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Principal Investigator: Zhen Fan
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $564,306
Funding agency: National Cancer Institute
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.
Terms: <Angiogenesis Inhibition><Angiogenic Inhibition><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-VEGF><Anti-VEGF Humanized Monoclonal Antibody><Anti-VEGF RhuMAb><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Antibodies><Antibody Therapy><Antigenic Determinants><Assay><Automobile Driving><Bi-specific antibodies><Bifunctional Antibodies><Binding><Binding Determinants><Bioassay><Biological Assay><Bispecific Antibodies><Bone-Derived Transforming Growth Factor><Breast Cancer><C2B8 Monoclonal Antibody><CD19><CD19 gene><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CSIF><CSIF-10><CTL assay><Cancer Genes><Cancer Treatment><Cancer-Promoting Gene><Cancers><Cell Body><Cell surface><Cells><Cessation of life><Clinical Evaluation><Clinical Testing><Clinical Treatment Moab><Clinical Trials><Clonal Expansion><Colorectal Cancer><Cytokine Synthesis Inhibitory Factor><Cytometry><Death><Development><Disseminated Malignant Neoplasm><EGF Receptor><EGFR><ERBB Protein><Engineering><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epitopes><Exhibits><FLK1><Future><Gastric Body Cancer><Gastric Cancer><Gastric Cardia Cancer><Gastric Fundus Cancer><Gastric Pylorus Cancer><Genomics><Goals><Growth Agents><Growth Factor><Growth Factor Receptors><Growth Substances><HER1><HER2 Monoclonal Antibody><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Herceptin><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-10><IL10><IL10A><IgG1><Immune><Immune Interferon><Immune response><Immunes><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Implant><Interferon Gamma><Interferon Type II><Interleukin 10 Precursor><Interleukin-10><KDR gene><MabThera><Malignant Breast Neoplasm><Malignant Cell><Malignant Gastric Neoplasm><Malignant Gastric Tumor><Malignant Hematologic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Milk Growth Factor><MoAb HER2><MoAb VEGF><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Monoclonal Antibody Anti-VEGF><Murine><Mus><Neoplasm Antibodies><Neoplasm Metastasis><OKT3 antigen><Oncogenes><Oncogenic><PDX model><Patient derived xenograft><Patients><Peptides><Phagocytosis><Platelet Transforming Growth Factor><Play><Pre-Clinical Model><Preclinical Models><Production><Proteins Growth Factors><Receptor Protein><Recombinant Humanized Anti-VEGF Monoclonal Antibody><Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor><Recurrence><Recurrent><RhuMAb VEGF><Rituxan><Role><Secondary Neoplasm><Secondary Tumor><Solid Neoplasm><Solid Tumor><Specificity><Stomach Cancer><T cell infiltration><T cell receptor repertoire sequencing><T cell receptor sequencing><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T3 Antigens><T3 Complex><T3 molecule><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><TGF B><TGF-alpha Receptor><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Therapeutic antibodies><Time><Transforming Genes><Transforming Growth Factor alpha Receptor><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Trastuzumab><Tumor Angiogenesis><Tumor Antibodies><Tumor Cell><Tumor Promotion><Urogastrone Receptor><VEGF Receptors><VEGFA><VEGFA gene><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Vaccines><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor A><Vascular Endothelial Growth Factor Receptor 2><Vascular Permeability Factor Receptor><Vasculotropin><Work><adaptive immune response><anti-cancer therapy><anti-tumor antibody><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><antigen-specific T cells><antitumor antibody><bevacizumab><bsAb><c-erb-2 Monoclonal Antibody><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer metastasis><cancer microenvironment><cancer progression><cancer therapy><cancer type><cancer-directed therapy><cell killing><clinical test><colon cancer patients><colorectal cancer patients><cytokine><design><designing><developmental><driving><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><gastric malignancy><host response><humanized mice><humanized mouse><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><lFN-Gamma><mAbs><malignancy><malignant breast tumor><malignant stomach neoplasm><malignant stomach tumor><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><monoclonal Abs><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><patient derived xenograft model><proto-oncogene protein c-erbB-1><receptor><reconstitute><reconstitution><research clinical testing><rhuMAb HER2><rhuMabVEGF><rituximab><social role><standard care><standard treatment><stomach fundus cancer><stomach pylorus cancer><thymus derived lymphocyte><translational opportunities><translational potential><tumor><tumor cell metastasis><tumor microenvironment><tumor progression>