Patent AU-2016202183-B2 (AU)
Title: Immunoglobulin constant region FC receptor binding agents
Inventor: BLOCK DAVID S
IPC: C07K16/06
Filed: 2016-04-07
Granted: 2017-11-23
Abstract: European ERMANY Patent Office office europ6en des brevets Questions about this communication ? Contact Customer Services at www.epo.org/contact Walton, Sedn Malcolm Mewburn Ellis LLP City Tower 40 Basinghall Street London EC2V 5DE ROYAUME UNI Date Reference Application No./Patent No. SMW/FP6666903 08769936.9 - 1403 / 2185589 Applicant/Proprietor University of Maryland, Baltimore, et al Decision to grant a European patent pursuant to Article 97(1) EPC Following examination of European patent application No. 08769936.9 a European patent with the title and the supporting documents indicated in the communication pursuant to Rule 71(3) EPC (EPO Form 2004C) or in the information (EPO Form 2004W, cf. Notice from the EPO dated 8 June 2015, OJ EPO 2015, A52) dated 14.07.15 is hereby granted in respect of the designated Contracting States. Patent No. 2185589 Date of filing 30.05.08 Priority claimed 01.06.07/USP 941644 19.12.07/USP 15127 20.12.07/USA 15547 Designated Contracting States and Proprietor(s) AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR University of Maryland, Baltimore 620 West Lexington Street, 4th Floor Baltimore, MD 21201/US AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR Gliknik Inc. 801 W. Baltimore Street, Suite 501A Baltimore, MD 21201/US This decision will take effect on the date on which the European Patent Bulletin mentions the grant (Art. 97(3) EPC). The mention of the grant will be published in European Patent Bulletin 16/01 of 06.01.16. Date page 2 Application No. 08769936.9 Examining Division Covone-Van Hees M Le Flao K Bumb P \es Patent,, CD, ANMERKUNG ZUR ENTSCHEIDUNG OBER DIE ERTEILUNG EINES EUROPAISCHEN PATENTS (EPA Form 2006) 1 EPA Informationsbroschare "Nationales Recht zum EPO" Diese BroschOre enthalt nOtzliche Informationen zu den formalen Erfordernissen und den Handlungen, die vor den Patentbeh6rden der Vertragsstaaten vorzunehmen sind, um Rechte in diesen Staaten zu erlangen. Da diese Handlungen einem standigen Wandel unterworfen sind, sollte simmer nur die neueste Ausgabe der BroschOre benutzt werden. Nachtragliche Informationen werden im Amtsblatt ver6ffentlicht. 2. Obersetzung der europiischen Patentschrift nach Artikel 65 (1) des Europiischen Patentabereinkommens Sie werden erneut darauf hingewiesen, dass bestimmte Vertragsstaaten nach Artikel 65 (1) EPU eine Ubersetzung der europaischen Patentschrift verlangen; hierauf wird in der Mitteilung gemaB Regel 71 (5) EPU verwiesen. 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WO 2008/151088 PCT/US2008/065428 IMMUNOGLOBULIN CONSTANT REGION Fc RECEPTOR BINDING AGENTS BACKGROUND OF THE INVENTION Field of the Invention [0001] This invention relates generally to the fields of immunology, inflammation, and tumor immunology. More specifically, the present invention relates to biologically active biomimetic molecules comprising immunoglobulin Fc domains, compositions comprising such biomimetics, and methods of using such biomimetics. [0002] The invention also relates to the treatment and prophylaxis of pathological conditions mediated by monocyte-derived cells, and more particularly to the use of stabilized functional portions of IgG Fc fragments for such treatment and prophylaxis. Description of the Background Art [0003] Immune globulin products from human plasma have been used since the early 1950's to treat immune deficiency disorders and more recently, and more commonly, for autoimmune and inflammatory diseases. [0004] Initially, immune globulin products were administered by intramuscular injection. More recently, intravenous immune globulin (IVIG) has been used and was initially shown to be effective in treatment of the autoimmune disease idiopathic thrombocytopenic purpura (ITP) (Imbach P, Barandun S, d'Apuzzo V, et al: High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981 Jun 6; 1(8232): 1228-3 1). Human IVIG (referred to herein as "hIVIG") is a formulation of sterile, purified immunoglobulin G (IgG) products manufactured from pooled human plasma that typically contains more than 95% unmodified IgG, with only small and variable amounts of immunoglobulin A (IgA) or immunoglobulin M (IgM) (see, for example, Rutter A, Luger TA: High-dose intravenous immunoglobulins: an approach to treat severe immune-mediated and autoimmune diseases of the skin. J Am Acad Dermatol 2001 Jun; 44(6): 1010-24). Today the single most common clinical use of hIVIG is in the treatment of ITP. [0005] While hIVIG has been an effective clinical treatment, there are several shortcomings to hIVIG formulations, including the potential for inadequate sterility, the WO 2008/151088 PCT/US2008/065428 presence of impurities, lack of availability, and lot-to-lot variation. In particular hIVIG preparations can vary greatly in their immunoglobulin A (IgA) content which can be of concern because IgA can cause allergic and anaphylactic reactions in IgA-deficient recipients. [0006] In view of the negative aspects of hIVIG, there exists a need for an improved means of treating autoimmune and inflammatory diseases. .4_ rioen a [0007] In addition, multiple pathological conditions of a wide variety of types are mediated by cells derived from monocytes. A simple therapeutic and/or prophylactic agent for use in many, if not all, such conditions would be invaluable. SUMMARY OF THE INVENTION [0008] The immuno-regulatory properties of IVIG reside in the Fc domain of IgG molecules. For example, in murine models of ITP, both unmodified IVIG and the Fc fragment alone demonstrate therapeutic efficacy in restoring platelet counts, while isolated IVIG Fab fragments are not therapeutic (Samuelsson, A., Towers, T.L. & Ravetch, J.V. Anti-inflammatory Activity of IVIG Mediated Through the Inhibitory Fc Receptor. Science 291, 484-486 (2001)). Moreover Fc, but not Fab fragments of IVIG, is also therapeutically effective in the treatment of both childhood and adult idiopathic thrombocytopenic purpura (Follea, G. et al. Intravenous plasmin-treated gammaglobulin therapy in idiopathic thrombocytopenic purpura. Nouv Rev Fr Hematol 27, 5-10 (1985); Solal-Celigny, P., Bernard, J., Herrera, A. & Biovin, P. Treatment of adult autoimmune thrombocytopenic purpura with high-dose intravenous plasmin-cleaved gammaglobulins. Scand J Haematol 31, 39-44 (1983); Debre, M. & Bonnet, M.-C. Infusion of Gcgamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342, 945-49 (1993); Burdach, S.E., Evers, K. & Geurson, R. Treatment of acute idiopathic thrombocytopenic purpura of childhood with intravenous immunoglobulin G: Comparative efficacy of 7S and 5S preparations. J Pediatr 109, 770-775 (1986)). [0009] The therapeutic effect of IVIG is initially mediated through the Fc gamma receptor (FcyR) and relies on Dendritic Cell (DC)-macrophage cross-talk for its long term tolerogenic effects. FcyRIIIa plays a requisite role in the initiator phase and FcyRIIb is required for the effector phase in murine models of ITP (Samuelsson, A., Document No. 9275805 For example, the formation of immune globulins which contain additional Fc domains in one linear branch as a result of fusion to an existing Fc domain is described in W02005/077981. 2a WO 2008/151088 PCT/US2008/065428 Towers, T.L. & Ravetch, J.V. Anti-inflammatory Activity of IVIG Mediated Through the Inhibitory Fe Receptor. Science 291, 484-486 (2001); Siragam, V. et al. Intravenous immunoglobulin ameliorates ITP via activating Fc[gamma] receptors on dendritic cells. Nat Med 12, 688 (2006)). Similarly, human studies demonstrate that anti-Fcy receptor antibodies are effective in the treatment of refractory ITP (Clarkson, S. et al. Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody. N Engl J Med 314, 1236-1239 (1986)). Importantly, long term tolerogenic effects are mediated by cell-cell interactions, as adoptive transfer of IVIG-treated DCs is effective in treating murine models of ITP (Siragam, V. et al. Intravenous immunoglobulin ameliorates ITP via activating Fc[gamma] receptors on dendritic cells. Nat Med 12, 688 (2006)). [0010] The immunomodulatory effects of IVIG require aggregation of the FcyR. Aggregation of FcyR is mediated by IgG dimers present in IVIG (5-15% of the total IVIG) (Bleeker, W.K. et al. Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase. Blood 95, 1856-1861 (2000)). For example, in a murine model of ITP, treatment with IVIG with a high content of "dimers" (dimers of whole immunoglobulin molecules) enhanced platelet counts while IVIG "monomers" (whole immunoglobulin molecules) were not effective (Teeling, J.L. et al. Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood 98, 1095-1099 (2001)). Furthermore, despite the fact that ion exchange resin and polyethylene glycol fractionation are routinely used in the manufacture of IVIG to remove IgG aggregates, the clinical efficacy of IVIG correlates with the presence of dimers in the patient's sera (Augener, W., Friedman, B. & Brittinger, G. Are aggregates of IgG the effective part of high-dose immunoglobulin therapy in adult idiopathic thrombocytopenic purpura (ITP)? Blut 50, 249-252 (1985)). Importantly, the percentage of dimers also correlates with vasoactive side effects, which are treatable with acetylhydrolase (Bleeker, W.K. et al. Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase. Blood 95, 1856-1861 (2000)). [0011] The present invention relates to biologically active biomimetic molecules, compositions comprising the same, and methods of using the same. These biomimetics have broad application for treating immunological and inflammatory disorders including but not limited to autoimmune diseases, and they have utility as bioimmunotherapy agents for cancer. Further, certain of these biomimetics also have utility as reagents, such as for use in immunological assays for testing immune cell function and in the diagnosis of disease. Moreover, the biomimetics and compositions of the present invention have the advantage of overcoming the above-listed limitations of hIVIG. The invention also relates to the treatment and prophylaxis of pathological conditions mediated by monocyte-derived cells, and more particularly to the use of stabilized functional portions of lgG Fc fragments for such treatment and prophylaxis. The present invention is as defined in the claims, specifically a compound comprising two or more multimerized units, wherein each of said units comprises a multimerizing region and a region comprising at least one Fc domain that is capable of binding to a Fcy receptor, wherein each of said units comprises two dimerized monomers, wherein each of said monomers comprises a multimerizing region monomer and a region comprising at least one Fc domain monomer, wherein the dimerization of the two monomers forms a multimerizing region and a region comprising at least one Fc domain that is capable of binding to a Fcy receptor, wherein the multimerizing regions of the two or more units multimerize to form the compound, and wherein the compound is capable of binding to a first Fcy receptor through a first Fc domain and to a second Fcy receptor through a second Fc domain, wherein the multimerizing region is selected from the group consisting of an IgG2 hinge, an IgE CH2 domain, a leucine zipper, an isoleucine zipper and a zinc finger, and wherein each of the regions comprising at least one Fc domain that is capable of binding to a Fcy receptor comprises an IgGl hinge, an IgGl CH2 domain and an IgG1 CH3 domain. The present invention also provides the composition, pharmaceutical composition, and compositions for uses as defined in the claims. The present disclosure also provides a number of embodiments as set out below. Insofar as any embodiment is outside of the claims it is illustrative and part of the disclosure for reference purposes. WO 2008/151088 PCT/US2008/065428 sdorders including bot not limited to cutoim n dseosesr and they bae tilhty ts biimunotherapy aes orcaer. Fnrher certain of heae bomomes ah he uthy asraet sc sfr nimuooia awy, o testing muecl function and-in the dwgnosi of disetaser Moreover, the biomietieo ae comitns of the present invertion have the advantage of oemig he aoeptr ted rimtationv of bwl G The idention a so relates to the treatment and prophyaeo of pathoogicao conditions mediated by mopnrcytederived ee, nod more patiarly to the rse of stabiaed function portions , f IgGiFc fragments for sch treatment and prophylaxi. [00121 In a first embodiment the present isolated serial stradomers comprising two or more associated stradomer monomers, wherein each of the stradomer monomers comprises two or more Fc domain monomers, wherein the association of the two or more stradomer monomers forms two or more Fe domains, and wherein the serial stradomer specifically binds to a first Fey receptor through a first of the two or more Fe domains and to a second Fey receptor through a second of the two or more Fe domains. In a preferred embodiment, the two or mnore stradomner monomers are associated through a covalent bond, a disulfide bond or chemical cross-linking. [00131 In a preferred embodiment of the isolated serial stradoners of the disclosure, present inventienthe isolated serial stradorners are comprised of two associated stradomer monomers. In an equally preferred embodiment, the isolated serial stradomers are comprised of two associated stradorner monomers wherein both of the stradomer monomers comprise two Fe domain monomers, and wherein the association of the two stradomer monorners forms twvo Fe domains. In a first particular example of these embodiments directed to isolated serial stradomers, at least one of the two Fe domains comprises an lgG hinge and an IgG CH2 dornain. In a second particular example each of the two Fe domains independently comprises an lgG hinge and an lgG CH2 domain. In a third particular exarnple at least one of the two Fe domains comprises an IgG hinge, an IgG CH2 dom ain and an Ig CH3 dom ain. In a fourth particular example each of the two Fe domains independently comprises an IgG hinge, an IgG CH2 domain and an IgG CH3 domain. In a fifth particular example at least one of the two Fe domains comprises an IgG I hinge or an IgG3 hinge, an IgG 1 CR2 domain or an IgG3 CR2 domain, and an IgG I CR3 domain or an IgG3 CH3 domain. In a sixth particular exarnple at least one of the two Fe domains comprises an IgG I hinge or an IgG3 hinge, and an IgG I CH2 domain or an WO 2008/151088 PCT/US2008/065428 IgG3 CH2 domain. In a seventh particular example each of the two Fc domains independently comprises an IgGI hinge or an IgG3 hinge, an IgGI CH2 domain or an IgG3 CH2 domain, and an IgGI CH3 domain or an IgG3 CH3 domain. In an eighth particular example each of the two Fe domains independently comprises an IgGI hinge, an IgG I CH2 domain, and an IgG 1 CH3 domain. In a ninth particular example each of the two Fc domains independently comprises an IgG3 hinge, an IgG3 CH2 domain, and an IgG3 CH3 domain. In a tenth particular example each of the two Fe domains independently comprises an IgGi hinge, an IgGi CH2 domain, and an IgG3 CH3 domain. [0014] Also in this first embodiment, the two or more Fe domains are each of a same immunoglobulin Fc class, and the immunoglobulin Fc class is selected from the group consisting of IgGI, IgG2, IgG3, and IgG4. Alternatively, the two or more Fe domains arc each of a different immunoglobulin Fc class, and said immunoglobulin Fe class is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4. [0015] Further in this first embodiment, the first and second Fey receptors are each independently an Fey receptor I, an Fey receptor 11, an Fey receptor III or an Fey receptor IV. Preferably the first and second Fey receptors are each Fey receptor Ila. disclosure provides [0016] In a second embodiment the present m ; ir o isolated serial stradomers comprising two associated stradomer monomers, wherein each of the stradomer monomers comprises two Fe domain monomers, wherein the association of the two stradomer monomers forms two Fe domains, wherein each of said two Fe domains independently comprises an IgG hinge, an IgG CH2 domain and an IgG CH3 domain, and wherein the serial stradomer specifically binds to a first Fey receptor through a first of the two Fe domains and to a second Fey receptor through a second of the two Fe domains. In a preferred embodiment, the two or more stradomer monomers are associated through a covalent bond, a disulfide bond or chemical cross-linking. [0017] In a first particular example of this second embodiment the two Fe domains are each of a same immunoglobulin Fc class, and the immunoglobulin Fe class is selected from the group consisting of IgGI, IgG2, IgG3, and IgG4. In a second particular example the two Fe domains are each of a different immunoglobulin Fe class, and said immunoglobulin Fe class is selected from the group consisting of IgGI, IgG2, IgG3 and IgG4. In a third particular example at least one of the Fe domains comprises an IgG hinge and an IgG CH2 domain. In a fourth particular example each of the Fe domains WO 2008/151088 PCT/US2008/065428 independently comprises an IgG hinge and an IgG CH2 domain. In a fifth particular example at least one of the Fe domains comprises an IgG hinge, an IgG CH2 domain and an IgG CH3 domain. In a sixth particular example each of the Fc domains independently comprises an IgG hinge, an IgG CH2 domain and an lgG CH3 domain. In a seventh particular example at least one of the Fe domains comprises an IgGI hinge or an IgG3 hinge, an IgG 1 CH2 domain or an IgG3 CH2 domain, and an IgG 1 CH3 domain or an IgG3 CH3 domain. In an eighth particular example each of the Fe domains independently comprises an IgG I hinge or an IgG3 hinge, an IgG 1 CH2 domain or an IgG3 CH2 domain, and an IgG 1 CH13 domain or an IgG3 CH3 domain. In a ninth particular example each of the Fe domains independently comprises an IgGI hinge, an IgGI CH2 domain, and an IgG 1 CH3 domain. In a tenth particular example each of the Fe domains independently comprises an IgG3 hinge, an IgG3 CH2 domain, and an IgG3 CH3 domain. In an eleventh particular example each of the Fe domains independently comprises an IgG I hinge, an IgGI CH2 domain, and an IgG3 CH3 domain. disclosure provides [0018] In a third embodiment the present invention-4s-diected-4e isolated serial stradomers further comprising a Fab domain, wherein each of the stradomer monomers comprises an Fab fragment heavy chain and two Fe domain monomers, wherein the Fab fragment heavy chain is in a position amino terminal or carboxy terminal to the two Fe domain monomers, wherein an Fab fragment light chain is independently associated with each Fab fragment heavy chain, and wherein the Fab domain has antigen binding activity. In a preferred embodiment, each of the stradomer monomers further comprises an immunoglobulin hinge monomer, and wherein the immunoglobulin hinge monomer is in a position between the Fab fragment heavy chain and the two Fe domain monomers, disclosure provides [0019] In a fourth embodiment the present invenfion isdrt core stradomers comprising a core moiety linked to two or more core stradomer units, wherein each of the two or more core stradomer units comprises at least one Fe domain, and wherein each of the core stradomer units is independently selected from the group consisting of: (a) an Fe fragment, wherein said Fe fragment comprises two associated Fe fragment monomers, wherein each of said Fc fragment monomers comprises an Fe domain WO 2008/151088 PCT/US2008/065428 monomer, and wherein the association of the two Fc fragment monomers forms an Fe domain, (b) an Fe partial fragment, wherein said Fc partial fragment comprises two associated Fe partial fragment monomers, wherein each of said Fc partial fragment monomers comprises an Fe domain monomer, and wherein the association of the two Fc partial fragment monomers forms an Fe domain, (c) an Fe domain, wherein said Fe domain comprises two associated Fe domain monomers, and wherein the association of the two Fe domain monomers forms an Fe domain, (d) a serial stradomer, wherein said serial stradomer comprises two or more associated stradomer monomers, wherein each of said stradomer monomers comprises two or more Fe domain monomers, and wherein the association of the two or more stradomer monomers forms two or more Fe domains, and (e) a cluster stradomer, wherein said cluster stradomer comprises two or more multimerized cluster stradomer units, wherein each of said cluster stradomer units comprises a multimerizing region and at least one Fe domain, wherein each of said cluster stradomer units comprises two associated cluster stradomer unit monomers, wherein each of said cluster stradomer unit monomers comprises a multimerizing region monomer and at least one Fe domain monomer, wherein the association of the two cluster stradomer unit monomers forms a multimerizing region and at least one Fe domain, and wherein the multimerizing regions of the two or more cluster stradomer units multimerize to form the cluster stradomer, and wherein the core stradomer specifically binds to a first Fey receptor through a first of the two or more core stradomer units and to a second Fey receptor through a second of the two or more core stradomer units. [0020] Preferably in this fourth embodiment, the core moiety is selected from the group consisting of an immunoglobulin J chain, albumin, liposome, bead, peptide and polyethylene glycol. [0021] In preferred embodiments directed to core stradomers the two or more core stradomer units are each independently an Fc fragment. Alternatively, the two or more core stradomer units are each independently a serial stradomer. WO 2008/151088 PCT/US2008/065428 [0022] In a further preferred embodiment directed to core stradomers the core stradomer comprises two core stradomer units, wherein each of the two core stradomer units is each independently a serial stradomer, wherein the serial stradomer comprises two associated stradomer monomers, wherein both of said stradomer monomers comprises two Fe domain monomers, and wherein the association of the two stradomer monomers forms two Fc domains. In a first particular example of this embodiment, at least one of the Fe domains of the two or more core stradomer units comprises an IgGI hinge or an IgG3 hinge, an IgGI CH2 domain or an IgG3 CH2 domain, and an IgGI CH3 domain or an IgG3 CH3 domain. In a second particular example at least one of the Fe domains of the two or more two core stradomer units comprises an IgGI hinge or an IgG3 hinge, and an IgG I CH2 domain. In a third particular example each of the Fe domains of the two or more two core stradomcr units independently comprises an IgGI hinge, an IgGI CH2 domain, and an IgGI CH3 domain. In a fourth particular example at least one of the Fe domains of the two or more two core stradomer units comprises an IgG hinge and an igG CH2 domain. In a fifth particular example each of the Fe domains of the two or more two core stradomer units independently comprises an IgG hinge and an IgG CH2 domain. In a sixth particular example each of the Fe domains of the two or more two core stradomer units independently comprises an IgG3 hinge, an IgG3 CH2 domain, and an IgG3 CH3 domain. In a seventh particular example each of the Fe domains of the two or more two core stradomer units independently comprises an IgGI hinge, an IgGI CH2 domain, and an IgG3 CH3 domain. [0023] In this embodiment, the first and second Fcy receptors are each independently an Fcy receptor I, an Fey receptor II, an Fey receptor III or an Fey receptor IV. Preferably, the first and second Fey receptors are each Fey receptor I11a. disclosure provides [0024] In a fifth embodiment the present inenfionis-direeted-te cluster stradomers comprising two or more multimerized cluster stradomer units, wherein each of the cluster stradomer units comprises a multimerizing region and at least one Fe domain, wherein each of the cluster stradomer units comprises two associated cluster stradomer unit monomers, wherein each of the cluster stradomer unit monomers comprises a multimerizing region monomer and at least one Fe domain monomer, wherein the association of the two cluster stradomer unit monomers forms a multimerizing region and at least one Fe domain, wherein the multimerizing regions of the two or more cluster WO 2008/151088 PCT/US2008/065428 stradomer units multimerize to form the cluster stradomer, and wherein the cluster stradomer specifically binds to a first Fey receptor through a first Fe domain and to a second Fcy receptor through a second Fc domain. [0025] In preferred embodiments, the multimerizing region is selected from the group consisting of an lgG2 hinge, an IgE CH2 domain, a leucine, an isoleucine zipper and a zinc finger. [0026] In further preferred embodiment, the cluster stradomers comp