actinium Actinium Pharmaceuticals, Inc. Employment.
Abstract
Introduction: In 2024, an estimated 299,010 new prostate cancer (PCa) cases will be diagnosed in the US, with 35,250 deaths. While PCa initially responds to androgen deprivation therapy (ADT), it often progresses to metastatic castration-resistant prostate cancer (mCRPC), a challenging condition with limited treatment options. Targeted radiotherapies like Pluvicto, a beta-emitting treatment targeting prostate-specific membrane antigen (PSMA), have shown promise but face limitations due to radiation properties and variability in PSMA expression. mCRPC is driven by persistent androgen receptor signaling and other pathways, often mediated by overexpressed cell surface receptors. We designed ATNM-400 against a target highly expressed in mCRPC that has been previously targeted with naked antibodies or antibody drug conjugates but have been ineffective clinically. Here, we tested ATNM-400, a first-in-class actinium-225 (Ac-225) antibody radioconjugate (ARC) in preclinical models of PCa with the hypothesis that targeted delivery of an alpha-emitter would offer stronger therapeutic potential than existing therapies to address a critical unmet need in mCRPC patients.
Methods: ATNM-400 was synthesized by conjugating ATNM400 antibody with p-SCN-Bn-DOTA, followed by radiolabeling with Ac-225. Binding affinity and internalization in PCa cell lines were evaluated using flow cytometry and radioactivity measurement. The biodistribution (BioD), pharmacokinetics (PK), and efficacy of ATNM-400 were tested in preclinical mouse models using 22Rv1 and DU145 PCa cell lines. The potential to overcome Pluvicto resistance in mCRPC was also studied both in vitro and in vivo.
Results: ATNM-400 demonstrated over 98% radiochemical purity and rapid internalization into PCa cells. Treatment of PCa cells with ATNM-400 demonstrated potent cytotoxic effects in a dose-dependent manner. In vivo BioD and PK studies in PCa models showed that ATNM-400 accumulated in tumors for up to 144 hours, with minimal accumulation in normal organs. Small animal SPECT/CT images in mouse xenograft models of PCa showed that Indium-111 radiolabeled ATNM400 selectively accumulated in tumors and cleared from healthy tissues. The radiation dose to organs, extrapolated from mouse dosimetry, suggested an acceptable safety profile. In vivo studies in multiple PCa models (22RV1 and DU145) using a single-dose of ATNM-400, showed a potent tumor growth
7 yrs ago
Under the terms of the agreement, Novartis would acquire all outstanding shares of Endocyte common stock for USD 24 per share. This offer values Endocyte's equity at USD 2.1 billion.Oct 18, 2018
novartis.com
Great potential wth cd33 radioligand targeting cd33 aml plus cd33 immusupressor cells. Market potential will be huge if successful in human trial.
Recent deals in the radioligand therapy space include Novartis's acquisition of Mariana Oncology for $1 billion and a licensing agreement with Ratio Therapeutics for a potential $745 million, while Sanofi entered the market with a $110 million deal with RadioMedix and Orano Med for a late-stage radioligand therapy. |
