Abstract 2885: IKS04, an antibody drug conjugate with a highly potent DNA crosslinker payload for the treatment of gastrointestinal cancers

Abstract IKS04 is an antibody drug conjugate (ADC) targeting human CA242, also known as CanAg, a tumor-associated carbohydrate antigen. This glycotope is highly expressed in most colorectal, pancreatic, gallbladder, and gastric cancers, with limited expression in normal tissues. While prior experience demonstrated that CA242 can be safely targeted with an ADC, the limited clinical efficacy observed with microtubule inhibitor payloads in gastrointestinal indications suggests that alternate payloads such as DNA crosslinkers could provide an improved therapeutic to target CA242+ tumors more effectively. The ADC was generated by site-specific bioconjugation of a pyrrolobenzodiazepine (PBD) prodrug payload to the antibody light chain at a drug-to-antibody ratio of 2. The linker-prodrug incorporates two glucuronide-trigger moieties that require lysosomal cleavage by beta-glucuronidase to both release and activate the PBD dimer payload. In vitro antiproliferative and bystander activity was evaluated by CellTiterGlo assay. In vivo efficacy studies for ADC alone and antibody co-administration were performed with subcutaneous human xenografts in CB17-SCID mice. CA242 expression was determined in formalin fixed tumor samples by immunohistochemistry and on cell lines by quantitative flow cytometry. In vitro, IKS04 results in potent and specific cell killing of panel of CA242+ target cells and potency correlated with antigen expression determined by flow cytometry. The PBD payload confers strong bystander activity in co-culture studies in vitro, an attribute that may allow treating tumors with heterogeneous antigen expression. The ADC was active against gastric and colorectal cancer xenograft models at single doses of 0.5 to 1 mg/kg, while the maytansinoid-based ADC benchmark cantuzumab ravtansine was inactive even at 2 mg/kg. Contrary to in vitro results, we observed a trend towards greater in vivo activity in models with lower antigen expression. This is suggestive of an antigen barrier effect where high target expression results in ADC accumulation at the tumor surface, precluding deeper penetration into tumor tissue. As the maximum tolerated ADC dose can be limited by target-independent payload toxicities, we increased the overall in vivo dose by addition of antibody to improve delivery. Consistent with this concept, co-administration of the unconjugated antibody with the ADC at a 5 to 50-fold excess improved the minimally effective dose in the CA242-high SNU16 gastric and HT29 colon cancer models compared to ADC alone while the antibody itself had no anti-tumor activity. IKS04 is an ADC with a DNA crosslinker payload that shows potent in vitro and in vivo efficacy against gastric and colorectal cancer tumor models. Co-administration of the unconjugated antibody can improve ADC delivery which drives increased efficacy in preclinical models without increasing toxicity. Citation Format: Jutta Deckert, Justyna Mysliwy, Adam Lodge, James Stephenson, Sarah Robinson, Robert J. Lutz. IKS04, an antibody drug conjugate with a highly potent DNA crosslinker payload for the treatment of gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2885.