40P - Development of radiolabelled plerixafor as a theranostic molecule for targeting CXCR4 receptor expressing cancers: A translational study

Background

The emerging science of nuclear medicine emphasizes the use of radionuclides tagged vector molecules delivered to specific targets. The radiolabelled vector, agonist, or antagonist provides a landscape of disease spread and help in targeted radionuclide therapy. Chemokines favor leukocyte infiltration, and tumor metastasis. Chemokines receptor 4 (CXCR4) is over-expressed in more than 70% malignancies. Plerixafor is a CXCR4 antagonist has been explored for radionuclide imaging, and targeted radionuclide therapies.

Methods

Various parameters (temp, pH, time, and reaction volume) for conjugation of Plerixafor with different bifunctional chelating agents (DTPA, NOTA) and conjugation of Plerixafor for radiolabelling with ⁶⁸Ga and ¹⁷⁷Lu for imaging and therapy were optimized. Quality control tests of radiotracers such as radionuclide; radiochemical purity; sterility; pyrogenicity; serum stability were performed. The binding affinity and cytotoxicity were performed in CXCR4 expressing cancer cell lines. In-vivo physiological distribution was conducted in normal rats. After obtaining Institutional Ethical clearance, ⁶⁸Ga-Plerixafor PET/CT imaging was performed in lymphoma patients and was correlated with ¹⁸F-FDG uptake for proof of concept.

Results

DTPA conjugated (1087 Da) and NOTA conjugated (1014 Da) Plerixafor determined mass spectra. Radionuclide and radiochemical purity of ⁶⁸Ga and ¹⁷⁷Lu Plerixafor was ≥ 99%. Synthesized radiotracers were stable, sterile and pyrogen-free, and suitable for intravenous administration. The radioligand binding assay confirmed high target efficacy (Kd= 57.16 nM) of ¹⁷⁷Lu-Plerixafor towards CXCR4 expressing cancer cells. Furthermore, the log absolute IC50 concentration of ¹⁷⁷Lu-Plerixafor in cytotoxicity studies was 2.628 nM. Nuclear receptor expression was also observed in immunocytochemistry. In-vivo physiological biodistribution of ⁶⁸Ga-Plerixafor was in the liver (6.36%), spleen (11.56%), and lung (3.57%). Compared to ¹⁸F-FDG, concordant uptake in lesions was seen in ⁶⁸Ga-Plerixafor PET/CT imaging.

Conclusions

High target efficacy of radiolabelled Plerixafor elicits theranostic potential for CXCR4 over-expressing cancers.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.