Abstract 6024: A novel carbonic anhydrase IX targeting radiopeptide, 64Cu-PD-32766 and 177Lu-PD-32766, exhibit promising theranostic potential in ccRCC tumors

癌症研究 医学 化学
作者
Yoshihide Mizukoshi,Shota Tsuchida,Hiroko Inaba,Tatsuro Kotake,Takanori Aoki,Kai Orihara,Yuichi Funase,Naoki Kanazawa,Hikaru Shimizu,Kaita Sawano,Kentaro Suzuki,Hayato Yanagida,Takeru Ehara,Hidetomo Kitamura,Satoshi Matsushima,Masato Murakami
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:84 (6_Supplement): 6024-6024
标识
DOI:10.1158/1538-7445.am2024-6024
摘要

Abstract Introduction: Carbonic Anhydrase IX (CA9) is a zinc metalloenzyme that regulates the pH for cell growth. CA9 is considered an attractive target and is upregulated in a variety of cancers, especially, in 95% of clear cell renal cell carcinoma (ccRCC) where there remains a large clinical unmet need despite the availability of several newly approved medicines. PeptiDream has identified PD-32766, a novel macrocyclic peptide, targeting CA9 and can be labeled with radionuclides such as copper (64Cu) and lutetium (177Lu), which enables tumor-specific PET bioimaging and radiotherapy. Here we report the theranostic translational feasibility of PD-32766 for ccRCC. Materials and Methods: PD-32766 was discovered using Peptide Discovery Platform System (PDPS), a proprietary screening system of PeptiDream. Binding affinity of PD-32766, 63Cu-PD-32766 and 175Lu-PD-32766 to CA9 was measured by SPR. For in vivo evaluation, we used a xenograft model in which VMRC-RCW (ccRCC cell line with similar CA9 expression level to clinical samples) was subcutaneously transplanted into nude mice. To assess biodistribution, 64Cu-PD-32766 or 177Lu-PD-32766 was dosed to VMRC-RCW xenograft mice, and the percentage of injected dose in tumors and major organs was quantified by cut and count method. To evaluate whether PET imaging can detect tumors, 64Cu-PD-32766 was dosed to VMRC-RCW xenograft mice and after dosing, PET scanning was performed. For therapeutic experiments, 177Lu-PD-32766 was dosed to VMRC-RCW xenograft mice and tumor volume was measured for 45 days after dosing. Results: SPR analysis revealed that PD-32766, 63Cu-PD-32766 and 175Lu-PD-32766 exhibits an affinity of less than 0.2 nM for CA9. In in vivo biodistribution experiment, 64Cu-PD-32766 and 177Lu-PD-32766 showed specific and strong accumulation in tumors 4 hours after dosing (88 and 107% ID/g, for 64Cu-PD-32766 and 177Lu-PD-32766, respectively) and were highly retained in the tumors at 48 hours after dosing (37 and 51% ID/g, for 64Cu-PD-32766 and 177Lu-PD-32766, respectively). Maximal intensity in other normal tissues were 23 and 9 %ID/g (tumor/kidney=3.8 and 11.9 for 64Cu-PD-32766 and 177Lu-PD-32766, respectively at 4 hrs.). PET bioimaging of 64Cu-PD-32766 clearly detected only tumors, consistent with the biodistribution data. In therapeutic experiments, 177Lu-PD-32766 (30 MBq/mouse single or QW x3) was well tolerated and strikingly improved mouse survival compared with control animals for 45 days after transplantation, which suggests a robust tumor growth inhibition of 177Lu-PD-32766 dosing. Taken together, PD-32766 showed specific tumor accumulation and strong therapeutic effect in a clinically relevant xenograft model of ccRCC. Conclusion: PD-32766 has preferable properties for imaging and therapy with radionuclides and a great potential for theranostic use in ccRCC. Citation Format: Yoshihide Mizukoshi, Shota Tsuchida, Hiroko Inaba, Tatsuro Kotake, Takanori Aoki, Kai Orihara, Yuichi Funase, Naoki Kanazawa, Hikaru Shimizu, Kaita Sawano, Kentaro Suzuki, Hayato Yanagida, Takeru Ehara, Hidetomo Kitamura, Satoshi Matsushima, Masato Murakami. A novel carbonic anhydrase IX targeting radiopeptide, 64Cu-PD-32766 and 177Lu-PD-32766, exhibit promising theranostic potential in ccRCC tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6024.
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