Developing novel bispecific antibodies for cancer treatment

项目总结 这个项目的总体目标是提高抗癌的治疗性抗体的活性。 通过开发新的双特异性抗体(BsAbs)进行转移。这个项目的中心假设是 针对癌细胞表面过度表达的受体或标志物而设计的单特异性BsAbs 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可诱导协同 肿瘤微环境中生长因子或细胞因子的吞噬作用与共靶向肿瘤 通过抗体介导的细胞吞噬作用(ADCP)产生更强的抗肿瘤活性 而不是两个亲本抗体的简单组合。申请人开发了一对BsAbs，一只小鼠 还有一个人，使用一种新的针对人表皮生长因子受体-2(HER2)的BsAb形式， 致癌驱动因素正在成为多种疾病基因信息治疗的有希望的靶点 乳腺癌和胃癌以外的癌症类型，并以血管内皮生长因子A(VEGFA)为靶点， 促进肿瘤血管生成和抑制肿瘤免疫反应的另一个关键驱动因素 微环境。初步研究表明，BsAbs具有显著的抗转移活性和 延长小鼠肿瘤模型的存活时间。在提出的工作中，将严格实现三个具体目标 追求：目标1是验证BsAbs比单纯的BsAbs具有更强的抗肿瘤活性这一工作假设 通过ADCP诱导VEGFA共吞噬结合亲本抗体。目标2是 确定适应性免疫反应在BsAbs作用机制中的参与程度 抗同基因小鼠肿瘤模型的转移。目标3是评估翻译的潜力 人源化小鼠中抗结直肠癌患者来源的异种移植(PDX)的BsAb。拟议的工作将 通过1)研究Fc-γ-R在BsAb介导的VEGFA协同作用中的作用 吞噬功能和BsAb介导的抗肿瘤活性，2)分析肿瘤内的免疫状况 BsAb与SIMPLE治疗后微环境和抗原特异性T细胞的检测 有和没有FcγR阻断的2种亲本抗体的组合，以及3)确定治疗 人源化小鼠体内抗HER2高表达结直肠癌PDX的BsAbs活性这项工作是 有望证明VEGFA共吞噬BsAbs是BsAbs的关键机制 在小鼠模型中表现出比亲本抗体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的抗肿瘤活性中起着额外的重要作用。这个 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 BsAbs治疗HER2过表达结直肠癌转移复发的临床试验 开发更多针对其他生长因子受体或标志物的BsAb 肿瘤细胞表面及其他促肿瘤生长因子和肿瘤微环境中的细胞因子。

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.