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: 7243585
• 负责人: MANUEL L PENICHET
• 金额: $ 5.43万
• 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/7243585
• 关键词: Anti; TfR; IgG3; Av; New

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(申请人提供)：我们开发了一种抗体融合蛋白，由亲和素与转铁蛋白受体(TFR)特异性的人IgG3融合而成。我们最初的目标是使用这种分子(抗TFR IgG3-Av)作为通用载体，将生物素化的药物输送到癌细胞中。我们已经发现，抗TFR IgG3-Av通过受体介导的内吞作用将生物素分子有效地运送到癌细胞中，并且这些分子在内化后保持活性。此外，我们还意外地发现，抗TFR的IgG3-Av，而不是重组的抗TFR的IgG3或非特异性的IgG3-Av，对血液系统恶性肿瘤细胞具有很强的内在抗增殖/促凋亡活性。重要的是，这种细胞毒活性可以通过生物素化化合物的加入而进一步增强。我们现在假设，抗TFR IgG3-Av可以单独使用或与其他药物联合使用，作为一种治疗无法治愈的浆细胞恶性肿瘤：多发性骨髓瘤(MM)的新药。本研究旨在研究抗转铁蛋白受体抗体IgG3-Av对人多发性骨髓瘤细胞株增殖和凋亡的影响，并探讨其抑制增殖和诱导细胞凋亡的机制。我们还将研究相加/协同效应。 将抗TFR IgG3-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)，以及目前用于治疗多发性骨髓瘤的药物，如沙利度胺和地塞米松联合使用。基于我们的发现，我们将测试单独或与其他抗癌药物联合使用抗TFR IgG3-Av对多发性骨髓瘤患者的原始骨髓瘤细胞和在免疫缺陷小鼠中生长的人多发性骨髓瘤的疗效。因此，拟议的实验将导致更好地了解抗TFR IgG3-Av的作用机制，并将表明这种新的治疗方法是否有潜力用于MM的治疗。我们预计，这种治疗方法的用途将不仅限于体内消除骨髓瘤细胞，还可以用于体外方法，包括在体外扩增造血祖细胞用于MM患者自体移植时有效地清除骨髓瘤细胞。我们想强调的是，本研究结果的影响并不局限于MM。类似的方法也可以应用于其他血液系统恶性肿瘤，如白血病和淋巴瘤。