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

描述（由申请人提供）：我们开发了一种抗体融合蛋白，由亲和素与人类转铁蛋白受体（TfR）特异性IgG3融合而成。我们最初的目标是使用这种分子（抗tfr IgG3-Av）作为一种通用载体，将生物素化的药物输送到癌细胞中。我们发现抗tfr IgG3-Av通过受体介导的内吞作用有效地将生物素化分子传递到癌细胞中，并且这些分子在内化后仍保持活性。此外，我们意外地发现抗tfr IgG3- av，而不是重组抗tfr IgG3或非特异性IgG3- av，对造血恶性细胞系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添加生物素化化合物进一步增强。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。我们拟确定抗tfr IgG3-Av对人MM细胞系增殖和凋亡的影响，并确定其抑制增殖和诱导凋亡的机制。我们还将研究加性/协同效应

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.