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

我们已经开发了一种抗体融合蛋白，由亲和素与特异于 转铁蛋白受体（TfR）。我们最初的目标是使用这种分子（抗TfR IgG 3-Av）作为通用的免疫调节剂。 载体将生物素化试剂递送到癌细胞中。我们已经发现抗TfR IgG 3-Av有效地 通过受体介导的内吞作用将生物素化分子递送到癌细胞中，并且这些分子 在内化后保持活跃。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，具有强的内在抗TfR抗体。 抗造血恶性细胞系的增殖/促凋亡活性。重要的是，这种细胞毒性 通过加入生物素化的化合物可以进一步增强活性。我们现在假设反- TfR IgG 3-Av可单独使用或与其他药物联合使用，作为一种新的药物， 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 选择的人MM细胞系的增殖和凋亡，并确定负责 抑制增殖和诱导凋亡。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。 基于我们的发现，我们将测试抗TfR IgG 3-Av单独或与其他抗癌药物组合的功效。 针对从MM患者中获得的原发性骨髓瘤细胞和在骨髓瘤中生长的人MM肿瘤的药物 免疫缺陷小鼠因此，建议的实验将导致更好地理解的机制 抗TfR IgG 3-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，这种治疗的效用将不仅限于消除骨髓瘤 但也可用于体外方法，包括有效清除骨髓瘤细胞 在MM中用于自体移植的造血祖细胞的离体扩增期间 患者我们想强调的是，从目前的研究中获得的结果的影响并不是 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。

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.