Pioneering success of anti-CTLA4 antibody (Ipilimumab) and the impressive clinical data on agents that target PD-1 or its ligands have opened novel avenues in the area for caner immunotherapy. However, along with impressive clinical activity, immune-related toxicities have also been observed in significant (25-30% with anti-CTLA4 and up to 15% with anti-PD1) patient population. Sustained inhibition of PD-1 signaling as a result of a very long half-life (>15-20 days) and >70% target occupation for months are likely contributing to severe adverse effects observed in clinical trials with antibodies targeting PD-1 signaling. In the present study, we sought to characterize in detail a novel peptide antagonist of the PD1 signaling providing desired anti-tumor efficacy with shorter exposure and thus transient immune activation for effective management of severe adverse effects.
Design of peptide to disrupt PD-1 signalling pathway was carried out by selecting individual fragments from PD-1 ectodomain reported to participate in binding. 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 equipotent antagonism in disruption of PD1-PDL1/2 interaction and highly effective in restoration of proliferation and effector functions of mouse splenocytes and monkey and human PBMCs using species specific ligands. In preclinical models of melanoma, breast, kidney and colon cancers, AUR-012 showed superior showed superior efficacy compared to therapeutic agents currently used in the clinic in inhibition of both primary tumour growth and metastasis. Additionally, AUR-012 showed additive anti-tumor activity in a pre-established tumor models when combined with tumor vaccination or a chemotherapeutic agent such as cyclophosphamide known to induce “immunological cell death”. Anti-tumoral activity was correlated with increased drug distribution within the tumor while promoting intratumoral recruitment of CD4+ and CD8+ T cells. Furthermore, AUR -012 was well tolerated in 14 days repeated dose toxicity studies at 100x efficacious doses.
The above findings demonstrating equipotent activity antagonism of both PD-L1 and PD-L2 signaling coupled with impressive efficacy in preclinical models support further development of AUR-012 for clinical use.
Citation Format: Pottayil G. Sasikumar, Leena K. Satyam, Rajeev Shrimali, Raghuveer Ramachandra, Ketha A. Reddy, Adurthi Sreenivas, Amit Dhudashia, Dodderi S. Samiulla, Murali Ramachandra. Equipotent antagonism, transient immune activation and excellent antitumor efficacy with a peptide inhibitor of PD-1 immune check point pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1231. doi:10.1158/1538-7445.AM2013-1231