B7-h4 therapeutic binding molecules for the treatment of cancer

A method of treating cancer in a subject, comprising administering to the subject an antibody-drug conjugate (ADC) that specifically binds to B7-H4 in an amount from about 0.8 mg/kg to about 4.8 mg/kg, the ADC comprising:

• i. an antibody or antigen binding fragment thereof which binds to a B7-H4 polypeptide, comprising:
• a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), a heavy chain CDR3 (HCDR3), a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:
• 7, SEQ ID NO:
• 8, SEQ ID NO:
• 9, SEQ ID NO:
• 10, SEQ ID NO:
• 11, and SEQ ID NO:
• 12, respectively, or a functional variant thereof;
• and
• ii. a cleavable linker and cytotoxic agent conjugated to the antibody or antigen binding fragment thereof having the formula:

A pharmaceutical composition comprising an antibody-drug conjugate (ADC) that specifically binds to B7-H4 which is administered in an amount from about 0.8 mg/kg to about 4.8 mg/kg, the ADC comprising:

• i. an antibody or antigen binding fragment thereof which binds to a B7-H4 polypeptide, comprising:
• a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), a heavy chain CDR3 (HCDR3), a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:
• 7, SEQ ID NO:
• 8, SEQ ID NO:
• 9, SEQ ID NO:
• 10, SEQ ID NO:
• 11, and SEQ ID NO:
• 12, respectively, or a functional variant thereof;
• and
• ii. a cleavable linker and cytotoxic agent conjugated to the antibody or antigen binding fragment thereof having the formula:

A pharmaceutical composition comprising an antibody-drug conjugate (ADC) that specifically binds to B7-H4 which is administered in an amount from about 25 mg to about 900 mg, the ADC comprising:

• i. an antibody or antigen binding fragment thereof which binds to a B7-H4 polypeptide, comprising:
• f) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), a heavy chain CDR3 (HCDR3), a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:
• 7, SEQ ID NO:
• 8, SEQ ID NO:
• 9, SEQ ID NO:
• 10, SEQ ID NO:
• 11, and SEQ ID NO:
• 12, respectively, or a functional variant thereof;
• g) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 1, SEQ ID NO:
• 2, SEQ ID NO:
• 3, SEQ ID NO:
• 4, SEQ ID NO:
• 5, and SEQ ID NO:
• 6, respectively, or a functional variant thereof;
• h) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 13, SEQ ID NO:
• 14, SEQ ID NO:
• 15, SEQ ID NO:
• 16, SEQ ID NO:
• 17, and SEQ ID NO:
• 18, respectively, or a functional variant thereof;
• i) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 19, SEQ ID NO:
• 20, SEQ ID NO:
• 21, SEQ ID NO:
• 22, SEQ ID NO:
• 23, and SEQ ID NO:
• 24, respectively, or a functional variant thereof;
• or
• j) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 25, SEQ ID NO:
• 26, SEQ ID NO:
• 27, SEQ ID NO:
• 28, SEQ ID NO:
• 29, and SEQ ID NO:
• 30, respectively, or a functional variant thereof;
• ii. a cleavable linker;
• and
• iii. a cytotoxic agent.

A method of treating cancer in a subject, comprising administering to the subject an antibody-drug conjugate (ADC) that specifically binds to B7-H4, the ADC comprising:

• i. an antibody or antigen binding fragment thereof which binds to a B7-H4 polypeptide, comprising:
• k) a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), a heavy chain CDR3 (HCDR3), a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:
• 7, SEQ ID NO:
• 8, SEQ ID NO:
• 9, SEQ ID NO:
• 10, SEQ ID NO:
• 11, and SEQ ID NO:
• 12, respectively, or a functional variant thereof;
• l) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 1, SEQ ID NO:
• 2, SEQ ID NO:
• 3, SEQ ID NO:
• 4, SEQ ID NO:
• 5, and SEQ ID NO:
• 6, respectively, or a functional variant thereof;
• m) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 13, SEQ ID NO:
• 14, SEQ ID NO:
• 15, SEQ ID NO:
• 16, SEQ ID NO:
• 17, and SEQ ID NO:
• 18, respectively, or a functional variant thereof;
• n) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 19, SEQ ID NO:
• 20, SEQ ID NO:
• 21, SEQ ID NO:
• 22, SEQ ID NO:
• 23, and SEQ ID NO:
• 24, respectively, or a functional variant thereof;
• or
• o) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:
• 25, SEQ ID NO:
• 26, SEQ ID NO:
• 27, SEQ ID NO:
• 28, SEQ ID NO:
• 29, and SEQ ID NO:
• 30, respectively, or a functional variant thereof;
• ii. a cleavable linker;
• and
• iii. a cytotoxic agent;
• wherein at least about 25% of cancer cells in the subject are B7-H4 positive cells.