Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices

Stefan Dengl, Klaus Mayer, Felix Bormann, Harald Duerr, Eike Hoffmann, Bianca Nussbaum, Michael Tischler, Martina Wagner, Andreas Kuglstatter, Lea Leibrock, Can Buldun, Guy Georges and Ulrich Brinkmann ()
Additional contact information
Stefan Dengl: Roche Innovation Center Munich
Klaus Mayer: Roche Innovation Center Munich
Felix Bormann: Roche Innovation Center Munich
Harald Duerr: Roche Innovation Center Munich
Eike Hoffmann: Roche Innovation Center Munich
Bianca Nussbaum: Roche Innovation Center Munich
Michael Tischler: Roche Innovation Center Munich
Martina Wagner: Roche Innovation Center Munich
Andreas Kuglstatter: Roche Innovation Center Basel
Lea Leibrock: Roche Innovation Center Basel
Can Buldun: Roche Innovation Center Munich
Guy Georges: Roche Innovation Center Munich
Ulrich Brinkmann: Roche Innovation Center Munich

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Generation of bispecific antibodies (bsAbs) requires a combination of compatible binders in formats that support desired functionalities. Here, we report that bsAb-matrices can be generated by Format Chain Exchange (FORCE), enabling screening of combinatorial binder/format spaces. Input molecules for generation of bi/multi-valent bsAbs are monospecific entities similar to knob-into-hole half-antibodies, yet with complementary CH3-interface-modulated and affinity-tagged dummy-chains. These contain mutations that lead to limited interface repulsions without compromising expression or biophysical properties of educts. Mild reduction of combinations of educts triggers spontaneous chain-exchange reactions driven by partially flawed CH3-educt interfaces resolving to perfect complementarity. This generates large bsAb matrices harboring different binders in multiple formats. Benign biophysical properties and good expression yields of educts, combined with simplicity of purification enables process automation. Examples that demonstrate the relevance of screening binder/format combinations are provided as a matrix of bsAbs that simultaneously bind Her1/Her2 and DR5 without encountering binder or format-inflicted interferences.

Date: 2020
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DOI: 10.1038/s41467-020-18477-7

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