Developing novel bispecific antibodies for cancer treatment

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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.