Beyond bispecificity: Controlled Fab arm exchange for the generation of antibodies with multiple specificities. Issue 1 (31st December 2022)

• Record Type: Journal Article
• Authors: Yanakieva, Desislava; Pekar, Lukas; Evers, Andreas; Fleischer, Markus; Keller, Stephan; Mueller-Pompalla, Dirk; Toleikis, Lars; Kolmar, Harald; Zielonka, Stefan; Krah, Simon
• Is Part Of: MAbs. Volume 14:Issue 1(2022)
• Publication Date: 2022-12-31
• Subjects: cFAE -- controlled Fab arm exchange -- duobody -- fusion protein -- IgG-VHH -- multispecific -- NK cell engager -- tetraspecific -- trispecific -- VHH; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2021.2018960
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Controlled Fab arm exchange (cFAE) has proven to be a generic and versatile technology for the efficient generation of IgG-like bispecific antibodies (DuoBodies or DBs), with several in clinical development and one product, amivantamab, approved by the Food and Drug Administration. In this study, we expand the cFAE-toolbox by incorporating VHH-modules at the C-termini of DB-IgGs, termed DB-VHHs. This approach enables the combinatorial generation of tri- and tetraspecific molecules with flexible valencies in a straightforward fashion. Using cFAE, a variety of multispecific molecules was produced and assessed for manufacturability and physicochemical characteristics. In addition, we were able to generate DB-VHHs that efficiently triggered natural killer cell mediated lysis of tumor cells, demonstrating the utility of this format for potential therapeutic applications.