Abstract 1763: Gastric cancer antibody fragment drug-conjugates (FDCs): Succeeding in solid tumors where ADCs fail
Authors: Deonarain Mahendra P. , Yahioglu Gokhan , Stamati Ioanna , Edwards Bryan , Diez-Posada Soraya , Perez-Castro Isabel , Pomowski Anja , Bouche Laura , Stewart Ashleigh , Maciuszek Monika , Ness Sam , Ngiam Malcolm , Xue Quinn 
Published: June 2022

Abstract
Antibody Drug Conjugates (ADCs) are failing due to 3 critical limitations: Low potency, ineffective solid-tumor penetration and poor tolerability. The industry is full of approaches where full-length Immunoglobulins have been engineered to carry defined numbers of payloads with higher-loadings of less potent payloads appearing to be well-tolerated. However, antibody fragments (e.g. single-chain Fcs-scFvs), which have many advantages including rapid tumor penetration, faster clearance, inexpensive manufacture, have been technologically challenging to apply in oncology. Our novel approach enables scFvs to have a high Drug:Antibody loading ratio (DAR) whilst retaining effective binding and other favorable biophysical properties, leading to a new product class tailored for solid tumors. Antikor has two FDC products in development for solid tumors, notably gastric: anti-HER2 FDC (ANT-043) and a second target (ANT-045) which will be disclosed during this presentation. ANT-043 has pM potencies in a range of HER2-expressing cell-lines, including trastuzumab-resistant models, excellent tumor ablation effects in breast, ovarian and gastric cancer xenograft models and superior tolerability compared to an ADC in rat toxicology studies at a dose of 1mg/kg/weekly. Quantitative payload tumor uptake and fluorescent immuno-histological studies demonstrate superior solid tumor penetration across the entire tumor and diffusion from blood vessels. In collaboration with our partners, Essex Biotechnology, Antikor is taking ANT-043 into IND-enabling studies for clinical development. ANT-045, which emerged from Antikor’s proprietary FDC ‘discovery engine’, is progressing towards IND-filing and updated data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal cancers. ANT-045 has excellent in vitro cell-kill potency (pM IC50s) and excellent stability and superior in vivo tumor cure efficacy, compared to a leading clinical stage benchmark ADC. This presentation will focus on Antikor’s FDC discovery platform (stable high-DAR scFv-display libraries, tailored linker-payloads and design features) that has the potential to generate first-in-class products for difficult to treat solid tumors for patient benefit and promising to succeed where ADCs have failed to deliver.
Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Bryan Edwards, Soraya Diez-Posada, Isabel Perez-Castro, Anja Pomowski, Laura Bouche, Ashleigh Stewart, Monika Maciuszek, Sam Ness, Malcolm Ngiam, Quinn Xue. Gastric cancer antibody fragment drug-conjugates (FDCs): Succeeding in solid tumors where ADCs fail [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 1763.