Preclinical Antitumor Activity of a Novel Anti-c-KIT Antibody-Drug Conjugate against Mutant and Wild-type c-KIT-Positive Solid Tumors

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Tinya AbramsSiew C Schleyer

Abstract

Purpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non-small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti-c-KIT ADC approach to evaluate the anticancer activity in multiple disease models.Experimental Design: A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models.Results: LOP628 exhibited potent antiproliferative activity on c-KIT-positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic...Continue Reading

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Citations

Feb 2, 2019·American Journal of Clinical Dermatology·Da Meng, Richard D Carvajal
Jan 3, 2020·International Journal of Molecular Medicine·Masuko Katoh, Masaru Katoh
Aug 29, 2020·Expert Opinion on Biological Therapy·Roland B Walter
Oct 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tal TilayovNiv Papo
Nov 10, 2020·Melanoma Research·Trevor S AndersonDevin B Lowe
Aug 10, 2019·Molecular Cancer Therapeutics·Shigehiro KoganemaruToshihiko Doi
Mar 5, 2020·Molecular Cancer Therapeutics·Sudeep BanerjeePartha Ray
Feb 23, 2021·Journal of Extracellular Vesicles·Mark BarokHeikki Joensuu
Apr 4, 2021·Cancers·Meet PatelNeelu Puri
Jul 10, 2021·Bioorganic Chemistry·Adel S GirgisAhmed A F Soliman
Jul 25, 2021·Cancers·Junaid ArshadJonathan C Trent
Aug 28, 2021·Journal of Clinical Medicine·Jamie L Stokke, Deepa Bhojwani

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