A Multicenter, Randomized, Controlled Phase 2 Study: Efficacy and Safety of I-131-1095 Radiotherapy in Combination With Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Who Are 18F-DCFPyL Prostate-specific Membrane Antigen (PSMA)-Avid, Chemotherapy-naive, and Progressed on Abiraterone

This is a multicenter, randomized, controlled, phase 2 clinical trial designed to evaluate the safety and efficacy of I-131-1095 radiotherapy in combination with enzalutamide compared to enzalutamide alone in participants with prostate-specific membrane antigen (PSMA)-avid metastatic castration resistant prostate cancer (mCRPC) who have progressed on abiraterone. Participants must be chemotherapy-naive and must be ineligible or refuse to receive taxane-based chemotherapy at time of study entry. PSMA-avidity will be determined by central imaging review based on assessment of 18F-DCFPyL PET/CT imaging during screening. Eligible participants meeting the PSMA-avidity criteria will be randomized in a 2:1 ratio to receive either I-131-1095 in combination with enzalutamide (80 participants) or enzalutamide alone (40 participants). An interim analysis for efficacy will be performed after a minimum of 48 evaluable participants have PSA data for at least three months following the first dose of randomized treatment.
All participants will be followed for efficacy, safety assessments, survival status, adverse events of special interest, and new anti-cancer therapy for at least one year or to the end of the study (whichever is later) following the first dose of randomized treatment. Safety data will be monitored by an independent Data Monitoring Committee and the sponsor.

开始日期2019-05-30

申办/合作机构

Progenics Pharmaceuticals, Inc.

NCT03030885 / Completed临床1期IIT

A Phase 1, Open-Label, Dose Ascending Study to Evaluate the Safety and Tolerability of the Therapeutic Radiopharmaceutical 131I-MIP-1095 for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

The main purpose of this study to determine the safety of an experimental medicine called 131I-MIP-1095. 131I-MIP-1095 is an investigational drug, meaning it has not been approved by the U.S. Food & Drug Administration (FDA).

开始日期2017-01-19

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

NCT00712829 / Completed临床1期

A Phase I Study Evaluating the Safety, Pharmacokinetics, Tissue Distribution, Metabolism of Small Molecule Inhibitors of Prostate Specific Membrane Antigen: Determination of I-123 Radiation Dosimetry for 123-I-MIP-1072 and 123-I-MIP-1095

This is a single blinded, randomized, cross-over design. Up to 12 patients will be randomly administered a single 10.0 mCi dose of 123I-MIP-1072 or 123I-MIP-1095 (study drugs). The second (alternate) study drug will be administered approximately 14 days after the first. A final follow-up visit will occur approximately 2 weeks after the injection of the alternate study drug.

开始日期2008-05-01

申办/合作机构

Molecular Insight Pharmaceuticals, Inc.

100 项与 131I-MIP-1095 相关的临床结果

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100 项与 131I-MIP-1095 相关的转化医学

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100 项与 131I-MIP-1095 相关的专利（医药）

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项与 131I-MIP-1095 相关的文献（医药）

2024-08-01·Nuclear Medicine Communications

A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer

Article

作者: Liu, Richard F. ; Mamo, Aline ; Ferrario, Cristiano ; Labidi, Soumaya ; Probst, Stephan M. ; Rose, April A.N. ; Fallah, Parvaneh

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment.MethodsWe conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed.ResultsEleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia.Conclusion131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.

2023-11-01·Clinical Nuclear Medicine

A Phase 1, Open-label, Dose-Ascending Study to Evaluate the Safety and Tolerability of the Therapeutic Radiopharmaceutical 131I-MIP-1095 for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Article

作者: O'Donoghue, Joseph A ; Weber, Wolfgang A ; Bodei, Lisa ; Laccetti, Andrew L ; Morris, Michael J

Purpose131I-MIP-1095 is a targeted radiotherapeutic that contains 131I, a β-particle emitter, and MIP-1095, a urea-based ligand for prostate-specific membrane antigen. We report the first phase 1, dose-escalation study of 131I-MIP-1095 in patients with metastatic castration-resistant prostate cancer (mCRPC).MethodsThis study enrolled men with mCRPC refractory to second-generation antiandrogen(s) and taxane chemotherapy. Dosimetry/biodistribution assessments were performed. Safety and tolerability were determined in subjects who qualified for therapeutic administration of 131I-MIP-1095 with maximum tolerated activity examined in a dose-ascending manner (3 + 3 design methodology). Disease outcomes including prostate-specific antigen (PSA) change, tumor response, survival, and circulating tumor cell concentration were assessed.ResultsA total of 9 subjects with mCRPC were included in this study. On the basis of dosimetry results, 5 of 9 patients were treated: 3 in cohort 1 (50 mCi) and 2 in cohort 2 (75 mCi). Accrual stopped at the cohort 2 activity level in response to the US Food and Drug Administration mandate for 131I-MIP-1095 manufacturing concerns. Parotid/salivary glands (3.5 Gy/Bq), liver (2.2 Gy/Bq), kidneys (1.3 Gy/Bq), and spleen (0.7 Gy/Bq) demonstrated the greatest extent of 131I-MIP-1095 exposure. There were no deaths, serious adverse events, or drug discontinuations due to treatment-emergent adverse events. Grade 1–2 thrombocytopenia, anemia, leukopenia, and dry mouth most commonly occurred. One subject (33.3%) exhibited maximum decline for the PSA response of 50% or greater.Conclusion131I-MIP-1095 demonstrated favorable dosimetry, biodistribution, and safety, as well as a modest PSA response supporting further investigation for treatment of men with mCRPC.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03030885, Registered January 25, 2017 (https://clinicaltrials.gov/ct2/show/NCT03030885).

2020-03-01·Bioorganic & Medicinal Chemistry

Synthesis and evaluation of novel radioiodinated PSMA targeting ligands for potential radiotherapy of prostate cancer

Article

作者: Zhao, Ruiyue ; Alexoff, David ; Zha, Zhihao ; Ploessl, Karl ; Zhu, Lin ; Choi, Seok Rye ; Kung, Hank F ; Yao, Xinyue

Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l-tyrosine and l-glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with ¹²⁵I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC₅₀ = 1-13 nM). In vitro cell uptake studies demonstrated that compounds containing an l-tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l-tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [¹²⁵I]8 and [¹²⁵I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [¹²⁵I]19a/19b and [¹²⁵I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [¹²⁵I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2-3-fold lower uptake in the liver and blood than that observed for [¹²⁵I]MIP-1095. [^125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.

项与 131I-MIP-1095 相关的新闻（医药）

2024-10-10

·PRNewswire

Metastatic Castration-Resistant Prostate Cancer Clinical Trial Pipeline Appears Robust With 90+ Key Pharma Companies Actively Working in the Therapeutics Segment | DelveInsight

Metastatic Castration-Resistant Prostate Cancer (mCRPC) refers to prostate cancer that has spread (metastasized) to other parts of the body and continues to progress despite treatments that lower testosterone levels (androgen deprivation therapy or ADT) major pharmaceutical companies are heavily investing in research and development of new treatments, including immunotherapy (e.g., sipuleucel-T) and targeted therapies, which are seen as the next frontier in treating mCRPC. The use of precision medicine to identify genetic profiles in patients has further expanded the potential for targeted treatment. LAS VEGAS , Oct. 10, 2024 /PRNewswire/ -- DelveInsight's ' Metastatic Castration-Resistant Prostate Cancer Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mCRPC therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mCRPC pipeline domain. Key Takeaways from the Metastatic Castration-Resistant Prostate Cancer Pipeline Report DelveInsight's mCRPC pipeline report depicts a robust space with 90+ active players working to develop 100+ pipeline therapies for mCRPC treatment. Key mCRPC companies such as Regeneron Pharmaceuticals, AstraZeneca, Hinova Pharmaceuticals, Zenith Epigenetic, Eli Lilly and Company, Astellas Pharma, Seagen, Pfizer, Progenics Pharmaceutical, Molecular Insight Pharmaceuticals, Bayer, Accutar Biotechnology Inc, Hinova Pharmaceuticals, Forma Therapeutics, Inc., HALDA THERAPEUTICS INC., Tavanta Therapeutics, Lantheus, Pfizer, AB Science, Syntrix Pharmaceuticals, Exelixis, Laekna Therapeutics Shanghai Co. Ltd., Cardiff Oncology, Ipsen, Norroy Bioscience, Astellas Pharma, Novartis, Johnson & Johnson, Tempest Therapeutics, and others are evaluating new mCRPC drugs to improve the treatment landscape. Promising mCRPC pipeline therapies such as REGN 4336, Capivasertib, Deutenzalutamide, ZEN003694, Abemaciclib, Enfortumab vedotin, Talazoparib, I-131-1095, Pelgifatamab corixetan, AC176, HP518, FT-7051, HLD-0915, TAVT-45, PNT2002, Mevrometostat, Masitinib, SX-682, XL092, LAE001, Onvansertib, Tazemetostat, 177Lu-NYM032, PRL-02, 225 Actinium PSMA 617, ARX51, TPST-1120, and others are under different phases of mCRPC clinical trials. In October 2024, Curium announced that it had entered into a strategic partnership with PDRadiopharma Inc, a wholly-owned subsidiary of PeptiDream, for the clinical development, regulatory filing, and commercialization in Japan of 177Lu-PSMA-I&T and 64Cu-PSMA-I&T. The two agents 177Lu-PSMA-I&T and 64Cu-PSMA-I&T target prostate-specific membrane antigen (PSMA) expressed on prostate cancer cells and are being investigated for prostate cancer treatment and diagnostics. In July 2024, the US FDA granted fast-track designation to the prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical 225Ac-FL-020 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). In July 2024, Merck and Orion Corporation announced the mutual exercise of option providing Merck global exclusive rights to Opevesostat, an investigational CYP11A1 inhibitor, for the treatment of Metastatic Castration-Resistant Prostate Cancer. In July 2024, the US FDA granted fast-track designation to the antibody-drug conjugate (ADC) BNT324/DB-1311 to potentially treat patients with unresectable advanced or metastatic castration-resistant prostate cancer (mCRPC) whose disease had progressed on or after standard systemic regimens. In July 2024, FutureChem announced that the FC-705 has received orphan drug designation from the Ministry of Food and Drug Safety (MFDS) for the treatment of prostate cancer. In June 2024, CAR T-Cell Therapy demonstrated promising results for mCRPC according to Phase I trial results. In January 2024, Lava Therapeutics announced that it has signed a clinical trial collaboration and supply agreement with Merck to evaluate its prostate cancer therapy LAVA-1207 as a combination treatment with MSD's Keytruda (pembrolizumab). In July 2024, Blue Earth Therapeutics announced the signing of a clinical research collaboration with University College London (UCL). The collaboration is centered on a Phase I/II trial designed to evaluate the safety, tolerability, radiation dosimetry, and antitumor activity of the 225Ac-rhPSMA-10.1 in men with metastatic castrate-resistant prostate cancer who have previously responded to lutetium 177 (177Lu)-PSMA therapy. Request a sample and discover the recent advances in mCRPC treatment drugs @ Metastatic Castration-Resistant Prostate Cancer Pipeline Report The mCRPC pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mCRPC drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mCRPC clinical trial landscape. Metastatic Castration-Resistant Prostate Cancer Overview Metastatic castration-resistant prostate cancer (mCRPC) is an advanced stage of prostate cancer that continues to grow and spread despite hormone therapy aimed at lowering testosterone levels. The term "metastatic" refers to cancer spreading to other parts of the body, such as the bones, lymph nodes, or distant organs, while "castration-resistant" indicates that the cancer no longer responds to treatments that reduce testosterone, a key driver of prostate cancer growth. mCRPC is typically more aggressive and challenging to treat than earlier stages of prostate cancer. The causes of mCRPC stem from genetic and environmental factors. Genetic mutations in the androgen receptor pathway can make cancer cells less dependent on testosterone, allowing them to thrive even under hormone-suppressing treatments. Environmental factors like diet, lifestyle, and exposure to certain chemicals may also contribute to the development and progression of prostate cancer. Symptoms of mCRPC often include pain in bones, fatigue, difficulty urinating, weight loss, and general weakness. As the cancer spreads, it can impair the function of other organs, depending on the site of metastasis. Diagnosis of mCRPC usually involves a combination of tests, including prostate-specific antigen (PSA) blood tests, imaging studies like CT scans, MRIs, or bone scans, and sometimes biopsies to confirm the spread and resistance to treatment. Treatment options for mCRPC are more complex and may include newer hormonal therapies (e.g., abiraterone, enzalutamide), chemotherapy (docetaxel or cabazitaxel), immunotherapy (e.g., sipuleucel-T), or targeted therapies such as PARP inhibitors. Bone-targeting therapies, radiation, and palliative care can also be used to manage symptoms and improve the quality of life. Treatment is typically tailored to the individual based on the extent of the disease and the patient health. Find out more about mCRPC treatment drugs @ Drugs for Metastatic Castration-Resistant Prostate Cancer Treatment A snapshot of the mCRPC Pipeline Drugs mentioned in the report: Learn more about the emerging mCRPC pipeline therapies @ Metastatic Castration-Resistant Prostate Cancer Clinical Trials Metastatic Castration-Resistant Prostate Cancer Therapeutics Assessment The mCRPC pipeline report proffers an integral view of the mCRPC emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Metastatic Castration-Resistant Prostate Cancer Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous Therapeutics Assessment By Molecule Type: Small molecule, Cell therapy, Peptides, Polymer, Small molecule, Gene therapy Therapeutics Assessment By Mechanism of Action: Androgen receptor degradation enhancers, Antibody-dependent cell cytotoxicity, Proto-oncogene protein c-akt inhibitors, Androgen receptor antagonists, Bromodomain and extraterminal domain protein inhibitors, Cyclin-dependent kinase 4 inhibitors, Cyclin-dependent kinase 6 inhibitors, Ionizing radiation emitters, PPAR alpha antagonists. Key Metastatic Castration-Resistant Prostate Cancer Companies: Regeneron Pharmaceuticals, AstraZeneca, Hinova Pharmaceuticals, Zenith Epigenetic, Eli Lilly and Company, Astellas Pharma, Seagen, Pfizer, Progenics Pharmaceutical, Molecular Insight Pharmaceuticals, Bayer, Accutar Biotechnology Inc, Hinova Pharmaceuticals, Forma Therapeutics, Inc., HALDA THERAPEUTICS INC., Tavanta Therapeutics, Lantheus, Pfizer, AB Science, Syntrix Pharmaceuticals, Exelixis, Laekna Therapeutics Shanghai Co. Ltd., Cardiff Oncology, Ipsen, Norroy Bioscience, Astellas Pharma, Novartis, Johnson & Johnson, Tempest Therapeutics, and others. Key Metastatic Castration-Resistant Prostate Cancer Pipeline Therapies: REGN 4336, Capivasertib, Deutenzalutamide, ZEN003694, Abemaciclib, Enfortumab vedotin, Talazoparib, I-131-1095, Pelgifatamab corixetan, AC176, HP518, FT-7051, HLD-0915, TAVT-45, PNT2002, Mevrometostat, Masitinib, SX-682, XL092, LAE001, Onvansertib, Tazemetostat, 177Lu-NYM032, PRL-02, 225 Actinium PSMA 617, ARX51, TPST-1120, and others. Dive deep into rich insights for new drugs for mCRPC treatment, visit @ Metastatic Castration-Resistant Prostate Cancer Drugs Table of Contents For further information on the mCRPC Cancer pipeline therapeutics, reach out @ Metastatic Castration-Resistant Prostate Cancer Treatment Drugs Related Reports Metastatic Castration-Resistant Prostate Cancer Market Metastatic Castration-Resistant Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCRPC companies including AstraZeneca, Merck Sharp & Dohme, Hinova Pharmaceuticals, Pfizer, Astellas Pharma, Modra Pharmaceuticals, AB Science, Eli Lilly and Company, Zr Pharma & GmbH, Bristol-Myers Squibb, Ipsen, Exelixis, Takeda, Janssen Research & Development, Tesaro, Lantheus Holdings, Kintor Pharmaceutical, MacroGenics, Daiichi Sankyo, Madison Vaccines, Novartis, Point Biopharma, Xencor, Essa Pharma, Telix International, Bayer, Arvinas, among others. Metastatic Prostate Cancer Market Metastatic Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key metastatic prostate cancer companies including AstraZeneca, Arvinas, Madison Vaccines, Phosplatin Therapeutics, Hinova Pharmaceuticals, Bristol Myers Squibb, Merck, MacroGenics, Daiichi Sankyo, Seagen, Taiho Pharmaceutical, Modra Pharmaceuticals, Xencor, Point Biopharma, Lantheus Holdings, Zenith Epigenetics, Essa Pharma, Telix Pharmaceuticals, Kintor Pharmaceutical, AB Science, Eli Lilly and Company, Exelixis among others. Metastatic Castration-Sensitive Prostate Cancer Market Metastatic Castration-Sensitive Prostate Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key mCSPC companies including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. Metastatic Castration-Sensitive Prostate Cancer Pipeline Metastatic Castration-Sensitive Prostate Cancer Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key mCSPC companies, including Myovant Sciences, Pfizer, Bayer, Orion, Novartis, AstraZeneca, Pfizer, Janssen, Merck, Eli Lilly, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

快速通道免疫疗法临床1期临床结果

2024-04-26

·生物谷

四川大学王红宁教授团队在细菌胞外囊泡介导耐药基因转移和促进细菌对抗生素耐药方面取得重要研究进展

近年来，细菌胞外囊泡(Extracellular vesicles, EVs)作为一种新兴的基因水平转移方法已经成为人们研究的热点。EVs是由细胞产生和释放到细胞外环境中的膜性囊泡，由脂质双分子层包裹脂多糖、磷脂、核酸、蛋白质等物质形成的杯状纳米颗粒，直径通常为 20-200 nm，EVs在基因转移、促进病原菌致病、协助细菌在应激条件存活以及调节细菌相互作用等方面发挥着重要作用。近日，四川大学生命科学学院王红宁教授研究团队在国际权威期刊International Journal of Antimicrobial Agents和 Journal of Antimicrobial Chemotherapy分别发表题为 “ESBL- Escherichia coli extracellular vesicles mediate bacterial resistance to β-lactam and mediate horizontal transfer of blaCTX-M-55”和“Membrane vesicles derived from Enterococcus faecalis promote the co-transfer of important antibiotic resistance genes located on both plasmids and chromosomes”的研究论文，证明EVs可以将耐药基因从一种病原菌传播给多种病原菌，同时可以介导位于质粒和染色体上的耐药基因转移，促进了耐药基因在不同细菌间的散播，对细菌耐药性传播提供了新的认识。发表在《International Journal of Antimicrobial Agents》期刊上题为 “ESBL- Escherichia coli extracellular vesicles mediate bacterial resistance to β-lactam and mediate horizontal transfer of blaCTX-M-55”的研究论文发现产超广谱β-内酰胺酶大肠杆菌（ESBL-E.coli）的EVs可以介导细菌对β-内酰胺耐药并介导blaCTX-M-55的水平转移，该研究证明了EVs在ESBL-E.coli β-内酰胺耐药传播中起着重要作用，提高了耐药基因水平传播的风险。该研究以多种携带blaCTX-M-55耐药基因的ESBL-E.coli的EVs为研究对象，对 EVs 在大肠杆菌 β-内酰胺耐药性传播中的作用开展评估。结果表明ESBL-EVs 可以在β-内酰胺抗生素存在的情况下保护敏感菌免受抗生素影响，并且这种保护作用依赖于 EVs 的完整性，呈现出EVs剂量和时间依赖效应。同时研究表明EVs 介导的基因水平转移是一种比较普遍的转移途径，多种携带不同质粒类型的 ESBL-E.coli的EVs可以介导blaCTX-M-55 的水平转移，转移频率基本在10-5-10-7之间。但这种转移具有一定的选择性，会更倾向于在亲缘关系更近的种属中进行。该研究为阐明EVs介导的耐药传播新机制提供了理论依据。EVs 与受体菌 EC600 发生融合。其中EC600被DiO染料染成绿色，EVs被DiD染料染成红色尽管EVs介导耐药基因水平转移近几年已在多种细菌和耐药基因中被报道，但研究对象主要集中在革兰氏阴性菌，对于革兰氏阳性菌的囊泡介导耐药基因转移的研究几乎没有。王红宁教授团队首次发现囊泡也能在革兰氏阳性菌中介导耐药基因转移。近日在《Journal of Antimicrobial Chemotherapy》期刊上发表的题为“Membrane vesicles derived from Enterococcus faecalis promote the co-transfer of important antibiotic resistance genes located on both plasmids and chromosomes”的研究论文首次报道了革兰氏阳性菌粪肠球菌的MVs介导携带ARGs的质粒和转座子的共同转移，这一发现大大扩展了目前已知的肠球菌的水平基因转移机制。该研究选择猪源耐利奈唑胺粪肠球菌CQ20作为膜囊泡（Membrane Vesicles，MVs）的供体菌株，选择人源利奈唑胺敏感粪肠球菌SC032、屎肠球菌BM4105和大肠杆菌作为受体菌株。通过WGS或PCR证明了CQ20、MVs和获得ARGs的囊泡转化子中存在质粒（pCQ20-1和pCQ20-2）和携带optrA耐药基因的转座子Tn6674，并成功实现了CQ20-MVs中的质粒pCQ20-1和pCQ20-2以及转座子Tn6674向粪肠球菌SC032和屎肠球菌BM4105中的转移，但不能向大肠杆菌中转移，进而证明了粪肠球菌MVs可以介导ARGs从动物源性肠球菌转移到人源性肠球菌，而无法从革兰氏阳性菌转移到革兰氏阴性菌这一结论。同时实验也证明了通过囊泡获得ARGs的囊泡转化子仍然能够通过MVs继续传播这些ARGs。该研究为MVs在肠球菌中介导耐药基因的传播提供了新证据。获得ARGs的囊泡转化子SC032-MVs中ARGs的遗传环境四川大学生命科学学院硕士研究生徐荷婷、赵蒙宇分别为两篇论文的第一作者，王红宁教授、唐艺芝副教授分别为通讯作者，雷昌伟副研究员，博士生李超、李金朋、韩蕴、文仁桥，硕士生陈兴贵、林小龙共同参与了研究。研究得到了国家自然科学基金重点项目、区域联合基金重点项目、自然基金面上项目（31830098 、32273061、U21A20257）国家重点研发计划（2022YFC2303900）等资助。参考文献：ESBL- Escherichia coli extracellular vesicles mediate bacterial resistance to β-lactam and mediate horizontal transfer of blaCTX-M-55. Int J Antimicrob Agents. 2024 Mar 16;63(5):107145. doi: 10.1016/j.ijantimicag.2024.107145.Membrane vesicles derived from Enterococcus faecalis promote the co-transfer of important antibiotic resistance genes located on both plasmids and chromosomes. J Antimicrob Chemother. 2024 Feb 1;79(2):320-326. doi: 10.1093/jac/dkad381.原文链接：https://life.scu.edu.cn/info/1095/4674.htm本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床研究微生物疗法

2023-12-16

·药智网

前列腺癌药物的江湖纷争

前列腺癌的病因及发病机制十分复杂，其确切病因尚不明确。目前，前列腺癌早期可以通过手术、放疗、雄激素剥夺疗法(ADT)等进行成功治疗。但前列腺癌早期临床症状不明显，因此确诊时多数患者已属中晚期。近年来，随着一系列突破性进展的取得，前列腺癌药物的江湖纷争出现新的变化。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。01治疗方案有限，常见疗法包括化疗和内分泌疗法前列腺是雄激素依赖性器官，其生长发育与雄激素受体（AR）信号通路密切相关。AR在前列腺癌的发生、发展中起重要作用。AR通路抑制剂通过减少循环睾酮及雄激素-AR受体复合物，降低前列腺癌中的AR活性。目前，前列腺癌早期可以通过手术、放疗、雄激素剥夺疗法(ADT)等进行成功治疗。但前列腺癌早期临床症状不明显，因此确诊时多数患者已属中晚期，中晚期前列腺癌患者首选治疗方案为雄激素剥夺治疗(ADT)。ADT是晚期转移性前列腺癌患者的主要全身性基础治疗，也是各种新型联合治疗方案的基础。ADT包括多种实施方案，其中，单纯去势（外科或者药物去势）是最广为接受的核心治疗方式。近年来，出现了一系列突破性进展，主要是ADT与新型内分泌治疗药物或化疗药物的联合使用，改善了转移性前列腺癌的总体治疗效果。但最终，几乎所有患者经ADT治疗18~36个月后会出现药物抵抗，最终进展为去势抵抗性前列腺癌(CRPC)，此阶段的患者中位生存期大约只有12个月。下图为前列腺癌进展到不同阶段的治疗方法及用药方案。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。表1 前列腺癌主要治疗药物分类及作用机制数据来源：公开数据，药智咨询整理02第二代AR拮抗剂等新药的上市，刺激前列腺癌市场增长2021年，中国前列腺癌治疗药物市场规模为77.45亿元，2017-2021年复合增长率为14.79%。同时，近年来多个第二代AR拮抗剂在国内上市，包括恩扎卢胺（2019年），阿帕他胺（2020年），瑞维鲁胺（2022年6月）等，预计第二代AR拮抗剂等新药的上市将促进前列腺癌治疗药物市场持续增长。图1 中国前列腺癌治疗药物市场规模数据来源：药智数据，药智咨询整理2021年，中国前列腺癌治疗药物中市场份额最高的为亮丙瑞林（27.16%），其次为戈舍瑞林（23.61%）。这两个药物为GnRHR激动剂，是雄激素剥夺疗法（ADT）中常用的药物，ADT是激素敏感性前列腺癌联合用药的基础，所以市场份额高。阿比特龙是由强生公司开发的CYP17A酶不可逆抑制剂，CYP17A酶是雄激素生物合成过程中的限速酶，存在于睾丸、肾上腺以及前列腺癌细胞中。2011年获FDA批准上市，2015年被美国泌尿外科协会推荐用于治疗各种类型的转移性去势抵抗性前列腺癌（mCRPC）患者，2015年4月在中国获批上市。阿比特龙临床试验疗效显著，2017年进入医保，进入医保后迅速放量，2017-2021年复合增长率高达71.34%。2021年，阿比特龙销售额达13.92亿元，同比2020年增长5.19%。阿比特龙2020年进入国家集采，进入集采后阿比特龙的销售额依然保持增长。恩扎卢胺由Medivation和安斯泰来公司合作开发，2012年获FDA批准用于治疗CRPC，2019年在中国获批上市。恩扎卢胺是第二代非甾体类抗雄激素药物，相比于第一代AR抑制剂仅竞争性地结合AR，其抗AR活性比第一代强数倍。恩扎卢胺是少数无需联合类固醇激素治疗的选择，相较于阿比特龙（需要与泼尼松联用以控制不良反应）具有显著安全性优势。2019年至今在全球抗前列腺癌市场中恩扎卢胺所占市场份额最大；而国内该药于2019年上市，上市后销售额增长迅速，2021市场规模为1.96亿元，同比2020年增长4170.32%，预计未来国内用药结构将向全球看齐，恩扎卢胺将保持高速增长。03在研药物数量多，靶点集中在FOLH1、AR等全球前列腺癌在研治疗药物约657个，中国前列腺癌在研治疗药物约145个；全球在研靶点集中在PSMA（FOLH1）、AR、GnRH receptor等靶点。图2 全球及中国前列腺癌治疗上市在研药物数量和靶点图片来源：药智数据-全球药物分析系统前列腺特异性膜抗原（PSMA,又称叶酸水解酶1（FOLH1））是一种跨膜糖蛋白，目前的研究表明PSMA在超过90%的前列腺癌细胞表面都出现了过表达，并且在晚期和去势抵抗性患者的癌细胞中表达水平更高。可通过影像学评估PSMA的表达情况，与传统的扫描检查相比，PSMA PET/CT在检测前列腺癌病灶方面有着独特的优势，在前列腺癌早期和病程分期上能做出更有效的判断，PSMA PET/CT凭借其高特异性多模态显像的优势显著提高诊断敏感性和准确性。目前上市和在研的PSMA药物多是放射性药物，包括已上市药物177Lu-PSMA-617，和在研药物PNT2002（177Lu标记的放射性药物）、131I-MIP-1095（131I标记的放射性药物）、225Ac-PSMA-I&T（225Ac标记的放射性药物）等。其中，诺华研发的放射性配体疗法（177Lu-PSMA-617）于2022年3月获FDA批准，治疗范围包括已扩散的、接受过其他治疗的前列腺癌患者。177Lu-PSMA-617包括靶向性化合物（PSMA-617）和治疗性同位素（177Lu），能够实现精准癌症治疗。177Lu-PSMA-617与表达PSMA的前列腺癌细胞结合，反射性元素产生的放射线更集中在肿瘤组织局部，在杀死癌细胞的同时减少对健康细胞的损伤。目前，mCRPC一线治疗主要推荐优选新型内分泌治疗（NHT），国内可及的方案有恩扎卢胺、阿比特龙等。但临床结果发现新型内分泌治疗药物并不是对所有的去势抵抗性前列腺癌（CRPC）都有效，一部分患者对这些药物存在原发性耐药，对于初始有效的mCRPC患者，最终也还是发生继发性耐药。耐药机制主要是由于AR基因发生变异，包括AR扩增、AR突变、AR剪切变异体（ARVs）等。沉默AR基因表达的治疗策略是治疗CRPC的潜在有效方法。反义寡核苷酸（ASO）可以从本质上阻断特定基因靶标，阻止其相关蛋白质的合成，因此已成为多种人类疾病的替代治疗方法。阿斯利康开发了反义核苷酸AZD5321，临床前研究表明，AZD5312与AR mRNA杂交，从而阻断AR蛋白的翻译，能够有效抑制全长AR(AR-FL)及其剪接变体的表达，这既能抑制AR诱导的肿瘤细胞生长，又能促进AR过表达的肿瘤细胞凋亡，从而在恩杂鲁胺耐药的CRPC模型中产生抗肿瘤活性。但该药物于2014年开始进行I期临床试验，目前暂无进展。04小结目前针对晚期前列腺癌治疗通路有限，深受现有治疗方案交叉耐药的瓶颈；mCRPC的中位生存时长短，患者往往进展到二线治疗时丧失治疗积极性，存在巨大未被满足的临床需求。亟需一个全新的治疗方式和理念，带领临床患者走出治疗困境。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。参考文献：[1]闵淑慧，胡依，郭芮绮.1990-2019年中国前列腺癌疾病负担分析及趋势预测.中国肿瘤ISSN 1004-0242，CN 11-2859/R.[2]http://www.phirda.com/artilce_27200.html?cId=1[3]De Velasco MA,Kura Y,Sakai K,Hatanaka Y,Davies BR,Campbell H,Klein S,Kim Y,MacLeod AR,Sugimoto K,Yoshikawa K,Nishio K,Uemura H.Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy.JCI Insight.2019 Sep 5;4(17):e122688.声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 八斤转载开白 | 马老师 18996384680（同微信）如需定制医药咨询服务，请扫描下方二维码咨询！阅读原文，是受欢迎的文章哦

放射疗法抗体药物偶联物

100 项与 131I-MIP-1095 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14978

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
转移性去势抵抗性前列腺癌	临床2期	美国	Progenics Pharmaceuticals, Inc.	2019-05-30
转移性去势抵抗性前列腺癌	临床2期	加拿大	Progenics Pharmaceuticals, Inc.	2019-05-30
前列腺癌	临床前	美国	Molecular Insight Pharmaceuticals, Inc.	2008-05-01

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03939689 (ARROW, ESMO2024) 人工标引	临床2期	转移性去势抵抗性前列腺癌	120	Enzalutamide+131I-LNTH-1095	(鬱製蓋鏇觸選衊遞願淵) = 構製觸簾襯簾積顧願齋選鹽衊構齋夢衊鬱襯糧 (蓋願糧製鹽廠鏇襯範願 ) 更多	积极	2024-09-15
				Enzalutamide	(鬱製蓋鏇觸選衊遞願淵) = 壓窪獵鏇憲憲齋鑰觸醖選鹽衊構齋夢衊鬱襯糧 (蓋願糧製鹽廠鏇襯範願 ) 更多