Abstract 3869: Proteomics highlights which G-protein coupled receptors are candidates for ADC development

Abstract

Antibody-drug conjugates (ADCs) are a recent and exciting development for targeted therapy of cancer. Their efficacy is governed by ADC-intrinsic characteristics such as avidity, drug load and linker chemistry, and mechanisms of activation and action, which can be controlled or clarified in the early stages of ADC development. In contrast, the properties that define a promising ADC target are still somewhat unclear. OGAP is a unique proteomic database that integrates information at the tissue, disease and protein isoform level across diseases, indications, and normal tissues to clarify protein expression levels and profiles. Specifically, it currently holds information on ∼2,000,000 human protein peptide sequences, ∼16,000 human proteins sequenced, ∼7,000 cancer membrane proteins, ∼50 tissues/organs, and ∼60 diseases. Building on OGAP and a proprietary sample preparation and processing workflow that relies on state-of-the-art high-throughput mass spectrometry and data processing to provide quantitative information on over 4,000 membrane-enriched proteins from ∼ 15,000 unique peptide sequences per analysis, we have established a novel predictive tool to establish each protein's potential to serve as a target for ADC development. The tool considers proteomic and target-specific information on antigenicity, structure, function, expression level, regulation, and tissue distribution in order to highlight the most suitable candidates for ADC development. We will demonstrate the utility of this process for the protein family of G-protein coupled receptors (GPCRs), which according to a recent bioinformatics prediction encompasses 899 distinct members in the human genome. These cell surface receptors are the target of more than one third of conventional drugs, yet their potential for ADCs is largely unexplored. Here we show that proteomics in the context of the OGAP database can highlight which of this large family of receptors have the potential to become true ADC targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3869. doi:1538-7445.AM2012-3869

MEN1309/OBT076, a First-In-Class Antibody–Drug Conjugate Targeting CD205 in Solid Tumors

“…Given the promise of ADCs for precision cancer therapy, the identification of novel targets and development of unique therapeutics is paramount. Using the OGAP target discovery system (6) to incorporate molecular, cellular, phenotypic, and clinical information with protein and gene expression data from a panel of tumor and normal tissues, we identified CD205 as one such target.…”

Conjugates of Small Molecule Drugs with Antibodies and Other Proteins

“…Many receptors, such as G protein coupled receptors (GPCRs), have adapted a mechanism to desensitize to repeated or prolonged exposure by recycling rapidly back to cytoplasmic membrane through early endosomes [ 20 ], which makes them less ideal as ADC targets. However, an ADC targeting the GPCR family member endothelin receptor type B (ETBR), Anti-ETBR-MC-vc-PAB-MMAE, has been advanced to clinical development [ 21 ], which suggests that unexplored GPCRs with effective internalization could be potential targets for the ADCs [ 22 ].…”