Claims for Patent: 8,617,554

Summary for Patent: 8,617,554

Title:	Anti-human CD52 immunoglobulins
Abstract:	The present invention relates to humanized immunoglobulins, mouse monoclonal antibodies and chimeric antibodies that have binding specificity for human CD52. The present invention further relates to a humanized immunoglobulin light chain and a humanized immunoglobulin heavy chain. The invention also relates to isolated nucleic acids, recombinant vectors and host cells that comprise a sequence which encodes a humanized immunoglobulin or immunoglobulin light chain or heavy chain, and to a method of preparing a humanized immunoglobulin. The humanized immunoglobulins can be used in therapeutic applications to treat, for example, autoimmune disease, cancer, non-Hodgkin\'s lymphoma, multiple sclerosis and chronic lymphocytic leukemia.
Inventor(s):	Roberts; Bruce L (Southborough, MA), Shankara; Srinivas (Shrewsbury, MA), Brondyk; William Harold (Mansfield, MA), Siders; William M (Franklin, MA)
Assignee:	Genzyme Corporation (Cambridge, MA)
Application Number:	13/320,019
Patent Claims:	1. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the light chain and heavy chain of said antibody comprise the three complementarity determining regions (CDRs) found in a) SEQ ID NOs: 3 and 16, respectively; b) SEQ ID NOs: 4 and 17, respectively; c) SEQ ID NOs: 5 and 18, respectively; d) SEQ ID NOs: 6 and 19, respectively; e) SEQ ID NOs: 7 and 20, respectively; f) SEQ ID NOs: 8 and 21, respectively; g) SEQ ID NOs: 9 and 22, respectively; h) SEQ ID NOs: 10 and 23, respectively; i) SEQ ID NOs: 11 and 24, respectively; j) SEQ ID NOs: 12 and 25, respectively; k) SEQ ID NOs: 12 and 137, respectively; or l) SEQ ID NOs: 13 and 26, respectively. 2. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain and the light chain of said antibody comprise the amino acid sequences of SEQ ID NOs: 279 and 280, respectively, without the signal sequences. 3. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the light chain of said antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 138, 145-148, 153-157, and 164-168. 4. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the light chain of said antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 273, 275, 278, 280, and 282, without the signal sequences. 5. An antibody light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 102, 138, 145-148, 153-157, 164-168, 273, 275, 278, 280, and 282, without the signal sequences if present. 6. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain of said antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 136, 137, 139-144, 149-152, and 158-163. 7. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain of said antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 272, 274, 276, 277, 279, and 281, without the signal sequences. 8. An antibody heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 103, 136, 137, 139-144, 149-152, 158-163, 272, 274, 276, 277, 279, and 281, without the signal sequences if present. 9. The monoclonal antibody or antigen-binding portion of claim 1, wherein the antibody is a humanized antibody, a mouse antibody, or a chimeric antibody. 10. The monoclonal antibody or antigen-binding portion of claim 1, wherein the framework regions of the heavy chain utilize a VH3-72 or VH3-23 human germline sequence, and wherein the framework regions of the light chain utilize a VK2 A18b human germline sequence. 11. The monoclonal antibody or antigen-binding portion of claim 1, wherein the antibody comprises heavy chain (H)-CDR1, H-CDR2, H-CDR3, and light chain (L)-CDR1, L-CDR2, and L-CDR3 whose amino acid sequences are: a) SEQ ID NOs: 51, 59, 69, 29, 36, and 43, respectively; b) SEQ ID NOs: 50, 60, 69, 29, 37, and 43, respectively; c) SEQ ID NOs: 50, 61, 68, 29, 38, and 43, respectively; d) SEQ ID NOs: 50, 61, 69, 29, 36, and 43, respectively; e) SEQ ID NOs: 50, 62, 69, 29, 39, and 43, respectively; f) SEQ ID NOs: 52, 61, 70, 30, 40, and 43, respectively; g) SEQ ID NOs: 53, 63, 71, 31, 36, and 44, respectively; h) SEQ ID NOs: 54, 64, 71, 31, 36, and 45, respectively; i) SEQ ID NOs: 55, 63, 72, 31, 36, and 46, respectively; j) SEQ ID NOs: 56, 65, 73, 32, 41, and 47, respectively; k) SEQ ID NOs: 56, 65, 294, 32, 41, and 47, respectively; or l) SEQ ID NOs: 56, 66, 74, 33, 41, and 48, respectively. 12. The monoclonal antibody or antigen-binding portion of claim 1, wherein the light chain and heavy chain of said antibody comprise the amino acid sequences of: a) SEQ ID NOs: 3 and 16, respectively; b) SEQ ID NOs: 4 and 17, respectively; c) SEQ ID NOs: 5 and 18, respectively; d) SEQ ID NOs: 6 and 19, respectively; e) SEQ ID NOs: 7 and 20, respectively; f) SEQ ID NOs: 8 and 21, respectively; g) SEQ ID NOs: 9 and 22, respectively; h) SEQ ID NOs: 10 and 23, respectively; i) SEQ ID NOs: 11 and 24, respectively; j) SEQ ID NOs: 12 and 25, respectively; or k) SEQ ID NOs: 13 and 26, respectively. 13. The monoclonal antibody or antigen-binding portion of claim 1, wherein said heavy chain and light chain comprise the amino acid sequences of a) SEQ ID NOs: 103 and 102, respectively; b) SEQ ID NOs: 136 and 138, respectively; c) SEQ ID NOs: 137 and 138, respectively; d) SEQ ID NOs: 139 and 147, respectively; e) SEQ ID NOs: 149 and 155, respectively; f) SEQ ID NOs: 149 and 156, respectively; g) SEQ ID NOs: 158 and 165, respectively; h) SEQ ID NOs: 158 and 166, respectively; i) SEQ ID NOs: 159 and 165, respectively; j) SEQ ID NOs: 159 and 166, respectively; k) SEQ ID NOs: 161 and 166, respectively; or l) SEQ ID NOs: 163 and 166, respectively. 14. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain and the light chain of said antibody comprise the amino acid sequences of SEQ ID NOs: 272 and 273, respectively, without the signal sequences. 15. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain and the light chain of said antibody comprise the amino acid sequences of SEQ ID NOs: 274 and 275, respectively, without the signal sequences. 16. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain and the light chain of said antibody comprise the amino acid sequences of SEQ ID NOs: 276 and 278, respectively, without the signal sequences. 17. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain and the light chain of said antibody comprise the amino acid sequences of SEQ ID NOs: 277 and 278, respectively, without the signal sequences. 18. A monoclonal anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, wherein the heavy chain and the light chain of said antibody comprise the amino acid sequences of SEQ ID NOs: 281 and 282, respectively, without the signal sequences. 19. The monoclonal antibody of any one of claims 1, 3, 6, and 11-13, wherein said antibody is an IgG1, IgG2, IgG3, or IgG4 molecule. 20. The antigen-binding portion of any one of claims 1, 3, and 6, wherein said portion is a single chain antibody, Fv, Fab, Fab', F(ab').sub.2, Fd, single chain Fv molecule (scFv), bispecific single chain Fv dimer, diabody, domain-deleted antibody or single domain antibody (dAb). 21. The monoclonal antibody or antigen-binding portion of claim 1, wherein said antibody or portion binds to an amino acid sequence comprising SEQ ID NO: 104, and optionally, the binding of said antibody or portion to SEQ ID NO: 104 is reduced by an alanine substitution at one or more of residues 4, 7, 8, and 11 of SEQ ID NO: 104. 22. The monoclonal antibody or antigen-binding portion of any one of claims 1, 3, and 6, wherein said antibody or antigen-binding portion has one or more properties selected from the group consisting of: a) depletes T or B lymphocytes, or both; b) preferentially depletes T lymphocytes as compared to B lymphocytes; c) increases circulating serum levels of TNF-alpha, IL-6, or MCP-1; d) mediates antibody-dependent cell mediated cytotoxicity (ADCC) of CD52-expressing cells; e) mediates complement-dependent cytotoxicity (CDC) of CD52-expressing cells; f) binds to human CD52 in the presence of neutralizing antibodies to alemtuzumab; and g) promotes intracellular signaling in human T or B lymphocytes, or both. 23. A composition comprising the monoclonal antibody or antigen-binding portion of any one of claims 1, 2, 3, 4, 6, 7 and 11-18, and a pharmaceutically acceptable vehicle or carrier. 24. An isolated nucleic acid encoding the heavy chain, or the light chain, or both, of an antibody or antigen-binding portion of any one of claims 1, 2, 3, 4, 5, 7, and 11-18. 25. The isolated nucleic acid of claim 24, wherein said isolated nucleic acid comprises: a) a heavy chain nucleotide sequence selected from the group consisting of SEQ ID NOs: 283, 285, 287, 288, 290, and 292, or said nucleotide sequence without the sequence encoding a signal peptide; b) a light chain nucleotide sequence selected from the group consisting of SEQ ID NOs: 284, 286, 289, 291, and 293, or said nucleotide sequence without the sequence encoding a signal peptide; or c) the nucleotide sequences of both a) and b). 26. The isolated nucleic acid of claim 25, wherein said isolated nucleic acid comprises a heavy chain nucleotide sequence and a light chain nucleotide sequence selected from the group consisting of: a) SEQ ID NO: 283 and SEQ ID NO: 284, respectively, both without sequences encoding signal peptides; b) SEQ ID NO: 285 and SEQ ID NO: 286, respectively, both without sequences encoding signal peptides; c) SEQ ID NO: 287 and SEQ ID NO: 289, respectively, both without sequences encoding signal peptides; d) SEQ ID NO: 288 and SEQ ID NO: 289, respectively, both without sequences encoding signal peptides; e) SEQ ID NO: 290 and SEQ ID NO: 291, respectively, both without sequences encoding signal peptides; and f) SEQ ID NO: 292 and SEQ ID NO: 293, respectively, both without sequences encoding signal peptides. 27. A host cell comprising a first nucleic acid sequence encoding the heavy chain of a monoclonal antibody or antigen-binding portion of any one of claims 1, 2, 3, 4, 6, 7, and 11-18, said first nucleic acid sequence operably linked to an expression control element, and a second nucleic acid sequence encoding the light chain of said monoclonal antibody or antigen-binding portion, said second nucleic acid sequence operably linked to an expression control element. 28. A method of expressing an anti-human CD52 antibody or an antigen-binding portion that binds to human CD52, comprising maintaining the host cell of claim 27 under conditions appropriate for expression of the antibody or portion, and expressing said antibody or portion. 29. A method for inducing immunosuppression in a patient, comprising administering to the patient an effective amount of the antibody or antigen-binding portion of any one of claims 1, 2, 3, 4, 6, 7, and 11-18. 30. The method of claim 29, wherein the patient has an autoimmune disease. 31. A method for targeting CD52.sup.+cells in a cancer patient, comprising administering to the patient an effective amount of the monoclonal antibody or antigen-binding portion of any one of claims 1, 2, 3, 4, 6, 7, and 11-18. 32. A method of inhibiting angiogenesis in a patient in need thereof, comprising administering an effective amount of the monoclonal antibody or portion of any one of claims 1, 2, 3, 4, 6, 7, and 11-18, to the patient. 33. The method of claim 29, wherein the patient is receiving transplantation. 34. The method of claim 30, wherein said autoimmune disease is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, or vasculitis. 35. The method of claim 31, wherein the cancer patient has leukemia. 36. The method of claim 31, wherein the cancer patient has lymphoma. 37. The method of claim 31, wherein the cancer patient has T cell malignancy, and the antibody or portion preferentially depletes T cells as compared to B cells. 38. The method of claim 31, wherein the cancer patient has a solid tumor. 39. The method of claim 29, further comprising administering to the patient a neutrophil or NK cell stimulatory agent. 40. The method of claim 31, further comprising administering to the patient a neutrophil or NK cell stimulatory agent. 41. The method of claim 29, further comprising administering to the patient a T regulatory cell stimulatory agent. 42. The method of claim 31, further comprising administering to the patient a T regulatory cell stimulatory agent. 43. The method of claim 32, wherein the patient has a solid tumor. 44. The method of claim 32, wherein the patient has neovascularization.

Details for Patent 8,617,554

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2029-05-13
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2029-05-13
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2029-05-13