DNA-Dependent Protein Kinase Inhibitor Peposertib Enhances Efficacy of¹⁷⁷Lu-Based Radioimmunotherapy in Preclinical Models of Prostate and Renal Cell Carcinoma

Article

作者: Osellame, Laura D ; Sirrenberg, Christian ; Guo, Nancy ; Zimmermann, Astrid ; Rigopoulos, Angela ; Zenke, Frank T ; Scott, Fiona E ; Burvenich, Ingrid J G ; Wheatcroft, Michael P ; Cao, Zhipeng ; Johnstone, Cameron N ; Ivashkevich, Alesia N ; Wichmann, Christian W ; Scott, Andrew M ; McDonald, Alexander F ; Yan, Edwin B

Novel radiation sensitizers, including inhibitors targeting DNA damage response, have been developed to enhance the efficacy of anticancer treatments that induce DNA damage in cancer cells. Peposertib, a potent, selective, and orally administered inhibitor of DNA-dependent protein kinase, impedes the nonhomologous end-joining mechanism for DNA double-strand break (DSB) repair. We investigated radioimmunotherapy alone or with peposertib in preclinical models of renal cell carcinoma (RCC) or prostate cancer. Methods: ¹⁷⁷Lu-DOTA-girentuximab (targeting carbonic anhydrase IX) or ¹⁷⁷Lu-DOTA-rosopatamab (targeting prostate-specific membrane antigen) was used to deliver β-radiation to tumors via a single intravenous dose (3 or 6 MBq) in mice bearing SK-RC-52 RCC or LNCaP prostate cancer xenografts, respectively. Peposertib (50 mg/kg daily for 14 d) was administered via oral gavage. Biodistribution and in vivo imaging of ¹⁷⁷Lu-based radioimmunotherapy were performed for both preclinical models. Tumor growth and body weight were monitored until the endpoint. Assessment of DNA damage was performed by measuring DSBs through analysis of γH2AX foci formation in tumor sections. Results: Ex vivo biodistribution and in vivo SPECT/MRI revealed excellent tumor uptake of each radiopharmaceutical. Mouse body weight was stable in all treatment arms. Peposertib alone did not show a significant antitumor effect. The addition of peposertib to ¹⁷⁷Lu-DOTA-girentuximab showed enhanced antitumor efficacy compared with ¹⁷⁷Lu-DOTA-girentuximab alone in the SK-RC-52 animal model, with a 4 of 4 complete response rate in the ¹⁷⁷Lu-DOTA-girentuximab (6 MBq) plus peposertib arm. Peposertib combined with low-dose ¹⁷⁷Lu-DOTA-girentuximab (3 MBq) demonstrated antitumor activity comparable to ¹⁷⁷Lu-DOTA-girentuximab (6 MBq) monotherapy. In the LNCaP prostate cancer model, the combination of ¹⁷⁷Lu-DOTA-rosopatamab (6 MBq) and peposertib achieved a 3 of 4 complete response rate. Increased DSBs were observed with the addition of peposertib to ¹⁷⁷Lu-based radioimmunotherapy. Conclusion: The combination of peposertib with ¹⁷⁷Lu-based radioimmunotherapy was well tolerated in preclinical models of RCC and prostate cancer. Our findings suggest a synergistic effect between peposertib and ¹⁷⁷Lu-based radioimmunotherapy, wherein peposertib enhanced the efficacy of radioimmunotherapy. This synergy indicates the potential to reduce the necessary dose of radioimmunotherapy for effective cancer treatment.

2025-02-10·Journal of Clinical Oncology

CUPID ( ⁶⁴ Cu-TLX592 phase I PK, biodistribution and dosimetry): A proof-of-concept study of TLX592-targeted alpha therapy in prostate cancer.

作者: Cade, David ; Cardaci, Giuseppe ; Wheatcroft, Michael ; Patel, Neel ; Capp, Anne ; Lenzo, Nat ; Singh, Aviral

177Background: Antibody-based PSMA-targeting therapies have potential to overcome limitations of small molecule approaches such as undesirable off-target side effects. TLX592 utilizes RADmAb technology engineered to optimize clearance rates while retaining advantages of antibody-based approaches including high target selectivity & rapid internalization. 225 Ac is a high energy emitter with a short path length. 225 Ac-PSMA-RADmAb is a "next generation" targeted alpha therapy for patients with prostate cancer (PC) who progress after 177 Lu-based therapy. We report preliminary results from an open-label, first-in-human mass dose escalation study of TLX592 in patients with advanced PC. To demonstrate proof-of-targeting, copper-64 ( 64 Cu), detectable by PET, was used as a surrogate for 225 Ac. Methods: 11 patients with PC confirmed with PSMA imaging as either oligometastatic (≤5 metastatic lesions; Groups 1-3, dose escalation) or higher tumor burden (≥10 metastatic lesions; Group 4) were assigned to the following: 1) 300 MBq, 2mg 64 Cu-TLX592 (n=3); 2) 300 MBq, 2mg 64 Cu-TLX592+8mg unlabeled TLX592 (10mg mass dose; n=3); 3) 300 MBq, 2mg 64 Cu-TLX592+18mg unlabeled TLX592 (20mg mass dose; n=2); or 4) 300 MBq, 2mg 64 Cu-TLX592+18mg unlabeled TLX592 (20mg mass dose, based on dose escalation results; n=3). PET/CT scans were performed 1h±5, 4±0.5h, & 20±4h after infusion for Groups 1-3 & 4h±0.5h, 20±3h & 48±4h after infusion for Group 4. Blood samples were collected before each imaging period, & vital signs were collected before infusion, after infusion, 1h after infusion, & prior to each imaging period. The primary endpoint was tumor-to-healthy tissue SUV & residence times. Secondary endpoints included safety assessments & absorbed radiation doses. Results: TLX592 blood clearance was more rapid than TLX591 (T ½ =19.86+1.96, T ½ =33.65+11.04h, resp.) with similar organ uptake. TLX592 circulating levels increased with mass dose. Whole-body effective dose (mean±SD mSv/MBq) was 0.043±0.007 & 0.042±0.002 in Groups 3 & 4, resp. Residence times for Groups 3 & 4 are shown (Table). At 20h, TLX592 uptake in bone lesions in Group 4 correlated with 68 Ga-PSMA-11 uptake (r=.756, P =.003). No serious adverse events were observed. Conclusions: Preliminary results demonstrate successful proof-of-concept of RADmAb technology, intended for use with therapeutic alpha-emitting radionuclides. Rapid antibody clearance has potential to minimize radiation exposure & augment the safety & tolerability profile of antibody-based therapies. Clinical trial information: NCT04726033 . Residence times (mean±SD) MBq.hr.MBq -1 . Source OrganGroup 3Group 4Kidneys0.305±0.0590.370±0.064Liver5.440±1.1885.443±0.771Lungs0.890±0.1391.227±0.184Salivary glands0.005±0.0010.006±0.003Bone/red marrow0.576±0.4240.513±0.218Spleen0.444±0.1040.470±0.201Remainder of body7.615±0.0499.990±0.448

2025-02-10·Journal of Clinical Oncology

ProstACT GLOBAL: A phase 3 study of ¹⁷⁷ Lu-rosopatamab (TLX591) with and without the best standard of care for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug.

作者: Lenzo, Nat ; Sartor, Alton Oliver ; Cade, David ; Agarwal, Neeraj ; Tagawa, Scott T.

TPS303Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the 177 Lu-labeled, chelator-conjugated antibody, 177 Lu-rosopatamab, as a potential first-line RIT candidate for the treatment of PC. Methods: This multinational, multicenter, prospective, randomized, open label phase 3 study will have 2 parts: a dosimetry and safety lead-in (n=30) and a randomized treatment expansion (n=490). In Part 1, patients will be divided into 3 groups (n=10 each) to receive 2 single intravenous (IV) injections of 76 millicuries (mCi) each, 14 days apart, of 177 Lu-rosopatamab with best standard of care (SoC) combinations with abiraterone, enzalutamide, or docetaxel to fully characterize biodistribution and safety profiles of 177 Lu-DOTA-rosopatamab + SoC combinations. SoC received will be determined prior to treatment with 177 Lu-rosopatamab. In Part 2, patients will be enrolled in a 2:1 ratio to receive either the best SoC or 2 single IV injections of 76 mCi each (equivalent to a 45 mCi/m 2 dose in a standard 1.7m 2 individual) of 177 Lu-rosopatamab, given 14 days apart, plus best SoC. SoC will be determined prior to randomization, and a change in planned SoC will not be permitted. Eligible patients must have PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x10 9 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68 Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Key secondary endpoint is OS. Additional secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, and health-related quality of life. Clinical trial information: NCT04876651 .

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2024-06-06

·FiercePharma

France's Orano Med debuts radiotherapy manufacturing plant near Indianapolis

The Indianapolis buildout follows Orano Med’s decision to start work on a similar facility in Valenciennes, France, to serve the European market. Amid a nuclear medicine boom, France’s Orano Med has chosen the U.S. to establish a manufacturing plant as it progresses on its radiopharma journey. Orano Med—which is working on targeted alpha therapies for cancer—on Thursday inaugurated its first Alpha Therapy Laboratory (ATLab) in Brownsburg near Indianapolis, Indiana. The site marks the world’s first industrial-scale facility dedicated to production of lead-212-based radioligand therapies, according to the company. Radiopharmaceuticals are guided radioactive drugs that can help diagnose diseases in smaller amounts and can treat cancers and other conditions in higher quantities. Unlike current approved beta-emitting-isotope-based radiotherapies like Novartis’ Pluvicto and Lutathera, Orano Med’s approach leverages the alpha-emitting isotope lead-212. Traditionally, radiotherapies have utilized beta particles because beta emitters were more easily available, Julien Dodet, CEO and president of Orano Med, said via email. That said, the Orano CEO figures using alpha particles can help boost the effectiveness of drug prospects. Orano Med has invested $20 million into ATLab Indianapolis, which it says will cover 30,000 square feet of floor space and create 25 new jobs within the company. The Indianapolis buildout follows Orano Med’s decision to start work on a similar facility in Valenciennes, France, to serve the European market. Together, the facilities are expected to allow Orano Med to crank out 10,000 radiopharma doses per year across the globe by 2025. The company aims to be able to produce 100,000 doses by 2030, according to its press release. Orano Med—a subsidiary of the nuclear materials leader Orano—is a clinical-stage biotech working to developing lead-212-based radiotherapies against cancer. Orano Med CEO Dodet noted that it’s important for radioligand therapy developers to hash out manufacturing and supply early given that radiotherapies must be produced “just-in-time” to be delivered to patients, thanks to the short half-life of isotopes. Despite the growing demand for radiopharmaceuticals—and especially for alpha emitters—existing manufacturing facilities are aging, with many relying on radioisotopes derived from Cold War-era sources or purchased from the U.S. Department of Energy, “which cannot keep up with demand," the CEO added. Radiopharmaceuticals have recently garnered significant interest among oncology-focused companies, with Novartis continuing to lead the charge. While Novartis already markets two FDA-approved radiotherapies, the company showed its continued interest in the field with its recent purchase of Mariana Oncology for up to $1.75 billion. As for its approved radiotherapies, Pluvicto and Lutathera generated a combined $1.6 billion last year. Manufacturers and suppliers have been getting in on the action too, such as CDMO Nucleus RadioPharma, which recently inked its first commercial contract to help manufacture ARTBIO’s Pb212-radiolabeled therapies from its facility in Rochester, Minnesota.