Abstract 4505: Discovery of a cebrelon-based PTPN1/PTPN2 dual targeting degrader for cancer immunotherapy
Authors: Qu Zihan , Bai Yunpeng , Dong Jiajun , Zhang Zheng , Huang Bo , Miao Yiming , Tao Andy W. , Low Philip S. , Zhang Zhong-Yin 
Published: March 2024

Cancer immunotherapy has achieved notable clinical success, yet its broader application is impeded primarily by immune evasion mechanisms, predominantly stemming from factors such as tumor antigen loss, intrinsic low antigen presentation, and the inherent impermeability of current macromolecules, including cells, antibodies, and proteins. Consequently, there exists a pressing demand for more permeable agents that target intracellular components as viable alternatives.

Among the various molecular players involved in immune evasion, PTPN1 and PTPN2, two protein tyrosine phosphatases (PTPs), play a non-redundant role in regulating tumor antigen presentation. They achieve this by modulating the JAK/STAT signaling pathway within tumor cells, with their deletion having been demonstrated to enhance MHC-I presentation across various cell types. Furthermore, PTPN1 and PTPN2 also negatively regulate T cell receptor (TCR) signaling in T cells, as supported by genetic studies. Consequently, these two proteins present as promising targets for the development of innovative cancer immunotherapies due to their dual impact on both tumor cells and T cells. Addressing the intrinsic impermeability challenges associated with macromolecules, we embarked on the development of small molecule agents that specifically target PTPN1 and PTPN2, culminating in the successful creation of a low-nanomolar proteolysis targeting chimera (PROTAC), designated as X1. PROTAC X1 exhibits sustained low-nanomolar binding affinity and exceptional selectivity toward PTPN1 and PTPN2 in in vitro settings. Furthermore, it has demonstrated a nano-molar half-maximal degradation concentration (DC50) in Jurkat T cells and numerous cancer cell lines, while concurrently exhibiting efficacy in eliciting TCR signaling and enhancing MHC-I presentation. Additionally, X1-treated CAR-T cells exhibited augmented cytotoxicity through increased IFN-γ secretion, thereby reinforcing its efficacy in T cell activation. To ascertain the anti-tumor efficacy of X1, we administered X1 to C57BL/6 mice bearing MC38 tumors, resulting in a significant retardation of tumor progression. Subsequent investigations revealed that X1 treatment induced an inflammatory response in the tumor microenvironment, characterized by enhanced T cell infiltration and the activation of CD8+ T cells. Notably, no discernible adverse effects, such as autoimmune symptoms, were observed during treatment. Collectively, these findings indicate that X1 represents a potent and safe agent for cancer immunotherapy. This study not only elucidates the mechanism of action of PTPN1B/TC-PTP pharmacological degradation as a viable approach for cancer treatment but also solidifies the potential of PTPN1B/TC-PTP degradation as a novel avenue for cancer immunotherapy.

Citation Format: Zihan Qu, Yunpeng Bai, Jiajun Dong, Zheng Zhang, Bo Huang, Yiming Miao, Andy W. Tao, Philip S. Low, Zhong-Yin Zhang. Discovery of a cebrelon-based PTPN1/PTPN2 dual targeting degrader for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4505.