Antibody compositions comprising Fc mutations and site-specific conjugation properties for use in treating cancer, immunological disorders, and methods thereof
Antibodies that bind Her2, EGFR, Trop2, CDH3 or other TAAs containing a triple mutation at L234A, L235A, and L328C and methods of making such triple mutated antibodies are disclosed herein. Consequently, the triple mutated antibodies contain a modified effector function through Fc silencing and are capable of site-specific conjugation at L328C to form an antibody-drug-conjugate (ADC) which can be administered to patients and provide a method of treating cancer, immunological and neurological disorders.
1 . A method of treating cancer in an individual comprising, (i) administering to said individual a therapeutic effective amount of an antibody boron conjugate (ABC), wherein said ABC comprises an antibody, comprising a triple amino acid mutation, wherein the triple amino acid mutation comprises a L234A modification, a L235A modification, and a L328C modification, wherein the amino acid mutation position numbering is according to the EU index as set forth in Kabat, and wherein said triple amino acid mutation suppresses binding to FcγRI, FcγIIA, and FcγRIIIA and reduces antibody-dependent cellular cytotoxicity (ADCC) and wherein said triple mutation further reduces C1q binding and reduces complement-dependent cytotoxicity (CDC), and wherein the cancer is selected from the group consisting of acute myeloid leukemia, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, b-cell chronic lymphocytic leukemia, B-cell Hodgkin's lymphoma, B-cell non-Hodgkin's, lymphoma, bladder cancer, breast cancer, chronic lymphatic leukemia, clear cell renal cell carcinoma, colorectal cancer, diffuse large B-cell lymphoma, glioblastoma, gastric cancer, hairy cell leukemia, head and neck cancer, hematologic cancers, Hodgkin lymphoma, melanoma, metastatic Merkel cell carcinoma, multiple myeloma, neuroblastoma, non-hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer, stomach neoplasms, squamous cell carcinoma, triple-negative breast cancer, urothelial cancer, genital cancer, cervical cancer, esophageal cancer, gastroesophageal junction adenocarcinoma, and glioma.
2 . The method of claim 1 , wherein the antibody composition comprises an Her2 antibody.
3 . The method of claim 1 , wherein the antibody composition comprises a Trop2 antibody.
4 . The method of claim 1 , wherein the antibody composition comprises a CDH3 antibody.
5 . The method of claim 1 , wherein the antibody composition comprises a tumor associated antigen (TAA) antibody.
6 . The method of claim 1 , wherein the antibody comprises a TAA, wherein the TAA is selected from the group consisting of GPNMB, DLL3, ENPP3, SLITRK6, CA9, PSMA, CDH6, Glypican 3, EDNRB, NECTIN-4, SLC34A2, Her3, and NRP1.
7 . The method of claim 1 , wherein the ABC further comprises a stretcher unit.
8 . The method of claim 1 , wherein the ABC further comprises a spacer unit.
9 . The method of claim 1 , wherein the ABC further comprises an amino acid unit.
10 . The method of claim 1 , wherein the ABC further comprises a pharmaceutically acceptable excipient.
11 . The method of claim 1 , further comprising a combination with radiation therapy.
12 . The method of claim 1 , further comprising a combination with chemotherapy.