Phase 1/2, Open-Label Study of the Safety, Dosimetry and Efficacy of a 3-Dose Regimen of Escalating Doses of 177Lu-DOTA-EB-TATE in Adult Patients With Metastatic, Radioactive Iodine Non-Responsive Oncocytic (Hurthle-Cell) Thyroid Cancer

Background:
Oncocytic (Hurthle cell) thyroid cancer (HTC) is a rare disease with few treatment options. Researchers are developing a radioactive drug that targets a protein that appears in high numbers on HTC cancer cells.
Objective:
To test a radioactive drug (177LuDOTA-EB-TATE) in people with HTC.
Eligibility:
People aged 18 years and older with HTC. The HTC must have failed to respond to conventional radioactive treatment; it must also have spread to other parts of the body.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have imaging scans and a test of their heart function.
177LuDOTA-EB-TATE is infused into a vein. Participants will receive 4 infusions spaced 8 to 12 weeks apart. They will stay in the hospital for 4 to 10 days after each infusion. During and after each infusion, participants will remain in a lead-lined room until their radiation levels go down; this usually takes about 24 hours.
Participants will have 4 to 6 follow-up visits in the weeks after each infusion. Procedures will vary at each visit, but may include more imaging scans; blood and urine tests; and tests of heart function. Participants will have 2 single-photon emission computerized tomography (SPECT) scans. SPECT scans show where the study drug is sticking to tumors or maybe other parts of their body. They will lie on a table while a machine rotates around them. Participants will fill in questionnaires about how their thyroid condition affects their life.
Participants will have follow-ups visits for 5 years after their last study treatment.

开始日期2026-09-23

申办/合作机构

National Institute of Diabetes & Digestive & Kidney Diseases

NCT05475210

/ Unknown status临床1期

Phase I, Open-Label Study of the Safety and Dosimetry of a 3-Dose Regimen of Escalating Doses of 177Lu-DOTA-EB-TATE in Adult Patients With Advanced, Well- Differentiated Neuroendocrine Tumors

This is a Phase I clinical trial to assess the safety and dosimetry profiles of 177Lu-DOTA-EB-TATE in patients with advanced, metastatic or inoperable, somatostatin receptor-positive, well-differentiated GEP-NETs.

开始日期2022-06-18

申办/合作机构

Molecular Targeting Technologies, Inc.

[+1]

NCT03308682

/ Unknown status临床1期IIT

Safety and Dosimetry of a Long-lasting Radiolabeled Somatostatin Analogue 177Lu-DOTA-EB-TATE in Patients With Advanced Metastatic Neuroendocrine Tumors

This is an open-label, non-controlled, non-randomized study to investigate the long-lasting radiolabeled somatostatin analogue based peptide receptor radionuclide therapy and evaluation safety and dosimetry of 177Lu-DOTA-EB-TATE in patients with advanced metastatic neuroendocrine tumors. A single dose of 0.50GBq-0.70GBq (13.5-18.9 mCi) of 177Lu-DOTA-EB-TATE will be injected intravenously. and monitored at 2, 24, 72,120 and 168 hours post-injection with semiquantitative method based on quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) performance.

开始日期2017-04-30

申办/合作机构

北京协和医院

[+1]

100 项与 177Lu-DOTA-EB-TATE 相关的临床结果

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100 项与 177Lu-DOTA-EB-TATE 相关的转化医学

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100 项与 177Lu-DOTA-EB-TATE 相关的专利（医药）

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项与 177Lu-DOTA-EB-TATE 相关的文献（医药）

2023-06-01·Clinical nuclear medicine

Evaluation of Safety, Biodistribution, and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analog 177Lu-DOTA-EB-TATE With and Without Amino Acid Infusion

Article

作者: Guochang Wang ; Zhaohui Zhu ; Qingxing Liu ; Jingjing Zhang ; Xiaoyuan Chen ; Yuanyuan Jiang

Purpose:

Kidney is considered to be one of the dose-limiting organs in peptide receptor radionuclide therapy (PRRT). Amino acid cocktail infusion has been applied to reduce renal absorbed dose by inhibiting the proximal tubular reabsorption of the radiopeptide. An Evans blue-modified 177Lu-labeled octreotate (177Lu-DOTA-EB-TATE) has an extended circulation in the blood, which may make the amino acid infusion unnecessary. The aim of this study was to evaluate the safety, biodistribution, and dosimetry of 177Lu-DOTA-EB-TATE with and without amino acid infusion.

Patients and Methods:

Ten patients with metastatic neuroendocrine tumors were randomly divided into 2 groups. The effect of amino acid infusion on renal uptake was assessed in a crossover randomized setting. Group A received 177Lu-DOTA-EB-TATE at a dose of 3.7 GBq without amino acid infusion for the first cycle and with amino acid infusion for the second cycle; group B received 177Lu-DOTA-EB-TATE at a dose of 3.7 GBq with amino acid infusion for the first cycle and without amino acid infusion for the second cycle. All patients underwent serial whole-body planar imaging at 1, 24, 96, and 168 hours and SPECT scan at 24 hours after radioligand administration. Abdominal CT was performed 2 days before PRRT for SPECT/CT fusion. The dosimetry was calculated using the HERMES software. Dosimetry evaluation was compared on a between-group and intrapatient basis.

Results:

Administrations of 177Lu-DOTA-EB-TATE with or without amino acids were well tolerated. No grade 4 hematotoxicity was observed in any of the patients. Grade 3 thrombocytopenia was reported in 1 patient. No nephrotoxicity of any grade was recorded. No significant difference was observed in creatinine (75.1 ± 21.7 vs 67.5 ± 18.1 μmol/L, P = 0.128), blood urea nitrogen (4.5 ± 0.8 vs 5.1 ± 1.4 mmol/L, P = 0.612), or GFR (109.3 ± 25.2 vs 100.9 ± 24.9 mL/min, P = 0.398) before and after PRRT. For each cycle, there was no significant difference in whole-body effective dose, kidney effective dose, as well as residence time of the kidneys between group A and B (P > 0.05). By intrapatient comparison, without and with amino acid infusion also did not show significant difference in whole-body effective dose (0.14 ± 0.05 vs 0.12 ± 0.04 mSv/MBq, P = 0.612), kidney effective dose (1.09 ± 0.42 vs 0.73 ± 0.31 mSv/MBq, P = 0.093), and residence time of the kidneys (2.95 ± 1.58 vs 3.13 ± 1.11 hours, P = 0.674).

Conclusions:

177Lu-DOTA-EB-TATE PRRT with and without amino acid infusion demonstrated a favorable safety profile in neuroendocrine tumor patients. Administration of 177Lu-DOTA-EB-TATE without amino acid infusion has acceptable slightly increased kidney absorbed dose and residence time of the kidneys, and does not affect kidney function. Further investigation in a larger cohort and long-term follow-up are warranted.

2022-01-01·Theranostics

Safety and efficacy of peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTA-EB-TATE in patients with metastatic neuroendocrine tumors

Article

作者: Zhu, Zhaohui ; Wang, Guochang ; Zhang, Jingjing ; Liu, Qingxing ; Jiang, Yuanyuan ; Sui, Huimin ; Chen, Xiaoyuan ; Wang, Jiarou ; Wang, Rongxi

Rationale: This study aimed to assess the safety, efficacy, and survival of ¹⁷⁷Lu-DOTA-EB-TATE in patients with metastatic neuroendocrine tumors (NETs). Methods: Thirty patients with metastatic NETs were prospectively enrolled and treated with ¹⁷⁷Lu-DOTA-EB-TATE (3 intended cycles at 8 to 12-week intervals, 3.7 GBq/cycle). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The treatment response was graded according to RECIST 1.1 and PERCIST 1.0 criteria. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS). Results: Patients tolerated therapy well without acute adverse effects. During peptide receptor radionuclide therapy (PRRT), no grade 4 toxicity was observed in any of the patients; grade 3 hematotoxicity was recorded in 4 patients, including grade 3 thrombocytopenia in 4 patients (13.3%) and grade-3 anemia in 1 patient (3.3%); grade 3 hepatotoxicity was recorded in 1 (3.3%) patient, and no grade 2/3/4 nephrotoxicity was observed. On long-term follow-up, none of the patients developed grade 4 hematotoxicity or nephrotoxicity of any grade, reversible grade 3 hematotoxicity (thrombocytopenia) occurred in 1 patient. There was no incidence of leukemia or myelodysplastic syndrome for the duration of follow-up. Of 27 patients with RECIST-measurable disease, partial response and stable disease were seen in 9 and 14 patients, respectively, resulting in a response rate of 33.3% and disease control rate of 85.2%. Of 29 patients evaluable for response on ⁶⁸Ga-DOTATATE PET/CT, 14 had partial response and 11 had stable disease, with a response rate of 48.3% and disease control rate of 86.2%. The follow-up period ranged from 5 to 57 months after the first ¹⁷⁷Lu-DOTA-EB-TATE PRRT with a median follow-up of 46 months. The median PFS was 36 months, and the median OS was not reached. Ki-67 index of greater than 10% was associated with poorer PFS (P = 0.012). Conclusions: Our results suggest that PRRT with approximately 3.7 GBq ¹⁷⁷Lu-DOTA-EB-TATE has acceptable toxicity profile and is effective in treating metastatic NET with high disease control rate. In addition, ¹⁷⁷Lu-DOTA-EB-TATE achieved a favorable survival outcome with encouraging PFS.

2021-03-01·Journal of nuclear medicine : official publication, Society of Nuclear Medicine1区 · 医学

Peptide Receptor Radionuclide Therapy of Late-Stage Neuroendocrine Tumor Patients with Multiple Cycles of¹⁷⁷Lu-DOTA-EB-TATE

1区 · 医学

Article

作者: Chen, Xiaoyuan ; Wang, Rongxi ; Guo, Hua ; Zhu, Zhaohui ; Wang, Hao ; Liu, Qingxing ; Jacobson, Orit ; Sui, Huimin ; Zhang, Jingjing ; Cheng, Yuejuan ; Zang, Jie ; Ren, Jiakun

This study aimed to evaluate the safety and efficacy of multiple cycles of ¹⁷⁷Lu-DOTA-Evans blue (EB)-TATE peptide receptor radionuclide therapy (PRRT) at escalating doses in neuroendocrine tumors (NETs). Methods: Thirty-two NET patients were randomly divided into 3 groups and treated with escalating doses. Group A received 1.17 ± 0.09 GBq/cycle; group B, 1.89 ± 0.53 GBq/cycle; and group C, 3.97 ± 0.84 GBq/cycle. The treatment was planned for up to 3 cycles. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Treatment response was evaluated according to the European Organisation for Research and Treatment of Cancer criteria and modified PERCIST. Results: Administration of PRRT was well tolerated, without life-threatening adverse events (CTCAE grade 4). CTCAE grade 3 hematotoxicity was recorded in 1 patient (16.6%) in group B (thrombocytopenia) and 3 patients (21.4%) in group C (thrombocytopenia in 3, anemia in 1). CTCAE grade 3 hepatotoxicity (elevated aspartate aminotransferase) was recorded in 1 patient in group A (8.3%) and 1 patient in group C (7.1%). No nephrotoxicity was observed. According to the criteria of the European Organisation for Research and Treatment of Cancer, the overall disease response rates were similar in groups A, B, and C (50.0%, 50.0%, and 42.9%, respectively), and the overall disease control rates were higher in groups B (83.3%) and C (71.5%) than in group A (66.7%). According to modified PERCIST, a lower disease response rate but a similar disease control rate were found. When a comparable baseline SUV_max ranging from 15 to 40 was selected, the percentage change in SUV_max increased slightly in group A (2.1% ± 40.8%) but decreased significantly in groups B and C (-38.7% ± 10.0% and -14.7% ± 20.0%, respectively) after the first PRRT (P = 0.001) and decreased in all 3 groups after the third PRRT (groups A, B, and C: -6.9% ± 42.3%, -49.2% ± 30.9%, -11.9% ± 37.9%, respectively; P = 0.044). Conclusion: Dose escalations of up to 3.97 GBq/cycle seem to be well tolerated for ¹⁷⁷Lu-DOTA-EB-TATE. ¹⁷⁷Lu-DOTA-EB-TATE doses of 1.89 and 3.97 GBq/cycle were effective in tumor control and more effective than 1.17 GBq/cycle.

项与 177Lu-DOTA-EB-TATE 相关的新闻（医药）

2026-09-01

·BioSpace

Molecular Targeting Technologies Receives Pharma Tech Outlook’s 2026 “Radiopharmaceutical Therapy Solution of the Year” Award for EvaThera™

Industry Recognition Highlights EvaThera™ as a Next-Generation Pharmacokinetic Engineering Platform for Precision Radiopharmaceutical Therapy WEST CHESTER, Pa.--(BUSINESS WIRE)--Molecular Targeting Technologies, Inc. (MTTI), a clinical-stage biotechnology company developing next-generation targeted radiopharmaceuticals, today announced that Pharma Tech Outlook has named MTTI its Radiopharmaceutical Therapy Solution of the Year 2026 , recognizing EvaThera™ , MTTI’s proprietary pharmacokinetic engineering platform based on Evans Blue (EB)-mediated reversible albumin binding. The recognition highlights EvaThera™’s differentiated approach to radiopharmaceutical development: engineering pharmacokinetics to enhance the performance of targeted radiopharmaceuticals . By combining reversible albumin binding with established and investigational targeting ligands, EvaThera™ is designed to extend circulation, increase tumor exposure, and prolong tumor retention. MTTI believes this approach represents an important complementary dimension of innovation in radiopharmaceutical therapy. Molecular targeting determines where a therapeutic agent goes; pharmacokinetic engineering can help determine how long and how effectively it remains there. According to Pharma Tech Outlook , the recognition reflects growing industry interest in optimizing how therapeutic radiation is delivered as an important dimension of innovation alongside the discovery and validation of molecular targets. Why EvaThera™ Matters EvaThera™ is a target-agnostic, modular pharmacokinetic engineering platform designed to enhance the pharmacokinetic properties of targeted radiopharmaceuticals through reversible albumin binding. Rather than relying exclusively on the discovery of new molecular targets, EvaThera™ is designed to complement established and investigational targeting ligands by optimizing their circulation and tumor-exposure characteristics. The platform is being developed across multiple molecular targets and therapeutic radionuclides, providing pharmaceutical and biotechnology developers with a potential strategy for pharmacokinetic enhancement of existing and next-generation radiopharmaceutical programs. MTTI believes that the next generation of radiopharmaceutical therapy will be shaped not only by identifying the right biological targets, but also by engineering how therapeutic radiation is delivered . EvaThera™ is designed to complement—not replace—molecular targeting by enhancing pharmacokinetics and potentially improving the therapeutic index of targeted radiopharmaceuticals. Clinical Evidence Supporting the EvaThera™ Platform The EvaThera™ platform is supported by clinical experience with 177 Lu-EBTATE , an albumin-binding somatostatin receptor 2 (SSTR2)-targeted radiopharmaceutical being developed for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Clinical evidence supporting the EvaThera™ concept: Clinical experience with 177 Lu-EBTATE in 81 patients demonstrated sustained tumor retention for up to 15 days , supporting the ability of Evans Blue-mediated albumin binding to extend tumor exposure following administration. Enhanced tumor exposure: Comparative clinical analyses demonstrated up to approximately eight-fold higher tumor uptake and/or retention with 177 Lu-EBTATE relative to 177 Lu-DOTA-TATE. In preclinical studies, 177 Lu-EBTATE demonstrated up to 35-fold greater tumor uptake and retention compared with 177 Lu-DOTA-TATE in certain models. Lower administered radioactivity in the evaluated regimen: The evaluated two-cycle 177 Lu-EBTATE regimen represented approximately 12.5% of the cumulative administered radioactivity of a conventional four-cycle Lutathera® regimen . This comparison refers to administered activity and should not be interpreted as a direct measure of whole-body or organ radiation exposure. Encouraging renal safety profile: Clinical experience to date has shown an encouraging renal safety profile, with no clinically significant nephrotoxicity observed through one year of follow-up in the evaluated population . Together, these findings provide clinical evidence supporting the underlying EvaThera™ pharmacokinetic engineering concept: prolonging systemic circulation and tumor retention may increase tumor radiation exposure and potentially improve the therapeutic index of targeted radiopharmaceuticals. A Modular Platform Across Targets and Radionuclides EvaThera™ is being developed as a modular technology designed to integrate with multiple targeting ligands and therapeutic radionuclides. The EvaThera™ platform is being advanced across multiple oncology targets, including: SSTR2 , through the clinical development of 177 Lu-EBTATE for GEP-NETs; Integrin αvβ3 , including programs targeting solid tumors such as non-small cell lung cancer; FAP , with programs advancing toward fibroblast activation protein-targeted radiopharmaceutical applications; and GRPR , with programs advancing toward gastrin-releasing peptide receptor-targeted applications across additional solid tumors. EvaThera™ is also being developed for integration with different therapeutic radionuclides, including 177 Lu , a beta-emitting radionuclide, and 225 Ac , an alpha-emitting radionuclide. This radionuclide-flexible design may allow the platform to address different therapeutic strategies and disease settings. Strategic Opportunity for Pharmaceutical and Radiopharmaceutical Developers The modular nature of EvaThera™ creates potential opportunities beyond MTTI’s proprietary pipeline. Pharmaceutical and biotechnology companies may be able to explore EvaThera™ as a pharmacokinetic enhancement strategy for existing or investigational radiopharmaceutical programs , potentially without requiring the identification and validation of an entirely new molecular target. Potential applications include: Enhancing tumor exposure and retention of established targeting ligands; Exploring pharmacokinetic optimization of investigational radiopharmaceuticals; Supporting development of next-generation beta- or alpha-emitting radiotherapeutics; and Creating opportunities for strategic licensing, co-development, and portfolio enhancement . MTTI is actively engaging pharmaceutical, biotechnology, and radiopharmaceutical companies interested in evaluating EvaThera™ as a pharmacokinetic engineering technology for existing and next-generation radiopharmaceutical programs. Executive Perspectives “We are honored to receive this recognition from Pharma Tech Outlook ,” said Chris Pak, Ph.D., Chairman and Chief Executive Officer of MTTI. “We believe the next generation of radiopharmaceutical therapy will come not only from discovering new molecular targets, but from fundamentally improving how therapeutic radiation is delivered. EvaThera™ represents our effort to establish pharmacokinetic engineering as a new dimension of precision radiopharmaceutical therapy. By enhancing tumor exposure and retention, we believe pharmacokinetic engineering has the potential to complement molecular targeting and help advance the therapeutic index of targeted radiopharmaceuticals.” “EvaThera™ offers pharmaceutical and radiopharmaceutical developers a new opportunity to optimize the pharmacokinetic performance of existing or investigational targeting strategies,” said Norman LaFrance, M.D., Chief Strategy Officer of MTTI. “The ability to enhance pharmacokinetics without requiring discovery of an entirely new molecular target could provide an attractive complementary strategy for developing next-generation radiopharmaceutical therapies. We believe this creates meaningful opportunities for strategic collaborations, licensing, and co-development with companies seeking to enhance their radiopharmaceutical pipelines.” A Broader Vision for Precision Radiopharmaceutical Therapy As precision oncology advances, MTTI believes the future of radiopharmaceutical therapy will be defined not only by what tumors are targeted, but also by how efficiently, safely, and precisely therapeutic radiation is delivered . Through EvaThera™, MTTI is developing a scalable pharmacokinetic engineering platform designed to enhance tumor exposure and retention of established and investigational targeting ligands across multiple molecular targets and therapeutic radionuclides. The recognition by Pharma Tech Outlook underscores growing industry interest in pharmacokinetic engineering as a complementary strategy to molecular targeting for improving the therapeutic potential of precision radiopharmaceutical therapies. By enabling pharmacokinetic optimization of established targeting strategies, EvaThera™ may provide pharmaceutical developers with an opportunity to enhance existing radiopharmaceutical programs while potentially reducing reliance on novel target discovery alone . MTTI is actively seeking strategic relationships with pharmaceutical, biotechnology, and radiopharmaceutical companies interested in evaluating EvaThera™ for potential licensing, co-development, or integration with existing and next-generation radiopharmaceutical programs. About Molecular Targeting Technologies, Inc. Molecular Targeting Technologies, Inc. (MTTI) is a clinical-stage biotechnology company advancing precision radiopharmaceuticals through its proprietary EvaThera™ pharmacokinetic engineering platform , based on Evans Blue-mediated reversible albumin binding. The first clinical application supporting the EvaThera™ platform is 177 Lu-EBTATE , which is being advanced toward pivotal Phase III clinical development for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). MTTI is also expanding the platform across additional oncology targets, including integrin αvβ3, FAP, and GRPR , with therapeutic programs utilizing both lutetium-177 and actinium-225 . MTTI is actively engaging pharmaceutical and biotechnology companies interested in evaluating EvaThera™ for potential licensing, co-development, and integration with existing or next-generation radiopharmaceutical programs . For additional information, visit or . Forward-Looking Statements This press release contains forward-looking statements regarding the potential capabilities and future applications of the EvaThera™ technology, the development and commercialization of the Company’s product candidates, anticipated clinical and regulatory milestones, potential strategic collaborations and licensing opportunities, intellectual property, and future business prospects. These statements are based on current expectations and assumptions and are subject to risks and uncertainties that could cause actual results to differ materially. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. MTTI undertakes no obligation to update these forward-looking statements except as required by applicable law. The complete Pharma Tech Outlook feature article is available at: Contacts Media Contact Molecular Targeting Technologies, Inc. Chris Pak, Ph.D. Chairman and Chief Executive Officer Email: cpak@mtarget.com

2026-08-13

·多肽定制

多肽药物偶联的研究进展

【摘要】多肽药物偶联物（peptide–drug conjugate, PDC）是由肿瘤归巢肽、连接子（linker）与细胞毒性载荷三部分通过共价键组装而成的一类新型靶向药物，兼具小分子药物合成便利、结构均一的优势与抗体药物的靶向特异性，已成为继抗体药物偶联物（ADC）之后肿瘤靶向治疗领域发展最快的药物形式之一。与传统化疗药物相比，PDC能够借助受体介导的内吞作用将细胞毒性载荷选择性递送至肿瘤细胞，从而显著降低全身毒性、改善药代动力学性质并提高治疗窗。2018年和2022年，美国食品药品监督管理局（FDA）先后批准放射性多肽偶联药物Lutathera（177Lu-DOTA-TATE）和Pluvicto（177Lu-PSMA-617）上市，标志着PDC类药物正式进入临床常规应用。本文以文献库中收录的多篇国内外综述与实验研究为素材，系统总结了PDC的设计原理（靶向肽筛选、载荷选择、连接子化学）、代表性药物的临床研究进展，以及提高PDC疗效的前沿策略，并对该领域面临的挑战与未来发展方向进行了展望。一、引言：从"魔法子弹"到多肽药物偶联物恶性肿瘤是严重威胁人类健康的重大疾病。世界卫生组织（WHO）的统计显示，2018年全球新发癌症病例约1810万例，死亡约960万例；据预测，到2040年全球每年新发癌症病例将攀升至2750万例。在过去60余年中，化疗一直是肿瘤治疗的基石性手段。然而，传统化疗药物（如吉西他滨、紫杉醇、多柔比星、喜树碱等）对正常细胞与肿瘤细胞缺乏选择性，系统性给药后往往分布于全身，导致骨髓抑制、心脏毒性、神经毒性等严重不良反应；同时，肿瘤细胞可通过下调药物摄取转运体、激活P-糖蛋白外排、代谢失活等机制产生多药耐药（MDR），进一步限制化疗疗效。此外，多数化疗药物水溶性差、代谢不稳定，药代动力学性质不理想。因此，如何将强效的细胞毒药物"精准投递"至肿瘤组织，是抗肿瘤药物研发的核心命题。 "靶向治疗"的理念最早可追溯至德国科学家Paul Ehrlich于百年前提出的"魔法子弹"（magic bullet）设想，即设计一种既能选择性识别病灶细胞又能发挥杀伤作用的分子。这一理念催生了抗体药物偶联物（ADC）的诞生：通过将单克隆抗体与细胞毒性载荷以连接子共价偶联，借助抗体的靶向性实现载荷的肿瘤选择性递送。目前已有多种ADC获FDA批准上市，但ADC仍存在固有局限：完整抗体分子量约150 kDa，难以穿透实体瘤致密的细胞外基质；抗体的多个赖氨酸或半胱氨酸偶联位点导致药物-抗体比（DAR）不均一（通常为3~8），批间差异大、药代动力学复杂；制备成本高、存在免疫原性风险，且循环半衰期长易引发脱靶毒性。多肽药物偶联物（PDC）应运而生。PDC由三部分构成：负责靶向识别的多肽载体（tumor-homing peptide）、连接子以及细胞毒性载荷（payload）。相比ADC，PDC分子量通常仅2~5 kDa，可通过化学合成获得结构完全均一的产物，生产成本低、免疫原性低，且凭借小尺寸优势能够快速分布于组织、深度穿透实体瘤，部分多肽甚至可穿越血脑屏障（BBB），用于脑部肿瘤的治疗。在2018年与2022年，放射性核素偶联的Lutathera和Pluvicto先后获批，验证了PDC类药物的临床价值；此后，AEZS-108、ANG1005、BT8009等一批针对不同靶点的PDC相继进入II/III期临床研究，多肽药物偶联已成为肿瘤精准治疗领域最受瞩目的新赛道之一。二、肿瘤靶向肽及其筛选策略靶向肽是PDC实现肿瘤选择性的关键模块，要求能特异性地识别肿瘤细胞表面过表达（通常为正常组织的3倍以上）或特异性表达的受体，并在结合后介导偶联物的内吞。目前肿瘤靶向肽的获得主要依赖三条技术路线：噬菌体展示技术、化学合成肽库筛选和基于靶点结构的计算机模拟设计。 2.1 噬菌体展示技术噬菌体展示技术是将编码目标多肽的基因克隆至噬菌体基因组中，使多肽以融合蛋白形式展示于噬菌体表面，再利用抗原-抗体特异性结合原理，经3~5轮生物淘洗（biopanning）富集与靶蛋白结合紧密的噬菌体克隆，最后通过测序推断出靶向多肽的氨基酸序列。常用的展示系统包括单链丝状噬菌体与T4噬菌体。目前经噬菌体展示筛选获得的肿瘤靶向肽众多，例如靶向淋巴瘤细胞的DV3（LGASWHRPDK）、靶向整合素αvβ3/αvβ5的RGD-4C（CDCRGDCFC）、靶向肿瘤新生血管氨肽酶N（CD13）的NGR（CNGRCVSGCAGRC）等。其中研究最为深入的是NGR肽：意大利MolMed公司基于NGR肽与肿瘤坏死因子α（TNF-α）构建的NGR-hTNF偶联物，已完成针对结肠癌、卵巢癌、非小细胞肺癌、小细胞肺癌及恶性胸膜间皮瘤等的多项II/III期临床研究，充分体现了噬菌体展示筛选的转化价值。 2.2 化学合成肽库筛选随着固相多肽合成（SPPS）技术的成熟，研究者可以低成本、高通量地合成由4~12个天然或非天然氨基酸组成的短肽化合物库，通过氨基酸替换、序列重排与化学修饰构建数百万种候选分子；随后借助亲和色谱体系测定优选序列与先导序列的表观解离常数（Kd），从而筛选出与靶点亲和力强的短肽。例如靶向粒细胞白血病细胞的LKKP肽和靶向恶性黑色素瘤细胞的PYEE肽均来源于化学合成肽库。该方法产物纯度高、可引入非天然氨基酸，为PDC靶向肽的优化提供了丰富的分子来源。 2.3 计算机模拟设计基于蛋白质数据库（PDB）提供的靶点晶体结构，可运用分子对接与分子动力学模拟分析多肽与靶蛋白之间的作用力类型、结合能量及关键氨基酸残基距离，进而设计系列候选多肽并择优合成。例如，特异结合基质金属蛋白酶9（MMP9）的多肽序列CTFKEIVPDLC即是通过计算机模拟筛选获得。此类方法尤其适用于缺乏天然配体或配体-受体相互作用信息有限的新靶点，已成为靶向肽发现的重要补充手段。 2.4 常见靶点与代表性靶向肽根据靶点性质，PDC靶向肽主要分为几大类：（1）整合素靶向肽：RGD三肽基序最早由Ruoslahti和Pierschbacher于20世纪80年代在纤连蛋白中发现，可被超过10种整合素识别，其中整合素αvβ3（玻连蛋白受体）在活化内皮细胞与肿瘤新生血管中高表达，而在多数成人上皮细胞中几乎不表达，是理想的抗血管生成靶点；环状iRGD（CRGDKGPDC）除结合αvβ3/αvβ5外，还可在肿瘤组织中被蛋白酶切割暴露C末端CendR基序（RXXK/R），转而结合神经纤毛蛋白-1（NRP-1），激活组织穿透途径，显著增强偶联药物的瘤内递送效率。（2）激素受体靶向肽：促性腺激素释放激素（GnRH/LHRH）受体在卵巢癌、前列腺癌、肺癌和乳腺癌等多种肿瘤中高表达，D-Lys6-GnRH-I因引入D-赖氨酸而结合亲和力更高、抗酶解能力更强，且其侧链ε-氨基可作为正交偶联位点；生长抑素受体（尤其SSTR2）在神经内分泌肿瘤中广泛过表达，奥曲肽、兰瑞肽、伐普肽等环状类似物已成为放射性PDC和化疗PDC的重要载体。（3）跨膜受体靶向肽：如靶向EGFR的GE11（YHWYGYTPQNVI）、靶向LRP-1的19肽angiopep-2（TFFYGGSRGKRNNFKTEEY，可经受体介导转胞吞穿越血脑屏障）、靶向hY1R的[F7,P34]NPY（hY1R在90%以上的乳腺肿瘤及其转移灶中过表达）等。（4）新兴靶点：Nectin-4（膀胱癌等多种实体瘤）、EphA2、PSMA、IL-11Rα及CD13等。为便于系统把握PDC的靶向模块，现将文献报道的常用靶点、对应靶向肽序列及其代表性偶联物详述如下。（1）整合素αvβ3/αvβ5——RGD肽家族。整合素是由非共价结合的α、β亚基组成的异二聚体跨膜受体，负责连接细胞外基质与胞内细胞骨架，介导细胞黏附、迁移与增殖。RGD（Arg-Gly-Asp）三肽基序最早由Ruoslahti和Pierschbacher于20世纪80年代在纤连蛋白中发现，可被超过10种整合素识别（包括全部αv整合素、α5β1、α8β1与αIIbβ3）。其中整合素αvβ3（又称玻连蛋白受体）在活化内皮细胞、新生血管与多种肿瘤细胞表面高表达，而在多数成人上皮细胞中表达水平极低，是抗血管生成治疗和肿瘤靶向递送的理想靶点。天然RGD肽易被酶解且亲和力有限，故实际应用中多以环化策略提高稳定性与亲和力：代表性序列包括环状RGD-4C（CDCRGDCFC，经两个半胱氨酸形成二硫键环化）、c(RGDyK)、c(RGDfV)等，其中c(RGDfV)对αvβ3、αvβ1与αvβ5的IC50分别约为89、335与440 nmol/L，其N-甲基化衍生物西仑吉肽（cilengitide，RGDf(NMe)V）曾是进入临床研究的整合素拮抗剂。进一步的环肽改造还产生了兼具穿透功能的iRGD（CRGDKGPDC，9肽）：iRGD先经RGD基序结合αvβ3/αvβ5整合素，随后被细胞表面相关蛋白酶切割，暴露C末端隐藏的CendR基序（RXXK/R），转而结合神经纤毛蛋白-1（NRP-1），激活组织与细胞穿透途径，可将共价或非共价连接的载荷带出血管、深入肿瘤实质。（2）LHRH-R——GnRH靶向肽。促性腺激素释放激素（GnRH，又称黄体生成素释放激素LHRH）是下丘脑分泌的十肽激素（pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2），通过结合七次跨膜G蛋白偶联受体GnRH-R促进垂体分泌FSH与LH。多种人类肿瘤（以卵巢癌、前列腺癌、肺癌和乳腺癌为主）相对于正常组织特异性表达或过表达GnRH-R，使其成为PDC的经典靶点。天然的GnRH-I、GnRH-II与海七鳃鳗来源的GnRH-III均可结合肿瘤表面受体；其中应用最广的是D-Lys6-GnRH-I：将天然序列第6位甘氨酸替换为D-赖氨酸后，肽段结合亲和力提高、β-转角结构更稳定、抗蛋白酶降解能力增强，且赖氨酸侧链ε-氨基提供了与细胞毒载荷正交偶联的位点。该肽已用于构建AEZS-108（AN-152，偶联多柔比星）等进入后期临床研究的PDC。（3）生长抑素受体（SSTR）——奥曲肽等环肽类似物。生长抑素以SST-14与SST-28两种活性形式存在，通过高亲和膜受体SSTR1-5发挥内分泌调节与神经递质作用。SSTR在神经内分泌肿瘤（胰腺、垂体、前列腺、肺类癌等）以及乳腺癌、结直肠癌、卵巢癌等非神经内分泌肿瘤中广泛过表达，其中SSTR2是最常过表达的亚型。由于天然生长抑素在体内被快速酶解，临床上多用D-氨基酸替换并缩短肽链得到的环状类似物，包括奥曲肽（d-Phe-c[Cys-Phe-d-Trp-Lys-Thr-Cys]-Thr-ol）、兰瑞肽（d-2Nal-c[Cys-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2）与伐普肽（d-Phe-c[Cys-Tyr-d-Trp-Lys-Val-Cys]-Trp-NH2），三者均主要结合SSTR2。基于SSTR2的PDC家族是目前临床转化最成功的领域：已上市药物Lutathera（177Lu-DOTA-TATE）即采用DOTA螯合177Lu连接至TATE（奥曲肽类八肽）实现神经内分泌肿瘤的肽受体放射性核素治疗；此外还有111In-DTPA-奥曲肽（pentetreotide）等经典诊断探针，以及偶联DM1的PEN-221、偶联紫杉醇的PTX-OCT等在研品种。（4）EGFR——GE11等噬菌体展示肽。表皮生长因子受体（EGFR/ErbB1）属于ErbB受体酪氨酸激酶家族，在多种肿瘤组织中上调，通常经网格蛋白介导的内吞进入细胞，适合作为PDC的递送入口。通过噬菌体展示肽库筛选获得的高亲和EGFR靶向肽包括GE11（YHWYGYTPQNVI，12肽）、CMYIEALDKYAC（二硫键环化）、LTVSPWY与YWPSVTL等，其中GE11研究最为广泛，已用于构建多种化疗药、核酸与纳米载体的靶向递送体系。（5）LRP-1——angiopep-2。 angiopep-2是由19个氨基酸组成的多肽（TFFYGGSRGKRNNFKTEEY），能够结合在脑组织高表达的低密度脂蛋白受体相关蛋白-1（LRP-1），经受体介导转胞吞作用穿越血脑屏障（BBB），是脑胶质瘤等中枢神经系统肿瘤PDC设计的关键载体。其序列中含有两个赖氨酸，为多点偶联细胞毒载荷提供了便利；ANG1005即通过琥珀酰酯键将3分子紫杉醇连接至1分子angiopep-2，已进入治疗脑转移瘤的II期临床研究。（6）CD13——NGR肽。 NGR（Asn-Gly-Arg）基序靶向肿瘤新生血管高表达的氨肽酶N（CD13），代表性环状序列为CNGRCG。意大利MolMed公司将NGR肽与肿瘤坏死因子α融合构建的NGR-hTNF（NGR015），利用NGR的血管靶向将TNF-α富集于肿瘤血管，已针对结肠癌、卵巢癌、非小细胞肺癌、小细胞肺癌及恶性胸膜间皮瘤等完成多项II/III期临床研究。（7）其他具有潜力的靶点体系。神经肽Y受体hY1R在90%以上的乳腺肿瘤及100%的乳腺癌转移灶中过表达，且健康乳腺组织以hY2R为主，hY1R亚型选择性类似物[F7,P34]NPY可实现乳腺癌特异性递送，99mTc标记的[F7,P34]NPY类似物已在患者中完成乳腺癌显像验证；Nectin-4在膀胱癌等多种实体瘤中高表达，双环肽毒素偶联物BT8009（BCY肽-MMAE）已进入II期研究；PSMA靶向的G-202（前体掩蔽肽策略）、叶酸受体靶向的EC145（vintafolide）亦分别推进至II/III期。此外，噬菌体展示来源的G3-C12肽（ANTPCGPYTHDCPVKR，靶向galectin-3）静注后特异性富集于肾脏近端小管，被用于肾靶向递送卡托普利；七肽P7可结合肺癌细胞表面高表达的Hsp90，用于构建多西他赛偶联物DTX-P7。靶点/受体靶向肽氨基酸序列类型/长度代表性偶联物整合素αvβ3 RGD RGD 线性三肽紫杉醇/表柔比星偶联物整合素αvβ3 RGD-4C CDCRGDCFC 环肽（二硫键）多种化疗药偶联物整合素αvβ3/αvβ5、NRP-1 iRGD CRGDKGPDC 环状9肽 cRGD-siEGFR等 LHRH-R D-Lys6-LHRH Glp-H-W-S-Y-K-L-R-P-G 线性十肽 AEZS-108（DOX） SSTR2/5 奥曲肽 d-Phe-c[Cys-Phe-d-Trp-Lys-Thr-Cys]-Thr-ol 环状八肽 Lutathera、PEN-221、PTX-OCT SSTR2 兰瑞肽 d-2Nal-c[Cys-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2 环状八肽放射性偶联物 EGFR（ErbB1） GE11 YHWYGYTPQNVI 线性12肽化疗药/核酸递送体系 LRP-1（血脑屏障） angiopep-2 TFFYGGSRGKRNNFKTEEY 线性19肽 ANG1005（紫杉醇×3） CD13 NGR CNGRCG 环状五肽 NGR015（hTNF-α） hY1R [F7,P34]NPY NPY类似物（36肽）线性36肽 MTX偶联物、99mTc显像探针 Nectin-4 BCY 双环肽结构双环肽 BT8009（MMAE） PSMA 掩蔽肽 D-γ-E-γ-E-γ-E-E 线性多肽 G-202（12ADT）叶酸受体叶酸偶联肽 DRDDS间隔 — EC145（去乙酰长春碱肼） galectin-3（肾靶向） G3-C12 ANTPCGPYTHDCPVKR 线性14肽 G3-C12-CAP（卡托普利） Hsp90 P7 七肽线性7肽 DTX-P7（多西他赛）三、细胞毒性载荷载荷是PDC发挥杀伤作用的"弹头"。理想载荷应具备合适的偶联官能团、足够强的细胞毒性（肿瘤细胞IC50通常要求达到低纳摩尔水平）以及可接受的理化性质。按性质不同，PDC载荷可分为化学药物、高活性毒素、生物大分子与放射性核素四类。 3.1 传统化疗药物载荷紫杉醇（PTX）是卵巢癌、肺癌和乳腺癌的一线/二线用药，通过结合β-微管蛋白稳定微管而阻断有丝分裂，但水溶性差、易诱发MDR。将紫杉醇与八聚精氨酸偶联形成的紫杉醇-八聚精氨酸共轭物（TOC）可下调MDR蛋白表达，对紫杉醇敏感和耐药的人卵巢癌细胞株OVCA 433的IC50分别仅为紫杉醇的1/14和1/47；紫杉醇-奥曲肽偶联物（PTX-OCT）则可特异性结合肿瘤高表达的SSTR2受体。喜树碱（CPT）以拓扑异构酶I为靶点，但其活性内酯环进入体循环后易水解失活，与靶向整合素的多肽ALOS4偶联后内酯环稳定性显著提高，并可借助多肽的靶向动力富集于肿瘤组织。多柔比星（DOX）和道诺霉素属蒽环类，通过嵌入DNA、稳定拓扑异构酶II复合物抑制核酸合成，但存在累积性心脏毒性与耐药问题；50 μmol/L的TAT-多柔比星对耐药细胞株KB-V1的细胞死亡率达86%，显著高于单用多柔比星的14%。此外，甲氨蝶呤、苯丁酸氮芥、吉西他滨等也已被用于PDC构建，例如吉西他滨可在体内脱氨失活为dFdU，偶联后可改善其代谢稳定性。 3.2 高活性毒素载荷借鉴ADC的开发经验，PDC越来越多地采用活性远超传统化疗药的高毒性载荷，包括微管抑制剂单甲基奥瑞他汀E（MMAE）与美登素衍生物DM1、DNA损伤剂吡咯并苯二氮卓（PBD）二聚体、拓扑异构酶I抑制剂SN-38与依喜替康（exatecan）等。双环毒素偶联物BT8009即以MMAE为载荷；PEN-221则将DM1通过二硫键连接至奥曲肽。高毒性载荷允许以更低的给药剂量达到杀瘤效果，但要求连接子具备足够高的循环稳定性，防止载荷过早释放造成全身毒性。 3.3 生物大分子与新型功能载荷除化学药物外，PDC还可偶联多种生物大分子载荷：TNF-α（如NGR-hTNF，靶向肿瘤新生血管CD13）、裂解肽（如EP-100偶联的阳离子α-螺旋裂解肽ClIP-71、靶向VEGFR的QR-KLU）、siRNA（如cRGD-siEGFR可沉默EGFR基因）、反义寡核苷酸（AONs，如内化肽Pip偶联的Pip-AONs可延长脊髓性肌萎缩症模型小鼠生存期）等。近年来，蛋白降解靶向嵌合体（PROTAC）和免疫检查点降解剂也被引入PDC：将PD-L1降解剂BMS-8与cRGD偶联得到的BMS-L1-RGD在黑色素瘤模型中展现出增强的PD-L1降解与抑瘤效果；PMT-O9-1A则将抗PD-L1肽与天然产物降解剂巴马汀（palmatine）通过二硫键连接，通过"胞外阻断+胞内降解"双重机制改善肺癌治疗效果。 3.4 放射性核素载荷放射性核素是PDC特有的载荷类型，兼具诊断与治疗功能（theranostics）。β-发射体177Lu、γ/俄歇电子发射体111In、90Y等通过与螯合剂DOTA或DTPA结合后连接至靶向肽，可实现肿瘤的分子影像与放射性核素治疗。已上市的Lutathera（177Lu-DOTA-TATE）与Pluvicto（177Lu-PSMA-617）即为该类型的代表。此外，靶向生长抑素受体的111In-DTPA-奥曲肽已上市数十年，是核医学领域最经典的肽类诊断探针。四、连接子化学：PDC设计的核心环节连接子将靶向肽与载荷连接起来，是决定PDC成药性的枢纽。理想的连接子需满足双重条件：在血液循环中保持足够稳定，保证偶联物完整到达肿瘤部位；到达靶组织或被内吞进入溶酶体后，能响应特定刺激高效裂解，释放出活性载荷。连接子的长度、亲疏水性、电荷及裂解机制均会影响偶联物的药代动力学性质与治疗窗。根据裂解特性，连接子可分为不可裂解与可裂解两大类，后者又可细分为pH敏感型、酶敏感型与氧化还原敏感型，并可引入自降解间隔子实现级联释放。 4.1 不可裂解连接子不可裂解连接子通过酰胺键、醚键、硫醚键等稳定的化学键将肽与药物相连，到达靶组织后连接子本身不裂解，载荷需以"连接子-药物"整体形式或经溶酶体降解后发挥活性。常用结构包括6-氨基己酸、短肽片段CGGW及穿膜肽TAT等，多为4个氨基酸的短肽或含5~8个碳原子的碳链，化学性质稳定，可调节偶联物的极性，适用于不以游离药物形式发挥作用的载荷。 4.2 pH敏感型连接子肿瘤细胞增殖代谢旺盛，糖酵解增强导致乳酸堆积，肿瘤微环境pH通常约为6.8，显著低于血液的7.3左右；内吞后的内体/溶酶体腔室pH更低（4.5~6.0）。pH敏感型连接子利用这一pH梯度实现肿瘤特异性释放：腙键、肟键、缩醛键、乙烯醚键、原酸酯键等酸不稳定化学键在生理pH下稳定，而在酸性环境中水解。研究表明，神经肽Y（NPY）经酸敏感腙键偶联道诺霉素后，其细胞毒性显著高于经酰胺键连接的对应物。低pH插入肽（pHLIP）则是利用肿瘤酸性微环境"插入"细胞膜的典型策略：pHLIP在低pH下形成α-螺旋并将C末端及其载荷跨膜导入胞内，pHLIP-SS-DOX在pH 6.0时表现出明显细胞毒性并可逆转多药耐药。 4.3 酶敏感型连接子酶敏感型连接子以肿瘤部位高表达的蛋白酶为裂解触发因素，最具代表性的是组织蛋白酶B底物与基质金属蛋白酶（MMP）底物。组织蛋白酶B在肺癌、脑癌、前列腺癌、乳腺癌等多种恶性肿瘤中高表达，可特异性识别并切割GFLG四肽及缬氨酸-瓜氨酸（Val-Cit）二肽序列；MMP2/MMP9在直肠癌、神经母细胞瘤、膀胱癌、肝癌中高表达，可切割PLGLAG、GPLGIAGQ、GPVGLIGK等短肽片段。此类连接子在血液循环中稳定，进入富含靶酶的肿瘤细胞溶酶体后才发生酶解，实现载荷的定点释放。BT8009即采用Val-Cit连接子，经肿瘤细胞溶酶体中的组织蛋白酶B切割后释放MMAE。 4.4 氧化还原敏感型连接子还原型谷胱甘肽（GSH）在肺癌、胰腺癌、头颈部癌和乳腺癌等肿瘤组织中的浓度显著高于正常组织，肿瘤细胞内还原性环境为二硫键连接子提供了裂解条件。含有二硫键的连接子在循环中稳定，进入肿瘤细胞后被GSH还原断裂，释放载荷。四川大学团队将半乳糖凝集素-3靶向肽G3-C12（ANTPCGPYTHDCPVKR）通过二硫键连接血管紧张素转化酶（ACE）抑制剂卡托普利，实现了肾脏靶向递送：注射后0.05 h药物即在肾脏内完全释放，肾组织AUC较游离药物提高2.7倍，体内肾ACE抑制活性显著增强，为慢性肾病治疗提供了新思路。 4.5 自降解间隔子与级联释放为解耦"酶切位点"与"药物释放"两个环节，研究者设计了自降解（self-immolative）间隔子。对氨基苄醇（PABC）是典型代表：其氨基端通过酰胺键与酶水解单元（如组织蛋白酶B底物）相连，羟基端以碳酸酯/氨基甲酸酯键连接载荷；当酶切单元被蛋白酶裂解后，PABC发生1,6-消除反应，自发降解并释放完整活性药物，实现"一次酶切、级联释放"，可有效避免释放含连接子残基的药物衍生物。 4.6 连接子结构对PDC毒性的调控连接子化学结构不仅决定释放动力学，还直接调控偶联物的毒性谱。Beck-Sickinger团队以hY1R靶向肽[F7,P34]NPY为模型，系统比较了酰胺键、酯键、二硫键、酶切位点及"二硫键+酯键"混合型五种连接子连接荧光基团和甲氨蝶呤后的行为：活细胞成像显示载荷释放动力学随连接子类型显著不同，而细胞活力实验证实，释放越快的连接子对应的MTX偶联物毒性越高，且毒性均依赖hY1R介导的内化。该研究为PDC连接子的理性选择提供了定量依据：载荷释放速度需与靶点内吞动力学相匹配，以实现"快释放、高活性"与"低脱靶"之间的平衡。从化学结构角度，PDC连接子按其裂解触发条件可分为酶可裂解、酸可裂解、还原可裂解与不可裂解四大类，各类连接子的化学键类型、释放机制与代表应用可归纳如下表。连接子类型典型化学键/结构裂解触发条件释放机制优缺点代表应用酯键（琥珀酰/戊二酰）琥珀酸酯、戊二酸酯酯酶/酰胺酶酶促水解合成简便，但血浆稳定性有限 AEZS-108（戊二酰-DOX）、ANG1005（琥珀酰-紫杉醇）酰胺键酰胺酰胺酶酶促水解稳定性较好，需匹配靶组织蛋白酶谱 NGR015（CNGRCG-hTNF-α）酸可裂解腙键、亚胺、肟、原酸酯、缩醛、乙烯醚、聚缩酮肿瘤微环境pH≈6.8及内体/溶酶体pH 4.5~6.0 酸性水解血液循环中稳定，靶区酸性触发释放腙键-多柔比星偶联物、pHLIP-SS-DOX 还原可裂解二硫键细胞内高浓度GSH/半胱氨酸硫醇-二硫键交换还原选择性高，但血浆中可能提前断裂 G3-C12-CAP（肾靶向）、EC145、PEN-221 组织蛋白酶B底物肽 GFLG、Val-Cit 溶酶体组织蛋白酶B 酶切肿瘤溶酶体特异性释放，应用最广 BT8009（Val-Cit-PABC-MMAE） MMP底物肽 PLGLAG、GPLGIAGQ、GPVGLIGK 肿瘤微环境MMP-2/9 酶切可胞外释放，利于旁观者效应多种MMP敏感PDC 自降解间隔子 PABC（对氨基苄醇）酶切后级联 1,6-消除自降解释放未修饰的完整活性药物 Val-Cit-PABC体系不可裂解硫醚、三唑（点击化学）、氧肟 —（不裂解）载荷随连接子整体经溶酶体降解血浆极稳定，避免提前释放需以偶联物形式发挥活性的载荷需要强调的是，连接子化学结构对PDC疗效与毒性的影响已有系统性的定量研究。Beck-Sickinger团队以hY1R靶向肽[F7,P34]NPY为模型，通过固相合成构建了酰胺键、酯键、二硫键、酶切位点（GFLG）及"二硫键+酯键"混合型共五种连接方式的荧光与甲氨蝶呤（MTX）偶联物（ChemMedChem 2015, 10, 804-814）。活细胞成像显示，偶联物的胞内释放动力学高度依赖连接子类型：酶切位点连接的偶联物在荧光实验中最稳定、释放较慢，而酯键与二硫键偶联物释放较快；细胞活力实验进一步证实，释放动力学与细胞毒性呈正相关——释放越快的连接子对应MTX偶联物对hY1R阳性乳腺癌细胞的毒性越高，且所有毒性均依赖于hY1R介导的内化。值得注意的是，研究者设计的"二硫键+酯键"混合型连接子（SPDP-bME）在细胞内既可经二硫键还原、又可经酯键水解释放出未修饰的游离MTX，避免了连接子残基保留导致药效下降的问题，体现了多功能连接子的设计价值。该系列研究同时表明：人血浆稳定性测试中，含酶切位点（GFLG）的偶联物稳定性最高，最适于体内应用，提示在开发PDC时应根据载荷特性和靶点内化动力学权衡"循环稳定性"与"胞内释放速率"这对矛盾。五、代表性PDC药物及临床研究进展 5.1 已获批上市的PDC Lutathera（177Lu-DOTA-TATE）于2018年获FDA批准，是全球首个上市的PDC类药物，用于生长抑素受体阳性的胃肠胰神经内分泌肿瘤（GEP-NETs）治疗。其结构以含酪氨酸的生长抑素类似物Tyr3-octreotate（TATE）为靶向肽，经酰胺键连接DOTA螯合的β-发射体177Lu。III期临床显示，一线Lutathera联合长效奥曲肽治疗可将2~3级晚期GEP-NETs患者的中位无进展生存期（PFS）延长约14个月。Pluvicto于2022年3月获批，用于PSMA阳性转移性去势抵抗性前列腺癌（mCRPC），其靶向肽含PSMA结合基序Glu-NH-CO-NH-Lys，连接子引入2-萘丙氨酸与氨甲环酸，载荷同为177Lu-DOTA。此外，诊断用111In-DTPA-奥曲肽（生长抑素受体阳性肿瘤显像）早已上市，堪称PDC的"鼻祖"。 5.2 处于临床研究阶段的代表性PDC （1）AEZS-108（AN-152）：以D-Lys6-GnRH-I为载体、多柔比星为载荷、戊二酸为连接子，通过酯酶/酰胺酶裂解释放DOX，靶向LHRH受体，是最早进入III期临床的化疗型PDC之一。其前体AN-152/AN-207在多种LHRH-R阳性肿瘤模型（卵巢癌、前列腺癌、子宫内膜癌、乳腺癌）中抑瘤效果显著优于等摩尔游离药物而毒性更低，AN-152对MCF-7细胞IC50为13.7 nmol/L；AN-207因2-吡咯啉多柔比星活性更强但血浆稳定性差而止步于临床前。AEZS-108治疗铂耐药卵巢癌和复发性子宫内膜癌的II期研究显示疗效显著且耐受性良好，随后进入III期研究（NCT01767155）。（2）ANG1005：由3分子紫杉醇经琥珀酰酯连接子共价连接至angiopep-2，可经LRP-1介导的转胞吞穿越血脑屏障。临床前数据显示其脑摄取量约为紫杉醇的4.5倍；I期研究在复发恶性胶质瘤中证实其可将紫杉醇递送过BBB并达到治疗浓度；针对乳腺癌脑转移与软脑膜癌病的随机III期研究（NCT03613181）正在进行。（3）NGR-hTNF：CD13靶向肽CNGRC融合TNF-α，通过靶向肿瘤新生血管发挥广谱抗瘤作用，治疗恶性胸膜间皮瘤的III期研究（NCT01098266）已完成。（4）G-202（mipsagargin）：以PSMA特异性底物肽为掩蔽部分、毒胡萝卜素衍生物12ADT为载荷的前药型PDC，在PSMA阳性肿瘤微环境中经切割激活，已完成II期研究（NCT01777594）。（5）EP-100：LHRH肽直接融合阳离子α-螺旋裂解肽ClIP-71，通过膜裂解杀伤LHRH-R阳性肿瘤细胞，卵巢癌II期研究（NCT01485848）显示其与紫杉醇联用可使部分肝转移患者获益。（6）PEN-221：奥曲肽经二硫键连接DM1，用于晚期神经内分泌肿瘤与小细胞肺癌（NCT02936323）。（7）CBX-12：pHLIP偶联拓扑异构酶I抑制剂依喜替康，针对铂耐药/难治性卵巢癌的II期研究（NCT06315491）正在进行，临床前显示其与PARP抑制剂及抗PD-1联用可显著抑制肿瘤生长并诱导长期免疫记忆。（8）BT8009：靶向Nectin-4的双环肽（Bicycle）经Val-Cit连接子偶联MMAE，双环肽通过TATA支架环化三个半胱氨酸形成约4 kDa的高度约束结构，兼具小分子快速组织分布、深度肿瘤穿透与抗体样高亲和选择性的优势；其I/II期研究（NCT04561362）及尿路上皮癌II/III期研究（NCT06225596）均在招募中，同类药物BT5528（靶向EphA2）I期研究（NCT04180371）亦已开展。（9）BMTP-11：IL-11Rα靶向环肽CGRRAGGSC融合凋亡诱导类肽D(KLAKLAK)2，通过线粒体膜破坏诱导凋亡，已在骨转移前列腺癌患者中完成I期研究。（10）国内研究方面，OSTP-DDP等新型PDC在卵巢癌A2780细胞模型中展现出靶向抑制活性，IL-4Rα靶向裂解肽融合物对原发性渗出性淋巴瘤具有抑制作用，反映了国内在该领域的积极布局。为便于查阅，现将文献报道中处于临床研究阶段的代表性PDC汇总如下表。药物名称靶向肽/载体靶点载荷连接子与释放机制临床阶段 AEZS-108（AN-152） D-Lys6-LHRH LHRH-R 多柔比星戊二酰（glutaryl）酯键，酯酶/酰胺酶裂解 III期 ANG1005 angiopep-2 LRP-1 紫杉醇×3 琥珀酰（succinyl）酯键，酯酶/酰胺酶裂解 II期 NGR015 CNGRCG（NGR肽） CD13受体 hTNF-α 酰胺酶裂解 III期 CT2103 聚谷氨酸 — 紫杉醇酯酶裂解 III期 EP-100 LHRH LHRH-R 裂解肽CLIP71 酰胺酶裂解 I期 EC145（vintafolide）叶酸偶联肽（DRDDS间隔）叶酸受体去乙酰长春碱肼（DAVBLH）二硫键，谷胱甘肽还原裂解 III期 G-202 掩蔽肽D-γ-E-γ-E-γ-E-E PSMA 12ADT（毒胡萝卜素衍生物）酶解触发 II期 BT8009 双环肽（BCY） Nectin-4 MMAE Val-Cit-PABC连接子，组织蛋白酶B裂解 II期上表可见，处于后期临床阶段的PDC涵盖了激素受体（LHRH-R）、肿瘤新生血管标志物（CD13）、叶酸受体、PSMA及Nectin-4等多种靶点类型，载荷从小分子化疗药到蛋白毒素、裂解肽不一而足；连接子策略则根据靶点的内化途径与药物释放需求灵活选择酯键、酰胺键、二硫键或酶底物肽序列，体现出"靶点—连接子—载荷"三要素系统优化的设计理念。 5.3 PDC在非肿瘤领域的拓展 PDC的应用正在从肿瘤拓展至其他疾病领域。除上述肾脏靶向的G3-C12-卡托普利偶联物外，靶向细菌与病毒的PDC（如偶联抗生素或抗病毒载荷）、用于自身免疫病和代谢疾病的PDC也处于研发之中。PDC"靶向肽+连接子+载荷"的模块化架构天然适配"任意靶点-任意载荷"的组合逻辑，为多种疾病的精准用药提供了通用平台。六、增强PDC疗效的前沿策略 6.1 多价与双特异性靶向单体靶向肽的亲和力通常有限，多价化策略通过二聚、三聚乃至四聚化显著提高结合亲和力与肿瘤蓄积：二聚RGD肽对整合素αvβ3的亲和力较单体提高约10倍，三聚/四聚RGD衍生物活性优于单体及更高价聚簇；EphA2二聚肽结合亲和力较单体提高约13倍，二聚EphA2靶向PDC在乳腺癌和胰腺癌模型中有效靶向循环肿瘤细胞并抑制肺转移；HER2靶向同源二聚环肽（RNWELRLK-PEG4）2在HER2阳性乳腺癌中表现出增强的亲和力、抗肿瘤活性与降低的全身毒性。双特异性策略则使单一PDC同时识别同一靶蛋白的不同结构域（如EGFR胞外肽LARLLT+胞内靶向载荷吉非替尼、HER2结构域II/IV融合肽），进一步提升结合效率与治疗窗口。 6.2 环化、双环与订书肽修饰线性肽易被蛋白酶降解且构象柔性大、亲和力低，环化可显著改善其代谢稳定性与靶点亲和力：环状RGD在中性pH溶液中的稳定性约为线性RGD的30倍，原因在于环化降低了结构柔性并促进Arg/Asp侧链间盐桥形成；双环肽（bicyclic peptide）通过支架约束三个半胱氨酸形成双环结构，肽-铋双环在生理pH下快速形成且可稳定数周，其活性较线性类似物最高提升130倍、蛋白水解稳定性提升19倍；订书肽（stapled peptide）通过Grubbs催化形成烃类桥连，稳定α-螺旋构象，如p53来源订书肽的螺旋含量、抗酶解能力与结合亲和力均显著提高；knottin（结蛋白）类多环肽（30~50个氨基酸）热稳定性和蛋白水解稳定性极高，knottin-吉西他滨偶联物（KDC）以低纳摩尔亲和力靶向整合素并经整合素介导内吞在胞内释放载荷。 6.3 白蛋白结合与长效化 PDC分子量小、肾清除快，血浆半衰期短。借鉴长效胰岛素和GLP-1受体激动剂的经验，引入脂肪酸等白蛋白结合基团可大幅延长循环时间：地特胰岛素（B29赖氨酸连接肉豆蔻酸）与德谷胰岛素（经谷氨酸连接十六碳二酸）均为已上市的长效胰岛素；司美格鲁肽在Lys26侧链连接C18硬脂二酸，通过白蛋白结合使半衰期延长至约165 h，于2017年获FDA批准治疗2型糖尿病、2021年获批用于肥胖管理；替尔泊肽采用C20脂肪酸基团；一周一次的icodec胰岛素（1,18-十八碳二酸，人血浆半衰期约196 h）于2024年3月在欧洲获批。除脂肪酸外，4-(4-碘苯基)丁酸衍生物与截短伊文思蓝（tEB）等小分子白蛋白结合基团也被用于延长放射性PDC的血浆驻留时间。将脂肪酸侧链直接引入PDC靶向肽，已在小鼠模型中证明可提高血浆稳定性并延长抗肿瘤作用时程。 6.4 氨基酸替换与化学修饰 D-氨基酸替换、α,α-二取代氨基酸（如Aib）、N-甲基化及类肽化（peptoid）等化学修饰可赋予肽段抗酶解能力：全D型及末端部分D-氨基酸替换可保持或增强抗菌肽活性并显著提高血清稳定性；KRYRR五肽中D-氨基酸异构体在肿瘤异种移植模型中的细胞滞留与靶向能力增强；GLP-1第8位丙氨酸替换为甘氨酸后抵抗DPPIV降解；Aib和2-萘丙氨酸替换使Ipamorelin的人体终末半衰期延长至2 h。这些修饰策略同样适用于PDC靶向肽的稳定性优化。 6.5 克服生物屏障：细胞穿膜肽与BBB穿透细胞穿膜肽（CPP）可在无受体参与下跨膜转导载荷，但多数缺乏细胞特异性。将CPP与靶向肽（CTP）组合是兼顾"入胞效率"与"靶向选择性"的有效策略：例如将整合素靶向肽RGDC经二硫键连接环状CPP、以酯键连接卡巴他赛的PDC，到达肿瘤部位后二硫键被GSH裂解、环状CPP协助载荷入胞并经酯酶/酸性环境释放药物，在前列腺癌和乳腺癌模型中抑瘤活性与靶向性均增强。BBB穿透方面，除angiopep-2外，TfR靶向肽HAIYPRH偶联SN-38（经组织蛋白酶B可裂解连接子）的PDC可跨BBB选择性进入胶质母细胞瘤细胞并触发细胞毒效应；环形无正电荷CPP（EPP6）以及肽-铋双环化也显著提升穿膜与跨内皮转运效率。 6.6 新型功能载荷与自组装策略除前述PROTAC/降解剂载荷外，自组装多肽-药物结合物正在成为PDC的重要衍生方向：RGD靶向肽+自组装序列GNNNQNY+喜树碱组成的SAP-CPT可在靶细胞表面原位组装成纳米级寡聚体，增强内吞与杀伤；ROS响应型PDC（线粒体靶向肽KLAK+硫缩酮连接子+喜树碱）在肿瘤高ROS环境下解组装释放载荷；透明质酸包覆的双分子多柔比星自组装胶束（PDC-DOX2）借助CD44受体主动靶向肿瘤。巨胞饮（macropinocytosis）靶向是新兴方向之一：KRAS突变肿瘤细胞通过巨胞饮大量摄取胞外营养，针对该通路的PDC可显著提高突变肿瘤内的载荷蓄积与凋亡诱导。此外，肽的后期卤代修饰（如卤代色氨酸RGD）可提高对整合素αvβ3的亲和力与选择性。七、挑战与展望尽管PDC发展迅速，仍面临若干共性挑战：其一，多肽在体内代谢快、血浆稳定性差、肾清除迅速，半衰期短，需要通过环化、非天然氨基酸替换、白蛋白结合等手段系统优化；其二，连接子在循环中的过早释放或靶点处释放不完全将直接损害治疗窗，连接子设计需与靶点内吞动力学及载荷活性精细匹配；其三，PDC的合成纯度与规模化生产（尤其含多个偶联位点或复杂修饰的分子）仍需进一步工程化；其四，多数PDC靶向单一受体，肿瘤异质性可能导致疗效波动，多靶点、双特异性设计有望缓解。展望未来，双环肽（Bicycle）平台、mRNA展示与噬菌体展示等筛选技术将持续扩充靶向肽库；放射性核素偶联（177Lu、225Ac等α核素）与诊疗一体化（theranostics）将推动PDC在核医学领域的应用；硼中子俘获疗法（BNCT）等先进放疗技术与肽类载体的结合亦值得关注。同时，PDC与免疫检查点抑制剂等联用的协同策略已在临床前模型中显示出诱导长期免疫记忆的潜力。随着"靶向肽-智能连接子-高效载荷"三大模块的协同优化，多肽药物偶联有望成为继ADC之后肿瘤精准治疗与多疾病靶向用药的重要新范式。扫码联系我们电话：18455186404 微信：salepeptide 定制多肽，肽库生物

2026-07-07

·BioSpace

Molecular Targeting Technologies Presents First Clinical Validation of the Evans Blue Platform, Demonstrating Up to 15-Day Tumor Retention Using Approximately 12.5% of the Radioactivity Required for Conventional PRRT

Largest Reported Clinical Dataset for an Albumin-Binding Radiotherapeutic Supports the Evans Blue Platform as a Foundational Technology for Next-Generation Targeted Radiopharmaceuticals WEST CHESTER, Pa.--(BUSINESS WIRE)--Molecular Targeting Technologies, Inc. (MTTI), a clinical-stage biotechnology company developing next-generation radiopharmaceutical platform technologies, today announced that clinical data from 81 patients—the largest reported clinical dataset for an albumin-binding radiotherapeutic—will be presented at the 5th Targeted Radiopharmaceuticals Summit. The dataset provides what the Company believes is the first clinical validation of its proprietary Evans Blue (EB) platform, a reversible albumin-binding technology designed to enhance the pharmacokinetics and therapeutic performance of targeted radiopharmaceuticals. The presentation supports an emerging paradigm in radiopharmaceutical oncology: optimizing pharmacokinetics may become as important as discovering new molecular targets. The Evans Blue platform is designed to enhance the therapeutic performance of existing and next-generation targeted radiopharmaceuticals across multiple validated molecular targets. Clinical imaging and dosimetry demonstrated tumor retention for up to 15 days, approximately eight-fold greater tumor uptake , and efficient therapeutic radiation delivery while requiring only approximately 12.5% of the cumulative administered radioactivity used in conventional peptide receptor radionuclide therapy (PRRT). These findings suggest that improving pharmacokinetics through reversible albumin binding may substantially improve therapeutic efficiency while reducing the administered radioactivity required to achieve comparable tumor radiation delivery. Key clinical and preclinical findings include: Largest reported clinical dataset evaluating an albumin-binding PRRT in 81 patients with GEP-NETs. Tumor retention sustained for up to 15 days after a single administration. Approximately eight-fold greater tumor uptake and retention than conventional 177 Lu-DOTA-TATE, based on clinical dosimetry evaluations. Comparable tumor radiation dose delivery achieved using approximately 12.5% of the cumulative administered radioactivity required for conventional PRRT. Across multiple Evans Blue–enabled radiopharmaceuticals, preclinical studies demonstrated up to 35-fold greater tumor retention, than conventional 177 Lu-DOTA-TATE supporting the broad applicability of the Evans Blue platform across validated molecular targets, including SSTR2 and integrin αvβ3. In preclinical studies, 225 Ac-EBTATE demonstrated antitumor activity comparable to that observed with RayzeBio's RYZ101 while using approximately 40% of the administered radioactivity under the study conditions evaluated. 177 Lu-EBTATE demonstrated superior, dose-dependent, and durable antitumor efficacy compared with 177 Lu-DOTA-TATE in human lung adenocarcinoma and pancreatic xenograft models. 177 Lu-EBRGD combined with anti-PD-1 immunotherapy produced complete long-term survival and substantially outperformed monotherapy and sequential treatment in preclinical colorectal cancer models. Modular platform compatible with diverse radionuclides, targeting ligands, peptide classes, and both beta- and alpha-emitting therapeutic payloads, supporting broad applicability across multiple radiopharmaceutical programs. Because the Evans Blue platform functions independently of the targeting ligand, it has the potential to enhance a broad range of approved and investigational targeted radiopharmaceuticals across multiple molecular targets. Its modular design enables integration with diverse targeting ligands, radionuclides, and therapeutic payloads, providing a versatile platform for extending the lifecycle of established radiopharmaceuticals while enabling development of next-generation targeted radiotherapeutics. "Radiopharmaceutical oncology is entering a new era in which optimizing pharmacokinetics may become as important as discovering new molecular targets. Our clinical dataset from 81 patients provides what we believe is the first clinical validation of reversible albumin binding. We believe the Evans Blue platform has the potential to provide a broadly applicable pharmacokinetic enhancement platform for existing approved radiopharmaceuticals as well as next-generation therapeutic candidates across multiple validated molecular targets,” said Norman LaFrance, M.D., Chief Strategy Officer. "We believe the Evans Blue platform has the potential to redefine the development of targeted radiopharmaceuticals. Rather than replacing established radiopharmaceuticals, our strategy is to enhance the therapeutic performance of established and next-generation radiopharmaceuticals through reversible albumin binding. The Evans Blue platform is designed to increase tumor exposure, improve therapeutic efficiency, and enhance the clinical and commercial potential of both proprietary and partner radiopharmaceutical programs. Our vision is to establish Evans Blue as the foundational enabling technology powering the next generation of targeted radiopharmaceuticals through internal innovation, strategic collaborations, and licensing partnerships," said Chris Pak, Ph.D., Chairman and Chief Executive Officer. MTTI is actively seeking strategic collaborations with pharmaceutical and biotechnology companies interested in applying the Evans Blue platform to enhance approved and investigational radiopharmaceuticals through research collaborations, co-development, licensing, or other strategic partnerships. The Company welcomes discussions with partners seeking to improve the therapeutic performance of existing and next-generation targeted radiopharmaceuticals through the Evans Blue platform. About Molecular Targeting Technologies, Inc. Molecular Targeting Technologies (MTTI) is a clinical-stage biotechnology company developing the proprietary Evans Blue (EB) platform, a reversible albumin-binding technology designed to enhance pharmacokinetics, improve tumor targeting, and optimize the therapeutic performance of targeted radiopharmaceuticals. The Company's pipeline includes EB-TATE, EB-RGD, EB-FAPI, and EB-GRPR, reflecting the broad applicability of the Evans Blue platform across multiple molecular targets. For more information, visit . Forward-Looking Statements This press release contains forward-looking statements regarding the development, potential applications, and future evaluation of MTTI's Evans Blue platform and related product candidates. These statements involve risks and uncertainties that may cause actual results to differ materially from those expressed or implied. Preclinical and clinical observations may not be predictive of future clinical outcomes or regulatory decisions. MTTI undertakes no obligation to update these statements except as required by applicable law. Contacts Media Contact: Chris Pak, Ph.D., Chairman and Chief Executive Officer; Email: cpak@mtarget.com

100 项与 177Lu-DOTA-EB-TATE 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
甲状腺Hurthle细胞癌	临床2期	美国	National Institute of Diabetes & Digestive & Kidney Diseases	2026-09-23
APUD瘤	临床1期	美国	Molecular Targeting Technologies, Inc.	2022-06-18

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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


SNMMI2026	临床1期	神经内分泌肿瘤 somatostatin receptor (SSTR) overexpression	6	177Lu-DOTA-EB-TATE 1.85 GBq	遞鑰膚觸窪繭醖築艱餘(窪製願鹹鹹壓窪襯網蓋) = Hematologic toxicity was dose-limiting, with one patient in this study experiencing persistent Grade 3 febrile neutropenia at the 3.70 GBq dose level. Another patient from an external cohort also experienced a dose-limiting toxicity (DLT) at the same dose level, 構壓網遞願餘艱鏇範夢 (顧鑰齋遞繭膚鹽獵齋壓 )	积极	2026-05-27
NCT03478358 (Pubmed \| Clin Nucl Med)	临床1期	-	10	177Lu-DOTA-EB-TATE without amino acid infusion	構積夢構齋獵醖衊廠觸(艱製鬱壓膚築鏇糧憲遞) = 憲窪網糧簾積製鹽廠淵觸鏇構構鹹窪鏇餘淵齋 (繭窪蓋餘艱鏇齋繭衊襯 ) 更多	-	2023-04-18
				177Lu-DOTA-EB-TATE with amino acid infusion	構積夢構齋獵醖衊廠觸(艱製鬱壓膚築鏇糧憲遞) = 膚衊鬱醖艱遞繭蓋襯鏇觸鏇構構鹹窪鏇餘淵齋 (繭窪蓋餘艱鏇齋繭衊襯 ) 更多
SNMMI2020	N/A	晚期神经内分泌肿瘤	-	Group A (1.17 ± 0.09 GBq/dose)	壓獵壓簾膚艱襯膚淵窪(範鬱壓獵蓋觸艱壓鹽餘) = 0.63% (1/160) occurrence in all of the performed blood tests 憲壓糧積鹹網壓糧獵糧 (獵壓壓艱衊壓觸憲鑰淵 ) 更多	-	2020-05-15
				Group B (1.89 ± 1.53 GBq/dose)
NCT03478358 (Treatment Using 177Lu-DOTA-EB-TATE, Pubmed \| Eur J Nucl Med Mol Imaging)	临床1期	神经内分泌肿瘤	-	Group A	餘構蓋膚範窪構觸蓋製(夢壓鏇鑰餘觸衊願膚廠) = 膚蓋觸構膚遞膚醖憲範願衊顧蓋獵鹽壓廠窪網 (鹽淵繭窪廠憲鬱窪鏇遞 )	-	2020-04-01
				Group C	餘構蓋膚範窪構觸蓋製(夢壓鏇鑰餘觸衊願膚廠) = 簾襯築廠壓廠製膚鹽蓋願衊顧蓋獵鹽壓廠窪網 (鹽淵繭窪廠憲鬱窪鏇遞 )