Details

Autor(en) / Beteiligte

• Vilalta, Marta
• Punna, Sreenivas
• Li, Shijie “Chris”
• Malathong, Viengkham
• Lange, Christopher
• McMurtrie, Darren
• Yang, Ju
• Roth, Howard
• McMahon, Jeffrey
• Campbell, James J.
• Ertl, Linda S.
• Ong, Ryan
• Wang, Yu
• Zhao, Niky
• Chhina, Vicky
• Kumamoto, Alice
• Yau, Simon
• Dang, Tong
• Zhang, Penglie
• Schall, Thomas J.
• Singh, Rajinder

Titel

Abstract B26: Tumor reduction by a small molecule human PD-1/PD-L1 inhibitor in a melanoma/PBMC co-implantation model

Ist Teil von

• Cancer immunology research, 2020-04, Vol.8 (4_Supplement), p.B26-B26

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Introduction: FDA-approved antibody-based therapies targeting the Programmed cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) immune checkpoint axis have gained considerable attention and success in cancer immunotherapy recently. As a next-generation therapy, small-molecule PD-1/PD-L1 checkpoint inhibitors may provide the potential for increased tumor penetration, shorter half-life (to better manage immune related adverse events), and lower cost of goods. We embarked on an effort to identify and develop small molecules capable of targeting the immune checkpoint molecules PD-1/PD-L1, with an aim to improve anticancer immune responses in vivo. Methods: Co-crystallized human PD-1/PD-L1 provided structural information from which we developed a number of small-molecule checkpoint inhibitors. Active compounds were first profiled by an ELISA assay measuring inhibition of the PD-1/PD-L1 interaction, followed by functional cell-based reporter and mixed lymphocyte reaction (MLR) assays. PD-1/PD-L1 inhibitory compounds thus identified were further selected for in vivo model testing. Since our human-specific PD-1/PD-L1 inhibitors did not cross-react with murine PD-1/PD-L1, we co-implanted A375 human melanoma cells along with human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD/SCID mice to test their efficacy in vivo. Results: The optimized human PD-1/PD-L1 inhibitors exhibited marked activities in both the cell-based reporter and MLR assays. Moreover, lead compound CCX4503 reduced tumor growth in vivo to a similar extent as the positive control anti-human PD-L1 antibody. Antitumor activity was completely dependent on the presence of human PBMCs. The tumor microenvironment analysis by flow cytometry indicated that the antitumor activity of CCX4503 was accompanied by a significantly higher CD8+ T-Cell/CD4+ T-cell ratio. An X-ray structure of CCX4503 co-crystallized with PD-L1 revealed several vital interactions within the PD-1-binding-region of PD-L1, providing information about the structural basis by which the compound disrupts the PD-1/PD-L1 immune checkpoint interaction. Summary: We have identified and advanced unique small-molecule inhibitors of human PD-1/PD-L1 by rational design. Molecules resulting from these efforts, such as CCX4503, exhibited marked inhibition of the PD-1/PD-L1 interaction and signaling in vitro, and also clear antitumor effects in an animal model system in vivo. Citation Format: Marta Vilalta, Sreenivas Punna, Shijie “Chris” Li, Viengkham Malathong, Christopher Lange, Darren McMurtrie, Ju Yang, Howard Roth, Jeffrey McMahon, James J. Campbell, Linda S. Ertl, Ryan Ong, Yu Wang, Niky Zhao, Vicky Chhina, Alice Kumamoto, Simon Yau, Tong Dang, Penglie Zhang, Thomas J. Schall, Rajinder Singh. Tumor reduction by a small molecule human PD-1/PD-L1 inhibitor in a melanoma/PBMC co-implantation model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B26.