Systemic immune response to a CD40 agonist antibody in nonhuman primates

The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune cells including B cells, dendritic cells, and monocytes, as well as other normal cells and some malignant cells. CD40 is constitutively expressed on antigen-presenting cell...

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Bibliographic Details
Published in:	Journal of leukocyte biology Vol. 115; no. 6; pp. 1084 - 1093
Main Authors:	Caudell, David L, Dugan, Gregory O, Babitzki, Galina, Schubert, Christine, Braendli-Baiocco, Annamaria, Wasserman, Ken, Acona, Gonzalo, Stern, Martin, Passioukov, Alexandre, Cline, J Mark, Charo, Jehad
Format:	Journal Article
Language:	English
Published:	England 29-05-2024
Subjects:	Animals Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Humanized - pharmacology CD40 Antigens - agonists CD40 Antigens - immunology Humans Macaca fascicularis Neoplasms - drug therapy Neoplasms - immunology CD40 dendritic cells spleen lymph node immunotherapy nonhuman primate B cells T cells
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Summary:	The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune cells including B cells, dendritic cells, and monocytes, as well as other normal cells and some malignant cells. CD40 is constitutively expressed on antigen-presenting cells, and ligation promotes functional maturation, leading to an increase in antigen presentation and cytokine production, and a subsequent increase in the activation of antigen-specific T cells. It is postulated that CD40 agonists can mediate both T cell-dependent and T cell-independent immune mechanisms of tumor regression in mice and patients. In addition, it is believed that CD40 activation also promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of cancer cells is an important factor in the generation of tumor-specific T cell responses that contribute to tumor cell elimination. Notably, CD40 agonistic therapies were evaluated in patients with solid tumors and hematologic malignancies with reported success as a single agent. Preclinical studies have shown that subcutaneous administration of CD40 agonistic antibodies reduces systemic toxicity and elicits a stronger and localized pharmacodynamic response. Two independent studies in cynomolgus macaque (Macaca fascicularis) were performed to further evaluate potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1938-3673 1938-3673
DOI:	10.1093/jleuko/qiae031