Developing novel bispecific antibodies for cancer treatment

开发用于癌症治疗的新型双特异性抗体

• 批准号: 10276280
• 负责人: Zhen Fan
• 金额: $ 49.74万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/10276280
• 关键词: 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; Goals; Gold; Growth Factor; Growth Factor Receptors; Hematologic Neoplasms; Human; IgG1; Immune; Immune response; Immunosuppression; Implant; Interferon Type II; Interleukin-10; Lead; 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 receptor repertoire sequencing; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Time; Transforming Growth Factor beta; Trastuzumab; Tumor Angiogenesis; Tumor Antibodies; Tumor-infiltrating immune cells; VEGFA gene; Vaccines; Work; adaptive immune response; angiogenesis; antigen-specific T cells; base; 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; tumor; tumor microenvironment; tumor progression

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提高抗癌治疗抗体的活性 通过开发新的双特异性抗体（BsAbs）来治疗转移。这个项目的核心假设是， BsAb被设计为对癌细胞表面上过表达的受体或标志物具有一种特异性， 对肿瘤微环境中丰富的可溶性生长因子或细胞因子的其它特异性诱导共 肿瘤微环境中生长因子或细胞因子的吞噬作用与共靶向癌症一起沿着 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 而不是两种亲本抗体的简单组合。申请人开发了一对BsAb，一只小鼠 和一个人，使用靶向人表皮生长因子受体-2（HER 2）的新BsAb形式， 致癌驱动因子正在成为各种基因组信息治疗的有希望的靶点， 乳腺癌和胃癌以外的癌症类型，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BsAb的初步研究显示出显著的抗转移活性， 延长小鼠肿瘤模型的生存期。在拟议的工作中，将严格执行三个具体目标 目的：1是验证工作假设，即BsAbs比简单的BsAbs发挥更强的抗肿瘤活性。 通过ADCP诱导VEGFA共吞噬作用，这是2种亲本抗体的组合。目标二是 确定获得性免疫应答参与BsAb作用机制的程度 针对同基因小鼠肿瘤模型的转移。目的3是评估的翻译潜力， 在人源化小鼠中针对结肠直肠癌患者来源的异种移植物（PDX）的BsAb。拟议的工作将 通过1）研究FcγR在BsAb介导的VEGFA共表达中的作用， 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 在用BsAb处理后与用简单BsAb处理后相比， 具有和不具有FcγR阻断的2种亲本抗体的组合，和3）确定治疗性抗体的剂量。 BsAb在人源化小鼠中对HER 2过表达结肠直肠癌PDX的活性。这项工作是 预期证明BsAb的VEGFA共吞噬作用是BsAb与VEGFA共吞噬的关键机制。 在小鼠模型中发挥比2种亲本抗体的简单组合更强的抗肿瘤活性，并且 T细胞介导的活性在协同BsAb的抗肿瘤活性中发挥额外的重要作用。的 这项工作的影响预计会很大，因为如果研究成功，研究结果将支持未来的研究。 BsAb治疗HER 2过表达结肠直肠癌的转移和复发的临床试验， 开发额外的BsAb以靶向在细胞表面过表达的其他生长因子受体或标志物， 癌细胞表面和肿瘤微环境中的其他促肿瘤生长因子和细胞因子。