Abstract 2901: Gastric cancer antibody fragment drug-conjugates (FDCs): From concept to clinical development

Published on Aug 15, 2020in Cancer Research9.727
· DOI :10.1158/1538-7445.AM2020-2901
Mahendra Deonarain19
Estimated H-index: 19
Gokhan Yahioglu24
Estimated H-index: 24
+ 9 AuthorsQuinn Xue1
Estimated H-index: 1
Antibody Drug Conjugates (ADCs) are failing due to 3 critical limitations: Low potency, ineffective solid-tumour 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 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) 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 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. 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, Antikor is taking ANT-043 into IND-enabling studies for clinical development. In a new development, ANT-045, which emerged from Antikor9s proprietary FDC phage-display ‘discovery engine9, is progressing well and new data will illustrate how ANT-045 could have a broader patient benefit in gastro-intestinal cancers. Like ANT-043, our follow-up product has excellent in vitro cell-kill potency (pM IC50s) and excellent stability and biophysical properties and illustrates how linker-payload modification (size, hydrophilicity) is critical for the tailoring of the binding and pharmacokinetic properties of this emerging format of ADC. This presentation will focus on Antikor9s FDC discovery platform (stable high-DAR scFv-display libraries, tailored linker-payloads and design features) that has the potential to generate a new products for difficult to treat solid tumours 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, Anja Pomowski, Isabel Perez-Castro, Ben Stenton, Laura Bouche, Ashleigh Stewart, Malcolm Ngiam, Quinn Xue. Gastric cancer antibody fragment drug-conjugates (FDCs): From concept to clinical development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2901.
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Introduction: Antibody-Drug Conjugates (ADCs) have undergone a recent resurgence with 5 product approvals over the last 2 years but for those close to the field, it’s been repeated cycles of setbac...
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#1Mahendra P Deonarain (University of Hertfordshire)
#1Mahendra Deonarain (Imperial College London)H-Index: 19
Last. Quinn XueH-Index: 1
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The pharmacokinetic-pharmacodynamic relationship is extremely complex and tumour drug penetration is one key parameter influencing therapeutic efficacy. In the context of antibody-drug conjugates (ADCs), which has undergone many innovation cycles and witnessed many failures, this feature is being addressed by a number of alternative technologies. Immunoglobulin-based ADCs continue to dominate the industrial landscape, but smaller formats offer the promise of more-effective cytotoxic payload deli...