Session: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Molecular Mechanisms of Myelomagenesis and Its Dependencies
Hematology Disease Topics & Pathways:
Lymphoma (any), Technology and Procedures, imaging
Methods We obtained human amyloid extracts from the heart (κ1), liver (κ1), spleen (λ1) and kidney (λ6). Lyophilized human amyloid extracts were suspended in 25ml of sterile PBS and homogenized for 3 minutes and centrifuged at 12,000g for 30 minutes. 100mg of the resulting pellet was resuspended in sterile saline. Balb/c mice were then injected subcutaneously with amyloid extract. For imaging experiments, cGMP grade CAEL-101 was radiolabeled with 124I, a positron emitting radioisotope used for PET imaging, with the standard iodegen reaction. Approximately 5 days after human amyloid extract was implanted to form subcutaneous amyloidomas, animals were injected with 200μCi of [124I]CAEL-101 and imaged 1 and 4 days post injection using an Inveon microPET scanner. SUVmax for amyloidomas and contralateral background were obtained by drawing regions of interest in the PMOD software package and calculating tumor-to-background (T:B) ratios at 1 and 4 days post tracer infusion.
Results We found that [124I]CAEL-101 successfully imaged 100% of mice bearing human amyloid extracts (κ1, λ1 and λ6 subtypes derived from heart, liver, spleen, and kidney). Human amyloidomas were visualized at both at 1 and 4 days post tracer infusion, with significantly increasing T:B radio by day 4, as expected when imaging large molecular weight antibodies. T:B ratios ranged from 2.1 to 4.2 at 4 days. Mice implanted with κ subtypes demonstrated significantly better in vivo T:B ratios (4.1 +/- 0.20), compared to λ subtypes (2.8 +/- 0.46), although all amyloidomas exhibited T:B uptake > 2.1, which would be clinically significant.
Conclusions We have demonstrated for the first time the potential of using radiolabeled CAEL-101 as a companion diagnostic to image real-time targeting of human amyloidosis in vivo. This is highly translatable due to the fact that CAEL-101 has shown great promise in early stage clinical trials to clear insoluble amyloid plaques. Importantly, we successfully used PET imaging to visualize cardiac derived amyloid fibrils from AL amyloidosis patients. Therefore, we anticipate that dedicated gated cardiac PET/CT imaging of radiolabeled CAEL-101 will be successful at visualizing cardiac amyloid deposits in patients, especially with the rich blood flow in cardiac tissue and newer generation highly sensitive, high resolution digital PET scanners, in contrast to the non-cardiac optimized whole body scans used in prior studies with antibody-based PET. Given that we were able to image 100% of implanted human amyloidomas derived from heart, spleen, liver and kidney consisting of both κ and λ subtypes, we envision using CAEL-101 PET imaging to (1) diagnose systemic amyloidosis, (2) stratify patients for CAEL-101 immunotherapy, and (3) quantify peripheral organ amyloid fibril deposition pre and post anti-amyloid therapy.
Disclosures: Solomon: Caelum Biosciences: Consultancy, Equity Ownership. Lentzsch: Bayer: Consultancy; BMS: Consultancy; Janssen: Consultancy; Caelum Biosciences: Consultancy, Other: Dr. Lentzsch recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017., Patents & Royalties: Shareholder for Caelum Biosiences. Mintz: Caelum Biosciences: Research Funding.
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