A Rationally Designed Peptide Antagonist of the PD-1 Signaling Pathway as an Immunomodulatory Agent for Cancer Therapy

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 þ 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.

Nanotechnologies for enhancing cancer immunotherapy

“…And the small-molecule-inhibitor therapy is considered as a more affordable cancer treatment in the future [201]. To date, the small molecule inhibitor CA-170, and its precursor AUNP-12 (a peptide antagonist [204]), and macrocycle (BMS-986189) have been approved into clinical trials. Although CA-170 has recently been questioned whether it is a potent PD-L1 inhibitor [205], the invention and application of small molecule inhibitors are still being actively explored.…”

Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

“…Nonylphenol ethoxylate (NP-12), a polypeptide antagonist of the PD-1 signaling pathway, is used as an immunomodulator for cancer treatment 44 . In mouse models of colon cancer and melanoma, NP-12 inhibits PD-1/PD-L1 interaction and suppresses tumor growth and metastasis 45 . CA-170, a small molecule that has been tested in clinical trials, inhibits both the PD-L1 pathway and the VISTA pathway 46 .…”

“…Notably, peptide inhibitors remain in an early stage of development, although they are promising in suppressing immune checkpoints. Furthermore, high drug doses are generally required, thus often leading to undesired adverse effects because of the off-target binding associated with higher drug concentrations 44 , 45 , 49 .…”

CA-170 – A Potent Small-Molecule PD-L1 Inhibitor or Not?

“…Aurigene and Curis have not disclosed the structures of CA-170 , however, based on the analysis of Aurigene patents and the fact that it is derived from the AUNP-12 peptide with known structure [35], CA-170 is most likely the compound 4 from the patent WO 2015/033301 A [36], being a peptidomimetic, composed of a L-serine, D-asparagine and l -threonine connected via diacylhydrazine and urea linker moieties, as presented in Figure 1 B. The same structures are advertised under the name CA-170 on following webpages of chemical vendors [37,38,39,40].…”