title: Antibody-Drug Conjugates for Tumor Targeting-Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins.
abstract: Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents, combining the specificity of antibodies for tumor targeting and the destructive potential of highly potent drugs as payload. An essential component of these immunoconjugates is a bifunctional linker capable of reacting with the antibody and the payload to assemble a functional entity. Linker design is fundamental, as it must provide high stability in the circulation to prevent premature drug release, but be capable of releasing the active drug inside the target cell upon receptor-mediated endocytosis. Although ADCs have demonstrated an increased therapeutic window, compared to conventional chemotherapy in recent clinical trials, therapeutic success rates are still far from optimal. To explore other regimes of half-life variation and drug conjugation stoichiometries, it is necessary to investigate additional binding proteins which offer access to a wide range of formats, all with molecularly defined drug conjugation. Here, we delineate recent progress with site-specific and biorthogonal conjugation chemistries, and discuss alternative, biophysically more stable protein scaffolds like Designed Ankyrin Repeat Proteins (DARPins), which may provide such additional engineering opportunities for drug conjugates with improved pharmacological performance.
authors.affiliation: Department of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Merten
authors.affiliation: Department of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Institute of Pharmacology, University of Bern , Inselspital INO-F, CH-3010 Bern, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Brandl
authors.affiliation: Department of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Plückthun
authors.affiliation: Department of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Institute of Pharmacology, University of Bern , Inselspital INO-F, CH-3010 Bern, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Zangemeister-Wittke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D057930:Click Chemistry / Q000379:methods; D061565:Cycloaddition Reaction / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000627:therapeutic use*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates