Fenwick et al. identified a rare, novel class of high-affinity anti-PD-1 Abs which had an antagonist activity comparable to blocking PD-1 Abs in recovering HIV-specific CD8+ T cells from functional exhaustion, but which did not block PD-L1 binding or compete for binding with blocking anti-PD-1 Abs such as pembrolizumab. These non-blocking Abs predominantly signaled through CD28 via activation of the AKT-NF-κB pathway. Combining non-blocking and blocking anti-PD-1 Abs significantly improved tumor clearance and survival in the PD-1 HuGEMM MC38 mouse tumor model and thus could be beneficial in cancer immunotherapy.
Contributed by Katherine Turner
Classical antagonistic antibodies (Abs) targeting PD-1, such as pembrolizumab and nivolumab, act through blockade of the PD-1-PDL-1 interaction. Here, we have identified novel antagonistic anti-PD-1 Abs not blocking the PD-1-PDL-1 interaction. The nonblocking Abs recognize epitopes on PD-1 located on the opposing face of the PDL-1 interaction and overlap with a newly identified evolutionarily conserved patch. These nonblocking Abs act predominantly through the CD28 coreceptor. Importantly, a combination of blocking and nonblocking Abs synergize in the functional recovery of antigen-specific exhausted CD8 T cells. Interestingly, nonblocking anti-PD-1 Abs have equivalent antitumor activity compared with blocker Abs in two mouse tumor models, and combination therapy using both classes of Abs enhanced tumor suppression in the mouse immunogenic tumor model. The identification of the novel nonblocker anti-PD-1 Abs and their synergy with classical blocker Abs may be instrumental in potentiating immunotherapy strategies and antitumor activity.