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Updated: Sep 30, 2025
Use of Single Chain MHC Technology to Investigate Co-agonism in Human CD8+ T Cell Activation
Published on: February 28, 2019
Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through
Franziska Heckel1,2, Anna H Turaj1,2, Hayden Fisher1,2,3,4
1Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
Abstract:
Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel of CD27 mAb including a clinical candidate, we investigate the determinants of CD27 mAb agonism. Epitope mapping and in silico docking analysis show that mAb binding to membrane-distal and external-facing residues are stronger agonists. However, poor epitope-dependent agonism could partially be overcome by Fc-engineering, using mAb isotypes that promote receptor clustering, such as human immunoglobulin G1 (hIgG1, h1) with enhanced affinity to Fc gamma receptor (FcγR) IIb, or hIgG2 (h2). This study provides the critical knowledge required for the development of agonistic CD27 mAb that are potentially more clinically efficacious.
Insights
Novel CD27 monoclonal antibodies (mAb) show improved tumor-fighting potential. Engineering these antibodies can enhance their effectiveness, potentially leading to better cancer treatments by optimizing CD27 agonism.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Agonistic CD27 monoclonal antibodies (mAb) show promise in preclinical cancer models but have limited clinical success.
- Suboptimal CD27 agonism may explain the modest clinical responses observed with current CD27 mAb therapies.
Purpose of the Study:
- To investigate the key factors determining CD27 mAb agonism.
- To identify strategies for enhancing the clinical efficacy of CD27 mAb.
Main Methods:
- Utilized a novel panel of CD27 mAb, including a clinical candidate.
- Performed epitope mapping and in silico docking analysis to assess mAb binding sites.
- Employed Fc-engineering techniques, modifying antibody isotypes (hIgG1, h2) to enhance Fc gamma receptor (FcγR) interactions and promote receptor clustering.
Main Results:
- mAb binding to membrane-distal and external-facing residues demonstrated stronger agonistic activity.
- Fc-engineering, particularly with hIgG1 (h1) and hIgG2 (h2) isotypes, partially overcame poor epitope-dependent agonism by promoting receptor clustering.
- Enhanced FcγRIIb affinity in hIgG1 contributed to improved agonism.
Conclusions:
- Epitope selection is critical for potent CD27 agonism.
- Fc-engineering offers a viable strategy to enhance the efficacy of CD27 mAb therapies.
- This research provides foundational knowledge for developing more clinically effective agonistic CD27 mAb.
