Proteins comprising hla-g antigen binding domains and their uses

Patent metadata

Field	Value
Publication number	US-2022033505-A1
Application number	US-202117388056-A
Country	US
Kind code	A1
Filing date	Jul 29, 2021
Priority date	Jul 29, 2020
Publication date	Feb 3, 2022
Grant date	—

Abstract

The invention provides antigen binding domains that bind human leukocyte antigen G (HLA-G) protein comprising the antigen binding domains that bind HLA-G, polynucleotides encoding them, vectors, host cells, methods of making and using them.

First claim

We claim:

1 ) An isolated protein comprising an antigen binding domain that binds human leukocyte antigen G (HLA-G), wherein the antigen binding domain that binds HLA-G comprises
a) a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of a heavy chain variable region (VH) of SEQ ID NO: 50 and a light chain complementarity determining region (LCDR) 1, a LCDR2 and a LCDR3 of a light chain variable region (VL) of SEQ ID NO: 51; or b) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 52 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 53; or c) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 54 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 55; or d) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 56 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 57; or e) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 58 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 59; or f) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 60 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 61; or g) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 62 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 63; or h) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 64 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 65; or i) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 66 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 67; or j) the HCDR1, the HCDR2 and the HCDR3 of the VH of SEQ ID NO: 68 and the LCDR1, the LCDR2 and the LCDR3 of the VL of SEQ ID NO: 69.

2 ) The isolated protein of claim 1 , comprising the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of
a) SEQ ID NOs: 70, 71, 72, 88, 89, and 90, respectively; b) SEQ ID NOs: 73, 71, 74, 91, 89, and 92, respectively; c) SEQ ID NOs: 75, 76, 77, 93, 89, and 94, respectively; d) SEQ ID NOs: 78, 79, 80, 95, 89, and 96, respectively; e) SEQ ID NOs: 81, 82, 83, 97, 89, and 98, respectively; f) SEQ ID NOs: 78, 71, 84, 99, 89, and 100, respectively; g) SEQ ID NOs: 78, 71, 84, 101, 89, and 100, respectively; h) SEQ ID NOs: 85, 86, 87, 102, 103, and 104, respectively; or i) SEQ ID NOs: 78, 71, 84, 95, 89, and 96, respectively.

3 ) The isolated protein of claim 1 , wherein the antigen binding domain that binds HLA-G is a scFv or a Fab.

4 ) The isolated protein of claim 3 , wherein the scFv comprises, from the N- to C-terminus, a VH, a first linker (L1) and a VL (VH-L1-VL) or the VL, the L1 and the VH (VL-L1-VH).

5 ) The isolated protein of claim 4 wherein the L1 comprises the amino acid sequence of SEQ ID NO: 8.

6 ) The isolated protein of claim 1 , wherein the antigen binding domain that binds HLA-G comprises the VH of SEQ ID NOs: 50, 52, 54, 56, 58, 60, 62, 64, 66, or 68 and the VL of SEQ ID NOs: 51, 53, 55, 57, 59, 61, 63, 65, 67, or 69.

7 ) The isolated protein of claim 6 , wherein the antigen binding domain that binds HLA-G comprises:
a) the VH of SEQ ID NO: 50 and the VL of SEQ ID NO: 51; b) the VH of SEQ ID NO: 52 and the VL of SEQ ID NO: 53; c) the VH of SEQ ID NO: 54 and the VL of SEQ ID NO: 55; d) the VH of SEQ ID NO: 56 and the VL of SEQ ID NO: 57; e) the VH of SEQ ID NO: 58 and the VL of SEQ ID NO: 59; f) the VH of SEQ ID NO: 60 and the VL of SEQ ID NO: 61; g) the VH of SEQ ID NO: 62 and the VL of SEQ ID NO: 63; h) the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65; i) the VH of SEQ ID NO: 66 and the VL of SEQ ID NO: 67; or j) the VH of SEQ ID NO: 68 and the VL of SEQ ID NO: 69;

8 ) The isolated protein of claim 6 , wherein the antigen binding domain that binds HLA-G comprises the amino acid sequence of SEQ ID NOs: 265, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 266, 267, 268, or 269.

9 ) The isolated protein of claim 1 , wherein the protein is a bispecific protein.

10 ) The isolated protein of claim 9 , further comprising an Fc region.

11 ) The isolated protein of claim 9 , wherein the bispecific protein comprises an antigen binding domain that binds CD3E.

12 ) The isolated protein of claim 11 , wherein the antigen binding domain that binds CD3E comprises:
a) the HCDR1 of SEQ ID NO: 364, the HCDR2 of SEQ ID NO: 365, the HCDR3 of SEQ ID NO: 366, the LCDR1 of SEQ ID NO: 371, the LCDR2 of SEQ ID NO: 372 and the LCDR3 of SEQ ID NO: 373; b) the VH of SEQ ID NO: 346 and the VL of SEQ ID NO: 347; c) the VH of SEQ ID NO: 348 and the VL of SEQ ID NO: 349; d) a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 361, a HCDR2 of SEQ ID NO: 362, a HCDR3 of SEQ ID NO: 363, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 367, a LCDR2 of SEQ ID NO: 368 and a LCDR3 of SEQ ID NO: 369; e) the VH of SEQ ID NO: 339 and the VL of SEQ ID NO: 340; f) the HCDR1 of SEQ ID NO: 361, the HCDR2 of SEQ ID NO: 362, the HCDR3 of SEQ ID NO: 363, the LCDR1 of SEQ ID NO: 367, the LCDR2 of SEQ ID NO: 368 and the LCDR3 of SEQ ID NO: 370; g) the VH of SEQ ID NO: 339 and the VL of SEQ ID NO: 341; h) the VH of SEQ ID NO: 339 and the VL of SEQ ID NO: 342; i) the VH of SEQ ID NO: 339 and the VL of SEQ ID NO: 343; j) the VH of SEQ ID NO: 339 and the VL of SEQ ID NO: 344; or k) the VH of SEQ ID NO: 339 and the VL of SEQ ID NO: 345.

13 ) The isolated protein claim 10 , wherein the Fc region comprises at least one mutation that results in reduced binding of the protein to a Fcγ receptor (FcγR).

14 ) The isolated protein of claim 13 , wherein the at least one mutation that results in reduced binding of the protein to the FcγR is L234A/L235A/D265S, wherein residue numbering is according to the EU index.

15 ) The isolated protein of claim 10 , wherein the protein comprises at least one mutation in the Fc domain, wherein the mutation promotes heavy chain heterodimerization.

16 ) The isolated protein of claim 15 , wherein the at least one mutation in the Fc domain is selected from the group consisting of T350V/L351Y/F405A/Y407V and T350V/T366L/K392L/T394W, wherein residue numbering is according to the EU index.

17 ) A pharmaceutical composition comprising the isolated protein of claim 1 and a pharmaceutically acceptable carrier.

18 ) A polynucleotide encoding the isolated protein of claim 1 .

19 ) A vector comprising the polynucleotide of claim 18 .

20 ) A host cell comprising the vector of claim 19 .

21 ) A method of producing the isolated protein of claim 1 , comprising culturing the host cell of claim 20 in conditions that the protein is expressed, and recovering the protein produced by the host cell.

22 ) A method of treating a HLA-G expressing cancer in a subject, comprising administering a therapeutically effective amount of the isolated protein of claim 1 to the subject for a time sufficient to treat the HLA-G expressing cancer.

23 ) A method of reducing the amount of HLA-G expressing tumor cells in a subject, comprising administering the isolated protein of claim 1 to the subject for a time sufficient to reduce the amount of HLA-G expressing tumor cells.

24 ) The method of claim 22 , wherein the HLA-G expressing cancer is a lung cancer, a pancreatic cancer, a renal cancer, a head and neck cancer, an ovarian cancer, an esophageal cancer, a colorectal cancer, a uterine cancer, or a breast cancer.

25 ) An is

Assignees

• Janssen Biotech Inc

Inventors

• Obermajer Natasa
• Zwolak Adam
• Laquerre Sylvie
• Brehmer Dirk
• De Lange Desiree
• Häsler Julien
• Versmissen Shana
• Petley Theodore D
• Van De Ven Kelly
• Yi Fang
• Singh Sanjaya

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title

• C07K16/2833 Primary

  against MHC-molecules, e.g. HLA-molecules · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K16/468

  Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies · CPC title