Ovarian cancer therapy using CD40 Ligand (CD40L)

晚期卵巢癌是一种困难的疾病，迫切需要新的治疗方法。cd 40配体 由于大多数卵巢癌细胞表达CD 40，因此CD 40 L是治疗这种疾病的候选者。 受体的CD 40 L刺激这种受体杀死癌细胞，但对正常细胞没有细胞毒性作用。 在体内，CD 40 L单药治疗显著抑制人卵巢癌异种移植物的生长， 免疫缺陷小鼠与顺铂联合，CD 40 L抑制肿瘤生长达99%。值得注意的是，CD 40 L是 也是免疫系统中的关键分子，并激活树突状细胞产生强大的抗肿瘤CD 8 + T细胞。 细胞反应。因此，用CD 40 L治疗卵巢癌提供了一种可能性：（1） 直接杀伤CD 40受体阳性卵巢癌细胞;和（2）刺激抗肿瘤CD 8+细胞毒性T细胞 细胞然而，CD 40 L进入临床的关键障碍是第一代CD 40 L的生产 CD 40 L被其唯一制造商放弃。多聚体生物治疗现在提出填补这一空白， 产生下一代的CD 40 L该创新是CD 40 L的高活性2-三聚体形式， 能够聚集CD 40受体，这是CD 40细胞信号传导的基本要求。这种2-三聚体蛋白是 通过将CD 40 L细胞外结构域与2臂支架蛋白（Acrp 30）基因融合， Acrp 30-CD 40 L融合蛋白（MegaCD 40 L-）。提出三个目的：（1）检测小鼠MegaCD 40 L-1的表达， 在ID 8小鼠卵巢癌模型中的抗肿瘤和免疫激活作用;（2）制备人 （3）为了测试在培养的人卵巢癌细胞上有活性的体内治疗性“MegaCD 40 L”， 人MegaCD 40 L-对小鼠中人卵巢癌异种移植物的作用。这些研究将提供 为后续II期SBIR项目奠定基础，以制备适用于临床的cGMP MegaCD 40 L 卵巢癌和其他癌症的研究。

Advanced ovarian cancer is a difficult condition for which new treatments are urgently needed. CD40 ligand (CD40L) is a candidate for the treatment of this disease because most ovarian cancer cells express the CD40 receptor. CD40L stimulation of this receptor kills the cancer cells, but has no cytotoxic effects on normal cells. In vivo, CD40L monotherapy markedly inhibited the growth of human ovarian cancer xenografts in immunodeficient mice. In combination with cisplatin, CD40L inhibited tumor growth by 99%. Of note, CD40L is also a key molecule in the immune system and activates dendritic cells to generate strong anti-tumor CD8+ T cell responses. Therefore, treating ovarian cancer with CD40L offers the possibility of a one-two punch: (1) Direct killing of CD40 receptor-positive ovarian cancer cells; and (2) Stimulation of anti-tumor CD8+ cytotoxic T cells. However, the crucial roadblock for moving CD40L into the clinic is that the production of 1st generation CD40L was dropped by its sole manufacturer. Multimeric Biotherapeutics now proposes to fill this void by producing a next-generation form of CD40L. The innovation is a highly active 2-trimer form of CD40L which is able to cluster the CD40 receptor, an essential requirement for CD40 cell signaling. This 2-trimer protein is made by genetically fusing the CD40L extracellular domain with a 2-armed scaffold protein (Acrp30) to make Acrp30-CD40L fusion protein (MegaCD40L"). Three Aims are proposed: (1) To test murine MegaCD40L" for its antitumor and immune activating effects in the ID8 mouse model of ovarian cancer; (2) To prepare human MegaCD40L" that is active on human ovarian cancer cells in culture; and (3) To test the in vivo therapeutic effects of human MegaCD40L" on human ovarian carcinoma xenografts in mice. These studies will provide the foundation for a follow-on Phase II SBIR project to prepare cGMP MegaCD40L" suitable for clinical studies of ovarian and other cancers.