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Last Updated: October 23, 2019

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Claims for Patent: 10,377,824

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Summary for Patent: 10,377,824
Title:Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
Abstract: The present invention provides isolated monoclonal antibodies that specifically bind LAG-3, and have optimized functional properties compared to previously described anti-LAG-3 antibodies, such as antibody 25F7 (US 2011/0150892 A1). These properties include reduced deamidation sites, while still retaining high affinity binding to human LAG-3, and physical (i.e., thermal and chemical) stability. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided, as well as immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies. The present invention also provides methods for detecting LAG-3, as well as methods for treating stimulating immune responses using an anti-LAG-3 antibody of the invention. Combination therapy, in which the antibodies are co-administered with at least one additional immunostimulatory antibody, is also provided.
Inventor(s): Lonberg; Nils (Woodside, CA), Srinivasan; Mohan (Cupertino, CA)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:16/125,028
Patent Claims:1. A method for inhibiting growth of tumor cells in a subject comprising administering to the subject an antibody comprising heavy and light chain variable regions that bind human LAG-3, wherein the heavy chain CDR1, CDR2, and CDR3 regions comprise the amino acid sequences of SEQ ID NOs: 15, 16, and 17, respectively, and the light chain CDR1, CDR2, and CDR3 regions comprise the amino acid sequences of SEQ ID NOs: 18, 19, and 20, such that growth of the tumor is inhibited in the subject.

2. The method of claim 1, wherein the antibody comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.

3. The method of claim 1, wherein the antibody is a human IgG4 antibody.

4. The method of claim 1, wherein the antibody is a full-length antibody.

5. The method of claim 3, wherein the antibody comprises a serine to proline mutation at amino acid residue 228.

6. The method of claim 1, wherein the antibody is a bispecific molecule.

7. The method of claim 1, wherein the antibody exhibits one or a combination of the following properties: (a) binding to monkey LAG-3; (b) lack of binding to mouse LAG-3; (c) inhibits binding of LAG-3 to major histocompatibility (MEW) class II molecules; (d) stimulates an immune response; and (e) binds to human LAG-3 with a KD of 0.27.times.10-9 M or less.

8. The method of claim 1, wherein the tumor cells are a melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer or gastric cancer.

9. The method of claim 1, further comprising administering at least one additional immunostimulatory antibody.

10. The method of claim 9, wherein the at least one additional immunostimulatory antibody is selected from the group consisting of: an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

11. The method of claim 10, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab (MDX1106), lambrolizumab, and AMP514.

12. The method of claim 10, wherein the anti-PD-L1 antibody is selected from the group consisting of MPDL3280A (RG7446), MEDI4736, and MDX1105.

13. The method of claim 10, wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab (MDX010), the antibody produced by hybridoma A3.6B10 deposited under ATCC Accession No. HB-12318, the antibody produced by hybridoma A3.4H2 deposited under ATCC Accession No. HB-12319, and CP-675206.

14. The method of claim 9, wherein the antibodies are administered (a) sequentially as separate compositions with each antibody in a pharmaceutically acceptable carrier; (b) concurrently as separate compositions with each antibody in a pharmaceutically acceptable carrier; or (c) concurrently as a single composition in a pharmaceutically acceptable carrier.

15. A method of treating cancer in a subject in need thereof comprising administering to the subject an antibody that binds human LAG-3, wherein the heavy chain CDR1, CDR2, and CDR3 regions comprise the amino acid sequences of SEQ ID NOs: 15, 16, and 17, respectively, and the light chain CDR1, CDR2, and CDR3 regions comprise the amino acid sequences of SEQ ID NOs: 18, 19, and 20, respectively.

16. The method of claim 15, wherein the antibody comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12; and (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.

17. The method of claim 15, wherein the antibody is a human IgG4 antibody.

18. The method of claim 15, wherein the antibody is a full-length antibody.

19. The method of claim 17, wherein the antibody comprises a serine to proline mutation at amino acid residue 228.

20. The method of claim 15, wherein the antibody is a bispecific molecule.

21. The method of claim 15, wherein the antibody exhibits one or a combination of the following properties: (a) binding to monkey LAG-3; (b) lack of binding to mouse LAG-3; (c) inhibits binding of LAG-3 to major histocompatibility (WIC) class II molecules; (d) stimulates an immune response; and (e) binds to human LAG-3 with a KD of 0.27.times.10-9 M or less.

22. The method of claim 15, wherein cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer or gastric cancer.

23. The method of claim 15, further comprising administering at least one additional immunostimulatory antibody.

24. The method of claim 23, wherein the at least one additional immunostimulatory antibody is selected from the group consisting of: an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

25. The method of claim 24, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab (MDX1106), lambrolizumab, and AMP514.

26. The method of claim 24, wherein the anti-PD-L1 antibody is selected from the group consisting of MPDL3280A (RG7446), MEDI4736, and MDX1105 and the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab (MDX010), the antibody produced by hybridoma A3.6B10 deposited under ATCC Accession No. HB-12318, the antibody produced by hybridoma A3.4H2 deposited under ATCC Accession No. HB-12319, and CP-675206.

27. The method of claim 23, wherein the antibodies are administered (a) sequentially as separate compositions with each antibody in a pharmaceutically acceptable carrier; (b) concurrently as separate compositions with each antibody in a pharmaceutically acceptable carrier; or (c) concurrently as a single composition in a pharmaceutically acceptable carrier.

28. A method of treating cancer in a subject in need thereof comprising administering to the subject a full-length IgG4 human monoclonal antibody that binds human LAG-3, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 35 and the light chain comprises the amino acid sequence of SEQ ID NO: 37.

29. The method of claim 28, further comprising administering (a) an anti-PD-1 antibody; (b) an anti-PD-L1 antibody; or (c) an anti-CTLA-4 antibody.

30. A method of treating cancer in a subject in need thereof comprising administering to the subject (a) a IgG4 human monoclonal antibody that binds human LAG-3 wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 12 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:14, and wherein the antibody comprises a serine to proline mutation at amino acid residue 228; and (b) nivolumab (MDX1106), wherein the cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer or gastric cancer.

Details for Patent 10,377,824

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Bristol Myers Squibb YERVOY ipilimumab INJECTABLE; INJECTION 125377 001 2011-03-25   Start Trial Bristol-Myers Squibb Company (Princeton, NJ) 2032-07-02 RX Orphan search
Bristol Myers Squibb OPDIVO nivolumab INJECTABLE;INJECTION 125527 001 2015-03-04   Start Trial Bristol-Myers Squibb Company (Princeton, NJ) 2032-07-02 RX search
Bristol Myers Squibb OPDIVO nivolumab INJECTABLE;INJECTION 125527 002 2015-03-04   Start Trial Bristol-Myers Squibb Company (Princeton, NJ) 2032-07-02 RX search
Bristol Myers Squibb OPDIVO nivolumab INJECTABLE;INJECTION 125554 001 2015-11-23   Start Trial Bristol-Myers Squibb Company (Princeton, NJ) 2032-07-02 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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