Abstract 2711: Development of a new innovative multifunctional immune checkpoint inhibitor

Autor: Hiroki Nagase, Keiko Fukushima, Yoshinao Shinozaki, Atsushi Takatori, Asuka Hattori, Takahiro Inoue, Mayu Shinohara, Nobuko Koshikawa, Takayoshi Watanabe, Jason Lin
Rok vydání: 2018
Předmět:
Zdroj: Cancer Research. 78:2711-2711
ISSN: 1538-7445
0008-5472
Popis: Blockade of PD-1, PD-L1 or CTLA-4 is an attractive strategy for Immuno-Oncology (I-O) therapy. Moreover, combination approaches, which inhibit non-redundant pathways of PD-1/PD-L1 and CTLA-4, have been reported to show enhanced anti-tumor activity as well as improved progression-free survival in clinical trials of melanoma. The use of immune checkpoint blockade (ICB) drugs, however, can lead to severe or life-threatening complications of autoimmune disorders such as diabetes, thyroiditis, pulmonary fibrosis and vitiligo. Therefore, new innovations are critical to overcome possibilities of unintended immunoactivation and minimize drug cross-reactions and complications. Here, we designed and synthesized a novel alkylating Pyrrole-Imidazole (PI) polyamide with indole-seco-CBI capable of disrupting expressions of human PD-1, PD-L1 and CTLA-4 genes (CCC07-01) by binding to a common motif. Our initial evaluation process confirmed that the induction of tumor- and tumor-environment-specific combinatorial ICB therapy was possible by only a single agent. CCC07-01 administration significantly suppressed PD-1, PD-L1 and CTLA-4 mRNA and protein expressions at low nanomolar doses (15, 10, 5 nM respectively) in several cell lines. Furthermore, logP characterization experiments found CCC07-01 to be sufficiently lipophilic that enhanced the molecule's capability to accumulate and be retained in tumor tissues. Additionally, elevated doses of CCC07-01 induced substantial cytotoxicity in SW480, RKO and A2058 cancer cells (IC50=27, 12 and 11 nM, respectively) but primary cells derived from normal human tissues were not affected. These results illuminated the therapeutic possibility of CCC07-01 through, at low doses, its anti-tumor effect in tumor microenvironments and generalized cytotoxicity at increased dosage levels. CCC07-01's enhanced retention in tumor may also contribute to lower risks of triggering adverse autoimmune events compared to other ICB approaches. Preliminary results from human RKO colon carcinoma xenograft NGS mice, following the engraftment of human HLA-matched peripheral blood mononuclear cells (PBMC), showed significant tumor reduction 14 days after the injection of CCC07-01 (2.3 mg/kg, p < 0.05) and displayed detectable amounts of predominant effector memory CD8 T cells in the spleen 14 days post-administration (9.2 mg/kg, p < 0.05). The approach of simultaneously targeting elements in immune checkpoints, as demonstrated by CCC07-01, can lead to new therapeutic opportunities and reduce healthcare costs by curbing undesired autoimmune complications. Together with Zenyaku Kogyo, we envision a breakthrough in the field of current antibody-based ICB therapy as we continue to evolve and improve the use of PI polyamides as a viable candidate for ICB. Citation Format: Hiroki Nagase, Keiko Fukushima, Asuka Hattori, Mayu Shinohara, Atsushi Takatori, Takayoshi Watanabe, Nobuko Koshikawa, Takahiro Inoue, Jason Lin, Yoshinao Shinozaki. Development of a new innovative multifunctional immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2711.
Databáze: OpenAIRE
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