ImmunoPET Imaging of LAG-3 Expression in Tumor Microenvironment with Ga-labelled Cyclic Peptides Tracers: from Bench to Bedside

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2024 Jul 26

PMID 39060024

Authors

Ming Zhou

Bei Chen

Chenxi Lu

Jinhui Yang

Peng Liu

Xiaobo Wang

Shuo Hu

Affiliations

Soon will be listed here.

Abstract

Background: Lymphocyte activation gene 3 (LAG-3) has been considered as the next generation of immune checkpoint and a promising prognostic biomarker of immunotherapy. As with programmed cell death protein-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen-4 inhibitors, positron emission tomography (PET) imaging strategies could benefit the development of clinical decision-making of LAG-3-related therapy. In this study, we developed and validated Ga-labeled cyclic peptides tracers for PET imaging of LAG-3 expression in bench-to-bedside studies.

Methods: A series of LAG-3-targeted cyclic peptides were modified and radiolabeled with GaCl and evaluated their affinity and specificity, biodistribution, pharmacokinetics, and radiation dosimetry in vitro and in vivo. Furthermore, hu-PBL-SCID (PBL) mice models were constructed to validate the capacity of [Ga]Ga-CC09-1 for mapping of LAG-3 lymphocytes infiltrates using longitudinal PET imaging. Lastly, [Ga]Ga-CC09-1 was translated into the first-in-human studies to assess its safety, biodistribution and potential for imaging of LAG-3 expression.

Results: A series of cyclic peptides targeting LAG-3 were employed as lead compounds to design and develop Ga-labeled PET tracers. In vitro binding assays showed higher affinity and specificity of [Ga]Ga-CC09-1 in Chinese hamster ovary-human LAG-3 cells and peripheral blood mononuclear cells. In vivo PET imaging demonstrated better imaging capacity of [Ga]Ga-CC09-1 with a higher tumor uptake of 1.35±0.33 per cent injected dose per gram and tumor-to-muscle ratio of 17.18±3.20 at 60 min post-injection. Furthermore, [Ga]Ga-CC09-1 could detect the LAG-3 lymphocyte infiltrates in spleen, lung and salivary gland of PBL mice. In patients with melanoma and non-small cell lung cancer, primary lesions with modest tumor uptake were observed in [Ga]Ga-CC09-1 PET, as compared with that of [F]FDG PET. More importantly, [Ga]Ga-CC09-1 delineated the heterogeneity of LAG-3 expression within large tumors.

Conclusion: These findings consolidated that [Ga]Ga-CC09-1 is a promising PET tracer for quantifying the LAG-3 expression in tumor microenvironment, indicating its potential as a companion diagnostic for patients stratification and therapeutic response monitoring in anti-LAG-3 therapy.

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