89Zr-Labeled Anti-PD-L1 Antibody Fragment for Evaluating In Vivo PD-L1 Levels in Melanoma Mouse Model
Caleb Bridgwater1, Anne Geller2, Xiaoling Hu3
1Department of Radiology, University of Louisville, Louisville, Kentucky, USA.
Abstract:
The rise of programmed death-1 (PD-1)/PD-L1 immune checkpoint inhibitor therapy has been one of the most promising developments in melanoma research. However, not all the melanoma patients respond to such immune checkpoint blockade. There is a great need of biomarkers for appropriate melanoma patient selection and therapeutic efficacy monitoring. The objective of this study is to develop a novel radiolabeled anti-PD-L1 antibody fragment, as an imaging biomarker, for evaluating the in vivo PD-L1 levels in melanoma. The Df-conjugated F(ab')2 fragment of the anti-mouse PD-L1 antibody was successfully synthesized and radiolabeled with 89Zr. Both Df-F(ab')2 and 89Zr-Df-F(ab')2 maintained the nano-molar murine PD-L1 targeting specificity and affinity. 89Zr-Df-F(ab')2 showed less uptake in normal liver tissue in mice compared with its full antibody counterpart 89Zr-Df-anti-PD-L1. Positron emission tomography (PET)/computed tomography images clearly showed that 89Zr-Df-F(ab')2 possessed superior pharmacokinetics and imaging contrast over the radiolabeled full antibody, with much earlier and higher tumor uptake (5.5 times more at 2 h post injection) and much lower liver background (51% reduction at 2 h post injection). The specific and high murine PD-L1-targeting uptake at tumor foci coupled with fast clearance of 89Zr-Df-F(ab')2 highlighted its potential for in vivo PET imaging of murine PD-L1 levels and future development of radiolabeled anti-human PD-L1 fragment for potential application in melanoma patients.
Insights
Researchers developed a new imaging biomarker, 89Zr-Df-F(ab)2, for melanoma. This radiolabeled antibody fragment effectively visualizes programmed death-ligand 1 (PD-L1) in vivo, aiding patient selection for immunotherapy.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Programmed death-1 (PD-1)/PD-L1 inhibitors show promise in melanoma treatment, but patient response varies.
- Biomarkers are needed for selecting melanoma patients and monitoring immunotherapy efficacy.
Purpose of the Study:
- To develop a novel radiolabeled anti-PD-L1 antibody fragment as an imaging biomarker.
- To evaluate its ability to assess in vivo PD-L1 levels in melanoma.
Main Methods:
- Synthesized and radiolabeled a Df-conjugated F(ab')2 fragment of an anti-mouse PD-L1 antibody with 89Zr.
- Assessed targeting specificity and affinity.
- Compared pharmacokinetic and imaging properties with a full antibody counterpart using PET/CT in mice.
Main Results:
- The 89Zr-labeled fragment (89Zr-Df-F(ab')2) maintained high specificity and affinity for murine PD-L1.
- It demonstrated significantly lower liver uptake compared to the full antibody.
- PET/CT imaging revealed superior pharmacokinetics, earlier and higher tumor uptake, and reduced liver background with 89Zr-Df-F(ab')2.
Conclusions:
- 89Zr-Df-F(ab')2 shows potential as an in vivo PET imaging biomarker for PD-L1 levels in melanoma.
- Its favorable properties suggest future development of radiolabeled anti-human PD-L1 fragments for clinical application in melanoma patients.
