title: Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody.
abstract: The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met downregulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage lymphoma (Cbl) E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met overexpressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to downregulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: B
authors.initials: B
authors.lastname: Kim
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Lee
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Jeong
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: Y M
authors.initials: YM
authors.lastname: Oh
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Song
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Jung
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Choi
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Cheong
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: D U
authors.initials: DU
authors.lastname: Kim
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Park
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: Y K
authors.initials: YK
authors.lastname: Han
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: G W
authors.initials: GW
authors.lastname: Kim
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Choi
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: P H
authors.initials: PH
authors.lastname: Song
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea.
authors.forename: K A
authors.initials: KA
authors.lastname: Kim
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C067419:CBL protein, human; D000068818:Cetuximab