Abstract 1530: Gastric cancerantibody fragment drug-conjugates (FDCs): Applying a successful concept to solid tumours
Authors: Deonarain Mahendra P. , Yahioglu Gokhan , Stamati Ioanna , Diez-Posada Soraya , Edwards Bryan , Pomowski Anja , Perez-Castro Isabel , Ness Sam , Bouche Laura , Yap Jeaniffer , Desmond Howard , Davies Lowri , Ngiam Malcolm , Xue Quinn 
Published: April 2023

Antibody Drug Conjugates (ADCs) have failed to deliver the successes seen in breast and urological tumours in Gastro-intestinal tumours such as stomach, colorectal and pancreatic due to 3 critical limitations: Low potency, ineffective solid-tumour penetration and poor tolerability. Approaches utilizing full-length Immunoglobulins dominate the industry, however, antibody fragments (e.g. single-chain Fvs-scFvs), which have many advantages including rapid tumour 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 favourable biophysical properties, leading to a new product class tailored for solid tumours.

Antikor has two FDC products in development for solid tumours, notably gastric: anti-HER2 FDC (ANT-043) and a second target (ANT-045, to be disclosed). ANT-043 has pM potencies in a range of HER2-expressing cell-lines, including trastuzumab-resistant models, excellent tumour 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 tumour uptake and fluorescent immuno-histological studies demonstrate superior solid tumour penetration across the entire tumour and diffusion from blood vessels. In collaboration with our partners, Essex Biotechnology PLC, Antikor is taking ANT-043 into 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 tumour 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 tumours for patient benefit and promising to succeed where ADCs have failed to make an impact.

Citation Format: Mahendra P. Deonarain, Gokhan Yahioglu, Ioanna Stamati, Soraya Diez-Posada, Bryan Edwards, Anja Pomowski, Isabel Perez-Castro, Sam Ness, Laura Bouche, Jeaniffer Yap, Howard Desmond, Lowri Davies, Malcolm Ngiam, Quinn Xue. Gastric cancerantibody fragment drug-conjugates (FDCs): Applying a successful concept to solid tumours [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1530.