Back to Search Start Over

Preclinical Evaluation of IMGC936, a Next-Generation Maytansinoid-based Antibody–drug Conjugate Targeting ADAM9-expressing Tumors

Authors :
Juniper A. Scribner
Stuart W. Hicks
Kerstin W. Sinkevicius
Nicholas C. Yoder
Gundo Diedrich
Jennifer G. Brown
Jacquelynn Lucas
Megan E. Fuller
Thomas Son
Anahita Dastur
Jeff Hooley
Christopher Espelin
Marian Themeles
Francine Z. Chen
Ying Li
Michael Chiechi
Jenny Lee
Bhaswati Barat
Lusiana Widjaja
Sergey Gorlatov
James Tamura
Valentina Ciccarone
Olga Ab
Kerry A. McEachem
Scott Koenig
Eric H. Westin
Paul A. Moore
Thomas Chittenden
Richard J. Gregory
Ezio Bonvini
Deryk Loo
Source :
Molecular Cancer Therapeutics. 21:1047-1059
Publication Year :
2022
Publisher :
American Association for Cancer Research (AACR), 2022.

Abstract

ADAM metallopeptidase domain 9 (ADAM9) is a member of the ADAM family of multifunctional, multidomain type 1 transmembrane proteins. ADAM9 is overexpressed in many cancers, including non–small cell lung, pancreatic, gastric, breast, ovarian, and colorectal cancer, but exhibits limited expression in normal tissues. A target-unbiased discovery platform based on intact tumor and progenitor cell immunizations, followed by an IHC screen, led to the identification of anti-ADAM9 antibodies with selective tumor-versus-normal tissue binding. Subsequent analysis revealed anti-ADAM9 antibodies were efficiently internalized and processed by tumor cells making ADAM9 an attractive target for antibody–drug conjugate (ADC) development. Here, we describe the preclinical evaluation of IMGC936, a novel ADC targeted against ADAM9. IMGC936 is comprised of a high-affinity humanized antibody site-specifically conjugated to DM21-C, a next-generation linker-payload that combines a maytansinoid microtubule-disrupting payload with a stable tripeptide linker, at a drug antibody ratio of approximately 2.0. In addition, the YTE mutation (M252Y/S254T/T256E) was introduced into the CH2 domain of the antibody Fc to maximize in vivo plasma half-life and exposure. IMGC936 exhibited cytotoxicity toward ADAM9-positive human tumor cell lines, as well as bystander killing, potent antitumor activity in human cell line-derived xenograft and patient-derived xenograft tumor models, and an acceptable safety profile in cynomolgus monkeys with favorable pharmacokinetic properties. Our preclinical data provide a strong scientific rationale for the further development of IMGC936 as a therapeutic candidate for the treatment of ADAM9-positive cancers. A first-in-human study of IMGC936 in patients with advanced solid tumors has been initiated (NCT04622774).

Details

ISSN :
15388514, 15357163, and 04622774
Volume :
21
Database :
OpenAIRE
Journal :
Molecular Cancer Therapeutics
Accession number :
edsair.doi.dedup.....983671aae2ce218836c163550c2f9835
Full Text :
https://doi.org/10.1158/1535-7163.mct-21-0915