表皮生长因子受体（EGFR）属于受体酪氨酸激酶，在细胞增殖、分化和迁移的过程中发挥重要作用。研究发现，与正常组织相比，EGFR的突变或者高表达与非小细胞肺癌、结肠癌等肿瘤的发生密切相关，是抗肿瘤药物开发中的重要靶点[1]。尽管多款EGFR抗体和第三代EGFR TKI已经在肿瘤治疗中获得了广泛成功，但对于因耐药而导致的标准治疗失败或治疗后复发的肿瘤患者，仍存在未满足的临床需求[2]。近年来，随着ADC技术的快速发展，ADC药物的开发为肿瘤患者提供了新的治疗方案[3]，靶向EGFR的ADC药物有望克服现有靶向EGFR治疗的耐药机制，为更多晚期非小细胞肺癌、结直肠癌等患者带来临床获益。
HLX42由高度特异性的人源化lgG1 EGFR抗体分子、可裂解的新型连接子-荷载毒素偶联制备而成，其药物抗体比（drug-to-antibody ratio, DAR）约为8。其中，HLX42的荷载毒素为一种新型DNA拓扑异构酶I（Topoisomerase I）小分子抑制剂，通过造成DNA双链断裂，阻断DNA复制，从而导致肿瘤细胞凋亡。静脉输注后，HLX42的连接子-毒素能够在肿瘤微环境中特异性裂解释放，具备较强的旁观者杀伤效应，独特的作用机制使得HLX42较同类ADC产品具有更大的治疗窗口，增强ADC在实体肿瘤中的治疗效果。HLX42在临床前药效研究、药代动力学研究及安全性评价中展现出良好的抗肿瘤活性和安全性，相关数据已于2023欧洲肿瘤内科学会（ESMO）大会以壁报形式首次发布。在第三代EGFR TKI（奥希替尼）或抗EGFR单克隆抗体（西妥昔单抗）耐药的非小细胞肺癌、结直肠癌等肿瘤模型中，HLX42显示出良好的肿瘤杀伤效果，有望克服现有靶向EGFR治疗的耐药机制，填补更多晚期/转移性实体瘤患者未满足的临床需求。
复宏汉霖以患者为中心、从临床需求出发，目前已打造出多元化、高质量的创新产品管线，涵盖约60个分子，覆盖单抗、双抗、ADC、融合蛋白、小分子药物等药物形式，其中超过80%的产品为自主开发。未来，公司将继续以抗体为核心，积极探索新靶点、新机制，不断拓展产品疾病领域和新分子类型，推动更多创新产品的临床研究，期待早日为更多患者带来可负担的高品质生物药。
【参考文献】
[1] Ni cholson, Robert Ian, Julia Margaret Wendy Gee, and Maureen Elaine Harper. EGFR and cancer prognosis. European journal of cancer 37 (2001): 9-15.
[2] Tan, Chee Seng, D. Gilligan, and S. Pacey. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. The Lancet Oncology 16.9(2015): e447-59.
[3] Ponziani S, Di Vittorio G, Pitari G, et al. Antibody-Drug Conjugates: The New Frontier of Chemotherapy. Int J Mol Sci. 2020 Jul 31;21(15):5510.
关于NCT06210815
本研究为一项评估HLX42（抗EGFR的抗体偶联药物【ADC】）在晚期/转移性实体瘤患者中的安全性、耐受性的开放、剂量递增、首次人体Ⅰ期临床研究。研究将采用“3+3”剂量递增方法，患者将接受7个不同剂量水平（0.1 mg/kg、0.3 mg/kg、0.6 mg/kg、1.2 mg/kg、2.0 mg/kg、3.0 mg/kg、4.0 mg/kg）的HLX42静脉输注给药，每三周一次。剂量限制性毒性（DLT）观察期为HLX42首次给药后的三周。本研究的主要终点为DLT观察期内每个剂量组发生DLT事件的患者比例，以及HLX42的最大耐受剂量（MTD）。次要终点包含安全性、药代动力学参数、免疫原性、初步疗效、药效学指标，以及潜在预测性和耐药性生物标志物。
关于复宏汉霖
复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已在中国上市5款产品，在国际上市2款产品，19项适应症获批，7个上市申请分别获中国药监局、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，上海徐汇基地和松江基地（一）均已获得中国和欧盟GMP认证。
复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖20多种创新单克隆抗体，并全面推进基于自有抗PD-1单抗H药汉斯状的肿瘤免疫联合疗法。继国内首个生物类似药汉利康（利妥昔单抗）、中国首个自主研发的中欧双批单抗药物汉曲优（曲妥珠单抗，欧洲商品名：Zercepac，澳大利亚商品名：Tuzucip和Trastucip）、汉达远（阿达木单抗）和汉贝泰（贝伐珠单抗）相继获批上市，创新产品汉斯状（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。
First Subject Dosed for Phase 1 Clinical Trial of Henlius’ ADC Candidate HLX42
Shanghai, China, March 14, 2024 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the first subject was dosed for a phase 1 clinical trial of HLX42 (NCT06210815), an investigational EGFR-Targeting antibody-drug conjugate (ADC), for the treatment of advanced/metastatic solid tumours. HLX42 was developed by the company based on the collaboration with MediLink Therapeutics and was approved for conducting clinical trial by the National Medical Products Administration (NMPA) and U.S. Food and Drug Administration (FDA). In December 2023, FDA granted Fast Track Designation to HLX42 for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC) patients with disease progression on EGFR targeted therapies.
Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinases family and plays an important role in maintaining normal cell functions such as cell proliferation, differentiation and migration. Mutation or overexpression of EGFR is considered to be closely associated with the occurrence of various solid tumours including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), etc. Studies have shown that targeting EGFR is a valid strategy for anticancer therapy [1]. Despite the great success of monoclonal antibodies targeting EGFR and 3rd generation EGFR Tyrosine kinase inhibitors (TKIs), there are still great unmet medical needs for effective therapies for patients who are refractory to current therapies or relapse after standard of care [2]. ADC technology has vastly advanced in the last several years and provide a new treatment option for tumour patients [3]. The EGFR-targeting ADC has the potential to overcome the resistance to EGFR monoclonal antibodies and EGFR TKIs, which may bring clinical benefits to more patients with advanced NSCLC/CRC who are resistant or refractory to standard EGFR targeted therapy.
HLX42 is a novel EGFR-targeting ADC, comprised of a high-affinity humanised IgG1 mAb targeting EGFR conjugated with a novel cytotoxic payload through cleavable linkers, with the drug-to-antibody ratio is about 8. The cytotoxic payload is a novel DNA topoisomerase-I inhibitor which can cause double-strand breaks (DSBs) of DNA, block the replication machinery, thus trigger cancer cell apoptosis. When injected intravenously into the body, HLX42 linker-payload will be cleaved and released in tumour microenvironment (TME) with strong bystander killing effects. This unique mechanism of TME activation and payload release allows HLX42 to possess a higher therapeutic index and potency for treatment of solid tumours. HLX42 has exhibited good anti-tumour effects and a favorable safety profile in preclinical efficacy studies, pharmacokinetic studies and safety evaluation and the results were published as poster presentation at the 2023 European Society of Medical Oncology (ESMO) Congress. Meanwhile, HLX42 has shown potent tumour suppression in several CDX and PDX models that were EGFR TKIs or cetuximab resistant, which is expected to overcome the resistance of existing EGFR targeted therapies and fill the unmet clinical needs of more patients with advanced/metastatic solid tumours.
Underpinned by the patient-centric strategy, Henlius has pro-actively built a diversified and high-quality product pipeline, including about 60 molecules across monoclonal antibody (mAb), polyclonal antibody (pAb), ADC, fusion protein, and small molecule drug, of which more than 80% are self-developed. Regarding antibody technology as a core, Henlius will continue exploring novel targets and molecular mechanisms in more disease areas and conducting clinical studies for more innovative products to provide patients with quality and affordable biologics.
About NCT06210815
This open-label, dose-escalation, first-in-human phase 1 clinical trial aims to evaluate the safety and tolerability of HLX42 in patients with advanced/metastatic solid tumours. Patients will receive HLX42 intravenously every three weeks at seven dose levels (0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg, 2.0 mg/kg, 3.0 mg/kg, and 4.0 mg/kg) following a “3+3” design. The dose-limiting toxicity (“DLT”) observation period is three weeks after the first dose of HLX42. The primary endpoints of this study were the proportion of patients with DLT events in each dose cohort during the DLT observation period, and the maximum tolerated dose (MTD) of HLX42. Secondary endpoints include safety, pharmacokinetic parameters, immunogenicity, preliminary efficacy, pharmacodynamic measures, and potential predictive biomarkers and drug-resistance biomarkers.
About Henlius
Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. Up to date, 5 products have been launched in China, 2 has been approved for marketing in overseas markets, 19 indications are approved worldwide, and 7 marketing applications have been accepted for review in China, the U.S., and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation center and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Facility and Songjiang First Plant, both certificated by China and the EU GMP.
Henlius has pro-actively built a diversified and high-quality product pipeline covering over 20 innovative monoclonal antibodies (mAbs) and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab for injection, trade name in Europe: Zercepac; trade names in Australia: Tuzucip and Trastucip), the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), making it the world's first anti-PD-1 mAb for the first-line treatment of SCLC. What's more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.
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