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君实生物与杭州多禧签署药品开发合同进一步丰富药物研发管线

2019-12-05 来源:
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12月3日,君实生物发布公告称,其与杭州多禧生物科技有限公司签署了《药品开发及许可合同》。

根据协议约定,君实生物通过独占许可授权方式从杭州多禧生物获得许可使用 DAC-002(注射用重组人源化抗 Trop2 单抗-Tub196 偶联剂),在授权许可区域(除日本、韩国以外的全部亚洲国家及区域)内负责 DAC-002 后续的临床试验、药品注册、商业化生产、销售及其他商业活动。根据该协议, 杭州多禧将获得3000万元人民币的首付款和226.8万元人民币的样品制备费用, 从 DAC-002 在许可区域内获批临床至获批上市,君实生物将按研发进展向杭州多禧支付累计不超过 2.7 亿元人民币的研发及上市里程碑款,并在 DAC-002 实现商业化销售后向杭州多禧支付年销售收入 6%-10%的收益分成。

DAC-002是抗Trop2单抗通过智能连结体偶联抗微管蛋白Tubulysin B类似物的药物,主要用于治疗Trop2阳性三阴性乳腺癌、小细胞肺癌、胰腺癌等实体肿瘤,目前已向国家药品监督管理局申报临床试验并获受理。

协议代价:杭州多禧将获得3,000万元人民币首付款和226.8万元人民币样品制备费用;临床试验期间,君实生物(1877.HK)将支付累计不超过2.7亿元人民币的研发及上市里程碑款,并于产品获批上市后向杭州多禧支付年销售收入6%至10%的收益分成。

ADC(Antibody-drugconjugate,抗体药物偶联物)通常由重组单克隆抗体(mAb)通过合成接头共价结合细胞毒性化学物质组成,使ADC产品同时具备细胞毒性小分子药物的抗肿瘤效力及mAb的高选择性、稳定性和有利的药代动力学特征。

Trop2的功能:DAC-002中单抗部分的靶点为Trop2(Trophoblastcell-surfaceantigen2,滋养层细胞表面抗原2)。Trop2是一种跨膜蛋白,主要通过调节钙离子信号通路、细胞周期蛋白表达及降低纤黏蛋白黏附作用促进肿瘤细胞生长、增殖和转移,也可以与β-连环蛋白相互作用,对细胞核癌基因的转录和细胞的增殖起作用。

Trop2与肿瘤的关系:研究表明,正常情况下,Trop2在正常组织中的表达量很低,其细胞外结构域在多种肿瘤特别是绝大部分恶性上皮瘤形成中高度表达(占病例的64%至90%),使Trop2成为靶向治疗的优势候选。据百奥泰生物披露,Trop2在约80%至90%的三阴乳腺癌(TNBC)、50%的胃癌(GC)、50%以上的非小细胞肺癌。

 

 

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