ANTI-GPC3 AND ANTI-CD137 MULTISPECIFIC ANTIBODIES AND METHODS OF USE

1 . A multispecific antibody or antigen-binding fragment thereof, comprising a first antigen binding domain that specifically binds to human Glypican 3 (GPC3) and a second antigen binding domain that specifically binds to human CD137, wherein the second antigen binding domain that specifically binds to human CD137 comprises:

(i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 65, (b) a HCDR2 of SEQ ID NO: 80, and (c) a HCDR3 of SEQ ID NO: 81;

(ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 65, (b) a HCDR2 of SEQ ID NO: 73, and (c) a HCDR3 of SEQ ID NO: 67;

(iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 65, (b) a HCDR2 of SEQ ID NO: 66, and (c) a HCDR3 of SEQ ID NO: 67; or

(iv) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 55, (b) a HCDR2 of SEQ ID NO: 56, and (c) a HCDR3 of SEQ ID NO: 57.

2 . (canceled)

3 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the second antigen binding domain that specifically binds to human CD137 comprises:

(i) a heavy chain variable region comprising SEQ ID NO: 84 or an amino acid sequence at least 90% identical to SEQ ID NO: 84;

(ii) a heavy chain variable region comprising SEQ ID NO: 86 or an amino acid sequence at least 90% identical to SEQ ID NO: 86;

(iii) a heavy chain variable region comprising SEQ ID NO: 75 or an amino acid sequence at least 90% identical to SEQ ID NO: 75;

(iv) a heavy chain variable region comprising SEQ ID NO: 70 or an amino acid sequence at least 90% identical to SEQ ID NO: 70; or

(v) a heavy chain variable region comprising SEQ ID NO: 60 or an amino acid sequence at least 90% identical to SEQ ID NO: 60.

4 - 5 . (canceled)

6 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the second antigen binding domain that specifically binds to human CD137 binds to an epitope of human CD137 comprising amino acids F36, P47 and P49.

7 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the first antigen binding domain that specifically binds to human GPC3 comprises:

a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 10, (b) a HCDR2 of SEQ ID NO: 11, and (c) a HCDR3 of SEQ ID NO: 12; and

a light chain variable region that comprises (d) a LCDR1 of SEQ ID NO: 13, (e) a LCDR2 of SEQ ID NO: 14, and (f) a LCDR3 of SEQ ID NO: 15.

8 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the first antigen binding domain that specifically binds to human GPC3 comprises: a heavy chain variable region comprising SEQ ID NO: 5 or an amino acid sequence at least 90% identical to SEQ ID NO: 5, and a light chain variable region comprising SEQ ID NO: 7 or an amino acid sequence at least 90% identical to SEQ ID NO: 7.

9 - 10 . (canceled)

11 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein:

(a) the first antigen binding domain that specifically binds to human GPC3 comprises: a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 10, (b) a HCDR2 of SEQ ID NO: 11, and (c) a HCDR3 of SEQ ID NO: 12; and a light chain variable region that comprises (d) a LCDR1 of SEQ ID NO: 13, (e) a LCDR2 of SEQ ID NO: 14, and (f) a LCDR3 of SEQ ID NO: 15, and

(b) the second antigen binding domain that specifically binds to human CD137 comprises:

(i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 65, (b) a HCDR2 of SEQ ID NO: 80, (c) a HCDR3 of SEQ ID NO: 81;

(ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 65, (b) a HCDR2 of SEQ ID NO: 73, (c) a HCDR3 of SEQ ID NO: 67;

(iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 65, (b) a HCDR2 of SEQ ID NO: 66, (c) a HCDR3 of SEQ ID NO: 67; or

(iv) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 55, (b) a HCDR2 of SEQ ID NO: 56, (c) a HCDR3 of SEQ ID NO: 57.

12 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein;

(a) the first antigen binding domain that specifically binds to human GPC3 comprises: a heavy chain variable region that comprises SEQ ID NO: 5, and a light chain variable region that comprises SEQ ID NO: 7; and

(b) the second antigen binding domain that specifically binds to human CD137 comprises:

(i) a heavy chain variable region that comprises SEQ ID NO: 84;

(ii) a heavy chain variable region that comprises SEQ ID NO: 86;

(iii) a heavy chain variable region that comprises SEQ ID NO: 75;

(iv) a heavy chain variable region that comprises SEQ ID NO: 70; or

(v) a heavy chain variable region that comprises SEQ ID NO: 60.

13 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the multispecific antibody or antigen-binding fragment is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab′ fragment, or a F(ab′) 2 fragment; or

wherein the first antigen binding domain that specifically binds to human GPC3 is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a single domain antibody, a Fab fragment, a Fab′ fragment, or a F(ab′) 2 fragment, and the second antigen binding domain that specifically binds to human CD137 is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a single domain antibody, a Fab fragment, a Fab′ fragment, or a F(ab′) 2 fragment; or

wherein the multispecific antibody or antigen-binding fragment thereof is a bispecific antibody.

14 - 15 . (canceled)

16 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the multispecific antibody or antigen-binding fragment comprises a linker selected from SEQ ID NO:16 to SEQ ID NO: 51 and SEQ ID NO: 88 to SEQ ID NO: 93.

17 - 18 . (canceled)

19 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the multispecific antibody or antigen-binding fragment comprises a heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4, and/or a light chain constant region of the type of kappa or lambda, and

wherein the heavy chain constant region comprises a CH1 and/or an Fc domain.

20 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the multispecific antibody or antigen-binding fragment thereof has one or more of the following: antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), reduced glycosylation, no glycosylation, hypofucosylation, or increased bisecting GlcNac structures.

21 - 22 . (canceled)

23 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the multispecific antibody or antigen-binding fragment thereof comprises a Fc domain, and wherein the Fc domain is an IgG1 with reduced effector function or an IgG4, optionally the Fc domain comprises an amino acid sequence of SEQ ID NO: 9.

24 . (canceled)

25 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein:

a) a heavy chain variable region of the first antigen binding domain that specifically binds to human GPC3, a CH1 domain, an Fc domain, and the heavy chain variable region of the second antigen binding domain that specifically binds to human CD137 are arranged in a first polypeptide in the direction of N terminus to C terminus;

optionally, C terminus of the Fc domain is linked to N terminus of the heavy chain variable region of the second antigen binding domain via a linker; and

b) a light chain variable region of the first antigen binding domain that specifically binds to human GPC3 and a first light chain constant region are arranged in a second polypeptide in the direction of N terminus to C terminus.

26 . The multispecific antibody or antigen-binding fragment thereof of claim 1 , wherein the multispecific antibody or antigen-binding fragment comprises a first polypeptide of SEQ ID NO: 1 and a second polypeptide of SEQ ID NO: 3.

27 . A pharmaceutical composition comprising the multispecific antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.

28 . A method of treating a cancer expressing GPC3 comprising administering to a patient in need an effective amount of the multispecific antibody or antigen-binding fragment thereof of claim 1 .

29 - 39 . (canceled)

40 . An isolated nucleic acid that encodes the multispecific antibody or antigen-binding fragment thereof of claim 1 .

41 . A vector comprising the nucleic acid of claim 40 .

42 . A host cell comprising the nucleic acid of claim 40 .

43 . A process for producing a multispecific antibody or antigen-binding fragment thereof comprising cultivating the host cell of claim 42 and recovering the antibody or antigen-binding fragment thereof from the culture.