Anti-CD40 Monoclonal Antibody Synergizes with CTLA-4 Ig in Promoting Long-Term Graft Survival in Murine Models of Transplantation

• Type of Material: Article
• Authors: Christopher R Gilson, Emory University; Zvonimir Milas, Emory University; Shivaprakash Gangappa, Emory University; Diane Hollenbaugh, Bristol-Myers Squibb Pharmaceutical Research Institute; Thomas C Pearson, Emory University; Mandy L Ford, Emory University; Christian P Larsen, Emory University
• Language: English
• Date: 2009-08-01
• Publisher: American Association of Immunologists
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 by The American Association of Immunologists, Inc.
• Final Published Version (URL): http://www.jimmunol.org/content/183/3/1625
• Title of Journal or Parent Work: Journal of Immunology
• ISSN: 0022-1767
• Volume: 183
• Issue: 3
• Start Page: 1625
• End Page: 1635
• Grant/Funding Information: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
• Keywords: CD154; CD40; costimulation; transplantation tolerance
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

Blockade of the CD40/CD154 signaling pathway using anti-CD154 antibodies has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems. Unfortunately, thromboembolic side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 antibodies may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 antibody (7E1) for characteristics and effects mirroring those of anti-CD154: 7E1-G1 (an IgG1 isotype) and 7E1-G2b (an IgG2b isotype). In vitro proliferation assays to measure the agonist properties of the two anti-CD40 antibodies revealed similar responses when plate-bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. Importantly, 7E1-G2b was as effective as anti-CD154 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimerism and skin graft survival, while 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40 bearing antigen presenting cells. These data suggest that an appropriately designed anti-CD40 antibody can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens.