Beyond bispecificity: Controlled Fab arm exchange for the generation of antibodies with multiple specificities.

Desislava Yanakieva, Lukas Pekar, Andreas Evers, Markus Fleischer, Stephan Keller, Dirk Mueller-Pompalla, Lars Toleikis, Harald Kolmar, Stefan Zielonka, Simon Krah

mAbs 2022 Jan-Dec

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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.

Citation

Desislava Yanakieva, Lukas Pekar, Andreas Evers, Markus Fleischer, Stephan Keller, Dirk Mueller-Pompalla, Lars Toleikis, Harald Kolmar, Stefan Zielonka, Simon Krah. Beyond bispecificity: Controlled Fab arm exchange for the generation of antibodies with multiple specificities. mAbs. 2022 Jan-Dec;14(1):2018960