A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes

Natasa Vukovic, Samer Halabi, Joan Salvador Russo-Cabrera, Bart Blokhuis, Pedro Berraondo, Frank A.M. Redegeld, Dietmar M.W. Zaiss

Research output: Contribution to journalArticlepeer-review

Abstract

The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical models. Therefore, in order to combine the promising potential of IgE molecules with increased target selectivity of bsAbs, we developed dual tumor-associated antigen-targeting bispecific human IgE antibodies. As proof of principle, we used two different pairing approaches - knobs-into-holes and leucine zipper-mediated pairing. Our data show that both strategies were highly efficient in driving bispecific IgE formation, with no undesired pairings observed. Bispecific IgE antibodies also showed a dose-dependent binding to their target antigens, and cell bridging experiments demonstrated simultaneous binding of two different antigens. As antibodies mediate a major part of their effector functions through interaction with Fc receptors (FcRs) expressed on immune cells, we confirmed FcεR binding by inducing in vitro mast cell degranulation and demonstrating in vitro and in vivo monocyte-mediated cytotoxicity against target antigen-expressing Chinese hamster ovary cells. Moreover, we demonstrated that the IgE bsAb construct was significantly more efficient in mediating antibody-dependent cell toxicity than its IgG1 counterpart. In conclusion, we describe the successful development of first bispecific IgE antibodies with superior antibody-dependent cell toxicity-mediated cell killing in comparison to IgG bispecific antibodies. These findings highlight the relevance of IgE-based bispecific antibodies for clinical application.

Original languageEnglish
Article number102153
Number of pages12
JournalJournal of Biological Chemistry
Volume298
Issue number8
Early online date16 Jun 2022
DOIs
Publication statusPublished - 1 Aug 2022

Keywords

  • bispecific
  • IgE
  • KiH
  • ADCC
  • monocyte
  • immunotherapy
  • cancer therapy
  • antibody engineering

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