cIRCR201-dPBD, a Novel Pyrrolobenzodiazepine Dimer-Containing Site-Specific Antibody-Drug Conjugate Targeting c-Met Overexpression Tumors.

Autor:	Min B; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea., Jin J; Department of Convergence Technical Support, New Drug Development Center, 123 Osongsaengmyeng-ro, Cheongju-si, Chungbuk 28160, Korea., Kim H; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.; Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea., Her NG; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea., Park C; LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea., Kim D; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea., Yang J; Animal Research and Molecular Imaging Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea., Hwang J; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea., Kim E; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea., Choi M; LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea., Song HY; LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea., Nam DH; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea.; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea., Yoon Y; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.; Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea.; Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2020 Sep 29; Vol. 5 (40), pp. 25798-25809. Date of Electronic Publication: 2020 Sep 29 (Print Publication: 2020).
DOI:	10.1021/acsomega.0c03102
Abstrakt:	c-Met, as a receptor expressed on the cell membrane, contributes to the growth and metastasis of tumors, as well as angiogenesis, mainly through the hepatocyte growth factor (HGF)/c-Met axis during tumor progression. Although several c-Met inhibitors, including small molecules and monoclonal antibody inhibitors, are currently being investigated, their clinical outcomes have not been promising. Development of an antibody-drug conjugate (ADC) against c-Met could be an attractive therapeutic strategy that would provide superior antitumor efficacy with broad-spectrum c-Met expression levels. In the present study, site-specific drug-conjugate technology was applied to develop an ADC using the human-mouse cross-reactive c-Met antibody and a prodrug pyrrolobenzodiazepine (PBD). The toxin payload was uniformly conjugated to the light-chain C-terminus of the native cIRCR201 antibody (drug-to-antibody ratio = 2), as confirmed using LC-MS. Using a high-throughput screening system, we found that cIRCR201-dPBD exhibited varying sensitivities depending on the expression levels of c-Met, and it induced receptor-mediated endocytosis and toxin-mediated apoptosis in 47 different cancer cell lines. cIRCR201-dPBD also showed significant antitumor activity on the MET -amplified cancer cells using in vivo xenograft models. Therefore, cIRCR201-dPBD could be a promising therapeutic strategy for tumors with c-Met expression. Competing Interests: The authors declare no competing financial interest.
Databáze:	MEDLINE
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