Abstract 456: Raptamer-drug conjugates as molecularly targeted cancer therapeutics

Abstract

Abstract While antibody-drug conjugates (ADC) are an attractive modality for targeted cancer therapy, they face limitations. These include a reduced volume of distribution with limited penetration into solid tumors, and an expensive, long and complicated production process, especially for large-scale manufacturing. These factors hinder the activity of these medications in certain tumors, and limit equitable access to all population segments. Use of aptamers as a therapeutic targeting moiety, holds the promise of building on the success of ADCs. Aptamers have several advantages over mAbs as a targeting moiety including: (i) smaller size that enables better tissue/tumor penetration; (ii) chemical synthesis which allows rapid and affordable scale-up; (iii) superior safety profile from lack of immunogenicity and short half-life which reduces off-target adverse events; and (iv) room temperature stability. Therefore, the use of aptamers in conjunction with drugs (similar to ADCs) holds promise for tumor management. We have recently identified a novel therapeutic target for certain cancers (COF-01) using analysis of proteomics data and immunohistochemistry from patient-derived tumors. COF-01 was shown to have highly specific increases in protein and mRNA expression in several cancers including non-small cell lung cancer, head and neck cancer and pancreatic cancer. COF-01 expression correlated with poor overall survival. Here, we present a new therapeutic approach that targets COF-01-positive cells using next generation drug conjugated aptamers. We have generated novel next-generation base-modified ssDNA aptamers (Raptamers) against COF-01 using a cell- and protein-based selection that utilizes our proprietary bead-based oligonucleotide libraries. The binding affinities of these COF-01 Raptamer candidates were determined by concentration curves using biolayer interferometry. Dissociation constants for the COF-01 Raptamers ranged from 80 nM - 200 nM. Anti-COF-01 Raptamer-drug conjugates (Rap-DCs) were developed by conjugating the Raptamers to monomethyl auristatin F via a cleavable linker. In vitro efficacy data has shown that the COF-01 Rap-DCs can selectively induce cytotoxicity in COF-01-positive human cells. There was a significant decrease in cell viability of COF-01-positive cells when compared to COF-01-negative control cells. This study provides proof-of concept for the use of high-affinity Raptamers against novel molecular targets, such as COF-01. This platform can be used to develop Raptamers against emergent neo-antigens on cancer cells that have escaped other therapies. Citation Format: Stephanie P. Vega, Dev Chatterjee, Atul Varadhachary, Michael Ritchie, Michael Heffernan, Daniel Ciznadija. Raptamer-drug conjugates as molecularly targeted cancer therapeutics [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 456.