title: Site-specific antibody drug conjugates for cancer therapy.
abstract: Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors--target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0-8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics.
authors.affiliation: Genentech, Inc; South San Francisco, CA USA.
authors.forename: Siler
authors.initials: S
authors.lastname: Panowski
authors.affiliation: Genentech, Inc; South San Francisco, CA USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhakta
authors.affiliation: Genentech, Inc; South San Francisco, CA USA.
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.affiliation: Genentech, Inc; South San Francisco, CA USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.affiliation: Genentech, Inc; South San Francisco, CA USA.
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000918:Antibody Specificity; D000079963:Brentuximab Vedotin; D016503:Drug Delivery Systems; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008453:Maytansine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D000068878:Trastuzumab; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D018796:Immunoconjugates; D008453:Maytansine; D000079963:Brentuximab Vedotin; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine
keywords: THIOMAB; antibody drug conjugate; cytotoxic drug; internalization; linker; site-specific conjugation; tumor antigen