Lifastuzumab vedotin

TUB-030 and TUB-040 demonstrate high and long-lasting anti-tumor efficacy in a range of preclinical models TUB-030 is directed against the tumor-associated antigen 5T4 which addresses a wide range of solid tumor indications; TUB-040 targets NaPi2b, a well-characterized target in ovarian and lung cancer Both candidates show a wide therapeutic window; first Phase 1 clinical evaluation to be initiated in 2024 MUNICH--(BUSINESS WIRE)-- Tubulis today presented comprehensive preclinical data on its two lead antibody-drug conjugate (ADC) candidates TUB-030 and TUB-040 at this year’s Annual Meeting of the American Association for Cancer Research (AACR) in San Diego. The poster presentations contained preclinical data, highlighting the ability of the two next-generation Tubutecan ADCs to create effective and durable responses even in low target-expressing tumor mouse models. Tubulis is leveraging a proprietary suite of platform technologies to build a pipeline of uniquely matched ADC candidates that combine the right targeting molecule, conjugation chemistry and payload to deliver the true therapeutic value of the ADC approach. The company’s lead candidates, both targeting solid tumor indications, are in late-stage preclinical testing, with TUB-040 ready for clinical evaluation. "These compelling preclinical data sets for both of our lead ADC candidates, TUB-030 and TUB-040, support how our proprietary platforms create ADCs with unique biophysical properties allowing for continued and durable on-tumor delivery of the payload. The in vivo studies have demonstrated that both candidates show strong, long-lasting anti-tumor activity, even at lower expression levels of the respective targets," said Jonas Helma-Smets, Chief Scientific Officer of Tubulis. "Our ADCs are highly differentiated compared to other ADCs on the market and we look forward to translating these findings into the clinic with the goal of improving overall survival and duration of response in patients across a broad range of solid tumors. Starting with TUB-040, we aim to initiate first clinical trials this year and thereby provide clinical proof-of-concept for our next-generation ADCs and our differentiated platform approach to ADC design." Both ADC candidates are comprised of a humanized, target-specific, Fc-silenced IgG1 antibody conjugated to the topoisomerase-1 inhibitor Exatecan with Tubulis’ Tubutecan linker-payload platform via the proprietary P5 conjugation platform, resulting in highly stable and homogenous drug-to-antibody-ratio of 8 (DAR8) ADCs. Compared to maleimide-conjugated ADCs, TUB-030 and TUB-040 both showed superior stability and minimal loss of linker-payload conjugation. Highlights of Tubulis’ preclinical data presented at AACR 2024: TUB-040 TUB-040 is built with novel Tubutecan linker-payload chemistry and superb biophysical properties, targeting Napi2b, a highly overexpressed antigen in ovarian cancer and lung adenocarcinoma The ADC candidate is highly stable and highly inert in circulation, enabling powerful and continued on-tumor delivery of the payload, leading to complete eradication of tumors with a low dose single treatment in multiple ovarian cancer mouse models Enabled by the differentiated Tubutecan linker-payload and strong bystander activity, TUB-040 showed significantly better durability of antitumor activity in preclinical models compared to lifastuzumab vedotin In ovarian cancer and non-small-cell lung cancer (NSCLC) patient derived xenograft mouse models, treatment with TUB-040 led to robust long-lasting tumor regressions Repeat-dose toxicology studies of TUB-040 in non-human primates demonstrated that TUB-040 was well tolerated with minor and reversible adverse effects TUB-030 TUB-030 is built with novel Tubutecan linker-payload chemistry and superb biophysical properties, targeting 5T4, a tumor-associated antigen expressed in a broad range of solid tumors The ADC candidate demonstrated target-specific cytotoxicity as well as strong bystander activity, facilitating the destruction of cells that do not express the target antigen but are in the direct vicinity of the targeted tumor cell, thereby broadening the effect of the ADC A single treatment with TUB-030 was shown to eliminate tumors in a triple negative breast cancer mouse model, whereas PF06263507, a clinically tested comparator ADC led to re-growth of tumors. In over 25 patient derived xenograft mouse models of various types of cancer, TUB-030 showed high efficacy rates even at low 5T4 expression levels and achieved long-lasting and durable anti-tumor activity TUB-030 was well tolerated in non-human primates and showed highly restricted binding to normal fresh frozen human tissues The full abstracts were published in an online-only proceedings supplement to the AACR journal, Cancer Research in March and can be accessed here. About Tubulis Tubulis generates uniquely matched protein-drug conjugates through the combination of novel proprietary technologies and disease-specific biologic insight. Our goal is to expand the therapeutic potential of antibody-drug conjugates (ADCs) by increasing design flexibility while overcoming constraints of toxicity, efficacy and indication. Tubulis will build new conjugates to fill its growing pipeline and will continue to collaborate with industry partners to usher in a new ADC era and deliver better outcomes for patients. Visit or follow us on LinkedIn.

关注并星标CPHI制药在线3月14日，Tubulis宣布成功完成一笔规模较大且超额认购的1.28亿欧元(1.388亿美元)B2轮融资。Tubulis正在开发新型的抗体药物偶联物(ADC)管线，具有适应症定制的靶向分子和有效载荷组合。       B2轮融资将主要支持Tubulis下一代ADC的临床评估进展，并帮助实现主要候选产品TUB-040和TUB-030的临床概念验证。       TUB-040靶向肿瘤抗原Napi2b，这是卵巢癌和肺癌的一个很好的靶点，而TUB-030靶向5T4，这是一种在实体瘤中经常过表达的抗原。这两种候选药物的临床前概念验证数据将在4月份的美国癌症研究协会(AACR)年会上公布。       该公司预计将于2024年开始其第一个1/2a期临床试验，包括剂量递增和剂量优化队列。这笔资金还将用于扩展Tubulis的技术平台套件，为开发多功能和可定制ADC新型载荷。随着新的美国投资者的加入，Tubulis计划通过建立一家美国子公司来扩大其企业足迹。       关于Napi2b       钠依赖性磷酸转运蛋白2B（SLC34A2、NaPi2b、NaPi-IIb和NPT2）是一种多通道的膜蛋白，是溶质载体SLC34家族的成员，该家族由NaPi-IIa（SLC34A1）、NaPi-IIb（SLC34A2）和NaPi-IIc（SLC34A3）构成。其中NaPi-IIb蛋白通过钠离子共转运介导无机磷酸盐进入上皮细胞，负责维持全身的磷酸盐平衡。NaPi-IIb包含两个保守序列的倒置重复单元，由一个大的细胞外环连接，两个末端都位于细胞膜内。       NaPi2b与多种疾病有关，包括SLC34A2基因突变引起的肺泡微石症，NaPi2b表达减少导致的炎症性肠病，以及几种类型的癌症（卵巢癌、肺癌、乳腺癌和甲状腺乳头状癌）。临床前和早期临床证据表明，NaPi2b在高级别浆液性上皮性卵巢癌、输卵管癌和原发性腹膜癌以及甲状腺癌、乳腺癌和非鳞状非小细胞肺癌中表达，在正常组织中表达有限。NaPi2b在肿瘤中高表达的第一个证据来自20世纪80年代和90年代的研究，该研究表明单克隆抗体MX35在卵巢肿瘤中具有高反应性，尽管当时抗原的身份尚不清楚。2008年，发现MX35抗体靶向的表位为NaPi2b，在90%的卵巢上皮性癌症细胞系中表现出反应性。随后的研究结果证实，NaPi2b及其SLC34A2基因在良性输卵管上皮和分化良好的浆液性、子宫内膜样癌以及在较小程度上的粘液性卵巢癌中高表达，但在正常卵巢上皮中不存在。因此，NaPi2b成为肿瘤治疗中非常有吸引力的靶点之一。       NaPi2b靶点与多种疾病有关       图片来源：参考来源3       被寄予厚望的首款Napi2b ADC最终折戟沉沙       Mersana Therapeutics是一家处于临床阶段的生物制药公司，利用其差异化和专有的ADC平台快速开发具有最 佳疗效，安全性和耐受性的新型ADC。此ADC平台具有细胞毒性和免疫刺激有效载荷，可以针对给定靶标和适应症定制和优化ADC，可克服第一代平台的局限性。       Mersana的主要候选产品upifitamab rilsodotin（UpRi）是全球首款针对NaPi2b的Dolaflexin ADC。UpRi曾在卵巢癌这一领域布局了多项研究，UPLIFT是一项针对铂类耐药卵巢癌患者的单臂注册试验。这项研究包括：UPGRADE-A，一项评估UpRi与卡铂联合使用的1/2期临床试验;和UP-NEXT，一项3期临床试验，评估在复发性铂类敏感性卵巢癌中使用铂双联药物治疗后，UpRi作为单一疗法维持治疗。2022年12月14日，欧盟委员会（EC）将upifitamab rilsodotin（UpRi）指定为治疗卵巢癌的孤儿药。       然而仅仅半年时间，UpRi就从万众期待到跌落谷底。2023年6月15日，Mersana宣布停止对两项临床试验UP-NEXT和UPGRADE-A的新患者招募，因为UpRi的临床中报告了5例5级严重（致死）不良事件。根据Mersana提交给FDA的UpRi安全性分析报告显示，接受UpRi治疗的铂耐药卵巢癌患者的严重出血事件发生率较高，并且观察到5例5级(致命)出血事件。市场对此消息反应颇为剧烈，Mersana股价当日大跌59%。       给予Mersana更致命一击的是来自UPLIFT顶线数据。2023年7月27日，UpRi治疗铂类耐药卵巢癌患者UPLIFT顶线数据公布，UpRi在全部患者群体中的ORR为13.1%，在NaPi2b阳性组中的ORR也仅为15.6%，未达到试验的主要终点。至此，这款计划将于去年年底申报上市的ADC药物，失败的非常彻底。       得一提的是，Mersana在引进Synaffix的定点偶联GlycoConnect 技术后，在Dolasynthen平台的基础上还开发了一款NaPi2b的ADC —XMT1592。XMT-1592曾开展过一项1/2期临床试验，旨在确定XMT-1592 在高级别浆液性卵巢癌和非小细胞肺癌的最大耐受剂量 （MTD） 或推荐的 2期剂量 （RP1592D）。遗憾的是，如今XMT-1592在Mersana管线中也已经消失。       NaPi2b ADC何时迎来曙光？       其实NaPi2b最早始于罗氏的开发。Lifastuzumab vedotin是一款由基因泰克研发的Napi2b ADC，有效荷载为MMAE，2018年基因泰克公布的Lifastuzumab vedotin用于治疗铂类耐药卵巢癌中的2期随机试验结果表明，ORR有提高，LIFA组vs pegylated liposomal doxorubicin（PLD）组为34% vs 15%（p=0.03）或36% vs 14%（p=0.02, Napi2b高表达），但mPFS变化不显著，即使在Napi2b高表达人群中，也只达到5.3 vs 3.4 month。查询Lifastuzumab vedotin相关临床试验发现，已有的三项临床试验均在2017年完成或终止，基因泰克似乎是已经搁置了这款药物的开发。       罗氏的搁置和Mersana的折戟给NaPi2b ADC前景蒙上了一层阴霾，但依然有一些“孤勇者”闯入此领域。除了此次融资成功Tubulis 的TUB-040外，还有两款处于临床前阶段的NaPi2b ADC Zymeworks的ZW220和宜联生物的YL205值得持续关注和期待。       ZW220ZW220是Zymeworks基于其TOPO1i ADC技术平台构建的靶向NaPi2b ADC，由人源化IgG1抗体与新型喜树碱拓扑异构酶I抑制剂ZD06519偶联，linker由马来酰亚胺-GGFG-AM组成。Zymeworks在2023年AACR上展示了在临床前研究中ZW220的作用机制和治疗潜力。       YL205根据不久前公布的2024 AACR摘要标题，宜联生物两款药物入选，其中一款名为“Preclinical development of YL205, a noval NaPi2b-targeting antibody-drug conjugate (ADC) with novel topoisomerase Ⅰinhibitor-based linker-payload for treatment of solid tumors”，显示YL205为靶向NaPi2b。YL205出自宜联自主开发的ADC平台TMALIN，酶可裂解4肽拓扑异构酶抑制剂，定点偶联DAR 8，对不同表达丰度的小鼠卵巢癌、NSCLC肿瘤模型均显示了抗肿瘤作用。今年3月14，CDE宜联生物向CDE递交了YL205的临床试验申请。       参考来源       1.企业官网       2.Fenollar-Ferrer, Cristina, and Lucy R Forrest. “Structural models of the NaPi-II sodium-phosphate cotransporters.” Pflugers Archiv : European journal of physiology vol. 471,1 (2019): 43-52. doi:10.1007/s00424-018-2197-x       3. Banerjee, Susana et al. “Targeting NaPi2b in ovarian cancer.” Cancer treatment reviews vol. 112 (2023): 102489. doi:10.1016/j.ctrv.2022.102489【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~