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

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

  • ACS Omega. 2020 Sep 29;5(40):25798-25809. doi: 10.1021/acsomega.0c03102.
Byeongkwi Min 1 2,  Jonghwa Jin 3,  Hyeree Kim 1 4,  Nam-Gu Her 2,  Changsik Park 5,  Donggeon Kim 2,  Jehoon Yang 6,  Juhyeon Hwang 2,  Eunmi Kim 2,  Minji Choi 5,  Ho Young Song 5,  Do-Hyun Nam 1 2 7,  Yeup Yoon 1 2 8
Affiliations

Affiliations

  • 1 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06355, Republic of Korea.
  • 2 Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea.
  • 3 Department of Convergence Technical Support, New Drug Development Center, 123 Osongsaengmyeng-ro, Cheongju-si, Chungbuk 28160, Korea.
  • 4 Samsung Biomedical Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea.
  • 5 LegoChem Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea.
  • 6 Animal Research and Molecular Imaging Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea.
  • 7 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
  • 8 Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea.
PMID: 33073104 DOI: 10.1021/acsomega.0c03102
Abstract

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.

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