BISPECIFIC ANTIGEN-BINDING MOLECULES AND METHODS OF USE

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Patent No.: US None
App. No.: 19/176,544

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Abstract

The present invention provides bispecific antigen-binding molecules having a monovalent arm specific to a first target antigen (e.g., a T cell antigen, such as CD3) and a bivalent arm specific for a second target antigen (e.g., a tumor antigen, such as HER2). Bispecific antigen-binding molecules are useful in the treatment of disorders, such as cancer (e.g., HER2-positive cancer). The invention also features methods of producing bispecific antigen-binding molecules, methods of treating disorders using bispecific antigen-binding molecules, and compositions including bispecific antigen-binding molecules.

Claims (165)

1 - 237 . (canceled)

238 . A method of:

(a) treating or delaying the progression of a HER2-positive cancer in a subject in need thereof; or

(b) enhancing immune function in a subject having a HER2-positive cancer,

wherein the method comprises administering to the subject a bispecific antigen-binding molecule that specifically binds CD3 and HER2 comprising a monovalent arm and a bivalent arm, wherein:

(a) the monovalent arm comprises a Fab A that specifically binds CD3, wherein the C-terminus of the Fab A is fused to an N-terminus of a first Fc subunit, and wherein the Fab A comprises the following HVRs:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1,

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2,

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3,

(iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4,

(v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and

(vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

(b) the bivalent arm comprises a Fab B1 and a Fab B2 that each specifically binds HER2, wherein the C-terminus of the Fab B2 is fused to the N-terminus of the Fab B1 , and the C-terminus of the Fab B1 is fused to an N-terminus of a second Fc subunit, wherein the Fab B1 and the Fab B2 each comprise the following HVRs:

(i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11,

(ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36,

(iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37,

(iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38,

(v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and

(vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and

239 . The method of claim 238 , wherein:

(a) the Fab A comprises a VH A region and a VL A region, wherein the VH A region comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 7, and the VL A region comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8;

(b) the Fab B1 comprises a VH B1 region and a VL B1 region, wherein the VH B1 region comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 41, and the VL B1 region comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 49; and

(c) the Fab B2 comprises a VH B2 region and a VL B2 region, wherein the VH B2 region comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 41, and the VL B2 region comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 49.

240 . The method of claim 239 , wherein:

(a) the VH A region comprises the amino acid sequence of SEQ ID NO: 7, and the VL A region comprises the amino acid sequence of SEQ ID NO: 8;

(b) the VH B1 region comprises the amino acid sequence of SEQ ID NO: 41, and the VL B1 region comprises the amino acid sequence of SEQ ID NO: 49; and

(c) the VH B2 region comprises the amino acid sequence of SEQ ID NO: 41, and the VL B2 region comprises the amino acid sequence of SEQ ID NO: 49.

241 . The method of claim 238 , wherein the HER2-positive cancer is:

(a) characterized by tumor cells that express HER2 at an average copy number of 200,000 or more copies per cell; and/or

(b) a breast cancer, a gastric cancer, a colorectal cancer, a non-small cell lung cancer, a renal cancer, a bladder cancer, a pancreatic cancer, a prostate cancer, a liver cancer, a head and neck cancer, a melanoma, an ovarian cancer, a mesothelioma, a glioblastoma, an endometrial cancer, or an osteosarcoma.

242 . The method of claim 238 , wherein the bispecific antigen-binding molecule is administered to the subject:

(a) in a dosage of about 0.01 mg/kg to about 10 mg/kg, of about 0.1 mg/kg to about 10 mg/kg, or of about 1 mg/kg;

(b) subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally; and/or

243 . The method of claim 242 , wherein:

(a) the PD-1 axis binding antagonist or additional therapeutic agent is to be administered concurrently with, prior to, or subsequent to the administration of the medicament; and/or

(b) the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

244 . The method of claim 243 , wherein the PD-1 axis binding antagonist is:

(i) a PD-1 binding antagonist selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (pembrolizumab), MEDI-0680 (AMP-514), PDR001 (spartalizumab), REGN2810 (cemiplimab), and BGB-108;

(ii) a PD-L1 binding antagonist selected from the group consisting of MPDL3280A (atezolizumab), MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab); or

(iii) a PD-L2 binding antagonist, wherein the PD-L2 binding antagonist is an antibody or an immunoadhesin.

245 . A method of: