PT  - JOURNAL ARTICLE
AU  - Rousseau, Julie
AU  - Chan, Patrick Hau Wing
AU  - Merkens, Helen
AU  - Li, Lily
AU  - Bergqvist, Peter
AU  - Colpo, Nadine
AU  - Uribe, Carlos
AU  - Samudio, Ismael
AU  - Orvig, Chris
AU  - Roskelley, Calvin
AU  - McNagny, Kelly
AU  - Lin, Kuo-Shyan
AU  - Benard, Francois
TI  - <strong>First evidence of Podocalyxin as a new target for α-radioimmunotherapy of aggressive solid tumors</strong>
DP  - 2020 May 01
TA  - Journal of Nuclear Medicine
PG  - 1082--1082
VI  - 61
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/61/supplement_1/1082.short
4100  - http://jnm.snmjournals.org/content/61/supplement_1/1082.full
SO  - J Nucl Med2020 May 01; 61
AB  - 1082Introduction: Podocalyxin (PODXL) is a sialoglycoprotein with aberrant overexpression demonstrated in various cancers. PODXL is involved in mobility and invasiveness of tumor cells and thus a promising target to treat advanced cancer and/or metastases by radioimmunotherapy (RIT). PODO447 is a high affinity monoclonal antibody (mAb) that recognizes a highly tumor-specific glyco-epitope of PODXL. The aim of this study was to develop a RIT strategy to treat PODXL expressing tumors using PODO447 labeled with 225Ac. Methods: H4py4pa conjugated PODO447 (H4py4pa:PODO447 reaction molar ratio 3:1) was radiolabeled with 225Ac. 225Ac quantification was based on the measure of the daughters after reaching equilibrium. Radiochemical purity was determined by iTLC-SG chromatography; specific activity by size exclusion chromatography using HPLC and gamma-spectrometry. MIA PaCa-2 cells, which express PODXL and its glycoepitope, were used to evaluate the immunoreactivity. Biodistribution studies were performed at 4, 24, 72, 168 and 240h post-injection (p.i) in MIA PaCa-2 tumor-bearing mice (12.6±0.4 μg, 20.4±0.5 kBq, n=8/group). The maximum tolerated injected activity (MTIA) was determined by monitoring blood cell counts from healthy mice injected with 225Ac-py4pa-PODO447 (2.4, 4.9 and 10.1 kBq, 20 μg, n=8/group). A RIT assay was then performed using the MIA PaCa-2 model as compared to controls injected with either NaCl or an irrelevant 225Ac-py4pa immunoconjugate: 225Ac-py4pa-CT (19.4±2.5 μg, 4.7±0.6 kBq, n=7-8/group). Results: H4py4pa-PODO447 was effectively radiolabeled with 225Ac (radiochemical purity >99%, 0.5-4.1 kBq/μg, immunoreactivity >75%). Significant tumor uptakes, with high tumor to background ratios, were observed 4h and until 72h p.i (14.4±0.9 and 17.0±2.3 %ID/g, respectively), and dropped at Day 7 (9.6±0.9 %ID/g). 225Ac-py4pa-PODO447 showed a dose-dependent hematological toxicity with a MTIA of 4.9 kBq (transient toxicity: 41 and 21% of platelets and leukocytes remaining at nadir, p<0.001 for both, recovery observed at 23 and 42 days p.i respectively). The size of the MIA PaCa-2 tumors treated with 4.9 kBq of 225Ac-py4pa-PODO447 started to decrease as early as 3 days p.i with the maximum effect observed 15 days p.i: 16±7 mm3 (versus 98±32 and 240±140 for the 225Ac-py4pa-CT and NaCl groups respectively, p<0.001 as compared to both control groups). After 15 days, the tumors in the 225Ac-py4pa-PODO447 group began to increase in size and reached their original volume 30 days p.i but remained smaller than the controls (79±65 versus 271±103 and 822±214 mm3 for the 225Ac-py4pa-CT and NaCl treated mice, p<0.001 for both). As compared to control mice that received NaCl, 225Ac-py4pa-PODO447 treated animal showed significantly smaller tumors during the time course of the experiment and an increased survival (67.5 versus 45.5 days, p<0.0001). As compared to the 225Ac-py4pa-CT, the significant effect of 225Ac-py4pa-PODO447 on tumor growth was observed until 46 days p.i and at the end of the experiment similar survival medians were observed. Conclusions: 225Ac-py4pa-PODO447 enabled control of tumor growth in a preclinical α-RIT study using a PODXL-positive cancer model. The use of a fractionated protocol and/or a pre-targeting strategy might decrease toxicity and increase the radiation dose that could be delivered to tumors. This strategy could therefore significantly improve the treatment of aggressive PODXL-expressing cancers.