Journal article
Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents
The Journal of nuclear medicine (1978), Vol.57(4), pp.640-645
04/01/2016
DOI: 10.2967/jnumed.115.164624
PMCID: PMC4887080
PMID: 26742713
Abstract
Very-late-antigen-4 (VLA-4, alpha(4)beta(1) integrin, CD49d/CD29) is a transmembrane adhesion receptor that plays an 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. Methods: Specificity of Cu-64-LLP2A (Cu-64-CB-TE1A1P-PEG(4)-LLP2A), a high-affinity VLA-4 peptidomimetic-based radiopharmaceutical, was evaluated in alpha(4) knock-out mice and by competitive blocking in wild-type tumor-bearing mice. Cu-64-LLP2A PET/CT (static and dynamic) imaging was conducted in C57BL6/KaLwRij mice bearing murine 5TGM1-GFP syngeneic tumors generated after intravenous injection via the tail. Blood samples were collected for serum protein electrophoresis. Bone marrow and splenic cells extracted from tumor-bearing and control mice (n = 3/group) were coincubated with the optical analog LLP2A-Cy5 and mouse B220, CD4, Gr1, and Mac1 antibodies and analyzed by fluorescence-activated cell sorting. Human radiation dose estimates for Cu-64-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. Results: Cu-64-LLP2A and LLP2A-Cy5 demonstrated high specificity for VLA-4-positive mouse 5TGM1-GFP myeloma and nonmalignant 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. SUVs and the number of medullar lesions detected by Cu-64-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 Cu-64-LLP2A and F-18-FDG demonstrated comparable SUV in the prominent lesions in the femur. Human radiation dose estimates indicated urinary bladder wall as the dose-limiting organ (0.200 mGy/MBq), whereas the dose to the red marrow was 0.006 mGy/MBq. The effective dose was estimated to be 0.017 mSv/MBq. Seven of the ten human samples displayed a high proportion of cells intensely labeled with LLP2A-Cy5 probe. Conclusion: Cu-64-LLP2A and LLP2A-Cy5 demonstrated binding specificity for VLA-4 in an immune-competent murine MM model. Cu-64-LLP2A displayed favorable dosimetry for human studies and is a potential imaging candidate for overexpressed VLA-4.
Details
- Title: Subtitle
- Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents
- Creators
- Deepti Soodgupta - Washington University in St. LouisHaiying Zhou - MallinckrodtWissam Beaino - University of PittsburghLan Lu - Washington University in St. LouisMichael Rettig - Washington University in St. LouisMark Snee - Washington University in St. LouisJames Skeath - Washington University in St. LouisJohn F. DiPersio - Washington University in St. LouisWalter J. Akers - MallinckrodtRichard Laforest - MallinckrodtCarolyn J. Anderson - University of PittsburghMichael H. Tomasson - Washington University in St. LouisMonica Shokeen - Mallinckrodt
- Resource Type
- Journal article
- Publication Details
- The Journal of nuclear medicine (1978), Vol.57(4), pp.640-645
- Publisher
- Soc Nuclear Medicine Inc
- DOI
- 10.2967/jnumed.115.164624
- PMID
- 26742713
- PMCID
- PMC4887080
- ISSN
- 0161-5505
- eISSN
- 1535-5667
- Number of pages
- 6
- Grant note
- R01CA176221; U54CA199092; 1R21CA180211 / NIH NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30CA091842 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000448 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) P30AR057235 / NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS)
- Language
- English
- Date published
- 04/01/2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984359773102771
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