TARGETING CA19.9 FOR RADIOIMMUNOTHERAPY AND THERAPEUTIC MONITORING IN PANCREATIC CANCER Lanning RM1,2, Houghton J2, Abdel-Atti D2, Gupta S2, Sawada R3, Scholz WW3, and Lewis JS2 of Radiation Oncology; 2Dept of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY; 3Mabvax Therapeutics, San Diego, CA
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RESULTS (continued)
Fig 2: In vivo pre-clinical RIT at multiple doses matched for equivalent tumor absorbed dose between 90Y and 177Lu constructs. Treatments at all doses exhibited significant growth delay. N = 8 each group.
In vivo Biodistribution
Fig 1
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Radioimmunotherapy Dose Selection
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Control (PBS) 5B1 (mass balanced) 177Lu-CHX-A"-DTPA-5B1 (75 µCi) 177Lu-CHX-A"-DTPA-5B1 (450 µCi) 90Y-CHX-A"-DTPA-5B1 (25 µCi) 90Y-CHX-A"-DTPA-5B1 (250 µCi)
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Fig 1: DOTA constructs - uptake for the 90Y-DOTA-5B1 and 177Lu-DOTA-5B1 were 79±6 & 77±27 and 23±6 & 38±14 %ID/g, respectively at 48 and 120h. N = 5 for each group
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RESEARCH POSTER PRESENTATION DESIGN © 2012
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Fig 2
89Zr-DFO-5B1
Uptake at Day 40 after RIT 177Lu
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Control (PBS) Gemcitabine 177Lu-CHX-A"-DTPA-5B1 (150 µCi) 177Lu-CHX-A"-DTPA-5B1 (150 µCi) + GEM 90Y-CHX-A"-DTPA-5B1 (50 µCi) 90Y-CHX-A"-DTPA-5B1 (50 µCi) + GEM
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Fig 4 Fig 3 & 4: 89Zr-DFO-5B1 PET imaging on day 60 posttherapy – uptake in treated and control tumors. PostPET necropsy - ↑ tumor uptake for all the treated mice versus the controls. N = 4 each group.
Fig 5 & 6: 177Lu-CHX-A”-5B1 radioimmunotherapy (300 µCi) in mice bearing BxPC3-luciferase tumors. T2-weighted MRI demonstrated significant growth delay with RIT. Bioluminescence also significantly decreased. Post-therapy necropsy in treated mice showed minimal residual tumor. N = 8 (RIT) and N = 6 (control). * - significantly different.
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Radioimmunotherapy scaffolds targeting CA19.9 in preclinical models demonstrate significant tumor cytotoxicity with either 90Y or 177Lu Tumor selectivity of 5B1 constructs remained elevated over controls at the completion of therapy Radiolabeled constructs targeted to CA19.9 prove versatile in both delivering and monitoring therapy
REFERENCES 1. Viola-Villegas NT et al. Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology. J Nucl Med. 54:1876-82 (2013).
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CONCLUSIONS
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RADIOIMMUNOTHERAPY IN ORTHOTOPIC PANCREATIC CANCER
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• Tumor uptake of 5B1 measured at completion of RIT using 89Zr-DFO5B1 and positron emission tomography (PET). • RIT performed in an orthotopic BxPC3-luciferase expressing murine PCa model with MRI anatomical imaging and bioluminescence signal measured to assess tumor response.
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RADIOIMMUNOTHERAPY RESPONSE 89 BY Zr-5B1 PET
Tumor Volume (mm )
Therapy Schema
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Fig 3
• Radiochemical conjugate yields >65% and after column purification >95% • CHX-A”-DPTA-5B1 constructs demonstrated significantly better IR than the DOTA-5B1 constructs (95.3% vs 85.6%, P<0.001). • DTPA-5B1 constructs showed excellent tumor localization at 48 and 120 hours post-injection. • Combined therapy with RIT and gemcitabine did not show significant synergism at select doses (Fig 7). Radioimmunotherapy - Combination Therapy
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METHODS • 5B1 antibody functionalized with DOTA or CHX-A”-DTPA and chelated to either 90Y or 177Lu. • Immunoreactivity (IR) for each radioconjugate determined by a cell binding assay in CA19.9(+) human BxPC3 PCa cells. • Biodistribution studies performed in nude mice bearing BxPC3 PCa ectopic xenografts. • Radioimmunotherapy initiated in tumor bearing mice at a tumor volume of ~100mm3. • Preclinical RIT studies performed at different doses and in combination with gemcitabine.
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Outcomes for locally advanced or metastatic pancreatic cancer (PCa) are dismal with survival measured in months. Treatment options are limited to systemic chemotherapy and radiation therapy, which only modestly improve survival. There is an unmet need for new therapies and diagnostic imaging modalities. We adapted 5B1, an anti-CA19.9 human antibody which showed exquisite tumor uptake in PET studies1, to serve as a radioimmunotherapy (RIT) construct.
RESULTS
Normalized Tumor Volume
OBJECTIVE
Normalized Tumor Volume
1Dept
CONTACT / FUNDING For questions or comments, please contact Ryan Lanning at
[email protected], or Jason Lewis at
[email protected] Funding: NIH grants P30 CA08748, F32CA180452-01A1, 5R25CA096945-09, 2R42CA128362 and HHSN261201300060C
P400
