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Last Updated: August 14, 2020

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Claims for Patent: 8,217,147

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Summary for Patent: 8,217,147
Title:Identification and engineering of antibodies with variant Fc regions and methods of using same
Abstract: The present invention relates to molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds Fc.gamma.RIIIA and/or Fc.gamma.RIIA with a greater affinity, relative to a comparable molecule comprising the wild-type Fc region. The molecules of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection. The molecules of the invention are particularly useful for the treatment or prevention of a disease or disorder where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by Fc.gamma.R is desired, e.g., cancer, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.
Inventor(s): Stavenhagen; Jeffrey (Brookville, MD), Gorlatov; Sergey (Gaithersburg, MD), Rankin; Christopher (Clarksburg, MD), Tuaillon; Nadine (Gaithersburg, PA)
Assignee: MacroGenics, Inc. (Rockville, MD)
Application Number:11/502,820
Patent Claims:1. An antibody having a variant Fc region, or a fragment thereof which comprises said variant Fc region, wherein said variant Fc region comprises amino acid modifications relative to a wild-type Fc region such that said variant Fc region binds Fc.gamma.RIIIA with a greater affinity relative to an antibody comprisinga the wild-type Fc region and wherein said amino acid modifications are: (A) a substitution at position 243 with leucine, at position 292 with proline, at position 300 with leucine, at position 305 with isoleucine, and at position 396 with leucine; (B) a substitution at position 243 with leucine, at position 292 with proline, at position 300 with leucine, and at position 396 with leucine; or (C) a substitution at position 243 with leucine, at position 292 with proline, and at position 300 with leucine; wherein the positions are numbered according to the EU index as in Kabat.

2. The antibody or fragment thereof of claim 1, wherein said variant Fc region further specifically binds Fc.gamma.RIIB with a lower affinity than a comparable antibody comprising the wild-type Fc region binds Fc.gamma.RIIIA or Fc.gamma.RIIB, and wherein said amino acid modifications are the substitutions of section (C).

3. The antibody or fragment thereof of claim 1 or 2, wherein the Fc region is a human IgG Fc region.

4. The antibody or fragment thereof of claim 3, wherein the human IgG Fc region is a human IgG1, IgG2, IgG3, or IgG4 Fc region.

5. The antibody or fragment thereof of claim 1, wherein said antibody is a monoclonal antibody, a humanized antibody, or a human antibody.

6. The antibody or fragment thereof of claim 1, wherein said antibody is a humanized antibody.

7. The antibody or fragment thereof of claim 1, wherein said antibody comprises a variable domain which binds to CD16A or CD32B.

8. The antibody or fragment thereof of claim 1, wherein said antibody is antibody 2B6 (ATCC PTA-4591).

9. The antibody or fragment thereof of claim 1, wherein said antibody is a humanized version of antibody 2B6 (ATCC PTA-4591), and wherein said humanized antibody includes the six CDRs of antibody 2B6.

10. The antibody or fragment thereof of claim 1, wherein said variant Fc region competitively inhibits the binding of antibody 2B6 (ATCC PTA-4591) to CD32B.

11. A nucleic acid comprising a nucleotide sequence encoding the antibody or fragment thereof of any of claim 1 or 2.

12. A vector comprising the nucleic acid of claim 11.

13. The vector of claim 12 which is an expression vector.

14. A host cell comprising the nucleic acid of claim 13.

15. A method for recombinantly producing the antibody or fragment thereof of claim 1 or 2, said method comprising: (i) culturing in a medium a host cell comprising a nucleic acid encoding said antibody under conditions suitable for the expression of said antibody; and (ii) recovery of said antibody from said medium.

16. A antibody or an antigen binding fragment thereof, wherein said antibody and said fragment specifically bind a cancer antigen, said antibody and said fragment comprising a variant Fc region, wherein said variant Fc region comprises amino acid modifications relative to a wild-type Fc region such that said antibody specifically binds Fc.gamma.RIIIA with a greater affinity than the antibody comprising the wild-type Fc region binds Fc.gamma.RIIIA and wherein said amino acid modifications are: (A) a substitution at position 243 with leucine, at position 292 with proline, at position 300 with leucine, at position 305 with isoleucine, and at position 396 with leucine; (B) a substitution at position 243 with leucine, at position 292 with proline, at position 300 with leucine, and at position 396 with leucine; or (C) a substitution at position 243 with leucine, at position 292 with proline, and at position 300 with leucine; wherein the positions are numbered according to the EU index as in Kabat.

17. The antibody or fragment thereof of claim 16, wherein said variant Fc region further specifically binds Fc.gamma.RIIB with a lower affinity than an antibody comprising the wild-type Fc region binds Fc.gamma.RIIB, and wherein said amino acid modifications are the substitutions of section (C).

18. The antibody or fragment thereof of claim 16 or 17, wherein said variant Fc region mediates enhanced antibody dependent cell mediated cytotoxicity relative to a comparable antibody comprising a wild-type Fc region.

19. The antibody or fragment thereof of claim 16 or 17, wherein said antibody is trastuzumab, rituximab, an anti-CD14 antibody, edrecolomab, an anti-EGFR IgG antibody, an anti-.alpha.V.beta.3 integrin antibody, an anti CD52 IgG1 antibody, an anti-CD22 antibody, or an anti-CD20 antibody.

20. The antibody or fragment thereof of claim 16 or 17, wherein said cancer antigen is a KS 1/4 pan-carcinoma antigen; a melanoma associated or melanoma specific antigen; an ovarian carcinoma antigen (CA125); a prostate specific antigen; a prostate specific membrane antigen; a colorectal tumor-associated antigen; a tumor-specific transplantation type of cell-surface antigen (TSTA); a differentiation antigen; an epidermal growth factor receptor (EFGR) antigen; a HER2/neu antigen, a polymorphic epithelial mucin (PEM) antigen, a malignant human lymphocyte (APO-1) antigen; or a cutaneous T cell lymphoma antigen.

21. A composition comprising a therapeutically effective amount of the antibody of claim 1 or 2, and a pharmaceutically acceptable carrier.

22. A composition comprising a therapeutically effective amount of the antibody of claim 5, and a pharmaceutically acceptable carrier.

23. A composition comprising a therapeutically effective amount of the antibody of claim 16 or 17, and a pharmaceutically acceptable carrier.

24. The composition of claim 23, further comprising one or more additional anti-cancer agents.

25. The compositions of claim 24, wherein said one or more anti-cancer agents is a chemotherapeutic agent, a radiation therapeutic agent, a hormonal therapeutic agent, or an immunotherapeutic agent.

26. A nucleic acid comprising a nucleotide sequence encoding a heavy chain of an antibody of claim 1.

27. A vector comprising the nucleic acid of claim 26.

28. The vector of claim 27 which is an expression vector.

29. A host cell comprising the nucleic acid of claim 28.

30. A method for recombinantly producing the antibody or fragment thereof of claim 1, said method comprising: culturing in a medium a host cell comprising a nucleic acid comprising the nucleotide sequence encoding the light chain of said antibody and a nucleic acid comprising the nucleotide sequence encoding the heavy chain of said antibody, under conditions suitable for the expression of said antibody; and recovery of said antibody from said medium.

31. The antibody or fragment thereof of claim 1, wherein said variant Fc region has an enhanced ADCC activity relative to a comparable antibody comprising the wild type Fc region.

Details for Patent 8,217,147

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Genentech RITUXAN rituximab SOLUTION;INTRAVENOUS 103705 001 1997-11-26   Start Trial MacroGenics, Inc. (Rockville, MD) 2025-08-10 RX search
Genentech RITUXAN rituximab SOLUTION;INTRAVENOUS 103705 002 1997-11-26   Start Trial MacroGenics, Inc. (Rockville, MD) 2025-08-10 RX search
Genentech HERCEPTIN trastuzumab VIAL; INTRAVENOUS 103792 001 1998-09-25   Start Trial MacroGenics, Inc. (Rockville, MD) 2025-08-10 RX Orphan search
Genentech Inc RITUXAN HYCELA rituximab; hyaluronidase (human recombinant) SOLUTION;SUBCUTANEOUS 761064 001 2017-06-22   Start Trial MacroGenics, Inc. (Rockville, MD) 2025-08-10 RX Orphan search
Genentech Inc RITUXAN HYCELA rituximab; hyaluronidase (human recombinant) SOLUTION;SUBCUTANEOUS 761064 002 2017-06-22   Start Trial MacroGenics, Inc. (Rockville, MD) 2025-08-10 RX Orphan search
Genentech Inc HERCEPTIN HYLECTA trastuzumab; hyaluronidase-oysk INJECTABLE;SUBCUTANEOUS 761106 001 2019-02-28   Start Trial MacroGenics, Inc. (Rockville, MD) 2025-08-10 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

International Patent Family for US Patent 8,217,147

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