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

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.

Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

“… 103 , 104 The combination of antibody-based antigen specificity with payload cytotoxic potency results in an increased therapeutic index, favorable pharmacokinetic profile, and acceptable toxicological activity. 40 – 46 Up to now, the FDA has approved nine ADCs, including gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab deruxtecan, sacituzumab govitecan and others, for oncological application ( www.FDA.gov ). These ADCs target HER2, CD22, CD30, Trop-2, and others for treatment of various types of cancer.…”

“… 40 – 46 Currently, five single targeting ADCs specific to MET, namely ABBV-399 (telisotuzumab vedotin), SHR-A1403, TR1801-ADC, HucMet27-based ADC, and cIRCR201-dPBD have been preclinically validated ( Table 2 ). 40 – 44 The obtained results indicate that these MET-targeting ADCs are highly effective against cancer cellular models and patient-derived xenografts (PDXs) that harbor different forms of MET dysregulation. These forms of dysregulation include overexpression, amplification, exon-14 skipping, and activation mutation regardless of the level of MET signaling status involving cancer cell addiction.…”

“…These forms of dysregulation include overexpression, amplification, exon-14 skipping, and activation mutation regardless of the level of MET signaling status involving cancer cell addiction. 40 – 44 Two MET-based dual-targeting ADCs, including B10v5x225-H/M-vc-MMAE (targeting both MET and EGFR) and PCMdt-MMAE (targeting both MET and RON) have been preclinically studied ( Table 2 ). 45 , 46 B10v5x225-H/M-vc-MMAE is a dual-targeting ADC specific to both MET and EGFR.…”

“… 40 A similar correlation trend has also been observed in animal studies, in which the effectiveness of MET-targeting ADCs is positively correlated with xenograft tumors expressing different levels of MET expression. 40 – 44 Moreover, the use of advanced drug-linker technologies and the selection of highly potent payloads have dramatically lowered the threshold of MET expression required for an ADC to exert significant cytotoxicity. 42 , 44 These observations have potential implication in clinical trials for selecting patient populations showing variable levels of MET expression.…”

“… 14 Currently, therapeutics such as small-molecule kinase inhibitors (SMKIs) ( Table 1 ), 15 – 27 conventional therapeutic monoclonal antibodies (cTMABs), 28 – 33 and antibody-based biotherapeutics targeting MET ( Table 2 ) have been validated in preclinical studies and many of them have advanced into clinical trials. 34 – 46 Significantly, four SMKIs, crizotinib, cabozantinib, tepotinib, and capmatinib, have been approved for clinical application ( Table 1 ) ( www.FDA.gov ). Nevertheless, MET-targeting cTMABs, although some of them under clinical trials for almost 10 years, have made little progress.…”