First-in-Humans Evaluation of Safety and Dosimetry of⁶⁴Cu-LLP2A for PET Imaging

Abstract

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 microenvironmental cells. [ 64 Cu]Cu-CB-TE1A1P-LLP2A ( 64 Cu-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 64 Cu-LLP2A for potential use in MM patients.Methods: Single dose [ nat Cu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed in CD-1 (Hsd:ICR) male and female mice. 64 Cu-LLP2A was synthesized in accordance with the good manufacturing practice compliant procedures. Three MM and six healthy participants underwent 64 Cu-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 64 Cu-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 64 Cu-LLP2A were observed in the human participants.Conclusions: 64 Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.

Targeted imaging of very late antigen-4 for noninvasive assessment of lung inflammation-fibrosis axis

“…64 Cu-LLP2A is a high-affinity VLA-4-targeting tracer with an established safety profile and favorable kinetics in first-in-human studies [ 50 ] and that is on the verge of clinical translation in at least two clinical conditions, i.e., multiple myeloma [Clinical Trial # NCT03804424] [ 50 ] and sickle cell disease [Clinical Trial # NCT04925492]. However, the application of 64 Cu-LLP2A PET in inflammatory diseases has been limited to a few studies [ 20 , 46 ].…”

Molecular imaging of bone metastasis

“…One such tracer currently under development in the Shokeen and Dehdashti Labs at Washington University is [ 64 Cu]Cu-CB-TE1A1P-LLP2A ( 64 Cu-LLP2A), for imaging the expression of integrin very late antigen-4 (VLA4) ( Fig. 5 ) [ 47 ]. Integrin very late antigen-4 (VLA4) is expressed in multiple myeloma cells and pathogenic inflammatory microenvironmental cells, making it a biomarker of interest [ [48] , [49] , [50] ].…”

“…Integrin very late antigen-4 (VLA4) is expressed in multiple myeloma cells and pathogenic inflammatory microenvironmental cells, making it a biomarker of interest [ [48] , [49] , [50] ]. In a phase I first-in-human study, the tracer was determined to be safe for use in humans [ 47 ]. While the optimal use of this tracer will be determined in future Phase II studies, this work demonstrates the potential of imaging markers that interact with the bone and bone marrow microenvironment.…”

Effect of the type of N-substituent in the benzo-18-azacrown-6 compound on copper(ii) chelation: complexation, radiolabeling, stability in vitro, and biodistribution in vivo

“…[8][9][10][11] Copper-64/67 radiopharmaceuticals based on cyclen, cyclam, their cross-bridged derivatives and sarcofaginederivatives with acetate and phosphonate or without pendant arms are currently undergoing clinical trials. 4,[12][13][14] Copper cations exist predominantly as divalent metal cations and form complexes with coordination numbers of 4-6. As a borderline cation according to the HSAB theory, Cu 2+ can be effectively chelated not only by donor oxygen atoms, but also by aliphatic amines and pyridine nitrogens.…”

“…8–11 Copper-64/67 radiopharmaceuticals based on cyclen, cyclam, their cross-bridged derivatives and sarcofagine-derivatives with acetate and phosphonate or without pendant arms are currently undergoing clinical trials. 4,12–14…”