A rationally designed peptide antagonist of the PD-1 signaling pathway as an immunomodulatory agent for cancer therapy

Pioneering success of antibodies targeting immune checkpoints such as PD-1 and CTLA4 has opened novel avenues for caner immunotherapy. Along with impressive clinical activity, severe immune-related adverse events (irAEs) due to the breaking of immune self- tolerance are becoming increasingly evident in antibody-based approaches. As a strategy to better manage severe adverse effects, we set out to discover an antagonist targeting PD-1 signaling pathway with a shorter pharmacokinetic profile. Herein we describe a peptide antagonist NP-12 that displays equipotent antagonism towards PD-L1 and PD-L2 in rescue of lymphocyte proliferation and effector functions. In preclinical models of melanoma, colon cancer and kidney cancers, NP-12 showed significant efficacy comparable to commercially available PD-1 targeting antibodies in inhibiting primary tumor growth and metastasis. Interestingly, anti-tumor activity of NP-12 in a pre-established CT26 model correlated well with pharmacodynamic effects as indicated by intratumoral recruitment of CD4 and CD8 T cells, and a reduction in PD-1+ T cells (both CD4 and CD8) in tumor and blood. Additionally, NP-12 also showed additive anti-tumor activity in pre-established tumor models when combined with tumor vaccination or a chemotherapeutic agent such as cyclophosphamide known to induce "immunological cell death". In summary NP-12 is the first rationally designed peptide therapeutic targeting PD-1 signaling pathways exhibiting immune activation, excellent anti-tumor activity and potential for better management of immune-related adverse events.