Journal article
Induction of an altered CD40 signaling complex by an antagonistic human monoclonal antibody to CD40
The Journal of immunology (1950), Vol.194(9), pp.4319-4327
05/01/2015
DOI: 10.4049/jimmunol.1402903
PMID: 25795759
Abstract
Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.
Details
- Title: Subtitle
- Induction of an altered CD40 signaling complex by an antagonistic human monoclonal antibody to CD40
- Creators
- Katherine C Bankert - Department of Microbiology, University of Iowa, Iowa City, IA 52242Kyp L Oxley - Department of Microbiology, University of Iowa, Iowa City, IA 52242Sonja M Smith - Department of Microbiology, University of Iowa, Iowa City, IA 52242John P Graham - Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242Mark de Boer - Fast Forward Pharmaceuticals BV, Utrecht, the NetherlandsMarielle Thewissen - Fast Forward Pharmaceuticals BV, Utrecht, the NetherlandsPeter J Simons - Bioceros Holding BV, Utrecht, the NetherlandsGail A Bishop - Department of Microbiology, University of Iowa, Iowa City, IA 52242; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and VA Medical Center, Iowa City, IA 52242 gail-bishop@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.194(9), pp.4319-4327
- Publisher
- United States
- DOI
- 10.4049/jimmunol.1402903
- PMID
- 25795759
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- P30 ES005605 / NIEHS NIH HHS
- Language
- English
- Date published
- 05/01/2015
- Academic Unit
- Microbiology and Immunology; President; Biochemistry and Molecular Biology
- Record Identifier
- 9984001201802771
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