Reitinger C, Ipsen Escobedo A, Hornung C, Heger L, Dudziak D, Lux A, Nimmerjahn F (2022)
Publication Type: Journal article
Publication year: 2022
Book Volume: 13
Article Number: 970290
DOI: 10.3389/fimmu.2022.970290
Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo, we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.
APA:
Reitinger, C., Ipsen Escobedo, A., Hornung, C., Heger, L., Dudziak, D., Lux, A., & Nimmerjahn, F. (2022). Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity. Frontiers in Immunology, 13. https://dx.doi.org/10.3389/fimmu.2022.970290
MLA:
Reitinger, Carmen, et al. "Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity." Frontiers in Immunology 13 (2022).
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