Abstract 1751: Developing a next generation antibody drug conjugate for treatment of gastrointestinal cancers
Authors: Mysliwy Justyna H. , Lodge Adam , Williamson Daniel , Thirlway Jenny , Deckert Jutta , Lutz Robert J. 
Published: June 2022

Abstract
Background: Gastrointestinal cancers (GI) are among the most common cancers worldwide. Current treatment options rely on a chemotherapy backbone combined with targeted antibody therapies, but the prognosis generally remains poor. Iksuda has developed a next-generation Antibody Drug Conjugate (ADC) targeting a cancer-specific carbohydrate antigen (CanAg) which is highly overexpressed in GI cancers but has no expression on normal tissues. This CanAg-targeting ADC is comprised of a proprietary PBD prodrug coupled to an anti-CanAg antibody using PermaLink conjugation technology. The PBD prodrug is designed with a tumor-selective trigger to attenuate its potency before entry of the ADC into the target cancer cells. PermaLink conjugation chemistry ensures conjugate stability. Here, the potential of this anti-CanAg ADC was explored in preclinical models as a proof of concept for targeting GI cancers.
Methods: The ADC is composed of a PBD prodrug conjugated to an anti-CanAg antibody through PermaLink to generate conjugate with a drug to antibody ratio of approximately 2. This CanAg-targeting ADC was evaluated in vitro in the CanAg-expressing Colo205 cancer cell line. In vivo efficacy studies were conducted in SCID mice with CanAg-expressing human cancer xenografts representing colorectal (Colo 205), gastric (N87) and pancreatic cancers (BxPC3). An exploratory toxicology study was conducted in cynomolgus monkeys.
Results: The CanAg-targeting ADC showed highly potent, specific activity in the Colo205 colorectal cancer cell line with IC50 values in the pM range. A single administration of anti-CanAg ADC in CanAg-positive GI xenograft models showed significant dose-dependent antitumor activity and induced complete tumor regressions with no observable toxicity. In the gastric cancer model, the anti-CanAg ADC gave a complete response by day 36 when dosed at 0.3 mg/kg, and 1 and 3 mg/kg doses exhibited long-lasting tumor regression. In the pancreatic cancer model, administration of anti-CanAg ADC at 0.3 mg/kg induced 76% tumor growth inhibition (TGI) on day 21, and at 1 mg/kg, and 3 mg/kg showed complete tumor regression by day 40 with no subsequent tumor recurrence for the 3mg/kg dose. In colorectal cancer, the anti-CanAg ADC exhibited 58% and 98% TGI with 0.3 mg/kg and 1 mg/kg doses respectively, and with the 3 mg/kg dose regressed tumor with no recurrence. The anti-CanAg ADC was well tolerated in cynomolgus monkeys with 1 mg/kg defined as the highest non-severely toxic dose (HNSTD).
Conclusions: This anti-CanAg ADC has shown favorable preclinical anti-tumor activity in gastrointestinal cancers. Our findings support the clinical development of the anti-CanAg ADC for the treatment of GI cancers.
Citation Format: Justyna H. Mysliwy, Adam Lodge, Daniel Williamson, Jenny Thirlway, Jutta Deckert, Robert J. Lutz. Developing a next generation antibody drug conjugate for treatment of gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1751.