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

我们开发了一种抗体融合蛋白，由亲和素与人类 IgG3 融合而成，特异性针对 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）作为通用药物 将生物素化药物递送到癌细胞中的载体。我们发现抗TfR IgG3-Av有效 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 内化后保持活跃。此外，我们意外地发现抗TfR IgG3- Av，但不是重组抗 TfR IgG3 或非特异性 IgG3-Av，拥有强大的内在抗-TfR IgG3 或非特异性 IgG3-Av。 针对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 可单独使用或与其他药物联合使用，作为针对不治之症的新药 浆细胞恶性肿瘤：多发性骨髓瘤（MM）。我们建议确定抗 TfR IgG3-Av 对 选定的人类 MM 细胞系的增殖和凋亡，并确定其机制 抑制增殖并诱导细胞凋亡。我们还将研究相加/协同效应 抗 TfR IgG3-Av 与其他细胞毒性/敏化剂（例如生物素化假单胞菌）组合 外毒素 A (PE) 和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。 根据我们的研究结果，我们将测试单独使用抗 TfR IgG3-Av 或与其他抗癌药物联合使用的功效 针对从 MM 患者获得的原发性骨髓瘤细胞和针对生长在 MM 中的人类 MM 肿瘤的药物 免疫缺陷小鼠。因此，所提出的实验将有助于更好地理解该机制 抗 TfR IgG3-Av 的作用，并将表明这种新型疗法是否有用于治疗的潜力 MM的。我们预计这种疗法的用途将不仅限于消除骨髓瘤 体内细胞，但也可用于体外方法，包括有效清除骨髓瘤细胞 造血祖细胞的离体扩增用于多发性骨髓瘤自体移植 患者。我们想强调的是，目前研究结果的影响并不 仅限MM。类似的方法可以应用于其他造血系统恶性肿瘤，例如白血病 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.