Seribantumab

-- Dosing ongoing in Phase 1 clinical trial cohorts evaluating Claudin 18.2 ADC EO-3021 in combination with ramucirumab or dostarlimab in patients with advanced gastric/gastroesophageal junction (GEJ) cancer -- -- Expect to report initial data from combination cohorts in 4Q 2025 or 1Q 2026 -- -- On-track to report additional monotherapy data from dose escalation and expansion cohort of ongoing Phase 1 clinical trial in 2Q 2025 -- -- Preclinical data for HER3 ADC EO-1022 to be presented at American Association for Cancer Research (AACR) Annual Meeting 2025; plan to file an Investigational New Drug (IND) application in 2026 -- BOSTON, March 6, 2025 /PRNewswire/ -- Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, today announced financial results for the quarter and full-year ended December 31, 2024, and highlighted recent business achievements. "We continue to advance our Claudin 18.2 ADC program, EO-3021, for the treatment of advanced gastric/GEJ cancer in the earlier lines settings," said Joseph Ferra, President and Chief Executive Officer of Elevation Oncology. "Based on the competitive anti-tumor activity and differentiated safety profile observed to date, we believe EO-3021 has the potential to benefit a broad patient population. Currently, we are evaluating EO-3021 in combinations with approved therapies in the first- and second-line settings, where we have a first-mover advantage and the opportunity to address significant markets, while also progressing our monotherapy cohort toward an additional data readout in the second quarter of 2025." Mr. Ferra continued, "In the first quarter, we introduced prospective Claudin 18.2 testing to the monotherapy dose expansion cohort of our ongoing Phase 1 trial. This will further enhance our understanding of the patients most likely to benefit from treatment with our ADC and ultimately inform the design of future registrational studies. In addition, we continue to develop our HER3 ADC EO-1022 for the treatment of a wide range of HER3-expressing solid tumors and look forward to sharing preclinical data at the AACR Annual Meeting next month. We believe both EO-3021 and EO-1022 have the potential to elevate cancer care and are eager to share updates on both programs as we move through 2025." Recent Business Achievements Claudin 18.2 ADC EO-3021: In January 2025, Elevation Oncology implemented prospective Claudin 18.2 expression testing as part of the patient screening process in its ongoing Phase 1 clinical trial of monotherapy EO-3021. The dose expansion portion of the trial is now enrolling patients with ≥ 25% of tumor cells at IHC 1+/2+/3+, representing a moderately broader population compared to the exploratory efficacy analysis, which will continue to include patients with ≥ 20% of tumor cells at IHC 2+/3+. In January 2025, Elevation Oncology initiated dosing in the combination cohorts of its Phase 1 clinical trial of EO-3021. The combination cohorts are evaluating EO-3021 in combination with dostarlimab, a PD-1 inhibitor, in the first-line setting and with ramucirumab, a VEGFR2 inhibitor, in the second-line setting for the treatment of advanced gastric/GEJ cancer. In December 2024, Elevation Oncology presented preclinical proof-of-concept data supporting the combination potential of EO-3021 with VEGFR2 or PD-1 inhibitors at the ESMO Immuno-Oncology Annual Congress 2024 (ESMO-IO). The in vivo data showed: Treatment with EO-3021 and DC101, a surrogate of VEGFR2 inhibitor ramucirumab, exhibited statistically superior tumor growth inhibition (TGI) compared to treatment with either EO-3021 or DC101 alone (TGI: 88.2% for EO-3021 in combination with DC101, compared to 20.1% for EO-3021 and 59.2% for DC101 alone). Treatment with EO-3021 and a PD-1 inhibitor exhibited statistically superior TGI compared to treatment with either EO-3021 or a PD-1 inhibitor alone (TGI: 79.9% for EO-3021 in combination with a PD-1 inhibitor, compared to 33.8% for EO-3021 and 25.0% for a PD-1 inhibitor alone). 92% (11/12) of mice treated with the combination of EO-3021 and a PD-1 inhibitor achieved a complete response (CR), compared to 50% (6/12) mice treated with EO-3021 monotherapy and 17% (2/12) mice treated with a PD-1 inhibitor alone. HER3 ADC EO-1022: In December 2024, Elevation Oncology nominated EO-1022 as its HER3 ADC development candidate for the treatment of HER3-expressing solid tumors including breast cancer and non-small cell lung cancer. EO-1022 is designed to be a differentiated HER3 ADC, leveraging seribantumab's desirable internalization properties, the latest site-specific ADC technology and the MMAE payload. Expected Upcoming Milestones EO-3021: Report additional safety and efficacy data from the ongoing Phase 1 clinical trial of monotherapy EO-3021, including from the dose escalation and expansion cohorts, in the second quarter of 2025. Report initial data from the combination cohorts of the Phase 1 clinical trial of EO-3021 in the fourth quarter of 2025 or the first quarter of 2026. EO-1022: Present preclinical data for EO-1022 at AACR Annual Meeting in the second quarter of 2025. File an IND application for EO-1022 in 2026. Fourth Quarter and Full Year 2024 Financial Results As of December 31, 2024, Elevation Oncology had cash, cash equivalents and marketable securities totaling $93.2 million, compared to $83.1 million as of December 31, 2023. The increase in cash reflects net proceeds of $44.2 million, which Elevation Oncology raised through its at-the-market (ATM) facility in the first half of 2024, partially offset by cash used to fund operating activities. Research and development (R&D) expenses for the fourth quarter of 2024 were $6.6 million, compared to $4.7 million for the fourth quarter of 2023. The increase in R&D expenses in the fourth quarter of 2024 was primarily due to increased clinical trial expenses for the lead program EO-3021. For the year ended December 31, 2024, R&D expenses were $28.6 million, compared to $25.4 million for the year ended December 31, 2023. The increase was primarily driven by continuous investment in the lead and pipeline programs. General and administrative (G&A) expenses for the fourth quarter of 2024 were $4.0 million, compared to $3.3 million for the fourth quarter of 2023. The increase in G&A expenses in the fourth quarter of 2024 was primarily due to increased personnel costs, including stock compensation expenses. For the year ended December 31, 2024, G&A expenses were $16.1 million, compared to $14.9 million for the year ended December 31, 2023. The increase was primarily due to increased professional fees and personnel expenses, partially offset by a decrease in premiums paid on directors' and officers' insurance. Net loss for the fourth quarter of 2024 was $10.4 million, compared to $7.9 million for the fourth quarter of 2023. Financial Outlook Elevation Oncology expects that its cash, cash equivalents and marketable securities as of December 31, 2024, will be sufficient to fund its current operations into 2026. About Elevation Oncology, Inc. Elevation Oncology is an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs. We are leveraging our ADC expertise to advance a novel pipeline, initially targeting two clinically validated targets in oncology, Claudin 18.2 and HER3. Our lead candidate, EO-3021, is a potential best-in-class Claudin 18.2 ADC and is currently being evaluated in a Phase 1 trial (NCT05980416) as a monotherapy, and in combinations with dostarlimab or ramucirumab, in patients with advanced, unresectable or metastatic gastric/gastroesophageal adenocarcinoma. We are also advancing EO-1022, a HER3 ADC for the treatment of patients living with solid tumors that express HER3, through preclinical development. For more information, visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated clinical and preclinical development activities, expected timing of announcements of clinical and preclinical results, potential benefits of product candidates, potential market opportunities for product candidates, the ability of product candidates to treat their targeted indications and Elevation Oncology's expectations about its cash runway. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These forward-looking statements may be accompanied by such words as "aim," "anticipate," "believe," "could," "estimate," "expect," "forecast," "goal," "intend," "may," "might," "plan," "possible," "potential," "will," "would," and other words and terms of similar meaning. Although Elevation Oncology believes that the expectations reflected in such forward-looking statements are reasonable, Elevation Oncology cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval are inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Elevation Oncology's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Elevation Oncology's ability to advance its product candidates, the timing and results of preclinical studies and clinical trials, approvals and commercialization of product candidates, the receipt and timing of potential regulatory designations, Elevation Oncology's ability to fund development activities and achieve development goals, Elevation Oncology's ability to protect intellectual property, Elevation Oncology's ability to establish and maintain collaborations with third parties, and other risks and uncertainties described under the heading "Risk Factors" in documents Elevation Oncology files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Elevation Oncology undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Elevation Oncology Investor and Media Contact Gracie Tong Senior Director, Investor Relations and Corporate Communications [email protected] SOURCE Elevation Oncology WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

01 HER3的结构概述 ERBB家族 ERBB家族是受体酪氨酸激酶(RTK)中的重要组成部分，在细胞生长、发育和肿瘤中扮演关键角色。ERBB家族由四个成员组成：表皮生长因子受体(EGFR/ERBB1/HER1)、ERBB2(HER2/neu)、ERBB3(HER3)和ERBB4(HER4)。广泛表达于上皮细胞、间充质细胞、神经元细胞和心肌细胞等多种细胞类型中。它们的结构和功能既相似又有差异，共同调控细胞的生理过程。多种人类癌症的发展与ERBB家族成员的表达改变和信号通路异常密切相关。此外，ERBB家族成员之间还存在相互作用和信号串扰，进一步复杂了肿瘤的生物学行为。 图1 ERBB3 及其在 ERBB 家族中的二聚化伴侣的示意图 HER3的结构 HER3的基因位于12q13，编码180kDa的跨膜酪氨酸激酶受体。其结构包含配体结合胞外域(ECD)、跨膜区、胞内近膜区、酪氨酸激酶域(TKD)和胞内C末端信号尾。它广泛表达于胚胎发育阶段和人体成年组织，包括胃肠道、泌尿生殖道、呼吸道等多个系统的细胞，且具有组织特异性。 图2 HER3 的结构示意图 HER3的氨基酸序列 Extracellular Helical Cytoplasmic 20-643 644-664 665-1342 HER3的配体 在生理状态下，HER3的激活主要由其与神经调节蛋白(NRGs)相互作用触发，NRGs属于EGF家族的配体。它们可以通过自分泌和旁分泌的方式从内皮细胞释放。在没有配体时，HER3处于束缚构象，当与配体结合后，会引起ECD区域的构象改变，二聚化臂释放，HER3与其他受体(如HER2、EGFR)形成异源二聚体。在HER家族中，HER2比较特殊，它没有配体且始终处于激活构象，而HER3主要与HER2形成异二聚体，其中HER2-HER3异二聚体是该家族中信号传导活性最强的二聚体。 图3 HER3 受体的结构变化和激活的示意图 HER3的生理功能 HER3作为HER受体酪氨酸激酶家族成员，与其他家族成员共同调节正常细胞的多种关键功能： ①参与调节细胞的增殖，确保细胞数量的稳定增长； ②调控细胞凋亡，维持细胞生死平衡； ③促进细胞分化，使细胞获得特定的功能； ④保障细胞存活，为细胞的正常生命活动提供支持。 HER3在肿瘤中的作用 ①促进肿瘤进展：在多种恶性肿瘤中，如乳腺癌、卵巢癌、肺癌等，常出现HER3的高表达，导致癌细胞不受控制地生长、增强其迁移能力、抑制其凋亡，逃避机体的免疫监视和清除，从而促进肿瘤的发展和恶化。 ②介导治疗耐药：HER3在肿瘤细胞对多种治疗手段产生耐药性的过程中扮演着重要角色。 02 HER3的相关信号通路 HER3相关信号通路 HER3通常需与配体结合启动下游信号，但在HER2过表达时可无配体激活。激活后与不同受体形成异源二聚体，招募多种信号分子，激活下游PI3K/AKT、MAPK/ERK、JAK-STAT、PLCγ-PKC等信号通路，影响细胞增殖、凋亡等过程，促进肿瘤细胞增殖、侵袭和转移，在多种癌症中高表达，是癌症治疗的潜在靶点。 图4 HER3 介导的信号网络 此外，HER3与非HER家族RTKs(如IGF-1R、FGFR、MET)、雌激素受体(ER)、Notch等存在信号串扰，在肿瘤进展和治疗耐药中发挥重要作用。 图5 HER3 与其他因子的信号串扰 HER3的内源性抑制机制 HER3的内源性抑制机制对维持细胞正常生理状态、防止肿瘤发生发展至关重要。主要通过内吞途径和相关蛋白调控实现，内吞途径可内化HER3受体，调控其信号强度和持续时间，Nrdp1等蛋白则参与其降解过程。若这些机制异常，HER3信号会失调，促进肿瘤发展和耐药。加速HER3降解可增强肿瘤抑制活性，部分药物和抗体可通过此机制发挥抗癌作用。 HER3与其他受体共表达的影响 HER3的过表达常常和HER2及/或EGFR的过表达相关联，在HER2+乳腺癌和部分EGFR阳性肺癌中，HER3作为共受体发挥着重要作用。 03 HER3在肿瘤中的作用 HER3在肿瘤中的表达与突变 HER3单独存在不影响肿瘤转化，但在多种实体瘤(如乳腺癌、卵巢癌、肺癌、结肠癌、胰腺癌、黑色素瘤、胃癌、头颈部癌以及前列腺癌等)中存在扩增现象，其表达与肿瘤转移和不良预后相关。不过，HER3的预后价值存在争议，可能受肿瘤异质性、疾病阶段等多种因素影响。 图6 不同类型癌症中 HER3 的表达 此外，HER3表达水平或可作为部分靶向治疗的生物标志物。HER3的体细胞突变虽少，但在多种癌症中均有被发现，其中最常见的突变类型为功能获得性错义突变，主要发生在ECD和TKD区域，不同位置的HER3突变对肿瘤的影响不同，部分突变可增强致癌性和导致治疗耐药。突变的HER3致癌形式似乎不依赖配体，且需要HER2的参与。 图7 HER3 基因突变重点 HER3与治疗耐药性 图8 HER3 参与不同癌症治疗过程中的耐药性  临床前研究利用基因编辑工具和抑制剂，证实HER3介导的细胞活动在癌症对多种治疗的耐药性中起重要作用。动物模型显示抑制HER3可抑制肿瘤生长。 ①在靶向治疗中，抑制EGFR或HER2信号可导致HER3补偿性激活，导致对EGFR-TKI、曲妥珠单抗、西妥昔单抗等靶向药物产生耐药性。 ②在内分泌治疗中，HER3与ER信号网络相互作用影响耐药性。 ③化疗时，HER3激活与多种癌症的化疗耐药相关，可能通过激活相关信号通路或促进耐药蛋白表达实现。 ④放疗中，HER3介导的生存信号具有放射保护作用，沉默HER3可提高放疗敏感性，其机制涉及DNA损伤修复和细胞凋亡的调控。 ⑤联合抑制HER3和其他治疗方法有潜力克服耐药性，但目前临床应用效果不一，还需探索合适的生物标志物。 图9 癌细胞中潜在的 HER3 驱动的生存和耐药机制 04 HER3的靶向治疗 因HER3激酶活性弱、表达模式多样和下游信号复杂，靶向抗体成为主要治疗策略。多种抗HER3单克隆抗体、双特异性抗体和抗体-药物偶联物处于临床开发阶段，部分在特定肿瘤类型中显示出一定疗效，但联合治疗常伴随不良事件增加，且缺乏有效的预测生物标志物。 图10 临床上的 HER3 靶向治疗 单克隆抗体 通过工程设计阻断受体-配体结合或阻碍异二聚体形成。多种抗HER3单克隆抗体处于临床开发阶段，如Patritumab、Seribantumab、Lumretuzumab、Elgemtumab、CDX-3379等，它们通过结合HER3的不同结构域，抑制配体结合、阻断二聚体形成及下游信号传导，但多数mAbs因缺乏临床获益或联合治疗受限而终止开发，且有较多不良反应。 表1 靶向 HER3 的单克隆抗体的临床实验 双特异性抗体 能同时靶向两个不同蛋白表位，以克服单药治疗的局限性和耐药机制。如Duligotuzumab、MM-111、Isitarumab、Zenocutuzumab、SI-B001等，通过独特机制抑制肿瘤细胞生长，在多种癌症模型中显示出疗效，部分正在进行临床试验，但也面临疗效和安全性挑战。 表2 靶向 HER3 的双特异性抗体的临床实验 抗体-药物偶联物 由靶向mAbs与细胞毒性药物通过可裂解或不可裂解的连接子连接而成。如U3-1402、EV20衍生的ADCs等，在多种癌症模型中展现出强大的抗肿瘤活性，部分已进入后期临床试验。 表3 靶向 HER3 的抗体-药物偶联物的临床实验 Pan-HER策略 针对多种HER受体的抑制剂，如AZD8931、Sym013等，在临床前研究中表现出良好的抗癌效果，但Sym013因不明毒性终止临床开发。 HER3疫苗 可激发机体自身的免疫系统，诱导多克隆抗体产生，引发持久的抗肿瘤免疫反应，部分处于临床试验阶段，如pING-hHER3FL、针对HER2/HER3的树突状细胞疫苗等。 HER3靶向治疗的潜在策略 E3泛素连接酶(如Nrdp1、NEDD4)可促进HER3的泛素化降解，有望成为药物设计靶点；miR-205、miR-125a等多种microRNA能与HER3的mRNA结合，调控其表达，影响肿瘤细胞生长和药物敏感性；MYC、FoXO1等转录因子可调节HER3基因表达，在肿瘤发生和耐药中起重要作用。 图11 HER3 靶向癌症治疗的潜在方法 靶向HER3面临的障碍 HER受体家族结构相似，导致靶向HER3药物特异性欠佳，存在影响其他受体的风险。肿瘤适应性强，易产生二次耐药。联合疗法虽增强疗效，但可能增加毒性，平衡疗效与安全性至关重要。 HER3在正常组织发育和维持中不可或缺，缺乏活性激酶域，难以用传统小分子激酶抑制剂靶向。目前开发的HER3靶向抗体临床效果有限，原因包括未考虑配体非依赖二聚化和构象依赖性结合等。 05 HER3在多种癌症中的异常表达及影响 图12 HER3 的TCGA数据 乳腺癌 HER3在50-70%的乳腺癌病例中过表达，HR+/HER2-亚型表达最高，其表达上调与肿瘤转移、肿瘤体积增大以及复发风险增加有关。在乳腺癌细胞中，HER3主要定位于细胞核，但在配体刺激下会转运到细胞质。细胞核中的HER3可能通过影响基因表达等机制，在乳腺癌的发生发展中发挥作用。此外，HER3的基因改变在乳腺癌中占5.6%，包括扩增和激活突变，突变多位于ECD区域，可使受体激活不依赖配体，且与拉帕替尼耐药有关。 结直肠癌 HER3过表达与结直肠癌的淋巴转移和不良进展相关，影响患者的预后。其异常表达可能促进癌细胞的侵袭和转移能力，在结直肠癌的进展过程中起到推动作用。 头颈部鳞状细胞癌 HER3表达与癌细胞的转移增加和患者总生存期降低有关。膜性HER3表达与患者生存率降低显著相关，提示膜定位的HER3可能参与了头颈部鳞状细胞癌的恶性进展过程。 非小细胞肺癌 HER3的高表达与晚期NSCLC及不良预后相关，其配体NRG可增强肿瘤侵袭性，与其他EGFR家族成员共表达会加剧病情。靶向HER3以克服NSCLC中的EGFR-TKI耐药。HER3虽激酶活性低，但能与HER2等二聚化激活关键信号通路，促进非小细胞肺癌的发展和耐药。 其他癌症 在胰腺癌、胃癌、卵巢癌、前列腺癌、膀胱癌和黑色素瘤等多种癌症中，HER3也存在异常表达。例如，胰腺癌中HER3过表达与不良预后相关；胃癌中HER3核表达与血管和淋巴浸润有关；卵巢癌中HER3表达情况与患者预后相关；前列腺癌中HER3核表达与肿瘤进展相关；黑色素瘤中HER3表达与患者预后相关。此外，在儿童胶质瘤(毛细胞型星形细胞瘤)和小儿肉瘤(横纹肌肉瘤)中，也发现了HER3的过表达。HER3在不同癌症中的细胞定位不同，所发挥的功能也存在差异，在肿瘤的发生、发展、转移以及患者预后方面都有着复杂的作用机制。 参考文献 Chen Y, Lu A, Hu Z, Li J, Lu J. 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