Anti-MUC16 antibodies, antibody-drug conjugates, and bispecific antigen-binding molecules that bind MUC16 and CD3, and uses thereof
Mucin 16 (MUC16) is highly expressed in ovarian cancer and expression on cancer cells is shown to protect tumor cells from the immune system. The present invention provides novel full-length human IgG antibodies that bind to human and MUC16 (monospecific antibodies). The present invention also provides novel bispecific antibodies (bsAbs) that bind to both MUC16 and CD3 and activate T cells via the CD3 complex in the presence of MUC16-expressing tumors. According to certain embodiments, the present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human and monkey CD3, and a second antigen-binding molecule that specifically binds human and monkey MUC16. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing MUC16. The bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced MUC16-targeted immune response is desired and/or therapeutically beneficial. For example, the bispecific antibodies of the invention are useful for the treatment of various cancers, including ovarian cancer. The present invention also includes anti-MUC16 antibody drug conjugates which inhibit tumor growth in vivo. In some embodiments, the anti-MUC16 antibodies are useful in diagnostic methods for identifying the presence of MUC16 in tissue and/or plasma samples.
1 . A group of nucleic acid molecules encoding a bispecific antigen-binding molecule that binds human CD3 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: 1732, 1734 and 1736;
(b) a second nucleic acid molecule encoding a HCVR comprising HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22 and 24; 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 NO: 28, TAS, and SEQ ID NO: 32.
2 . The group of nucleic acid molecules of claim 1 , wherein:
(a) the first nucleic acid molecule encodes a HCVR comprising the amino acid sequence of SEQ ID NO: 1730;
(b) the second nucleic acid molecule encodes a HCVR comprising the amino acid sequence of SEQ ID NO: 18; and
(c) the third nucleic acid molecule encodes a LCVR comprising the amino acid sequence of SEQ ID NO: 26.
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, or a human IgG4 heavy chain constant region.
6 . The group of nucleic acid molecules of claim 3 , wherein:
(a) the first nucleic acid molecule encodes a first heavy chain comprising the amino acid sequence of SEQ ID NO: 1961;
(b) the second nucleic acid molecule encodes a second heavy chain comprising the amino acid sequence of SEQ ID NO: 1959; and
(c) the third nucleic acid molecule encodes a light chain comprising the amino acid sequence of SEQ ID NO: 1960.
7 . The group of nucleic acid molecules of claim 2 , wherein the first nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 1729, the second nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 17, and the third nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 25.
8 . A group of nucleic acid molecules encoding a bispecific antigen-binding molecule that binds human CD3 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: 1868, 1870 and 1872;
(b) a second nucleic acid molecule encoding a HCVR comprising HCDR1, HCDR2, HCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 20, 22 and 24; 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 NO: 28, TAS, and SEQ ID NO: 32.
9 . The group of nucleic acid molecules of claim 8 , wherein:
(a) the first nucleic acid molecule encodes a HCVR comprising the amino acid sequence of SEQ ID NO: 1866;
(b) the second nucleic acid molecule encodes a HCVR comprising the amino acid sequence of SEQ ID NO: 18; and
(c) the third nucleic acid molecule encodes a LCVR comprising the amino acid sequence of SEQ ID NO: 26.
10 . The group of nucleic acid molecules of claim 8 , 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.
11 . The group of nucleic acid molecules of claim 10 , 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.
12 . The group of nucleic acid molecules of claim 10 , 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, or a human IgG4 heavy chain constant region.
13 . The group of nucleic acid molecules of claim 10 , wherein:
(a) the first nucleic acid molecule encodes a first heavy chain comprising the amino acid sequence of SEQ ID NO: 1962;
(b) the second nucleic acid molecule encodes a second heavy chain comprising the amino acid sequence of SEQ ID NO: 1959; and
(c) the third nucleic acid molecule encodes a light chain comprising the amino acid sequence of SEQ ID NO: 1960.
14 . The group of nucleic acid molecules of claim 8 , wherein the first nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 1865, the second nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 17, and the third nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO: 25.
15 . An expression vector or a group of expression vectors comprising the group of nucleic acid molecules of claim 1 .
16 . An expression vector or a group of expression vectors comprising the group of nucleic acid molecules of claim 8 .
17 . An isolated host cell comprising the expression vector or the group of expression vectors of claim 15 .
18 . An isolated host cell comprising the expression vector or the group of expression vectors of claim 16 .
19 . A method of producing a bispecific antigen-binding molecule that binds human CD3 and human MUC16, comprising culturing the host cell of claim 17 under conditions permitting production of the bispecific antigen-binding molecule, and recovering the bispecific antigen-binding molecule so produced.
20 . The method of claim 19 , further comprising formulating the bispecific antigen-binding molecule as a pharmaceutical composition with a suitable carrier.
21 . A method of producing a bispecific antigen-binding molecule that binds human CD3 and human MUC16, comprising culturing the host cell of claim 18 under conditions permitting production of the bispecific antigen-binding molecule, and recovering the bispecific antigen-binding molecule so produced.
22 . The method of claim 21 , further comprising formulating the bispecific antigen-binding molecule as a pharmaceutical composition with a suitable carrier.