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Structural Basis of a Novel Agonistic Anti-OX40 Antibody

Jing Zhang1, Xiaoyong Jiang1, Han Gao1

  • 1Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.

Biomolecules
|September 23, 2022
PubMed

Insights

Novel anti-OX40 agonistic antibodies show potential in cancer therapy by stimulating T cells. Structural insights reveal cross-linking dependency, guiding the development of more potent cancer treatments.

Area of Science:

  • Immunology
  • Structural Biology
  • Cancer Therapeutics

Background:

  • Agonistic antibodies targeting OX40 (a co-stimulating receptor on T cells) are promising cancer treatments, potentially complementing immune checkpoint blockers.
  • Current OX40 agonists face challenges in clinical development due to insufficient potency and poorly understood epitope-activity relationships.

Purpose of the Study:

  • To identify and characterize a novel anti-OX40 agonistic antibody, DF004.
  • To elucidate the structural basis for OX40 antibody agonism and its implications for therapeutic development.

Main Methods:

  • In vitro proliferation assays of human CD4+ T cells.
  • In vivo tumor growth inhibition in a mouse model.
  • Crystallography and structural modeling of anti-OX40 antibodies (DF004 and RG7888) binding to OX40.

Main Results:

  • DF004 demonstrated agonistic activity, stimulating T cell proliferation and inhibiting tumor growth.
  • Structural analysis revealed DF004 binds CRD2 of OX40, distinct from RG7888's CRD3 binding site, suggesting non-epitope-specific agonism.
  • Structural modeling indicated that optimal agonistic activity requires precise clustering of three Fc receptor/antibody/OX40 complexes for TRAF complex formation, explaining limited potency.

Conclusions:

  • The intrinsic potency of OX40 agonistic antibodies is limited by their reliance on cross-linking for signal transduction.
  • Understanding the structural requirements for agonism provides a foundation for designing next-generation, cross-linking-independent OX40 agonists with enhanced therapeutic efficacy.
Keywords:
OX40 antibodyagonisticcross-linkingcrystal structureepitope specificity

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