Trastuzumab Pamirtecan

Continued execution of BioNTech’s oncology strategy with focus on two pan-tumor programs including two announced transactions: mRNA-based cancer immunotherapy candidates and BNT327, a bispecific antibody candidate targeting PD-L11 and VEGF-A Entered a global strategic co-development and co-commercialization collaboration with Bristol Myers Squibb (“BMS”) to jointly execute a broad clinical development program to evaluate and advance BNT327 across numerous solid tumor types Announced strategic transaction to acquire CureVac N.V. (“CureVac”) to strengthen the research, development, manufacturing and commercialization of mRNA-based cancer immunotherapy candidates Presented multiple clinical updates across diversified oncology pipeline at medical meetings validating the Company’s oncology combination strategy Approval received for new variant-adapted COVID-19 vaccine by the European Commission (“EC”); further launch preparation underway as recommended by regulators, with deliveries expected to be ready as early as August, subject to regulatory approval in respective markets Second quarter 2025 revenues of €0.3 billion2, net loss of €0.4 billion and basic and diluted loss per share of €1.60 ($1.823) Maintained strong financial position with €16.0 billion in cash, cash equivalents and security investments as of June 30, 2025; Partnership with Bristol Myers Squibb expected4 to further strengthen BioNTech’s financial position with $1.5 billion expected to be reflected in third quarter 2025 cash position Full year 2025 financial guidance reaffirmed5 Conference call and webcast scheduled for August 4, 2025, at 8:00 a.m. EDT (2:00 p.m. CEST) MAINZ, Germany, August 4, 2025 (GLOBE NEWSWIRE) -- BioNTech SE (Nasdaq: BNTX, “BioNTech” or “the Company”) today reported financial results for the six months ended June 30, 2025 and provided an update on its corporate progress. “In the second quarter, we took significant steps to advance BioNTech into a multiproduct biotechnology company by strengthening the two pillars of our oncology strategy,” said Prof. Ugur Sahin, M.D., Chief Executive Officer and Co-Founder of BioNTech. “We entered into a collaboration with BMS to accelerate and expand the development of our PD-L1xVEGF-A bispecific antibody candidate BNT327 and announced a strategic transaction to acquire CureVac to complement our own capabilities and proprietary technologies in mRNA design, delivery formulations, and mRNA manufacturing. These transformative transactions contribute to our mission of delivering truly transformative options for patients in need.” Financial Review for Second Quarter and First Half of 2025 Revenues for the three months ended June 30, 2025, were €260.8 million, compared to €128.7 million for the comparative prior year period. For the six months ended June 30, 2025, revenues were €443.6 million, compared to €316.3 million for the comparative prior year period. The increases were mainly driven by higher revenues derived from BioNTech’s COVID-19 vaccine collaboration. Research and development (“R&D”) expenses were €509.1 million for the three months ended June 30, 2025, compared to €584.6 million for the comparative prior year period. For the six months ended June 30, 2025, R&D expenses were €1,034.7 million, compared to €1,092.1 million for the comparative prior year period. The decreases were mainly driven by the reprioritization of clinical trials towards focus programs. Sales, general and administrative (“SG&A”) expenses, in total, amounted to €137.4 million for the three months ended June 30, 2025, compared to €183.8 million for the comparative prior year period. For the six months ended June 30, 2025, SG&A expenses were €258.0 million, compared to €316.4 million for the comparative prior year period. The decreases were primarily driven by a reduction in external services. Net loss was €386.6 million for the three months ended June 30, 2025, compared to a net loss of €807.8 million for the comparative prior year period. For the six months ended June 30, 2025, net loss was €802.4 million, compared to a net loss of €1,122.9 million for the comparative prior year period.Basic and diluted loss per share was €1.60 for the three months ended June 30, 2025, compared to a basic and diluted loss per share of €3.36 for the comparative prior year period. For the six months ended June 30, 2025, basic and diluted loss per share was €3.33, compared to a basic and diluted loss per share of €4.67 for the comparative prior year period. Cash and cash equivalents plus security investments as of June 30, 2025, reached €15,989.3 million, comprising €10,269.5 million in cash and cash equivalents, €3,363.8 million in current security investments and €2,356.0 million in non-current security investments. Shares outstanding as of June 30, 2025, were 240,398,724, excluding 8,153,476 shares held in treasury. “Joining BioNTech is a privilege, especially during this decisive phase in which we aim to capitalize on our innovative pipeline with clear strategic focus. While we continue to significantly invest into the execution of our strategy, our commitment to operational and financial discipline is starting to show tangible results,” said Ramón Zapata, Chief Financial Officer at BioNTech. “With the strategic BMS collaboration we will further strengthen our topline and cash position. As such, we will receive an upfront cash-payment of $1.5 billion in Q3 that we anticipate to be recognized as revenue over the development phase of BNT327.” Anticipated Financial Effect4 of the BMS Partnership As part of the agreement with BMS, BioNTech expects to receive $1.5 billion in an upfront cash payment this year, and for this payment to be reflected in the Company’s reported cash position as of the third quarter 2025. BioNTech also expects to receive $2.0 billion in total non-contingent anniversary cash payments from 2026 through 2028. The upfront and non-contingent cash payments, amounting to $3.5 billion, are expected to be recognized as revenues over the development phase of BNT327. In addition, BioNTech will be eligible to receive up to $7.6 billion in development, regulatory and commercial milestones, with the majority of milestone payments expected to be triggered upon approvals and during commercialization. All milestones payments are anticipated to be reflected in the Company’s cash position and to be recognized as revenues following milestone achievement. Under the agreement, BioNTech and BMS will share joint development and manufacturing costs of BNT327 on a 50:50 basis, subject to certain exceptions. Global profits and losses will be equally shared between BioNTech and BMS. 2025 Financial Year Guidance Reaffirmed5: BioNTech expects its revenues for the full 2025 financial year to be in the range of €1,700 - €2,200 million and revenue phasing primarily concentrated in the last three to four months, driving the full year revenue figure. The revenue guidance assumes: relatively stable pricing and market share as compared to 2024; inventory write-downs and other charges estimated to be approximately 15% of BioNTech’s share of gross profit from COVID-19 vaccines sales in Pfizer Inc.’s (“Pfizer”) territory; anticipated revenues from a pandemic preparedness contract with the German government, from collaborations and from the BioNTech Group service businesses. Current and potential further developments in law, public policy, international trade, and public sentiment as they continue to evolve could further negatively impact the anticipated COVID-19 vaccine revenues and expenses. Planned 2025 Financial Year Expenses and Capex BioNTech expects to continuously focus investments on R&D and scaling the business for late-stage development and commercial readiness in oncology, while remaining cost-disciplined. Strategic capital allocation will continue to be a key driver of the Company’s trajectory. As part of BioNTech’s strategy, the Company may continue to evaluate appropriate corporate development opportunities with the aim of driving sustainable long-term growth and create future value. The full interim unaudited condensed consolidated financial statements can be found in BioNTech’s Report on Form 6-K for the period ended June 30, 2025, filed today with the United States Securities and Exchange Commission (“SEC”) and is available at www.sec.gov. Endnotes1 An overview of target abbreviations is compiled in a directory at the end of this press release.2 All numbers in this press release have been rounded.3 Calculated applying the average foreign exchange rate for the three months ended June 30, 2025, as published by the German Central Bank (Deutsche Bundesbank).4 These statements, including the anticipated timing of certain events, are based on BioNTech’s current expectations regarding the BMS collaboration and are subject to the successful co-development, approval and co-commercialization of BNT327. These statements are also based in part on assumptions and judgments that the Company has made, which may be subject to significant uncertainties. Although the Company’s approach to revenue recognition is based on facts and circumstances known to the Company and various other assumptions that the Company believes to be reasonable under the circumstances, the revenue assessment is ongoing, and its actual results may deviate from its current expectations. Revenue of initially constrained milestone payments may be recognized at the point of satisfaction or over time, including catch-up effects for prior periods as applicable. More information can be found in BioNTech’s Report on Form 6-K for the three and six months ended June 30, 2025, filed today, and in BioNTech’s Report on Form 20-F for the year ended December 31, 2024 filed on March 10, 2025, both of which are available at www.sec.gov.5 Financial guidance excludes external risks that are not yet known and/or quantifiable, including, but not limited to the effects of ongoing and/or future legal disputes and related activities as well as certain potential one-time effects and charges related to portfolio prioritization. It includes effects identified from licensing arrangements, collaborations and M&A transactions to the extent disclosed and completed and may be subject to update. It excludes the effect of the announced transaction to acquire CureVac, which is ongoing. The Company does not expect to report a positive net income figure for the 2025 financial year. These statements are also based in part on assumptions and judgments that the Company has made, which may be subject to significant uncertainties. Although the Company’s approach to revenue recognition is based on facts and circumstances known to the Company and various other assumptions that the Company believes to be reasonable under the circumstances, the revenue assessment is ongoing and its actual results may deviate from its current expectations. Operational Review for the Second Quarter 2025, Key Post Period-End Events and 2025 Outlook Variant-adapted COVID-19 Vaccine BioNTech and Pfizer have submitted regulatory applications to the European Medicines Agency (“EMA”) and to the United States Food and Drug Administration (“FDA”) for approval of their LP.8.1-adapted monovalent COVID-19 vaccine for the 2025-2026 vaccination season. In July, BioNTech and Pfizer’s LP.8.1-adapted monovalent COVID-19 vaccine was approved by the European Commission following recommendation for marketing authorization by the EMA’s Committee for Medicinal Products for Human Use (“CHMP”). The new variant-adapted COVID-19 vaccine will be ready to ship to applicable EU member states in August. Selected Oncology Pipeline Updates Next-Generation Immunomodulators and Combinations BNT327 is a bispecific antibody candidate combining PD-L1 checkpoint inhibition with VEGF-A neutralization. A global Phase 3 clinical trial (ROSETTA Lung-01; NCT06712355) is being conducted to evaluate BNT327 as a first-line treatment in combination with chemotherapy compared to atezolizumab in combination with chemotherapy in patients with untreated extensive-stage small cell lung cancer (“ES-SCLC”). A global Phase 2 clinical trial (NCT06449209) to evaluate BNT327 in combination with chemotherapy in patients with untreated ES-SCLC and in patients with SCLC whose disease progressed after first- or second-line treatment is fully enrolled and treatment is ongoing. Data from this clinical trial is expected in 2025. In June, BNT327 received Orphan Drug Designation from the FDA for the treatment of SCLC. A global Phase 2/3 clinical trial (ROSETTA Lung-02; NCT06712316) is being conducted to evaluate BNT327 in combination with chemotherapy compared to pembrolizumab and chemotherapy in patients with first-line non-small cell lung cancer (“NSCLC”). A global Phase 2 clinical trial (NCT06449222) is being conducted to evaluate BNT327 in combination with chemotherapy as a first- and second-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (“TNBC”). Data from this clinical trial is expected in 2025. A global Phase 3 clinical trial in patients with first-line TNBC (ROSETTA Breast-01) is planned to start in 2025. In June, at the 2025 American Society of Clinical Oncology (“ASCO”) Annual Meeting, preliminary data were presented from an ongoing Phase 2 clinical trial (NCT05918107) evaluating BNT327 in combination with chemotherapy in first-line mesothelioma. The preliminary data indicated anti-tumor activity and a manageable safety profile. Two trial-in-progress posters were also presented for ROSETTA Lung-01 and ROSETTA Lung-02. In the last quarter, BioNTech initiated several signal-seeking clinical trials to evaluate BNT327 with the Company’s proprietary novel assets: In May, the first patient was dosed in a Phase 1/2 clinical trial (NCT06827236) evaluating BNT327 in combination with BioNTech and Duality Biologics (Suzhou) Co. Ltd.’s (“DualityBio”) HER2 antibody-drug conjugate (“ADC”) candidate BNT323/DB-1303 in patients with HR+ or HR-, HER2-low, ultra-low, or null advanced metastatic breast cancer or TNBC. In May, the first patient was dosed in a Phase 1/2 clinical trial (NCT06892548) evaluating BNT327 in combination with BioNTech and DualityBio’s B7-H3 ADC candidate BNT324/DB-1311 in patients with advanced lung cancers. In July, the first patient was dosed in a Phase 2 clinical trial (NCT06953089) evaluating BNT324/DB-1311 in combination with BNT327 or with BioNTech and DualityBio’s TROP2 ADC candidate BNT325/DB-1305 in patients with advanced solid tumors. A Phase 1/2 clinical trial (NCT07070232) to evaluate BNT327 in combination with BioNTech and MediLink Therapeutics’s (“MediLink”) HER3 ADC candidate BNT326/YL202 and BNT326/YL202 as monotherapy in advanced solid tumors is expected to start in 2025. A Phase 1/2 clinical trial (NCT07079631) to evaluate BNT327 and/or chemotherapy in combination with BioNTech and Genmab AS’s (“Genmab”) novel EpCAM x 4-1BB bispecific antibody BNT314/GEN1059 in patients with advanced colorectal cancer is expected to start in 2025. Antibody-Drug Conjugates BNT323/DB-1303 (trastuzumab pamirtecan) is an ADC candidate targeting HER2 that is being developed in collaboration with DualityBio. A Phase 1/2 clinical trial (NCT05150691) is being conducted to evaluate BNT323/DB-1303 in patients with advanced HER2-expressing tumors. A potentially registrational cohort with HER2-expressing (IHC3+, 2+, 1+ or ISH-positive) patients with recurrent endometrial cancer is ongoing. Data are planned to be shared at a medical conference in 2026. A global Phase 3 clinical trial (NCT06340568) to evaluate BNT323/DB-1303 in patients with advanced endometrial cancer is expected to start in 2025. BNT324/DB-1311 is an B7-H3-targeted ADC candidate that is being developed in collaboration with DualityBio. In June, preliminary data from the ongoing Phase 1/2 clinical trial (NCT05914116) evaluating BNT324/DB-1311 in patients with advanced solid tumors were presented at the 2025 ASCO Annual Meeting. In 73 patients with heavily pretreated castration-resistant prostate cancer (“CRPC”), BNT324/DB-1311 was observed to have a manageable safety profile and showed encouraging preliminary clinical activity. mRNA Cancer Immunotherapies BNT116 is based on BioNTech’s fully owned, off-the-shelf FixVac platform, and is designed to elicit an immune response to six tumor-associated antigens that were identified to be frequently expressed in NSCLC. A Phase 1 clinical trial (LuCa-MERIT-1; NCT05142189) is being conducted in collaboration with Regeneron Pharmaceuticals Inc. (“Regeneron”) to evaluate BNT116 as monotherapy and in several combinations including with chemotherapy, cemiplimab, and some of BioNTech’s proprietary assets across various treatment lines and clinical settings in patients with NSCLC. In May, the first patient was dosed in a new cohort in the LuCa-MERIT-1 clinical trial to evaluate BNT116 in combination with BNT324/DB-1311. Data from a cohort from the LuCa-MERIT-1 clinical trial evaluating BNT116 in combination with cemiplimab in patients with NSCLC who have received chemoradiotherapy will be provided in a mini-oral session at the 2025 World Conference on Lung Cancer (“WCLC”) in Barcelona, Spain, September 6-9, 2025. Corporate Update for the Second Quarter 2025 In June, BioNTech and BMS entered into an agreement for the global co-development and co-commercialization of BNT327 across numerous solid tumor types. Under the agreement, BMS will pay BioNTech $1.5 billion in an upfront cash payment and $2 billion total in non-contingent anniversary payments from 2026 through 2028. In addition, BioNTech will be eligible to receive up to $7.6 billion in additional development, regulatory and commercial milestones. In June, BioNTech entered into a definitive Purchase Agreement pursuant to which BioNTech intends to acquire all of the shares of CureVac, a clinical-stage biotech company developing a novel class of transformative medicines in oncology and infectious diseases based on mRNA. The transaction is expected to close in 2025. In May, BioNTech signed a grant agreement with the United Kingdom (“UK”) Government to broaden the Company’s R&D activities for innovative medicines in the UK. As part of the agreement, BioNTech is committed to investing up to £1 billion over the next 10 years. The Company’s efforts will be supported by a grant of up to £129 million for a period of 10 years by the UK Government, which marks one of the largest grants of its kind in UK history for a pharmaceutical company. Upcoming Investor and Analyst Events AI Day: October 1, 2025, in London, United Kingdom Innovation Series R&D Day: November 11, 2025, in New York City, United States Conference Call and Webcast Information BioNTech invites investors and the general public to join a conference call and webcast with investment analysts today, August 4, 2025, at 8:00 a.m. EDT (2:00 p.m. CEST) to report its financial results and provide a corporate update for the second quarter of 2025. To access the live conference call via telephone, please register via this link. Once registered, dial-in numbers and a PIN number will be provided. The slide presentation and audio of the webcast will be available via this link. Participants may also access the slides and the webcast of the conference call via the “Events & Presentations” page of the Investor section of the Company’s website at www.BioNTech.com. A replay of the webcast will be made available shortly after the closing of the call and archived on the Company’s website for 30 days following the call. About BioNTechBiopharmaceutical New Technologies (BioNTech) is a global next generation immunotherapy company pioneering novel investigative therapies for cancer and other serious diseases. BioNTech exploits a wide array of computational discovery and therapeutic modalities with the intent of rapid development of novel biopharmaceuticals. Its diversified portfolio of oncology product candidates aiming to address the full continuum of cancer includes mRNA cancer immunotherapies, next-generation immunomodulators and targeted therapies such as antibody-drug conjugates (ADCs) and innovative chimeric antigen receptor (CAR) T cell therapies. Based on its deep expertise in mRNA development and in-house manufacturing capabilities, BioNTech and its collaborators are researching and developing multiple mRNA vaccine candidates for a range of infectious diseases alongside its diverse oncology pipeline. BioNTech has established a broad set of relationships with multiple global and specialized pharmaceutical collaborators, including Bristol Myers Squibb, Duality Biologics, Fosun Pharma, Genentech, a member of the Roche Group, Genevant, Genmab, MediLink, OncoC4, Pfizer and Regeneron. For more information, please visit www.BioNTech.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: BioNTech’s expected revenues and net profit/(loss) related to sales of BioNTech’s COVID-19 vaccine in territories controlled by BioNTech’s collaboration partners, particularly for those figures that are derived from preliminary estimates provided by BioNTech’s partners; the rate and degree of market acceptance of BioNTech’s COVID-19 vaccine and, if approved, BioNTech’s investigational medicines; expectations regarding anticipated changes in COVID-19 vaccine demand, including changes to the ordering environment and expected regulatory recommendations to adapt vaccines to address new variants or sublineages; the initiation, timing, progress, results, and cost of BioNTech’s research and development programs, including BioNTech’s current and future preclinical studies and clinical trials, including statements regarding the expected timing of initiation, enrollment, and completion of studies or clinical trials and related preparatory work and the availability of results, and the timing and outcome of applications for regulatory approvals and marketing authorizations; BioNTech’s expectations regarding potential future commercialization in oncology, including goals regarding timing and indications; the targeted timing and number of additional potentially registrational clinical trials, and the registrational potential of any clinical trial BioNTech may initiate; discussions with regulatory agencies; BioNTech’s expectations with respect to intellectual property; the impact of BioNTech’s collaboration and licensing agreements, including BioNTech’s partnership with Bristol Myers Squibb; BioNTech’s planned acquisition of CureVac; the development, nature and feasibility of sustainable vaccine production and supply solutions; the deployment of AI across BioNTech’s preclinical and clinical operations; BioNTech’s expectations with respect to developments in law, public policy, and international trade; BioNTech’s estimates of revenues, research and development expenses, selling, general and administrative expenses and capital expenditures for operating activities; BioNTech’s expectations regarding upcoming payments relating to litigation settlements; BioNTech’s expectations for upcoming scientific and investor presentations; and BioNTech’s expectations of net profit / (loss). In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this press release are based on BioNTech’s current expectations and beliefs of future events, and are neither promises nor guarantees. You should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties, and other factors, many of which are beyond BioNTech’s control and which could cause actual results to differ materially and adversely from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to: the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for clinical trials, projected data release timelines, regulatory submission dates, regulatory approval dates and/or launch dates, as well as risks associated with preclinical and clinical data, including the data discussed in this release, and including the possibility of unfavorable new preclinical, clinical or safety data and further analyses of existing preclinical, clinical or safety data; the nature of the clinical data, which is subject to ongoing peer review, regulatory review and market interpretation; BioNTech’s pricing and coverage negotiations regarding its COVID-19 vaccine with governmental authorities, private health insurers and other third-party payors; the future commercial demand and medical need for initial or booster doses of a COVID-19 vaccine; the impact of tariffs and escalations in trade policy; competition from other COVID-19 vaccines or related to BioNTech’s other product candidates, including those with different mechanisms of action and different manufacturing and distribution constraints, on the basis of, among other things, efficacy, cost, convenience of storage and distribution, breadth of approved use, side-effect profile and durability of immune response; the timing of and BioNTech’s ability to obtain and maintain regulatory approval for its product candidates; the ability of BioNTech’s COVID-19 vaccines to prevent COVID-19 caused by emerging virus variants; BioNTech’s and its counterparties’ ability to manage and source necessary energy resources; BioNTech’s ability to identify research opportunities and discover and develop investigational medicines; the ability and willingness of BioNTech’s third-party collaborators to continue research and development activities relating to BioNTech's development candidates and investigational medicines; the impact of COVID-19 on BioNTech’s development programs, supply chain, collaborators and financial performance; unforeseen safety issues and potential claims that are alleged to arise from the use of products and product candidates developed or manufactured by BioNTech; BioNTech’s and its collaborators’ ability to commercialize and market BioNTech’s COVID-19 vaccine and, if approved, its product candidates; BioNTech’s ability to manage its development and related expenses; regulatory and political developments; BioNTech’s ability to effectively scale its production capabilities and manufacture its products and product candidates; risks relating to the global financial system and markets; and other factors not known to BioNTech at this time. You should review the risks and uncertainties described under the heading “Risk Factors” in BioNTech’s Report on Form 6-K for the period ended June 30, 2025 and in subsequent filings made by BioNTech with the SEC, which are available on the SEC’s website at www.sec.gov. These forward-looking statements speak only as of the date hereof. Except as required by law, BioNTech disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release in the event of new information, future developments or otherwise. CONTACTS Investor RelationsDouglas Maffei, PhDInvestors@biontech.de Media Relations Jasmina Alatovic Media@biontech.de Target Overview Interim Condensed Consolidated Statements of Profit or Loss Interim Condensed Consolidated Statements of Financial Position Interim Condensed Consolidated Statements of Cash Flows

点击蓝字 关注我们本文刊登于《肿瘤药学》2025, 15(1): 10-20. DOI: 10.3969/j.issn.2095-1264.2025.01.02.【引用本文】陆佩瑶, 陈丽华, 向阳 . 抗体偶联药物在妇科肿瘤中的研究 进展 [J]. 肿瘤药学 , 2025, 15(1): 10-20. DOI: 10.3969/j.issn.2095-1264.2025.01.02.作者：陆佩瑶，陈丽华，向 阳通信作者：向阳，中国医学科学院北京协和医学院北京协和医院妇产科/国家妇产疾病临床医学研究中心，教授，主任医师。     以宫颈癌、子宫内膜癌和卵巢癌为主的妇科肿瘤是威胁女性健康的一大类疾病。2022年我国女性宫颈癌发病率为21.81/10万，死亡率为8.06/10万；子宫 体 肿 瘤 发 病 率 为 11.25/10 万 ，死 亡 率 为1.96/10 万；卵巢癌发病率为 8.84/10 万，死亡率为4.73/10 万［1］。目前，妇科恶性肿瘤的治疗仍以手术、放疗和化疗为主。传统化疗缺乏肿瘤特异性、对正常细胞损伤大，严重的不良反应常使患者难以耐受，进而影响治疗效果。近年来，免疫治疗和靶向治疗为肿瘤患者提供了新的治疗方向。免疫治疗副作用整体较轻，其中免疫检查点抑制剂（immune checkpoint inhibitor，ICI）在妇科肿瘤中取得了较好的成效。然而，不同人群疗效差异大，整体有效性低。精准有效的靶向治疗是近年来临床研究和治疗更新的热点之一，但传统靶向治疗往往缺乏较强的细胞毒性，且易发生耐药。因此，如何精准地向目标肿瘤细胞输送细胞毒性药物，避免损伤正常细胞，是肿瘤药物治疗中待解决的难题。     抗体偶联药物（antibody-drug conjugate， ADC）是一种新兴的治疗药物。2000 年，吉妥珠单抗（gemtuzumab ozogamicin）作为第一款ADC被批准用于白血病的治疗，随后ADC研究在肿瘤领域快速进展，尤其在乳腺癌、尿路上皮癌和多种血液系统肿瘤中取得了良好的治疗效果。随着对 ADC 机制的不断深入了解和技术的更新与突破，目前全球已有16 种 ADC 上市，其中 7 种在中国获批（表 1）。ADC在妇科肿瘤领域也正在蓬勃发展，其中两种药物已获批上市。同时，多个临床试验正在进行，初步结果显示ADC在妇科肿瘤治疗中有较好的应用前景。本文对ADC的基本结构与作用特点、在妇科肿瘤中的应用进展及其未来发展趋势进行系统综述。1  ADC概述     ADC 主要由抗体（antibody）、连接子（linker）和载药（payload）组成，可通过特异性识别肿瘤表面抗原进入肿瘤细胞内部，并释放载药，杀伤肿瘤细胞（图1）。其主要作用机制分为以下五个步骤：（1）抗体与肿瘤细胞上的靶抗原结合；（2）抗体-药物复合物通过受体介导的内吞作用进入内吞体；（3）复合物在内吞体中裂解或抗体部分在溶酶体中降解；（4）载药被释放到细胞质中；（5）载药通过损伤DNA或抑制微管组装导致细胞死亡。因此，ADC兼具单克隆抗体的靶特异性与细胞毒素的毒性，既可以避免传统化疗药物严重的全身毒性，又可以基于肿瘤中普遍高表达的靶点提高治疗的有效性，还可以弥补传统靶向治疗毒性不足的缺陷（图1）。1.1 ADC的一般结构1.1.1　抗体 理想的 ADC 抗体应靶向仅在肿瘤组织中高表达、而在健康组织中低表达的肿瘤抗原。如人表皮生长因子受体 2（human epidermal growth factor receptor 2， HER2）在肿瘤中的表达较正常细胞高 100倍［2］。目前的靶点选择通常包括肿瘤细胞过表达的抗原或驱动基因编码的抗原，如FRα、Trop2、PSMA、Mesothelin、CD56、CD70、Nectin4、HER2、EGFR等，以及肿瘤微环境中的重要抗原，如脉管结构中的VEGFR2和基质中的Collagen Ⅳ等［3］。抗体还应具有良好的亲和力，以实现与肿瘤抗原的结合，介导药物的内吞。目前的ADC主要基于IgG，尤其是具有较长血清半衰期的IgG1，其Fc片段具有高抗原亲和力，同时还具有抗体依赖性细胞介导的细胞毒性（antibody-dependent cell-mediatedcytotoxicity， ADCC）、补体依赖性的细胞毒性（complement dependent cytotoxicity， CDC）和抗体依赖性细胞介导的吞噬作用（antibody-dependent cell-mediated phagocytosis， ADCP），可能产生额外的抗肿瘤作用［4］。理想的抗体还应具备较低的免疫原性，尽可能减轻免疫反应并延长抗体在循环中的存续时间。从第二代ADC开始，人源化或嵌合抗体已经基本取代了鼠源抗体，降低了免疫原性，减少了药物的副作用。1.1.2　连接子 连接子将载药结合于单克隆抗体，并使载药随抗体递送至靶细胞。因此，理想的连接子需要连接足够数量的载药，在循环中保持稳定，以避免过早解偶联导致的全身脱靶毒性，抵达肿瘤细胞后则应高效释放载药，使其发挥细胞毒性。连接子分为不可裂解和可裂解两类。使用不可裂解连接子的ADC在被内吞至细胞后，抗体部分被溶酶体降解，释放药物。而可裂解连接子，如二硫化物和二肽连接子，对肿瘤细胞内的酸性 pH、高谷胱甘肽水平或蛋白酶作用具有敏感性，可较早准确释放细胞毒性药物，提高载药释放效率，但也可能因过早释放导致脱靶毒性。此时裂解释放的载药不含抗体降解产生的带电荷氨基酸残基，可以穿过细胞膜，对邻近肿瘤细胞产生“旁观者效应”（图1）［5］。1.1.3　载药 应用于 ADC 的载药需要兼具高细胞毒性和良好的稳定性，同时，具有强疏水性、可透膜的药物还可借助旁观者效应扩散至附近可能不表达靶抗原的肿瘤细胞，发挥杀伤作用。目前最常用的载药是微管蛋白抑制剂和可导致 DNA 损伤的化疗药物。如奥瑞他汀（应用最广泛的为 MMAE 和MMAF）、美登素（应用最广泛的为 DM1 和 DM4）及艾日布林等可抑制微管的组装，引起细胞周期停滞，因此仅对增殖细胞起作用［6］。而 DNA 损伤药物，如拓扑异构酶Ⅰ抑制剂7-乙基-10-羟基喜树碱（SN-38）和喜树碱类衍生物（DXd）等，可以结合并稳定拓扑异构酶-DNA复合物，导致DNA双链断裂，进而诱发细胞凋亡，具有非细胞周期毒性，在有丝分裂不活跃的肿瘤中更有效［7］。1.2 ADC的药物毒性尽管理论上 ADC 能够靶向肿瘤细胞并减少对正常组织的损害，但仍然存在一定的药物毒性，包括血液学毒性、神经毒性、眼毒性和胃肠道毒性。荟萃分析显示，ADC 的治疗相关不良事件（treatment-related adverse event， TRAE）总 体 发 生 率 为91.2%，最常见的是淋巴细胞减少症、恶心、中性粒细胞减少症、视力模糊和周围神经病变等，大部分为低级别可控不良事件；严重不良事件主要为血液学毒性和神经毒性，最常见的包括中性粒细胞减少症、感觉迟钝、血小板减少症、发热性中性粒细胞减少症和淋巴细胞减少症［8］。     ADC 的主要药物毒性以脱靶、非肿瘤作用为主，与载药密切相关。临床数据表明，大多数 ADC相关不良事件在发生谱、发生率和严重程度上与载药的不良事件相似［8-9］，并且无论靶抗原差异如何，相同载药的不同ADC通常具有相似的毒性特征［10］。如携带奥瑞他汀的ADC通常会导致周围神经病变，而以美登素作为载药的 ADC 可诱导肝毒性和血小板减少症。这种不良反应的发生机制主要与作为载药的化疗药物提前释放有关，过早的解偶联使载药进入循环并扩散至正常细胞，造成典型的化疗相关毒性，如血细胞减少和胃肠道反应。在使用可裂解连接子的ADC中，旁观者效应也可通过载药的扩散增加对邻近正常组织的毒性。其他脱靶毒性机制还包括完整 ADC 在非肿瘤细胞中的非特异性内吞，以及抗体Fc结构域相关受体介导的非特异性摄取，前者可能与部分 ADC 特异性的眼毒性相关［11］，而后者被认为可能是多种 ADC 诱发特异性间质性肺病的机制［12］。      另一部分药物毒性由靶抗原在正常组织中的表达引起，为靶向的非肿瘤作用，其不良反应特征与靶抗原的分布紧密关联。例如，德曲妥珠单抗（trastuzumab deruxtecan， T-DXd）可观察到特异性心脏毒性，这与曲妥珠单抗的分布特点有关；而同样以DXd为载药、靶向滋养层细胞表面抗原-2（trophoblast cell surface antigen 2， Trop2）的 Dato-DXd 则与其他 Trop2 靶向 ADC 相似，有较高的皮疹和口炎发病率，可能与皮肤和黏膜组织中 Trop2 高表达有关［13］。因此，尽管ADC的主要不良反应往往与负载的细胞毒药物有关并表现出相似的毒性特征，但由于靶抗原不同，也可以观察到独特的不良反应，甚至可能出现与靶点相关的严重不良事件，如靶向新生血管生成相关受体 EphA2 的 ADC 可能引发危及生命的出血或凝血事件，需予以关注。2  ADC在妇科肿瘤中的应用2.1　以TF为靶点      组织因子（tissue factor， TF）是一种重要的跨膜蛋白，可参与外源性凝血途径，对肿瘤的发展、转移和血管生成有重要作用。TF 在 94%~100% 的宫颈癌组织中表达，其水平显著高于宫旁正常组织［14-15］。因此，TF成为宫颈癌治疗的重要靶点。      Tisotumab vedotin（TV）由抗TF单克隆抗体与微管蛋白抑制剂 MMAE通过可裂解连接子连接而成。Ⅰ/Ⅱ期试验 InnovaTV 201初步研究显示了 TV在复发/转移性宫颈癌患者中的安全性与抗肿瘤活性，最常见的TRAE包括鼻出血、疲劳、恶心、结膜炎、脱发和食欲下降［16］。随后进行的InnovaTV 204试验纳入102例复发/转移性宫颈癌患者给予TV单药治疗，结果显示，客观缓解率（objective response rate， ORR）为 24%，中位缓解持续时间（duration of response，DOR）为 8.3 个月，中位无进展生存期（progress freesurvival， PFS）为4.2个月，中位总生存期（overall survival， OS）为 12.1 个月［17］。基于 InnovaTV 204 试验的结果，2021 年 9 月，FDA 加速批准 TV 用于治疗期间或治疗后疾病进展的复发性或转移性宫颈癌。在日本针对复发/转移性宫颈癌患者开展的Ⅰ/Ⅱ期试验 InnovaTV 206 则确认了 TV 在日本患者中的安全性与疗效［18］。另外一项Ⅲ期试验InnovaTV 301比较了 TV 与化疗在复发/转移性宫颈癌患者中的疗，结果表明，与化疗相比，TV 组 ORR 明显改善（17.8% vs. 5.2%），死亡风险降低了 30%，中位 OS 显著延长（11.5 个月 vs. 9.5 个月），PFS 也显著延长［19］。这些结果显示，对于化疗期间或化疗后出现疾病进展的复发/转移性宫颈癌患者，TV 可能成为有效的治疗选择。2022 年，美国国立综合癌症网络（National Comprehensive Cancer Network， NCCN）宫颈癌指南推荐TV用于复发/转移性宫颈癌的二线及以上治疗，并已于 2023 年将 TV 更新为二线及以上复发/转移性宫颈癌的首选药物之一。2.2　以HER2为靶点      HER2 是由 ERBB2 编码的受体酪氨酸激酶，属于表皮生长因子受体家族，在多种实体瘤中过表达。例如，子宫内膜癌组织标本中 HER2 阳性率为39.7%~44%，其中浆液性子宫内膜癌的 HER2 阳性率可达61%［20-21］。2.2.1 T-DXd T-DXd 由靶向 HER2 的曲妥珠单抗、肿瘤选择性的可裂解连接子和拓扑异构酶Ⅰ抑制剂组成，在宫颈癌、子宫内膜癌和卵巢癌的早期研究中均呈现出阳性结果。     针对HER2表达的局部进展期或转移患者的Ⅱ期研究 DESTINY-PanTumor02 将患者分为 7 个队列，分别纳入 40 例 HER2 阳性宫颈癌、子宫内膜癌和卵巢癌患者。研究结果显示，宫颈癌、子宫内膜癌和卵巢癌患者的 ORR 分别为 50.0%、57.5% 和45.0%，DOR 分别为 14.2 个月、未达到和 11.3 个月，中位PFS分别为7.0个月、11.1个月和5.9个月，中位OS 分别为 13.6 个月、26.0 个月和 13.2 个月［22］，最常见的 TRAE 是恶心、贫血、腹泻、呕吐和疲倦。经 T-DXd 治疗后，上述患者均获得了持久的临床效益，且安全性可控。不仅如此，T-DXd 在免疫组化HER2 3+人群中的疗效也较其他人群更为突出。2023 年 欧 洲 肿 瘤 内 科 学 会（European Society forMedical Oncology， ESMO）大 会 公 布 了 DESTINYPanTumor 01 研究的结果：针对 HER2 激活突变患者，其中 3 例宫颈癌患者和 2 例子宫内膜癌患者经T-DXd 治 疗 后 ORR 分 别 为 66.7%（2/3）和 100%（2/2）［23］。2023年美国临床肿瘤学会（American Societyof Clinical Oncology， ASCO）大会公布的 HERALD/EPOC1806研究结果指出，针对 cfDNA 检测到 HER2基因扩增的宫颈癌、子宫内膜癌和卵巢癌患者，经 T-DXd治疗后可获得较高的 ORR、较长的缓解时间和可控的安全性［24］。STATICE 试验则专门研究了 T-DXd在HER2阳性晚期或复发性子宫癌肉瘤患者中的作用，HER2高表达组和HER2低表达组均显示出良好的疗效［25］。这些阳性结果为T-DXd成为HER2过表达妇科肿瘤的潜在标准治疗提供了有力证据。然而，对于HER2突变妇科肿瘤患者的远期获益，仍需更大样本量的临床试验来证实。2.2.2　维迪西妥单抗（RC-48） 维迪西妥单抗是另一种靶向HER2的ADC，以MMAE为载药，最早应用于胃癌和尿路上皮癌。2023年一项研究显示，包含维迪西妥单抗的联合方案（联合放疗、PD-1/PD L1抑制剂、GM-CSF和IL-2）在HER2阳性妇科肿瘤中 ORR 达 66.7%［26］。最新研究结果表明，维迪西妥单抗单药应用于 HER2 阳性复发/转移性宫颈癌患者的二线及以上治疗，ORR 为 36.4%，中位 DOR 为5.52个月，疾病控制率（disease control rate， DCR）达86.4%，中位 PFS 为 4.37 个月，中位 OS 未达到，最常见的TRAE包括肝酶升高和白细胞减少［27］。该研究进一步支持了维迪西妥单抗在 HER2 阳性复发/转移性宫颈癌患者中的应用，尤其是多线治疗失败的患者。2.2.3 DB-1303 DB-1303也是靶向HER2的ADC，载药为拓扑异构酶Ⅰ抑制剂 P1003。一项Ⅰ/Ⅱa 期研究对既往全身治疗失败的HER2阳性或突变肿瘤患者应用 DB-1303 治疗，结果表明，DB-1303 在晚期/转移性实体瘤患者中耐受性良好，并具有令人鼓舞的初步抗肿瘤活性。其中1例子宫内膜癌患者达到客观缓解（33.3%，1/3）［28］。基于上述初步结果，FDA已批准DB-1303用于治疗晚期或转移性HER2阳性子宫内膜癌的快速通道认定。2.3　以FRα为靶点      叶酸是一种细胞生长、增殖过程中必需的物质，而叶酸受体-α（folate receptor α， FRα）在叶酸的细胞摄取过程中起着重要作用。研究发现，FRα在64%的子宫内膜癌和82%的卵巢癌中表达［29］。2.3.1　索米妥昔单抗 索米妥昔单抗（mirvetuximab soravtansine， MIRV）是全球首个靶向 FRα 的ADC，由抗 FRα 抗体、二硫化物连接子和抗微管蛋白DM4组成。MIRV在子宫内膜癌中目前仅有一项Ⅰ期临床研究数据，11例FRα阳性子宫内膜癌患者经过 MIRV 治疗后，有 2 例临床获益［30］，表明 MIRV在子宫内膜癌患者中的应用价值仍需要更多支持证据。而MIRV对于晚期或复发性卵巢癌患者的治疗作用已有较强证据支持，尤其是既往接受过 1~3线全身治疗的FRα阳性、铂耐药卵巢癌患者可能从MIRV治疗中获益。如Ⅱ期试验SORAYA研究纳入106 例 FRα 高表达铂耐药卵巢癌患者进行 MIRV 单药治疗，ORR 为 32.4%，中位 DOR 为 6.9 个月，中位PFS 为 4.3 个月，中位 OS 为 13.8 个月，最常见的TRAE包括视物模糊、角膜病变和恶心［31］。基于此，MIRV已成为首个被FDA批准用于铂耐药复发性卵巢癌的 ADC。MIRASOL 试验是一项比较 MIRV 与标准化疗在铂耐药晚期高级别上皮性卵巢癌患者中的疗效的Ⅲ期临床试验，结果显示，MIRV组中位PFS（5.62 个月 vs. 3.98 个月）、中位 OS（16.46 个月 vs.12.75个月）和 ORR（42.3% vs. 15.9%）均明显优于化疗组，且TRAE发生率较低［32］。Ⅲ期临床试验FOR⁃WARD Ⅰ也在 FRα 高表达铂耐药卵巢癌患者中得到了相似的结果，MIRV 治疗组 ORR 优于化疗组（24% vs. 10%）［33］。2.3.2 Luveltamab tazevibulin （STRO-002）STRO-002 是一种靶向 FRα 的新型 ADC。STRO-002-GM 1研究中，STRO-002在复发/进展的子宫内膜样癌中 DCR 达到 68.8%［34］。该研究也探索了STRO-002在晚期进展的铂耐药/难治性上皮性卵巢癌患者中的疗效与安全性，结果显示，31 例患者中有 10 例获得客观缓解，最常见的 3~4 级 TRAE 为中性粒细胞减少、关节痛和神经病变［35］。STRO-002已于 2021 年通过应用于卵巢癌的 FDA 快速通道认证。2.3.3 Farletuzumab ecteribulin（MORAb-202）MORAb-202 也是一种以 FRα 为靶点的 ADC，载药为甲磺酸艾日布林。MORAb-202在 FRα 阳性晚期实体瘤患者中的Ⅰ期研究纳入12例卵巢癌患者，显示出有效活性和安全性［36］。随后扩展部分纳入 45例FRα阳性铂耐药卵巢癌患者，前期和后期队列的ORR 分别为 25.0% 和 52.4%，中位 PFS 分别为 6.7 个月和8.2个月，前期队列的中位OS为10.5个月，后期队列的 OS 目前尚未达到［37］。初步试验结果表明，MORAb-202也可能成为 FRα 阳性铂耐药卵巢癌患者的治疗药物。2.4　以Trop2为靶点     Trop2 是一种肿瘤相关钙信号转导蛋白，62%~96.2% 的子宫内膜癌中有 Trop2 表达［38-39］。戈沙妥珠单抗（sacituzumab govitecan， IMMU-132）是首个靶向 Trop2 的新型 ADC，由抗 Trop2 抗体、可裂解连接子与SN-38组成。SN-38是伊立替康的活性代谢产物，是一种拓扑异构酶Ⅰ抑制剂。IMMU-132-0118试验纳入18例难治性转移性子宫内膜癌患者，采用戈沙妥珠单抗治疗，ORR为22.2%，中位PFS为3.2个月，中位 OS为 11.9个月［40］。针对 28例晚期子宫内膜癌患者的Ⅱ期试验 TROPiCS-03也显示了相似的疗效［41］。在Trop2过表达复发性子宫内膜癌患者中，戈沙妥珠单抗疗效更佳，21 例患者 ORR 为35%，中位 PFS 为 5.7 个月，中位 OS 为 22.5 个月［42］。但整体而言，戈沙妥珠单抗治疗复发或转移性子宫内膜癌仍需更多证据支持。2.5　以NaPi2b为靶点   钠依赖性磷酸盐转运蛋白 2B（sodium-dependent phosphate transport protein 2B， NaPi2b）是一种在全身磷酸盐稳态中起关键作用的转运蛋白。免疫组化染色结果显示，高达93%的卵巢癌组织样本表达NaPi2b，而正常卵巢组织染色大多呈阴性［43］。2.5.1 Lifastuzumab vedotin（LIFA） LIFA 是 一种靶向 NaPi2b 的 ADC，以 MMAE 为载药。Ⅰa 期试验结果显示，30 例铂耐药卵巢癌患者经 LIFA 单药治疗后，46% 达到部分缓解（partial response， PR），中位 DOR 为 342 天［44］。一项Ⅱ期试验比较了 LIFA与聚乙二醇脂质体多柔比星（pegylated liposomaldoxorubicin， PLD）在铂耐药卵巢癌患者中的疗效，结果显示，LIFA组与PLD组中位PFS分别为5.3个月和3.1个月，ORR分别为34%和15%，但差异均无统计学意义［45］。2.5.2 Upifitamab rilsodotin （UpRi） UpRi 是 另一种以NaPi2b为靶点的ADC，载药为抗有丝分裂化合物AF-HPA。一项针对多种实体瘤的Ⅰ期剂量递增研究结果显示，22例卵巢癌患者经 UpRi治疗后，有 2 例达到 PR［46］。该试验的扩展研究入组了 27 例卵巢癌患者，其结果在 2020 年 ESMO 大会上公布，ORR为 35%，DCR为 80%［47］。基于以上初步数据在268 例铂耐药卵巢癌患者中开展的Ⅱ期试验 UP⁃LIFT 却未能复制同样的结果，NaPi2b 阳性人群中ORR 仅 15.6%，置信区间下限低于标准治疗单药化疗的12%，因主要终点未达到，已停止研发［48］。2.6　以间皮素为靶点     研究显示，细胞表面糖蛋白间皮素（mesothelin）在71%的卵巢癌中表达，成为卵巢癌药物治疗的可能靶点之一［49］。Anetumab ravtansine（AR）是一种抗间皮素抗体、可裂解二硫化物连接子和DM4组成的ADC。AR 在针对晚期或转移性实体瘤的Ⅰ期研究显示出良好的安全性与潜在的治疗价值，在61例卵巢癌患者中，观察到 1 例完全缓解（complete response， CR），4 例 PR，29 例 疾 病 稳 定（stable disease， SD），最常见的TRAE是疲乏、恶心、腹泻、厌食和呕吐［50］。然而，在比较 AR+贝伐珠单抗与紫杉醇+贝伐珠单抗治疗铂耐药或难治性卵巢癌的疗效的Ⅱ期随机临床研究中，由于无效性分析时后者的结局优于前者（中位PFS为5.3个月vs. 9.6个月），研究已经终止［51］。2.7　以CDH6为靶点     人钙黏蛋白 6（human cadherin-6， CDH6）是一种单跨膜蛋白，在浆液性卵巢癌中表达特异性升高，可增强上皮-间充质转化，促进细胞迁移和侵袭，参与淋巴结转移，并与预后相关［52］。Raludotatug deruxtecan（R-DXd）是一种靶向CDH6 的 ADC，以拓扑异构酶抑制剂 DXd 作为载药。R-DXd 单药治疗在既往接受过治疗的卵巢癌患者中表现良好且安全性可控，首次人体Ⅰ期研究显示 ORR 为38%，最常见的TRAE是恶心、疲劳、呕吐和腹泻［53］。3  ADC耐药     随着ADC研发和应用的快速进展，其耐药性也成为需要关注的问题。耐药包括治疗失败及治疗有效性降低，可能在药物治疗后发生（继发性耐药），也可能在治疗开始时就存在（原发性耐药）［54］。主要的耐药机制与ADC的作用机制密切相关，任何水平的改变均可能导致肿瘤细胞获得耐药性，包括：（1）抗体与靶抗原结合的改变，如靶抗原数量减少、结构改变及掩蔽作用。（2）内吞作用的改变，主要通过改变内吞和运输途径干扰 ADC 进入溶酶体中降解。（3）溶酶体降解作用的改变，如通过提高溶酶体内的 pH 值降低其蛋白水解活性，干扰 ADC 的降解。（4）载药释放的改变，主要通过抑制载药进入细胞质所需转运蛋白的表达，使ADC裂解或降解释放的载药在溶酶体中积累并失效。（5）载药作用的改变，包括通过靶标突变、细胞周期静止、凋亡途径改变降低载药作用靶点对载药的敏感性，以及增加载药外排。（6）其他尚不明确的机制，例如PI3K/AKT等多种信号通路的激活均可能增加肿瘤细胞对ADC的抗性［54-55］。值得注意的是，由于目前ADC尚未在妇科肿瘤患者中长期广泛应用，其耐药相关数据和结论主要来源于乳腺癌领域的研究，ADC在妇科肿瘤中的耐药情况及机制仍待进一步探索。4　双特异性ADC     针对当前存在的毒性和耐药问题，一个改良方向是研发双特异性 ADC。双特异性 ADC 可分为两类：针对同一抗原不同表位的双表位ADC和针对不同抗原的双靶点 ADC。双表位 ADC 多以 HER2、间充质上皮转换因子（mesenchymal epithelial transition factor， MET）和FRα为靶点，而双靶点ADC主要结合表皮生长因子受体（epidermal growth factor re⁃ceptor， EGFR）和其他靶点。双表位/靶点通过增加内吞和促进溶酶体运输产生协同作用，减少耐药可能 ，并 增 强 药 物 对 肿 瘤 细 胞 的 选 择 性 ，降 低 其毒性［56-57］。      目前，双特异性 ADC 均处于临床研究阶段，大部分研究对象为乳腺癌、胃癌和肺癌患者，但也有部分试验同时招募多种晚期实体瘤患者。这些临床试验未来公布的结果中，可能包含对妇科肿瘤领域双特异性ADC研究有价值的内容。IMGN-151是一种靶向 FRα 的双表位 ADC，以美登素衍生物 DM21 为载药，在复发性子宫内膜癌和复发性高级别浆液性上皮性卵巢癌、原发性腹膜癌或输卵管癌患者中的首次人体研究（NCT05527184）正在进行中。5 ADC的联合使用策略     面对减少毒性和耐药的挑战，另一个探索方向是 ADC 与其他治疗联合应用，包括化疗、靶向治疗和免疫治疗。ADC 与化疗药物联合可在肿瘤杀伤方面表现出协同活性；靶向药物可与ADC同时抑制多个信号通路或对一种信号通路进行双重阻断，从而以更小剂量达到有效杀伤肿瘤的目标；抗血管生成药物可促进肿瘤血管正常化，有助于提高ADC在肿瘤内的渗透性；而ADC与免疫治疗联合可以通过不同机制降低肿瘤的免疫耐受，促进免疫治疗对肿瘤的作用［58］。      目前，多项临床试验聚焦于ADC与其他治疗的联合策略，并已初步显示出令人鼓舞的结果。InnovaTV 205 研究探索了 TV 联合卡铂或帕博利珠单抗治疗复发/转移性宫颈癌患者的疗效，结果显示，一线 TV+卡铂组 ORR 为 54.5%，中位 PFS 为6.9个月，中位OS未达到；一线TV+帕博利珠单抗组ORR 为 40.6%，中位 PFS 为 5.3 个月，中位 OS 未达到；二/三线 TV+帕博利珠单抗组 ORR 为 35.3%，中位 PFS 为 5.6 个月，中位 OS 为 15.3 个月［59］，表明 TV联合卡铂或帕博利珠单抗都可能成为复发/转移性宫颈癌患者的可选治疗方案。FORWARD Ⅱ研究分别评估了MIRV联合贝伐珠单抗、联合卡铂和贝伐珠单抗，以及联合帕博利珠单抗在 FRα 阳性卵巢癌患者中的治疗效果。最终结果显示，MIRV联合贝伐珠单抗的ORR为47%，中位 DOR 为 9.7 个月，中位 PFS 为 8.3 个月［60］；联合卡铂和贝伐珠单抗的ORR为81%，中位DOR为10.7个月，中位 PFS 为 12.0 个月［61］，均有良好的治疗效果；而联合帕博利珠单抗的疗效则不理想。基于该试验的结果，2023 年 NCCN 指南将 MIRV 和贝伐珠单抗联合治疗推荐用于 FRα 阳性的铂耐药复发卵巢癌患者。6　总结与展望      ADC是一种新型抗肿瘤药物，因其独特的结构有弥补现有抗肿瘤治疗不足的潜力，在妇科肿瘤中也具有令人期待的应用前景，特别是对于治疗选择有限的复发/转移性患者。目前，TV 治疗复发/转移性宫颈癌和MIRV治疗铂耐药复发性卵巢癌已获得FDA 批准，并已成为 NCCN 宫颈癌指南推荐的二线及以上复发/转移性宫颈癌的首选药物之一，但尚未在国内上市。在国内获批后，将为复发/转移性妇科肿瘤患者提供更多有效的治疗选择。德曲妥珠单抗、维迪西妥单抗和戈沙妥珠单抗已在国内上市，但适应证尚不包含妇科肿瘤。当前的临床试验结果初步显示了这些药物在妇科肿瘤领域的应用潜能，但均以小样本量早期试验为主。期待未来开展更多这几种药物针对妇科肿瘤的临床研究，以获得更强的证据支持，进而使其获批用于妇科肿瘤患者。其他正在研发中的药物，包括 DB-1303用于子宫内膜癌、STRO-002 用于子宫内膜癌和卵巢癌、MORAb-202 和 R-DXd 用于卵巢癌等，都处于更早的研究阶段，尽管获得了积极的结果，但在妇科肿瘤领域的作用仍待更多有效证据的确认。      虽然研究和应用已表明 ADC 具有独特的优势和令人鼓舞的疗效，但是其药物毒性与耐药性仍不可忽视。特别是部分ADC 与细胞毒药物不同的特异性不良反应，如MIRV的眼毒性，需要在使用过程中重点关注。而不同ADC在妇科肿瘤中的耐药情况及机制尚不明确，需要更多样本和相关研究进行探索。      为了增加 ADC 的有效性，减少毒性和耐药，首先可以从其结构和作用机制入手进行优化。ADC作为一种靶向特异性抗原的药物，靶抗原的基因突变或蛋白表达对于其疗效至关重要。以靶向HER2的 T-DXd 为例，其在 HER2 激活突变或基因扩增的患者中均显示出良好的治疗效果，在 HER2 阳性妇科肿瘤患者中也有持久的临床效益，且在高表达人群中疗效更突出。因此，在复发/转移性妇科肿瘤患者中进行各靶点的检测，可能为对应ADC的应用提供针对性支持，为高表达患者带来较好的疗效。这也为妇科肿瘤 ADC 的进一步创新研发提供了一个重要方向，即寻找各类肿瘤患者中普遍具有基因突变或蛋白表达的靶抗原。以T-DXd为例，在子宫癌肉 瘤 中 分 别 检 测 到 5%~25%、15%~35% 和 20%~40%的免疫组织化学 HER2 3+、2+和 1+。基于此高阳性率，研究者设计了 STATICE 试验，并获得了 TDXd 用于治疗子宫癌肉瘤患者的有利结果。沿着相似的路径，除上述提到的 TF、HER2、FRα、Trop2、NaPi2b、间皮素、CDH6 外，目前尚有多个潜在的优良靶点值得进一步研究并设计成为可能的 ADC 靶抗 原 ，如 子 宫 内 膜 癌 中 的 CD116，卵 巢 癌 中 的MUC16、PTK7、CD116、AXL、EFNA-4、DPEP3等。      ADC的下一步更新迭代还依赖于抗体、连接子和载药的进一步创新发展。抗体的亲和力对 ADC的靶向性调节至关重要，过低的亲和力使其不足以有效结合至靶抗原并被内吞发挥抗肿瘤作用，而过高的亲和力则可能使其过度结合于表达靶抗原的正常细胞，造成严重的毒性。一种研究方向是开发可变抗原亲和力的工程化抗体，如使用对肿瘤过表达蛋白酶敏感的肽来掩蔽抗体的 Fab 结构域，增强其肿瘤特异性。连接子的特性也是 ADC 有效性和特异性的关键。目前临床获批使用的ADC中，超过80% 采用了可裂解连接子，通过在肿瘤细胞环境中裂解增强了特异性，但仍存在因提前释放产生毒性的情况。因此，重要的更新方向是设计裂解条件更具有选择性的可裂解连接子，如受肿瘤细胞中过表达的水解酶硫酸酯酶、β-半乳糖苷酶等切割的连接子。载药方面，目前以微管蛋白抑制剂和可导致DNA损伤的化疗药物为主，下一代载药的拓展方向包括毒性更强的小分子降解物、可激活免疫的药物及多药负载等。      除ADC的设计更新外，增加特异性和有效性的其他研究方向主要包括研发双特异性 ADC 和将ADC与其他治疗联合。前者仍处于起步阶段，可开发的方向包括针对同一抗原不同表位的双表位ADC和针对不同抗原的双靶点ADC。然而，其在妇科肿瘤领域的临床数据仍接近空白，需要更多研究探索双特异性 ADC 对妇科肿瘤患者的疗效。ADC联合策略已经在妇科肿瘤中取得一些有效成果。MIRV与贝伐珠单抗联合治疗铂耐药复发性卵巢癌已获得 NCCN 指南推荐，ADC 与免疫治疗联合的研究也正在如火如荼地开展，可能是未来的突破口之一。      总的来说，ADC在国内尤其在妇科肿瘤领域应用时间尚短，因此需要格外谨慎地对其适应证和TRAE 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DOI: 10.1200/jco.2021.39.15_suppl.5504.［61］ O’MALLEY D M, RICHARDSON D L, VERGOTE I B, et al. 833P mirvetuximab soravtansine (MIRV), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with carboplatin (CARBO) and bevacizumab (BEV): final results from a study in patients (pts) with recurrent platinum sensitive ovarian cancer [J]. Ann Oncol, 2020, 31: S626-S627. DOI: 10.1016/j.annonc.2020.08.972.    《肿瘤药学》是由湖南省卫生健康委员会主管，湖南省肿瘤医院（中南大学湘雅医学院附属肿瘤医院）主办的我国唯一一本肿瘤领域对接药学领域的核心期刊，是中国抗癌协会系列期刊。自2016年已连续9年入选《中国科技核心期刊》目录。目前已被美国《化学文摘》、荷兰《医学文摘》、波兰《哥白尼索引》、美国《乌利希期刊指南》、中国生物医学文摘数据库、知网、万方、维普等数据库收录。经携手合作与共同努力，本刊正式入选“中国科技期刊卓越行动计划(二期)”集群(集团)化试点项目。并于2024年成功立项“湖南省培育世界一流湘版科技期刊建设工程项目”。网站链接：www.zgzlyx.com工作邮箱：zgzlyx2011@163.com电话号码：0731-89762609声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。来源：肿瘤药学杂志编辑：lagertha审核：南星