Bispecific anti-MUC16 x anti-CD28 antibodies and uses thereof
The present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD28, and a second antigen-binding molecule that specifically binds human MUC16. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing MUC16, such as ovarian tumors. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an up-regulated or induced targeted immune response is desired and/or therapeutically beneficial.
1 . A group of nucleic acid molecules encoding a bispecific antigen-binding molecule that binds human CD28 and human MUC16, wherein the group of nucleic acid molecules comprises:
(a) a first nucleic acid molecule encoding a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, HCDR3 domains, respectively, wherein the first nucleic acid molecule comprises the nucleotide sequences of SEQ ID NOs: 19, 21, and 23;
(b) a second nucleic acid molecule encoding a HCVR comprising HCDR1, HCDR2, HCDR3 domains, respectively, wherein the second nucleic acid molecule comprises the nucleotide sequences of SEQ ID NOs: 3, 5 and 7; and
(c) a third nucleic acid molecule encoding a light chain variable region (LCVR) comprising LCDR1, LCDR2, LCDR3 domains, respectively, wherein the third nucleic acid molecule comprises the nucleotide sequences of SEQ ID NOs: 11, 13 and 15.
2 . The group of nucleic acid molecules of claim 1 , wherein:
(a) the first nucleic acid molecule encodes a HCVR and comprises the nucleotide sequence of SEQ ID NO: 17;
(b) the second nucleic acid molecule encodes a HCVR and comprises the nucleotide sequence of SEQ ID NO: 1; and
(c) the third nucleic acid molecule encodes a LCVR and comprises the nucleotide sequence of SEQ ID NO: 9.
3 . The group of nucleic acid molecules of claim 1 , wherein the bispecific antigen-binding molecule is a bispecific antibody, the first nucleic acid molecule encodes a first heavy chain, the second nucleic acid molecule encodes a second heavy chain, and the third nucleic acid molecule encodes a light chain.
4 . The group of nucleic acid molecules of claim 3 , wherein the first heavy chain or the second heavy chain, but not both, comprises a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.
5 . The group of nucleic acid molecules of claim 3 , wherein the first heavy chain, the second heavy chain, or both the first and second heavy chains comprise a human IgG1 heavy chain constant region.
6 . The group of nucleic acid molecules of claim 3 , wherein the first heavy chain, the second heavy chain, or both the first and second heavy chains comprise a human IgG4 heavy chain constant region.
7 . An expression vector comprising the group of nucleic acid molecules of claim 1 , or a group of expression vectors comprising, respectively, the group of nucleic acid molecules of claim 1 .
8 . An isolated host cell comprising the expression vector or the group of expression vectors of claim 7 .
9 . An isolated host cell comprising the group of nucleic acid molecules of claim 1 .
10 . An isolated host cell comprising the group of nucleic acid molecules of claim 2 .
11 . A method of producing a bispecific antigen-binding molecule that binds human CD28 and human MUC16, comprising culturing the host cell of claim 8 under conditions permitting production of the bispecific antigen-binding molecule, and recovering the bispecific antigen-binding molecule so produced.
12 . The method of claim 11 , further comprising formulating the bispecific antigen-binding molecule as a pharmaceutical composition with a suitable carrier.
13 . An expression vector comprising the group of nucleic acid molecules of claim 2 , or a group of expression vectors comprising, respectively, the group of nucleic acid molecules of claim 2 .
14 . A group of nucleic acid molecules encoding a bispecific antigen-binding molecule that binds human CD28 and human MUC16, wherein the group of nucleic acid molecules comprises:
(a) a first nucleic acid molecule encoding a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22 and 24;
(b) a second nucleic acid molecule encoding a HCVR comprising HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 4, 6 and 8; and
(c) a third nucleic acid molecule encoding a light chain variable region (LCVR) comprising LCDR1, LCDR2, LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 12, 14 and 16.
15 . The group of nucleic acid molecules of claim 14 , wherein:
(a) the first nucleic acid molecule encodes a HCVR comprising the amino acid sequence of SEQ ID NO: 18;
(b) the second nucleic acid molecule encodes a HCVR comprising the amino acid sequence of SEQ ID NO: 2; and
(c) the third nucleic acid molecule encodes a LCVR comprising the amino acid sequence of SEQ ID NO: 10.
16 . The group of nucleic acid molecules of claim 14 , wherein the bispecific antigen-binding molecule is a bispecific antibody, the first nucleic acid molecule encodes a first heavy chain, the second nucleic acid molecule encodes a second heavy chain, and the third nucleic acid molecule encodes a light chain.
17 . The group of nucleic acid molecules of claim 16 , wherein the first heavy chain or the second heavy chain, but not both, comprises a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.
18 . The group of nucleic acid molecules of claim 16 , wherein the first heavy chain and the second heavy chain comprise a human IgG1 heavy chain constant region.
19 . The group of nucleic acid molecules of claim 16 , wherein the first heavy chain and the second heavy chain comprise a human IgG4 heavy chain constant region.
20 . An expression vector comprising the group of nucleic acid molecules of claim 14 , or a group of expression vectors comprising, respectively, the group of nucleic acid molecules of claim 14 .
21 . An expression vector comprising the group of nucleic acid molecules of claim 15 , or a group of expression vectors comprising, respectively, the group of nucleic acid molecules of claim 15 .
22 . An isolated host cell comprising the expression vector or the group of expression vectors of claim 20 .
23 . An isolated host cell comprising the group of nucleic acid molecules of claim 14 .
24 . An isolated host cell comprising the group of nucleic acid molecules of claim 15 .
25 . A method of producing a bispecific antigen-binding molecule that binds human CD28 and human MUC16, comprising culturing the host cell of claim 22 under conditions permitting production of the bispecific antigen-binding molecule, and recovering the bispecific antigen-binding molecule so produced.
26 . The method of claim 25 , further comprising formulating the bispecific antigen-binding molecule as a pharmaceutical composition with a suitable carrier.