Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity.

Abstract

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.

• Authors: Carmen Reitinger, Andrea Ipsen-Escobedo, Chiara Hornung, Lukas Heger, Diana Dudziak, Anja Lux, Falk Nimmerjahn
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 970290 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 36248847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Reitinger, Ipsen-Escobedo, Hornung, Heger, Dudziak, Lux and Nimmerjahn.

Chemical References

• Antibodies, Monoclonal
• Immunoglobulin G
• Receptors, IgG
• urelumab

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Glycosylation
• Humans
• Immunoglobulin G
• Mice
• Receptors, IgG (metabolism)