Lumretuzumab

HER2 ADC爆火之后，热度最高的或属HER3 ADC。2023年10月19日，默沙东以220亿美元的总价打包拿下了第一三共的三款ADC药物权益，其中进度最为领先的就是HER3 ADC药物patritumab-dxd。紧随默沙东之后，百时美施贵宝也选择重金入局，以8亿美元首付款、总交易金额最高可达84亿美元，引进百利天恒HER3双抗ADC药物BL-B01D1。持续的重磅交易，进一步引发HER3的研发热情，或许也预示了HER3的拐点。从1989年HER3靶点被发现到现在，30年时间里，包括罗氏、安进、第一三共在内的多家大药企都曾折戟于此。但现在，HER3与成药之间的距离，又近了一些。不过，HER3靶点的未来属于谁，现在还没有定论。至少，领跑者patritumab-dxd，在2025年ASCO大会上公布的3期试验数据来看，战斗力并不强悍：PFS获益有限，加上特有的间质性肺炎问题，让patritumab-dxd的前景面临了更多的不确定性。更重要的是，OS未达到统计学意义。因此，5月29日，默沙东宣布撤回上市申请。这意味着，热闹的HER3靶点领域又有了新变数，属于后来者超车的机会可能来了。被ADC改变的命运HER3靶点的命运，某种程度上是被ADC改变的。HER3与明星靶点EGFR、HER2同属HER家族，前两者早在多年前就已成药，HER3则由于结合力低、内在激酶活性极低等问题迟迟无法成药。由于HER3内在激酶活性极低，无法被制成小分子激酶抑制剂，单抗便成为HER3研发的起点。包括第一三共的U3-1287、罗氏的RO5479599在内的多款HER3单抗相继进入临床试验。遗憾的是，围绕着HER3单抗的研发基本都以失败告终。临床试验发现，这些HER3单抗普遍有效性不足。由于HER3单抗通过结合HER3，阻挡NRG配体发挥作用，但HER3结合力较低可能会影响药效。HER3药物的研发也由此进入了一段冷静期。随着ADC、双抗等技术逐渐成熟，HER3的药物研发才迎来了第二春。相比于单抗，ADC的优势是通过诱导受体内吞和降解导致癌细胞死亡，不必完全依赖HER3诱导癌细胞死亡。Patritumab-dxd则是该领域的潜在破局者。在2023年日本肿瘤内科学会年会期间，第一三共公布了Patritumab-dxd的一期临床试验数据。其中，针对非小细胞肺癌的数据显示，中位随访23个月，5.6 mg/kg U3-1042组患者的客观缓解率为40.2%，无进展生存期为6.4个月，总生存期为15.8个月。值得注意的是，这一结果针对的是已平均接受过4线治疗的患者，超过15个月的总生存期，对于晚期或转移性如EGFR突变NSCLC患者来说，已经算是史无前例的数据。尤其是对待EGFR耐药患者，Patritumab-dxd的客观缓解率也达到了39%，中位缓解持续时间达到6.9个月，无进展生存期达到8.2个月。也正因此，Patritumab-dxd主攻该群体，快速推进二、三期临床的研究，试图快速上岸。新拐点又至距离获批，Patritumab-dxd原本只差临门一脚。完成收购后不久，2023年12月22日第一三共和默沙东宣布，patritumab-dxd的上市申请，获FDA受理并予以优先审评，适应症为既往至少接受过两种系统治疗的EGFR突变型局部晚期或转移性非小细胞肺癌。虽然在2024年年中被拒，但不管是默沙东还是第一三共均指出，CRL与第三方生产问题有关，而不是有关疗效或安全性的任何问题。情况确实如此。第一三共、默沙东很快重新提交了patritumab-dxd的上市申请，并在去年9月份指出，验证性Herthena-Lung02试验已达到其主要终点，显示与化疗相比，无进展生存期有“统计学意义”的改善。换句话说，Patritumab-dxd可以上岸。结果并没有如愿，2025年ASCO上公布的3期研究Herthena-Lung02最新研究数据，引发了市场关于其竞争力的担忧。结果显示，HER3-DXd在主要终点PFS方面，相较对照组确实有统计学上的改善：P=0.011。但在数值上却很糟糕，patritumab-dxd组中位PFS为5.8个月，化疗组为5.4个月，也就是说仅仅只有0.4个月的改善，HR=0.77。更关键的是，OS数据未达到统计学意义，同时DXD有效载荷的已知问题间质性肺炎无法避免：虽然大部分是低级别的，但ILD仍然导致了两个5级事件。获益有限，毒副作用让人担忧，这无疑让市场对其后续的临床竞争力存疑，尤其是patritumab-dxd属于默沙东以15亿美元预付款获得许可的分子之一，质疑声显然更大了。也正因此，在数据结果公布后，市场对于patritumab-dxd的命运概括为：悬而未决。最终，以撤回上市收场。来自HER3 ADC的启示当然，patritumab-dxd遇阻，并不会影响HER3靶点的命运，因为还有后来者们正在摩拳擦掌。同样是在ADC赛道，对于包括映恩生物等在内的后来者来说，这可能意味着是一个难得的超车机会，毕竟不同选手的分子竞争要点，不尽相同。而如果被超车，默沙东显然是最郁闷的。基于DXd-ADC平台，第一三共已经研发出了一款成功的HER2 ADC药物DS-8201，这款药物展示出对乳腺癌的超强杀伤作用，成功证明了DXd ADC平台在多个靶点上的广泛适用性，甚至重塑了整个ADC的未来空间。对于默沙东来说，其愿意为第一三共处于临床阶段的三款ADC高价买单，某种程度上也是基于对第一三共DXd ADC平台的信任，认为在DS-8201身上出现的颠覆性效果，有可能会在其他靶点的ADC药物上重现。只是目前来看，可能并没有那么顺利，这也给了平台型企业更多警示。先通过一种药物的成功证明自身平台的价值，在平台价值获得肯定后，再将平台拓展至创新靶点，从而持续的推出新产品的策略，看上去完美无瑕，但在创新药领域，可能没有那么容易。来源 | 氨基观察（药智网获取授权转载）撰稿 | 郑晓责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。合作、投稿 | 马老师 18323856316（同微信） 阅读原文，是受欢迎的文章哦

SUZHOU, China I May 6, 2025 I CStone Pharmaceuticals (“CStone”, HKEX: 2616), an innovation-driven biopharmaceutical company focused on anti-cancer therapies, announced today that poster presentations of preclinical data of CS2011 (EGFR/HER3 bispecific antibody), CS5007 (EGFR/HER3 bispecific ADC), CS5005 (SSTR2 ADC) and CS5006 (ITGB4 ADC), key assets in CStone Pipeline 2.0, have been delivered at the 2025 American Association for Cancer Research (AACR) Annual Meeting. Key Highlights: EGFR and HER3 are members of the human epidermal growth factor receptor (HER) family and are validated therapeutic targets in advanced solid tumors. EGFR overexpression drives tumor progression in approximately 70% of colorectal cancers (CRC), 60% of lung cancers, and over 90% of head and neck squamous cell carcinomas (HNSCC). Meanwhile, HER3 upregulation frequently emerges as a resistance mechanism to MAPK/PI3K inhibitors, EGFR tyrosine kinase inhibitors (TKIs), and hormone therapies. CS2011 is a bispecific antibody with high binding affinity to both EGFR and HER3 . It effectively blocks downstream signaling of both targets, thereby inhibiting tumor growth on EGFR/HER3 positive tumor cells. 1.         CS2011 targets almost all HER family signaling except HER2 homodimers, addressing tumor heterogeneity effectively. 2.         CS2011 demonstrates potent binding affinity to EGFR and/or HER3 individually and enhanced dual binding affinity to EGFR and HER3 concurrently driven by avidity-based synergy. 3.         CS2011 inhibits tumor growth by binding to EGFR and/or HER3-positive tumor cells. 4.         CS2011 shows superior in vivo and in vitro anti-tumor activity versus potential major competitors. （1）      Compared to anti-EGFR, anti-HER3 and competing bispecific antibody, CS2011 induces faster and deeper internalization in tumor cells across varying EGFR & HER3 expression levels. （2）    CS2011 demonstrated potent inhibition of EGFR downstream signaling, comparable to anti-EGFR antibodies, and superior inhibition of HER3-mediated signaling compared to competitive bispecific antibody. （3）      CS2011 exhibited robust anti-proliferative activity in tumor cells with diverse EGFR and HER3 expression levels. （4）      In in vivo CDX tumor models, CS2011 demonstrated superior tumor-growth inhibition compared to anti-EGFR or anti-HER3 monoclonal antibodies alone and showed comparable efficacy to the combination treatment. 5.         CS2011 exhibited a pharmacokinetic (PK) profile comparable to those of monoclonal antibodies in rodents. In summary, CS2011 has demonstrated potent blockage activity on EGFR and HER3 and exhibited synergistic effects on their downstream signaling. It thereby shows the potent tumor growth inhibitory effects in in vitro and in vivo experiments. The patent of CS2011 has been filed in March 2025, and its Investigational New Drug (IND) application is expected to be submitted in the near term. CS5007 is a bispecific ADC targeting both EGFR and HER3, developed with CStone’s proprietary ADC platform. It is composed of EGFR/HER3 bispecific antibody backbone (CS2011), a hydrophilic β-glucuronide linker and a clinically validated topoisomerase I inhibitor, Exatecan. This integrated approach, featuring precise targeting, optimized linker stability, and proven therapeutic payload, positions CS5007 as a potential best-in-class candidate for precision oncology. 1.         CS5007 targets almost all human epidermal growth factor receptor (HER) family signaling except for HER2 homodimers, covering broad tumor types and effectively addressing tumor heterogeneity. 2.         CS5007 demonstrated high-affinity binding to EGFR single-positive, HER3 single-positive, and EGFR/HER3 double-positive tumor cells. 3.         CS5007 triggered high-rate internalization on tumor cells. 4.         CS5007 demonstrated potent, antigen-dependent cytotoxicity against tumor cells in vitro across varying EGFR and HER3 expression levels and showed robust tumor-growth inhibition in CDX models. 5.         CS5007 exhibited superior in vitro stability compared to ADCs conjugated with tetrapeptide and dipeptide linkers. After 7 days of incubation in human/monkey serum, it retained approximately 70% of its drug payload, indicating a minimal release rate. 6.         CS5007 exhibited comparable pharmacokinetic (PK) profile to those ADCs composed of monoclonal antibodies in rodents. CS5007 demonstrates strong affinity for EGFR- and/or HER3-positive tumor cells and induces efficient internalization. Preclinical studies have shown excellent antitumor activity, favorable safety, and pharmacokinetic profiles. The patent of CS5007 has been filed in March 2025. Preclinical findings support further IND-enabling studies and clinical investigations in various advanced solid tumors. Somatostatin receptor 2 (SSTR2) is a G protein-coupled receptor (GPCR) that is overexpressed in various solid tumors, including neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and small cell lung cancer (SCLC). Due to its tumor-selective expression profile, SSTR2 has emerged as a promising target in the field of precision oncology. CS5005 is a first-in-class, SSTR2-targeting ADC, composed of CStone’s proprietary anti-SSTR2 antibody with high affinity and selectivity, hydrophilic β-glucuronide linker, and potent topoisomerase I inhibitor, Exatecan. In preclinical studies, CS5005 demonstrated potent, antigen-dependent tumor growth inhibition that was not affected by co-administration with SSA-derived therapies. Additionally, CS5005 exhibited superior stability, monoclonal antibody-like pharmacokinetic (PK) properties, and favorable tolerability in preliminary non-human primate toxicity studies. 1.         CS5005 demonstrated high affinity to SSTR2-positive cell lines and induced high-rate internalization on tumor cells. 2.         CS5005 exhibited cross-reactivity with SSTR2-expressing cells in non-human primates and demonstrated selective binding to SSTR2 with minimal interaction with other SSTRs. 3.         CS5005 demonstrated potent antigen-dependent cytotoxic activity against tumor cells in vitro and robust tumor-growth inhibition in CDX tumor model. 4.         The antitumor activity of CS5005 (SSTR2-DXd) is not compromised by concomitant ligand-derived treatments (e.g., octreotide, Lutathera ® ), thereby avoiding drug-drug interference commonly observed with current anti-SSTR2 therapies. 5.         CS5005 demonstrated superior in vitro stability due to its proprietary linker, outperforming ADCs conjugated with well-validated dipeptide and tetrapeptide linkers. 6.         Superior pharmacokinetic (PK) properties of CS5005 in rodents. 7.         Bioinformatics analysis of SCLC samples supports DLL3/SSTR2 dual targeting as a strategy to overcome tumor heterogeneity and expand the treatable patient population. In summary, CS5005 is a first-in-class, SSTR2-targeting ADC designed to selectively eliminate SSTR2-positive tumors, including small cell lung cancer, neuroendocrine carcinoma, and neuroendocrine tumors. It is composed of CStone’s proprietary high-affinity, high-selectivity anti-SSTR2 antibody, CStone’s proprietary hydrophilic β-glucuronide linker, and potent TOP1 inhibitor payload. CS5005 has demonstrated robust antitumor activity in both in vitro and in vivo studies, supporting its progression toward IND submission and clinical development. The patent of de novo antibody backbone of CS5005 has been filed in the first half of 2024. CS5008, an SSTR2/DLL3 bispecific ADC is under development. By simultaneously targeting SSTR2 and DLL3 that frequently co-express in SCLC, NETs, NECs and others, CS5008 aims to overcome tumor heterogeneity, a challenge faced by mono-specific therapies. CS5006 is a first-in-class antibody-drug conjugate (ADC) targeting the novel antigen integrin β4 (ITGB4), developed using CStone’s proprietary ADC platform. Leveraging an internally developed machine learning-based bioinformatics algorithm alongside rigorous in-house experimental validation, CStone identified elevated ITGB4 expression across multiple tumor types—including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), and head and neck squamous cell carcinoma (HNSCC)—with minimal expression observed in normal tissues. Preclinical in vivo and in vitro studies have demonstrated CS5006’s promising therapeutic potential, highlighting its ability to effectively killing tumor cells. 1.         Bioinformatics analysis identified high ITGB4 expression in colorectal tumor tissues, supporting ITGB4 as a promising tumor-associated antigen for CRC. In the tumor microenvironment, ITGB4 was selectively overexpressed on tumor cells while remaining low expression in normal tissues. 2.         Immunohistochemistry (IHC) staining confirmed limited ITGB4 expression in normal tissue but high expression in tumor tissues from patients with CRC, sq-NSCLC, HNSCC and ESCC. 3.         ITGB4 antibody demonstrated high affinity and internalization rate. 4.         CS5006 preclinical proof-of-concept models using ITGB4-vedotin and ITGB4-DXd showed potent antitumor activity in both in vitro and in vivo studies, along with favorable pharmacokinetic (PK) profiles. （1）      ITGB4-vedotin exhibited strong antigen-dependent cytotoxicity in ITGB4-positive tumor cell lines in vitro and demonstrated potent antigen-dependent tumor inhibition in CDX models in vivo . （2）      ITGB4-DXd also exhibited potent antigen-dependent cytotoxicity in vitro and strong tumor-inhibitory effects in vivo CDX tumor models. （3）      Both ITGB4-vedotin and ITGB4-DXd exhibited favorable PK characteristics. In summary, CS5006 is a first-in-class ADC targeting the novel tumor antigen ITGB4 and is currently undergoing comprehensive preclinical evaluation. Preclinical data have demonstrated strong antitumor activity across multiple animal models, particularly in solid tumors such as non-small cell lung cancer, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma. The compound also exhibited good tolerability, providing strong support for its further clinical development. The patent of CS5006 has been filed in April 2023. About CStone CStone (HKEX: 2616), established in late 2015, is an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer therapies. Dedicated to addressing patients’ unmet medical needs in China and globally, the Company has made significant strides since its inception. To date, the Company has successfully launched 4 innovative drugs and secured approvals for 16 new drug applications (NDAs) covering 9 indications. The company’s pipeline is balanced by 16 promising candidates, featuring potentially first-in-class or best-in-class antibody-drug conjugates (ADCs), multispecific antibodies, immunotherapies and precision medicines. CStone also prides itself on a management team with comprehensive experiences and capabilities that span the entire drug development spectrum, from preclinical and translational research to clinical development, drug manufacturing, business development, and commercialization. For more information about CStone, please visit www.cstonepharma.com . SOURCE: CStone Pharmaceuticals