title: Novel strategy for a bispecific antibody: induction of dual target internalization and degradation.
abstract: Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.
authors: Open Innovation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: J M
authors: JM
authors: Lee
authors: Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology (SAIT), Gyeonggi-do, South Korea.
authors: S H
authors: SH
authors: Lee
authors: Bioassay Group, Quality Evaluation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: J-W
authors: JW
authors: Hwang
authors: Open Innovation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: S J
authors: SJ
authors: Oh
authors: Open Innovation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: B
authors: B
authors: Kim
authors: Open Innovation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: S
authors: S
authors: Jung
authors: Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology (SAIT), Gyeonggi-do, South Korea.
authors: S-H
authors: SH
authors: Shim
authors: Cell Engineering Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: P W
authors: PW
authors: Lin
authors: Cell Engineering Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: S B
authors: SB
authors: Lee
authors: Samsung Advanced Institute of Technology (SAIT), Gyeonggi-do, South Korea.
authors: M-Y
authors: MY
authors: Cho
authors: Samsung Advanced Institute of Technology (SAIT), Gyeonggi-do, South Korea.
authors: Y J
authors: YJ
authors: Koh
authors: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: S Y
authors: SY
authors: Kim
authors: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: S
authors: S
authors: Ahn
authors: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: J
authors: J
authors: Lee
authors: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: K-M
authors: KM
authors: Kim
authors: Samsung Advanced Institute of Technology (SAIT), Gyeonggi-do, South Korea.
authors: K H
authors: KH
authors: Cheong
authors: Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology (SAIT), Gyeonggi-do, South Korea.
authors: J
authors: J
authors: Choi
authors: Open Innovation Team, Samsung Bioepis Co., Ltd., Incheon, South Korea.
authors: K-A
authors: KA
authors: Kim
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018033:Antibodies, Bispecific; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases