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：
7533462
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 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7533462
关键词：
Address Antibodies Antineoplastic Agents Apoptosis Apoptotic Autologous Transplantation Avidin Caspase Cell Line Cell Proliferation Cells Chimeric Proteins Cisplatin Dexamethasone Drug Combinations Exhibits Genes Goals Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human IgG3 Immunodeficient Mouse In Vitro Induction of Apoptosis Malignant - descriptor Malignant Neoplasms Modeling Molecular Profiling Multiple Myeloma Patients Pharmaceutical Preparations Plasma Cell Neoplasm Plasma Cells Proteins Pseudomonas aeruginosa toxA protein Recombinants SCID Mice Signal Pathway Stress Surface System Thalidomide Therapeutic Time Study Transferrin Receptor base cancer cell cytotoxic efficacy testing 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，该抗体融合蛋白是由抗铁蛋白受体（TFR）融合到人IgG3的抗原蛋白。我们的最初目标是将该分子（抗TFR IgG3-AV）用作通用载体，以将生物素化剂传递到癌细胞中。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的分子传递到癌细胞中，并且这些分子在内在后保持活跃。此外，我们出乎意料地发现，抗TFR IgG3-AV，但不具有重组抗TFR IgG3或非特异性IgG3-AV，它具有针对造血恶性细胞系的强内固有抗增殖/促凋亡活性。重要的是，通过添加生物素化合物可以进一步增强这种细胞毒性活性。现在，我们假设可以单独使用抗TFR IgG3-AV，也可以与其他药物结合使用，作为一种针对无法治愈的血浆细胞恶性肿瘤的新药物：多发性骨髓瘤（MM）。我们建议确定抗TFR IgG3-AV对选定人MM细胞系的增殖和凋亡的影响，并定义负责抑制增殖和诱导凋亡的机制。我们还将检查添加/协同效应将抗TFR IgG3-AV与其他细胞毒性/敏化剂（例如生物素化的假单胞菌Exotoxin A（PE）A（PE）以及当前用于治疗MM的药物（例如Thalidomamide和Texametherasone）治疗的药物。根据我们的发现，我们将单独测试抗TFR IgG3-AV的疗效，或与其他抗癌药物对从MM患者获得的原发性骨髓瘤细胞和免疫缺陷小鼠中生长的人类MM肿瘤相结合。因此，提出的实验将使人们更好地了解抗TFR IgG3-AV的作用机理，并表明这种新型的治疗性是否具有用于治疗MM的潜力。我们预计，这种治疗性的实用性将不仅限于消除体内骨髓瘤细胞，但也可以用于体外方法，包括在体内在体内扩展造血祖细胞时有效清除骨髓瘤细胞，用于在MM患者中用于自体移植。我们想强调，从本研究获得的结果的影响不限于MM。类似的方法可以应用于其他造血恶性肿瘤，例如白血病和淋巴瘤。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma.

DOI：
10.1615/forumimmundisther.v2.i2.90
发表时间：
2011-04-01
期刊：
Forum on immunopathological diseases and therapeutics
影响因子：
0
作者：
Baritaki S;Huerta-Yepez S;Cabrava-Haimandez MD;Sensi M;Canevari S;Libra M;Penichet M;Chen H;Berenson JR;Bonavida B
通讯作者：
Bonavida B

Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells.

DOI：
10.1007/s00262-008-0607-1
发表时间：
2009-06
期刊：
CANCER IMMUNOLOGY IMMUNOTHERAPY
影响因子：
5.8
作者：
Karagiannis, Panagiotis;Singer, Josef;Hunt, James;Gan, Samuel K. E.;Rudman, Sarah M.;Mechtcheriakova, Diana;Knittelfelder, Regina;Daniels, Tracy R.;Hobson, Philip S.;Beavil, Andrew J.;Spicer, James;Nestle, Frank O.;Penichet, Manuel L.;Gould, Hannah J.;Jensen-Jarolim, Erika;Karagiannis, Sophia N.
通讯作者：
Karagiannis, Sophia N.

Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.