转自：复星医药
2024年6月25-27日，2024年度世界抗体药物偶联亚洲大会（World ADC Asia）在韩国仁川盛大召开，复宏汉霖首次亮相世界抗体药物偶联大会系列会议（World ADC Event Series），于会上展示了公司多款创新ADC产品及拥有自主知识产权的ADC研发平台HanjugatorTM。值得一提的是，公司位于2#展位的展出受到高度关注，吸引众多业内人士前往交流合作。
本次大会上，复宏汉霖全球创新中心总经理单永强博士带来“From Product to Platform: Henlius’ Practices & Progress in ADC to Address Unmet Medical Needs”的主题报告，分享了公司在ADC领域的创新实践与研发进展，并与来自全球制药企业、科研机构等的ADC领域同道们广泛交流探讨。
作为一家国际化的创新生物制药公司，复宏汉霖始终以临床需求为导向，积极探索新靶点、新机制，不断拓展疾病领域和新分子类型。其中，立足于公司在抗体药物领域的一体化平台优势，复宏汉霖加速拓展抗体偶联药物（ADC）及多样化的靶向偶联药物（AXC/XXC）的开发，两款潜在FIC/BIC ADC 产品HLX42（EGFR ADC）和HLX43（PD-L1 ADC）皆在临床前研究中展现出良好的抗肿瘤活性和安全性，并分别取得中国国家药监局（NMPA）和美国食药监局（FDA）的临床实验许可，I期临床研究现于中国顺利开展。2023年，HLX42亦获FDA 授予快速通道认定（FTD），用于治疗经第三代EGFR TKI治疗后疾病进展的EGFR突变的晚期/转移性非小细胞肺癌。
与此同时，复宏汉霖已打造了一条丰富的ADC在研管线，多款差异化开发的候选药物正处于临床前研究阶段。此外，聚焦未满足的临床需求，复宏汉霖着力开发差异化、有临床价值的ADC产品，已建立起具有独立知识产权的抗体和连接子-荷载开发工具箱HanjugatorTM，以持续提升ADC产品的安全性和治疗窗，提高ADC的选择性及效能，拓展ADC药物的适应症应用。
本次大会上，复宏汉霖还以壁报形式展示了HLX42（EGFR ADC）及HLX43（PD-L1 ADC）的更新临床前研究数据，详情如下：
HLX42临床前研究
论文题目
新型靶向表皮生长因子受体（EGFR）的ADC药物HLX42的临床前研究，以解决肿瘤患者对西妥昔单抗（Cetuximab）或EGFR酪氨酸激酶抑制剂（TKI）的耐药问题
（HLX42: a Novel EGFR-Targeting ADC, for Cetuximab or TKI Resistant Cancer）
研究背景
表皮生长因子受体（EGFR）在多种类型的实体瘤中高度表达，其异常表达被普遍认为是是肿瘤发生和疾病进展的重要标志。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。目前，靶向EGFR的 ADC 已进入临床开发阶段，并展示出可接受的安全性和初步临床活性。然而，由于EGFR在正常上皮组织中广泛表达，传统的EGFR ADC 可能会引发严重的治疗相关毒性。
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。HLX42的连接子-毒素能够在肿瘤微环境中特异性裂解释放，不仅仅依赖于肿瘤细胞的内吞和溶酶体内蛋白酶切割，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。
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；同时在非小细胞肺癌、转移性结直肠癌的多种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、食蟹猴和人的血浆中保持稳定。
在体内药效学研究中，HLX42在对西妥昔单抗/EGFR TKI/抗PD-1单抗耐药的多种CDX/PDX模型中展现出强大的肿瘤抑制活性：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，在对奥希替尼单药响应较差的LU3075 肺癌PDX模型中，HLX42可根除所有病灶。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。在该模型中，使用8 mg/kg剂量的lgG linker-payload连续给药四周，TGI为58.1%，提示此类linker-payload可在肿瘤微环境中特异性裂解。此外，HLX42在HT29 结直肠癌 CDX模型和西妥昔单抗和/或PD-1抑制剂耐药的微卫星稳定（MSS）转移性结直肠癌 PDX模型中也显示出优异的抗肿瘤疗效。在对大鼠和非人灵长类动物进行的毒理学研究中，HLX42 具有良好的安全性。在早期毒理学研究中，HLX42 在大鼠和非人灵长类动物中展现出良好的安全性。
结论
综上所述，临床前数据显示HLX42是一款潜力巨大的EGFR ADC，有望填补晚期/转移性非小细胞肺癌和标准治疗失败的转移性结直肠患者的临床需求，值得进一步开展临床研究。
HLX43临床前研究
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
（HLX43, a PD-L1-Targeting ADC, for Cancer Resistant to PD-1/PD-L1 Blockade）
研究背景
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。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。
HLX43是一款新型PD-L1靶向的ADC候选药物，由高度特异性的PD-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（drug-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，不仅仅依赖肿瘤细胞的内吞和毒素降解作用。独特的作用机制能够使毒素更加有效的输送到表达PD-L1的肿瘤细胞，而不损伤正常细胞，从而大大降低毒素在外周组织中非特异性释放引发的全身毒性，从而使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。
试验方法
围绕抗原结合、内吞、血浆稳定性、免疫毒性等方面对HLX43进行了体外评估；同时在乳腺癌CDX及非小细胞肺癌和肝细胞癌的多种PDX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、食蟹猴和人的血浆中稳定性较高。HLX43对PD-1阳性的人类抗原呈递细胞（APC）无免疫毒性。
在体内药效研究中，HLX43在多种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。在MDA-MB-231CDX模型中，每周进行HLX43给药，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-GGFG-Dxd和anti-PD-L1-vc-MMAE组相比，HLX43在所有体内模型中展现出更优异的抗肿瘤效果。在 非小细胞肺癌 PDX 模型中，每周进行 HLX43给药，连续给药三周后，HLX43可诱导肿瘤显著消退。停止治疗 3 周后，8mg/kg剂量的HLX43给药组仍对病灶有持久的反应。在对该 PDX 进行 3 周治疗后，8 mg/kg剂量的IgG-linker-payload 给药组 TGI 为 61.6%，提示此类linker-payload可在肿瘤微环境中特异性裂解。在PD-L1 表达（IHC1+）或PD-L1 不表达（IHC-）的肝细胞癌PDX模型中，HLX43也能够诱导肿瘤的显著消退，并与抗血管内皮生长因子（anti-VEGF）抗体呈现出较强的协同作用。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
综上所述，临床前数据显示HLX43是一款潜力巨大的PD-L1 ADC，有望填补多种晚期/转移性实体瘤，尤其是标准治疗后出现疾病进展的晚期/转移性非小细胞肺癌和肝细胞癌患者的临床需求，值得进一步开展临床研究。
未来，复宏汉霖还将继续以抗体技术为核心，加速释放新型偶联技术发展动能，不断扩充和完善公司创新布局及产品管线，为全球患者带来更多高质量、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5款产品，在国际获批上市3款产品，23项适应症获批，3个上市申请分别获中国药监局和欧盟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，公司商业化生产基地已相继获得中国、欧盟和美国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50多个分子，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）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，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、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。
Henlius Shines at World ADC Asia 2024,
Showcasing Its Innovative R&D Accomplishments in ADC Area
From June 25-27, 2024, World ADC Asia 2024 was held in Incheon, South Korea. Henlius made its big debut at the World ADC Event Series and showcased its multiple Antibody Drug Conjugate (ADC) products as well as self-developed ADC technical platform Hanjugator™. Meanwhile, the company’s impressive display at booth #2 attracted great attention of the visitors and engaged potential innovative collaboration.
During the conference, Dr. Yongqiang Shan, General Manager of Henlius Global Innovation Center, delivered a keynote speech around the theme of “From Product to Platform: Henlius’ Practices & Progress in ADC to Address Unmet Medical Needs”, conducted wide-raging discussions with players from global research institutes and biopharmaceutical companies in ADC drug development.
As an innovative global biopharma company, Henlius actively explores the new target and mechanisms guided by clinical needs, continuously expanding its product portfolio in terms of therapeautic areas and modalities. Based on its competitive edge of an integrated antibody drug R&D platform, Henlius accelerated the development of ADC and targeted drug conjugates. Two potential first-in-class/best-in-class innovative ADC candidates, HLX42, an EGFR-targeting ADC and HLX43, a PD-L1-targeting ADC, have exhibited good anti-tumor efficacy and safety profile in preclinical studies. As of now, the two products have been approved for conducting clinical trial by the National Medical Products Administration (NMPA) and U.S. Food and Drug Administration (FDA), and phase 1 clinical trials were conducted in China. HLX42 was also granted Fast Track Designation (FTD) by the U.S. FDA, for the treatment of patients with advanced or metastatic EGFR-mutated non-small cell lung cancer whose disease has progressed on a 3rd-generation EGFR tyrosine kinase inhibitor (TKI).
In addition, Henlius has built a diversified ADC product pipeline, with differentiated-developed candidates under preclinical development. HanjugatorTM, the antibody and linker-payload modular toolbox with independent intellectual property, has been established by the company to develop differentiated and clinically valuable ADC products, continually improving ADC’s potency, selectivity, safety and therapeutic window, expanding ADC’s indication application.
Moreover, updated results from the preclinical studies of HLX42 and HLX43 were released as poster presentations. The exhibition details are as follows:
Preclinical study results of HLX42
Title
HLX42, a Novel EGFR-Targeting ADC, for Cetuximab or TKI Resistant Cancer
Background
EGFR is highly expressed in multiple types of solid tumors. And its aberrant expression is well recognized as a driving force in tumorigenesis and disease progression. Despite the great success of monoclonal antibody targeting EGFR and 3rd generation receptor 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. ADC targeting EGFR has entered the clinical stage and shown an acceptable safety profile and preliminary clinical activity. However, conventional EGFR ADCs may be associated with significant treatment-related toxicities since EGFR is broadly expressed in normal epithelial tissues.
HLX42 is a next-generation EGFR-targeting ADC, comprised of a high-affinity humanized IgG1 antibody targeting EGFR, conjugated to a novel topoisomerase-I inhibitor payload whose cleavage and release are tumor microenvironment dependent and do not require internalization by tumor cells into lysosomes. This unique mechanism of tumor microenvironment activation and payload release allows HLX42 to possess a higher therapeutic index and better safety profile.
Methods
HLX42 was examined in antigen binding, internalization and plasma stability assays; efficacy analyses were performed in CDX and PDX models of non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC).
Results
In vitro analyses demonstrated that HLX42 possessed similar affinity and internalization rate compared to parental antibody (HLX07), and it was stable in the plasma of rats, cynomolgus monkeys and humans.
In in vivo studies, HLX42 showed potent tumor suppression in several CDX and PDX models that were resistant to Cetuximab or EGFR TKIs or anti-PD-1 antibody. 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-GGFGDxd. Similarly, in the EBC-1 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks eradicated all lesions. All mice remained tumor free 24 days after the last dose, while tumor began to regrow in the anti-EGFR-vc-MMAE treated group. Furthermore, in the LU3075 PDX model which poorly responded to Osimertinib monotherapy, HLX42 eradicated all lesions.In another PDX model harboring EGFR exon19 deletion/T790M/C797S mutations, which exhibited complete tolerance to Osimertinib, a single dose treatment resulted in significantly complete response. After 4-week treatment in this PDX, the TGI of the IgG-linker-payload 8 mpk group was 58.1%, indicating the tumor microenvironment-specific lysis of linker-payload. HLX42 also showed strong efficacy in HT29 CRC CDX model and Cetuximab and/or anti-PD-1 resistant microsatellite stable (MSS) mCRC PDX model. In toxicology studies conducted in rats and non-human primates, HLX42 had favorable safety profile.
Conclusions
Taken together, these data strongly suggest that HLX42 is a highly promising ADC product with great clinical potential for the treatment of advanced/metastatic NSCLC and mCRC patients who failed from standard treatments which has urgent unmet medical needs.
Preclinical study results of HLX43
Title
HLX43, a PD-L1-Targeting ADC, for Cancer Resistant to PD-1/PD-L1 Blockade
Background
PD-1/PD-L1 monoclonal antibodies, as the most successful immune checkpoint inhibitors, have revolutionized the treatment of cancer. 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 tumors makes it an attractive target for ADC development, which might alter the treatment for PD-1/PD-L1 inhibitor refractory/resistant (R/R) cancers.
HLX43 is a PD-L1-targeting ADC, composed of an engineered version of the anti-PD-L1 humanized IgG1 antibody (HLX20), conjugated via a next-generation linker to a camptothecin-based toxin. The drug to antibody ratio is around 8. This novel linker-payload is preferentially activated for cleavage in the tumor microenvironment. And the tumor-specific release of the toxin is independent of the internalization of the ADC. This unique mechanism of action can efficiently deliver toxin into PD-L1-expressing malignant cells, while sparing the normal cells, which will greatly reduce the systemic toxicity associated with the non-specific release of toxin in the periphery.
Methods
HLX43 was examined in antigen binding, internalization, plasma stability and immunotoxicity assays. In vivo efficacy studies were performed in breast cancer CDX and PDX models from non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC).
Results
In vitro studies demonstrated that HLX43 possessed similar affinity and internalization rate compared to parental antibody, and it showed good stability in the plasma of rats, cynomolgus monkeys and humans. HLX43 shows no immunotoxicity towards PD-L1 positive human APCs.
In in vivo efficacy studies, HLX43 induced tumor regression in multiple PDX models, and was well tolerated, with no changes in body weight compared to control animals across all dosing groups. In the MDA-MB-231 CDX model, weekly administration of HLX43 for three times induced significant tumor regression and superior anticancer efficacy over the anti-PD-L1-GGFG-Dxd and anti-PD-L1-vc-MMAE at equivalent doses, while no body weight loss was observed. In the NSCLC PDX model, weekly administration of HLX43 for three times, HLX43 caused obvious regression of tumors. Even after stopping treatment for 3 weeks, HLX43 at 8 mg/kg groups still had durable response in lesions. After 3-week treatment in this PDX, the TGI of the IgG-linker-payload 8 mpk group was 61.6%, indicating the tumor microenvironment-specific lysis of linker-payload. HLX43 also induced significant tumor regression in HCC PDX model with (IHC1+) or without (IHC-) PD-L1 expression, meanwhile showed strong synergy with anti-VEGF antibody. In the toxicology studies in mice and cynomolgus monkeys, HLX43 was well tolerated in both species.
Conclusions
Taken together, these data strongly suggest that HLX43 is a highly promising ADC product with great clinical potential for treatment of advanced/metastatic solid tumors, especially for advanced/metastatic NSCLC and HCC patients with disease progression on standard treatments, which has urgent unmet medical needs.
Looking forward, Henlius will further take efforts to promote the layout of our innovative portfolio by focusing on antibody and novel conjugating technologies, bringing more high-quality and affordable therapeutics for 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, 5 products have been launched in China, 3 have been approved for marketing in overseas markets, 23 indications are approved worldwide, and 3 marketing applications have been accepted for review in China 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 centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP.
Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules 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: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., 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) 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.
