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.

项目摘要该项目的总体目标是改善针对癌症的治疗抗体的活动通过开发新型的双特异性抗体（BSABS）的转移。该项目的中心假设是 BSAB设计具有一种特异性，用于接收器或在癌细胞表面过表达和标记肿瘤微环境中固体生长因子或细胞因子丰富的其他特异性诱导共同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细胞通过抗体介导的细胞吞噬作用（ADCP），从而产生更强的抗肿瘤活性而不是2种父母抗体的简单组合。申请人已经开发了一对BSAB，一只鼠标一个人，使用针对人表皮生长因子受体2（HER2）的新的BSAB格式，致癌驱动器正在成为各种基因组知情疗法的承诺目标乳腺癌和胃癌以外的癌症类型，以及靶向血管内皮生长因子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微环境。对BSABS的初步研究表明，抗雷神的活性显着在小鼠肿瘤模型中长期生存。在提议的工作中，三个具体目标将是严格的追求：目标1是检验工作假设，即BSAB比简单的抗肿瘤活动更强大通过ADCP诱导的VEGFA共细细胞增多症的两种亲本抗体的组合。目标2是确定自适应免疫反应与BSAB的作用机理有关的程度针对合成小鼠肿瘤模型的转移。目标3是评估翻译的潜力人源化小鼠中针对结直肠癌患者衍生的Xenographtics（PDX）的BSAB。拟议的工作将通过1）研究FcγR参与BSAB介导的VEGFA共同的作用吞噬作用和BSAB介导的抗肿瘤活性，2）分析肿瘤中的免疫景观微环境和检测抗原特异性T细胞在用BSAB与简单的BSAB处理后的存在 2种带有和不含FcγR桶的亲本抗体的组合，以及3）确定治疗人源化小鼠中BSAB对过表达HER2过表达的结直肠癌PDX的活性。工作是预计将证明BSABS的VEGFA共细细胞增多症是BSABS的关键机制比小鼠模型中两种亲本抗体的简单组合具有更强的抗肿瘤活性，并且具有 T细胞介导的活性在协同BSAB的抗肿瘤活性方面起着其他重要作用。这这项工作的影响有望很高，因为如果研究成功，这些发现将支持未来 BSABS的临床测试以治疗转移和过表达HER2的结直肠癌的复发和开发其他BSAB，以靶向其他生长因子受体或标记过表达癌细胞表面和肿瘤微环境中的其他肿瘤生长因子和细胞因子。