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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

基本信息

批准号：
7321093
负责人：
MANUEL L PENICHET
金额：
$ 30.03万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/7321093
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

项目摘要

DESCRIPTION (provided by applicant): 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 antiproliferative/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.

描述（由申请人提供）：我们开发了一种抗体融合蛋白，其由与转铁蛋白受体（TfR）特异性的人IgG 3融合的抗生物素蛋白组成。我们最初的目标是使用这种分子（抗TfR IgG 3-Av）作为通用载体，将生物素化药物递送到癌细胞中。我们已经发现，抗TfR IgG 3-Av通过受体介导的内吞作用有效地将生物素化分子递送到癌细胞中，并且这些分子在其内化后保持活性。此外，我们意外地发现抗TfR IgG 3-Av，而不是重组抗TfR IgG 3或非特异性IgG 3-Av，对造血恶性细胞系具有强的内在抗增殖/促凋亡活性。重要的是，这种细胞毒性活性可以通过添加生物素化的化合物进一步增强。我们现在假设抗TfR IgG 3-Av可以单独使用或与其他药物联合使用，作为一种新型药物，用于治疗无法治愈的浆细胞恶性肿瘤：多发性骨髓瘤（MM）。我们建议确定抗TfR IgG 3-Av对选定的人MM细胞系增殖和凋亡的影响，并确定抑制增殖和诱导凋亡的机制。我们还将研究添加剂/协同效应将抗TfR IgG 3-Av与其他细胞毒性/致敏剂，如生物素化的假单胞菌外毒素A（PE）和目前用于治疗MM的药物（如沙利度胺和地塞米松）组合。基于我们的研究结果，我们将测试抗TfR IgG 3-Av单独或与其他抗癌药物组合对从MM患者获得的原发性骨髓瘤细胞和对在免疫缺陷小鼠中生长的人MM肿瘤的功效。因此，在本发明中，所提出的实验将导致更好地理解抗-TfR IgG 3的作用机制，Av和将表明，如果这种新的治疗有潜力用于治疗MM。我们预计，这种治疗的效用将不仅限于消除骨髓瘤细胞在体内，但也可以用于体外方法，包括有效清除骨髓瘤细胞在离体用于MM患者自体移植的造血祖细胞扩增。我们想强调的是，从目前的研究中获得的结果的影响并不限于MM。类似的方法可以应用于其他造血系统恶性肿瘤，如白血病和淋巴瘤。