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A mouse pancreatic organoid model to compare PD-L1 blocking antibodies
Guangyuan Li1, Susmita Ghosh1, JuMe Park1
1Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Abstract:
Immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape for cancer patients, but diabetes, a rare, severe immune-related endocrinopathy, is linked to ICI therapy. It is unclear whether glycosylation of ICIs may play a role in the development of this adverse event and how the physiological effects of different ICIs on pancreatic cells should be evaluated. We used a mouse pancreatic organoid model to compare three PD-L1 blocking antibodies in the presence or absence of IFNγ using a metabolic bioanalyzer. Modulation of ICI glycosylation altered its metabolic effects on mouse pancreatic organoids, suggesting that this model could be used to monitor and compare ICIs and to study the mechanisms underlying the development of IC-mediated diabetes.
Insights
Immune checkpoint inhibitors (ICIs) can cause diabetes. Modifying ICI glycosylation impacted their effects on pancreatic organoids, offering a new way to study ICI-induced diabetes.
Area of Science:
- Immunology
- Endocrinology
- Cancer Therapy
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment.
- A rare but severe side effect of ICIs is immune-related endocrinopathy, including diabetes.
- The role of ICI glycosylation in developing diabetes remains unclear.
Purpose of the Study:
- To investigate the impact of immune checkpoint inhibitor (ICI) glycosylation on pancreatic cells.
- To compare the effects of different PD-L1 blocking antibodies on pancreatic organoids.
- To establish a model for evaluating ICI-mediated diabetes.
Main Methods:
- Utilized a mouse pancreatic organoid model.
- Compared three PD-L1 blocking antibodies.
- Assessed metabolic effects using a metabolic bioanalyzer in the presence or absence of IFNγ.
- Investigated the influence of altered ICI glycosylation.
Main Results:
- Modulation of ICI glycosylation significantly altered metabolic effects on mouse pancreatic organoids.
- Different PD-L1 blocking antibodies exhibited distinct effects on pancreatic organoids.
- The presence of IFNγ influenced the metabolic response of organoids to ICIs.
Conclusions:
- ICI glycosylation is a potential factor in the development of ICI-mediated diabetes.
- The mouse pancreatic organoid model is a viable tool for monitoring and comparing ICIs.
- This model can aid in elucidating the mechanisms of immune checkpoint inhibitor-induced diabetes.
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