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Int. J. Mol. Sci. 2017, 18(9), 1968; doi:10.3390/ijms18091968

Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain

1
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, Korea
2
Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
3
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
4
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
The authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 11 August 2017 / Revised: 1 September 2017 / Accepted: 8 September 2017 / Published: 13 September 2017
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
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Abstract

Hepatocyte 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
Keywords: IRCR201; fully human antibody; cancer; c-Met; PSI domain; cross-reactivity IRCR201; fully human antibody; cancer; c-Met; PSI domain; cross-reactivity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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.

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