Abstract
318
Purpose: Deposition of insoluble amyloid in vital organs is the cause of mortality and morbidity in patients afflicted with systemic amyloidosis. Various experimental therapies are aimed at preventing insoluble amyloid formation, but such treatments generally do not clear existing amyloidosis lesions and therefore do not improve symptoms. However, we and others are testing novel immunotherapy treatments that have been shown to activate phagocytes to clear existing lesions. For example, CAEL-101 is a monoclonal antibody that has been shown to decrease amyloidosis lesions in preclinical models and improve cardiac function in patients with cardiac amyloidosis in early stage clinical studies. Given the longevity of this disease, our objective is to evaluate methods of early response to such immunotherapies that will enable us to evaluate an early efficacy endpoint to expedite early phase clinical trials. We therefore tested standard [18F]FDG-PET and compared it to [68Ga]Granzyme B PET in a preclinical amyloidosis mouse model of phagocyte-mediated immune clearance, which was reported to occur by early infiltration of neutrophils followed by phagocytosis of insoluble fibrils by macrophages (Wall et al. AJP 189:5 989 2019).
Methods: The amyloidosis rejection model was created by subcutaneously implanting λ fibrils in matrigel in BALB/c mice and waiting 3 days for early phagocyte activation. Static PET/CT images were acquired for 30 minutes on in Inveon PET scanner starting 1 hour after administration of PET tracers. Regions of interest were drawn over the amyloidoma and compared to the contralateral side.
Results: [68Ga]Granzyme B PET demonstrated modest uptake in the region of the phagocyte-mediated immune activation, with a target-to-background ratio of 2.7. In contrast, no significant preferential uptake was seen in the same region with [18F]FDG-PET/CT.
Conclusions: Granzyme B PET may provide a valuable tool for early assessment of the phagocyte activation following initiation of phagocyte-mediated immune clearance, which was not seen with [18F]FDG-PET/CT. Support: The PET Center early drug development program is supported by the Columbia Dept. of Radiology and Irving Institute CTSA Translational Therapeutics Accelerator (UL1TR001873).