复宏汉霖创新抗PD-L1×TIGIT双抗I/II期临床研究完成中国首例受试者用药

2022年7月6日，复宏汉霖（2696.HK）宣布，公司自主开发的HLX301（重组抗PD-L1与抗TIGIT双特异性抗体）用于局部晚期/转移性实体瘤或淋巴瘤治疗的I/II期临床研究于中国完成首例受试者给药。目前，全球范围内尚无同类靶向PD-1/L1和TIGIT的双特异性抗体获批上市，HLX301有望成为first-in-class抗PD-L1×TIGIT双抗。

含免疫球蛋白和ITIM结构域的T细胞免疫受体（T cell immunoglobulin and ITIM domain，TIGIT）是一种抑制性受体，在淋巴细胞中表达，包括自然杀伤（NK）细胞、活化的CD8+ T和CD4+ T细胞以及Treg（调节性T细胞）等，其重要配体为主要表达于APC（抗原提呈细胞）或肿瘤细胞表面的CD155（脊髓灰质炎病毒受体，PVR）^[1-2]。作为免疫检查点蛋白，TIGIT可通过多种作用机制抑制固有和适应性免疫，在肿瘤免疫抑制中的“踩刹车”作用和PD-1/PD-L1类似^[3]。

HLX301为复宏汉霖自主开发的创新型抗PD-L1与抗TIGIT双特异性抗体，其TIGIT结合域来源于公司人源化羊驼重链可变区单域抗体（VHH）噬菌体展示库筛选的对TIGIT具有高亲和力、高特异性的VHH，通过重组技术与抗PD-L1单抗组合。HLX301可与PD-L1和TIGIT特异性结合并同时阻断PD-1/PD-L1和TIGIT/PVR负向信号通路，抑制肿瘤细胞的生长，有望用于多种晚期肿瘤的治疗，包括非小细胞肺癌、头颈部鳞状细胞癌、食管鳞癌等。临床前研究结果表明，对比抗PD-L1单抗、抗TIGIT单抗以及两种单抗的联合疗法，HLX301可更有效恢复T细胞受体下游信号，提高抗肿瘤活性，且耐受性、安全性良好，体现出双抗疗法的协同增强效应，为后续临床研究的开展提供了科学基础。2022年2月，HLX301在澳大利亚用于局部晚期或转移性实体瘤治疗的I期临床研究完成首例受试者给药。3月，该产品用于晚期肿瘤治疗的I期临床试验申请获国家药品监督管理局批准。

复宏汉霖不断深耕未满足的临床需求，目前已打造出多元化的创新产品管线，在PD-1/L1、LAG-3、TIGIT、BRAF等创新靶点全面布局，以抗体技术为核心，积极开展双特异性抗体、抗体偶联药物（ADC）、融合蛋白等多种药物形式产品的开发。复宏汉霖将不断提高创新效率，早日为全球患者带来更多高质量、可负担的创新治疗方案。

关于该HLX301 I/II期临床研究

本研究是一项开放标签、多中心的I/II期临床试验，旨在评估HLX301在局部晚期/转移性实体瘤或淋巴瘤患者中的安全性、耐受性、药代动力学及初步抗肿瘤疗效。本研究分为三个部分：Ia期剂量递增阶段、Ib期剂量扩展阶段、II期临床扩展阶段。合格的受试者将接受每两周静脉输注单药HLX301的治疗。Ia期通过贝叶斯最优区间（BOIN）设计，研究HLX301的安全性并确定剂量限制性毒性（DLT）和最大耐受剂量（MTD）。Ib期将进一步评估HLX301的药代动力学、药效动力学特征及初步疗效，以确定II期临床试验推荐剂量（RP2D）。II期研究的主要目的为评估HLX301在局部晚期/转移性实体瘤或淋巴瘤患者中的疗效，主要终点为研究者评估的客观缓解率（ORR）、疾病控制率（DCR）和缓解持续时间（DOR），次要目的为确认HLX301的安全性并评估PD-L1表达水平与HLX301抗肿瘤活性之间的关系。

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，在欧洲上市1款产品，13项适应症获批，2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，上海徐汇基地已获得中国和欧盟药品GMP认证，松江基地（一）也已获得中国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^®）、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，其鳞状非小细胞肺癌和广泛期小细胞肺癌两项适应症的上市注册申请也正在审评中。公司亦同步就12个产品、10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。

First Subject Dosed in China on Phase 1/2 Trial of Henlius' Anti-PD-L1×TIGIT Bispecific Antibody

Shanghai, China, July 6^th, 2022-Shanghai Henlius Biotech, Inc. (2696.HK) today announced that the first subject has been dosed in a phase 1/2 clinical trial of HLX301, a recombinant anti-PD-L1 and anti-TIGIT bispecific antibody (BsAb), for the treatment of locally advanced or metastatic solid tumours or lymphomas in China. At present, no BsAb targeting PD-1/PD-L1 and TIGIT has been approved for marketing globally. HLX301 is expected to be a first-in-class anti-PD-L1×TIGIT BsAb.

T-cell immunoglobulin and ITIM domains (TIGIT) is an inhibitory receptor, mainly expressed on natural killer (NK) cells and activated CD8+ T cells, CD4+ T cells, and T regulatory cells. TIGIT binds to the ligand CD155 (poliovirus receptor, PVR), mainly expressed on antigen-presenting cells (APC) or the surface of tumour cells, to down-regulate T cell and NK cell functions^[1-2]. As an inhibitory receptor, TIGIT can inhibit innate and adaptive responses in various mechanisms of action and act as a “brake” like PD-1/PD-L1 does to stop T cells from attacking tumours^[3].

HLX301 is an innovative anti-PD-L1 and anti-TIGIT bispecific antibody, composed of an anti-PD-L1 IgG1 subtype monoclonal antibody coupled with an anti-TIGIT variable domain of heavy-chain antibody. Its TIGIT binding domain is derived from VHH fragments with high affinity and high specificity to TIGIT, selected from the company’s synthetic humanized llama VHH library. HLX301 can simultaneously block both PD-1/PD-L1 and TIGIT/PVR pathways, inhibit tumour growth. It is expected to treat a variety of advanced cancers, including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, etc. Pre-clinical studies reported that HLX301 is superior to blocking either pathway alone or anti-PD-L1 + anti-TIGIT combinational therapy, and can restore TCR signaling, stating a good tolerance and safety, thus paving the way for further clinical development. In February 2022, the first subjct has been dosed HLX301 in a phase 1 clinical study for the treatment of locally advanced or metastatic solid tumors in Australia. In March 2022, the application of a phase 1 clinical trial of HLX301 for the treatment of advanced tumours has been approved by the National Medical Products Administration.

Underpinned by the patient-centric strategy, Henlius has built an innovative product pipeline with many emerging targets, including PD-1/L1, LAG-3, TIGIT, BRAF, etc. and has been developing a forward-looking presence in bispecific antibodies, the antibody-drug conjugates (ADC) and fusion protein based on our own core antibody technologies. Looking forward, Henlius will continue its momentum for innovation, bringing more high-quality and affordable therapies to patients worldwide.

About HLX301 Phase 1/2 Trial

This open-label, multicentre, phase 1/2 study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumour efficacy of HLX301 in patients with locally advanced/metastatic solid tumour or lymphoma. The study consists of three parts: phase 1a dose escalation, phase 1b dose expansion, and phase 2 clinical expansion. Eligible patients will receive intravenous infusion of HLX301 as a single agent every two weeks. Phase 1a uses the Bayesian optimal interval (BOIN) design to investigate safety, and determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of HLX301. Phase 1b will further evaluate the pharmacokinetic and pharmacodynamic characteristics as well as the preliminary efficacy, to determine the recommended phase 2 dose (RP2D). The primary objective of the phase 2 study is to evaluate the antitumour activity of HLX301 in patients with locally advanced/metastatic solid tumour or lymphoma. The primary endpoints are objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) assessed by investigators. Secondary objectives are to evaluate the safety of HLX301 and to investigate the association between PD-L1 expression levels and the antitumour activity of HLX301 in these patients.

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, 1 in Europe, 13 indications approved worldwide, and 2 New Drug Application (NDA) 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 commercialization. It has established global innovation centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Plant certificated by China and the EU GMP and Songjiang First Plant certificated by China 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, trade name in Europe: Zercepac^®), 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 and its NDA for the treatment of squamous non-small cell lung cancer and extensive small-cell lung cancer (ES-SCLC) are under review. What's more, Henlius has conducted over 20 clinical studies for 12 products and 10 combination therapies.

【参考文献】

[1] Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8(2).

[2] Sanchez-Correa B, Valhondo I, Hassouneh F, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy. Cancers (Basel). 2019;11(6):877.

[3] Yue C, Gao S, Li S, Xing Z, Qian H, Hu Y, Wang W and Hua C (2022) TIGIT as a Promising Therapeutic Target in Autoimmune Diseases. Front. Immunol. 13:911919.