Uveal Melanoma

FRIENDSWOOD, Texas, April 28, 2025 (GLOBE NEWSWIRE) -- Castle Biosciences, Inc. (Nasdaq: CSTL), a company improving health through innovative tests that guide patient care, today announced its achievement of surpassing a significant milestone of 200,000 DecisionDx-Melanoma clinical test orders. DecisionDx-Melanoma is a 31-gene expression profile test that provides comprehensive, personalized results designed to improve risk-aligned management decisions for patients with stage I-III cutaneous melanoma. “We are excited by this milestone, which we believe is a testament to our shared desire with the melanoma healthcare community to improve the lives of patients,” said Derek Maetzold, president and chief executive officer of Castle Biosciences. “With every DecisionDx-Melanoma test, we aim to enable clinicians to make more informed, more precise treatment decisions that can improve patient outcomes.” Hear more from Maetzold and patients whose lives have been impacted by the DecisionDx-Melanoma test in this video. By harnessing the genetic information within a patient’s tumor biology and incorporating traditional clinicopathologic features, DecisionDx-Melanoma is designed to stratify patient risk and provide personalized results regarding a patient's individual predicted risk of recurrence and/or metastasis and likelihood of sentinel lymph node positivity. DecisionDx-Melanoma’s clinical value is supported by more than 50 peer-reviewed publications, has been shown to be associated with improved patient survival and has been studied in more than 10,000 patient samples. For more information about DecisionDx-Melanoma, visit www.CastleBiosciences.com. About DecisionDx-MelanomaDecisionDx-Melanoma is a 31-gene expression profile risk stratification test. It is designed to inform two clinical questions in the management of cutaneous melanoma: a patient’s individual risk of sentinel lymph node (SLN) positivity and a patient's personal risk of melanoma recurrence and/or metastasis. By integrating tumor biology with clinical and pathologic factors using a validated proprietary algorithm, DecisionDx-Melanoma is designed to provide a comprehensive and clinically actionable result to guide risk-aligned patient care. DecisionDx-Melanoma has been shown to be associated with improved patient survival and has been studied in more than 10,000 patient samples. DecisionDx-Melanoma’s clinical value is supported by more than 50 peer-reviewed and published studies, providing confidence in disease management plans that incorporate the test’s results. Through March 31, 2025, DecisionDx-Melanoma has been ordered more than 200,000 times for patients diagnosed with cutaneous melanoma. About Castle BiosciencesCastle Biosciences (Nasdaq: CSTL) is a leading diagnostics company improving health through innovative tests that guide patient care. The Company aims to transform disease management by keeping people first: patients, clinicians, employees and investors. Castle’s current portfolio consists of tests for skin cancers, Barrett’s esophagus, mental health conditions and uveal melanoma. Additionally, the Company has active research and development programs for tests in these and other diseases with high clinical need, including its test in development to help guide systemic therapy selection for patients with moderate-to-severe atopic dermatitis seeking biologic treatment. To learn more, please visit www.CastleBiosciences.com and connect with us on LinkedIn, Facebook, X and Instagram. DecisionDx-Melanoma, DecisionDx-CMSeq, i31-SLNB, i31-ROR, DecisionDx-SCC, MyPath Melanoma, DiffDx-Melanoma, TissueCypher, IDgenetix, DecisionDx-UM, DecisionDx-PRAME and DecisionDx-UMSeq are trademarks of Castle Biosciences, Inc. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which are subject to the “safe harbor” created by those sections. These forward-looking statements include, but are not limited to, statements concerning: DecisionDx-Melanoma’s ability to (i) provide comprehensive, personalized results to guide risk-aligned management decisions for patients with stage I-III cutaneous melanoma and (ii) help clinicians make more informed, more precise treatment decisions; and Castle’s ability to improve the lives of melanoma patients. The words “believe,” “can,” “could,” “potential” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements that we make. These forward-looking statements involve risks and uncertainties that could cause our actual results to differ materially from those in the forward-looking statements, including, without limitation: subsequent study or trial results and findings may contradict earlier study or trial results and findings or may not support the results obtained in these studies, including with respect to the discussion of our tests in this press release; actual application of our tests may not provide the aforementioned benefits to patients; and the risks set forth under the heading “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2024, and in our other filings with the SEC. The forward-looking statements are applicable only as of the date on which they are made, and we do not assume any obligation to update any forward-looking statements, except as may be required by law. Investor Contact:Camilla Zuckeroczuckero@castlebiosciences.com Media Contact:Allison Marshallamarshall@castlebiosciences.com Source: Castle Biosciences Inc. A video accompanying this announcement is available at: https://www.globenewswire.com/NewsRoom/AttachmentNg/922474ef-72a9-41fc-8ca8-b89137e201f9

Houston, Texas and Tuebingen, Germany, April 23, 2025 – Immatics N.V. (NASDAQ: IMTX, “Immatics” or the “Company”), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, today announced upcoming presentations on its lead cell therapy product candidate, IMA203 TCR T-cell therapy targeting PRAME, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting to be held from May 30 – June 3, 2025, in Chicago, Illinois. Updated data from the Phase 1b trial of IMA203 in patients with metastatic melanoma with substantially longer follow-up compared to the last presentation in October 2024, and including data from additional uveal melanoma patients enrolled since then, will be highlighted in an oral presentation. In addition, a trial-in-progress poster on SUPRAME, the ongoing Phase 3 clinical trial evaluating IMA203 in patients with unresectable or metastatic cutaneous melanoma who have received prior treatment with a checkpoint inhibitor, will be presented at the conference. Full abstracts will be available on the ASCO website on May 22, 2025, at 5:00 pm ET. Oral Presentation Title: Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanomaPresenting author: Martin Wermke, MDSession: Developmental Therapeutics – ImmunotherapyDate / Time: May 31, 2025 / 3:00 – 6:00 pm CDTAbstract ID: 2508 Poster Presentation Title: SUPRAME: A phase 3 trial comparing IMA203, an engineered T-cell receptor expressing T cell therapy (TCR T) vs investigator’s choice in patients with previously treated advanced cutaneous melanomaPresenting author: Jason Luke, MD, FACP, FASCOSession: Developmental Therapeutics - ImmunotherapyDate / Time: June 2, 2025 / 1:30 - 4:30 pm CDTAbstract ID: TPS2673 About IMA203 TCR T-cell Therapy and Target PRAMEIMA203 is an autologous, engineered T-cell receptor T-cell therapy (TCR T) that targets PRAME, an intracellular protein displayed as a peptide antigen on the surface of multiple solid tumors via HLA-A*02:01, with minimal expression on healthy tissues. With precise targeting and a turnaround time of approximately 14 days, IMA203 has demonstrated a favorable clinical profile in patients with unmet medical needs. IMA203 TCR T-cell therapy is currently being evaluated in a registration-enabling randomized controlled Phase 3 trial, “SUPRAME,” in patients with unresectable or metastatic cutaneous melanoma who have disease progression on or after at least one PD-1 inhibitor. In parallel, the Phase 1b clinical trial in patients with solid tumors expressing PRAME is ongoing with a focus on uveal melanoma. About ImmaticsImmatics combines the discovery of true targets for cancer immunotherapies with the development of the right T-cell receptors with the goal of enabling a robust and specific T-cell response against these targets. This deep know-how is the foundation for our pipeline of Adoptive Cell Therapies and TCR Bispecifics as well as our partnerships with global leaders in the pharmaceutical industry. We are committed to delivering the power of T cells and to unlocking new avenues for patients in their fight against cancer. Immatics intends to use its website www.immatics.com as a means of disclosing material non-public information. For regular updates you can also follow us on Instagram and LinkedIn. For more information, please contact: Media Trophic CommunicationsPhone: +49 151 74416179immatics@trophic.eu Immatics N.V.Jordan SilversteinHead of StrategyPhone: +1 346 319-3325InvestorRelations@immatics.com Attachment PDF Version

摘要：双特异性抗体（bsAbs）作为一种新型抗癌疗法，能同时靶向两种不同抗原，通过多种独特机制发挥作用，为癌症治疗带来新希望 。目前，部分 bsAbs 已获批用于血液系统恶性肿瘤和部分实体瘤的治疗，但在临床应用中仍面临毒性管理和耐药等挑战 。本文将详细介绍 bsAbs 的设计原理、作用机制、临床应用现状、局限性以及未来发展方向，旨在让读者全面了解这一领域的研究进展和应用前景 。一、双特异性抗体：癌症治疗的新希望癌症严重威胁人类健康，传统治疗手段存在诸多局限 。双特异性抗体（bsAbs）作为一种新型治疗药物，能同时瞄准两个不同的抗原或抗原表位，具有独特的结构和多样的设计可能性，这使其作用机制丰富多样，比如引导免疫细胞攻击肿瘤细胞，或阻断肿瘤相关的信号通路 。目前，已有 11 种 bsAbs 获得监管批准用于癌症治疗，其中 7 种用于血液系统恶性肿瘤，4 种用于部分实体瘤，还有大量相关临床试验正在进行 。不过，在临床使用过程中，bsAbs 也面临着细胞因子释放综合征（CRS）、免疫效应细胞相关神经毒性综合征（ICANS）等不良反应的挑战 。接下来，我们深入了解一下 bsAbs 的具体情况 。二、双特异性抗体的设计奥秘结构优化与功能调节：bsAbs 的设计灵感来源于内源性二价抗体，目前主要分为基于 Fc 区域和基于片段的两大类（原文 Figure 1 和 Figure 2，帮助读者直观理解内源性抗体、单克隆抗体和双特异性抗体的结构差异，以及 bsAbs 的不同设计类型） 。Fc 区域在抗体中负责介导效应功能，但也可能引发一些不良影响 。因此，人们通过选择不同的 IgG 亚类或进行氨基酸替换等方式来调整 Fc 区域的功能，以平衡其免疫激活和不良作用 。比如，选择 IgG2 或 IgG4 亚类可以降低与 FcγR 的结合，减少非特异性免疫细胞激活；而去除或减少 Fc N - 聚糖中的核心岩藻糖，则能增强与 FcγRIIIa 的结合，提升 ADCC 活性 。药代动力学与半衰期优化：bsAbs 的药代动力学特性和半衰期对其疗效有着重要影响 。基于 Fc 的 bsAbs 可以通过与新生儿 Fc 受体（FcRn）结合，实现抗体的循环利用，延长半衰期 。而基于片段的 bsAbs 虽然具有较高的组织渗透性，但半衰期较短 。为了解决这一问题，人们尝试了多种方法，如对基于片段的 bsAbs 进行修饰，使其与其他分子融合，像与人类血清白蛋白融合，或者为经典的 BiTEs 添加 Fc 区域，从而延长其在体内的停留时间。抗原结合价态的选择：bsAbs 根据抗原结合位点的数量可分为对称和不对称两种类型 。对称 bsAbs 通常具有四价结构，能平衡地靶向两个抗原；不对称 bsAbs 则提供了更灵活的靶向选择，如 1 + 1 或 1 + 2 等不同的结合形式。选择合适的抗原结合价态，有助于提高 bsAbs 对肿瘤细胞的靶向性和治疗效果 。降低 “脱靶毒性”：“on - target off - tumor” 毒性是 bsAbs 面临的一个重要问题，即抗体与肿瘤细胞和正常组织上的抗原都结合，从而产生不良影响 。为了改善这一情况，研究人员通过优化不同结合位点的特异性和亲和力，使 bsAbs 更倾向于与肿瘤细胞结合 。例如，ABL503 通过同时靶向 PD - 1 和 4 - 1BB，降低了肝脏毒性；TG - 1801 对 CD19 和 CD47 的不同亲和力设计，减少了对正常细胞的影响。此外，将 bsAbs 设计成在肿瘤微环境中激活的前药，也是减少对健康组织影响的一种策略 。三、双特异性抗体的作用机制大揭秘免疫细胞激活：双特异性 T 细胞衔接器（TCEs）能够同时结合 T 细胞和肿瘤细胞，激活 T 细胞，使其释放穿孔素和颗粒酶，从而杀死肿瘤细胞 。此外，TCEs 还能引发 T 细胞的增殖和迁移，重塑肿瘤微环境（TME）（原文 Figure 3，展示双特异性 T 细胞衔接器等 bsAbs 的作用机制示意图，帮助读者理解 TCEs 如何发挥作用）。除了 T 细胞，自然杀伤（NK）细胞也能被双特异性杀伤细胞衔接器（BiKEs）引导至肿瘤部位，发挥抗肿瘤作用 。例如，AFM13（CD30xCD16A）在治疗 CD30 + 淋巴瘤的临床试验中展现出显著的抗肿瘤活性 。免疫检查点调节：免疫检查点调节疗法是癌症治疗的重要突破，但也存在一些问题 。双特异性抗体可以同时阻断两个免疫检查点受体，如 PD - 1 和 CTLA - 4，相比于单克隆抗体组合，它能更精准地靶向肿瘤浸润淋巴细胞（TILs），增强抗肿瘤免疫反应，同时减少 “脱靶” 毒性 。例如，volrustomig 和 cadonilimab 都能优先靶向共表达 PD - 1 和 CTLA - 4 的 TILs 。此外，bsAbs 还可以结合共刺激受体，进一步激活 T 细胞，但如何控制 T 细胞的激活程度，使其在安全有效的范围内，仍是一个挑战 。信号通路阻断：bsAbs 可以通过阻断肿瘤细胞的关键信号通路来抑制肿瘤生长 。它们可以同时靶向两个不同的抗原或同一抗原的不同区域，阻止受体 - 配体相互作用，促进受体内化和降解，从而抑制下游信号传导 。比如，amivantamab 通过阻断 EGFR 和 cMET 信号通路，有效治疗 EGFR 突变的非小细胞肺癌；zanidatamab 则通过同时靶向 HER2 的不同结构域，抑制 HER2 信号传导，展现出强大的抗肿瘤活性 。四、双特异性抗体的临床应用成果血液系统恶性肿瘤：在血液系统恶性肿瘤的治疗中，bsAbs 取得了显著的成效 。以急性淋巴细胞白血病（ALL）为例，blinatumomab 在治疗复发 / 难治性 B 细胞 ALL 方面表现出色，不仅在成人和儿童患者中都有较高的完全缓解率，还获得了 FDA 的多项批准，用于不同阶段的 ALL 治疗 。在 B 细胞非霍奇金淋巴瘤（B - NHL）的治疗中，glofitamab、epcoritamab 和 mosunetuzumab 等针对 CD20 的 TCEs，在复发 / 难治性患者中展现出良好的疗效，显著提高了完全缓解率 。对于多发性骨髓瘤（MM），teclistamab、elranatamab 和 talquetamab 等靶向特定抗原的 bsAbs，为复发 / 难治性患者带来了新的希望，延长了患者的无进展生存期和总生存期（原文中相关表格，如 Table 1，展示这些 bsAbs 在血液系统恶性肿瘤治疗中的关键数据，包括批准时间、适应症、临床试验结果等，让读者更直观地了解其疗效） 。实体肿瘤：尽管在实体肿瘤的治疗中，bsAbs 面临着更多挑战，但也取得了一些突破 。tebentafusp 是一种针对葡萄膜黑色素瘤的 ImmTAC 分子，它的出现为这种对传统免疫治疗耐药的肿瘤提供了新的治疗选择，显著延长了患者的总生存期 。amivantamab 获批用于治疗 EGFRex20ins 非小细胞肺癌，tarlatamab 则被批准用于治疗复发 / 难治性广泛期小细胞肺癌，它们在临床试验中都展现出了一定的疗效 。此外，还有许多针对不同实体肿瘤抗原的 bsAbs 正在研发中，如针对 HER2、CLDN18.2 等抗原的药物，为未来实体肿瘤的治疗带来了新的希望 。五、双特异性抗体面临的挑战与应对策略毒性反应：细胞因子释放综合征（CRS）是 bsAbs 治疗中常见的不良反应，它是由于免疫细胞过度激活，导致促炎细胞因子大量释放引起的 。症状轻重不一，严重时可能危及生命 。目前，临床上主要通过密切监测、支持治疗和使用抗炎药物（如 tocilizumab）来管理 CRS 。免疫效应细胞相关神经毒性综合征（ICANS）也是一种严重的神经系统毒性，其发病机制与免疫细胞激活和细胞因子释放有关，症状包括震颤、失语等，严重时可进展为谵妄、癫痫甚至昏迷。ICANS 的管理主要依靠密切监测和支持治疗，皮质类固醇激素是常用的治疗药物 。输液相关反应（IRRs）通常在输液过程中或输液后短时间内出现，症状多样，可轻可重 。通过调整输液速度、预先使用药物（如抗组胺药、类固醇等）等方法可以减少 IRRs 的发生 。此外，使用 bsAbs 治疗还可能增加机会性感染的风险，尤其是在血液系统恶性肿瘤患者中，这与患者自身免疫状态、bsAbs 的 “脱靶” 效应以及联合治疗等因素有关，需要加强监测和预防。耐药机制：目前对 bsAbs 耐药机制的了解主要来自 TCEs 相关研究。免疫检查点蛋白的上调是潜在的耐药机制之一，例如在急性髓系白血病（AML）细胞系中，PD - L1 和 PD - L2 的表达上调会降低 AMG 330 的细胞毒性 。肿瘤细胞表面靶抗原表达的下调或丢失也会导致耐药，如部分接受 blinatumomab 治疗的患者会出现 CD19 表达缺失 。此外，MHC - I 下调或 IFN - γ 信号通路受损也可能与耐药有关 。同时，机体产生的抗药物抗体（ADAs）会与 bsAbs 结合，影响其疗效，甚至可能引发严重的不良反应 。应对策略：为了应对这些挑战，研究人员在不断探索新的方法 。在优化 bsAbs 设计方面，通过创新的工程技术，如开发多特异性抗体、引入新的抗原靶点等，可以提高 bsAbs 的疗效和特异性，减少 “脱靶” 毒性 。在联合治疗策略上，将 bsAbs 与化疗、抗体 - 药物偶联物（ADCs）等联合使用，有望发挥协同作用，克服耐药性 。此外，利用计算和人工智能技术辅助 bsAbs 的研发，可以加速新型 bsAbs 的开发和临床应用。六、总结与展望双特异性抗体在癌症治疗领域展现出了巨大的潜力，尤其是在血液系统恶性肿瘤的治疗中取得了显著的成效 。然而，在实体肿瘤治疗方面仍面临诸多挑战，如抗原表达异质性、肿瘤微环境的免疫抑制等 。未来，需要进一步优化 bsAbs 的设计和生产工艺，深入了解其作用机制和耐药机制，探索更有效的联合治疗方案 。同时，利用先进的技术手段，如计算和人工智能技术，将有助于加速 bsAbs 的研发和临床应用，为癌症患者带来更多的治疗选择和更好的治疗效果 。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。