Drug Conjugates of Antagonistic RSPO4 Mutant for Simultaneous Targeting of LGR4/5/6 for Cancer Treatment

• Published in: Journal of medicinal chemistry 2021-08, Vol.64 (17), p.12572-12581
• Main Authors: Cui, Jie, Toh, Yukimatsu, Park, Soohyun, Yu, Wangsheng, Tu, Jianghua, Wu, Ling, Li, Li, Jacob, Joan, Pan, Sheng, Carmon, Kendra S., Liu, Qingyun J.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00395

LGR4-6 (leucine-rich repeating containing, G-protein-coupled receptors 4, 5, and 6) are three related receptors with upregulated expression in gastrointestinal cancers to various extents, and LGR5 is enriched in cancer stem cells. Antibody-drug conjugates (ADCs) targeting LGR5 showed robust antitumor effect in vivo but could not eradicate tumors due to plasticity of LGR5-positive cancer cells. As LGR5-negative cancer cells often express LGR4 or LGR6 or both, we reasoned that simultaneous targeting of all three LGRs may provide a more effective approach. R-spondins (RSPOs) bind to LGR4-6 with high affinity and potentiate Wnt signaling. We identified an RSPO4 furin domain mutant (Q65R) that retains potent LGR binding but no longer potentiates Wnt signaling. Drug conjugates of a peptibody comprising the RSPO4 mutant and IgG1-Fc showed potent cytotoxic effects on cancer cell lines expressing any LGR in vitro and suppressed tumor growth in vivo without inducing intestinal enlargement or other adverse effects.