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Title: CD40/anti-CD40 antibody complexes which illustrate agonist and antagonist structural switches

Journal Article · · BMC Molecular and Cell Biology
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  1. AbbVie Bioresearch Center, Worcester, MA (United States)
  2. AbbVie Inc., North Chicago, IL (United States)
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CD40 is a 48 kDa type I transmembrane protein that is constitutively expressed on hematopoietic cells such as dendritic cells, macrophages, and B cells. Engagement of CD40 by CD40L expressed on T cells results in the production of proinflammatory cytokines, induces T helper cell function, and promotes macrophage activation. The involvement of CD40 in chronic immune activation has resulted in CD40 being proposed as a therapeutic target for a range of chronic inflammatory diseases. CD40 antagonists are currently being explored for the treatment of autoimmune diseases and several anti-CD40 agonist mAbs have entered clinical development for oncological indications. To better understand the mode of action of anti-CD40 mAbs, we have determined the x-ray crystal structures of the ABBV-323 (anti-CD40 antagonist, ravagalimab) Fab alone, ABBV-323 Fab complexed to human CD40 and FAB516 (anti-CD40 agonist) complexed to human CD40. These three crystals structures 1) identify the conformational CD40 epitope for ABBV-323 recognition 2) illustrate conformational changes which occur in the CDRs of ABBV-323 Fab upon CD40 binding and 3) develop a structural hypothesis for an agonist/antagonist switch in the LCDR1 of this proprietary class of CD40 antibodies. The structure of ABBV-323 Fab demonstrates a unique method for antagonism by stabilizing the proposed functional antiparallel dimer for CD40 receptor via novel contacts to LCDR1, namely residue position R32 which is further supported by a closely related agonist antibody FAB516 which shows only monomeric recognition and no contacts with LCDR1 due to a mutation to L32 on LCDR1. These data provide a structural basis for the full antagonist activity of ABBV-323.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1577174
Journal Information:
BMC Molecular and Cell Biology, Vol. 20, Issue 1; ISSN 2661-8850
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cysteine-rich Domain 1 of CD40 Mediates Receptor Self-assembly journal March 2013
Thrombophilia Associated with Anti-Cd154 Monoclonal Antibody Treatment and its Prophylaxis in Nonhuman Primates journal July 2004
An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti-tumour T-cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model journal May 2007
Inhibitory Fc  Receptor Engagement Drives Adjuvant and Anti-Tumor Activities of Agonistic CD40 Antibodies journal August 2011
Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated T regs journal January 2017
Structural principles of tumor necrosis factor superfamily signaling journal January 2018
Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer journal November 2013
Anti-CD40L Immune Complexes Potently Activate Platelets In Vitro and Cause Thrombosis in FCGR2A Transgenic Mice journal June 2010
Interaction with FcγRIIB Is Critical for the Agonistic Activity of Anti-CD40 Monoclonal Antibody journal July 2011
The IgG Fc Contains Distinct Fc Receptor (FcR) Binding Sites: The Leukocyte Receptors FcγRI and FcγRIIa Bind to a Region in the Fc Distinct from That Recognized by Neonatal FcR and Protein A journal May 2000
Development of a Chimeric Anti-CD40 Monoclonal Antibody That Synergizes with LEA29Y to Prolong Islet Allograft Survival journal December 2004

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59 BASIC BIOLOGICAL SCIENCES
CD40
crystal structure
agonist
antagonist
antibody