possessed

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EGFR的抗体偶联药物（ADC）HLX42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。

尽管多款EGFR抗体和第三代EGFR受体酪氨酸激酶抑制剂（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。靶向EGFR的ADC药物有望克服这一耐药机制，为更多晚期肿瘤患者带来临床获益 ^[1] 。HLX42是新型靶向EGFR的ADC候选药物，由高度特异性的EGFR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（drug-to-antibody-ratio, DAR）约为8。 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 ^[2] ，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。2023年8月，HLX42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。

论文标题

新型靶向表皮生长因子受体（EGFR）的ADC药物HLX42的临床前研究，以解决肿瘤对西妥昔单抗（Cetuximab）或EGFR酪氨酸激酶抑制剂（TKI）的耐药问题。

试验方法

围绕抗原结合、内吞和血浆稳定性等能力对HLX42进行了体外评估；同时在包括HT-29，NCI-H1993，EBC-1，LU3075等多种CDX和PDX模型中开展HLX42的体内药效试验。

试验结果

• 体外评估证明，HLX42具有与原抗体相似的亲和力和内吞效率。此外，HLX42在大鼠和食蟹猴血浆中保持稳定。

• 在体内药效学研究中，HLX42在对西妥昔单抗或EGFR TKI耐药的多种CDX/PDX模型中展现出强大的肿瘤抑制活性：在HT-29模型中，HLX42以8 mg/kg的剂量每周给药一次，连续给药三周，其TGI（tumour growth inhibition）为90.2%。与VC-MMAE这一传统ADC技术头对头比较，HLX42显示出更佳的体内疗效和更持久的抗肿瘤能力。在NCI-H1993模型中，HLX42以8 mg/kg的剂量每周给药一次，连续给药三周，其TGI为91.5%，而anti-EGFR Ab-GGFG-Dxd ADC给药组的TGI%仅为79.8%。类似地，在EBC-1模型中，HLX42以8 mg/kg的剂量每周给药一次，连续给药三周，可根除所有病灶。距最后一次给药三周后，8mg/kg剂量的HLX42仍可维持所有小鼠肿瘤完全缓解，而使用anti-EGFR Ab-VC-MMAE ADC的小鼠肿瘤在停药后重新生长。此外，HLX42与第三代EGFR TKI奥希替尼联用在LU3075 肺癌PDX模型中展示出显著的协同作用，而该模型对奥希替尼单药响应较差。在另一个EGFR外显子19缺失/T790M/C797S突变、对奥希替尼完全耐受的肺癌PDX模型中，HLX42 1mg/kg单次给药可实现肿瘤完全缓解。早期毒理研究中，HLX42在大鼠和食蟹猴中展现出良好的安全性。

结论

综上所述，临床前数据显示HLX42是一款潜在同类最佳的EGFR ADC，值得进一步开展临床研究。

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 HLX42, a Potential BIC EGFR-Targeting ADC Released at 2023 ESMO

Shanghai, China, October 24th, 2023 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the results from the preclinical study of HLX42, the novel EGFR 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.

Despite the great success of monoclonal antibody targeting EGFR and 3rd generation EGFR TKIs, there is still a significant unmet medical need for effective therapies for patients who are refractory to current therapies or relapse after standard of care. The EGFR-targeting ADC has the potential to overcome the resistance to EGFR monoclonal antibodies and Tyrosine kinase inhibitors (TKIs), which may bring additional clinical benefits to patients who are resistant or refractory to EGFR targeted therapy ^[1] . HLX42 is a novel EGFR-targeting ADC, comprised of a high-affinity humanized IgG1 antibody targeting EGFR, conjugated with a novel topoisomerase-I inhibitor payload, the drug to antibody ratio (DAR) is around 8.The 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 ^[2] . In August 2023, the investigational new drug (IND) application of HLX42 was accepted for review by the National Medical Products Administration (NMPA) of China.

Title

Preclinical evaluation of HLX42, a novel EGFR-targeting ADC, for Cetuximab or TKI resistant cancer.

Methods

HLX42 was examined in antigen binding, internalisation and plasma stability assays; efficacy analyses were performed in CDX and PDX models including HT-29, NCI-H1993, EBC-1, and LU3075, etc.

Results

In vitro analyses demonstrated that HLX42 possessed similar affinity and internalisation rate compared to parental antibody, and it was stable in the plasma of rats and cynomolgus monkeys.

In in vivo studies, HLX42 showed potent tumour suppression in several CDX and PDX models that were cetuximab or TKIs resistant. As in the HT-29 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks resulted in 90.2% TGI. Likewise, HLX42 showed better in vivo efficacy and elicited more durable antitumour responses in a head-to-head comparison with conventional ADC technologies such as VC-MMAE. In the NCI-H1993 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks resulted in 91.5% TGI compared to 79.8% TGI when treated with anti-EGFR Ab-GGFG-Dxd. Similarly, in the EBC-1 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks eradicated all lesions; all mice remained tumour free three weeks after the last dose, while tumour began to regrow in the anti-EGFR Ab-VC-MMAE treated group. HLX42, combined with a 3rd generation TKI, showed strong synergy in the LU3075 PDX model which poorly responded to Osimertinib monotherapy in the same experiment. In another NSCLC PDX model harboring EGFR exon19 deletion/T790M/C797S mutations, which exhibited complete resistance to Osimertinib. A single dose treatment resulted in significantly complete response. In our pilot toxicity studies conducted in rats and cynomolgus monkeys, HLX42 demonstrated good safety profiles in both species.

Conclusion

Taken together, these preclinical data strongly suggest that HLX42 is a potential best-in-class EGFR-targeting ADC which is worth further clinical investigations.

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] Tan C S, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer[J].The Lancet Oncology,2015,16(9)

[2] ]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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