1. Introduction and Objectives
Real-Time PET Imaging with Amyloid Fibril-Reactive Antibody CAEL-101 for Personalized AL Amyloidosis Immunotherapy Jing Fu, PhD1, Nikunj Bhatt, PhD2, Jongho Kim, MD, PhD2, John Castrillon2, Patrick Carberry, PhD2, Andrei Molotkov, MD, PhD2, Vaishali Sanchorawala, MD3, Lawreen Connors, PhD3, Suzanne Lentzsch, MD, PhD1, Akiva Mintz, MD, PhD2, 1Department of Medicine and 2Radiology, Columbia University Medical Center, New York, United States
3Amyloidosis Center, Boston University School of Medicine
Results
Conclusion
Introduction and Objectives
[124I]CAEL-101 PET imaged 100% of amyloidomas regardless of the subtype. κ subtype amyloidomas demonstrated significantly better in vivo binding compared to λ subtypes (TBR of 6 vs. 2) at day 4. We observed significantly increased TBR on day 4 vs. day 1. However, on the day 7, only the lower binding λ subtype amyloidomas demonstrated improved uptake compared to day 4 (TBR of 6 from 2). In contrast, the high binder κ subtypes demonstrated a dramatic decrease in TBR on day 7 and no longer demonstrated significant activity.
We have demonstrated for the first time the potential of [89Zr]CAEL-101 as a companion diagnostic to image real-time targeting of human amyloidosis. This is highly translatable due to the fact that CAEL-101 has shown great promise in an early stage clinical trial. We demonstrated that [89Zr]CAEL-101 has significantly better binding characteristics than [124I]CAEL-101 both in terms of TBR and in vivo stability. Interestingly, we found that dehalogenation of [124I]CAEL-101 occurred preferentially at the binding site, as only the low binding amyloidmas with significant residual plasma activity continued to increase their TBR on day 7 but the higher binder amyloidomas peaked on day 4 and showed significantly decreased TBR on day 7. This has translational significance because a previously reported clinical PET study with the 124I labeled murine analogue of CAEL-101 demonstrated limited sensitivity to image cardiac fibril deposition. Based on our results, this is likely due to the lower sensitivity of 124I compared to 89Zr and poor on-target stability, which prevented later imaging after day 4 to allow adjacent blood pool clearance. Thus our results are translationally significant as we demonstrate that [89Zr]CAEL-101 has 3x better TBR than [124I]CAEL-101, can be imaged up to 14 days post injection and has the potential to image cardiac amyloid fibrils.
AL amyloidosis is the most common type of systemic amyloidosis in the U.S. Mortality is high due to insoluble amyloid fibril deposits that are not cleared by current therapies. The murine monoclonal antibody 11-1F4 mAb targets amyloid deposits by binding to a conformational epitope in human light-chain amyloid fibrils. 11-1F4 mAb has demonstrated potential to clear insoluble human amyloidosis fibrils in mice, but its translation has been limited as a murine antibody. Therefore, CAEL-101, a chimeric form of 11-1F4 mAb was produced. We validated in vivo binding of CAEL-101 by radiolabeling it with 124I and demonstrating via PET the targeting of subcutaneous murine amyloidomas derived from human amyloid extracts. Furthermore, we recently demonstrated the therapeutic potential of CAEL-101 immunotherapy in an early phase clinical trial with 67% of patients showing significant organ response, including improvement of the global longitudinal strain in patients with cardiac amyloidosis. The overall goal of our work is to establish an optimal CAEL-101 PET probe as a translational biomarker for the diagnosis and stratification of patients with systemic amyloidosis.
[124I]CAEL-101 Target-To-Background Ratio (Mean)
To overcome this shortcoming, we tested the imaging properties of [89Zr]CAEL-101 as a translational PET agent. We found that it retained its immunoreactivity with superior TBR compared to [124I]CAEL-101 (18:1 vs 6:1). Furthermore, we found an actual increased TBR at day 7 in the high binding κ subtype after [89Zr]CAEL-101 injection, in contrast to the significant decrease seen with [124I]CAEL-101. Importantly, we still observed significant amyloidoma PET signal on day 14 post injection of [89Zr]CAEL-101.
References
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Wall, SJ et al. J Nucl Med :
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Fu J, et al, Blood 132 (S) 1003
Courtesy of Jonathan Wall
[89Zr]CAEL-101 PET/CT
Methods
Acknowledgements
We formed subcutaneous murine amyloidmas derived from human amyloid extracts of the heart, liver, spleen and kidney. Following amyloidoma engraftment, animals were injected with ~100μCi of [124I]CAEL-101 or [89Zr]CAEL-101 and imaged up to 14 days post injection using an Inveon PET. Target:background ratio (TBR) was calculated using SUVmean of amyloidomas and contralateral background.
This research was sponsored by Caelum Biosciences. This work was supported by the Translational Therapeutics Accelerator of the Columbia University Irving Institute CTSA (NCATS UL1TR001873; Reilly)
Day 1
Day 4
Day 7
Poster SP-190