Anti-TfR IgG3-Av: A New Drug Against Multiple Myeloma

抗 TfR IgG3-Av：一种抗多发性骨髓瘤的新药

• 批准号: 7615306
• 负责人: MANUEL L PENICHET
• 金额: $ 8.62万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-20 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615306
• 关键词: Address; Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Autologous Transplantation; Avidin; Caspase; Cell Line; Cell Proliferation; Cells; Chimeric Proteins; Cisplatin; Dexamethasone/Thalidomide; Drug Combinations; Exhibits; Exotoxins; Genes; Goals; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; IgG3; Immunodeficient Mouse; In Vitro; Induction of Apoptosis; Localized; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular Profiling; Multiple Myeloma; Patients; Pharmaceutical Preparations; Plasma Cell Neoplasm; Plasma Cells; Plasmacytoma; Proteins; Pseudomonas; Pseudomonas aeruginosa toxA protein; Recombinants; SCID Mice; Signal Pathway; Stem cells; Stress; Surface; System; Testing; Therapeutic; Time Study; Transferrin Receptor; base; cancer cell; cytotoxic; ex vivo expansion of hematopoietic progenitors; in vivo; leukemia/lymphoma; novel; novel therapeutics; preclinical study; purge; receptor expression; receptor mediated endocytosis; research study; subcutaneous; tumor; vector

We have developed an antibody fusion protein composed of avidin fused to a human IgG3 specific for the transferrin receptor (TfR). Our initial goal was to use this molecule (anti-TfR IgG3-Av) as a universal vector to deliver biotinylated agents into cancer cells. We have found that anti-TfR IgG3-Av effectively delivers biotinylated molecules into cancer cells by receptor mediated endocytosis and that these molecules remain active after their internalization. Furthermore, we have unexpectedly discovered that anti-TfR IgG3- Av, but not a recombinant anti-TfR IgG3 or a non-specific IgG3-Av, possesses a strong intrinsic anti- proliferative/pro-apoptotic activity against hematopoietic malignant cell lines. Importantly, this cytotoxic activity may be further enhanced by the addition of biotinylated compounds. We now hypothesize that anti- TfR IgG3-Av can be used alone or in combination with other agents as a novel drug against an incurable plasma cell malignancy: multiple myeloma (MM). We propose to determine the effect of anti-TfR IgG3-Av on both proliferation and apoptosis of selected human MM cell lines and to define the mechanism responsible for the inhibition of proliferation and induction of apoptosis. We will also examine the additive/synergistic effect of combining anti-TfR IgG3-Av with other cytotoxic/sensitizing agents, such as biotinylated Pseudomonas exotoxin A (PE) and drugs currently used in the treatment of MM such as Thalidomide and Dexamethasone. Based on our findings we will test the efficacy of anti-TfR IgG3-Av alone or combined with other anti-cancer drugs against primary myeloma cells obtained from MM patients and against human MM tumors growing in immunodeficient mice. Thus, the proposed experiments will result in a better understanding of the mechanism of action of anti-TfR IgG3-Av and will indicate if this novel therapeutic has potential for use in the treatment of MM. We anticipate that the utility of this therapeutic will not be restricted to the elimination of myeloma cells in vivo but can also be used for in vitro approaches including the efficient purging of myeloma cells during ex vivo expansion of hematopoietic progenitor-cells for use in autologous transplantation in MM patients. We would like to stress that the impact of the results obtained from the present studies is not restricted to MM. Similar approaches can be applied to other hematopoietic malignancies such as leukemias and lymphomas.

我们已经开发出一种抗体融合蛋白，它由亲和素与人免疫球蛋白3融合而成 转铁蛋白受体(TFR)。我们最初的目标是使用这种分子(抗TFR IgG3-Av)作为通用的 将生物素化试剂运送到癌细胞的载体。我们发现抗TFR IgG3-Av能有效地 通过受体介导的内吞作用将生物素分子输送到癌细胞中，这些分子 在他们内化后保持活跃。此外，我们还意外地发现，抗TFR IgG3- Av，而不是重组的抗TFR IgG3或非特异性的IgG3-Av，具有很强的内在抗原性 抗恶性血液病细胞系的增殖/促凋亡活性。重要的是，这种细胞毒性 添加生物素化化合物可以进一步增强活性。我们现在假设反- TFR-IgG3-Av可单独或与其他药物联合使用，作为治疗不治之症的新药。 浆细胞恶性肿瘤：多发性骨髓瘤。我们建议确定抗TFR IgG3-Av对血管内皮细胞生长的影响。 人多发性骨髓瘤细胞系的增殖和凋亡及其作用机制的研究 抑制细胞增殖和诱导细胞凋亡。我们还将研究相加/协同效应。 将抗转铁蛋白受体IgG3-Av与其他细胞毒性/致敏剂结合，如生物素化假单胞菌 外毒素A(PE)和目前用于治疗MM的药物，如沙利度胺和地塞米松。 根据我们的发现，我们将测试抗TFR IgG3-Av单独或与其他抗癌药物联合使用的效果 抗多发性骨髓瘤原代细胞和人多发性骨髓瘤生长的药物 免疫缺陷小鼠。因此，拟议的实验将使我们更好地理解这种机制。 抗TFR IgG3-Av的作用，并将表明这种新的治疗方法是否有潜力用于治疗 我们预计这种疗法的用途不会局限于消除骨髓瘤。 细胞在体内，但也可以用于体外方法，包括有效地清除骨髓瘤细胞 骨髓瘤自体移植中造血祖细胞的体外扩增 病人。我们要强调的是，目前研究结果的影响并不是 仅限于MM。类似的方法也适用于其他血液系统恶性肿瘤，如白血病。 和淋巴瘤。