VLR-CART Cancer Immunotherapy

VLR-CART癌症免疫疗法

• 批准号: 8833776
• 负责人: Lovick Edward Cannon
• 金额: $ 14.9万
• 依托单位: NOVAB, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2016-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833776
• 关键词: Address; Adult; Affinity; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Area; BCL1 Oncogene; Binding; Binding Sites; Biological; Biological Response Modifier Therapy; Biomedical Engineering; C-terminal; CAR receptor; CCND1 gene; Carbohydrates; Cell Line; Cells; Childhood; Chronic Lymphocytic Leukemia; Clinical; Cloning; Cytoplasmic Tail; Development; Diagnostic; Diagnostics Research; Engineering; Epitopes; Evolution; Family; Fc Receptor; Generations; Genetic Engineering; Genetic Variation; Geometry; Goals; Growth; Hagfish; Hematopoietic Neoplasms; Human; Immune; Immune Tolerance; Immune system; Immunization; Immunoglobulins; Immunotherapy; In Vitro; Jaw; Lampreys; Lentivirus Vector; Leucine-Rich Repeat; Libraries; Lymphocyte; Malignant Neoplasms; Mammalian Genetics; Mammals; Mission; Modeling; Molecular Cloning; Monoclonal Antibodies; Multiple Myeloma; Mus; Patients; Production; Property; Proteins; Reagent; Receptor Gene; Receptor Signaling; Recombinants; Refractory; Series; Shapes; Signal Transduction; Specificity; Structure; Surface; Surface Antigens; T-Lymphocyte; Technology; Testing; Therapeutic; Transmembrane Domain; Tumor Antibodies; Tumor Antigens; Tumor Cell Line; Tumor Tissue; Tumor-Derived; Vertebrates; Yeasts; antigen binding; base; cancer cell; cancer immunotherapy; cancer therapy; cancer type; cell killing; clinical efficacy; design; geometric structure; high throughput screening; improved; in vitro testing; in vivo; interest; killings; neoplastic cell; novel; polypeptide; public health relevance; receptor; receptor binding; receptor expression; tumor

DESCRIPTION (provided by applicant): The mission of Novab is to utilize the unique properties of lamprey generated Variable Lymphocyte Receptors (VLRs) to develop effective, complementary and/or superior therapeutics to those currently derived from mammalian monoclonal antibodies (mMAbs). In the current application, we seek to initiate and demonstrate proof of concept for one commercial project within this mission, which is the application of VLRs to the design of chimeric antigen receptors (CARs) that currently are used as the tumor targeting component of genetically- engineered T cell immunotherapies. Our hypothesis is that due to independent evolution from the immunoglobulins (Igs) of jawed vertebrates, lamprey VLRs raised against therapeutic cell targets will recognize epitopes that are unique from those obtained using standard mammalian immunization and MAb (i.e. Ig) production. Therefore, VLRs represent a novel platform for the identification of cancer cell targets and the generation of improved diagnostics and biotherapeutics (e.g. monoclonal VLRs or VLR-CARs). Recently, CARs expressing T cells (CARTs) have demonstrated a high degree of efficacy in a limited set of otherwise refractory cancers. Currently, CAR diversity is restricted by the identification and availability of effective MAb binding domains, which in turn is restricted by not only mammalian genetic diversity but also by Ig structural geometry and pre-existing immune tolerance barriers to most antigens of human origin. We predict that VLR technology will allow for more specific cancer cell targeting and appreciably expand the range of cancer types that can be effectively treated using CARTs. Specifically, we will test this prediction using two independent hematopoietic tumor models. Using high-throughput screening and molecular cloning technology, tumor- specific VLRs were generated against a mouse BCL tumor cell line and primary human multiple myeloma cells. These VLRs will be utilized as the antigen binding components of novel CARs. We will demonstrate if VLR- CARs can be used as viable anti-tumor treatments using a series of in vitro tests (Milestone 1) and immune- competent and immune-compromised mice (Milestone 2). Completion of the Milestones presented in this proposal will provide the fundamental proof of concept evidence that VLR-CARTs are a scientifically-viable platform for the development of effective anti-cancer biotherapeutics.

描述（由申请人提供）：Novab 的使命是利用七鳃鳗产生的可变淋巴细胞受体（VLR）的独特特性来开发相对于目前源自哺乳动物单克隆抗体（mMAb）的有效、补充和/或优越的治疗方法。在当前的应用中，我们寻求启动并展示这一任务中的一个商业项目的概念验证，即应用VLR来设计嵌合抗原受体（CAR），目前该受体被用作基因工程T细胞免疫疗法的肿瘤靶向成分。我们的假设是，由于有颌脊椎动物的免疫球蛋白 (Igs) 的独立进化，针对治疗细胞靶标的七鳃鳗 VLR 将识别与使用标准哺乳动物免疫和 MAb（即 Ig）生产获得的表位不同的表位。因此，VLR 代表了一个用于识别癌细胞靶点和生成 改进的诊断和生物治疗（例如单克隆 VLR 或 VLR-CAR）。最近，表达 T 细胞的 CAR (CART) 在少数难治性癌症中表现出高度疗效。目前，CAR 多样性受到有效 MAb 结合域的识别和可用性的限制，而这反过来不仅受到哺乳动物遗传多样性的限制，还受到 Ig 结构几何形状和针对大多数人类来源抗原的预先存在的免疫耐受屏障的限制。我们预测，VLR 技术将允许更具体的癌细胞靶向，并显着扩大可以使用 CART 有效治疗的癌症类型的范围。具体来说，我们将使用两个独立的造血肿瘤模型来测试这一预测。利用高通量筛选和分子克隆技术，针对小鼠 BCL 肿瘤细胞系和原代人多发性骨髓瘤细胞生成了肿瘤特异性 VLR。这些VLR将被用作新型CAR的抗原结合成分。我们将通过一系列体外测试（里程碑 1）以及免疫能力强和免疫受损的小鼠（里程碑 2）来证明 VLR-CAR 是否可以用作可行的抗肿瘤治疗。该提案中提出的里程碑的完成将为概念证据提供基本证明，证明 VLR-CART 是开发有效抗癌生物治疗药物的科学上可行的平台。