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2023年10月24日，复宏汉霖（2696.HK）宣布，基于与宜联生物的合作，公司开发的靶向PD-L1的抗体偶联药物（ADC）HLX43的临床前研究数据在2023 ESMO年会上以壁报形式展示。这也是复宏汉霖在ADC治疗领域最新研究成果的首次公开亮相。

近年来，以PD-1/PD-L1单克隆抗体为代表的免疫检查点抑制剂促进了肿瘤免疫治疗的高速发展，成为肿瘤患者各线治疗的主要手段之一 ^[1] 。然而，部分PD-L1阳性患者对该疗法无响应，或者出现耐药。PD-L1在肿瘤中的高表达使其成为ADC药物开发领域极具吸引力的靶点，有潜力改变PD-1/PD-L1抑制剂难治/耐药（R/R）型肿瘤的治疗格局 ^{[2 ]} 。HLX43是一款新型PD-L1靶向的ADC候选药物，由 高度特异性的 P D-L1人源化lgG1抗体分 子与新型DNA拓扑异构酶-I（Topoisomerase I）抑制剂毒素偶联制备而成， 其药物抗体比（dr ug-to-antibody-ratio, DAR）约为8。HLX43的新型连接子-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 ^[3] ，独特的作用机制使得HLX43 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 。2023年8月，HLX43的临床试验申请已经获得中国国家药品监督管理局（NMPA）受理。

论文题目

靶向PD-L1的ADC药物HLX43在多种PD-1/PD-L1难治/耐药模型中的临床前药效。

试验方法

围绕抗原结合、内吞和血浆稳定性等能力对HLX43进行了体外评估；同时在包括MDA-MB-231 CDX、BXPC-3 CDX、黑色素瘤PDX等多种模型中开展体内药效实验。

试验结果

• 体外评估证明，HLX43具有与原抗体相似的亲和力和内吞效率。此外，HLX43在大鼠和食蟹猴血浆中稳定性较高。

• 在体内药效研究中，HLX43在多种PD-L1+ CDX和PDX模型中诱导肿瘤消退，并且药物安全性良好，与对照组相比各剂量组给药小鼠体重均无明显变化：例如，在MDA-MB-231模型中每周给予动物8 mg/kg的HLX43，连续治疗三周后动物的肿瘤体积显著缩小，且药物未导致小鼠体重下降。与等剂量给药的anti-PD-L1 Ab-GGFG-Dxd ADC组相比，HLX43在所有体内模型中（包括PD-L1低表达、高度异质性和对PD-1/PD-L1抑制剂不响应的模型）展现出更优异的抗肿瘤效果。早期毒理试验结果显示，HLX43在大鼠和食蟹猴中具有良好的安全性。

结论

HLX43在临床前研究中显示出良好的疗效和安全性，这款新型PD-L1 ADC有望为PD-1/PD-L1抑制剂难治性/耐药的肿瘤患者（如非小细胞肺癌、头颈部鳞状细胞癌、食管鳞状细胞癌、黑色素瘤和结直肠癌）提供一种新颖的治疗方案。

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5款产品，在国际上市1款产品，19项适应症获批，2个上市申请分别获美国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，上海徐汇基地已获得中国和欧盟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 ^® ，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，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。

Results From the Preclinical Study of HLX43, a Potential FIC PD-L1-Targeting ADC Released at 2023 ESMO

Shanghai, China, October 2 4th , 2023 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the results from the preclinical study of HLX43, the novel PD-L1- targeting ADC which was developed by the company based on the collaboration with MediLink Therapeutics was released as a poster presentation at the 2023 European Society of Medical Oncology (ESMO) Congress.

Immune checkpoint inhibitors represented by PD-1/PD-L1 monoclonal antibodies have emerged in recent years and revolutionized all lines of treatment for tumour patients ^[1] . However, there are still many patients with positive PD-L1 expression who do not respond to or develop resistance to PD-1/PD-L1-targeted therapy. The favorable expression of PD-L1 in tumours makes it an attractive target for ADC development, which might alter the treatment landscape for PD-1/PD-L1 inhibitor refractory/resistant (R/R) cancers ^[2] . HLX43 is a PD-L1-targeting ADC, composed of a fully humanized anti-PD-L1 IgG1 antibody, conjugated with a novel topoisomerase-I inhibitor payload. The drug to antibody ratio(DAR) is around 8. The novel linker-payload of HLX43 is preferentially activated for cleavage in the tumour microenvironment(TME) ^[3] . This unique mechanism of action can efficiently deliver toxin into PD-L1-expressing malignant cells, while sparing the normal cells. In August 2023, the investigational new drug (IND) application of HLX43 was accepted for review by the National Medical Products Administration (NMPA) of China.

Title

Preclinical activity of HLX43, a PD-L1-targeting ADC, in multiple PD-1/PD-L1 refractory/resistant models.

Methods

HLX43 was examined in antigen binding, internalisation and plasma stability assays; in vivo efficacy studies were performed in several CDX and PDX models including MDA-MB-231, BXPC-3, and melanoma PDX(LD1-0024-362394).

Results

In vitro studies demonstrated that HLX43 possessed similar affinity and internalisation rate compared to parental antibody, and it showed good stability in the plasma of rats and cynomolgus monkeys.

In in vivo efficacy studies, HLX43 induced tumour regression in multiple PD-L1-positive CDX models and PDX models, and was well tolerated, with no changes in body weight compared to control animals across all dosing groups. As in the MDA-MB-231 model, weekly administration of HLX43 at 8 mg/kg for three times induced significant tumour regression, while no body weight loss was observed. Three models tested in the current study included those with weak PD-L1 expression and high heterogeneity, as well as PD-1/PD-L1 nonresponsive models. In all tested models, HLX43 always showed superior anticancer efficacy over the anti-PD-L1 Ab-GGFG-Dxd at equivalent doses. Preliminary toxicity assessments in rats and cynomolgus monkeys also demonstrated that HLX43 was safe.

Conclusion

HLX43 showed promising efficacy and safety results in our preclinical evaluation. This innovative novel PD-L1-targeting ADC has the potential to become a new treatment option for PD-1/PD-L1 inhibitor R/R cancers such as NSCLC, HNSCC, ESCA, SKCM and CRC. Our data warrant further development of HLX43 into the clinical setting.

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 has been approved for marketing in overseas markets, 19 indications are approved worldwide, and 2 marketing applications have been accepted for review in 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 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 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 tumours, squamous non-small cell lung cancer (sqNSCLC), 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.

参考文献

[1]Attili I, Tarantino P , Passaro A ,et al. Strategies to overcome resistance to immune checkpoint blockade in lung cancer[J].Lung cancer: Journal of the International Association for the Study of Lung Cancer, 2021(154-):154.

[2]Kwan B, Ramirez M, Jin S, et al. 783 SGN-PDL1V, a novel, investigational PD-L1-directed antibody-drug conjugate for the treatment of solid tumors[J]. 2021.

[3]Jiaqiang C, Shuai S, Qing Z, et al; Abstract 596: Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments. Cancer Res 1 April 2023; 83 (7_Supplement): 596.

(复星医药)

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