Abstract
Pioneering success of antibodies targeting immune checkpoints such as PD-1 and CTLA4 has opened novel avenues for cancer immunotherapy. Along with impressive clinical activity, severe immune-related adverse events (irAE) 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 toward 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 with commercially available PD-1-targeting antibodies in inhibiting primary tumor growth and metastasis. Interestingly, antitumor activity of NP-12 in a preestablished 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. In addition, NP-12 also showed additive antitumor activity in preestablished tumor models when combined with tumor vaccination or a chemotherapeutic agent such as cyclophosphamide known to induce "immunologic cell death." In summary, NP-12 is the first rationally designed peptide therapeutic targeting PD-1 signaling pathways exhibiting immune activation, excellent antitumor activity, and potential for better management of irAEs.
Highlights
Recent advances in achieving highly durable clinical responses via inhibition of immune checkpoint proteins including CTLA-4 and PD-1 have revolutionized the outlook for cancer therapy [1,2,3,4,5]
Identification of lead candidate As an alternative to antibody-based approach, we sought to discover and develop peptide-based immune checkpoint antagonists capable of targeting PD-1/PD-L1 signaling pathways. We reasoned that such therapeutic agents would likely allow better management of immune-related adverse events (irAE) due to relatively shorter pharmacokinetic exposure
NP-12 is a 29-amino acid branched peptide behaving as a PD-1 decoy generated from the selected portions of the human PD-1 receptor
Summary
Recent advances in achieving highly durable clinical responses via inhibition of immune checkpoint proteins including CTLA-4 and PD-1 have revolutionized the outlook for cancer therapy [1,2,3,4,5]. Immunotherapies including checkpoint inhibitors are being considered as the "fifth pillar" of cancer therapy, as witnessed by the approval of a number antibodies targeting PD-1/PD-L1 immune checkpoint signaling pathway spanning an expanding list of indications [6,7,8,9]. In contrast to blocking CTLA4, antibodies that target PD-1/PD-L1 signaling pathway have stolen the limelight primarily because of the observed efficacy in multiple clinical indications with toxicities that appear to be less common and less severe [10].
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