Novel multivalent/multifunctional agents derived from a humanized anti-insulin-li

源自人源化抗胰岛素-li的新型多价/多功能制剂

基本信息

批准号：
7926237
负责人：
THOMAS M CARDILLO
金额：
$ 19.27万
依托单位：
IMMUNOMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7926237
关键词：
A kinase anchoring protein Antibodies Award BAY 54-9085 Binding Biodistribution Businesses Cell Line Cells Clear Cell Clinical Cyclic AMP-Dependent Protein Kinases Development Dimerization Disease Docking Drug Kinetics Fab Immunoglobulins Funding Generations Goals Immunoglobulin G Immunoglobulins In Vitro Insulin Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Interferon Alfa-2a Ligands Link Malignant Epithelial Cell Measures Metastatic Renal Cell Cancer Modification Monoclonal Antibodies Mus Outcome Papillary Patients Proteins Radiation therapy Reagent Receptor Signaling Recovery Renal Cell Carcinoma Renal carcinoma Renal pelvis Research Resistance Signal Pathway Site Technology Tertiary Protein Structure Testing Therapeutic Time Translating Treatment Efficacy Treatment Protocols Tyrosine Kinase Inhibitor United States Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Woman Work Xenograft procedure analog autocrine bevacizumab cancer type catalyst chemotherapy cytokine therapy cytotoxic dimer experience improved in vivo inhibitor/antagonist innovation killings mTOR protein men novel novel therapeutics outcome forecast paracrine programs protein kinase A kinase public health relevance receptor research study tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Cancer of the kidney and renal pelvis killed approximately 13,010 men and women in the United States last year. One of the most challenging forms of this type of cancer is metastatic renal cell carcinoma (RCC). It has resisted attempts of curative radiotherapy and chemotherapy. Current treatment regimens include cytokine therapy with IFN-a2b and PTK targeted therapies with anti-vascular endothelial growth factor (VEGF) receptor antibodies or mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus. These new treatments have had only modest effects on patient outcomes when used alone or in combination. Another target that has emerged is the insulin-like growth factor-I receptor (IGF-IR). It is expressed on a wide range of RCC types and its expression has been linked to a positive association for poor patient survival. In addition, anti-IGF-IR antibodies have been shown to have an additive effect when used in conjunction with mTOR inhibitors due to their ability to inhibit the Akt-signaling pathway in RCC cells. We have a humanized anti-IGF-IR antibody, hR1 that has undergone modification to allow us to attach either four hR1 Fabs or four IFN-a2b molecules to it. These new molecules are being developed as a new generation of agents specific for treating renal cell carcinomas by multivalent antibodies and immunocytokines. This was done via our dock-and-lock (DNL) platform technology in which the dimerization and docking domains (DDD) and anchoring domains (AD) involved with the natural association of the cAMP-dependent protein kinase and the A-kinase anchoring proteins are used to link the various components to hR1. The resulting hexavalent hR1 reagent (Hex-hR1) will be composed of hR1 IgG linked to four hR1 Fabs. Additionally, we can generate a bivalent hR1 IgG reagent with four IFN-a2b molecules attached to the Fc-portion of the IgG molecule (1R-2b). Using Hex-hR1 and 1R- 2b agents in combination with an mTOR inhibitor (temsirolimus) we will take advantage of the additive effect seen when mTOR inhibitors are combined with an anti-IGF-IR antibody. Past experience with a hexavalent anti-CD20 agent (Hex-hA20) and an anti-CD20-IFN-a2b agent (20-2b) demonstrated superiority in comparison to either the parental antibody or a non-targeting IFN-a2b agent. We expect that Hex-hR1 will likewise be superior to hR1 when combined with chemotherapy and that targeting IFN-a2b to RCC will also result in significantly improved efficacy over that of a non-targeting IFN-a2b agent. We will test these interactions in vitro against a panel of RCC cell lines studying possible synergy or additive effects. Additionally, mice bearing s.c. RCC tumors will undergo efficacy experiments to determine if the effects seen in vitro translate to the in vivo setting. PUBLIC HEALTH RELEVANCE: Two new molecules are being developed as a new generation of agents specific for treating metastatic renal cell carcinomas by multivalent antibodies and immunocytokines. This was done via our dock-and-lock (DNL) platform technology in which the dimerization and docking domains (DDD) and anchoring domains (AD) involved with the natural association of the cAMP-dependent protein kinase and the Akinase anchoring proteins are used to link the various components to an anti-IGF-IR monoclonal antibody.

描述（由申请人提供）：去年，美国约有 13,010 名男性和女性死于肾癌和肾盂癌。此类癌症中最具挑战性的形式之一是转移性肾细胞癌（RCC）。它抵制了治疗性放疗和化疗的尝试。目前的治疗方案包括使用 IFN-a2b 的细胞因子治疗和使用抗血管内皮生长因子 (VEGF) 受体抗体或哺乳动物雷帕霉素靶点 (mTOR) 抑制剂（例如替西罗莫司）的 PTK 靶向治疗。这些新疗法单独或联合使用时对患者的治疗效果只有轻微的影响。另一个出现的靶点是胰岛素样生长因子-I 受体 (IGF-IR)。它在多种 RCC 类型中表达，并且其表达与患者生存率差呈正相关。此外，抗 IGF-IR 抗体与 mTOR 抑制剂联合使用时已被证明具有相加效应，因为它们能够抑制 RCC 细胞中的 Akt 信号通路。我们有一种人源化抗 IGF-IR 抗体 hR1，它经过修饰，使我们能够在其上附着四个 hR1 Fab 或四个 IFN-a2b 分子。这些新分子正在开发为新一代通过多价抗体和免疫细胞因子特异性治疗肾细胞癌的药物。这是通过我们的对接锁定 (DNL) 平台技术完成的，其中二聚化和对接结构域 (DDD) 和锚定结构域 (AD) 涉及 cAMP 依赖性蛋白激酶和 A 激酶锚定蛋白的自然关联用于将各种组件连接至 hR1。由此产生的六价 hR1 试剂 (Hex-hR1) 将由连接到四个 hR1 Fab 的 hR1 IgG 组成。此外，我们可以生成二价 hR1 IgG 试剂，其中四个 IFN-a2b 分子连接到 IgG 分子的 Fc 部分 (1R-2b)。将 Hex-hR1 和 1R-2b 药物与 mTOR 抑制剂（替西罗莫司）组合使用，我们将利用 mTOR 抑制剂与抗 IGF-IR 抗体组合时所见的相加效应。过去使用六价抗CD20剂(Hex-hA20)和抗CD20-IFN-a2b剂(20-2b)的经验证明与亲本抗体或非靶向IFN-a2b剂相比具有优越性。我们预计，当与化疗联合使用时，Hex-hR1 同样优于 hR1，并且针对 RCC 的靶向 IFN-a2b 也将比非靶向 IFN-a2b 药物的疗效显着提高。我们将在体外针对一组 RCC 细胞系测试这些相互作用，研究可能的协同作用或相加效应。此外，小鼠承担 s.c. RCC 肿瘤将进行功效实验，以确定体外观察到的效果是否会转化为体内环境。公共健康相关性：两种新分子正在开发中，作为新一代药物，通过多价抗体和免疫细胞因子特异性治疗转移性肾细胞癌。这是通过我们的对接锁 (DNL) 平台技术完成的，其中使用了涉及 cAMP 依赖性蛋白激酶和激酶锚定蛋白自然关联的二聚化和对接结构域 (DDD) 和锚定结构域 (AD)将各种成分与抗 IGF-IR 单克隆抗体连接起来。