[
Cu]-LLP2A discriminates BPRα (VLA
) vs. BPR (VLA
) melanomas in vivo, supporting translation of these BRAF-mutated melanoma models via prospective imaging and theragnostic studies. These findings increase the potential of LLP2A for therapeutic patient care by enabling it to target tumor mutations that are both clinically significant and resistant to therapy.
BPR:
Purpose: Unprecedented responses to immune checkpoint inhibitors and targeted therapy in melanoma are still seen, but a sizable portion of patients continue to deteriorate and have few curative choices. In subcutaneous and metastatic models of B16F10 murine melanoma, we have previously shown that the peptidomimetic LLP2A tagged with Cu- ([64Cu]-LLP2A) uptakes strongly and selectively for positron emission tomography (PET) imaging. Very Late Antigen-
(VLA-, integrin α4β1) is a transmembrane protein that is overexpressed in melanoma and other malignancies and promotes tumor development and metastasis. LLP2A interacts to VLA-4 with a high affinity. However, B16F10 does not accurately represent the biology of human melanoma because it lacks several oncogenic driver mutations, such as the BRAF mutations that are present in about ≥ 
% of clinical cases. In the present study, we assessed the PET tracer [Cu]-CB-TE1A1P-PEG4-LLP2A ([64Cu]-LLP2A) in new, translational BRAFV600E mutant melanoma models that differed in VLA-4 expression-BPR (VLA-4-) and BPRα (VLA-4+).
Procedures: BPR cells were transduced with α4 (CD49d) to increase the amount of intact VLA-VLA- (BPRα). on the cell surface. By using saturation binding experiments, [64Cu]-LLP2A's affinity for BPR and BPRα cells was identified. In B16F10, BPR, and BPR cells, the amount of [64Cu]-LLP2A internalization was measured using a plate-based assay. The PET/CT imaging and tracer bio distribution of mice with subcutaneous BPR and BPR tumors were assessed.
Results: High binding affinity for BPR was shown by BPRα (Kd
nM) , although binding to BPR cells was inconclusive. BPR internalization was not seen, although VLA BPRα and B16F10 showed comparable time-dependent [Cu]-LLP2A internalization. It was confirmed by significantly larger (p
) BPRα tumor uptake in bio distribution analyses that PET/CT demonstrated enhanced tracer uptake in BPR tumors compared to BBPRα tumors in vivo.
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