High affinity PD-1 agents and methods of use

Patent metadata

Field	Value
Publication number	US-10800830-B2
Application number	US-201515502439-A
Country	US
Kind code	B2
Filing date	Aug 7, 2015
Priority date	Aug 8, 2014
Publication date	Oct 13, 2020
Grant date	Oct 13, 2020

Abstract

High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.

First claim

That which is claimed is:

1. A method of treating an individual having cancer, having a chronic infection, or having an immunological disorder associated with immunosuppression, the method comprising:
administering to the individual a multispecific polypeptide comprising a first region corresponding to a high affinity programmed death-1 (PD-1) mimic polypeptide that:
i) lacks a wild-type PD-1 transmembrane domain; and
ii) comprises one or more amino acid changes selected from: (1) V39H or V39R; (2) L40V or L40I; (3) N41I or N41V; (4) Y43F or Y43H; (5) R44Y or R44L; (6) M45Q, M45E, M45L, or M45D; (7) S48D, S48L, S48N, S48G, or S48V; (8) N49C, N49G, N49Y, or N49S; (9) Q50K, Q50E, or Q50H; (10) T51V, T51L, or T51A; (11) D52F, D52R, D52Y, or D52V; (12) K53T or K53L; (13) A56S or A56L; (14) Q63T, Q63I, Q63E, Q63L, or Q63P; (15) G65N, G65R, G65I, G65L, G65F, or G65V; (16) Q66P; (17) V72I; (18) H82Q; (19) M83L or M83F; (20) R90K; (21) Y96F; (22) L97Y, L97V, or L97I; (23) A100I or A100V; (24) S102T or S102A; (25) L103I, L103Y, or L103F; (26) A104S, A104H, or A104D; (27) P105A; (28) K106G, K106E, K106I, K106V, K106R, or K106T; and (29) A107P, A107I, or A107V, wherein the amino acid position is relative to the PD-1 protein fragment set forth in SEQ ID NO: 2.

2. The method of claim 1 , wherein the one or more amino acid changes increases the affinity of the high affinity PD-1 mimic polypeptide for programmed cell death 1 ligand 1 (PD-L1) as compared to the affinity for PD-L1 of the human wild type PD-1 polypeptide as set forth in SEQ ID NO: 1.

3. The method of claim 1 , wherein the PD-1 mimic polypeptide has a K d of 1×10 −7 M or less for PD-L1.

4. The method of claim 1 , wherein the one or more amino acid changes is located at an amino acid position of PD-1 that contacts PD-L1.

5. A method of treating an individual having cancer, having a chronic infection, or having an immunological disorder associated with immunosuppression, the method comprising:
administering to the individual a multispecific polypeptide comprising a first region corresponding to a high affinity programmed death-1 (PD-1) mimic polypeptide that:
i) lacks a wild-type PD-1 transmembrane domain; and
ii) comprises amino acid changes located at amino acid positions selected from:

(a) V39, N41, Y43, M45, S48, N49, Q50, K53, A56, Q63, G65, Q66, L97, S102, L103, A104, K106, and A107;
(b) V39, N41, Y43, M45, S48, Q50, T51, D52F, K53, A56, Q63, G65, Q66, L97, S102, L103, A104, K106, and A107;
(c) V39, L40, N41, Y43, R44, M45, N49, K53, M83, L97, A100, and A107;
(d) V39, L40, N41, Y43, M45, N49, K53, Q66, M83, L97, and A107;
(e) V39, L40, N41, Y43, M45, N49, K53, Q66, H82, M83, L97, A100, and A107;
(f) V39, L40, N41, Y43, M45, N49, K53, M83, L97, A100, and A107;
(g) V39, L40, N41, Y43, R44, M45, N49, K53, L97, A100, and A107; and
(h) V39, L40, N41, Y43, M45, N49, K53, L97, A100, and A107;

wherein the amino acid positions are relative to the PD-1 protein fragment set forth in SEQ ID NO: 2.

6. The method of claim 5 , wherein cancer cells of the cancer are positive for PD-L1 expression.

7. The method of claim 5 , wherein the cancer comprises lung cancer, prostate cancer, breast cancer, bladder cancer, colon cancer, ovarian cancer, pancreatic cancer, kidney cancer, liver cancer, glioblastoma, medulloblastoma, leiomyosarcoma, head & neck squamous cell carcinomas, melanomas, neuroendocrine cancer, a leukemia, or a lymphoma.

8. A method of treating an individual having cancer, having a chronic infection, or having an immunological disorder associated with immunosuppression, the method comprising:
administering to the individual a multispecific polypeptide comprising a first region corresponding to a high affinity programmed death-1 (PD-1) mimic polypeptide that:
i) lacks a wild-type PD-1 transmembrane domain; and
ii) comprises amino acid changes selected from:

(a) {V39H or V39R}, {N41I or N41V}, {Y43F or Y43H}, {M45Q, M45E, M45L, or M45D}, {S48D, S48L, S48N, S48G, or S48V}, {N49C, N49G, N49Y, or N49S}, {Q50K, Q50E, or Q50H}, {K53T or K53L}, {A56S or A56L}, {Q63T, Q63I, Q63E, Q63L, or Q63P}, {G65N, G65R, G65I, G65L, G65F, or G65V}, {Q66P}, {L97Y, L97V, or L97I}, {S102T or S102A}, {L103I, L103Y, or L103F}, {A104S, A104H, or A104D}, {K106G, K106E, K106I, K106V, K106R, or K106T}, and {A107P, A107I, or A107V};
(b) {V39H or V39R}, {N41I or N41V}, {Y43F or Y43H}, {M45Q, M45E, M45L, or M45D}, {S48D, S48L, S48N, S48G, or S48V}, {Q50K, Q50E, or Q50H}, {T51V, T51L, or T51A}, {D52F, D52R, D52Y, or D52V}, {K53T or K53L}, {A56S or A56L}, {Q63T, Q63I, Q63E, Q63L, or Q63P}, {G65N, G65R, G65I, G65L, G65F, or G65V}, {Q66P}, {L97Y, L97V, or L97I}, {S102T or S102A}, {L103I, L103Y, or L103F}, {A104S, A104H, or A104D}, {K106G, K106E, K106I, K106V, K106R, or K106T}, and {A107P, A107I, or A107V};
(c) {V39H or V39R}, {L40V or L40I}, {N41I or N41V}, {Y43F or Y43H}, {R44Y or R44L}, {M45Q, M45E, M45L, or M45D}, {N49C, N49G, N49Y, or N49S}, {K53T or K53L}, {M83L or M83F}, {L97Y, L97V, or L97I}, {A100I or A100V}, and {A107P, A107I, or A107V};
(d) {V39H or V39R}, {L40V or L40I}, {N41I or N41V}, {Y43F or Y43H}, {M45Q, M45E, M45L, or M45D}, {N49C, N49G, N49Y, or N49S}, {K53T or K53L}, {Q66P}, {M83L or M83F}, {L97Y, L97V, or L97I}, and {A107P, A107I, or A107V};
(e) {V39H or V39R}, {L40V or L40I}, {N41I or N41V}, {Y43F or Y43H}, {M45Q, M45E, M45L, or M45D}, {N49C, N49G, N49Y, or N49S}, {K53T or K53L}, {Q66P}, {H82Q}, {M83L or M83F}, {L97Y, L97V, or L97I}, {A100I or A100V}, and {A107P, A107I, or A107V};
(f) {V39H or V39R}, {L40V or L40I}, {N41I or N41V}, {Y43F or Y43H}, {M45Q, M45E, M45L, or M45D}, {N49C, N49G, N49Y, or N49S}, {K53T or K53L}, {M83L or M83F}, {L97Y, L97V, or L97I}, {A100I or A100V}, and {A107P, A107I, or A107V};
(g) {V39H or V39R}, {L40V or L40I}, {N41I or N41V}, {Y43F or Y43H}, {R44Y or R44L}, {M45Q, M45E, M45L, or M45D}, {N49C, N49G, N49Y, or N49S}, {K53T or K53L}, {L97Y, L97V, or L97I}, {A100I or A100V}, and {A107P, A107I, or A107V}; and
(h) {V39H or V39R}, {L40V or L40I}, {N41I or N41V}, {Y43F or Y43H}, {M45Q, M45E, M45L, or M45D}, {N49C, N49G, N49Y, or N49S}, {K53T or K53L}, {L97Y, L97V, or L97I}, {A100I or A100V}, and {A107P, A107I, or A107V};

wherein the amino acid changes are relative to the PD-1 protein fragment set forth in SEQ ID NO: 2.

9. The method of claim 8 , wherein cancer cells of the cancer are positive for PD-L1 expression.

10. The method of claim 8 , wherein the cancer comprises lung cancer, prostate cancer, breast cancer, bladder cancer, colon cancer, ovarian cancer, pancreatic cancer, kidney cancer, liver cancer, glioblastoma, medulloblastoma, leiomyosarcoma, head & neck squamous cell carcinomas, melanomas, neuroendocrine cancer, a leukemia, or a lymphoma.

11. A method of treating an individual having cancer, having a chronic infection, or having an immunological disorder associated with immunosuppression, the method comprising:
administering to the individual a multispecific polypeptide comprising a first region corresponding to a high affinity programmed death-1 (PD-1) mimic polypeptide that:
i) lacks a wild-type PD-1 transmembrane domain; and
ii) comprises amino acid changes selected from:

(a) V39R, N41V, Y43H, M45E, S48G, N49Y, Q50E, K53T, A56S, Q63T, G65L, Q66P, L97V, S102A, L103F, A104H, K106V, and A107I;
(b) V39R, N41V, Y43H, M45E, S48N, Q50H, T51A, D52Y, K53T, A56L, Q63L, G65F, Q66P, L97I, S102T, L103F, A104D, K106R, and A107I;
(c) V39H, L40V, N41V, Y43H, R44Y, M45E, N49G, K53T, M83L, L97V, A100I, and A107I;
(d) V39H, L40V, N41V, Y43H, M45E, N49G, K53T, Q66P, M83L, L97V, and A107I;
(e) V39H, L40V, N41V, Y43H, M45E, N49S, K53T, Q66P, H82Q, M83L, L97V, A100V, and A107I;
(f) V39H, L40I, N41I,

Assignees

• Univ Leland Stanford Junior

Inventors

• Ring Aaron Michael
• Kruse Andrew
• Manglik Aashish
• Weissman Irving L
• Maute Roy Louis
• Mccracken Melissa N
• Gordon Sydney

Classifications

• A61K35/17

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title

• C07K14/70503 Primary

  Immunoglobulin superfamily · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title