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Updated: Jul 3, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Small molecule and PROTAC molecule experiments in vitro and in vivo, focusing on mouse PD-L1 and human PD-L1
Annoor Awadasseid1, Rui Wang2, Shishi Sun2
1Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China; Moganshan Institute ZJUT, Deqing 313202, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China; Department of Biochemistry & Food Sciences, University of Kordofan, El-Obeid 51111, Sudan.
Abstract:
In recent years, several monoclonal antibodies (mAbs) targeting PD-L1 have been licensed by the FDA for use in the treatment of cancer, demonstrating the effectiveness of blocking immune checkpoints, particularly the PD-1/PD-L1 pathway. Although mAb-based therapies have made great strides, they still have their limitations, and new small-molecule or PROTAC-molecule inhibitors that can block the PD-1/PD-L1 axis are desperately needed. Therefore, it is crucial to translate initial in vitro discoveries into appropriate in vivo animal models when creating PD-L1-blocking therapies. Due to their widespread availability and low experimental expenses, classical immunocompetent mice are appealing for research purposes. However, it is yet unclear whether the mouse (m) PD-L1 interaction with human (h) PD-1 in vivo would produce a functional immunological checkpoint. In this review, we summarize the in vitro and in vivo experimental studies of small molecules and PROTAC molecules, particularly the distinctions between mPD-L1 as a target and hPD-L1 as a target.
Insights
New small-molecule and PROTAC inhibitors targeting PD-L1 are needed for cancer therapy. This review examines in vitro and in vivo studies of these inhibitors, focusing on mouse versus human PD-L1 targets.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Monoclonal antibodies (mAbs) targeting PD-L1 have advanced cancer immunotherapy by blocking immune checkpoints.
- Limitations of current mAb therapies necessitate the development of novel small-molecule and PROTAC inhibitors for the PD-1/PD-L1 axis.
- Translating in vitro findings to in vivo models is critical for developing effective PD-L1-blocking therapies.
Purpose of the Study:
- To review in vitro and in vivo studies of small-molecule and PROTAC inhibitors targeting PD-L1.
- To elucidate the functional differences between targeting mouse (m) PD-L1 versus human (h) PD-L1 in vivo.
- To assess the utility of immunocompetent mice for preclinical evaluation of PD-L1-blocking agents.
Main Methods:
- Comprehensive literature review of in vitro and in vivo studies.
- Analysis of experimental data comparing mPD-L1 and hPD-L1 interactions.
- Evaluation of small-molecule and PROTAC inhibitor efficacy and mechanisms.
Main Results:
- Monoclonal antibodies targeting PD-L1 are FDA-approved for cancer treatment.
- The efficacy of mouse PD-L1 as a target for human PD-1 interaction in vivo remains unclear.
- Distinctions between mPD-L1 and hPD-L1 as targets for novel inhibitors are highlighted.
Conclusions:
- Novel small-molecule and PROTAC inhibitors targeting PD-L1 are crucial for advancing cancer immunotherapy.
- Further research is needed to validate the use of mouse models for human PD-L1-targeting therapies.
- Understanding species-specific PD-L1 interactions is key for effective drug development.
