Methods for treating cancer using anti-PD-1 antibodies

• US 9,084,776 B2
• Filed: 11/18/2014
• Issued: 07/21/2015
• Est. Priority Date: 05/09/2005
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company), ONO Pharmaceutical Company Limited
• Inventors: Korman, Alan J., Srinivasan, Mohan, Selby, Mark J., Chen, Bingliang, Cardarelli, Josephine M., Huang, Haichun, Wang, Changyu
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US14/547,026
• Publication Number:
  US 20150165025A1
• Time in Patent Office: 245 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 51/10 Antibodies or immunoglobulins; Fragments thereof , the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides isolated monoclonal antibodies, particularly human monoclonal antibodies, that specifically bind to PD-1 with high affinity. 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. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for detecting PD-1, as well as methods for treating various diseases, including cancer and infectious diseases, using anti-PD-1 antibodies. The present invention further provides methods for using a combination immunotherapy, such as the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat hyperproliferative disease, such as cancer. The invention also provides methods for altering adverse events related to treatment with such antibodies individually.

Claims

1. A method of treating a tumor in a subject in need thereof comprising administering a therapeutic dose of a human or humanized anti-PD-1 antibody or an antigen-binding portion thereof to the subject, wherein an anti-CTLA-4 antibody or an antigen-binding portion thereof has been administered to the subject prior to the administration of the anti-PD-1 antibody or antigen-binding portion thereof, wherein the administration of the anti-PD-1 antibody or antigen-binding portion thereof treats the tumor in the subject.

2. The method of claim 1, wherein the anti-PD-1 antibody or antigen-binding portion thereof cross-competes for binding to human PD-1 with:

(a) a reference antibody that comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

1 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

8;

(b) a reference antibody that comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

2 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

9;

(c) a reference antibody that comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

4 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

11;

or

(d) a reference antibody that comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

6 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO;

13;

wherein the anti-PD-1 antibody or antigen-binding portion thereof comprises (i) a heavy chain variable region (V_H) and (ii) a light chain variable region (V_L) that has at least about 85% sequence identity to an amino acid sequence selected from SEQ ID NO;

8, SEQ ID NO;

9, and SEQ ID NO;

11; and

wherein the anti-PD-1 antibody or antigen-binding portion thereof binds to human PD-1 with a K_D of 5×

10<sup>−

9</sup> nM or less.

3. The method of claim 2, wherein the K_D is measured by surface plasmon resonance (Biacore) analysis.

4. The method of claim 2, wherein the anti-PD-1 antibody or the antigen-binding portion thereof comprises amino acids EIVLTQSPATLSLSPGERATLSC (SEQ ID NO:

75), WYQQKPGQAPRLLIY (SEQ ID NO;

     76) and FGGGTKVEIK (SEQ ID NO;

     78).

5. The method of claim 2, wherein the V_H of the anti-PD-1 antibody or antigen-binding portion thereof comprises V_H-FR1, V_H-CDR1, V_H-FR2, V_H-CDR2, V_H-FR3, V_H-CDR3, and V_H-FR4, and the V_L comprises V_L-FR1, V_L-CDR1, V_L-FR2, V_L-CDR2, V_L-FR3, V_L-CDR3, and V_L-FR4, and wherein the V_L-FR1, V_L-FR2, and V_L-FR3 comprise amino acid sequences derived from a human V_K L6 germline sequence and the V_L-FR4 comprises an amino acid sequence derived from a human V_K JK1 or V_K JK4 germline sequence.

6. The method of claim 2, wherein the anti-PD-1 antibody is a humanized antibody.

7. The method of claim 2, wherein the anti-PD-1 antibody or antigen-binding portion thereof comprises a human constant region of IgG4.

8. The method of claim 7, wherein the human constant region comprises a mutation that increases stability of the antibody or antigen-binding portion thereof.

9. The method of claim 8, wherein the mutation is located in the hinge region of the constant region.