Antibodies to human programmed death receptor PD-1

• US 8,354,509 B2
• Filed: 06/13/2008
• Issued: 01/15/2013
• Est. Priority Date: 06/18/2007
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme BV (Merck & Co., Inc.)
• Original Assignee: MSD Oss BV (Merck & Co., Inc.)
• Inventors: Carven, Gregory John, Dulos, Gradus Johannes, van Eenennaam, Hans
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US12/663,950
• Publication Number:
  US 20100266617A1
• Time in Patent Office: 1,677 Days
• Field of Search: None
• US Class Current: 530/388.1
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• 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: G01N 2333/55 IL-2
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57488 involving compounds identifable in body fluids
• CPC Class Codes: G01N 33/6869 Interleukin

Abstract

Antibodies which block the binding of human Programmed Death Receptor 1 (hPD-1) to its ligands (hPD-L1 or hPD-L2) and their variable region sequences are disclosed. A method of increasing the activity (or reducing downmodulation) of an immune response through the PD-I pathway is also disclosed.

Claims

1. An isolated antibody or antibody fragment which binds to human PD-1 comprising:

a. three light chain CDRs of 15, 16 and 17; and

/or

b. three heavy chain CDRs of SEQ ID NOs;

18, 19 and 20.

2. The antibody of claim 1, further comprising a human heavy chain constant region and a human light chain constant region, wherein the human heavy chain constant region comprises a γ

4 or γ

1 human heavy chain constant region or a variant thereof, wherein the constant region variant comprises up to 5 conservatively modified amino acid substitutions.

3. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment:

a. binds human PD-1 with a K_D of about 100 pM or lower;

b. binds human PD-1 with a K_D of about 30 pM or lower;

c. binds to human PD-1 with about the same K_D as an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO;

31 and a light chain comprising the amino acid sequence of SEQ ID NO;

32;

d. binds to human PD-1 with about the same K_D as an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO;

31 and a light chain comprising the amino acid sequence of SEQ ID NO;

33;

e. binds to human PD-1 with a k_assoc of about 7.5×

105 l/M·

s or faster;

f. binds to human PD-1 with a k_assoc of about 1×

106 l/M·

s or faster;

g. binds to human PD-1 with a k_dissoc of about 2×

10-5 l/s or slower;

h. binds to human PD-1 with a k_dissoc of about 2.7×

10-5 l/s or slower;

i. binds to human PD-1 with a k_dissoc of about 3×

10-5 l/s or slower;

or

j. blocks binding of human PD-L1 or human PD-L2 to human PD-1 with an IC₅₀ of about 1 nM or lower.

5. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment is:

a. a chimeric antibody or a fragment thereof;

b. a human antibody or a fragment thereof;

c. a humanized antibody or a fragment thereof;

or

d. an antibody fragment selected from the group consisting of Fab, Fab′

, Fab′

-SH, Fv, scFv, F(ab′

)2, and a diabody.

6. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment increases activation of T cells.

7. The antibody or antibody fragment of claim 1, comprising:

a. a heavy chain variable region comprising an amino acid sequence selected from the group consisting of;

i. SEQ ID NO;

7 or a variant thereof having heavy chain CDRs SEQ ID NOs;

18, 19 and 20 and one, two or three conservatively modified amino acid substitutions; and

ii. amino acid residues 20 to 139 of SEQ ID NO;

30 or a variant thereof having heavy chain CDRs SEQ ID NOs;

18, 19 and 20 and one, two or three conservatively modified amino acid substitutions; and

b. a light chain variable region comprising an amino acid sequence selected from the group consisting of;

i. SEQ ID NO;

8 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and one, two or three conservatively modified amino acid substitutions;

ii. amino acid residues 20 to 130 of SEQ ID NO;

32 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and one, two or three conservatively amino acid modified substitutions;

iii. amino acid residues 20 to 130 of SEQ ID NO;

33 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and one, two or three conservatively modified amino acid substitutions; and

iv. amino acid residues 20 to 130 of SEQ ID NO;

34 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and one, two or three conservatively modified amino acid substitutions.

8. The antibody or antibody fragment of claim 1, comprising:

a. a heavy chain comprising an amino acid sequence selected from the group consisting of;

i. amino acid residues 20 to 466 of SEQ ID NO;

31 or a variant thereof having heavy chain CDRs SEQ ID NOs;

18, 19 and 20 and up to three conservatively modified amino acid substitutions, and

ii. amino acid residues 20 to 469 of SEQ ID NO;

35 or a variant thereof having heavy chain CDRs SEQ ID NOs;

18, 19 and 20 and up to three conservatively modified amino acid substitutions; and

b. a light chain comprising an amino acid sequence selected from the group consisting of;

i. amino acid residues 20 to 237 of SEQ ID NO;

36 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and up to three conservatively modified amino acid substitutions;

ii. amino acid residues 20 to 237 of SEQ ID NO;

37 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and up to three conservatively modified amino acid substitutions, and

iii. amino acid residues 20 to 237 of SEQ ID NO;

38 or a variant thereof having light chain CDRs SEQ ID NOs;

15, 16 and 17 and up to three conservatively modified amino acid substitutions.

9. The antibody or antibody fragment of claim 1, comprising:

a. a heavy chain variable region comprising an amino acid sequence selected from the group consisting of;

i. SEQ ID NO;

7; and

ii. amino acid residues 20 to 139 of SEQ ID NO;

30; and

b. a light chain variable region comprising an amino acid sequence selected from the group consisting of

i. SEQ ID NO;

8;

ii. amino acid residues 20 to 130 of SEQ ID NO;

32;

iii. amino acid residues 20 to 130 of SEQ ID NO;

33; and

iv. amino acid residues 20 to 130 of SEQ ID NO;

34.

10. The antibody or antibody fragment of claim 1, comprising:

a. a heavy chain comprising an amino acid sequence selected from the group consisting of;

i. amino acid residues 20 to 466 of SEQ ID NO;

31, and

ii. amino acid residues 20 to 469 of SEQ ID NO;

35; and

b. a light chain comprising an amino acid sequence selected from the group consisting of

i. amino acid residues 20 to 237 of SEQ ID NO;

36;

ii. amino acid residues 20 to 237 of SEQ ID NO;

37, and

iii. amino acid residues 20 to 237 of SEQ ID NO;

38.

4. An isolated antibody or antibody fragment which competes for a binding epitope on PD-1 with an antibody or antibody fragment comprising three light chain CDRs of SEQ ID NOs:

15, 16 and 17 and three heavy chain CDRs of SEQ ID NOs;

18, 19 and 20, wherein said competing antibody or antibody fragment has at least one of the following characteristics;

a. binds human PD-1 with a K_D of about 100 pM or lower;

b. binds human PD-1 with a K_D of about 30 pM or lower;

c. binds to human PD-1 with about the same K_D as an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO;

31 and a light chain comprising the amino acid sequence of SEQ ID NO;

32;

d. binds to human PD-1 with about the same K_D as an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO;

31 and a light chain comprising the amino acid sequence of SEQ ID NO;

33;

e. binds to human PD-1 with a k_assoc of about 7.5×

105 l/M·

s or faster;

f. binds to human PD-1 with a k_assoc of about 1×

106 l/M·

s or faster;

g. binds to human PD-1 with a k_dissoc of about 2×

10-5 l/s or slower;

h. binds to human PD-1 with a k_dissoc of about 2.7×

10-5 l/s or slower;

i. binds to human PD-1 with a k_dissoc of about 3×

10-5 l/s or slower;

or

j. blocks binding of human PD-L1 or human PD-L2 to human PD-1 with an IC₅₀ of about 1 nM or lower.

11. An isolated antibody comprising a heavy chain comprising amino acid residues 20 to 446 of SEQ ID NO:

31 and a light chain comprising amino acid residues of 20-237 of SEQ ID NO;

36.