Very-late-antigen-4 (VLA-4, α4β1 integrin, CD49d/CD29) is a transmembrane adhesion receptor that plays important role in cancer and immune responses. Enhanced VLA-4 expression has been observed in multiple myeloma (MM) cells and surrounding stroma. VLA-4 conformational activation has been associated with MM pathogenesis. VLA-4 is a promising MM imaging and therapeutic biomarker.
Specificity of (64)Cu-LLP2A ((64)Cu-CB-TE1A1P-PEG4-LLP2A), a high affinity VLA-4 peptidomimetic based radiopharmaceutical, was evaluated in α4-knock-out mice, and by competitive blocking in wild-type tumor bearing mice. (64)Cu-LLP2A/PET/CT (static and dynamic) imaging was conducted in C57BL6/KaLwRij mice bearing murine 5TGM1-GFP syngeneic tumors generated after intravenous tail-vein injection. Blood samples were collected for serum protein electrophoresis (SPEP). Bone marrow and splenic cells extracted from tumor bearing and control mice (n = 3/group) were co-incubated with the optical analogue LLP2A-Cy5, and mouse B220, CD4, Gr1 and Mac1 antibodies and analyzed by FACS. Human radiation dose estimates for (64)Cu-LLP2A were extrapolated from mouse biodistribution data (6 time-points, 0.78 MBq/animal, n = 4/group). Ten formalin-fixed paraffin-embedded bone marrow samples from deceased MM patients were stained with LLP2A-Cy5.
(64)Cu-LLP2A and LLP2A-Cy5 demonstrated high specificity for VLA-4 positive mouse 5TGM1-GFP myeloma and non-malignant inflammatory host cells such as T cells and myeloid/monocytic cells. Ex vivo flow cytometric analysis supported a direct effect of myeloma on increased VLA-4 expression in host hematopoietic microenvironmental elements. Standard uptake values and the number of medullar lesions detected by (64)Cu-LLP2A/PET corresponded with increased monoclonal (M) protein (g/dL) in tumor bearing mice over time (3.29 ± 0.58 at week 0 and 9.97 ± 1.52 at week 3). Dynamic PET with (64)Cu-LLP2A and FDG demonstrated comparable SUV uptake in the prominent lesions in the femur. Human radiation dose estimates indicated urinary bladder wall as the dose-limiting organ (0.094 mGy/MBq), while the dose to the red marrow was 0.005 mGy/MBq. The Effective Dose was estimated to be 0.011 mSv/MBq. Seven of the ten human samples displayed a high proportion of cells intensely labeled with LLP2A-Cy5 probe.
(64)Cu-LLP2A and LLP2A-Cy5 demonstrated binding specificity for VLA-4 in immune competent murine MM model. (64)Cu-LLP2A displayed favorable dosimetry for human studies and is a potential imaging candidate for over-expressed VLA-4.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Agricultural and Biological Sciences
2
6%
Neuroscience
2
6%
Other
4
13%
Unknown
12
38%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 October 2021.
All research outputs
#10,975,959
of 33,973,571 outputs
Outputs from Journal of Nuclear Medicine
#3,860
of 8,188 outputs
Outputs of similar age
#133,853
of 447,173 outputs
Outputs of similar age from Journal of Nuclear Medicine
#55
of 113 outputs
Altmetric has tracked 33,973,571 research outputs across all sources so far. This one has received more attention than most of these and is in the 67th percentile.
So far Altmetric has tracked 8,188 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.8. This one has gotten more attention than average, scoring higher than 52% of its peers.
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We're also able to compare this research output to 113 others from the same source and published within six weeks on either side of this one. This one is in the 45th percentile – i.e., 45% of its contemporaries scored the same or lower than it.
