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Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody

Oncogene volume 33, pages 34–43 (2014)Cite this article

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Abstract

The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met downregulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage lymphoma (Cbl) E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met overexpressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to downregulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.

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Acknowledgements

This study was supported by a grant of the Korea Healthcare technology R&D project, Ministry for Health & Welfare Affairs, Republic of Korea (A092255). We thank Dr Sangyeul Han for critical discussion and Dr Ogan Gurel for discussion and editing the manuscript. pcDNA-LRIG1 expression plasmid was kindly provided by Dr Håkan Hedman.

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  1. BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT)/Samsung Electronics Co. Ltd, Yongin-si, Republic of Korea

    J M Lee, B Kim, S B Lee, Y Jeong, Y M Oh, Y-J Song, S Jung, J Choi, S Lee, K H Cheong, D U Kim, H W Park, Y K Han, G W Kim, H Choi, P H Song & K A Kim

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Correspondence to K A Kim.

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Competing interests

The following authors are employed by the Samsung Advanced Institute of Technology: Ji Min Lee, Bogyou Kim, Saet Byoul Lee, Yunju Jeong, Young Mi Oh, Yun-Jeong Song, Sooyeon Jung, Jaehyun Choi, Seunghyun Lee, Kwang Ho Cheong, DongUk Kim, Hye Won Park, Geun Woong Kim, Hanna Choi, Paul H Song and Kyung-Ah Kim.

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Lee, J., Kim, B., Lee, S. et al. Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody. Oncogene 33, 34–43 (2014). https://doi.org/10.1038/onc.2012.551

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