Anti-HLA-G antibodies and use thereof
The present invention relates to anti-HLA-G antibodies and methods of using the same.
1. An isolated antibody that binds to human HLA-G, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6.
2. An isolated antibody that binds to human HLA-G, wherein the antibody comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; and (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5 and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6.
3. An isolated antibody that binds to human HLA-G, wherein the antibody comprises a VH sequence of SEQ ID NO:7 and a VL sequence of SEQ ID NO:8 or a humanized variant of the VH and VL of the antibody thereof, wherein the humanized variant comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6.
4. The anti-HLA-G antibody according to any one of claims 1 to 3 , wherein the antibody is characterized independently by the following properties:
the anti-HLA-G antibody
a) does not cross-react with a modified human HLA-G ß2M MHC I complex comprising SEQ ID NO:26;
b) does not cross-react with human HLA-A2 ß2M MHC I complex comprising SEQ ID NO:21 and SEQ ID NO: 19;
c) does not cross-react with a mouse H2Kd ß2M MHC I complex comprising SEQ ID NO:27;
d) does not cross-react with rat RT1A ß2M MHC I complex comprising SEQ ID NO:29;
e) inhibits ILT2 binding to monomeric HLA-G ß2M MHC I complex;
f) inhibits ILT2 binding to monomeric HLA-G ß2M MHC I complex, by more than 50%;
g) inhibits ILT2 binding to monomeric, dimeric, trimeric HLA-G ß2M MHC I complex by more than 50%;
h) inhibits ILT2 binding to JEG3 cells;
i) wherein the antibody binds to JEG3 cells, and wherein the antibody inhibits ILT2 binding to JEG3 cells; or
j) wherein the antibody binds to human HLA-G ß2M MHC I complex, and wherein the antibody inhibits ILT2 binding to monomeric, dimeric, or trimeric HLA-G ß2M MHC I complex by more than 60% and inhibits ILT4 binding to dimeric or trimeric HLA-G ß2M MHC I complex by more than 50%.
5. The antibody of any one of claims 1 - 3 , wherein the antibody is of IgG1 isotype.
6. The antibody of claim 5 , wherein the antibody is of IgG1 isotype with mutations L234A, L235A and P329G (numbering according to the EU index of Kabat).
7. A pharmaceutical formulation comprising the antibody of claim 6 and a pharmaceutically acceptable carrier.
8. A pharmaceutical formulation comprising the antibody of any one of claims 1 - 3 and a pharmaceutically acceptable carrier.
9. An isolated antibody that binds to human HLA-G, wherein the antibody comprises a VH sequence of SEQ ID NO:7 and a VL sequence of SEQ ID NO:8.