Hanson et al. described the generation and characterization of specific agonist mAbs, 37A10 and the humanized clinical candidate JTX-2011 (vopratelimab), targeting ICOS, which is associated with the clinical activity of anti-CTLA-4. In multiple syngeneic tumor models, ICOS mAb or anti-PD-1 monotherapy resulted in model-dependent antitumor efficacy and long-term immune protection, which was greatly enhanced by treatment with combinations of ICOS mAb and PD-1- or CTLA-4-blocking mAbs. Agonist ICOS mABs required functional Fc receptor cross-linking and TCR priming to induce ICOS expression, and had no superagonist activity.
Contributed by Katherine Turner
ABSTRACT: Immunotherapy checkpoint inhibitors, such as antibodies targeting PD-1 and CTLA-4, have demonstrated the potential of harnessing the immune system to treat cancer. However, despite encouraging results particularly with respect to survival, only a minority of patients benefit from these therapies. In clinical studies aimed at understanding changes in the immune system following immunotherapy treatment, ICOS (Inducible T cell CO-Stimulator) was shown to be significantly up-regulated on CD4+ T cells and this was associated with clinical activity, indicating that ICOS stimulatory activity may be beneficial in the treatment of solid tumors. In this report, we describe the generation of specific, species cross-reactive, agonist antibodies to ICOS, including the humanized clinical candidate, JTX-2011 (vopratelimab). Preclinical studies suggest that the ICOS stimulating antibodies require Fc receptor cross-linking for optimal agonistic activity. Notably, the ICOS antibodies do not exhibit superagonist properties but rather require T cell receptor (TCR)-mediated upregulation of ICOS for agonist activity. Treatment with the ICOS antibodies results in robust anti-tumor benefit and long-term protection in preclinical syngeneic mouse tumor models. Additional benefit is observed when the ICOS antibodies are administered in combination with anti-PD-1 and anti-CTLA-4 therapies. Based on the preclinical data, JTX-2011 is currently being developed in the clinical setting for the treatment of solid tumors.