潜在First-in-class，复宏汉霖创新型4-1BB×EGFR双抗HLX35临床试验申请获国家药监局批准

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关键词：临床

资讯来源：易企说17Talk

发布时间： 2022-01-07

NEWS

2022年1月4日，复宏汉霖（2696.HK）宣布，公司自主研制的HLX35（重组人源抗EGFR和抗4-1BB双特异性抗体注射液）获国家药监局临床试验申请（IND）批准，拟用于治疗晚期恶性实体瘤。公司计划于近期开展I期临床试验。目前，全球尚无靶向EGFR×4-1BB的双特异性抗体上市，HLX35有望成为first-in-class抗4-1BB×EGFR双抗。

基于临床上在肿瘤发生、进展、治疗等过程中发挥着重要作用的靶点EGFR和4-1BB，复宏汉霖不断探索新的治疗手段，以进一步填补相关治疗领域临床需求。4-1BB又称CD137，是肿瘤坏死因子受体超家族成员，表达于活化的T细胞表面，也可表达于NK细胞、NKT细胞、肥大细胞等 ^[1] 。4-1BB释放共刺激信号，激活CD8+T细胞的细胞毒性作用，帮助记忆T细胞的形成。此外，4-1BB信号可以激活NK细胞和树突状细胞，进一步维持细胞毒性T细胞的激活 ^[2] 。这些特征使得4-1BB成为增强癌症免疫治疗领域内备受青睐的靶点。绝大多数4-1BB单抗和双抗目前尚处于早期临床或临床前阶段，适应症包括晚期实体瘤、黑色素瘤和非霍奇金淋巴瘤等。部分早期临床研究的结果显示，4-1BB单抗和双抗具有可接受的安全性、耐受性和一定程度的抗肿瘤疗效。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。EGFR的突变和过表达与非小细胞肺癌、结直肠癌、头颈癌、乳腺癌、宫颈癌、膀胱癌、甲状腺癌、胃癌等实体瘤的发生密切相关 ^[3] 。抗EGFR单抗目前被批准的适应症主要是EGFR表达阳性的肿瘤，包括联合化疗或放疗或单药治疗非小细胞肺癌、结直肠癌和鳞状细胞癌等 ^[4] 。

HLX35是公司自主研发的创新型抗EGFR和抗4-1BB双靶点的双特异性抗体。根据临床前研究结果，HLX35显示出比抗4-1BB或抗EGFR单抗的单一或联合治疗都更加优越的肿瘤抑制效果。双特异性抗体药物可有效将两个靶点的优势合并在一起，HLX35可以结合在肿瘤表面的EGFR分子上，阻断EGFR的激活和下游信号通路的磷酸化，杀死肿瘤细胞；同时还可以在EGFR的参与下，结合免疫细胞（T细胞和NK细胞）表面上的4-1BB免疫激活分子，使更多的免疫细胞聚集在肿瘤周围，并刺激微环境中免疫细胞的活性，从而协同杀死肿瘤细胞，提高疗效。2020年11月，公司就HLX35与Binacea pharma Inc. 达成独家许可协议，授予其于除中国（包括港澳台地区）以外的全球范围进行研究、开发、生产和商业化权利。

复宏汉霖从临床需求出发，目前已打造出多元化的创新产品管线，在PD-1/L1、CTLA-4、LAG-3等免疫检查点全面布局，为免疫联合治疗的探索创造更多可能。公司持续丰富创新靶点布局，产品覆盖c-MET、TROP2、TIGIT和BRAF等新兴靶点，并积极开展双特异性抗体、抗体偶联药物（ADC）等产品的开发，同时公司将持续加码创新，加强优质创新资产的引进和合作，“内外兼修”，为全球患者带去高质量、可负担的创新治疗方案。

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4款产品，在欧盟上市1款产品，3个上市注册申请获得中国药监局受理。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研发中心，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，位于上海徐汇的生产基地已获得中国和欧盟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单抗斯鲁利单抗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，欧盟商品名：Zercepac®）、汉达远®（阿达木单抗）和汉贝泰®（贝伐珠单抗）相继获批上市，创新产品斯鲁利单抗MSI-H实体瘤的上市注册申请已纳入优先审评审批程序，HLX01利妥昔单抗类风湿关节炎新适应症、斯鲁利单抗鳞状非小细胞肺癌适应症的上市注册申请也正在审评中。公司亦同步就11个产品、8个免疫联合治疗方案在全球范围内开展20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。

Henlius Novel Anti-4-1BB×EGFR Bispecific Antibody HLX35 IND approved by NMPA

Shanghai, China, Jan 4 ^th, 2022 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the application for an investigational new drug (IND) of HLX35 (recombinant humanised anti-EGFR and anti-4-1BB bispecific antibody injection) for the treatment of advanced malignant solid tumors independently developed by the company was approved by the National Medical Products Administration (NMPA). The company is proposing to commence the Phase 1 clinical trial in Chinese Mainland (excluding Hong kong, Macau and taiwan region) in the near future. At present, no bispecific antibody targeting EGFR and 4-1BB has been approved for marketing globally. HLX35 is expected to be a first-in-class anti-4-1BB×EGFR bispecific antibody.

Based on EGFR and 4-1BB, two key targets in the anti-tumour process, Henlius explored new therapeutic methods to further meet the clinical needs of patients. Being a member of the tumour necrosis factor receptor superfamily, 4-1BB, also known as CD137, is expressed on the surface of activated T cells, NK cells, NKT cells, mast cells and so on ^[1]. It provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and facilitates the development memory T cells. In addition, 4-1BB signaling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation ^[2]. These features make 4-1BB a popular target for enhanced cancer immunotherapy. Most 4-1BB monoclonal antibodies (mAbs) and bispecific antibodies are currently in the early clinical or preclinical stage, with indications for advanced solid tumours, melanoma and non-Hodgkin's lymphoma. Early clinical studies showed that 4-1BB antibodies had acceptable safety, tolerability, and certain antitumor efficacy. 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, colorectal cancer, head and neck cancer, breast cancer, cervical cancer, bladder cancer, thyroid cancer, and gastric cancer ^[3]. Anti-EGFR mAb is currently approved for EGFR-positive tumours in combination chemotherapy or radiotherapy, or monotherapy for non-small cell lung cancer, colorectal cancer, and squamous cell carcinoma, etc ^[4].

HLX35 is an innovative anti-EGFR and anti-4-1BB bispecific antibody independently developed by Henlius. According to the results of pre-clinical studies, HLX35 showed a superior tumour-suppressive effect than mono or combo therapy of anti-4-1BB and anti-EGFR mAb. Bispecific antibody drugs effectively combine the advantages of both targets. HLX35 binds to the EGFR molecules on the tumour surface, suppresses the EGFR activation and downstream signaling pathways phosphorylation to kill tumour cells. Also, HLX35 binds to the 4-1BB molecules on the surface of immune cells (T and NK cells), with EGFR cross-linking to gather more immune cells around the tumor and stimulate the activity of immune cells in the microenvironment, to synergistically kill the tumour cells and improve the efficacy. In November 2020, the company has granted Binacea pharma Inc., in respect of HLX35, a license for it to research, develop, manufacture and commercialise the HLX35 globally except for China (including Hong Kong, Macau and Taiwan region).

Underpinned by the patient-centric strategy, Henlius has achieved an overall layout of the immune checkpoint products of PD-1/L1, CTLA-4, LAG-3, etc., proactively exploring immuno-oncology combination therapy. The company has also built an innovative product pipeline with many emerging targets, including c-MET, TROP2, TIGIT, BRAF, etc. and has been developing a forward-looking presence in bispecific antibodies and the antibody-drug conjugates (ADC). Looking forward, Henlius will continue its momentum for innovation, further strengthening the in-licensing and collaboration on external innovative assets, and bringing more high-quality and affordable therapies to patients worldwide.

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, 4 products have been launched in China, 1 in the European Union (EU), 3 New Drug Applications (NDAs) accepted for review in China. 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 commercialisation. It has established global R&D centres and a Shanghai-based manufacturing facility certificated by China and the EU Good Manufacturing Practice (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 serplulimab (anti-PD-1 mAb) as backbone. Apart from the launched products 汉利康® (rituximab), the first China-developed biosimilar, 汉曲优® (trastuzumab, Zercepac in the EU), the first China-developed mAb biosimilar approved both in China and in the EU, 汉达远® (adalimumab) and 汉贝泰® (bevacizumab), the NDA of innovative product serplulimab indicated for MSI-H solid tumors has been granted priority review, and the NDAs of HLX01 (rituximab) for the treatment of rheumatoid arthritis and serplulimab for the treatment of squamous non-small cell lung cancer are also under review. What's more, Henlius has conducted over 20 clinical studies for 11 products and 8 combination therapies worldwide, expanding its presence in major market as well as emerging market.

【参考文献】

[1] Croft M. The role of TNF superfamily members in T-cell function and diseases[J]. Nature Reviews Immunology, 2009, 9(4): 271-285.

[2] Hashimoto K. CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development[J]. Cancers, 2021, 13(10): 2288.

[3] Guo, G., Gong, K., Wohlfeld, B., Hatanpaa, K. J., Zhao, D., and Habib, A. A. (2015). Ligand-independent EGFR signaling. Cancer Res.75, 3436–3441.

[4] Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies. Clin Cancer Res. 2019;25(23):6899-6908.

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大会名称：2022第七届易贸生物产业大会EBC暨易贸生物产业展览

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