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.
Highlights
Agonistic CD27 monoclonal antibodies have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses
We found that the efficacy of depleting monoclonal antibodies (mAb) such as anti-CTLA-4 and anti-CD25 can be enhanced by CD27 mAb in a murine colon adenocarcinoma tumour model
Administration of anti-mCTLA-4 or anti-mouse CD27 (mCD27) delayed tumour growth compared to the isotype control, but did not elicit long-term survival whereas the mAb combination cured 40% (4/10) of mice (Fig. 1b)
Summary
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. Multiple agonistic mAb (e.g. directed to CD40, OX40, 4-1BB, GITR, CD27, CD28 and ICOS) have entered clinical trials but objective responses have been modest[6–8] We reason that this is due to an ongoing lack of understanding of the mechanisms that govern agonism and how best to leverage activity without toxicity in humans leading to the development and clinical translation of suboptimal mAb formats. Current evidence indicates that for CD40, OX40 and 4-1BB, mAb isotype and epitope specificity are critical for governing activity but that the requirements are unique for each receptor. It provided further indication that mAb isotype is a key determinant of CD27 mAb therapy but that this requirement may be context-dependent
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