Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain
AbstractHepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth. View Full-Text
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Park, H.; Kim, D.; Kim, E.; Sa, J.K.; Lee, H.W.; Yu, S.; Oh, J.; Kim, S.-H.; Yoon, Y.; Nam, D.-H. Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain. Int. J. Mol. Sci. 2017, 18, 1968.
Park H, Kim D, Kim E, Sa JK, Lee HW, Yu S, Oh J, Kim S-H, Yoon Y, Nam D-H. Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain. International Journal of Molecular Sciences. 2017; 18(9):1968.Chicago/Turabian Style
Park, Hyunkyu; Kim, Donggeon; Kim, Eunmi; Sa, Jason K.; Lee, Hee W.; Yu, Suji; Oh, Jiwon; Kim, Seok-Hyung; Yoon, Yeup; Nam, Do-Hyun. 2017. "Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain." Int. J. Mol. Sci. 18, no. 9: 1968.
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