Novel anti-PD-1 antibodies not acting through PD-1/pdl-1 blockade that enhance tumor clearance.

e15118Background: Monoclonal antibodies (Abs) that act through PD-1 blockade have had significant clinical success in cancer immunotherapeutic agents with current Abs relying on the blockade of the PD-1/PD-L1 interaction. Given the success of anti-PD-1 immunotherapies, our goal was to identify novel Abs with more potent anti-tumor activity, and/or acting through a mechanism independent of PD-1/PDL-1 blockade that would synergize with classical PDL-1 blocker Abs. Methods: Abs targeting human PD-1 were identified from a mouse immunization campaign and screened for the ability to block the PD-1/PDL-1 interaction and to recover antigen-specific CD8 T cells from functional exhaustion. An Ab family that was non-blocking of the PD-1/PDL-1 interaction showed antagonistic activity comparable to Pembrolizumab and Nivolumab. The binding epitope of these Abs was mapped through PD-1 site directed mutation and co-crystal structural studies. Functional synergies between blocking and non-blocking anti-PD-1 Abs was evalua...