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Published on: June 28, 2011
Development, Characterization, and Radiation Dosimetry Studies of 18F-BMS-986229, a 18F-Labeled PD-L1 Macrocyclic
Joonyoung Kim1, David J Donnelly2, Tritin Tran2
1Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA. joonyoung.kim@bms.com.
Purpose:
In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an 18F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients.
Procedures:
18F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. 18F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of 18F-BMS-986229 in healthy non-human primates (NHPs) was performed.
Results:
In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1 +) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that 18F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90-100 min after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq.
Conclusion:
18F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, 18F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.
Insights
A novel 18F-labeled peptide tracer, 18F-BMS-986229, enables precise, quantitative assessment of programmed death-ligand 1 (PD-L1) expression. This PET tracer shows promise for monitoring immunotherapy response in cancer patients.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiochemistry
Background:
- Cancer immunotherapy targeting the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) interaction is a promising strategy.
- Resistance to PD-1/PD-L1 inhibition can arise from variable tumor cell PD-L1 expression, necessitating advanced quantitative assessment beyond standard immunohistochemistry (IHC).
- A comprehensive and quantitative method is required to measure PD-L1 expression for improved treatment strategies.
Purpose of the Study:
- To develop and characterize a novel 18F-labeled macrocyclic peptide tracer for Positron Emission Tomography (PET) imaging.
- To evaluate the tracer's ability to comprehensively assess tumor PD-L1 expression in cancer patients.
- To investigate the potential of the tracer in monitoring longitudinal changes and predicting immunotherapy outcomes.
Main Methods:
- Characterization of 18F-BMS-986229 using in vitro and ex vivo autoradiography.
- In vivo PET imaging in mice to assess tracer uptake and target engagement with a PD-L1 inhibitor (BMS-986189).
- Whole-body radiation dosimetry study of 18F-BMS-986229 in healthy non-human primates (NHPs).
Main Results:
- In vitro autoradiography demonstrated high binding specificity (8:1 ratio) to PD-L1-expressing tumors.
- In vivo PET imaging in mice showed significant tracer uptake in PD-L1-positive tumors with high specific binding (>83%).
- The NHP dosimetry study indicated a low whole-body effective dose (0.025 mSv/MBq), supporting clinical applicability.
Conclusions:
- 18F-BMS-986229 has been preclinically validated as a PET tracer with high target specificity and low background uptake.
- The tracer's short blood half-life allows for same-day imaging, facilitating clinical use.
- 18F-BMS-986229 shows significant potential for quantifying PD-L1 expression and monitoring treatment responses in cancer immunotherapy.
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