Chemically Programmed Bispecific Antibodies for Cancer Therapy

用于癌症治疗的化学编程双特异性抗体

基本信息

批准号：
8884563
负责人：
CHRISTOPH RADER
金额：
$ 39.84万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-02 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884563
关键词：
Affinity Amino Acids Antibodies Antigens Binding Biological Bispecific Antibodies C-terminal CD3 Antigens CD94 Antigen Cancer Patient Cancer cell line Categories Cells Chemicals Chemistry Cytolysis Cytotoxic T-Lymphocytes Development Engineering Folic Acid Generations Generic Drugs Goals Haptens Health Human Immune Immunocompromised Host Immunology In Vitro Iodoacetamide Lactams Link Lysine Maleimides Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Molecular Molecular Weight Monoclonal Antibodies Mus Natural Killer Cells Peripheral Blood Mononuclear Cell Phage Display Pharmaceutical Preparations Proteins Public Health Recruitment Activity Research Safety Selenocysteine Site Solid Specificity Structure Surface Antigens T-Cell Receptor T-Lymphocyte Technology Testing Tissues Ursidae Family Validation Woman arm base cancer therapy cell killing cytotoxicity design diketone efficacy testing expression cloning human FOLR1 protein in vitro testing in vivo interest killings men neoplastic cell next generation novel programs prototype small molecule small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): Bispecific antibodies (biAbs) that exert cytotoxicity by binding to tumor cells with one arm and by simultaneously recruiting and activating tumor cell-lysing endogenous immune cells with the other arm are an emerging category of next-generation antibody drugs for cancer therapy. Our research team will develop and deliver conceptually novel chemically programmed biAbs that recognize tumor cells with a variable small molecule component and that recruit and activate T cells and NK cells with a generic antibody component. Chemically programmed biAbs are more versatile than conventional biAbs as they only require the cloning, expression, and purification of a single protein. Further, to target a variety of different tumor cell surface antigens, chemically programmed biAbs can make use of a wealth of small molecules derived from chemical libraries or from structure-based design campaigns, linking advances in both immunology and chemistry for the benefit of cancer patients. The proposed study will rigorously test the hypothesis that chemically programmed biAbs can recruit and activate T cells and NK cells that selectively and potently kill tumor cells n vivo. Specifically, we will develop and deliver two entirely different molecular formats of the generic antibody component and then chemically program biAbs to selectively target folate receptor 1 (FOLR1). FOLR1 was chosen as a prototype as this tumor cell surface antigen is a clinically investigated target for both small molecules and monoclonal antibodies in ovarian and lung cancer and in other devastating solid malignancies. The two molecular formats that will be interrogated are based on the reactive selenocysteine (Sec) and the reactive lysine (Lys) technologies that we developed for molecularly defined chemical programming of antibodies. In Aim 1 we will generate and validate chemically programmed (FOLR1 x CD3) and (FOLR1 x NKG2D) biAbs based on a single antibody module in Fab format with an engineered C-terminal Sec. In Aim 2 we will generate and validate chemically programmed (FOLR1 x CD3) and (FOLR1 x NKG2D) biAbs based on a dual antibody module in DART (Dual-Affinity Re-Targeting) format that displays a single reactive Lys residue. Chemically programmed biAbs in these two molecular formats will be analyzed and compared for their ability to recruit and activate T cells (via CD3) and NK cells (via NKG2D) to direct killing of FOLR1-expressing tumor cells. Finally, in Aim 3, we will test the efficacy and safety of our chemically programmed biAbs in immunocompromised mice engrafted with both human effector and target cells. Collectively, our campaign will deliver both novel concepts and constructs for next-generation antibody drugs that are explicitly designed for broad utility in cancer therapy.

描述（由申请人提供）：双特异性抗体（biAb）通过一只臂与肿瘤细胞结合并同时用另一臂招募和激活肿瘤细胞裂解内源性免疫细胞来发挥细胞毒性，是一类新兴的下一代抗体药物用于癌症治疗。我们的研究团队将开发和提供概念上新颖的化学编程双抗体，这些双抗体可识别具有可变小分子成分的肿瘤细胞，并具有通用抗体成分招募和激活 T 细胞和 NK 细胞。化学编程的双抗体比传统的双抗体更加通用，因为它们只需要克隆、表达和纯化单个蛋白质。此外，为了靶向多种不同的肿瘤细胞表面抗原，化学编程的双抗体可以利用源自化学库或基于结构的设计活动的大量小分子，将免疫学和化学的进步联系起来，造福癌症患者。拟议的研究将严格检验化学编程双抗体可以招募和激活 T 细胞和 NK 细胞，从而选择性地、有效地杀死体内肿瘤细胞的假设。具体来说，我们将开发并提供两种完全不同的分子形式的通用抗体成分，然后对 biAb 进行化学编程，以选择性地靶向叶酸受体 1 (FOLR1)。 FOLR1 被选为原型，因为这种肿瘤细胞表面抗原是卵巢癌、肺癌和其他破坏性实体恶性肿瘤中小分子和单克隆抗体的临床研究靶标。将要研究的两种分子形式基于我们为分子定义的抗体化学编程而开发的反应性硒代半胱氨酸 (Sec) 和反应性赖氨酸 (Lys) 技术。在目标 1 中，我们将基于 Fab 格式的单个抗体模块（带有工程化的 C 末端 Sec）生成并验证化学编程的 (FOLR1 x CD3) 和 (FOLR1 x NKG2D) 双抗体。在目标 2 中，我们将基于 DART（双亲和力重新靶向）格式的双抗体模块（显示单个反应性赖氨酸残基）生成并验证化学编程的 (FOLR1 x CD3) 和 (FOLR1 x NKG2D) 双抗体。将分析和比较这两种分子形式的化学编程双抗体招募和激活 T 细胞（通过 CD3）和 NK 细胞（通过 NKG2D）以直接杀死表达 FOLR1 的肿瘤细胞的能力。最后，在目标 3 中，我们将在移植了人类效应细胞和靶细胞的免疫受损小鼠中测试化学编程双抗体的功效和安全性。总的来说，我们的活动将为下一代抗体药物提供新颖的概念和结构，这些药物是专门为在癌症治疗中广泛应用而设计的。