Very late antigen-4 (VLA-4) is a transmembrane noncovalent heterodimer that is overexpressed in melanoma tumors and is associated with tumor growth, angiogenesis, and metastasis by promoting cancer cell adhesion and migration. We are developing conjugates of the ligand LLP2A which targets VLA-4 for PET imaging and radiopharmaceutical therapy. Here we present an ongoing structure-activity study to evaluate changing the bifunctional chelator from the standard DOTA to Lumi804, an octadentate, macrocyclic chelator based on four 1-hydroxypyridin-2-one (1,2-HOPO) coordinating units. We also investigated how incorporating an albumin binding agent (4-(p-iodophenyl)butyric acid, pIBA) affects biodistribution and therapeutic efficacy. The Lumi804 chelator forms very stable complexes with mid-to-late lanthanides including Tb(III) and Lu(III), and it also binds Zr(IV) and Th(IV) exceptionally well. PEG4-LLP2A and PEG4-pIBA-LLP2A were conjugated with DOTAGA or Lumi804, and then radiolabeled with Lu-177, Tb-161, or Zr-89 (Lumi804 only). All Lumi804-LLP2A conjugates were radiolabeled at room temperature in under 30 min, whereas the DOTAGA- conjugates required heating to at least 70 °C. Antigen binding affinity of 89Zr-, 177Lu-, and 161Tb-Lumi804-LLP2A for VLA-4 showed high affinity (low nM) in VLA-4-positive B16F10 mouse melanoma cells. Preliminary biodistribution data show comparable tumor targeting with improved non-tumor clearance for the Lumi804 agents, demonstrating that this new chelator may improve target selectivity in applications with many theranostic radionuclides.

VLA-4 targeted 177Lu(III), 161Tb(III), and 89Zr(IV) theranostic agents for imaging and treating melanoma

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