Back to Search Start Over

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

Authors :
Abrams T
Connor A
Fanton C
Cohen SB
Huber T
Miller K
Hong EE
Niu X
Kline J
Ison-Dugenny M
Harris S
Walker D
Krauser K
Galimi F
Wang Z
Ghoddusi M
Mansfield K
Lee-Hoeflich ST
Holash J
Pryer N
Kluwe W
Ettenberg SA
Sellers WR
Lees E
Kwon P
Abraham JA
Schleyer SC
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Sep 01; Vol. 24 (17), pp. 4297-4308. Date of Electronic Publication: 2018 May 15.
Publication Year :
2018

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 index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT-directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system. Conclusions: The preclinical findings suggest that the c-KIT-directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT-positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. Clin Cancer Res; 24(17); 4297-308. ©2018 AACR .<br /> (©2018 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
24
Issue :
17
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
29764854
Full Text :
https://doi.org/10.1158/1078-0432.CCR-17-3795