Abstract 5022: Peptide therapeutic inhibiting PD1 immune checkpoint ligands: Potential for greater anti-tumor immune response and better management of immune-related adverse events
Authors: Ramachandra Murali , Sasikumar Pottayil G. , Shrimali Rajeev K. , Adurthi Sreenivas , Ramachandra Raghuvir , Satyam Leena K. , Dhudashia Amit A. , Dhodheri Samiulla , Sunilkumar K B. 
Published: May 2015

Antibodies to immune checkpoint receptors have revolutionized the outlook of cancer therapy by achieving highly durable clinical responses. However, along with impressive clinical activity (response rate of ∼25% with either anti-CTLA4 or anti-PD1 as single agent, but &gt; 50% with a combination), severe immune-related adverse events (irAEs) due to the breaking of immune self- tolerance (25-30% with anti-CTLA4 and up to 15-17% with anti-PD1) are becoming increasingly evident. Sustained target inhibition as a result of a long half-life (&gt;15-20 days) and &gt;70% target occupancy for months are likely contributing to severe irAEs observed in the clinic with antibodies targeting immune checkpoint proteins. The antibodies targeting PD-1 signaling pathway are either based on receptor (PD-1) or its ligands (PD-L1 & PDL2). It has also been reported that PDL1 also interacts with B7-1(CD80) resulting in negative T-cell regulation. Our efforts are therefore focused on (a) developing a first in class peptide therapeutic inhibiting all three reported interaction of PD-1 pathway to improve the anti-tumor immune response (b) developing immune checkpoint blockers with potent anti-tumor activity but with a shorter pharmacokinetic profile as a strategy to better manage severe irAEs.

Peptide antagonist AUR-012, constructed with elements from human PD-1 receptor, displayed equipotent antagonism towards PD-L1 and PD-L2 with potent activity in rescue of lymphocyte proliferation and effector functions. Additionally crosslinking study to evaluate the effect of AUR-12 on B7.1 - PDL-1 interaction supports the finding that AUR-012 prevents the interaction of B7.1 with PD-L1. Rescue of proliferation of immune cells analyzed upon stimulation with anti-CD3/anti-CD-28 indicated a complete rescue of CD4+ and CD8+ T cells and a complete suppression of regulatory T cells. Sustained activation of circulatory immune cells and their ability to secrete IFN-γ up to 72 h indicate that pharmacodynamic effects persist even after the clearance of AUR-012 in animal models, thus supporting a dosing interval of up to 3 days. In models of melanoma, breast, kidney and colon cancers, AUR-012 showed efficacy in inhibition of both primary tumor growth and metastasis. Additionally, anti-tumor activity of AUR-012 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 PD1+ T cells (both CD4+ & CD8+) in tumor and blood. In 14-day repeated dose toxicity studies, AUR -012 was well tolerated at 100x of the efficacious doses.

These findings demonstrating inhibition of all PD-1/ PD-1 ligands mediated co-inhibitory signaling pathway and the observed correlation between anti-tumor activities with the modulation of specific T-cell populations support further development of AUR-012 in the clinic.

Citation Format: Murali Ramachandra, Pottayil G. Sasikumar, Rajeev K. Shrimali, Sreenivas Adurthi, Raghuvir Ramachandra, Leena K. Satyam, Amit A. Dhudashia, Samiulla Dhodheri, K B. Sunilkumar. Peptide therapeutic inhibiting PD1 immune checkpoint ligands: Potential for greater anti-tumor immune response and better management of immune-related adverse events. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5022. doi:10.1158/1538-7445.AM2014-5022