前列腺癌
医学
耐受性
LNCaP公司
癌症
药理学
谷氨酸羧肽酶Ⅱ
联合疗法
放射免疫疗法
体内分布
癌症研究
内科学
化学
体外
免疫学
抗体
单克隆抗体
不利影响
生物化学
作者
Christoph A. Schatz,Sabine Zitzmann-Kolbe,Ingrid Moen,Monika Klotz,Shankari Nair,Stefan Stargard,Roger M. Bjerke,Katrine Wickstrøm Biseth,Yuan Zeng. Feng,Bård Indrevoll,Véronique Cruciani,Jenny Karlsson,Bernard Haendler,Carsten H. Nielsen,Maria Z. Alfsen,Stefanie Hammer,Hartwig Hennekes,Alan S. Cuthbertson,Urs B. Hagemann,A Dawson Larsen
标识
DOI:10.1158/1078-0432.ccr-23-3746
摘要
Initially, prostate cancer responds to hormone therapy but eventually resistance develops. Beta emitter-based PSMA (prostate-specific membrane antigen)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs.The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide.Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi) (all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models.These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase 1 study has been initiated (NCT06052306).
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