CD40/anti-CD40 antibody complexes which illustrate agonist and antagonist structural switches.
BMC Mol Cell Biol
; 20(1): 29, 2019 08 05.
Article
in En
| MEDLINE
| ID: mdl-31382872
ABSTRACT
BACKGROUND:
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.RESULTS:
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.CONCLUSIONS:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
CD40 Antigens
/
Antibodies, Monoclonal
/
Antigen-Antibody Complex
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
BMC Mol Cell Biol
Year:
2019
Document type:
Article
Affiliation country:
United States