Development of a new hSIRPα-specific radiotracer for non-invasive PET imaging using genOway’s double humanized genO-hCD47/hSIRPα mouse and genO-MC38-hPD-L1-hCD47-LZ cell line

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Wagner et al. Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells. Front Immunol, 2023

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High expression of the “don’t eat me” CD47 protein by tumor cells and subsequent binding to SIRPα on macrophages is linked to immune escape, making the CD47/SIRPα axis a promising target in the landscape of immune checkpoint inhibitors (ICI)^1,2.

ICI efficacy can be further improved by the development of new methods to detect biomarkers, to help predict and monitor the responsiveness of patients. In this regard, the development of PET imaging,a non-invasive method that uses radiotracers, represents a promising approach.

In this paper, our collaborators from the University of Tübingen worked on the development of nanobodies (Nb) targeting the human CD47/SIRPα axis³. As previously reported, the small size and structure of Nb confer on them better tumor-penetrating capacity and safety, making them suitable both as radiotracers for PET imaging and as therapeutic compounds⁴. The authors developed a ⁶⁴Cu-hSIRPα-S36_K>R Nb. The Nb selectively binds to human SIRPα without blocking its interaction with CD47, making it inert and therefore a candidate for further use in imaging.

genOway’s double humanized genO-hCD47/hSIRPα mice and WT mice were inoculated with genO-MC38-hPD-L1-hCD47-Luciferase-Zsgreen cell line (genOway). Upon tumor uptake, mice were injected with ⁶⁴Cu-hSIRPα-S36_K>R and imaging was performed by PET scan (see figure). ⁶⁴Cu-hSIRPα-S36_K>R efficiently allowed assessment of the biodistribution of SIRPα+ cells in the TME and myeloid cell-enriched organs of the humanized mice (spleen, bone, liver blood and salivary glands) up to 6 hours. In contrast, a rapid clearance of the tracer was observed in the blood and tumor of control WT mice.

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Due to the physiological expression of human CD47 and human SIRPα, the double humanized mouse model represents an efficient tool to assess the biodistribution of compounds targeting one of these proteins. Additional investigations using genO-hCD47/hSIRPα mice and the genO-MC38-hPD-L1-hCD47-Luciferase-ZsGreen cell line are ongoing to assess the efficacy of candidate compounds to induce a tumor growth inhibition.

The double humanized genO-hCD47/hSIRPα mouse model and the genO-MC38-hPD-L1-hCD47-LZ cell line are available at genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.

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‍References:

1. Jia X et al. CD47/SIRPα pathway mediates cancer immune escape and immunotherapy. Int J Biol Sci, 2021
2. Duijn et al. CD47/SIRPα axis: bridging innate and adaptive immunity. J Immunotherap. of Cancer, 2020
3. Wagner et al. Two birds with one stone: human SIRPα nanobodies for functionalmodulation and in vivo imaging of myeloid cells. Front Immunol, 2023
4. Yang andShah. Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics. Front Immunol, 2020