TY - JOUR
T1 - First-in-Human Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging
AU - Laforest, Richard
AU - Ghai, Anchal
AU - Fraum, Tyler J.
AU - Oyama, Reiko
AU - Frye, Jennifer
AU - Kaemmerer, Helen
AU - Gaehle, Greg
AU - Voller, Tom
AU - Mpoy, Cedric
AU - Rogers, Buck E.
AU - Fiala, Mark
AU - Shoghi, Kooresh I.
AU - Achilefu, Samuel
AU - Rettig, Michael
AU - Vij, Ravi
AU - DiPersio, John F.
AU - Schwarz, Sally
AU - Shokeen, Monica
AU - Dehdashti, Farrokh
N1 - Funding Information:
We thank WUSM isotope production team for 64Cu. We thank the nurse coordinators and CCIR technical team for their exceptional assistance. This study was supported in-part by U54CA199092, R42CA257797, R01 CA248493, R35 CA210084 and R01CA176221. We thank the Mallinckrodt Institute of Radiology (MIR) pilot funds and the Foundation for Barnes-Jewish Hospital, the Response Assessment Shared Resource Cores of the Alvin J. Siteman Cancer Center supported in part by P30 CA91842. We thank the patients who provided samples to the Multiple Myeloma Tissue Bank Study at Washington University that were used in this study. We profusely thank the volunteers who participated in the imaging study. We thank Professor Katherine Weilbaecher and Professor Michael Tomasson for their guidance and support.
Publisher Copyright:
© 2023 Society of Nuclear Medicine Inc.. All rights reserved.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85143735939&partnerID=8YFLogxK
U2 - 10.2967/jnumed.122.264349
DO - 10.2967/jnumed.122.264349
M3 - Article
C2 - 36008121
AN - SCOPUS:85143735939
SN - 0161-5505
VL - 64
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 2
ER -