First-in-Human Evaluation of Safety and Dosimetry of ⁶⁴Cu-LLP2A for PET Imaging

Background: There remains an unmet need for molecularly targeted imaging agents in multiple myeloma (MM). The integrin, very late antigen-4 (VLA4), is differentially expressed in malignant MM cells as well as in the pathogenic inflammatory micro-environmental cells. [⁶⁴Cu]Cu-CB-TE1A1P-LLP2A (⁶⁴Cu-LLP2A) is a VLA4 targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated safety and human radiation dosimetry of ⁶⁴Cu-LLP2A for potential use in MM patients. Methods: Single dose [^natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed in CD-1 (Hsd:ICR) male and female mice. ⁶⁴Cu-LLP2A was synthesized in accordance with the good manufacturing practice compliant procedures. Three MM and six healthy participants underwent ⁶⁴Cu-LLP2A-PET/CT or PET/MR scans up to three time points to help determine tracer biodistribution, pharmacokinetics and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ absorbed doses and effective doses were calculated using the Organ Level INternal Dose Assessment (OLINDA) software. Tracer bioactivity was evaluated via cell binding assays and metabolites from human blood samples were analyzed with analytical radio-high performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level (NOEL)). Time-activity curves from human imaging data showed rapid tracer clearance from blood via kidneys and bladder. The effective dose of ⁶⁴Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and spleen had the highest organ uptake of 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated highest residence time. Image quality analysis supports early imaging time (4-5 h post injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all of the human studies (82.42 ± 13.47%). Blood metabolism studies confirmed a stable product peak (> 90%) up to 1 h post-injection of the radiopharmaceutical. No clinical or laboratory adverse events related to ⁶⁴Cu-LLP2A were observed in the human participants. Conclusions: ⁶⁴Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.