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

Maria A Argiriadi1, Lorenzo Benatuil2, Ievgeniia Dubrovska3

  • 1AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA, 01605, USA. maria.argiriadi@abbvie.com.

BMC Molecular and Cell Biology
|August 7, 2019
PubMed

Insights

Structural analysis of CD40 antibodies reveals how antagonists like ABBV-323 stabilize receptor dimers, offering a mechanism for treating inflammatory diseases and cancer.

Area of Science:

  • Immunology
  • Structural Biology
  • Drug Discovery

Background:

  • CD40 is a transmembrane protein on immune cells, crucial for immune responses.
  • Its role in chronic inflammation makes CD40 a therapeutic target for autoimmune diseases and cancer.

Purpose of the Study:

  • To elucidate the mechanism of action for anti-CD40 monoclonal antibodies (mAbs).
  • To understand the structural basis for CD40 antagonism and agonism.

Main Methods:

  • X-ray crystallography was used to determine the structures of ABBV-323 Fab alone and complexed with CD40.
  • The structure of a related agonist antibody, FAB516, complexed with CD40 was also determined.

Main Results:

  • Identified the specific CD40 epitope recognized by the antagonist ABBV-323.
  • Observed conformational changes in ABBV-323's complementarity-determining regions (CDRs) upon binding to CD40.
  • Revealed a structural hypothesis for the agonist/antagonist switch involving the light chain CDR1 (LCDR1).

Conclusions:

  • ABBV-323 antagonizes CD40 by stabilizing its functional antiparallel dimer through novel LCDR1 interactions (R32).
  • The agonist FAB516 shows monomeric recognition and lacks these LCDR1 contacts due to an L32 mutation.
  • These findings provide a structural foundation for the antagonist activity of ABBV-323.
Abstract

Keywords:
AgonistAntagonistAntibodyCD40Crystal structure

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