chemical agent can have any of a variety of desired effects in the targeted cells. As mentioned above, in some particularly useful embodiments the chemical agent is effective on a cell only when, or principally when, the agent is internalized into the cell. The disclosures of all publications, patents and patent applications, referred to herein, are incorporated herein by reference in their entirety. The disclosures of U.S. Application Serial No. 08/914,042, filed August 5, 1997; U.S. Patent Application Serial No. 09/128,572, filed August 4, 1998; PCT WO 99/07324, filed August 5, 1998; and PCT US99/17648, filed August 4, 1999 are also hereby incorporated herein in their entirety. ' EXAMPLES Example 1 7.8 g of branched, 8-arm PEG-COOH (20kDa; Shearwater Polymers, Inc., Huntsville, AL) and 0.25 g of p-nitrophenol were dissolved in 500 ml of tetrahydrofuran(THF) (Aldrich, making solution 3.6 mM with respect to the p-nitrophenol. The solution was cooled in an ice bath, and 0.9341 g of dicyclohexylcarbodiimide (DCC, Sigma) in THF was added to the reaction mixture in 4 aliquots. The reaction solution was stirred for 45 minutes in the ice bath. The temperature of the reaction solution was then raised to room temperature, and the reaction was then continued for another 101 hours. The reaction solution was then filtered through filter paper, and the filtrate was concentrated by evaporating the solvent with a rotary evaporator using a water pump. The clear concentrated solution (30 ml) was added to ether (750 ml). The precipitate was filtered, washed in ether, and dried in air. An aliquot of the product was dissolved in 0.1 N NaOH, and the concentration of the liberated p-nitrophenol was estimated by spectrophotometry at 400 nm using a molar extinction coefficient of ε = 1.8 x 10 4 1/mol-cm. The product (PEG- Onp), was determined to have an ONp content of 201.3 μmol/g. PEG-ONp (0.168 g, ONp content 201.3 μmol), prepared as described above, was dissolved in 2 ml anhydrous dimethylformamide (DMF), and 42.4 mg peptide TT23 (SEQ ID NO:22) was added to the solution. About 150 μl of triethylamine diluted 1 :2 with DMF was added to the reaction mixture three times at 15 minute intervals, and then the solution was stirred for 17 hours at room temperature. The reaction solution was added to cold ether (300 ml), and the conjugate precipitates were filtered, washed with 200 ml ether, and dried. Amino acid analysis of the conjugate, PEG-T23-OH, showed 1 mole of peptide TT23 incorporated per mole of PEG. Adriamycin (7.6MGi Sigma) and PEG-TT23-OH (85 mg) were dissolved in 2 ml DMF and DCC solid (14 mg) was added to the solution. The reaction was carried out for 17 hours, precipitated with 200 ml ether, filtered, and washed with ether. The precipitate was dried under vacuum and then dissolved in PBS buffer. The solution was dialyzed for 25 hours with 3 changes of PBS buffer. Adriamycin content of the product, PEG- TT23(SEQ ID NO:22)-ADR, was determined by spectrophotometry at 490 nm. Example 2 A control composition having the formula PEG-Gly-Phe-Leu-Gly-ADR (hereinafter, "PEG-GFLG-ADR;" SEQ ID NO:21) was prepared according to the procedure of Example 1. Example 3 A composition having the formula PEG-Gly-Leu-Glu-Arg-Ile-Leu-Leu-Gly-Phe- Leu-Gly-Adriamycin (hereinafter, "PEG-TT7-ADR;" SEQ ID NO: 14) was prepared according to the procedure of Example 1. Example 4 A composition having the formula PEG-Gly-Leu-Glu ffit -His-Ile-Leu-Leu-Gly-Phe- Leu-Gly- Adriamycin (SEQ ID NO: 15), was prepared according to the procedure of Example 1. Example 5 A composition having the formula PEG-Gly-Leu-Gln-His-Ile-Leu-Leu-Gly-Phe- Leu-Gly- Adriamycin (SEQ ID NO: 16) was prepared according to the procedure of Example 1. Example 6 A composition having the formula PEG-Gly-Leu-Asp-His-Ile-Phe-Leu-Gly-Phe- Leu-Gly- Adriamycin (SEQ ID NO: 17) is prepared according to the procedure of Example 1. Example 7 A composition having the formula PEG-Gly-Leu-Asn-His-Ile-Phe-Leu-Gly-Phe- Leu-Gly- Adriamycin (SEQ ID NO: 18) is prepared according to the procedure of Example 1. Example 8 A composition having the formula PEG-Thr-Gly-Leu-Gln-His-Ile-Leu-Leu-Gly- Phe-Leu-Gly-Adriamycin (hereinafter, "PEG-TT15-ADR"; SEQ ID NO: 19) was prepared according to the procedure of Example 1. Example 9 A composition having the formula PEG-Ser-Leu-Gln-His-Ile-Leu-Leu-Gly-Phe- Leu-Gly- Adriamycin (SEQ ID NO:20) is prepared according to the procedure of Example 1. Example 10 A composition having the formula PEG-Gly-Leu-Gln-His-Leu-Phe-Leu-Gly- Adriamycin (hereinafter, "PEG-TT13-ADR"; SEQ ID NO: 13) was prepared according to the procedure of Example 1. Example 11 A composition having the formula PEG-Thr-Gly-Leu-Asp-Arg-Ile-Leu-Leu- Adriamycin (hereinafter, "PEG-TT27-ADR";SEQ ID NO:24) is prepared according to the procedure of Example 1. Example 12 A composition having the formula PEG-Thr-Gly-Leu-Asp-Arg-Leu-Leu-Leu- Adriamycin (SEQ ID NO:25) is prepared according to the procedure of Example 1. Example 13 A composition having the formula PEG-Thr-Gly-Leu-Asn-Arg-Leu-Leu-Leu- Adriamycin (SEQ ID NO:26) is prepared according to the procedure of Example 1. Example 14 A composition having the formula PEG-Thr-Gly-Leu-Asn-Arg-Ile-Leu-Leu- Adriamycin (SEQ ID NO:27) is prepared according to the procedure of Example 1. Example 15 A composition having the formula PEG-Thr-Gly-Leu-Asp-Arg-Ile-Phe-Leu-Gly- Adriamycin (SEQ ID NO:28) is prepared according to the procedure of Example 1. Example 16 A composition having the formula PEG-Thr-Gly-Leu-Asp-Arg-Leu-Phe-Leu-Gly- Adriamycin (SEQ ID NO:29) is prepared according to the procedure of Example 1. Example 17 A composition having the formula PEG-Thr-Gly-Leu-Asn-Arg-Ile-Phe-Leu-Gly- Adriamycin (SEQ ID NO: 30) is prepared according to the procedure of Example 1. Example 18 A composition having the formula PEG-Thr-Gly-Leu-Asn-Arg-Leu-Phe-Leu-Gly- Adriamycin (SEQ ID NO:31) is prepared according to the procedure of Example 1. Example 19 The in vitro effects of PEG-TT23 (SEQ ID NO:22)-ADR prepared according to the procedure of Example 1, PEG-GFLG-ADR prepared according to the procedure of Example 2, and unconjugated adriamycin were tested on mouse CTLL-2 cells (ATCC No. TIB 214) as follows. CTLL-2 cells express the IL-2 high affinity receptor. Triplicate samples of 1 x 10 5 cells each were mixed with different concentrations of the purified compositions in 0.1 ml of culture medium (RPMI 1640, 10% fetal calf serum) in the wells of a 96-well microtiter plate (Falcon Microtest 111), and incubated for 48 hours at 37°C in a humidified, 5% CO 2 atmosphere. Thereafter, cell viability was assessed by a colorimetric method using the tetrazolium compound MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) and an electron coupling reagent, PMS (phenazine methosulfate). A.J. Cory et al, 3 Cancer Commun. 207 (1991); T.L. Riss & R.A. Moravec, 3 Mol Biol Cell 184a (Supp.; 1992); T.M. Buttke et al, 157 J. Immunol. Methods 233 (1993), hereby incorporated by reference. MTS is bioreduced by living cells into a soluble formazan product. The absorbency of the formazan at 490 nm can be measured directly from 96 well assay plates without additional processing. The quantity of formazan product as measured by the absorbency at 490 nm is directly proportional to the number of living cells in culture. Reagents for the MTS assay were obtained from Promega Corp. (Madison, Wisconsin). According to this method, 20 μl of MTS PMS solution (Promega No. G-5421) was added to each well of the assay plate. The plate was then further incubated at 37°C in a humidified, 5% CO 2 atmosphere for 4 hours. The absorbency of each well was then measured at 490 nm with an EL311 Microplate Autoreader (Bio-Tek Instruments). The mean absorbency for treatment was Λ % cytotoxity = (1 — s -) x 100 then calculated, and the percent cytotoxicity was determined using the formula: wherein A s represents the mean absorbency for each treatment and A c represents mean absorbency of the control treatment, i.e., cells not exposed to a conjugate. FIG. 1 shows that PEG-TT23-ADR (D) kills such CTLL-2 T cells at concentrations much lower than that required for PEG-GFLG-ADR (Δ) to effect similar levels of cytotoxicity. These results show that the presence of a ligand specific for binding to the IL- 2 receptor and inducing receptor-mediated endocytosis results in much greater cytotoxicity than a PEG- and adriamycin-containing conjugate lacking such ligand. Thus, a conjugate bearing an IL-2-receptor specific ligand is internalized with much greater efficiency that similar conjugates lacking such a ligand. The unconjugated adriamycin control(o) rapidly diffuses into the cells and kills them. As expected, cytotoxicities from PEG-TT23-ADR require higher concentrations of adriamycin than unconjugated adriamycin due to the requirement that PEG-TT23-ADR be internalized by endocytosis. Example 20 The in vitro effects of IL-2-receptor-targeted conjugates on IL-2 induced proliferation of murine splenocytes was examined. A sterile splenocyte suspension was prepared as follows. Spleens were aseptically removed from male C57 BL/6 mice and placed in sterile tissue culture medium (RPMI plus 10% fetal calf serum). The spleens were teased apart and gently aspirated using a Pasteur pipet. The resulting spleen cell suspension was then filtered through sterile gauze and centrifuged at 150 x g for 10 minutes at 20°C. The supernate was discarded, and erthrocytes in the cell pellet were selectively lysed by resuspending the pellet in lysis buffer (155 mMNH 4 Cl, 13.41 mM KHCO 3 , and 100 mM EDTA in dH 2 O). After 30 seconds, an equal volume of tissue culture medium was added to the suspension to restore isotonicity. The cell suspension was again centrifuged at 150 x g for 10 minutes at 20EC, and the resulting cell pellet was washed once using tissue culture medium. The washed cell pellet was finally resuspended in tissue culture medium, and cell density was adjusted to 5 x 10 6 cells/ml. To the wells of a 96-well assay plate (Falcon MICROTEST III), 50 μl volumes of the splenocyte suspension were added. Competitor (conjugate) solutions were prepared and diluted in tissue culture medium and added to the wells of the assay plate in 25 μl volumes. To control wells, 25 μl of tissue culture medium was added. The assay plate was then incubated for 60 minutes at 37°C in a humidified atmosphere containing 5% CO 2 and 95% air. To the wells of the assay plate, 25 μl of either tissue culture medium or a solution containing recombinant human IL-2 (Pharmingen) at a concentration of 20 ng/ml (in tissue culture medium) was added. The assay plate was then incubated for 48 hours at 37°C in a humidified atmosphere containing 5% CO 2 and 95% air. Final results were quantitated as follows. Viable cell counts were performed for each separate well of the assay plate using trypan blue exclusion method. Trypan blue is taken up and imparts a blue color to dead cells. Briefly, an aliquot of cells was twice diluted in 0.4% trypan blue stain (Sigma Chemical Co., St.Louis, Missouri) and incubated for 5 minutes before counting with a hemacytometer and an inverted microscope. The percentage of viable cells was calculated as the number of unstained cells per unit volume divided by the total number of stained and unstained cells x 100. Cell counts for each duplicate set of wells were averaged, and cell proliferation was calculated as percent change from control cells using the following formula: mean cell count, test % Change = [ 1] x 100 mean cell count, control Percent inhibition of IL-2 induced proliferation was calculated as follows. o / T 1, -w C(% chan § e +-L-2) " ( % Change . 2+ corapetitor )] % Inhibition = - x 100 % Change +IL.2 The materials tested in this example was PEG-TT23 prepared according to the procedure of Example 1 except that no adriamycin was conjugated thereto, and unconjugated peptide TT23. The results of conjugate inhibition of IL-2-induced proliferation of murine splenocytes with PEG-TT23 and peptide TT23 are shown in Figure 2. These results show that PEG-TT23 very effectively inhibits proliferation, whereas about 100-fold more unconjugated peptide TT23 is needed to achieve similar levels of inhibition. These results show that conjugate PEG-TT23 specifically binds to the IL-2 receptor. Example 21 Treatment of Collagen-Induced Arthritis (CIA) Collagen-induced arthritis (CIA) is a reliable model for pre-clinical testing of new immunomodulatory drugs for rheumatic diseases. CIA is induced in genetically susceptible mice by immunization with heterologous type II collagen (CII). The severity of CIA reflects the level of autoreactive T cells sensitized to CII, the production of Cll-reactive autoantibody and the release in joint tissues of a variety of pro-inflammatory cytokines and chemokines. Treatment protocols that interfere with the T cell activation step inhibit CIA. In this example, activated T cells were targeted with PEG-TT23-ADR, which has been shown to specifically bind to the IL-2 receptor (Example 20). The IL-2 receptor is only expressed by activated T cells. Thus, resting T cells are spared, and the intracellular toxic effects of the ADR-conjugate are directed to CIL-reactive T cells. BIO.RIII mice were injected with CII (200 μg) emulsified with complete Freund's adjuvant (CFA;200 μg H37Ra). At day 21, mice were boosted with 100 μg of CII; randomized for CIA severity (13/group), and an alternate day treatment protocol was begun. This secondary boost with CII is known to cause a rapid precipitation of arthritis onset. After such a secondary boost, BIO.RIII mice show a very rapid onset of arthritis and very severe diseases with a >90% incidence. Test groups received by i.p. injection: (A) PEG-TT23-ADR (2 mg/kg); (B) PEG-GFLG-ADR (2 mg/kg); (C) PBS (vehicle control). Mice were observed for 84 days for arthritis severity and weight changes. Group B showed a significant weight loss of about 10% ± 8% as compared to Group C (about 5% ± 5 %) P 0.04, that was not evident in Group A mice (about 3% ± 6%) P 0.26. Distribution curves of the cumulative daily arthritis scores revealed significant differences (P 0.02) among the 3 groups. Importantly, Group A mice showed a significantly greater number of mice with only minimum arthritis as compared to the normally severe disease found in the majority of PBS control mice (P 0.02). Several potentially beneficial drugs for rheumatoid arthritis are contra-indicated by toxicity at required dosages. These data suggest that delivering a specific therapeutic agent only to the particular subset of lymphocytes directly involved in disease pathology may allow effective therapy to be accomplished at lower, more tolerable dosages. Example 22 A method of treating T cell lymphoma in a human comprises (a) providing a composition according to the present invention, such as PEG-TT23-ADR (SEQ ID NO:22), wherein the chemical agent is a cytotoxin, and (b) systemically administering an effective amount of the composition to an individual. An effective amount of the composition is systemically administered to the individual such that the composition enters the bloodstream and contacts T cells. The composition binds to an IL-2 receptor on the T cells and stimulates internalization of the composition by endocytosis. The biodegradable spacer is digested by intracellular proteases, releasing the adriamycin. The adriamycin then kills the cell by intercalating with DNA in the cell. This procedure reduces the number of malignant T cells in the body of the individual, thereby having a positive effect in treatment of the disease. Example 23 Alterations in the immune status of patients with various cancers results in release of soluble IL-2 receptors (sIL-2R) in circulation. The sIL-2R levels in T-cell lymphocytic leukemia, T-cell acute lymphoblastic leukemia, and peripheral T-cell lymphoma are an indication of the degree of T-cell or immune activation due to concomitant immunologic processes in these disorders. S. Raziuddin et al., 73 Cancer 2426-2431 (1994). Further, sIL-2R levels remain elevated in Hodgkin's disease and non-Hodgkin's lymphoma patients, even at the stage of minimal residual disease after intensive chemotherapy or radiotherapy. M. Kandefer-Szenrzen et al., 45 Arch. Immunol. Ther. Exp. (Warsz) 443-448 (1997). Therefore, detection of elevated levels of sIL-2R in circulation can be used as a diagnostic assay for such cancers. In this example, compositions according to the present invention are used for detecting sIL-2R in circulation according to methods well known in the art. Peptides that bind to sIL-2R are used in modified ELISA or RIA assays for detecting such sIL-2R in circulation. The peptides are labeled with an enzyme or with a radiolabel. The labeled peptide is then mixed with a sample, such as a serum sample, and the mixture is incubated under conditions suitable for binding of the peptide to the sIL-2R to form a complex. This complex is then detected by colorimetric, fluorometric, radiometric, or similar assay. Elevated levels of circulating sIL-2R indicates the presence of cancer. Example 24 Preparation of pendant 20 KD PEG-8PA-ONp Purification of Starting Material: Innopeg 20M-8PA (15 g, Innophase Corporation) was dissolved in 100 ml of 5% water in methanol and the solution introduced into a Spectra/Por MWCO 12-14,000 dialysis bag and the solution dialyzed against 2 L of 5% aqueous methanol for 24 hours. The dialysate was replaced with fresh 5% aqueous methanol and dialysis continued 24 hours. The process was repeated one additional time and the material in the bag concentrated to a thick syrup. The majority of the solvent was removed at 80EC on the rotary evaporator using a vacuum pump and the glass recrystallized from 180 ml of acetone to yield 8.37 g of purified 20KD pPEG-8PA. The combined dialysates after concentration in vacua amounted to 5.59 g or 37.2% of the total. Before dialysis the polymer was determined to contain an average of 8.3 carboxyl groups per mole polymer by titration with 0.01N NaOH solution, while after dialysis the number was reduced to 6.5 carboxyl groups per mole. Even though the purified starting material contained 6.5 carboxyls per mole polymer, it is still referred to as 20KD pPEG-8PA. Reaction and Work-up (non-extractive): A 250 ml round bottom flask, equipped with magnetic stirring bar, distillation head and condenser was charged with 15.0 g (MW = 19,000 by GPC, 789.5 micromoles) of 20KD polyethylene glycol propionic acid (20KD- pPEG-8PA, dialyzed and recrystallized, 6.5 pendant carboxyl groups/mole polymer). Anhydrous toluene (150 ml) was added and heat was applied via a heating mantle to the rapidly stirred suspension. As the temperature increased, the starting material dissolved. Approximately 60 ml of toluene was distilled from the solution over a 30 minute period to remove any water. The remainder of the toluene was removed in vacua on a rotary evaporator using a water aspirator, and finally, traces of toluene were removed at 75°C on the rotary evaporator using a vacuum pump. The glassy syrup was dissolved in 150 ml of anhydrous dichloromethane and 1.62 g (11.66 mmole) of p-Nitrophenol (recrystallized twice from toluene) added followed by 150 mg (1.23 mmole) of 4-(dimethylamino) pyridine (DMAP). Finally, 2.24 g (11.68 mmole) of finely ground l-[3- (dimethylamino)propel]-3-ethyl carbodumide (EDC) was added in portions over a period of 30 minutes to the stirred solution under a nitrogen atmosphere. The reaction was stirred at room temperature for 4 hours. After the reaction period, glacial acetic acid (361 mg, 6.01 mmole, 345 microliters) was added to react with the excess p-nitrophenol and EDC, and stirring was continued 30 minutes. Finally, the DMAP catalyst was deactivated by the addition of 234 mg (1.23 mmole) of p-toluenesulfonic acid monohydrate and the solution concentrated in vacua to a thick syrup at 40°C and finally cooled to room temperature. Purification: Methanol (MeOH, 20 ml, more can be added if necessary) was added and the material stirred until complete dissolution of the glass had occurred. Isopropanol (IP A, 50 ml) was added and the solution cooled slightly with cold tap water. After a few minutes, a precipitate formed on the bottom of the flask. The solution containing the precipitate was stirred at room temperature while adding 150 ml IPA over a period of 5 minutes. The material was digested by stirring at room temperature a minimum of 30 minutes, cooling to 0EC in an ice bath and finally to -15°C in an ice/salt bath. The solid was filtered, washed with 80 ml of IPA at -15°C in several portions and air dried on the Buchner funnel to a damp solid (until no more IPA passed through the funnel). The solid was quantitatively removed from the Buchner funnel and re-purified as above using the same quantities of MeOH and IPA. After the second recrystallization/precipitation, the filter cake was washed with 25 ml of ether in three portions. The air dried material was powdered by passing through a 200 mesh sieve and the product vacuum dried overnight at room temperature to yield 15.09 g (97.1%) of 20KD pPEG-8PA-ONρ which was determined to contain 5.5 moles of ONp/mole polymer. The product was analyzed by TLC using 10/1/0.25 CHCI 3 /MeOH/AcOH (Merck, aluminum backed F-254 silica gel plates) and the plate first visualized under UV light. Only material at the origin could be seen as a dark spot. The plate was then dipped into concentrated ammonium hydroxide solution to visualize p-nitrophenol containing molecules. Only material at the origin developed the characteristic yellow color of p-nitrophenoxide anion. No free p-nitrophenol or p- nitrophenyl acetate could be detected in the product. Finally, the plate was strongly heated with a heat gun to drive off volatile materials, dipped into a 1.5% methanolic solution of silver nitrate and again strongly heated with the heat gun. A dark brown spot developed at the origin. No other contaminants were present. The product should be stored at -20°C and converted to the next intermediate within a 5-day period in order to minimize further chain elongation and cross-linking. Example 25 Preparation of Pendant 20KD pPEG-8PA-TT30 Reaction and Work-up: 20KD pPEG-8PA-PNp (MW = 19,650, 3.0 g, 152.7 micromoles and TT30 (SEQ ID NO:31) [1030 mg, 686.2 micromoles, 4.5 equivalents (as the bis-trifluoroacetate salt, MW = 1501)] were dissolved in 30 ml of DMF and 127 mg (1041 micromoles, 6.8 equivalents) of DMAP added. When complete dissolution of all solids was obtained, 134 mg (1041 micromoles, 181 microliter, 6.8 equivalents) of DIEA were added and the solution stirred at room temperature overnight. The reaction mixture was treated with 200 microliters of concentrated ammonium hydroxide for 30 minutes, 9.0 ml of glacial acetic acid added and the solution concentrated in vacuo at 50°C using a vacuum pump on a rotary evaporator. Purification by LH-20 Chromatography: The residue from above was dissolved in 50 ml of MeOH and introduced onto the top of a 5 x 65 cm LH-20 column packed in MeOH. The flask containing the original MeOH solution was rinsed three times with a - 10 ml of MeOH and the washings introduced onto the column. The solution at the top of the column was stirred with a spatula without disturbing the bed until homogeneous and then allowed to flow onto the column such that the liquid level was just above the bed and the flow stopped. The sample was allowed to equilibrate with the column for 15 to 30 minutes (preferably 20 minutes) before the flow was again started (flow rate = 10 ml/min.). Fresh solvent was added to the column, fractions collected, and analyzed by TLC (acetonitrile/n-butanol/toluene/acetic acid/water 1/1/1/1/1. ABTAW). The product eluted between 460 and 775 ml. The absence of free TT30 in samples containing product was established by visualization with both UV light and ninhydrin plus heat, while UV light alone confirmed the absence of DMAP and p-nitrophenol (plate can be dipped in concentrated ammonium hydroxide to confirm). Finally, visualization of the plate with 1.5% methanolic silver nitrate plus heat showed the presence of material at the origin in fractions containing only the product. Fractions were combined, concentrated in vacua and the residue dissolved in a minimum amount of MeOH. Ether (200 ml) was added in one portion to the rapidly stirred methanol solution and the suspension stirred at room temperature 1 hour. The suspension was, filtered, the filter cake washed with ether, air dried and vacuum dried overnight at room temperature to afford 3.53 g of 20KD pPEG- 8PA-TT30. A nitrogen determination on this product showed it to contain 3.91%N. Typically between 4.2 and 4.4 moles of TT45/mole polymer is incorporated using the above procedures. Example 26 Preparation of Pendant 20KD pPEG-8PA-TT30(SEQ ID NO:46)-DXR Reaction and Work-up: To a solution of 2.0g (81.14 micromoles) of 20KD pPEG- 8PA-TT30 (MW = 24,650, 4.25 mole TT45/mole polymer) and 188 mg of DXR HCI(324.5 micromoles, 4 equivalents) in 20 ml of anhydrous DMF was added 41.8 mg (324.6 micromoles, 56 microliters, 4 equivalents) of DIEA followed by 90.2 mg (649 micromoles, 8 equivalents) of p-nitrophenol and 19.8 mg (162.3 micromoles, 2 equivalents) of DMAP. EDC (124.4 mg, 649 micromoles, 8 equivalents) was added and finally another 41.8 mg (324.6 micromoles, 57 microliters) of DIEA. The reaction was stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction was treated with 50 microliters of glacial acetic acid for 60 minutes before concentrating in vacua at 45 to 50°C on a rotary evaporator equipped with a vacuum pump. Purification by LH-20 Chromatography: The residue was dissolved in 50 ml of methanol and introduced into the center of a 5.5 x 65 cm column of LH-20 packed in MeOH. A piece of shark-skin filter paper was placed on top of the column to prevent the bed from being distributed. The flask containing the sample was rinsed three times with about 10 ml of MeOH, the washings introduced onto the column, and the solution stirred with a spatula until homogeneous. The sample was allowed to flow onto the column such that the liquid level was just above the bed and the flow stopped. The sample was allowed to equilibrate on the column for 20 minutes and the flow re-initiated by introducing fresh MeOH according to standard procedures (flow-rate = 9.0 ml/min). As the separation proceeded, the drug conjugate moved quickly through the column eluting it between 350 and 550 ml. Some trailing into lower molecular weight components was observed. The product appeared well separated from unreacted doxorubicin and doxorubicin acetamide formed during the quench; however, TLC analysis of the fractions containing the product showed the presence of small amounts of free doxorubicin. The fractions were combined and concentrated and the residue replaced in the freezer while cleaning the column. As mentioned earlier, the column is cleaned using MeOH containing 0.6% concentrated hydrochloric acid (11 of MeOH containing 6.0 ml of concentrated hydrochloric acid). For the intermediate size column (5.5 x 65 cm), generally, 1 L of the acid solution followed by enough MeOH to bring the pH of a solution of 2 ml of the effluent in 10 ml of water to the same or higher pH of 2 ml of reagent grade MeOH in 10 ml of water. In addition, it is a good idea to collect about 300 to 500 ml of effluent after achieving the proper pH, concentrating it down, reconstituting in 10 ml of MeOH and obtaining the absorbency of the solution at 488 nm (ε = 10,000) to be sure that significant amounts of doxorubicin containing compounds are absent. In the case of the larger 6.5 x 65 cm column 1.51 of the acid should be used for cleaning. It is important that once the acid is introduced onto the column, the cleaning procedure should be continued until the column is clean and the pH adjusted to 6.5. Acid should not be allowed to sit on the column overnight or for longer periods of time, for example. Of course, the methanol can also be recycled. The sample was re-chromatographed exactly as above. Analysis of the combined fractions by TLC (ABTAW) showed the absence of free doxorubicin or doxorubicin acetamide. The combined sample was concentrated in vacuo and the dark red glass dissolved in 35 ml of water. After filtering the solution through a 0.45 micron microporous filter and rinsing the apparatus with a small amount of water, the solution was frozen in a dry-ice/acetone bath and lyophilized overnight. The almost brick-red product weighed 1.20 g. The product was found to contain 4.19 wt.% doxorubicin or .96 moles of DXR per mole of polymer by measuring the UV absorption at 488 nm ε = 10,000) in PBS buffer at pH 7.2. Of the 4.19 wt.% total doxorubicin 3.89% of this or 0.16% represents "free doxorubicin". Example 27 The in vitro cytotoxicity dose response curves of 20KD pPEG-8PA-TT30-DXR prepared according to the procedure of Example 26, and unconjugated Doxorubicin(DXR) were measured on three human cell lines: Human B-cell lymphoma cell line(Raji and Daudi), Human T-cell lymphoma cell line(Hut78), according to a procedure described in Example 19. The results are shown in Figure 3 and Figure 4. As expected, cytotoxicities from 20KD pPEG-8PA-TT30-DXR require higher concentrations of doxorubicin (Figure 3) than unconjugated Doxorubicin (Figure 4) due to the requirement that pPEG-8PA-TT30-DXR be internalized by endocytosis, while the unconjugated Doxorubicin control rapidly diffuses into the cells and kills them. These results show that the presence of a ligand specific for binding to the IL-2 receptor and inducing receptor-mediated endocytosis in the three human cell lines tested, thus reducing side effects caused by administration of free doxorubicin. Example 28 Preparation of 20KD mρPEG-8PA-GFLG-DXR. A conjugate of mpPEG (monomethyl pendant PEG), the GFLG spacer, and DXR (doxorubicin) was prepared. Preparation of 20KD mpPEG-8PA-ONp: It was important that precautions be taken to exclude water throughout this reaction sequence. A dry 500 ml one neck 24/40 round bottom flask was charged with 10.0 g (500 micromole, MW = 20,000) of 20KD mpPEG-8PA (Innophase) and 200 ml of dry toluene. Approximately 100 ml of toluene was distilled at atmospheric pressure while magnetically stirring to remove water. The stirring bar was removed and the balance of the toluene removed in vacuo. Under a dry Argon atmosphere, dry dichloromethane (100 ml) was added to the syrup followed by 973 mg (7000 micromoles) of p-nitrophenol and 81.1 mg (665 micromoles) of 4- dimethylaminopyridine (DMAP). Finely ground l-[3-dimethylaminopropyl]-3- ethylcarbodiimide hydrochloride (EDC, 1340 mg, 7000 micromoles) was added in one portion while magnetically stirring the yellow solution. The reaction was allowed to proceed 2 hours from the point at which all EDC had dissolved. Acetic acid (250 microliters) was added (to consume unreacted p-nitrophenol and EDC) and the mixture stirred an additional 30 minutes at which time 126.6 mg (665 micromoles) of p- toluenesulfonic acid monohydrate were added to neutralize the DMAP catalyst. Stirring was continued until all of the solid had dissolved, the stirring bar was removed, and the solution concentrated in vacuo at 30 to 35 °C. For the purification 25 ml of methanol (MeOH) was added and the mixture stirred at room temperature until complete dissolution occurred. Isopropanol (IPA, 45 ml) was added, and the solution cooled in an ice bath until solid product appeared. The balance of 155 ml of IPA was added over a 2 - 3 minute period. The suspension was stirred for 30 minutes at 0 °C, filtered under an argon blanket, the filter plug washed with 100 ml of 10% MeOH in IPA (v/v) at 0 °C in several portions and dried to a damp solid (under an argon blanket). The flocculation procedure was repeated as described above except that the flask was mildly heated (a 37 °C waterbath is sufficient) after addition of the methanol to cause dissolution of the damp solid, and cooling was initiated before adding any IPA. When a solid began to form, 200 ml of IPA was added over a 2 to 3 minute period. The isolated damp product was vacuum dried overnight to afford 10.16 g (98% yield) of 20KD mpPEG-8PA-ONp as an off-white powder. No free p-nitrophenol, DMAP or p-nitrophenyl acetate could be detected in the product when it was analyzed by TLC ABTAW (CH 3 CN/sec-BuOH/toluene/AcOH/H 2 O 1/1/1/1/1)]. The product was determined to contain 6.0 moles ONp/mole polymer (MW = 20, 730) by determining the absorbance of a solution of ~6 mg (weighted to the nearest 0.01 mg) in 50.0 ml 0. IN NaOH solution at 402.5 nm. Preparation of 20KD mpPEG-8PA-GFLG. 20KD mpPEG-8PA-ONp (10 g, 482.4 micromoles) was introduced into a 500 ml one neck 24/40 round bottom flask followed by 6 equivalents of the peptide GFLG (1136 mg, 2894 micromoles) and 30 ml of DMF while magnetically stirring the mixture under a dry argon blanket. After all solid had dissolved, 529 mg (4342 micromoles) of DMAP were added followed by 755 microliters (4342 micromoles) of diisopropylethyl amine (DIEA) and the solution stirred at room temperature 3 hours. Concentrated ammonium hydroxide (750 microliters) was added, stirring continued 90 minutes and 4.5 g p-toluenesulfonic acid added. After complete dissolution of the solid, 30 ml of IPA were added and the stirred light yellow solution cooled in an ice bath until solid product began to form. The flask was removed from the ice bath, stirred at room temperature and 170 ml of IPA added over a period of 2 to 3 minutes. The flask was again immersed in the ice bath, stirred for 30 minutes, filtered under a blanket of argon, the filter cake washed with 100 ml of 10% MeOH in IPA (v/v) at 0 °C in several portions and dried to a damp solid. The solid was again flocculated; however, the mixture was heated in a 40 °C water bath after adding 25 ml of MeOH to cause dissolution. The flask was cooled in an ice bath while stirring the solution until solid began to form, the flask removed from the bath and 200 ml of IPA added over a 2 to 3 minute period with rapid stirring. The flask was again immersed in the ice bath, stirred for 30 minutes, filtered under a blanket of argon, the filter cake washed with 100 ml of 10% MeOH in IPA (v/v) at 0 °C in several portions and dried to a damp solid. The isolated, off-white product was dried under high vacuum at room temperature overnight to yield 10.1 g of 20KD mpPEG-8PA-GFLG (yield = 92% based on PEG, 96.7% based on GFLG), which was found to contain 5.8 moles GFLG/mole polymer (MW = 22, 160) by nitrogen analysis. Constant volume diafiltration can also be used to purify this intermediate. No contaminants, particularly p- toluenesulfonic acid, could be detected in the product when it was analyzed by TLC (ABTAW). No yellow color developed on treatment of a sample with 0. IN NaOH solution, indicating the absence of p-nitrophenol. Preparation of 20KD mpPEG-8PA-GFLG-DXR. 20KD mpPEG-8PA-GFLG from above (9.89 g, 446.3 micromoles) was mixed with 5 equivalents of DXR HC1 (Faith Eagle) (1294 mg, 2231.5 micromoles), 10 equivalents of p-nitrophenol (620.4 mg, 4463 micromoles), 2 equivalents of DMAP (108.9 mg, 892.6 micromoles), 10 equivalents of finely ground EDC (855.6 mg, 4463 micromoles) and 25 ml of dry DMF under an argon atmosphere. To the magnetically stirred mixture was added 5 equivalents of DIEA, (388 microliters, 2231.5 micromoles) and the reaction allowed to proceed overnight (16 hours). Water (500 microliters) was added to quench the reaction and stirring continued 2 hours. Acetic acid (500 microliters) was added and the solution stirred until homogeneous. The crude product was flocculated by adding 45 ml of IPA with cooling until solid appeared. IPA (150 ml) was added over a period of 2 to 3 minutes with stirring while continuing to cool the flask. The suspension was stirred 30 minutes at 0 °C, the product filtered under argon, washed with 50 ml of 10% MeOH in IPA (v/v, 0 °C) in several portions and the damp product dried under high vacuum (11 - 13 g). The product was further purified by either chromatographing the crude product twice on LH-20 columns using methanol as eluent or by constant volume diafiltration using 10%) aqueous methanol. In either case the purified product was isolated by concentrating the solution in vacuo, dissolving the product in 25 to 35 ml of methanol and flocculating the product by the addition of 200 ml of IPA while cooling to 0 °C. Filtration under argon followed by washing with 50 ml of 10% MeOH in IPA at 0 °C and high vacuum drying afforded 10 to 10.9 g of the final drug conjugate which was determined to contain 2.5 to 3.0 moles of doxorubicin per mole of polymer. Free doxorubicin could be reduced to a level of 0.02% of the total doxorubicin depending on the method of purification. The product demonstrated excellent solubility in both PBS buffer and water. The final product was fully characterized using standard analytical techniques applicable to polymers. Example 29 20KD mpPEG-8PA-(SEQ ID NO: 27)-DXR (TT23) and 20KD mpPEG-8PA-(SEQ ID NO: 46)-DXR (TT30), conjugates of Doxorubicin, were evaluated in vivo as single agents against the Daudi human lymphoma tumor xenograft in a Daudi human tumor xenograft model to determine antitumor activity. TT23 and TT30 were synthesized according to the method of Example 28, except that as the peptide sequence, SEQ ID NOS: 27 and 46 were used instead of SEQ ID NO: 21 (gly-phe-leu-gly). Female nude mice weighing approximately 20 g were implanted subcutaneously (s.c.) by trocar with tumor fragments harvested from s.c. growing Daudi tumors in nude mice hosts. When tumors were approximately 5 mm x 7 mm (thirteen days after inoculation), the animals were pair-matched into treatment and control groups. Each group contained between 7-8 mice, each of which was ear-tagged and followed individually throughout the experiment. The administration of drugs or vehicle began the day the animals were pair-matched (Day 1). Mice were weighed twice weekly, and tumor measurements were taken by calipers twice weekly, starting on Day 1. These tumor measurements were converted to mg tumor weight by the formula L 2 x W/2, where L is length and W is width. The experiment was terminated when control tumors reached a size of approximately 1 gram. Upon termination, all mice were weighed, sacrificed, and their tumors excised. Tumors were weighed, and the mean tumor weight per group was calculated. In this model the mean treated tumor weight/mean control tumor weight x 100% (T/C) is subtracted from 100% to give the tumor growth inhibition (TGI) for each group. Some drugs caused tumor shrinkage in this xenograft model. With these agents, the final weight of a given tumor was subtracted from its own weight at the start of treatment on Day 1. This difference divided by the initial tumor weight was the percentage shrinkage. A mean percentage tumor shrinkage was calculated from data from the mice in a group that experienced regressions. If the tumor completely disappeared in a mouse, it was considered a complete regression or complete tumor shrinkage. Statistical analysis on the final actual tumor weights was done using the log rank p- value test. The antitumor activity of TT23 and TT30 against the Daudi human lymphoma tumor xenograft model was evaluated. TT23 and TT30 were administered at doses of 1 , 3, and 7.5 mg/kg intravenously on a qdx5 schedule. Doxorubicin was administered intravenously at doses of 1 and 3 mg/kg also on a qdx5 schedule. Actual final tumor weight, tumor growth inhibition, and partial and complete responses were the primary efficacy endpoints of this study (Table 1 in Figure 6). The tumor growth curve based on estimated tumor size is shown in Figure 5. TT23 was highly active against the Daudi lymphoma tumor model with final tumor weights of 409.0 (TGI-45.8%), 300.8 (TGI-64.5%), and 37.2 (TGI-94.0%) mg at doses of 1, 3, and 7.5 mg/kg, respectively. At the highest dose (7.5 mg/kg) administered, there were 3 partial and 1 complete response. TT23 was generally well tolerated, however, at the 7.5 mg/kg dose there were 3 toxic deaths and 16.1% weight loss on Day 8 with weight gain by Day 19. TT30 was also highly active against the Daudi lymphoma tumor model with final tumor weights of 83.6 (TGI-90.5%), 179.8 (TGI-81.9%), and 32.8 mg at doses of 1 , 3, and 7.5 mg/kg, respectively. There was a minimum of one partial response at all dose levels. At the highest dose (7.5 mg/kg) administered, there were 4 partial and 2 complete responses. TT30 was generally well tolerated, however, at the 7.5 mg/kg dose there were 2 toxic deaths and 17.6% weight loss on Day 8 with weight gain by Day 19. In comparison to TT23, there was a significant decrease (p = 0.006) in actual final tumor weight with TT30 at 1 mg/kg. At the 3 and 7.5 mg/kg dose levels, administration of TT23 and TT30 resulted in similar actual final tumor weights. Administration of TT30 at 1 and 3 mg/kg resulted in partial and complete responses; no responses were observed with TT23 at similar doses. In comparison to doxorubicin, statistically, TT23 resulted in similar actual final tumor weights at the same dose levels (1 and 3 mg/kg). There was a trend towards doxorubicin at 3 mg/kg having a smaller actual final tumor weight. In addition, one partial and four complete responses were seen with doxorubicin at 3 mg/kg. When comparing TT30 with doxorubicin, the actual final tumor weight was smaller (p = 0.012) with TT30 at 1 mg/kg. However, similar actual final weights were observed with TT30 and doxorubicin at 3 mg/kg. Both compounds appeared to be highly efficacious against the Daudi tumor model. When comparing the conjugates at high dose levels with standard doxorubicin, similar antitumor activity was observed, especially with TT30. However, at the lowest dose level (1 mg/kg), TT30 did appear to be more active than doxorubicin. This observation may support the assumption that the conjugated compounds may be more target-specific compared to doxorubicin. Example 30 Toxicity of two conjugates of PEG, ligand, and doxorubicin was compared to toxicity of doxorubicin alone. In a single dose study, PEG (20Kd)-TT-23-DXR (Example 1) was administered in 0.01 ml PBS buffer, pH, 7.2 at 12, 25 and 36 mg/kg (equivalent doxorubicin dose) by intravenous injection (i.v.) into male CD-I mice. Positive control groups consisted of free doxorubicin and Doxil, a liposomal doxorubicin preparation, all at equivalent doxorubicin doses, PBS was used as a negative control group. Each group consisted of 6 animals. Body weights and general toxicity of each animal was monitored over the next 10 days, at the end of which time all surviving animals were sacrificed by cervical dislocation. Bone marrow (femur, hind leg), kidney, and liver were removed from each animal and placed in 10% neutral buffered formalin for fixation. The tissues were embedded in paraffin. Section were prepared and stained with 0.1% toluidine blue. Mean body weight for animals treated with free doxorubicin, Doxil and PEG-TT-23 targeted doxorubicin conjugate groups are presented in Figures 7, 8 and 9, respectively. Significant dose dependent reductions in body weight and mortality were noted in the free doxorubicin group (Figure 7). Two out of 6 animals treated with 24 mg/kg dose and all the animals treated with the 36 mg/kg dose of free doxorubicin died from acute toxicity prior to the end of the study. The death of each these animals was preceded by profound weight loss. Although no mortality was noted with Doxil, a dose dependent reduction in body weight was also observed with the Doxil treated animals as well (Figire 8). In contrast, body weights were essentially equivalent to PBS controls at all dosing levels of PEG-TT-23 targeted doxorubicin conjugates (Figure 9). The most substantial pathological finding was that near total destruction of bone marrow occurred in some animals treated with 24 mg/kg dose of free doxorubicin. Moderate changes were observed in bone marrow in Doxil group at 24 mg/kg dose, but was severe at 36 mg/kg dose of Doxil. No changes were noted in bone marrow at any of these doses in the PEG-TT-23 -doxorubicin conjugate treated animals. There were no lesions in any of the liver or kidney at 24 mg/kg dose. A multiple dose study also was conducted. PEG (20Kd)-TT-23-DXR conjugate was injected in 0.01 ml PBS buffer, pH, 7.2, weekly for 6 weeks at 4 mg/kg (equivalent doxorubicin dose); by intravenous injection into male BALB/c mice. Positive control groups consisted of free doxorubicin and Doxil all at an equivalent doxorubicin dose, PBS was used as a negative control group. Each group consisted of 8 animals. Body weights and other signs of toxicity were noted every 24 hours. Animals were sacrificed 2 weeks following the last dose and bone marrow (femur, hind leg), kidneys, livers, and spleen were harvested and fixed in 2% formalin for subsequent histopathology . Mean body weights for each group are shown in Figure 10. Mean body weights versus time for the PEG-TT-23-DXR conjugates are essentially equivalent to the PBS control group, whereas both free doxorubicin and Doxil treated group demonstrate reduced body weight relative to the PBS control. Preliminary histopathology demonstrates no changes in liver, kidney, spleen or bone marrow were noted. The results of these two studies clearly demonstrate that the toxicity associated with free doxorubicin and liposomal formulated doxorubin (Doxil), is significantly reduced or eliminated with PEG-TT-23-Doxorubicin conjugate. Example 31 The in vitro cytotoxicity dose response curves of 20KD mpPEG-8PA-GFLG-DXR and unconjugated Doxorubicin (DXR) were measured in three human cell lines: Human B- cell lymphoma cell line (Raji and Daudi), Human T-cell lymphoma cell line (Hut 78), and in HIP G2 cells and SK Br-3 cells. The dose response curves were obtained. Figure 11 illustrates the results of in vitro cytotoxic activity against HuT 78 cells. Figure 12 illustrates the results of in vitro cytotoxic activity against Daudi cells. Figure 13 illustrates the results of in vitro cytotoxic activity against Raji cells. Figure 14 illustrates the results of in vitro cytotoxic activity against HEP G2 cells. Figure 15 illustrates the results of in vitro cytotoxic activity against SKBr-3 cells. Example 32 Treatment of HuT 78 cutaneous T-cell lymphoma was conducted with 20KD mpPEG-8PA-TT45-DXR, 20KD mpPEG-8PA-GFLG-DXR, 20KD mpPEG-8PA-TT30- DXR, and free DXR. The mouse strain used was NIH III nu/nu, female, 6-8wks. Old (Harlan Sprague Dawley). The tumor cell line used was HuT 78, ATCC TIB 161, human cutaneous T-cell lymphoma (American Type Culture Collection, Rockville, MD). The compounds used were 20KD mρPEG-8PA-TT45-DXR (DXR content = 5.03%); 20KD mpPEG-8PA-GFLG-DXR (DXR content = 4.45%); 20KD mpPEG-8PA- TT30-DXR (DXR content = 4.78%); and unconjugated DXR (DXR-HC1, Faith Eagle Enterprises, Ltd., Lot: FAEC 99-5055 3/10/99). The conjugates were prepared as described in Example 8. The experimental groups were: Group A: 10 6 HuT 78 Cells Only, Untreated Control (received PBS sham injection), n = 6; Group B: 10 6 HuT 78 Cells + 1.193mg CA 1043-41 (DXR = 3mg/Kg), n = 6; Group C: 10 6 H uT 78 Cells + 1.348mg CA 1043-88 (DXR = 3mg/Kg), n = 6; Group D: HP HuT 78 Cells + 1.255mg CA 1043-95 (DXR = 3mg/Kg), n = 6; and Group E: 10 6 HuT 78 Cells + 60μg Free DXR (DXR = 3mg/Kg), n = 6. Each of 30 mice were implanted with 10 6 HuT 78 cells by SC injection of 0.2 cc of inoculum into the right hind flank (HuT 78 inoculum was prepared in sterile RPMI 1640 medium + 10% fetal bovine serum, at a density of 5.0 x 10 6 cells/ml). When tumors were approximately 5 mm x 7 mm in size (day +46 post-tumor implant), the animals were pair- matched into treatment and control groups. This was considered study Day 1. Beginning on Day 1, test compounds were administered by IV injection (tail vein), in a volume of 0.1 cc (solutions were prepared in sterile PBS, pH = 7.2). Each dose of free DXR or DXR- containing conjugate contained a DXR-equivalent of 3mg DXR kg body weight. Dosing was repeated on subsequent Days 2, 3, 4, and 5. Therefore, the treatment phase of the study commenced from Day 1 through Day 5. The study was terminated on Day 18. Starting on Day 1, the animals were weighed and tumor dimensions, L and W (length and width) were measured every other day. The tumor measurements were then converted to tumor mass (mg) using the formula: Tumor Mass = L 2 x W/2. The resulting tumor mass values were averaged for each study group for each study Day. Percent increase in tumor mass was then calculated for each group for each study Day using the formula:% Increase in Tumor Mass (% ITM) = ((mean tumor mass on Day X - mean tumor mass on Day 1) x 100) /mean rumor mass on Day 1. In this way, the data were normalized based on the initial mean tumor mass on Day 1 of the treatment phase of the study. These data were then converted to percent inhibition of tumor growth for each group as follows: % Inhibition of Tumor Growth = (% ITM, Control Group - % ITM, Experimental Group) x 100 % ITM Control Group The results are shown in Figures 16 and 17. Figure 16 is a graph of % increase in tumor mass as compared to Day 1 vs study day showing the progression of tumor growth in a 18 day plot in the HuT 78 lymphoma treatment study. Figure 17 is a graph of % inhibition of tumor growth as compared to untreated control vs study day in the HuT 78 Lymphoma treatment study of inhibition of tumor growth. The mpPEG-GFLG-DXR conjugate was the most effective compound for tumor shrinkage at every timepoint measured, resulting in more inhibition of tumor growth (compared to untreated controls) than for PEG-TT45-DXR, PEG-TT30-DXR and unconjugated DXR. The above examples are presented to enable those skilled in the art to understand more clearly and practice the present invention. It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that which follows is intended to illustrate and not limit the scope of the invention. Other aspects of the invention will be apparent to those skilled in the art to which the invention pertains.

Claims: CLAIMS What is claimed is: 1. A conjugate comprising (a) a water-soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target-receptor-binding peptide; wherein the ligand comprises the sequence X 1 -X 2 -leu 1 -glu 2 -his 3 -leu 4 -leu 5 -leu 6 -X 3 -X 4 - X 5 -X 6 , wherein: X„ if present, is thr, ser or gly; X 2 if present, is thr, gly, or ser;. X 3 if present, is thr, ala or gly; and X 4 -X 5 -X 6 , if present, is phe-leu-gly or leu-phe-gly; and wherein, in the leu-glu-his-leu-leu-leu sequence, at least one amino acid is substituted as follows: leu, is optionally substituted with met, ile, or val; glv^ is optionally substituted with gin, asp, or asn; his 3 is optionally substituted with arg, lys, leu, or ile; leu 4 is optionally substituted with ile, and val; leu 5 is optionally substituted with ile, val, and phe; and leu 6 is optionally substituted with ile, val, and tip. 2. The conjugate of claim 1, wherein the target receptor is an IL-2-receptor. 3. The conjugate of claim 1 , wherein in said ligand sequence: X 2 s gly; grα, is substituted with asn; and hiis 3 is substituted with arg. 4. The conjugate of claim 1, wherein said ligand comprises gly-phe-leu-gly. 5. The conjugate of claim 1 wherein the biocompatible polymer is a polyalkylene oxide. 6. The conjugate of claim 5 wherein said polyalkylene oxide is polyethylene oxide. 7. The conjugate of claim 5 wherein said polyalkylene oxide is a member selected from the group consisting of alpha-substituted polyalkylene oxide derivatives, polyethylene glycol homopolymers and derivatives thereof, polypropylene glycol homopolymers and derivatives thereof, alkyl-capped polyethylene oxides, bis-polyethylene oxides, copolymers of poly(alkylene oxides), branched polyethylene glycols, star polyethylene glycols, pendant polyethylene glycols, block copolymers of poly (alky lene oxides) and activated derivatives thereof. 8. The conjugate of claim 6 wherein said polyalkylene oxide is an alkyl blocked pendant polyethylene glycol. 9. The conjugate of claim 8 wherein said pendant polyethylene glycol is a mono-methyl blocked pendant polyethylene glycol. 10. The conjugate of claim 1 wherein said chemical agent is selected from the group consisting of cytotoxins, immunosuppressants, transforming nucleic acids, gene regulators, labels, antigens, and drugs. 11. The conjugate of claim 1 wherein said chemical agent is a cytotoxin selected from the group consisting of doxorubicin, taxol, cisplatin, methofrexate, cyclophosphamide and derivatives thereof. 12. A conjugate comprising (a) a water-soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target-receptor-binding peptide, wherein said target-receptor binding peptide comprises at least one amino acid sequence other than SEQ ID NO 1, that is capable of binding to the target receptor. 13. A conjugate comprising (a) a water-soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target-receptor-binding peptide, wherein the side chains of said target-receptor binding peptide are free of carboxyl groups. 14. A conjugate comprising (a) a water-soluble, biocompatible polymer, (b) at least one molecule of a chemical agent covalently, releasably coupled to the polymer, and (c) at least one copy of a ligand comprising a target-receptor-binding peptide, wherein said target-receptor binding peptide comprises the sequence Gly-Phe-Leu-Gly or Gly-Leu-Phe- Gly. 15. The conjugate of claim 14, wherein the target receptor is an IL-2-receptor. 16. The conjugate of claim 14, wherein the target receptor is a cancer cell receptor. 17. The conjugate of claim 14, wherein the target receptor is a cancer cell receptor. 18. The conjugate of claim 14, wherein the biocompatible polymer is a polyalkylene oxide. 19. The conjugate of claim 18, wherein the polyalkylene oxide is polyethylene oxide. 20. The conjugate of claim 18, wherein the polyalkylene oxide is selected from the group consisting of alpha-substituted polyalkylene oxide derivatives, polyethylene glycol homopolymers and derivatives thereof, polypropylene glycol homopolymers and derivatives thereof, alkyl-capped polyethylene oxides, bis-polyethylene oxides, copolymers of poly(alkylene oxides), branched polyethylene glycols, star polyethylene glycols, pendant polyethylene glycols, block copolymers of poly(alkylene oxides) and the activated derivatives thereof. 21. The conjugate of claim 14 wherein said polyalkylene oxide is an alkyl blocked pendant polyethylene glycol. 22. The conjugate of claim 21 wherein said pendant polyethylene glycol is a mono-methyl blocked pendant polyethylene glycol. 23. The conjugate of claim 14, wherein the chemical agent is selected from the group consisting of cytotoxins, immunosuppressants, transforming nucleic acids, gene regulators, labels, antigens, and drugs. 24. The conjugate of claim 14, wherein the chemical agent is a cytotoxin selected from the group consisting of adriamycin, doxorubicin, taxol, cisplatin, methofrexate, cyclophosphamide and derivatives thereof. 25. A method of delivering a chemical agent into a target-receptor-bearing cell in a population of cells, the method comprising: contacting the population of cells with an effective amount of the conjugate of claim 14 under conditions wherein the ligand binds to a target receptor on the target-receptor- bearing cells and elicits internalization of the conjugate into the cells. 26. A method of detecting a disease associated with elevated levels of soluble target receptor in circulation, the method comprising: combining a conjugate of claim 14 with a body fluid to be tested under conditions suitable for binding of said conjugate to the soluble target receptor on the target-receptor in said body fluid to form a complex; and detecting said complex and determining whether said complex is present at elevated levels as compared to normal individuals. 27. A conjugate comprising: a water-soluble, biocompatible alkyl blocked pendant polyalkylene glycol; at least one molecule of a chemical agent covalently, releasably coupled to the alkyl blocked pendant polyalkylene glycol; and at least one copy of a ligand comprising a target-receptor-binding peptide. 28. The conjugate of claim 27, wherein the target receptor is an IL-2-receptor. 29. The conjugate of claim 27, wherein the target receptor is a cancer cell receptor. 30. The conjugate of claim 27, wherein the target receptor is a leukemia cell receptor. 31. The conjugate of claim 27, wherein the alkyl blocked pendant polyalkylene glycol is an alkyl blocked pendant polyethylene glycol. 32. The conjugate of claim 31 , wherein the alkyl blocked pendant polyethylene glycol is a mono-methyl blocked pendant polyethylene glycol. 33. The conjugate of claim 31 , wherein the alkyl blocked pendant polyethylene glycol is a dimethyl blocked pendant polyethylene glycol. 34. The conjugate of claim 27, wherein the chemical agent is selected from the group consisting of cytotoxins, immunosuppressants, transforming nucleic acids, gene regulators, labels, antigens, and drugs. 35. The conjugate of claim 27, wherein the chemical agent is a cytotoxin selected from the group consisting of doxorubicin, taxol, cisplatin, methofrexate, cyclophosphamide and derivatives thereof. 36. The conjugate of claim 27, wherein the target-receptor-binding peptide is selected from the group consisting of SEQ ID NO:2 through SEQ ID NO:l 1 and SEQ ID NO:22 through SEQ ID NO:47, amides thereof and biologically functional equivalents thereof. 37. The conjugate of claim 27, wherein the target-receptor-binding peptide is selected from the group consisting of SEQ ID NO:22, SEQ ID NO:31, SEQ ID NO:46 and amides thereof. 38. The conjugate of claim 27, wherein the conjugate comprises at least 3 molecules of the chemical agent. 39. The conjugate of claim 27, wherein the conjugate comprises at least 5 molecules of the chemical agent. 40. A method of delivering a chemical agent into a target-receptor-bearing cell in a population of cells, the method comprising: contacting the population of cells with an effective amount of the conjugate of claim 27 under conditions wherein the ligand binds to a target receptor on the target-receptor- bearing cells and elicits internalization of the composition into the cells. 41. A method of detecting a disease associated with elevated levels of soluble target receptor in circulation, the method comprising: combining a conjugate of claim 27 with a body fluid to be tested under conditions suitable for binding of said conjugate to the soluble target receptor on the target-receptor in said body fluid to form a complex; and detecting said complex and determining whether said complex is present at elevated levels as compared to normal individuals.

Inventors: ANDERSON CHRISTOPHER G, PRAKASH RAMESH K, ANDERSON, CHRISTOPHER, G., PRAKASH, RAMESH, K.
Applicants: ANDERSON CHRISTOPHER G, PRAKASH RAMESH K, WATSON PHARMACEUTICALS INC, ANDERSON, CHRISTOPHER, G., PRAKASH, RAMESH, K., WATSON PHARMACEUTICALS, INC.
Application year: 2001
Main classification: C07K14
IPC codes: A61K38, A61K47, C07K5, C07K14