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

Richard Laforest, Anchal Ghai, Tyler J. Fraum, Reiko Oyama, Jennifer Frye, Helen Kaemmerer, Greg Gaehle, Tom Voller, Cedric Mpoy, Buck E. Rogers, Mark Fiala, Kooresh I. Shoghi, Samuel Achilefu, Michael Rettig, Ravi Vij, John F. DiPersio, Sally Schwarz, Monica Shokeen, Farrokh Dehdashti

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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 performed on CD-1 (Hsd:ICR) male and female mice. 64Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-compliant 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 chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues 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 analysis supports an early imaging time (4-5 h after injection of the radiotracer) 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 laboratory 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.

Original languageEnglish (US)
Pages (from-to)320-328
Number of pages9
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine
Issue number2
StatePublished - Feb 1 2023


  • dosimetry
  • first-in-humans
  • radiochemistry
  • radiopharmaceuticals
  • safety
  • translational imaging

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging'. Together they form a unique fingerprint.

Cite this