Abstract 2850: Demonstration of anti-tumor efficacy in multiple preclinical cancer models using a novel peptide inhibitor (Aurigene-012) of the PD1 signaling pathway

Abstract

Programmed cell death-1 (PD-1), an immunoreceptor belonging to the CD28 family, plays an important role in negatively regulating immune responses. Blocking of PD-1 signalling pathway has been shown to result in restoration of defective immune cell functions in cancer and chronic infections. PD-1 targeted therapies in the ongoing clinical trials are based on either antibodies or fusion proteins. To exploit unique advantages of peptides over antibodies or fusion proteins towards addressing the limitations of the current clinical candidates, herein we report a peptide based strategy to block the PD-1 signaling pathway. Sequences critical for ligand-receptor interaction were identified and combined in a non-linear fashion. The strategy resulted in a novel peptide, AUR-012 (29-mer), which displayed sub-nanomolar potency in disruption of PD1-PDL1/2 interaction, and highly effective restoration of proliferation and effector functions of splenocytes and PBMCs. In vivo studies demonstrated an excellent PK-PD correlation with sustained PD for >24 h. In preclinical models of melanoma, breast and kidney cancers, AUR-012 showed superior efficacy compared to therapeutic agents currently used in the clinic in inhibition of both primary tumor growth and metastasis. Interestingly, dosing once in three days was equally efficacious as once a day dosing with no signs of overt toxicity and generation of neutralizing activity. These findings support further development of AUR-012 for potential clinical use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2850. doi:1538-7445.AM2012-2850

Anti-PD-L1 peptide improves survival in sepsis

“…PD-1 and PD-L1 mediate immunosuppression by recruiting the tyrosine phosphatase SHP-2 which dephosphorylates and inactivates proximal effector molecules including AKT and ZAP70 (35–37). Compound 8 is a highly potent antagonist of the PD-1 signaling, which disrupts the interaction of PD-1 with PD-L1, and shows an EC 50 of <50 nM in rescue of PD-L1 mediated inhibition of lymphocyte proliferation and effector functions in both human and mouse systems (US Patent #: 8907053) (31). Compound 8 has several theoretical advantages over anti-PD-1 or anti-PD-L1 antibodies.…”

“…The peptide, Compound 8, was developed at Aurigene Discovery Technologies Limited (Bangalore, Karnataka, India) (US patent #: 8907053) (31). Compound 8 is a 29 amino acid peptide that potently blocks PD-L1 signaling as demonstrated by an EC 50 <50 nM in rescue of PD-L1 mediated inhibition of lymphocyte proliferation and effector functions in both human and mouse systems (US patent #: 8907053).…”

Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators

“…It is claimed to inhibit tumor growth and metastasis in preclinical models of cancer and to be well tolerated with no obvious toxicity at any of the tested doses. AUNP‐12 ( 3 ) is postulated to have the structure shown in Figure …”

“…In a series of linear hepta‐ and octapeptides derived from the PD‐1 BC loop including a variety of central linkers they found compound 4 to be the most active (Figure ). The compound is also active in vivo in a lung metastasis model of B16F10 melanoma in mice (64 % reduction in metastasis at 5 mg kg −1 , subcutaneous application, once daily dosing, 14 days treatment) …”

“…These compounds inhibit the PD‐1–P‐L1 interaction measured by a mouse splenocyte proliferation assay. Compound 5 (Figure ) is active in vivo in a lung metastasis model of B16F10 melanoma in mice (54 % reduction in metastasis at 5 mg kg −1 , subcutaneous, once daily, 14 days) …”