Claims for Patent: 7,597,889

Summary for Patent: 7,597,889

Title:	Binding molecules derived from immunoglobulins which do not trigger complement mediated lysis
Abstract:	Disclosed are binding molecules which are recombinant polypeptides containing: (i) a binding domain capable of binding a target molecule, and (ii) an effector domain having an amino acid sequence substantially homologous to all or part of a constant domain of a human immunoglobulin heavy chain; characterized in that the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target, and more preferably wherein the effector domain is capable of specifically binding FcRn and/or Fc.gamma.RIIb. These are generally based on chimeric domains which are derived from two or more human immunoglobulin heavy chain CH2 domains domains. In preferred embodiments the regions 233-236, and 327-331, are modified, as are further residues to render the molecule null allotypic. Also disclosed are nucleic acids, host cells, production processes and materials, and uses. Pharmaceutical preparations are also disclosed.
Inventor(s):	Armour; Kathryn Lesley (Cambridge, GB), Clark; Michael Ronald (Cambridge, GB), Williamson; Lorna McLeod (Cambridge, GB)
Assignee:	Cambridge Enterprise Limited (Cambridge, GB)
Application Number:	09/674,857
Patent Claims:	1. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain having an amino acid sequence homologous to a constant domain of a human immunoglobulin heavy chain; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target, and the effector domain is capable of specifically binding Fc.gamma.RIIb and optionally FcRn, and wherein the effector domain comprises a chimeric C.sub.H2 domain which is derived from two or more human immunoglobulin heavy chain C.sub.H2 domains, which human immunoglobulins are selected from IgG1, IgG2 and IgG4, and wherein the effector domain has a reduced affinity for Fc.gamma.RI, Fc.gamma.RIIa and Fc.gamma.RIII and a reduced ability to mediate complement lysis by comparison with said constant domain of a human immunoglobulin heavy chain and wherein the chimeric C.sub.H2 domain is a human immunoglobulin heavy chain C.sub.H2 domain which has the following blocks of amino acids at the stated positions: 233P, 234V, 235A, 236G, 327G, 330S and 331S numbered with respect to the EU numbering system of Kabat, and is at least 98% identical to G1 .DELTA.ac (SEQ ID NO:3) or G4 .DELTA.c (SEQ ID NO:12) as shown in FIG. 17. 2. The binding molecule as claimed in claim 1 wherein the chimeric C.sub.H2 domain consists of G1.DELTA.ac (SEQ ID NO:3) or G4.DELTA.c (SEQ ID NO:12) as shown in FIG. 17. 3. The binding molecule as claimed in claim 1 wherein the binding domain derives from a different source to the effector domain. 4. The binding molecule as claimed in claim 1 wherein the target molecule is selected from the group consisting of the RhD antigen of red blood cells; a human platelet antigen (HPA); a neutrophil antigen; a T-cell receptor; an integrin; a glomerular basement membrane (GBM) collagen type IV; a Der P1; VAP-1; laminin; lutheran; platelet glycoprotein VI; and platelet glyprotein Ia/IIa. 5. The binding molecule as claimed in claim 4 wherein the binding domain is the binding site of an antibody selected from the group consisting of anti-CD52; anti-RhD; anti-HPA-1a; anti-VAP-1; murine anti-.alpha.3 (IV) NC1; anti-CD3; anti-Der p I; anti-laminin; and anti-lutheran. 6. A preparation comprising the binding molecule as claimed in claim 1 plus a pharmaceutically acceptable carrier. 7. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain having an amino acid sequence homologous to a constant domain of a human immunoglobulin heavy chain; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target, and the effector domain is capable of specifically binding Fc.gamma.RIIb and optionally FcRn, and wherein the effector domain comprises a chimeric C.sub.H2 domain which is derived from two or more human immunoglobulin heavy chain C.sub.H2 domains, which human immunoglobulins are selected from IgG1, IgG2 and IgG4, and wherein the effector domain has a reduced affinity for Fc.gamma.RI, Fc.gamma.RIIa and Fc.gamma.RIII and a reduced ability to mediate complement lysis by comparison with said constant domain of a human immunoglobulin heavy chain and wherein the chimeric C.sub.H2 domain is a human immunoglobulin heavy chain C.sub.H2 domain which has the following blocks of amino acids at the stated positions: 233P, 234V, 235A and no residue at 236, 327G, 330S and 331S, numbered with respect to the EU system of Kabat, and is at least 98% identical to G1 .DELTA.ab (SEQ ID NO:1) or G2 .DELTA.a (SEQ ID NO:2) as shown in FIG. 17. 8. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain having an amino acid sequence homologous to a constant domain of a human immunoglobulin heavy chain; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target, and the effector domain is capable of specifically binding Fc.gamma.RIIb and optionally FcRn, and wherein the effector domain comprises a chimeric C.sub.H2 domain which is derived from two or more human immunoglobulin heavy chain C.sub.H2 domains, which human immunoglobulins are selected from IgG1, IgG2 and IgG4, and wherein the effector domain has a reduced affinity for Fc.gamma.RI, Fc.gamma.RIIa and Fc.gamma.RIII and a reduced ability to mediate complement lysis by comparison with said constant domain of a human immunoglobulin heavy chain and wherein the chimeric C.sub.H2 domain is a human immunoglobulin heavy chain C.sub.H2 domain which has the following blocks of amino acids at the stated positions: 233P, 234V, 235A and no residue at 236, 327G, 330S and 331S, numbered with respect to the EU system of Kabat, and wherein the chimeric C.sub.H2 domain consists of G1.DELTA.ab (SEQ ID NO:1) or G2.DELTA.a (SEQ ID NO:2) as shown in FIG. 17. 9. The binding molecule as claimed in claim 7 wherein the binding domain derives from a different source to the effector domain. 10. The binding molecule as claimed in claim 7 wherein the target molecule is selected from the group consisting of the RhD antigen of red blood cells; a human platelet antigen (HPA); a neutrophil antigen; a T-cell receptor; an integrin; a glomerular basement membrane (GBM) collagen type IV; a Der P1; VAP-1; laminin; lutheran; platelet glycoprotein VI; and platelet glyprotein Ia/IIa. 11. The binding molecule as claimed in claim 10 wherein the binding domain is the binding site of an antibody selected from the group consisting of anti-CD52; anti-RhD; anti-HPA-1a; anti-VAP-1; murine anti-.alpha.3 (IV) NC1; anti-CD3; anti-Der p I; anti-laminin; and anti-lutheran. 12. A preparation comprising the binding molecule as claimed in claim 7 plus a pharmaceutically acceptable carrier. 13. The binding molecule as claimed in claim 5 wherein the anti-CD52 binding domain is CAMPATH-1; the anti-RhD is FOG1; the anti-Der p I is 2C7; the anti-CD3 is YTH12.5. 14. The binding molecule as claimed in claim 11 wherein the anti-CD52 binding domain is CAMPATH-1; the anti-RhD is FOG1; the anti-Der p I is 2C7; the anti-CD3 is YTH12.5. 15. The binding molecule as claimed in claim 4 wherein the HPA is HPA-1a. 16. The binding molecule as claimed in claim 10 wherein the HPA is HPA-1a. 17. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain comprising chimeric C.sub.H2 domain which consists of G1.DELTA.ac (SEQ ID NO:3) as shown in FIG. 17. 18. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain comprising chimeric C.sub.H2 domain which consists of G4.DELTA.c (SEQ ID NO:12) as shown in FIG. 17. 19. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain comprising chimeric C.sub.H2 domain which consists of G1.DELTA.ab (SEQ ID NO:1) as shown in FIG. 17. 20. A binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain comprising chimeric C.sub.H2 domain which consists of G2.DELTA.a (SEQ ID NO:2) as shown in FIG. 17. 21. An isolated nucleic acid comprising the nucleotide sequence encoding the effector domain of the binding molecule as claimed in claim 17, wherein said nucleic acid is DNA. 22. An isolated nucleic acid comprising the nucleotide sequence encoding the effector domain of the binding molecule as claimed in claim 18, wherein said nucleic acid is DNA. 23. An isolated nucleic acid comprising the nucleotide sequence encoding the effector domain of the binding molecule as claimed in claim 19, wherein said nucleic acid is DNA. 24. An isolated nucleic acid comprising the nucleotide sequence encoding the effector domain of the binding molecule as claimed in claim 20, wherein said nucleic acid is DNA. 25. An isolated nucleic acid comprising the nucleotide sequence encoding the effector domain of the binding molecule as claimed in claim 1, wherein said nucleic acid is DNA. 26. An isolated nucleic acid comprising the nucleotide sequence encoding the binding molecule as claimed in claim 1, wherein said nucleic acid is DNA. 27. The nucleic acid as claimed in claim 25 which is a replicable vector. 28. The nucleic acid as claimed in claim 27 wherein the nucleotide sequence is operably linked to a promoter. 29. An isolated host cell comprising or transformed with the vector of claim 28. 30. A process for producing a binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain having an amino acid sequence homologous to a constant domain of a human immunoglobulin heavy chain; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target, and the effector domain is capable of specifically binding Fc.gamma.RIIb and optionally FcRn, and wherein the effector domain comprises a chimeric C.sub.H2 domain which is derived from two or more human immunoglobulin heavy chain C.sub.H2 domains, which human immunoglobulins are selected from IgG1, IgG2 and IgG4, and wherein the effector domain has a reduced affinity for Fc.gamma.RI, Fc.gamma.RIIa and Fc.gamma.RIII and a reduced ability to mediate complement lysis by comparison with said constant domain of a human immunoglobulin heavy chain; the process comprising the steps of modifying a nucleotide sequence encoding a first human immunoglobulin heavy chain C.sub.H2 domain such that 2 or 3 amino acids in at least 1 region of the C.sub.H2 domain correspond to the amino acids from a second human immunoglobulin heavy chain C.sub.H2 domain, wherein said modification introduces the following blocks of amino acids at the stated positions: 233P, 234V, 235A, 236G, 327G, 330S and 331S numbered with respect to the EU numbering system of Kabat and wherein said chimeric C.sub.H2 domain is at least 98% identical to G1 .DELTA.ac (SEQ ID NO:3) or G4 .DELTA.c (SEQ ID NO:12) as shown in FIG. 17, introducing into a host cell a vector comprising said modified nucleotide sequence, culturing said host cell under conditions such that said binding molecule is produced, and isolating said binding molecule from said cell culture. 31. A method of binding a target molecule, said method comprising contacting said target molecule with said binding molecule of claim 1 under conditions to allow binding. 32. The method of claim 31 wherein the effector domain specifically binds Fc.gamma.RIIb, which binding causes inhibition of one or more of B cell activation; mast cell degranulation; and phagocytosis. 33. The method of claim 31 to inhibit the binding of a second binding molecule to the target molecule. 34. The method of claim 33 wherein the second binding molecule is an antibody. 35. The method of claim 31 wherein the target molecule is selected from the group consisting of the RhD antigen of red blood cells; a human platelet antigen (HPA); a neutrophil antigen; a T-cell receptor; an integrin; a glomerular basement membrane (GBM) collagen type IV; a Der P1; VAP-1; laminin; lutheran; platelet glycoprotein VI; and platelet glycoprotein Ia/IIa. 36. The method of claim 31 wherein said target molecule is in a patient suffering from a disorder selected from the group consisting of: i) Graft-vs-host disease, host-vs-graft disease, organ transplant rejection, bone-marrow transplant rejection, autoimmune vasculitis, arthritis or asthma, wherein the target molecule is a T-cell receptor; ii) autoimmune haemolytic anaemia or autoimmune thrombocytopenia, wherein the target molecule is selected from the group consisting of red blood cell Rhesus antigens D,C,c,E and e, the Kell (Kl) antigen and platelet glycoprotein GPIIb/IIIa and GPIb/IX/V; iii) foetal/neonatal alloimmune thrombocytopenia, wherein the target molecule is human platelet antigen (HPA)-1a or platelet glycoprotein IIIa; iv) dust mite allergy, wherein the target molecule is Der P1 protein of the house dust mite Dermatophagoides pteronyssinus; v) Chrohn's, wherein the target molecule is VAP-1; vi) haemolytic disease of the newborn (HDN), wherein the target molecule is selected from the group consisting of red blood cell Rhesus antigens D,C,c,E and e, and the Kell (Kl) antigen; vii) Goodpastures, wherein the target molecule is non-collagenous (NC1) domain of .alpha.3(IV) collagen; viii) sickle cell anaemia, wherein the target molecule is selected from the group consisting of: thrombospondin, laminin and lutheran; and ix) coronary artery occlusion, wherein the target molecule is selected from the group consisting of integrin .alpha..sub.2.beta..sub.1 (platelet glycoprotein Ia/IIa) and non-integrin platelet glycoprotein VI. 37. The method of claim 31 wherein the contacting step is a step of administering the binding molecule to a patient, or optionally to the mother of the patient where the patient is an unborn infant. 38. An isolated nucleic acid comprising the nucleotide sequence encoding the effector domain of the binding molecule as claimed in claim 7, wherein said nucleic acid is DNA. 39. An isolated nucleic acid comprising the nucleotide sequence encoding the binding molecule as claimed in claim 7, wherein said nucleic acid is DNA. 40. The nucleic acid as claimed in claim 38 which is a replicable vector. 41. The nucleic acid as claimed in claim 40 wherein the nucleotide sequence is operably linked to a promoter. 42. An isolated host cell comprising or transformed with the vector of claim 41. 43. A process for producing a binding molecule which is a recombinant polypeptide comprising: (i) a binding domain capable of binding a target molecule, which binding domain is the binding site of an antibody, and (ii) an effector domain having an amino acid sequence homologous to a constant domain of a human immunoglobulin heavy chain; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis, or cell mediated destruction of the target, and the effector domain is capable of specifically binding Fc.gamma.RIIb and optionally FcRn, and wherein the effector domain comprises a chimeric C.sub.H2 domain which is derived from two or more human immunoglobulin heavy chain C.sub.H2 domains, which human immunoglobulins are selected from IgG1, IgG2 and IgG4, and wherein the effector domain has a reduced affinity for Fc.gamma.RI, Fc.gamma.RIIa and Fc.gamma.RIII and a reduced ability to mediate complement lysis by comparison with said constant domain of a human immunoglobulin heavy chain; the process comprising the steps of modifying a nucleotide sequence encoding a first human immunoglobulin heavy chain C.sub.H2 domain such that 2, 3 or 4 amino acids in at least 1 region of the C.sub.H2 domain correspond to the amino acids from a second human immunoglobulin heavy chain C.sub.H2 domain, wherein said modification introduces the following blocks of amino acids at the stated positions: 233P, 234V, 235A and no residue at 236 and 327G, 330S and 331S numbered with respect to the ELU numbering system of Kabat and wherein said chimeric C.sub.H2 domain is at least 98% identical to G1 .DELTA.ab (SEQ ID NO:1) or G2 .DELTA.a (SEQ ID NO:2) as shown in FIG. 17, introducing into a host cell a vector comprising said modified nucleotide sequence, culturing said host cell under conditions such that said binding molecule is produced, and isolating said binding molecule from said cell culture. 44. The process as claimed in claim 43 wherein 2 amino acids in 1 region of the C.sub.H2 domain are modified to the corresponding amino acids from the second human immunoglobulin heavy chain C.sub.H2 domain. 45. A method of binding the target molecule, said method comprising contacting said target molecule with said binding molecule of claim 7 under conditions to allow binding. 46. The method of claim 45 wherein the effector domain specifically binds Fc.gamma.RIIb, which binding causes inhibition of one or more of B cell activation; mast cell degranulation; and phagocytosis. 47. The method of claim 45 wherein the binding molecule inhibits the binding of a second binding molecule to the target molecule. 48. The method of claim 47 wherein the second binding molecule is an antibody. 49. The method of claim 45 wherein the target molecule is selected from the group consisting of the RhD antigen of red blood cells; an HPA alloantigen of platelets; a neutrophil antigen; a T-cell receptor; integrin; GBM collagen; Der P1; HPA-1a; VAP-1; laminin, lutheran; platelet glycoprotein VI; and platelet glycoprotein Ia/IIa. 50. The method of claim 45 wherein said target molecule is in a patient suffering from a disorder selected from the group consisting of: i) Graft-vs-host disease, host-vs-graft disease, organ transplant rejection, bone-marrow transplant rejection, autoimmune vasculitis, arthritis or asthma, wherein the target molecule is a T-cell receptor; ii) autoimmune haemolytic anaemia or autoimmune thrombocytopenia, wherein the target molecule is selected from the group consisting of red blood cell Rhesus antigens D,C,c,E and e, the Kell (Kl) antigen and platelet glycoprotein GPIIb/IIIa and GPIb/IX/V; iii) foetal/neonatal alloimmune thrombocytopenia, wherein the target molecule is human platelet antigen (HPA)-1a or platelet glycoprotein IIIa; iv) dust mite allergy, wherein the target molecule is Der P1 protein of the house dust mite Dermatophagoides pteronyssinus; v) Chrohn's, wherein the target molecule is VAP-1; vi) haemolytic disease of the newborn (HDN), wherein the target molecule is selected from the group consisting of red blood cell Rhesus antigens D,C,c,E and e, and the Kell (Kl) antigen; vii) Goodpastures, wherein the target molecule is non-collagenous (NC1) domain of .alpha.3(IV) collagen; viii) sickle cell anaemia, wherein the target molecule is selected from the group consisting of: thrombospondin, laminin and lutheran; and ix) coronary artery occlusion, wherein the target molecule is selected from the group consisting of integrin .alpha..sub.2.beta..sub.1 (platelet glycoprotein Ia/IIa) and non-integrin platelet glycoprotein VI. 51. The method of claim 45 wherein the contacting step is a step of administering the binding molecule to a patient, or optionally to the mother of the patient where the patient is an unborn infant. 52. The method as claimed in claim 35 wherein the HPA is HPA-1a.

Details for Patent 7,597,889

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Greer Laboratories, Inc.	N/A	insects (whole body), mite dermatophagoides pteronyssinus	Injection	101835	09/15/1958		2018-05-08
Allermed Laboratories, Inc.	N/A	insects (whole body), mite dermatophagoides pteronyssinus	Injection	102213	03/12/1974		2018-05-08
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2018-05-08
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2018-05-08
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2018-05-08