Cetuximab

HMBD-001, a differentiated anti-HER3 monoclonal antibody discovered and developed with Hummingbird Bioscience’s AI Molecular Medicine (AIMM) platform, has advanced into Phase II clinical development Recommended doses for expansion (RDEs) identified for HMBD-001 in combination with cetuximab, supported by safety, tolerability, and preliminary efficacy data Advancement of HMBD-001 in clinical development demonstrates translation of Hummingbird Bioscience’s AIMM platform from drug design through clinical development and patient selection SINGAPORE, Sept. 30, 2026 (GLOBE NEWSWIRE) -- Hummingbird Bioscience (“Hummingbird”) a biotherapeutics company discovering and developing transformative medicines for diseases with significant unmet need, today announced that HMBD-001 has advanced into Phase II clinical development and that the first patient in the Phase II clinical study of HMBD-001-103 has been dosed. HMBD-001 is a differentiated anti-HER3 monoclonal antibody engineered with Hummingbird Bioscience’s Rational Antibody Discovery (RAD) platform, a core part of the AI Molecular Medicine (AIMM) platform. Phase II of the HMBD-001-103 clinical study is recruiting patients with advanced squamous cell cancers ( NCT05910827 ) across multiple countries, including China, Australia, Moldova and Singapore. An Investigational New Drug (IND) application for HMBD-001 has been approved by the U.S. Food and Drug Administration (FDA). Recommended doses for expansion (RDEs) for HMBD-001 in combination with the EGFR inhibitor cetuximab (marketed by Merck KGaA, Darmstadt, Germany as ERBITUX ® globally, except for the U.S. and Canada) were identified, with advancement into Phase II supported by clinical safety, tolerability, and preliminary efficacy observed to date. Merck KGaA, Darmstadt, Germany will continue to supply cetuximab for the Hummingbird Bioscience-sponsored study under a clinical trial collaboration and supply agreement , and both parties retain all commercial rights to the respective compounds. The advancement of HMBD-001 provides important clinical-stage validation of Hummingbird Bioscience’s AIMM platform, demonstrating the application of AI across the drug-development continuum: from understanding disease biology and designing differentiated therapeutics to informing clinical development strategy and identifying patients most likely to benefit. “Advancing HMBD-001 into Phase II is an important milestone for the program and for Hummingbird’s AI-first approach to drug development,” said Piers Ingram, PhD, Chief Executive Officer of Hummingbird Bioscience. “From designing HMBD-001 to identifying the disease settings and combination strategy where its differentiated mechanism may have the greatest impact, our AIMM platform has helped shape the program at multiple stages. We look forward to further evaluating the potential of HMBD-001.” Hummingbird Bioscience’s AIMM platform contributed to HMBD-001’s drug design and clinical development strategy. In drug design, the RAD platform identified a functionally critical epitope at the HER3 dimerization interface and engineered HMBD-001 to directly block HER3 heterodimerization with EGFR or HER2. This differentiated mechanism enables HMBD-001 to inhibit both ligand-dependent and ligand-independent HER3 activation to block oncogenic signaling. AIMM also informed the clinical development strategy for HMBD-001. Hummingbird Bioscience's proprietary AI Reasoning Engine (AIRE) enabled rapid identification of squamous cell carcinomas as tumor types enriched for HER3 dependency, and therefore particularly vulnerable to HER3/EGFR inhibition. These findings supported prioritizing squamous cancers as an indication and informed the trial design combining HMBD-001 with cetuximab, while accounting for potential resistance mechanisms against this combination therapy. “Genetic alterations commonly observed in squamous cell carcinomas can contribute to aberrant HER3 and EGFR signaling, which drive tumor cell proliferation and survival. Hummingbird’s AI-driven analyses identified a dependency on HER3/EGFR signaling in squamous cancers, providing a strong biological rationale for simultaneously targeting both pathways,” said Kon Yew Kwek, BM BCh, DPhil, Chief Medical Officer of Hummingbird Bioscience. “Following the encouraging clinical activity that we have seen, we will continue using our AIMM platform to help enrich our patient population, so that we can optimally deliver a chemo-free treatment to patients suffering from advanced squamous cancers and who will most likely benefit from HMBD-001 plus cetuximab.” The advancement of HMBD-001 in clinical development reflects Hummingbird Bioscience’s AI-first approach to drug discovery and development, which has recently received growing external recognition. Selected from over 600 global applicants, Hummingbird Bioscience won the Asia Pacific Trailblazer Award at the Nebius AI Discovery Awards. The company was also named one of three finalists in the Fierce AI Innovation Awards in the Preclinical Development category, selected as a finalist for the Scrip Awards in the Best Use of AI in Drug Discovery & Preclinical Development category, and honored on the NextGen Tech 30 list by Granite Asia. About HMBD-001 HMBD-001 is a novel, potentially best-in-class clinical-stage IgG1 antibody designed to target HER3, discovered and developed with Hummingbird Bioscience’s proprietary technologies. We believe HMBD-001 is the only anti-HER3 antibody in development that has the potential to fully block both ligand-dependent and -independent HER3 activation and oncogenic signaling, by targeting a key epitope located at the interface where HER3 forms heterodimers with HER2 or EGFR. In preclinical models evaluating HMBD-001, superior affinity and more potent tumor growth inhibition compared to existing anti-HER3 antibodies were observed. Additionally, combining HMBD-001 with EGFR inhibition further improved anti-tumor activity in squamous non-small cell lung cancer models. HMBD-001 is currently in Phase II multi-regional clinical trials for advanced squamous cell cancers ( NCT05910827 ). About Hummingbird Bioscience Hummingbird Bioscience is a clinical-stage biotherapeutics company integrating AI and rigorous experimental science to bring more precise, scientifically grounded medicines to patients faster. Its lab-in-the-loop AI Molecular Medicine platform, AIMM, draws on over a decade of proprietary experimental, translational, and clinical data, learning from every new data point to prioritize hypotheses, select targets and indications, and design and optimize biotherapeutics. By combining AI with biological expertise and wet-lab validation, Hummingbird Bioscience has advanced several programs from concept to clinic in as little as 12 months. Hummingbird Bioscience has engineered a deep pipeline with AIMM, including four programs in clinical trials and seven programs out-licensed or partnered. For more information, visit , and follow Hummingbird Bioscience on LinkedIn , X (formerly Twitter) , and YouTube . Hummingbird Bioscience Media Contact: Crystal Ho c.ho@hummingbirdbio.com media@hummingbirdbio.com +65 6979 5580 Hummingbird Bioscience Investor Contact: investors@hummingbirdbio.com

肿瘤相关的细胞外基质（ECM）和糖萼构成了一个动态屏障，提供物理屏蔽和免疫抑制信号，导致治疗耐药。越来越多的证据支持基于酶的策略来重塑这些屏障并改善治疗药物对肿瘤的可及性。本综述探讨了作为“路径清洁剂”的酶，通过切割ECM或糖萼成分来恢复免疫疗法的疗效。此外，某些酶可能发挥超出屏障重塑的作用，包括调节信号通路、增强免疫应答，甚至对肿瘤产生直接影响。在本综述中，不同类别的屏障重塑酶被讨论作为癌症免疫疗法的潜在辅助手段。本综述还强调了用于增强肿瘤特异性、疗效和安全性的生物工程方法和递送策略。尽管此类治疗策略显示出有希望的结果，但也讨论了证据等级和潜在的转化风险。改进的患者分层以及计算引导的酶发现和蛋白质工程，包括降低免疫原性的策略，可促进酶辅助免疫疗法的临床转化。1 引言 肿瘤微环境（TME）由肿瘤细胞、免疫细胞、成纤维细胞等构成，其框架由细胞外基质（ECM）维系。ECM主要包含胶原蛋白、蛋白聚糖、糖胺聚糖（GAG）、弹性蛋白、层粘连蛋白、纤连蛋白等多种糖蛋白。在健康组织中，ECM组成和硬度受到精细调控以维持稳态，而实体瘤则利用ECM促进免疫逃逸、转移和治疗抵抗。ECM重塑和致密化导致缺氧，进而引起化疗和放疗抵抗，并上调免疫抑制因子，影响免疫疗法效果。此外，肿瘤相关糖萼富含黏蛋白和高唾液酸化聚糖，通过物理屏蔽和免疫调节信号促进免疫逃逸。研究人员开始重新评估ECM/糖萼在肿瘤中的作用，并将其作为药物开发的潜在靶点。一种新兴策略是利用可作为“路径清洁剂”的酶，切割屏障成分为治疗药物开路并改变信号通路。然而，ECM/糖萼重塑不应被视为简单地拆除被动物理屏障，这些结构调节免疫运输、基质信号、血管完整性和转移生态位形成，因此需以可控方式进行切割，以避免过度或脱靶重塑。 2 乙酰肝素酶（HPSE） 乙酰肝素硫酸盐是一种硫酸化GAG，是ECM的组成部分，参与调节细胞运输。乙酰肝素酶（HPSE）是唯一能够切割ECM中乙酰肝素硫酸蛋白聚糖（HSPG）链的哺乳动物酶。活化的免疫细胞如T细胞、中性粒细胞、单核细胞和自然杀伤（NK）细胞可产生HPSE，但在某些条件下免疫细胞可能表现出HPSE表达降低或缺失，限制其穿透实体瘤致密ECM的能力。HPSE也因其促肿瘤功能（如促进转移和血管生成）而被广泛研究作为抑制靶点。但当局限于治疗性免疫细胞或定位于肿瘤界面时，HPSE介导的ECM重塑反而可增强免疫细胞浸润并改善免疫治疗效果。嵌合抗原受体（CAR）-T细胞疗法对实体瘤效果有限，部分原因是TME的免疫抑制和物理限制。研究发现长期体外扩增T细胞（LTE-T细胞）因p53介导的抑制而下调HPSE表达，促使研究人员探索HPSE重建策略。一项临床前研究表明，共表达肿瘤特异性CAR和HPSE的CAR-T细胞在ECM存在下展现出强大的肿瘤清除活性，体内实验显示HPSE表达型CAR-T细胞具有增强的瘤内积累、更优的肿瘤控制和延长的生存期。同样，NK细胞的扩增也会导致HPSE表达下降，通过表达膜锚定的酶活性HPSE构建体可恢复其ECM降解能力，增强肿瘤球体渗透和肿瘤控制。但HPSE工程化缺乏超出临床前证据的支持，其多效性效应强调了对空间和时间控制的需求。 3 透明质酸酶 透明质酸（HA）是一种线性非硫酸化GAG，HA富集的肿瘤形成物理屏障，限制生物制剂的治疗结果。高HA积累与抗体药物（如曲妥珠单抗和西妥昔单抗）耐药相关，并阻碍NK细胞迁移和抗体依赖性细胞介导的细胞毒性（ADCC）。PH20是一种人精子中天然表达的透明质酸酶，经聚乙二醇（PEG）修饰后开发出PEGPH20。尽管PEGPH20在临床前研究中增强了抗体依赖性和NK细胞介导的细胞毒性，但临床试验（SWOG S1313和HALO 109-301）显示其增加了胃肠道和血栓栓塞毒性，且未能改善总生存期。更新的策略包括将PH20整合到工程化免疫细胞平台中，例如分泌Fc融合PH20的抗间皮素CAR-T细胞在HA致密基质中增强了对肿瘤细胞的访问，共表达IL-7和PH20的双重工程化CAR-T细胞改善了肝细胞癌模型的瘤内积累和肿瘤消退。此外，利用生物正交化学将透明质酸酶偶联至CAR-T细胞表面，并结合酸性响应性连接子释放抗程序性死亡配体1（PD-L1），实现了深度肿瘤浸润和延长生存。基于细胞外囊泡的平台实现了局部高效的透明质酸酶递送，PH20表达型小细胞外囊泡（sEV-PH20）通过Toll样受体4（TLR4）信号激活CD103+树突状细胞（DC），增强CD8+ T细胞反应。pH和基质金属蛋白酶-2（MMP-2）双响应纳米载体实现了透明质酸酶、白细胞介素-12（IL-12）和抗PD-L1的联合递送，显著抑制肿瘤生长。透明质酸酶还可增强纳米疫苗性能，改善CD8+ T细胞浸润和肿瘤抑制。 4 胶原酶 胶原蛋白是ECM中最丰富的成分之一，在癌症进展中大量积累并经历广泛重塑，影响免疫细胞迁移并抑制其抗肿瘤活性。胶原介导的免疫抑制损害抗程序性细胞死亡蛋白1（PD-1）/PD-L1疗法和CAR-T细胞的效果。异常胶原积累还升高组织间隙液压力（IFP），减少治疗药物的对流输送。早期全身性胶原酶给药虽增加抗体摄取，但因缺乏特异性和脱靶效应限制了转化应用。近期策略聚焦于局部和响应性递送系统。在胰腺导管腺癌（PDAC）中，利用兼性厌氧大肠杆菌Nissle 1917（EcN）作为肿瘤靶向载体，将胶原酶和抗PD-L1装载于活性氧（ROS）响应性蛋白纳米笼中并偶联至EcN表面，实现了局部释放并降解致癌性I型胶原（Col1）同源三聚体，减弱下游整合素α3β1-黏着斑激酶（FAK）信号，降低免疫抑制，增加CD8+ T细胞浸润。另一种方法利用两种工程化EcN菌株分别释放细菌胶原酶（EcN-ColG）和免疫毒素（EcN-CDPE），后者由抗CD47纳米抗体与截短假单胞菌外毒素A融合而成，协同减少瘤内胶原并抑制肿瘤增殖。此外，利用热敏原位凝胶制剂共递送曲妥珠单抗和胶原酶，或通过DV1肽修饰的胶原酶纳米凝胶背包装载于抗MSLN-CAR-T细胞表面，结合CXCR4拮抗作用，均实现了增强的治疗渗透和肿瘤抑制。但胶原酶策略需谨慎考虑：在胶原占主导物理屏障的肿瘤中可能有益，而在胶原产生基质程序限制肿瘤扩散的情况下可能有害。 5 纳豆激酶 纤连蛋白是由癌症相关成纤维细胞（CAF）大量产生的ECM蛋白，异常积累会强化肿瘤微环境的物理屏障。纳豆激酶是一种由枯草芽孢杆菌产生的丝氨酸蛋白酶，以其强效纤溶活性著称。瘤内注射纳豆激酶通过降解纤连蛋白重塑肿瘤ECM，改善组织灌注、减轻缺氧并间接抑制CAF活性，从而增强化疗和放疗效果。值得注意的是，纳豆激酶预处理使CAR-T细胞瘤内积累增加六倍，并在乳腺肿瘤异种移植模型中取得优异治疗结果。但纳豆激酶作为细菌源性蛋白，其全身药代动力学、长期安全性和免疫原性仍需仔细评估。 6 唾液酸酶 生理条件下唾液酸发挥重要作用，但疾病状态下的高唾液酸化介导肿瘤细胞进展并与不良预后相关。过度的细胞表面唾液酸化形成保护性外衣，使肿瘤细胞逃避监视，机制包括限制NK细胞活化受体NKG2D与其配体的接触、唾液酸聚糖与免疫细胞上的抑制性唾液酸结合免疫球蛋白样凝集素（Siglec）受体相互作用等。初始尝试使用抗体-唾液酸酶偶联物，如霍乱弧菌唾液酸酶与曲妥珠单抗化学融合（T-Sia），以HER2依赖性方式去除唾液酸，增强ADCC。后续用鼠伤寒沙门氏菌唾液酸酶NanH替换并采用更稳定的连接化学获得T-Sia 2，减少了脱靶去唾液酸化，在曲妥珠单抗耐药模型中延缓肿瘤生长并延长生存，机制涉及增强CD8+ T细胞/NK细胞活性和巨噬细胞M1极化。进一步的研究包括抗PD-L1纳米抗体与放线菌属唾液酸酶的融合蛋白（Nb16-Sia），以及抗PD-1抗体与唾液酸酶的偶联物，后者通过靶向PD-1阳性淋巴细胞集中酶活性，增强T细胞效应功能。唾液酸酶还被整合入双特异性T细胞衔接器（BiTE）中，生成含唾液酸酶的三蛋白检查点抑制性T细胞衔接器（CiTE），增强T细胞介导的杀伤。工程化CAR-T细胞分泌产气荚膜梭菌神经氨酸酶（CpNA）可增强细胞毒性并减少分化，产生更幼稚的表型和更好的体内持久性。此外，诱导多能干细胞衍生的嵌合抗原受体-巨噬细胞（CAR-iMac）与唾液酸酶联合应用增强了吞噬作用和抗肿瘤活性。新型糖萼靶向方法如E-602（工程化人源唾液酸酶Neu2-IgG1 Fc融合蛋白）已在GLIMMER-01临床研究中展示出初步活性，而靶向B7-H3的工程化人源唾液酸酶E-688在临床前研究中表现良好。 7 黏蛋白酶 黏蛋白富含脯氨酸、苏氨酸和丝氨酸的串联重复区域，作为密集的O-糖基化位点，赋予其延伸的高度糖基化结构域，构成屏障功能。黏蛋白过表达（尤其是MUC1）常见于癌变并与不良预后相关。研究证明富含黏蛋白的糖萼厚度与免疫细胞介导的细胞毒性呈负相关。研究人员使用StcE（源自大肠杆菌O157:H7的黏蛋白选择性金属蛋白酶）切割肿瘤细胞表面的黏蛋白外域，恢复NK细胞介导的杀伤。通过将StcE以凝集素介导的方式锚定于NK细胞表面，或利用模块化亮氨酸拉链“Zip-NK”平台实现可控的表面展示，增强了抗HER2 CAR-NK细胞对富含黏蛋白癌细胞的细胞毒性。通过蛋白质工程获得的减毒变异体eStcE保留了黏蛋白糖肽基序的特异性，同时最小化脱靶效应。eStcE与抗HER2纳米抗体基因融合形成的融合蛋白选择性降解HER2+癌细胞上的黏蛋白，减少肿瘤负荷和转移。StcE还被整合入共展示CD47靶向纳米抗体的工程化细胞膜融合纳米囊泡（FNV）中，通过SpyTag-SpyCatcher实现可控共价展示，改善CD47-SIRPα阻断和巨噬细胞吞噬作用，并展现出优于游离StcE的安全性和更强的肿瘤控制。 8 转化挑战与未来方向 长期以来癌症药物发现仅聚焦于靶向肿瘤细胞，忽视了肿瘤微环境中其他关键角色。对ECM从被动支架到TME中免疫系统动态伙伴的观点转变，开辟了新的治疗策略和干预机会。已有多种策略被开发用于改造基质和细胞外特征，包括靶向产生基质的CAF、抑制ECM产生和交联、阻断转化生长因子β（TGF-β）信号等。酶介导的屏障重塑策略通过直接切割ECM/糖萼成分发挥作用，但面临精确控制酶活性、避免促转移风险、管理免疫原性以及优化递送系统等挑战。未来的方向包括改进患者分层、计算引导的酶发现和蛋白质工程以降低免疫原性，以及开发更精密的合成生物学工具以实现酶活性的时空控制，最终推动酶辅助免疫疗法向临床应用迈进。