DB-1310

Duality Biotherapeutics pulled back the curtain on its wide-reaching antibody-drug conjugate (ADC) pipeline this week, revealing new information on its 12-production portfolio as part of a filing declaring the biotech’s intent to go public on the Hong Kong stock exchange.  The document also provided more details on the candidates partnered with Germany-based drugmaker BioNTech, which first linked up with DualityBio in 2023 in an effort to diversify beyond its flagship mRNA vaccine business. For more on their collaboration, see BioNTech jumps on the ADC bandwagon. Between the BioNTech tie-up and other partnerships with BeiGene and Adcendo, DualityBio said its current deals represent more than $4 billion in total value. The Shanghai-based firm said it anticipates its late-stage ADCs to reach commercialisation in the next few years.Bispecifics and autoimmune diseases Altogether, DualityBio said it has developed 12 ADCs, of which half are already in the clinic — though several more are close to reaching that milestone, including DB-2304, the firm’s only autoimmune disease programme.The ADC targets blood dendritic cell antigen 2 (BDCA2), a receptor expressed on a specific cell type — plasmacytoid dendritic cells — that has been linked to the pathogenesis of lupus erythematosus (LE). DualityBio plans to file investigational new drug (IND) applications for both systemic and cutaneous LE this half. Other notable preclinical programmes include two bispecific ADCs, a newer iteration of the popular modality that enables the targeting of two different epitopes on either the same or different antigens, with the goal of reducing off-target toxicities, overcoming drug resistance and boosting ADC internalisation. For more on the latest advances in the space, see Spotlight On: Bispecific ADCs are gaining traction.The most advanced bispecific ADC is DB-1419, which targets both B7-H3 and PD-L1. According to DualityBio, the candidate is designed to simultaneously deliver a toxic DNA topoisomerase I inhibitor payload while also modulating T-cell activation. The first patient in a Phase I/IIa global trial is expected to be dosed this half. BioNTech collaborationThe filing also delved into a trio of programmes partnered with BioNTech. At the head of the pack is BNT323 (formerly DB-1303), a HER2-targeting ADC in three potentially registrational trials. DualityBio said it expects next year to file with the FDA seeking accelerated approval for the lead indication of HER2-expressing endometrial cancer.The candidate uses a stable, cleavable linker and topoisomerase-based payload to lower off-target toxicities and improve antitumour activity. Outside of endometrial cancer — for which BNT323 is the most advanced HER2-targeting ADC — the candidate has also shown activity against several solid tumours including breast, ovarian, colorectal and esophageal cancers.  The second programme is BNT324 (DB-1311), which targets B7-H3, a protein that plays a key role in tumour progression and metastasis and is overexpressed in several tumour types such as non–small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), castration-resistant prostate cancer (CRPC) and esophageal squamous cell carcinoma (ESCC). Currently in a Phase I/IIa trial for solid tumours including SCLC and CRPC, DualityBio plans to test the candidate as monotherapy and in immunotherapy combinations. BNT324 has fast track designation from the FDA for CRPC, as well as orphan drug designation for ESCC. Rounding out its BioNTech collaboration is BNT325 (DB-1305), a TROP2-targeting programme for “under-explored” indications such as ovarian cancer. The company said the compound also has combination potential for NSCLC, cervical cancer and triple-negative breast cancer, which may position it as “a potential backbone therapy in the TROP2 ADC landscape.” BNT325 is in a Phase I/IIa study for advanced solid tumours, including NSCLC, where “encouraging preliminary efficacy signals” have been observed.Unpartnered assetDualityBio’s most advanced wholly owned programme is DB-1310, a HER3-targeting ADC candidate the firm believes has “untapped opportunities to cover a broad patient population with limited reliance on biomarker-based patient selection and overcome resistance to standard of care.” Currently in Phase I testing, DualityBio expects to explore the asset in KRAS-mutant NSCLC, as well as in combination with AstraZeneca’s Tagrisso (osimertinib) for patients with EGFR-mutated NSCLC who are resistant to tyrosine kinase inhibitors.

涉及HER3靶点的ADC合作金额超百亿： BioNTech斥资超10亿美元与宜联生物合作开发新一代的HER3 ADC药物； 默沙东则与第一三共达成220亿美元的全球合作，共同开发包含HER3-DXd等3款ADC新药； 百利天恒将EGFR/HER3 ADC新药BL-B01D1的中国外全球权益授权给百时美施贵宝，潜在总交易额达84亿美元。 目前暂无上市的HER3靶向ADC上市，为何这些制药巨头如此青睐这一靶点，让我们来一探究竟。 HER3靶点与ADC HER3和HER2是同源家族的成员，HER2因其在抗癌领域的广泛应用而闻名，催生了诸如曲妥珠单抗和Enhertu（DS-8201）等多款具有重大影响的药物。然而，面对HER2 ADC领域的激烈竞争，全球的制药公司正在积极探索新的抗癌靶点，特别是那些与知名靶点具有相似功能或同属一类的分子。因此，HER3作为潜在的新靶点，已经吸引了业界的广泛关注和研究。 HER3二聚和信号级联 在多种类型的恶性肿瘤中，HER3的异常高表达现象普遍存在，这种过度表达与肿瘤的起始、进展以及患者的整体预后紧密相连。HER3作为一个缺乏显著内部酪氨酸激酶活性的分子，其靶向药物的研发过程充满了挑战。众多国际制药巨头和生物科技企业，包括阿斯利康、罗氏、诺华、葛兰素史克和再生元等，都在开发针对HER3的抗体或小分子治疗药物时面临了重重困难，这些挑战不仅考验了研发团队的耐心，也对整个行业的乐观情绪产生了影响。至今，尚无专门针对HER3的靶向治疗药物获得正式批准并进入市场。 HER3靶点临床开发终止的药物 HER3的成药难题主要源于其缺乏显著的细胞内酪氨酸激酶功能，这限制了针对HER3的单克隆或双特异性抗体的治疗效果。然而，这一局面有望通过ADC药物的独特作用机制得到突破。尽管ADC药物抗体部分能够特异性地与HER3结合，但其疗效并不完全依赖于HER3的激酶活性。此外，细胞毒素的有效释放和抗肿瘤活性的发挥，并不要求HER3的参与，从而实现了有效的肿瘤抑制和旁观者效应。 值得注意的是，HER3的内化速率较HER2和HER1（即EGFR）更快，这为ADC药物在肿瘤细胞中的高效作用提供了有利条件，从而可能提升治疗效果。 HER3 ADC的竞争格局 第一三共/默沙东Patritumab deruxtecan（HER3-DXd，U3-1402） HER3-DXd采用了第一三共专有的DXd ADC技术，由全人源抗HER3 IgG1单抗、基于四肽的可裂解linker和拓扑异构酶I抑制剂组成。 HER3-DXd的结构 目前HER3-DXd已提交上市申请，适应症为用于治疗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（NSCLC）患者。 虽然在今年7月，HER3-DXd的上市申请被FDA延期批准，原因主要是由于第三方制造设施检查相关的调查结果，其疗效和安全性数据并未存在问题，这也意味HER3-DXd仍有望成为首款获批上市的HER3 ADC。 HER3-DXd的BLA是基于关键性II期HERTHENA-Lung01研究的数据。研究结果显示，患者接受治疗后的ORR为29.8%，包括1例完全缓解和66例部分缓解；中位缓解持续时间（DOR）为6.4个月。在安全性方面，64.9%的患者发生3级以上治疗期间不良事件。 百利天恒BL-B01D1 BL-B01D1（伦康依隆妥单抗）是一种基于双特异性拓扑异构酶抑制剂的 ADC，可同时靶向作用于表皮生长因子受体和人表皮生长因子受体 3（EGFR×HER3）。 目前，BL-B01D1已启动多项3期临床。分别是： BL-B01D1-301：局部晚期或转移性非小细胞肺癌，EGFR-TKI后线，对比铂类化疗； BL-B01D1-302：局部晚期或转移性EGFR野生型非小细胞肺癌，PD-1/PD-L1和铂类化疗后线，对比多西他赛； BL-B01D1-303：复发性或转移性鼻咽癌，至少经过二线治疗，PD-1/PD-L1和铂类化疗后线，对比化疗（多西他赛、卡培他滨、吉西他滨）； BL-B01D1-305：复发性或转移性食管癌，PD-1/PD-L1+铂类化疗后线，对比化疗（伊立替康、紫杉醇、多西他赛）； BL-B01D1-306：局部晚期复发性或转移性HR+/HER2-乳腺癌，至少经过一种化疗治疗，对比化疗（艾日布林、长春瑞滨、卡培他滨、吉西他滨）； BL-B01D1-307：局部晚期获复发性三阴乳腺癌，紫杉醇后线，对比化疗（艾日布林、长春瑞滨、卡培他滨、吉西他滨）。 百利天恒预计BL-B01D1将于2026年或之前向中国NMPA提交首个适应症的NDA申请，最早于2028年向美国FDA提出首个BLA申请。 恒瑞医药SHR-A2009 SHR-A2009是恒瑞医药开发的一款HER3靶向的ADC，利用了HER3-29抗体，其与HER3蛋白及其表达细胞的结合活性是第一三共Patritumab的约4倍，并且在体外细胞内吞效率也优于Patritumab，DAR为4。 2024年1月1日，SHR-A2009获得FDA授予快速通道资格，用于治疗经第三代EGFR酪氨酸激酶抑制剂和含铂化疗后疾病进展的EGFR突变的转移性非小细胞肺癌（NSCLC）。 SHR-A2009的2期临床 目前，SHR-A2009正在开展针对非小细胞肺癌、乳腺癌和晚期实体瘤的2期临床。 SHR-A2009的1期研究结果显示，SHR-A2009针对NSCLC患者的ORR为30%，DCR为76.7%，中位DoR为7个月（94.4%EGFR突变；80.6%患者对3代EGFR-TKI耐药）；BL-B01D1针对38例经过多次治疗（其中34例曾接受第三代EGFR-TKI治疗）的EGFR突变阳性NSCLC患者，ORR为63.2%，DCR为89.5%。 宜联生物/BioNTech的YL202/BNT326 YL202/BNT326是一款靶向HER3的在研ADC药物，目前由宜联生物和BioNTech合作进行开发，目前正在开展1期临床。 2024年6月17日，FDA要求部分暂停正在进行的BNT326/YL202的I期试验（NCT05653752），暂停新受试者入组。原因是，BNT326/YL202可能在高剂量时造成“不可接受且显著的疾病或伤害风险”。 但在2024年8月19日，FDA通知正式解除了对YL202/BNT326临床I期试验（NCT05653752）的Partial Hold。详情可点击FDA解除对宜联生物HER3 ADC的1期临床的Partial Hold。 尽管YL202的1期临床出现了死亡案例，但其取得了均为高剂量组，因此宜联生物和BioNTech调整试验剂量，并且分析1期临床结果，其疗效可观。 YL202-INT-01-01试验的初步结果 在ASCO 2024年会上，宜联生物公布HER3-ADC YL202-INT-01-01试验的初步积极结果：在46例可评估药效患者中，ORR为37.0%（17/46 pts），DCR为93.5%；在DL3至DL5剂量组中，ORR为41.0%（16/39 pts），DCR为94.9%；在乳腺癌患者中ORR为54.5%（6/11 pts），DCR为100%。在NSCLC患者中的ORR可能只有36%。 信达生物IBI133 IBI133毒素采用exatecan，偶联技术为糖定点偶联，引进于Synaffix，DAR值为4。 IBI133的1/2期研究 目前正在进行评估IBI133单药或联合治疗不可切除的局部晚期或转移性实体瘤受试者中安全性、耐受性、药代动力学和初步有效性的多中心、开放、1/2期研究。 映恩生物DB-1310 DB-1310是映恩生物基于其DITAC技术平台开发的靶向HER3的ADC产品，由新型人源化抗Her3单克隆抗体通过马来酰亚胺可裂解linker与专有的DNA拓扑异构酶I抑制剂共价连接，DAR值约为8。 DB-1310目前处于一项在晚期/转移性实体瘤受试者中评估安全性、耐受性、药代动力学和初步抗肿瘤活性的I/IIa期、多中心、开放性、非随机首次人体研究阶段。 资料来源： 1.中信建投研报 2.Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. 3.瞪羚社.大热ADC药物接连受挫，HER3靶点是把双刃剑 4.抗体圈.FDA解除对宜联生物HER3 ADC的1期临床的Partial Hold 5.抗体圈.EGFR ADC：正在唱响中国之声 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。