title: Evolving Strategies for Target Selection for Antibody-Drug Conjugates.
abstract: Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a tumor antigen. The selection of antigen targets is critical to enabling a therapeutic window for the ADC and has proven to be surprisingly complex. We surveyed the tumor and normal tissue expression profiles of the targets of ADCs currently in clinical development. Our analysis demonstrates a surprisingly broad range of expression profiles and the inability to formalize any optimal parameters for an ADC target. In this context, we discuss additional considerations for ADC target selection, including interdependencies among biophysical properties of the drug, biological functions of the target and strategies for clinical development. The TPBG (5T4) oncofetal antigen and the anti-TPBG ADC A1-mcMMAF are highlighted to demonstrate the relevance of the target's biological function. Emerging platform technologies and novel biological insights are expanding ADC target space and transforming strategies for target selection.
authors.affiliation: Pfizer Inc., Oncology Research Unit, 401 N. Middletown Rd., Bldg. 200-4502, Pearl River, NY, 10965, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Damelin
authors.affiliation: Pfizer Inc., Oncology Research Unit, 401 N. Middletown Rd., Bldg. 200-4502, Pearl River, NY, 10965, USA.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Pfizer Inc., Oncology Research Unit, 401 N. Middletown Rd., Bldg. 200-4502, Pearl River, NY, 10965, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Myers
authors.affiliation: Pfizer Inc., Oncology Research Unit, 401 N. Middletown Rd., Bldg. 200-4502, Pearl River, NY, 10965, USA. puja.sapra@pfizer.com.
authors.forename: Puja
authors.initials: P
authors.lastname: Sapra
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D015195:Drug Design; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000235:genetics; D059467:Transcriptome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008565:Membrane Proteins; D020543:Proteome
keywords: 5T4; A1-mcMMAF; ADC; antibody-drug conjugate; site-specific conjugation