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Positive Phase 2 End of Study Data with Bel-sar in Early-Stage Choroidal Melanoma; Ongoing Phase 3 CoMpass Trial Recently Received Authorization to Start Enrolling Patients in Europe Multiple Clinical Complete Responses Observed with Single Low Dose of Bel-sar in Ongoing Phase 1 Trial in Non-Muscle Invasive Bladder Cancer (NMIBC); Phase 1 Expansion Preparation in Progress Strong Cash Position Expected to Support Operations into 2H 2026 BOSTON, Nov. 12, 2024 (GLOBE NEWSWIRE) -- Aura Biosciences, Inc. (NASDAQ: AURA), a clinical-stage biotechnology company developing precision therapies for solid tumors designed to preserve organ function, today reported financial results for the third quarter ended September 30, 2024, and provided recent business highlights. “This is a transformative time for our Company, as we presented the first positive data in NMIBC, which we believe provides clinical evidence of the potential of bel-sar in solid tumors beyond the eye,” said Elisabet de los Pinos, PhD, Chief Executive Officer of Aura Biosciences. “We believe that bel-sar’s innovative mechanism of action may provide the first immune-ablative treatment in bladder cancer, with the goal to potentially offer safe and durable responses with a focal approach that is easily delivered by urologists in the office.” In addition to positive early data from an ongoing Phase 1 trial of bel-sar in patients with NMIBC, the Company also recently presented positive Phase 2 end of study data in early-stage choroidal melanoma and continues to progress the ongoing Phase 3 CoMpass trial. “I am excited for bel-sar’s potential for patients who are diagnosed with indeterminate lesions or small choroidal melanoma where we currently have no good treatment options. We either wait for the disease to progress or treat with radiation, which leads to irreversible vision loss,” said Carol L. Shields, MD, Chief of the Ocular Oncology Service at Wills Eye Hospital and Professor of Ophthalmology at Thomas Jefferson University in Philadelphia. “If approved, bel-sar may represent the opportunity to treat choroidal melanoma at an earlier stage of medical intervention and set a new standard of care in a disease that has had no new therapies approved for decades.” Recent Pipeline Developments Early-Stage Choroidal MelanomaEarly-stage choroidal melanoma represents an area of high unmet need with no drugs approved. The Company previously received Orphan Drug Designation from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and Fast Track designation from the FDA for the treatment of early-stage choroidal melanoma. Update on Ongoing Phase 3 CoMpass Trial: CoMpass is the first registration-enabling study in early-stage choroidal melanoma. The study is a global, Phase 3, randomized trial evaluating bel-sar treatment against a sham control arm and includes an enrichment strategy to enroll 100 patients with documented growth, an approach agreed upon under a Special Protocol Assessment (SPA) agreement with the FDA. The Company recently received authorization from the EMA to commence the trial under the European Union (EU) Clinical Trial Regulation (CTR) process. This approval was later than anticipated due to a requirement for additional testing to support drug substance characterization that has been successfully met. This authorization permits the Company to start enrolling patients in the study in the EU. The study started enrolling in the United States in December 2023 and currently has sites activated in the United Kingdom, Australia and Canada.To identify appropriate patients to meet the enrichment strategy of documented growth, the Company has enabled a pre-screening ‘run in’ period. Globally, since June 2024, investigators have registered over 100 patients in pre-screening as having met initial enrollment criteria for the study. The Company continues to monitor the overall timeline for the study, with European sites in the process of being activated. The Company announced positive Phase 2 end of study results evaluating bel-sar as a first-line treatment for early-stage choroidal melanoma. Clinical Data: The Phase 2 results demonstrated that bel-sar achieved an 80% tumor control rate (n=8/10) and durability of response at 12 months among Phase 3-eligible patients who received the therapeutic regimen. Visual acuity preservation was achieved in 90% of these patients. We believe the Phase 2 results are a significant achievement that support the design of the ongoing Phase 3 trial. Safety Data: The safety profile of bel-sar was highly favorable in all participants. There were no treatment-related serious adverse events reported. Ocular treatment-related adverse events were mild (Grade 1). Additional Ocular Oncology Indications: In addition to early-stage choroidal melanoma, bel-sar is being explored for metastases to the choroid and cancers of the ocular surface. These three ocular oncology indications have a collective incidence of greater than 60,000 patients annually in the United States and Europe. Metastases to the Choroid The Company is initiating clinical development for bel-sar as a potential treatment for metastases to the choroid, an indication with high unmet medical need and no approved therapies. The Company aims to enroll the first patients in a Phase 2 trial in 2024. Metastases to the choroid represents the second potential ocular oncology indication for bel-sar, affecting approximately 20,000 patients annually in the United States and Europe. The Company previously received FDA Fast Track designation for bel-sar as a treatment in this indication. Cancers of the Ocular Surface The Company’s third potential ocular oncology indication is cancers of the ocular surface, which affect approximately 35,000 patients in the United States and Europe annually. The Company continues to advance its preclinical work designed to be IND-enabling in cancers of the ocular surface. Bladder Cancer The Company announced positive early data from an ongoing Phase 1 clinical trial of bel-sar in patients with NMIBC. Clinical Data: In these early data from the first 8 patients treated with a single low dose of bel-sar with light activation, a clinical complete response was observed in 4 out of 5 patients with low grade disease; visual tumor shrinkage was observed on cystoscopy in 2 out of 3 patients with high grade disease where tumor cells were still present on histopathological evaluation. For this analysis, clinical complete response was defined as the absence of tumor cells on histopathologic evaluation. In addition, immune activation was noted in all patients with available immune staining in both treated target and untreated non-target bladder tumors with rapid infiltration of effector CD8+ and CD4+ T-cells within days after treatment. This data provides evidence of a bladder urothelial field effect, potentially indicating a broader immune response in the bladder beyond the target tumor in these patients. Safety Data: In the safety analysis as of the September 9, 2024 data cut-off date (n=12), bel-sar was well-tolerated, with less than 10% Grade 1 and no Grade 2 or higher drug-related adverse events reported. No serious adverse events have been reported. Future Development: The Company plans to continue development of bel-sar in bladder cancer with an initial focus on low-grade, intermediate risk NMIBC patients, through a planned trial expansion to test additional doses and treatment regimens with the opportunity to assess early durability of response at 3 months. In parallel, the Company is planning regulatory discussions on the design of the next trial with the goal of expediting clinical development in this patient population. Recent Corporate Events The Company announced the appointment of Sabine Doris Brookman-May, MD, FEBU as the Company’s Senior Vice President, Therapeutic Area Head Urologic Oncology.The Company hosted a virtual ocular oncology investor event featuring Ivana Kim, MD (Mass Eye and Ear) and Prithvi Mruthyunjaya, MD, MHS (Stanford University Byers Eye Institute) to discuss the Phase 2 end of study data on Thursday, September 12, 2024. A replay of the webcast is available on the “Investors & Media” page under the “Events & Presentations” section of Aura’s website at https://ir.aurabiosciences.com/events-and-presentations.The Company hosted a virtual urologic oncology investor event featuring Max Kates, MD (Johns Hopkins), Joe Jacob, MD (Syracuse University), Neal Shore, MD (Carolina Urologic Research Center) and Gary Steinberg, MD (RUSH University) to discuss the early Phase 1 data on Thursday, October 17, 2024. A replay of the webcast is available on the “Investors & Media” page under the “Events & Presentations” section of Aura’s website at https://ir.aurabiosciences.com/events-and-presentations. Third Quarter 2024 Financial Results As of September 30, 2024, the Company had cash and cash equivalents and marketable securities totaling $174.4 million. The Company believes its current cash and cash equivalents and marketable securities are sufficient to fund its operations into the second half of 2026.Research and development expenses increased to $17.0 million for the three months ended September 30, 2024 from $15.4 million for the three months ended September 30, 2023 primarily due to manufacturing and development costs for bel-sar and higher personnel expenses related to growth of the Company.General and administrative expenses increased to $6.2 million for the three months ended September 30, 2024 from $5.1 million for the three months ended September 30, 2023. General and administrative expenses include $1.6 million and $1.2 million of stock-based compensation for the three months ended September 30, 2024 and 2023, respectively. The increase was primarily driven by personnel expenses, as well as increases in general corporate expenses related to the growth of the Company.Net loss for the three months ended September 30, 2024 was $21.0 million compared to $18.5 million for the three months ended September 30, 2023. About Aura Biosciences Aura Biosciences is a clinical-stage biotechnology company focused on developing precision therapies for solid tumors that aim to preserve organ function. Our lead candidate, bel-sar (AU-011), is currently in late-stage development for primary choroidal melanoma and in early-stage development in other ocular oncology indications and bladder cancer. Aura Biosciences is headquartered in Boston, MA. Our mission is to grow as an innovative global oncology company that positively transforms the lives of patients. For more information, visit aurabiosciences.com. Follow us on X (formerly Twitter) @AuraBiosciences and visit us on LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, and other federal securities laws. Any statements that are not statements of historical fact may be deemed to be forward-looking statements. Words such as “may,” “will,” “could,” “should,” “expects,” “intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “projects,” “seeks,” “endeavor,” “potential,” “continue” or the negative of such words or other similar expressions can be used to identify forward-looking statements. These forward-looking statements include express or implied statements regarding Aura’s future expectations, plans and prospects, including, without limitation, statements regarding the therapeutic potential of bel-sar for the treatment of various cancers; statements regarding Aura’s plans and expectations for its ongoing and future clinical trials of bel-sar in various oncology indications and the preclinical development of bel-sar in cancers of the ocular surface; statements regarding Aura’s beliefs and expectations for bel-sar’s ability to provide durable responses in bladder cancer patients and choroidal melanoma patients; statements regarding Aura’s expectations for an improved quality of life of patients after treatment with bel-sar and changes to the treatment paradigm for patients; statements regarding bel-sar’s potentially immune ablative effects; statements regarding bel-sar’s safety profile; statements regarding Aura’s beliefs and expectations for the high unmet medical need for an effective local treatment in ocular and urologic oncology; statements regarding Aura’s expectations for the estimated patient populations and related market opportunities for bel-sar; statements regarding the potential for regulatory approval of bel-sar; and statements regarding the Company’s expected cash runway. The forward-looking statements in this press release are neither promises nor guarantees, and investors 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 Aura’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements, including, without limitation, uncertainties inherent in clinical trials and in the availability and timing of data from ongoing clinical trials; the expected timing for submissions for regulatory approval or review by governmental authorities; the risk that the results of Aura’s preclinical and clinical trials may not be predictive of future results in connection with future clinical trials; the risk that early or interim data from ongoing clinical trials may not be predictive of final data from completed clinical trials; the risk that governmental authorities may disagree with Aura’s clinical trial designs even where Aura has obtained agreement with governmental authorities on the design of such trials, such as the Phase 3 SPA agreement with the FDA; whether Aura will receive regulatory approvals to conduct trials or to market products; whether Aura’s cash resources will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; Aura’s ongoing and planned preclinical activities; and Aura’s ability to initiate, enroll, conduct or complete ongoing and planned clinical trials. These risks, uncertainties and other factors include those risks and uncertainties described under the heading “Risk Factors” in Aura’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the United States Securities and Exchange Commission (SEC) and in subsequent filings made by Aura with the SEC, which are available on the SEC’s website at www.sec.gov. Except as required by law, Aura 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. These forward-looking statements are based on Aura’s current expectations and speak only as of the date hereof and no representations or warranties (express or implied) are made about the accuracy of any such forward-looking statements. Investor Contact:Alex DasallaHead of Investor Relations and Corporate CommunicationsIR@aurabiosciences.com Media Contact:Kimberly HaKKH Advisorskimberly.ha@kkhadvisors.com917-291-5744 Aura Biosciences, Inc.Condensed Consolidated Statement of Operations and Comprehensive Loss(Unaudited)(in thousands, except share and per share amounts) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Operating Expenses: Research and development $17,036 $15,428 $50,968 $44,952 General and administrative 6,196 5,060 17,341 15,256 Total operating expenses 23,232 20,488 68,309 60,208 Total operating loss (23,232) (20,488) (68,309) (60,208)Other income (expense): Interest income, including amortization and accretion income 2,258 1,981 7,395 5,981 Other expense (25) (5) (83) (50)Total other income 2,233 1,976 7,312 5,931 Loss before income taxes (20,999) (18,512) (60,997) (54,277)Income tax provision, net (43) — (88) — Net loss $(21,042) $(18,512) $(61,085) $(54,277)Net loss per common share—basic and diluted $(0.42) $(0.48) $(1.23) $(1.43)Weighted average common stock outstanding—basic and diluted 49,663,532 38,185,197 49,554,930 37,943,139 Comprehensive loss: Net loss $(21,042) $(18,512) $(61,085) $(54,277)Other comprehensive items: Unrealized gain (loss) on marketable securities 790 89 68 (62)Total other comprehensive income (loss) 790 89 68 (62)Total comprehensive loss $(20,252) $(18,423) $(61,017) $(54,339) Aura Biosciences, Inc.Condensed Consolidated Balance Sheets(Unaudited)(in thousands, except share and per share amounts) September 30, 2024 December 31, 2023 Assets Current assets: Cash and cash equivalents $25,407 $41,063 Marketable securities 148,970 185,087 Restricted cash and deposits — 19 Prepaid expenses and other current assets 9,104 5,625 Total current assets 183,481 231,794 Restricted cash and deposits, net of current portion 768 768 Right of use assets - operating lease 17,744 18,854 Other long-term assets 22 509 Property and equipment, net 3,325 3,150 Total Assets $205,340 $255,075 Liabilities and Stockholders’ Equity Current liabilities: Accounts payable 1,991 1,787 Short-term operating lease liability 3,126 2,687 Accrued expenses and other current liabilities 9,597 7,883 Total current liabilities 14,714 12,357 Long-term operating lease liability 15,958 16,870 Total Liabilities 30,672 29,227 Commitments and Contingencies Stockholders’ Equity: Common stock, $0.00001 par value, 150,000,000 authorized at September 30, 2024 and December 31, 2023, and 49,778,861 and 49,350,788 shares issued and outstanding at September 30, 2024 and December 31, 2023, respectively — — Additional paid-in capital 522,454 512,617 Accumulated deficit (348,393) (287,308)Accumulated other comprehensive income 607 539 Total Stockholders’ Equity 174,668 225,848 Total Liabilities and Stockholders’ Equity $205,340 $255,075

生物偶联药物（XDC）近年显示出巨大潜力。XDC药物的应用前景广阔，除了肿瘤之外，这类药物还有望给心血管疾病、糖尿病、自身免疫性疾病以及罕见病等患者带来新的治疗选择。 XDC药物的“公式”：靶向肿瘤的载体（Carrier）+二者的连接子（Linker）+诱导多种生物学功能的载荷（Payload）。 本文涉及到的XDC有： 抗体偶联药物（ADC） 多肽偶联药物（PDC） 抗体片段偶联药物（FDC） 放射性核素偶联药物（RDC） 小分子偶联药物（SMDC） 抗体寡核苷酸偶联物（AOC） 免疫刺激抗体偶联药物（ISAC） 病毒样药物偶联物（VDC） 抗体-siRNA偶联物（ARC） 前抗体偶联药物（Pro-ADC） 核酸适体药物偶联物（ApDC） 双环肽放射性偶联药物（BRC） 抗体生物聚合物偶联物（ABC） 降解剂-抗体偶联物（DAC） Centyrin-siRNA药物 1 抗体偶联药物（ADC） ADC药物是近年的大热点，自2000年首款药物获批以来，全球已有15款ADC产品获批上市。其中，Enhertu以25.66亿美元的销售额成为2023年最畅销的ADC药物。2023年全球ADC药物市场规模首次突破百亿美元大关。根据Nature Reviews Drug Discovery杂志文章预测到2028年，全球ADC药物收入规模将达260亿美元。当前全球ADC管线庞大，有超1000个ADC项目，其中400余款ADC分子活跃在临床试验的各个阶段。 ADC药物未来趋势： 1.通过核心三组件整体技术角度对ADC药物进行优化来解决不良反应、响应率有限以及耐药发生快等问题。 2.ADC药物多疗法联合给药探索带来更优的临床获益。 3.ADC药物从当前狂热期到平稳期的过渡，更好的差异化是未来的重点。 4.肿瘤不再是ADC药物的唯一战场，更多药企开始探索将ADC药物应用于非肿瘤适应症。 2 多肽偶联药物（PDC） PDC通过将细胞毒性药物连接到特定多肽上，实现对肿瘤细胞的精准打击。PDC的核心组成部分包括细胞靶向肽、连接链（linker）和有效载荷（payload），即细胞毒素。 PDC structure illustration 与上文提到的ADC药物相比，PDC药物分子量更小。多肽类药物分子量介于小分子药物（<500 Da）和生物制品（>5000 Da）之间，这使它更易穿透肿瘤基质进入到肿瘤细胞当中。而分子量在160KDa的ADC药物会更难进入到肿瘤细胞内部。由于结构和成分都更加简单，PDC会有更低的免疫原性，即不太会刺激机体发生免疫应激反应。PD可通过修饰肽链的氨基酸序列，改变共轭疏水性和电离性质，解决水溶性差、代谢不及时等问题。PDC能够快速被肾脏消除，使其对骨髓和肝脏的毒性更低。 PDC 相较单抗，多肽更易合成与纯化，这就使得PDC药物在生产、运输和储存上的成本都要更低。 目前，全球已有两款PDC药物获批上市，分别是诺华公司开发的Lutathera和Oncopeptipes公司开发的Pepaxto。Lutathera是一种肽受体放射性核素治疗药物，用于治疗胃肠胰腺神经内分泌肿瘤（GEP-NETs），而Pepaxto则是一种靶向氨肽酶类的PDC药物，用于复发/难治性多发性骨髓瘤（RRMM）的治疗。在PDC项目上全球大约有16款进入临床阶段的药物，比较领先的且活跃的多为海外公司。 PDC药物未来趋势： 1.随着多肽设计技术提升，PDC药物循环稳定性差的难题逐渐被解决。 2.PDC 药物应用范围不仅应用于癌症治疗，还可以应用于免疫调节、神经科学和代谢疾病等领域。 3.内卷时代，PDC整体市场仍处于发展早期，PDC药物将是中国XDC开发企业的差异化选择之一。 3 抗体片段偶联药物（FDC） 抗体片段偶联药物（Fc偶联药物，FDC），就是使用更小的抗体片段（单链scFv）替换更大的抗体分子。由于抗体片段分子量小，所以FDC的肿瘤穿透性较好。FDC的半衰期短，减少其在正常组织中的暴露，更好地安全性。可系统性地分析、改进抗体片段和毒素之间的连接物。 据不完全统计，目前全球有8款在研药物。Antikor Biopharma这家英国公司建立了抗体片段偶联药物（FDC）技术。它可以克服ADC的局限性，用来治疗难治型实体瘤。由于分子更小，FDC对实体瘤的穿透力强于ADC。又由于FDC的生物半衰期短于ADC，药物的毒副作用可得到更好的控制。其公司靶向HER2的ANT-043展现出良好的肿瘤杀伤和毒理耐受效果。与以Herceptin为基础的ADC药物相比较，ANT-043具有更强的肿瘤渗透力和更灵活的PK特性。根据ANT-043的临床前数据，Antikor将其靶向市场定位为HER2低表达的癌症，比如某些乳腺癌。作为下一代癌症治疗方法，FDC可以克服现有治疗选择的诸多局限性，具有极大的市场潜力，预计未来市场规模将超过180亿美元。 FDC药物未来趋势： 通过改变连接物的化学结构和长短，以及在偶联药物上添加PEG聚合物，可以精准调控FDC的毒素/抗体片段负载比例（DAR）、成药性、药效和安全性。 4 放射性核素偶联药物（RDC） RDC主要由靶向定位元件（抗体或小分子）、连接臂、螯合物和放射性同位素四个部分构成。根据靶向配体的不同，RDC可细分为抗体偶联核素药物（ARC）、小分子偶联核素药物和多肽偶联核素药物（PRC）。RDC发挥药效主要依赖物理辐射，因此不易产生耐药。从靶点上看，RDC药物以靶向前列腺特异性膜抗原（PSMA）的项目居多，同时也涉及在ADC药物中较受欢迎的Her2靶标，在适应症上，RDC药物主要集中在肿瘤领域。目前，全球已上市的RDC治疗药物表现突出的主要为Lutathera和Pluvicto两款。 RDC药物未来趋势： 诊疗一体化平台是RDC发展的大趋势，理想靶点越来越多，供应链一体化越来越完善。 5 小分子偶联药物（SMDC） SMDC小分子靶向配体、连接基和细胞毒分子（有效载荷）三个部分构成。其和ADC最大的区别在于靶向配体部分，ADC药物的配体是大分子抗体, 与抗原结合，而SMDC的配体是与转运蛋白高选择性结合，是分子量比较小的一个有机官能团。SMDC在实体瘤中，SMDC具有很好的细胞穿透性以及良好的体外和体内稳定性。据不完全统计，目前在研的SMDC管线约30个。 SMDC药物未来趋势： 最难的配体选择有很多突破，SMDC探索性管线越来越多，靶点呈现多样性，越来越多企业尝试布局该赛道。 6 抗体寡核苷酸偶联物（AOC） AOC是一类寡核苷酸与抗体共价连接而形成的寡核苷酸分子复合物。AOC通常有三个部分组成：靶向靶点的单抗、寡核苷酸药物载荷，以及连接子。它通过将寡核苷酸与特异性抗体通过化学键连接在一起，形成了一种能够精确靶向并调控基因表达的疗法。 AOC已经逐渐展现出了取代纳米颗粒作为递送寡核苷酸药物载体的趋势。AOC最初作为诊断工具得到应用，但最近逐渐发展为许多疾病的靶向治疗方法。随着寡核苷酸领域的成熟和选择性组织递送成为临床应用的重要挑战，AOC转变为潜在的单药疗法。AOC多采用半胱氨酸、赖氨酸、定点偶联技术等有其明显的特点和优势。比如寡核苷酸具有较好的亲水性，在偶联过程中可以少用有机试剂或者不用有机试剂。 目前全球开发AOC药物的企业有Avidity、Tallac Therapeutics、Dyne Therapeutics、Denali Therapeutics和Gennao Bio。这些公司开发的AOC项目面向的适应证涵盖肌肉疾病、中枢神经系统疾病和癌症。 AOC药物未来趋势： 调节基因表达的能力开启了个性化医疗的潜力，发展前景广阔。不同的偶联策略成熟，包括可剪切的连接子和非剪切的连接子，以适应不同的治疗需求。AOC会与其他治疗手段（如化疗、放疗、免疫疗法等）联合使用，大大提高治疗效果。 7 免疫刺激抗体偶联药物（ISAC） 免疫刺激抗体偶联物（Immunostimulatory antibody conjugates, ISAC）其设计策略与ADC类似，区别在于它将ADC中的药物载荷部分替换为免疫激动剂，以增强免疫反应。这些免疫激动剂的核心功能在于提升免疫系统的响应力，进而有效提高免疫系统对肿瘤细胞的攻击和清除能力。与ADC结构类似，同样由三个主要成分组成：肿瘤靶向抗体、连接子和特异性免疫调节剂。ISAC既能激活固有免疫，又能刺激适应性免疫，具有清除肿瘤细胞的双重治疗作用。同时与肿瘤微环境激活偶联药物(TMAC)部分功能相似，都是通过调剂免疫刺激和微环境，实现激活免疫杀伤和治疗敏感的作用。 从当前看IgG1是ISAC中使用的主要抗体。ISAC目前使用的载荷多为TLR7、TLR8、TLR9激动剂或STING激动剂。 ISAC药物未来趋势： 更强大的数据收集和AI建立肿瘤微环境模型,更好的模拟和预测，能更加优效的进行ISAC设计，能克服其毒性、免疫原性、药代动力学方面的挑战。其中免疫激动剂或调节剂作为新型载荷能有突破性进展。 8 病毒样药物偶联物（VDC） VDC（Virus-like Drug Conjugate，VDC）是采用将病毒衣壳设计为非感染性蛋白质纳米颗粒（病毒样颗粒，VLP)作为高效递送载体的偶联药物形式。VDC 具有双重作用机制，首先可导致肿瘤细胞的急性坏死，然后通过创建高免疫原性环境来诱导抗肿瘤特异性免疫反应，从而实现更强大和持久的治疗。 2022年3月21日，欧盟授予其首个病毒样药物偶联物（VDC）候选产品AU-011孤儿药资格，用于治疗葡萄膜黑色素瘤。AU-011是一种病毒样药物偶联物（VDC）疗法，由纳米病毒颗粒（病毒样颗粒，VLP）与一种红外光激活的强效细胞毒性药物偶联而成。这种设计之下，药物的靶向端可选择性地附着在修饰的硫酸乙酰肝素蛋白聚糖（HSPG）表面，实现对实体肿瘤细胞的靶向与结合，偶联的红外光激活细胞毒药物被激活后，就能破坏肿瘤细胞，导致肿瘤细胞急性坏死的同时，激活免疫系统产生抗肿瘤应答。 VDC药物未来趋势： VDC结构复杂，目前整体生物学确定性和技术发展都处于早期。但未来会在眼科和泌尿科的肿瘤中发挥更多作用。 9 抗体-siRNA偶联物（ARC） 抗体-siRNA偶联物(ARC)是一类新型大分子，由单克隆抗体和siRNA组成，利用抗体和细胞膜受体之间的特异性相互作用，可将siRNA递送到靶细胞中。siRNAs是一类属于小分子非编码核糖核酸家族的药物，分子量约为13kDa，通过碱基配对将RNA诱导的沉默复合体(RISC)招募到mRNA上，从而靶向和沉默癌基因、抑癌基因和其他调控基因的表达。 ARC药物未来趋势： 越来越多的间接激活方式使用到其中，肿瘤细胞的内吞效率、抗体偶联的siRNA数目、抗体与siRNA的中间连接子选择以及内吞后的ARC在细胞内从内涵体或溶酶体中释放的效率都更好的优化。同时拓展更多的遗传性疾病适应症。 10 前抗体偶联药物（Pro-ADC） Pro-ADC是一种新型的药物形式，其原理是利用抗体将细胞毒性药物前药化，并精准输送至肿瘤细胞中发挥作用。这种药物通过抗体与肿瘤细胞表面的特异性抗原结合，将药物前药化并靶向肿瘤细胞，从而实现对肿瘤细胞的高效杀伤。最早由CytomX Therapeutics于2013年公开提出，前抗体药物（Probody）来源于prodrug（前药）+antibody（抗体），指在初始状态下不发挥功能，只有在经过生物体内经化学反应或酶作用转化后，才具备活性的药物。 a，包含卷曲螺旋肽（例如靶向 CD19、整合素 αVβ6 或 CD3 的肽段，均处于临床前开发阶段）或具有蛋白酶可裂解接头的亲和结合肽（例如 praluzatamab ravtansine，一种靶向 CD166 的 PDC 和 CX-2029，一种靶向 CD71 的 PDC，两者均在早期试验中进行测试）的前体-药物偶联物 （PDC） 的示意图。两种类型的掩蔽部分都会阻断 Fab 内的表位结合区域，从而抑制偶联物与其在非恶性组织上的靶受体的结合。在肿瘤微环境 （TME） 中，肿瘤相关蛋白酶降解间隔区，从而激活 Fab 部分并促进特定的肿瘤细胞靶向。b，响应pH值变化或带负电荷的离子浓度的PDC。对于pH依赖性PDC，失活的Fab区域内的组氨酸残基在弱酸性TME中变得质子化，但在生理条件下保持未质子化，通过构象变化促使抗原结合。对于使用蛋白质相关化学开关 （PaCS） 的 PDC，Fab 区域和抗原表位在与生理 pH 值相关的浓度下被带负电荷的离子（如氯化物、碳酸氢盐和硫化物）失活（阻断）。由于其中一些离子被中和，这些部分暴露在TME中，从而重新激活靶标结合。 采取这种设计的前抗体药物可以重启以前由于毒性而无法实现的新组合，创造或扩大治疗窗口，药物选择的靶点可以存在于健康组织中，从而扩大了“不可成药”的药物目标范围。 Pro-ADC药物未来趋势： 更精妙的酶激活系统研究设计，可以特异性地激活Pro-ADC；利用光敏剂和光照射激活Pro-ADC，可以实现对药物释放的精确控制；一些Pro-ADC设计为在肿瘤微环境的低pH条件下激活，因为肿瘤组织通常比正常组织酸性更强。 11 核酸适体药物偶联物（ApDC） ApDC（Aptamer−Drug Conjugates,）就是把ADC其中的抗体换成适配体(Apdamer)，而适配体作为识别配体，指导治疗药物靶向疾病部位或调节靶向生物标志物的生物学功能。核酸适配体是利用基于活细胞的指数富集配基系统进化技术筛选得到的寡核苷酸序列，序列长度大多在15-60碱基之间。核酸适配体有“化学抗体”之称，因其与靶标物质的结合能力可与抗体媲美。 ApDCs作用靶点丰富，因为DNA/RNA序列和结构的多样性非常高，理论上SELEX技术可以针对几乎所有目标选择适配体，能够匹配的靶点比抗体药多很多。ApDC的载药位置、载药数量精确可控，质量控制简单，且可实现协同治疗。ApDC的肿瘤靶向迅速，对实体瘤的穿透能力强。核酸在人体内大量存在，所以它的免疫原性相对比较低。 ApDC药物未来趋势： ApDC未来能够通过技术升级，从而显著延长血液半衰期。借鉴反义核酸和小干扰核酸药物多年研发积累，未来特异性强、分子靶点明确的核酸适体药物将会陆续研制成功。 12 双环肽放射性偶联药物（BRC） 即通过Linker将放射核素与双环肽分子连接。双环肽分子集抗体、小分子药物及肽类的特性于一身，具有与抗体类似的亲和性和精确的靶向特异性；同时，由于它们分子量较小，使得其能够快速深入地渗透组织，从而实现从组织内部靶向病灶；其肽类的性质则提供了“可调控”的药物动力学半衰期和肾脏清除途径，从而避免了其他药物形式中常见的肝脏和胃肠道毒性。放射性配体疗法是诺华公司着重开发的创新治疗模式之一。它通过将放射性元素与靶向肿瘤特异性蛋白的配体连接在一起，在靶向杀伤肿瘤细胞的同时，降低对健康组织的损伤。 BRC药物未来趋势： 因为双环肽分子集抗体、小分子药物及肽类的优势于一身，非常有望成为下一代肿瘤疗法的黑马。越来越多的MNC布局BRC。 13 Centyrin-siRNA药物 Centyrin是一种小型高度稳定的蛋白质，能以很高的特异性和亲和力结合目标抗原，从早期内体到溶酶体的各种pH条件下均能稳定。Centyrin蛋白有着很多独特的特性，包括优异的稳定性和溶解度、包括体积较小、可大肠杆菌生产，免疫原性较低，化学偶联方法与生产方式相对比较简单等，这让它们特别适合靶向递送寡核苷酸。 FDA授予ABX1100儿科罕见病资格认定（RPD），ABX1100是一种靶向肌肉中Gys1基因的研究性Centyrin-siRNA偶联物，用于治疗庞贝病。庞贝病是一种罕见致命性疾病，可在任何年龄发病，包括婴儿期。其特点是随着时间的推移进展为衰弱性肌无力，该病由负责分解肌肉细胞糖原的酸性α-葡萄糖苷酶突变引起的。ABX1100是一种治疗庞贝病的新方法，旨在减少肌肉中糖原的积累。 Centyrin-siRNA药物未来趋势： Centyrins抗原结合区的改造使其具有更多靶细胞结合的可能性，未来作用不可估量，但目前仍任重而道远。 14 抗体生物聚合物偶联物（ABC） 抗体生物聚合物偶联物（Antibody-biologic conjugates，ABC），将二药或者多药合一，从而降低成本，也可降低相关副作用，双特异性抗体（可理解为A抗体偶联B抗体），抗体偶联蛋白药物是其中常见的两类ABC。 ABC药物未来趋势： ABC除蛋白类药物，核酸药物外，现在生物酶也开始进行抗体偶联，未来ABC可能会扩展到更大的应用范围。 15 降解剂-抗体偶联物（DAC） DAC是由PROTAC和抗体偶联而成，目前PROTAC药物由三部分构成，包括目标蛋白结合物、泛素连接酶配体和连接子。但PROTAC通常面临细胞摄取差和生物利用度低的问题，在健康细胞和癌细胞之间缺乏区分可能会引发脱靶毒性，而DAC模式的出现为PROTAC药物提供了新的思路。 DAC药物未来的趋势： DAC药物虽处于发展的早期阶段，未来发展的要点有：扩展抗体靶点和结构；明确设计参数；拓展到分子胶和bioPROTAC；还可用于疾病检测、疾病机制探索和可控治疗。 最全！15种XDC药物全类型梳理及发展趋势预测 作者 | Yang  审核编辑 | Dr. Tuu ▎2024国际药物研发论坛推荐 瞄准全球最前沿的创新技术，由中关村生命科学园发起的2024国际药物研发论坛将于11月22日在北京召开，聚焦创新药物研发和可持续发展，围绕细胞与基因治疗药物研发及产业化、靶向肿瘤药物的研究进展探讨如何整合各方资源，在新技术上、新靶标、新机制、新化合物等方面寻求突破，打通“基础研究-新药创制-成果转化”三大环节之间的壁垒，努力建设新药创制生态圈，推动我国新药创制事业的源头创新、持续创新和循环创新。 本次论坛邀请了来自中国、英国、日本、瑞士、美国的顶尖基础研究及药物研发领域的科学家，包括罗敏敏教授，Adil Mardinoglu 教授，Shuai Ke教授，Minoru Takasato教授，Maya Zhang博士，Bernd Wollscheid教授，王军研究员等国内外知名专家出席，针对创新药物新技术研究，细胞基因疗法开发，靶向肿瘤药物研究带来最前沿的分享。 *议程以现场实际为准 扫码报名国际峰会，了解最新源头创新 2023年国际药物研发论坛往期回顾：