期刊
JOURNAL OF NUCLEAR MEDICINE
卷 64, 期 2, 页码 320-328出版社
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.122.264349
关键词
radiochemistry; radiopharmaceuticals; dosimetry; first-in-humans; safety; translational imaging
There is an unmet need for targeted imaging agents for multiple myeloma (MM). The radiopharmaceutical 64Cu-LLP2A, which targets VLA4, has shown potential for managing MM patients. This study evaluated the safety and radiation dosimetry of 64Cu-LLP2A in MM patients.
There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental 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 the safety and human radiation dosimetry of 64Cu-LLP2A for potential use in MM patients. Methods: A single-dose [natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was per-formed on CD-1 (Hsd:ICR) male and female mice. 64Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-com-pliant procedures. Three MM patients and six healthy participants underwent 64Cu-LLP2A-PET/CT or PET/MRI at up to 3 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 OLINDA software. Tracer bioactivity was evaluated via cell -binding assays, and metabolites from human blood samples were analyzed with analytic radio-high-performance liquid chromatogra-phy. When feasible, VLA4 expression was evaluated in the biopsy tis-sues using 14-color flow cytometry.Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time-activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of 64Cu-LLP2A in humans was 0.036 +/- 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 +/- 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analy-sis supports an early imaging time (4-5 h after injection of the radio -tracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% +/- 13.47%). Blood metabolism studies confirmed a stable product peak (.90%) up to 1 h after injection of the radiopharmaceutical. No clinical or labo-ratory adverse events related to 64Cu-LLP2A were observed in the human participants.Conclusion: 64Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.
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