MYTX-011

深度聚焦多肽、多肽偶联药物研发、质控、工艺开发，展位咨询&免费入场券：联系电话181 1603 6798，上下滑动查看议程文章来源： 胖猫的生命医学札记引言：ADC赛道席卷全球，在研的ADC药物多达几百款，各种BD交易不断刺激大家的神经，BCG 针对下一代的ADC药物研发，汇编了一个包含182个已获批准或正在全球临床开发中的抗体药物结合物（ADC）管线的数据，并针对这些研发管线进行了分析和总结。生物医学是实验和事实驱动的科学，所以除了事实之外都是假设，分清事实和观点非常重要，所以认真思考和解读事实和数据，比直接听观点重要很多，评估决策系统有效性，服务于之后的布局。1、市场空间预测抗体-药物偶联物 （ADC） 已成为肿瘤学中一种关键的治疗方式，与多种适应症的标准化疗相比，其临床优势更为明显。因此，预计到2028年，已获批的ADC和处于III期开发的ADC的收入将达到260亿美元（图1）。图注1：补充图1 | 市场上或处于III期开发中的抗体-药物偶联物预测收入。其中“其他”类别包括10种已批准及III期ADCs，预计2023至2028年间销售额不足10亿美元。数据来源：EvaluatePharma（2023年10月）；BCG analysis。尽管抗体药物偶联物（ADCs）取得了成功，但其长期应用增长面临两大挑战。首先，经验证的有效载荷作用机制（MoAs）较少，限制了可治疗的疾病范围。目前批准的ADC有效载荷涵盖三种细胞毒作用机制：抗有丝分裂、DNA烷化和拓扑异构酶1抑制，这些机制通常需要肿瘤特异性过表达的目标抗原来确保有效且安全的载荷递送。因此，这些ADCs主要针对已知的肿瘤抗原，如HER2、CD20和BCMA。其次，非特异性和不充分的有效载荷传递限制了抗体药物偶联物（ADCs）的治疗窗口。目前批准使用的ADCs的传递组件通常包括通过半胱氨酸还原随机连接到单克隆抗体载体的可裂解肽连接器。过早释放有效载荷、瘤体穿透能力差、药物与抗体比例不稳定及聚集是常见问题。为了探索下一代ADC技术对这些挑战的影响，从五个设计维度层面——靶点、有效载荷作用机制、抗体、连接剂和偶联方法分析调研了了ADC临床管道中的创新情况，并评估了扩大ADC可治疗适应症或增宽其治疗窗口的可能性（图2、图3）。图注2: 临床开发中ADC不同角度上的统计。在临床管线中使用的特定设计的创新。列举了每个设计创新方面的前10个目标和技术列举图注3:ADC 从靶点、Payload、抗体、Linker、偶联方式上创新数量分布（图2扩展图）2、临床管线评估在开发中的ADC管线根据其克服两大主要挑战的潜力被分为两类（见补充图2a）。第一类资产具有新的靶点和/或作用机制，具有首创性潜力。第二类资产则利用已建立的靶点/药效组合，并通过创新的给药组件实现最佳类别的特性。以第一代资产为例，第一三共的帕替图单抗德鲁西替坎针对HER3，最近的HERTHENA-Lung01二期试验数据显示，在接受过EGFR抑制剂和铂类化疗的EGFR突变患者中，整体反应率（ORR）为30%，相较于同类患者群体的实际世界ORR 14%。默克公司和科伦生物技术的SKB264是一个第二类资产的例子，其靶点和药效作用机制与已批准的ADC药物sacituzumab govitecan（Trodelvy；吉利德）相同。SKB264通过采用2-甲基砜基嘧啶连接器增强了循环稳定性，与sacituzumab govitecan相比。在接受过治疗的转移性三阴性乳腺癌患者的二期研究中，SKB264的ORR为40%，56%的患者出现3级或更高级别的不良事件（AEs），相较于sacituzumab govitecan在类似患者群体中21%的ORR和74%的AE率，表现更为优异。（图4）图注4:两种创新类型的ADC分类通过对168种临床开发中的ADC进行分析（抗体药物偶联。总体而言，约85%的资产针对实体瘤适应症，其中乳腺癌和肺癌最为常见。在进入III期ADC中，约60%为二型资产，它们利用已建立的靶点和有效载荷的作用机制，并改进了递送组件，这可能反映了该技术近期的成功和晚期开发中较低的风险承受能力。在早期开发阶段，生物学风险更为明显；约75%的I/II期ADC是一型资产，具有新颖的靶点和有效载荷机制组合。（图5）图注5:两种创新策略下的管线不同临床阶段的数量3、靶点和适应症分析生物学靶点是ADC的一个重要创新领域，在临床中有61个独特的靶点正在研究中。总体而言，约90%的靶点是在癌细胞上高表达的抗原，约10%的靶点与肿瘤微环境的独特特征相关。例如，Pyxis Oncology的PYX-201靶向纤维连接蛋白，这是癌相关成纤维细胞高度分泌的一种细胞外蛋白。靶向基质成分的ADC可能对具有高基质-肿瘤比例的肿瘤（如乳腺癌和前列腺癌）有效，并通过基质细胞的遗传稳定性阻止耐药性的演变。（图6）图注6:A：肿瘤类型（实体瘤和血液瘤的资产）。B：对多种肿瘤类型进行研究的资产将被分别计算4、Payload、抗体、Linker、偶联方式上的创新分析为了评估ADC创新的潜在影响，我们根据我们的创新框架对下一代技术进行了分类，并评估了与市场上ADCs的对比情况。在此，我们重点介绍了一些可能因其新颖性和/或有前景的临床前和临床数据而引起关注的下一代设计杠杆。（图7、图8)4.1下一代Payload小分子降解剂作为一种新兴的药物载体，因其高特异性、皮摩尔级的效力以及能够针对与癌症相关的广泛细胞内蛋白而备受关注。Orum Therapeutic的ORM-5029是一种针对GSPT1的选择性降解剂，GSPT1是一种在多种癌症中过表达的GTP酶，包括胃癌、结直肠癌和乳腺癌。在临床前研究的乳腺癌模型中，其抗癌活性与曲妥珠单抗德鲁西替康（Enhertu；第一三共）相似。即将公布的ORM-5029的一期临床数据将是抗体-降解剂偶联物的首次临床数据。4.2下一代抗体通过设计具有可变抗原结合亲和力的抗体，可以减少非靶组织的毒性并增加肿瘤特异性暴露。策略包括用易被肿瘤过表达的蛋白酶切割的肽掩模来保护Fab区域，以及开发具有优化的pH敏感结合特性的抗体。尽管过去存在失败案例，但抗体工程具有扩大治疗窗口和治疗低靶标表达水平患者的潜力。例如，Mythic Therapeutic的MYTX-011就是在内体pH较低的情况下设计有较低的抗原亲和力，以增强有效成分从内体逃逸的能力。在临床前研究中，与母体抗体和一种临床上针对c-Met的ADC相比，MYTX-011显示出增强的内化、细胞毒活性以及针对表达c-Met的肿瘤模型的体内疗效。4.3下一代连接技术新兴的连接技术专注于控制有效载荷的释放，不依赖于内源性酶介导的切割。TagWork的临床前抗体药物偶联物TGW101采用外源性化学激活剂来诱导有效载荷释放。与VC肽连接剂相比，在结直肠癌和卵巢癌异种移植模型中显示出优越的抗肿瘤活性。控制有效载荷释放可以限制组织外毒性，并支持针对在癌症中过表达的非内化蛋白的资产进一步开发。4.4下一代偶联技术通过将非天然氨基酸整合到抗体载体中，可以通过肟键实现特异性偶联。Ambrx 的 ARX788 是一种针对 HER2 的 ADC，它通过非天然氨基酸以特异性方式连接了不可切割的 PEG 连接器。一期数据显示，与已批准的针对 HER2 的 ADC 相比，ARX788 在血清中显示出抗肿瘤活性和改善的稳定性。减少药物过早释放可以增加输送到肿瘤细胞的药物量，并提高响应率。5、结论随着ADCs的兴起和新技术的出现，公司必须有效评估新兴平台，制定投资策略以最大化专业知识和能力，并决定采取FIC还是BIC。短期内不太可能出现“一刀切”的技术。相反，预计公司将构建多样化的组件集合，以实现针对特定目标和适应症的“即插即用”开发。免责声明：本文信息来源于网络，本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。END深度聚焦多肽、多肽偶联药物研发、质控、工艺开发，7月相约苏州，联系电话18116036798戳“阅读原文”立即报名多肽药物论坛吧!

NASHVILLE, Tenn.--(BUSINESS WIRE)-- Sarah Cannon Research Institute (SCRI), one of the world’s leading oncology research organizations conducting community-based clinical trials, announced today that it will highlight its latest research insights through more than 145 presentations at the 2024 American Society of Clinical Oncology (ASCO®) Annual Meeting from Friday, May 31 – Tuesday, June 4 in Chicago, Ill. Over 100 investigators from across SCRI’s network are co-authors on clinical trial updates that will be showcased at the Annual Meeting, including data from more than 65 early-phase clinical trials. “We look forward to connecting with colleagues from around the world at ASCO’s Annual Meeting to discuss the latest developments in advancing therapies for cancer patients,” says Howard A. “Skip” Burris, III, MD, President, SCRI. “The depth and breadth of clinical research being presented by SCRI experts signifies our commitment to accelerating drug development and providing greater access to cutting-edge therapies closer to home.” For a comprehensive list of abstracts and presentations, visit SCRI’s ASCO Site. To learn more about our research experts, visit our Leadership Page. Noteworthy Presentations Breast Cancer Erika Hamilton, MD, SCRI, will present “H3B-6545 in Women with Locally Advanced/Metastatic Estrogen Receptor-Positive, HER2 Negative Breast Cancer” in an oral presentation during the Breast Cancer – Metastatic Rapid Oral Abstract Session on Monday, June 3 from 11:30 a.m. - 1:00 p.m. CDT in Hall D1. Joyce O'Shaughnessy, MD, SCRI at Texas Oncology I The US Oncology Network, will deliver “Association of MammaPrint Index and 3-Year Outcome of Patients with HR+HER2- Early-Stage Breast Cancer Treated with Chemotherapy with or without Anthracycline” in an oral presentation during the Breast Cancer—Local/Regional/Adjuvant Rapid Oral Abstract Session on Friday, May 31 from 2:45 p.m. - 4:15 p.m. CDT in E451. Denise Yardley, MD, SCRI, will give the oral presentation, “Baseline Characteristics and Efficacy Endpoints for Patients with Node-Negative HR+/HER2− Early Breast Cancer: NATALEE Trial” during the Breast Cancer—Local/Regional/Adjuvant Rapid Oral Abstract Session on Friday, May 31 from 2:45 p.m. - 4:15 p.m. CDT in E451. Lung Cancer David Spigel, MD, SCRI, will discuss “ADRIATIC: Durvalumab as Consolidation Treatment for Patients with Limited-Stage Small-Cell Lung Cancer” in an oral presentation during the Plenary Session on Sunday, June 2 from 1:00 p.m. - 4:00 p.m. CDT in Hall B1. Clinical Trial Access Ishwaria Subbiah, MD, MS, SCRI, will present “5-Year Multicenter Analysis of Clinical Trial Participation and Total Cost of Care for Older Adults with Cancer” in an oral presentation during the Quality Care/Health Services Research Rapid Oral Abstract Session on Monday, June 3 from 1:15 p.m. - 2:45 p.m. CDT in S102. In addition to scientific presentations, SCRI leadership will participate in and lead ASCO sessions, including: Meredith McKean, MD, MPH, SCRI, is a discussant in the Oral Abstract Session, Melanoma/Skin Cancers, on Friday, May 31 from 2:45 p.m. - 5:45 p.m. CDT in Hall D1, where she will present “PD-1–Refractory Advanced Melanoma: How Do We Get to the Finish Line?” Dr. Burris will deliver the “Presentation and Recognition of Conquer Cancer Top Donors” in the Opening Session on Saturday, June 1 from 9:30 a.m. - 12:00 p.m. CDT in Hall B1. Dr. Hamilton will chair the Clinical Science Symposium, Next-Generation Antibody-Drug Conjugates: The Revolution Continues, and present “The ABCs of ADCs: What Does the Future Hold?” on Sunday, June 2 from 9:45 a.m. - 11:15 a.m. CDT in Hall D1. Abdul Naqash, MD, SCRI at OU Health - Stephenson Cancer Center, will chair the Oral Abstract Session, Developmental Therapeutics—Immunotherapy, on Monday, June 3 from 11:30 a.m. - 2:30 p.m. CDT in Hall D2. Andrew McKenzie, PhD, SCRI & Genospace, and Vivek Subbiah, MD, SCRI, will serve as panelists in the Case-Based Panel, Beyond Tumor Types: Advancing Tumor-Agnostic Drug Development and the Role of the Tumor Microenvironment, on Monday, June 3 from 3:00 p.m. - 4:00 p.m. CDT in Hall D2. Cesar Perez, MD, SCRI at Florida Cancer Specialists & Research Institute, will present “Emerging Data for Antibody Drug Conjugates in Head and Neck Squamous Cell Carcinoma,” during the Breaking Ground in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Novel Therapies Beyond PD-L1 Immunotherapy Education Session on Tuesday, June 4 from 8:00 a.m. - 9:15 a.m. CDT in S100a. Additional Poster Presentations with SCRI First Authors Saturday, June 1 “Validation of PD-L1 as a Predictive Biomarker of Response in Operable Gastroesophageal Adenocarcinoma: A Meta-Analysis and Meta-Regression of Neoadjuvant Chemoimmunotherapy Trials,” Antonella Cammarota, MD, SCRI at HCA Healthcare UK, 1:30 p.m. - 4:30 p.m. CDT, Hall A. “Phase 1 Trial Safety and Efficacy of Ragistomig, a Bispecific Antibody Targeting PD-L1 and 4-1BB, in Advanced Solid Tumors,” Gerald Falchook, MD, SCRI at HealthONE, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “NALIRIFOX versus Nab-Paclitaxel and Gemcitabine in Treatment-Naïve Patients with Metastatic Pancreatic Ductal Adenocarcinoma: Updated Overall Survival Analysis with 29-Month Follow-Up of NAPOLI 3,” Maen Hussein, MD, SCRI at Florida Cancer Specialists & Research Institute, 1:30 p.m. - 4:30 p.m. CDT, Hall A. “Safety and Preliminary Efficacy of EIK1001 in Combination with Atezolizumab in Participants with Advanced Solid Tumors,” & “Preliminary Results from a Phase 1 Study of AC699, an Orally Bioavailable Chimeric Estrogen Receptor Degrader, in Patients with Advanced or Metastatic Breast Cancer,” Manish Patel, MD, SCRI at Florida Cancer Specialists & Research Institute, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “Results from Phase 1a/1b Analyses of TTX-080, a First in Class HLA-G Antagonist, in Combination with Cetuximab in Patients with Metastatic Colorectal Cancer and Head and Neck Squamous Cell Carcinoma,” Susanna Ulahannan, MD, MMEd, SCRI at OU Health - Stephenson Cancer Center, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “Phase 1/2 Study of NGM707, an ILT2/ILT4 Dual Antagonist Antibody, in Advanced Solid Tumors: Interim Results from Dose-Escalation,” Judy Wang, MD, SCRI at Florida Cancer Specialists & Research Institute, 9:00 a.m. - 12:00 p.m. CDT, Hall A Sunday, June 2 “Trastuzumab Deruxtecan vs Trastuzumab Emtansine in Patients with HER2+ Metastatic Breast Cancer: Updated Survival Results of DESTINY-Breast03,” Dr. Hamilton, 9:00 a.m. - 12:00 p.m. CDT, Hall A. Monday, June 3 “Subcutaneous Epcoritamab Administered Outpatient for Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Follicular Lymphoma: Results from Phase 2 EPCORE NHL-6," David Andorsky, MD, SCRI at Rocky Mountain Cancer Centers I The US Oncology Network, 9 a.m. - 12 p.m. CDT, Hall A “MYTX-011 in Patients with Previously Treated Locally Advanced or Metastatic NSCLC: Initial Dose Escalation Results in The Phase 1 KisMET-01 Study,” Melissa Johnson, MD, SCRI, 1:30 p.m. - 4:30 p.m. CDT, Hall A. “Clinical Activity and Safety of Naptumomab Estafenatox and Docetaxel in Patients with Checkpoint Inhibitor –Pretreated Advanced/Metastatic Non-Small Cell Lung Cancer: Preliminary Results of a P2 Trial,” Tim Larson, MD, SCRI at Minnesota Oncology I The US Oncology Network, 1:30 p.m. - 4:30 p.m. CDT, Hall A. “Treatment of Acute Myeloid Leukemia with Orca-T,” Jeremy Pantin, MD, SCRI at TriStar Centennial, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “Safety and Tolerability of Durvalumab + Carboplatin/Paclitaxel Followed by Durvalumab ± Olaparib in Patients with Newly Diagnosed Advanced or Recurrent Endometrial Cancer in the DUO-E/GOG-3041/ENGOT-EN10 Trial,” Jessica Thomes Pepin, MD, SCRI at Minnesota Oncology I The US Oncology Network, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “OPTec: A Phase 2 Study to Evaluate Outpatient Step-Up Administration of Teclistamab, a BCMA-Targeting Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma,” Robert Rifkin, MD, SCRI at Rocky Mountain Cancer Centers I The US Oncology Network, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “Clinical Trial Participation and End-of-Life Care Among Older Adults: A Multi-Center Longitudinal Observational Cohort Analysis of 121,717 Patients with Cancer,” Dr. I. Subbiah, 9:00 a.m. - 12:00 p.m. CDT, Hall A. “Performance of Comprehensive Genomic Profiling versus Single Gene Testing in Guideline-Recommended Biomarker Selection in Non-Small Cell Lung Cancer,” Dr. V. Subbiah, 1:30 p.m. - 4:30 p.m. CDT, Hall A. About Sarah Cannon Research Institute Sarah Cannon Research Institute (SCRI) is one of the world’s leading oncology research organizations conducting community-based clinical trials. Focused on advancing therapies for patients over the last three decades, SCRI is a leader in drug development. In 2022, SCRI joined with former US Oncology Research to expand clinical trial access across the country. It has conducted more than 750 first-in-human clinical trials since its inception and contributed to pivotal research that has led to the majority of new cancer therapies approved by the FDA today. SCRI’s research network brings together more than 1,300 physicians who are actively enrolling patients into clinical trials at more than 250 locations in 24 states across the U.S. Learn more about our research offerings. View source version on businesswire.com: Contacts Becca Gelman Becca.Gelman@scri.com Source: Sarah Cannon Research Institute View this news release online at: