IKS04, a CanAg-Targeting Antibody-Drug Conjugate with Pyrrolobenzodiazepine, Shows Enhanced Efficacy with Unconjugated Antibody Coadministration in Animal Models.

Abstract

CanAg (CA242) is a carbohydrate antigen highly overexpressed in most gastrointestinal (GI) cancers with minimal expression in normal tissue, making it an attractive target for ADC therapeutics in these cancers. Previous efforts to target CanAg with ADCs have shown limited clinical efficacy, possibly due to resistance to the tubulin inhibitor payloads used. IKS04 is a novel CanAg targeting ADC comprised of an anti-CanAg humanized monoclonal antibody Isumab04 and a highly potent pyrrolobenzodiazepine (PBD) prodrug payload. However, the use of potent payloads such as PBDs can limit the maximum tolerated dose (MTD) of ADCs, which in turn limits tumor tissue penetration and efficacy, particularly for high-expression targets such as CanAg. Coadministration of unconjugated antibody can potentially improve tumor tissue penetration, resulting in increased ADC efficacy. In this study, we evaluated the impact of Isumab04 coadministration on the distribution and efficacy of IKS04 in human tumor xenograft mouse models with different CanAg expression levels. While the addition of Isumab04 antibody showed minimal impact on IKS04 cell killing activity in vitro in cells with moderate and high CanAg expression, coadministration of Isumab04 with IKS04 improved tumor tissue distribution of the ADC in both tumor spheroids and in vivo tumor models. This improved distribution correlated with increased efficacy in vivo, where increasing doses of unconjugated antibody resulted in greater efficacy until apparent tumor saturation was reached. These results support the use of antibody coadministration to improve the efficacy of ADCs targeting high-expression antigens with highly potent payloads.