Semi-targeted Immuno-Therapeutic Approach for Treatment of Obesity

治疗肥胖症的半靶向免疫治疗方法

• 批准号: 8521855
• 负责人: Richard August Shimkets
• 金额: $ 27.59万
• 依托单位: ABEOME CORPORATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521855
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Affinity; Animal Model; Antibodies; Antigen Targeting; Antigens; Apoptosis; Burn injury; CNR1 gene; Cell Death; Cell Volumes; Cell membrane; Cell surface; Cells; Chickens; Coupled; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Diagnostic; Diagnostic Reagent; Diagnostics Research; Disease; Drug Combinations; Drug Delivery Systems; Energy Intake; Epithelial; Europe; Family suidae; Fatty acid glycerol esters; Goals; Health; Heart; Human; Hybridomas; Immune; Immunization; Immunofluorescence Microscopy; Immunotherapeutic agent; Immunotherapy; Individual; Integral Membrane Protein; Label; Legal patent; Libraries; Lipids; Mesenchymal Stem Cells; Methods; Modification; Molecular Conformation; Molecular Medicine; Monoclonal Antibodies; Morbid Obesity; Mus; Non obese; Obesity; Outcome; Ovarian; Pharmaceutical Preparations; Phase; Physical activity; Pluripotent Stem Cells; Population; Prevention; Property; Protocols documentation; Rattus; Reagent; Regimen; Research; Scientist; Sorting - Cell Movement; Surface; Technology; Testing; Therapeutic; Tissues; Visceral; Work; alternative treatment; base; cancer cell; cancer type; cell type; human monoclonal antibodies; human stem cells; human tissue; immunogenic; in vitro testing; in vivo; lipid biosynthesis; obesity treatment; public health relevance; research clinical testing; subcutaneous; therapeutic development; therapeutic target; transdifferentiation

DESCRIPTION (provided by applicant): Obesity is considered the number one health problem in the US and Europe, affecting 10% to 30% of adult populations. Obese individuals are more likely to acquire a variety of secondary diseases including diabetes, heart problems, immune deficiencies, some types of cancer, and osteoarthritis and they die younger than non-obese individuals. Obesity results from the development of too many fat cells (adipocytes) and the enlargement of existing fat cells throughout the body. Reducing caloric intake and increasing physical activity are often not sustainable and there are few safe alternative treatments. There are no treatments that take advantage of modern molecular medicine's advances in immunotherapy. Therapeutic applications of monoclonal antibodies (mAbs) offer a way to target treatments to specific tissues. However, despite substantial work showing that mAbs to adipocyte plasma membrane antigens (PMAs) may be used to suppress fat development in animal models, there are currently no mAbs for either therapeutic or diagnostic applications in human obesity. Thus, the immediate goal for this Phase I project is to use Abeome's rapid and efficient DiSH" (Direct Selection of Hybridomas) technology to isolate a battery of mAbs specific for PMAs on the surface of human visceral preadipocytes and adipocytes. Our long-term goal is to develop immuno-therapeutics that offer a variety of adipocyte- targeted outcomes, such as stimulating transdifferentiation of white adipocytes to brown adipocytes, inhibiting adipogenesis, or inducing apoptosis. Our Phase I Specific Aims are as follows. #1. Immunize 20 mice with human visceral preadipocytes and identify 10 mice with the best antibody titers to PMAs of human visceral preadipocytes and adipocytes. #2. Isolate at least one hundred hybridomas making antibodies to human visceral preadipocytes and adipocytes using Abeome's DiSH-PMA protocol. #3. Using whole cell ELISAs and immunofluorescence microscopy (IFM) identify 20 mAb reagents that react with surface PMAs on human visceral preadipocytes and adipocytes but not with human adipocyte derived stem cells (ADSC), human mesenchymal stem cells (hMSC), human subcutaneous preadipocytes or adipocytes, or control cells from other human tissues. Abeome and its academic collaborators plan to submit a Phase II proposal to further develop adipocyte- specific mAbs as therapeutic, diagnostic and research agents. We will identify specific human mAbs that can be stably coupled to drug delivery agents and tested in vitro. The most appropriate drug delivery method will be tested in vivo to deliver a compound that stimulates transdifferentiation of white adipocytes to brown-like adipocytes or a compound that specifically inhibits adipogenesis or that induces apoptosis. Antibody targeted drug delivery will then be tested in appropriate animal models. The data generated in these studies will serve as the basis for clinical evaluation of this immuno-therapeutic approach to treating obesity.

描述（由申请人提供）：肥胖被认为是美国和欧洲的第一大健康问题，影响着 10% 至 30% 的成年人口。肥胖者更有可能患上各种继发性疾病，包括糖尿病、心脏病、免疫缺陷、某些类型的癌症和骨关节炎，而且他们比非肥胖者更早去世。肥胖是由于体内脂肪细胞（脂肪细胞）过多以及现有脂肪细胞增大所致。减少热量摄入和增加体力活动通常是不可持续的，而且几乎没有安全的替代疗法。没有任何治疗方法可以利用现代分子医学在免疫疗法方面的进步。 单克隆抗体 (mAb) 的治疗应用提供了一种针对特定组织进行靶向治疗的方法。然而，尽管大量工作表明针对脂肪细胞质膜抗原（PMA）的单克隆抗体可用于抑制动物模型中的脂肪发育，但目前尚无可用于人类肥胖症治疗或诊断应用的单克隆抗体。因此，该一期项目的近期目标是利用 Abeome 快速高效的 DiSH”（杂交瘤直接选择）技术，在人内脏前脂肪细胞和脂肪细胞表面分离出一系列针对 PMA 的单克隆抗体。我们的长期目标是开发能够提供多种针对脂肪细胞的结果的免疫治疗药物，例如刺激白色脂肪细胞的转分化。 脂肪细胞变成棕色脂肪细胞，抑制脂肪生成，或诱导细胞凋亡。 我们第一阶段的具体目标如下。 #1.用人内脏前脂肪细胞免疫20只小鼠，并鉴定10只对人内脏前脂肪细胞和脂肪细胞的PMA抗体效价最佳的小鼠。 #2.分离至少一百个杂交瘤 使用 Abeome 的 DiSH-PMA 方案制备针对人内脏前脂肪细胞和脂肪细胞的抗体。 ＃3。使用全细胞 ELISA 和免疫荧光显微镜 (IFM) 鉴定出 20 种 mAb 试剂可与人内脏前脂肪细胞和脂肪细胞上的表面 PMA 发生反应，但不与人脂肪细胞衍生干细胞 (ADSC)、人间充质干细胞发生反应 (hMSC)，人皮下前脂肪细胞或脂肪细胞，或来自其他人体组织的对照细胞。 Abeome 及其学术合作者计划提交一项 II 期提案，以进一步开发脂肪细胞特异性单克隆抗体作为治疗、诊断和研究药物。我们将鉴定可以与药物输送剂稳定偶联并进行体外测试的特定人类单克隆抗体。最合适的药物输送方法是 体内测试可递送刺激白色脂肪细胞转分化为棕色样脂肪细胞的化合物或特异性抑制脂肪生成或诱导细胞凋亡的化合物。然后将在适当的动物模型中测试抗体靶向药物递送。这些研究中产生的数据将作为这种治疗肥胖的免疫治疗方法的临床评估的基础。