Developing novel bispecific antibodies for cancer treatment

开发用于癌症治疗的新型双特异性抗体

基本信息

批准号：
10659117
负责人：
Zhen Fan
金额：
$ 29.41万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659117
关键词：
Angiogenesis Inhibition Antibodies Antibody Therapy Automobile Driving Binding Biological Assay Bispecific Antibodies CD19 gene CD3 Antigens CTL assay Cell surface Cells Cessation of life Clinical Trials Clonal Expansion Colorectal Cancer Cytometry Development Disseminated Malignant Neoplasm Engineering Epidermal Growth Factor Receptor Epitopes Exhibits Future Genomics Goals Growth Factor Growth Factor Receptors Hematologic Neoplasms Human IgG1 Immune Immune response Immunosuppression Implant Interferon Type II Interleukin-10 KDR gene Malignant Neoplasms Measures Mediating Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Oncogenes Oncogenic Patients Peptides Phagocytosis Play Pre-Clinical Model Production Recurrence Role Solid Neoplasm Specificity T cell infiltration T cell receptor repertoire sequencing T-Cell Depletion T-Lymphocyte Testing Therapeutic Therapeutic antibodies Time Transforming Growth Factor beta Trastuzumab Tumor Angiogenesis Tumor Antibodies Tumor Promotion VEGFA gene Vaccines Work adaptive immune response antigen-specific T cells bevacizumab cancer cell cancer therapy cancer type cell killing colon cancer patients cytokine design humanized mouse improved malignant breast neoplasm malignant stomach neoplasm metastatic colorectal mouse model neoplastic cell novel novel therapeutics overexpression patient derived xenograft model receptor reconstitution research clinical testing rituximab standard care translational potential tumor tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY The overall goal of this project is to improve activities of therapeutic antibodies against cancer metastasis through developing novel bispecific antibodies (BsAbs). The central hypothesis of this project is that BsAbs designed with one specificity for a receptor or marker overexpressed on the cancer cell surface and the other specificity for a soluble growth factor or cytokine abundant in the tumor microenvironment induce co- phagocytosis of the growth factor or cytokine in the tumor microenvironment along with the co-targeted cancer cells via antibody-mediated cellular phagocytosis (ADCP) and thereby produce stronger antitumor activities than simple combination of 2 parental antibodies. The applicant has developed a pair of BsAbs, one mouse and one human, using a new BsAb format targeting human epidermal growth factor receptor-2 (HER2), an oncogenic driver that is emerging as a promising target for genomically informed therapy across a variety of cancer types beyond breast and gastric cancer, and targeting vascular endothelial growth factor A (VEGFA), another key driver that promotes tumor angiogenesis and suppresses tumor immune responses in the tumor microenvironment. Preliminary studies with the BsAbs showed remarkable anti-metastasis activity and prolonged survival in mouse tumor models. In the work proposed, three specific aims will be rigorously pursued: Aim 1 is to test the working hypothesis that the BsAbs exert stronger antitumor activities than simple combination of the 2 parental antibodies through inducing VEGFA co-phagocytosis via ADCP. Aim 2 is to determine the extent to which adaptive immune response is involved in the mechanisms of action of the BsAbs against metastasis of syngeneic mouse tumor models. Aim 3 is to assess the translational potential of the BsAbs against colorectal cancer patient-derived xenografts (PDXs) in humanized mice. The proposed work will be carried out through 1) investigating the role of engagement of FcγR in BsAb-mediated VEGFA co- phagocytosis and in BsAb-mediated antitumor activity, 2) analyzing the immune landscape in the tumor microenvironment and detecting presence of antigen-specific T cells upon treatment with BsAb vs with simple combination of 2 parental antibodies with and without FcγR blockade, and 3) determining the therapeutic activity of the BsAbs against HER2-overexpressing colorectal cancer PDXs in humanized mice. The work is expected to demonstrate that VEGFA co-phagocytosis by the BsAbs is a key mechanism by which the BsAbs exert stronger antitumor activity than simple combination of the 2 parental antibodies in the mouse models, and that T cell-mediated activities play an additional important role in synergizing the BsAb's antitumor activity. The impact of this work is expected to be high because if the study is successful, the findings will support future clinical testing of BsAbs to treat metastasis and recurrence of HER2-overexpressing colorectal cancer and development of additional BsAbs to target other growth factor receptors or markers overexpressed on the cancer cell surface and other tumor-promoting growth factors and cytokines in the tumor microenvironment.

项目概要该项目的总体目标是提高抗癌抗体的活性通过开发新型双特异性抗体（BsAb）来实现转移该项目的中心假设是： BsAb 设计为针对癌细胞表面过度表达的受体或标记物具有一种特异性，并且对肿瘤微环境中丰富的可溶性生长因子或细胞因子的其他特异性诱导共肿瘤微环境中生长因子或细胞因子的吞噬作用以及共同靶向的癌症通过抗体介导的细胞吞噬作用（ADCP）作用于细胞，从而产生更强的抗肿瘤活性申请人已开发出一对 BsAb，一只小鼠。和一名人类，使用针对人表皮生长因子受体 2 (HER2) 的新 BsAb 形式，致癌驱动因素正在成为各种基因组学治疗的有希望的目标乳腺癌和胃癌以外的癌症类型，并针对血管内皮生长因子 A (VEGFA)，促进肿瘤血管生成并抑制肿瘤免疫反应的另一个关键驱动因素 BsAb 的初步研究显示出显着的抗转移活性和在提出的工作中，将严格实现三个具体目标。追求：目标 1 是检验双特异性抗体比简单双特异性抗体具有更强的抗肿瘤活性的工作假设目标 2 通过 ADCP 诱导 VEGFA 共吞噬作用来组合 2 个亲本抗体。确定双特异性抗体作用机制中适应性免疫反应的参与程度目的 3 是评估同源小鼠肿瘤模型的转化潜力。在人源化小鼠中针对结直肠癌患者来源的异种移植物（PDX）的双特异性抗体。可以通过以下方式进行： 1) 研究 FcγR 在 BsAb 介导的 VEGFA 协同作用中的参与作用吞噬作用和 BsAb 介导的抗肿瘤活性，2) 分析肿瘤中的免疫景观与简单的 BsAb 治疗相比，微环境和检测抗原特异性 T 细胞的存在 2 种亲本抗体（有和没有 FcγR 阻断）的组合，以及 3) 确定治疗方案 BsAb 在人源化小鼠中对抗 HER2 过表达结直肠癌 PDX 的活性。预计将证明 BsAb 共同吞噬 VEGFA 是 BsAb 发挥作用的关键机制在小鼠模型中比两种亲本抗体的简单组合发挥更强的抗肿瘤活性，并且 T 细胞介导的活性在协同 BsAb 的抗肿瘤活性方面发挥着额外的重要作用。这项工作的影响预计会很高，因为如果研究成功，研究结果将支持未来 BsAb 治疗 HER2 过表达结直肠癌转移和复发的临床测试开发额外的 BsAb 以靶向其他生长因子受体或过度表达的标记物癌细胞表面以及肿瘤微环境中的其他促肿瘤生长因子和细胞因子。