PD-1 binding proteins

• US 8,168,757 B2
• Filed: 03/03/2009
• Issued: 05/01/2012
• Est. Priority Date: 03/12/2008
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Finnefrock, Adam C., Fu, Tong-Ming, Freed, Daniel C., Casimiro, Danilo R., Li, Fengsheng, Tang, Aimin
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US12/922,066
• Publication Number:
  US 20110008369A1
• Time in Patent Office: 1,155 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The present invention features PD-1 binding proteins, a subset of which inhibits binding of PD-L1 to the PD-1 receptor. These binding proteins can be employed to modulate the immune system through the manipulation of the PD-1 signaling pathway, enhancing host immunity to treat infections and cancer.

Claims

1. An isolated PD-1 binding protein comprising a first variable region and a second variable region, wherein said binding protein specifically binds a human PD-1 epitope contained within a PD-L1-blocking target region, wherein said first variable region is a heavy chain variable (V_h) region comprising:

a first V_h CDR comprising either SEQ ID NO;

6 or an amino acid sequence differing from SEQ ID NOs;

6 by one amino acid;

a second V_h CDR comprising either SEQ ID NO;

7 or an amino acid sequence differing from SEQ ID NOs;

7 by one amino acid; and

,

a third V_h CDR comprising either SEQ ID NO;

8 or an amino acid sequence differing from SEQ ID NOs;

8 by one amino acid.

2. The binding protein of claim 1, wherein said second variable region is a light chain variable (V_l) region comprising:

a first V_l CDR comprising either SEQ ID NO;

9 or an amino acid sequence differing from SEQ ID NOs;

9 by one amino acid;

a second V_l CDR comprising either SEQ ID NO;

10 or an amino acid sequence differing from SEQ ID NOs;

10 by one amino; and

a third V_l CDR comprising either SEQ ID NO;

11 or an amino acid sequence differing from SEQ ID NOs;

11—

by one amino acid.

3. The binding protein of claim 1, wherein

said V_h region comprises said first V_h CDR consisting of SEQ ID NO:

6, said second V_h CDR consisting of SEQ ID NO;

7, and said third V_h CDR consisting of SEQ ID NO;

8; and

,

said V_l region comprises said first V_l CDR consisting of SEQ ID NO;

9, said second V_l CDR consisting of SEQ ID NO;

10, and said third V_l CDR consisting of SEQ ID NO;

11.

4. The binding protein of claim 3, wherein said binding protein is an antibody.

5. The binding protein of claim 1, wherein said binding protein is an antibody comprising a first variable region which is a heavy chain variable (V_h) region and a second variable region which is a light chain variable (V_l) region, and wherein said V_h region comprises:

SEQ ID NO;

4 or a humanized SEQ ID NO;

4.

6. The binding protein of claim 5, wherein said V_h region comprises SEQ ID NO:

4.

7. The binding protein of claim 5, wherein said V_l region comprises SEQ ID NO:

5.

8. The binding protein of claim 5, wherein said binding protein is an antibody and said antibody comprises a heavy chain comprising said V_h region and hinge, CH₁, CH₂ and CH₃ regions from an IgG₁, IgG₂, IgG₃ or IgG₄ subtype;

and a light chain comprising said V_l region and either a human kappa C_l or human lambda C_l.

9. A pharmaceutical composition comprising the a PD-1 binding protein of claim 1 and a pharmaceutically acceptable carrier.

10. The binding protein of claim 1, wherein said binding protein is an antibody comprising a first variable region which is a heavy chain variable (V_h) region and a second variable region which is a light chain variable (V_l) region, and wherein said V_l region comprises SEQ ID NO:

5 or a humanized SEQ ID NO;

5.

11. The binding protein of claim 10, wherein said V_l region comprises SEQ ID NO:

5.

12. The binding protein of claim 10, wherein said V_h region comprises SEQ ID NO:

4.

13. The binding protein of claim 5, wherein said V_h region comprises SEQ ID NO:

4 and said V_l region comprises SEQ ID NO;

5.

14. The binding protein of claim 10, wherein said binding protein is an antibody and said antibody comprises a heavy chain comprising said V_h region and hinge, CH₁, CH₂ and CH₃ regions from an IgG₁, IgG₂, IgG₃ or IgG₄ subtype;

and a light chain comprising said V_l region and either a human kappa C_l or human lambda C_l.

19. A pharmaceutical composition comprising the a PD-1 binding protein of claim 3 and a pharmaceutically acceptable carrier.

15. An isolated PD-1 binding protein comprising a first variable region and a second variable region, wherein said binding protein specifically binds a human PD-1 epitope contained within a PD-L1-blocking target region wherein said first variable region is a light chain variable (V_l) region comprising

a first V_l CDR comprising either SEQ ID NO:

9 or an amino acid sequence differing from SEQ ID NOs;

9 by one amino acid;

a second V_l CDR comprising either SEQ ID NO;

10 or an amino acid sequence differing from SEQ ID NOs;

10 by one amino acid; and

,

a third V_l CDR comprising either SEQ ID NO;

11 or an amino acid sequence differing from SEQ ID NOs;

8 by one amino acid.

16. A pharmaceutical composition comprising the a PD-1 binding protein of claim 15 and a pharmaceutically acceptable carrier.

17. An isolated PD-1 binding protein comprising a first variable region and a second variable region, wherein said binding protein specifically binds a human PD-1 epitope contained within a PD-L1-blocking target region, wherein said first variable region is a heavy chain variable (V_h) region of SEQ ID NO:

4 and said second variable region is a light chain variable (V_l) region of SEQ ID NO;

5.

18. A pharmaceutical composition comprising the a PD-1 binding protein of claim 17 and a pharmaceutically acceptable carrier.