MULTISPECIFIC ANTIBODIES AND METHODS OF THEIR PRODUCTION AND USE

Claims

1. A tetraspecific antibody monomer having binding specificity for CD3, CD19, PD-1 and 4-1BB, wherein the monomer has an N-terminus and a C-terminus comprising, sequentially arranged from N-terminus to C-terminus: the first domain of scFv at the N-terminus, Fab domain, Fc domain, the second domain of scFv, and the third scFv at the C-terminus, wherein the first domain of scFv has binding specificity for PD-1, the Fab domain has binding specificity for 4-1BB, the second domain of scFv has binding specificity for CD19, and the third domain of scFv has binding specificity for CD3.

2. A tetraspecific antibody monomer according to claim 1, wherein said tetraspecific antibody monomer comprises: a) 3 CDR SEQ ID NO: 18 and 3 CDR SEQ ID NO: 20; b) 3 CDR SEQ ID NO: 26 and 3 CDR SEQ ID NO: 28; c) 3 CDR SEQ ID NO: 54 and 3 CDR SEQ ID NO: 56; And d) 3 CDR SEQ ID NO: 2 and 3 CDR SEQ ID NO:

4.

3. A tetraspecific antibody monomer according to claim 1 or 2: i) wherein the first domain of the scFv has binding specificity for PD-1, wherein the Fab domain has binding specificity for 4-1BB, and wherein the second domain of the scFv has binding specificity for CD19 and wherein the third domain of the scFv has binding specificity for CD3; or ii) wherein the first scFv domain, the second scFv domain, or the third scFv domain comprises a gly-gly-gly-ser(G4S)n linker, where n is 2, 3, or 4; or iii) comprises an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 18, 20, 26, 28, 54, 56, 2 or 4.

4. A tetraspecific antibody monomer according to any one of claims 1-3, wherein: i) a first, second or third domain of an scFv comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 18, 20, 54, 56, 2 or 4; or ii) the Fab domain comprises an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 26 or 28.

5. A tetraspecific antibody having binding specificity for CD3, CD19, PD-1 and 4-1BB, comprising two tetraspecific antibody monomers according to any one of claims 1 to 4.

6. A pharmaceutical composition for treating cancer having a cell expressing CD19, comprising a pharmaceutically acceptable carrier and a tetraspecific antibody according to claim 5 in a therapeutically effective amount.

7. The pharmaceutical composition of claim 5, further comprising a therapeutic agent selected from a radioisotope, a radionuclide, a toxin, a chemotherapeutic agent, or a combination thereof.

8. A method for treating cancer having a cell expressing CD19 in a human, comprising administering to the subject an effective amount of the tetraspecific antibody of claim 5 or the pharmaceutical composition of claim 6.

9. The method of claim 8, further comprising co-administering an effective amount of a therapeutic agent, wherein the therapeutic agent comprises an antibody, a chemotherapeutic agent, an enzyme, an anti-estrogen agent, a receptor tyrosine kinase inhibitor, a kinase inhibitor, a cell cycle inhibitor, an immune checkpoint inhibitor, an inhibitor of DNA, RNA or protein synthesis, a RAS inhibitor, an inhibitor of PD1, PD-L1, CTLA4, 4-1BB, OX40, GITR, ICOS, LIGHT, TIM3, LAG3, TIGIT, CD40, CD27, HVEM, BTLA, VISTA, B7H4, CSF1R, NKG2D, CD73 or a combination thereof.