Evaluation of VLA-4 (integrin α4β1) as a shared target for radiopharmaceutical therapy across solid tumors.

Abstract

Radiopharmaceutical therapy (RPT) is a promising approach to treating solid tumors, but therapeutic advances are impeded by the lack of broadly expressed targets and shared molecular vulnerability across different tumor types. We evaluate VLA-4 (integrin α4β1) as a potential target for RPT in solid tumors using radiolabeled copper-64 ([64Cu]Cu-) and copper-67 ([67Cu]Cu-CB-TE1A1P-PEG4-LLP2A) LLP2A, a peptidomimetic ligand of VLA-4, for preclinical imaging and RPT testing. Expression analysis of ITGA4, encoding the alpha 4 subunit of VLA-4, revealed overexpression in hematological malignancies and various solid tumors compared to healthy tissue. Flow cytometry showed medium to high VLA-4 expression in 77% of tested cancer cell lines. PET/CT imaging with [64Cu]Cu-LLP2A demonstrated tracer uptake in tumors and lymphoid tissues. In toxicity studies, [67Cu]Cu-LLP2A administered at 37-74 MBq was well-tolerated, causing only thymic atrophy without long-term hematological or tissue toxicity. Tumor dose response was observed in B16-F10 melanoma models. Using orthotopic syngeneic models (B16-F10, B78, 4T1, GL261, TH-MYCN, and E2A-PBX1) and human cancer models (SK-MEL-37, 143B, and IMR-5), we conducted PET/CT imaging and biodistribution studies, with selected models used for [64Cu]Cu-LLP2A dosimetry calculations. Given VLA-4's broad expression across cancer tissues, demonstrated on-target effects, acceptable toxicity profile, and favorable dosimetry in preclinical models, further investigation of [67Cu]Cu-LLP2A as an RPT agent is warranted.