Vukovic, Natasa and Halabi, Samer and Salvador Russo-Cabrera, Joan and Blokhuis, Bart and Berraondo, Pedro and Redegeld, Frank A. M. and Zaiss, Dietmar M. W. (2022) A human IgE bispecific antibody shows potent cytotoxic capacity mediated by monocytes. JOURNAL OF BIOLOGICAL CHEMISTRY, 298 (8): 102153. ISSN , 1083-351X
Full text not available from this repository. (Request a copy)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 tumorassociated 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 FceR binding by inducing in vitro mast cell degranulation and demonstrating in vitro and in vivo monocyte-mediated cytotoxicity against target antigenexpressing 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FC-EPSILON-RI; MACROPHAGES; IMMUNOTHERAPY; MECHANISMS; TUMORS; EGFR; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Nov 2023 13:25 |
| Last Modified: | 27 Nov 2023 13:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/56815 |
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