Engineering Bispecific Antibodies that Target ERBB-2 on Breast Cancer Cells

The purpose of this project is to 1) construct novel bispecific antibodies that can redirect the activity of T cells against a tumor and 2) develop in vivo animal models that more closely resemble human cancer, for evaluating these agents. In the past year we have focused on the design and testing o...

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Bibliographic Details
Main Author: Kranz, David M
Format: Report
Language:English
Subjects:
ANIMAL MODELS
ANTIBODIES
Biochemistry
BISPECIFIC ANTIBODIES
BREAST CANCER
ERBB-2
FOLATE RECEPTORS
IMMUNOTHERAPY
IN VIVO ANALYSIS
Medicine and Medical Research
T LYMPHOCYTES
THERAPY
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Summary:The purpose of this project is to 1) construct novel bispecific antibodies that can redirect the activity of T cells against a tumor and 2) develop in vivo animal models that more closely resemble human cancer, for evaluating these agents. In the past year we have focused on the design and testing of antibody-based agents that will increase the activity of T cells and that will sustain this activity against a tumor. This aspect of the project has made use of novel bispecific folate/antibody conjugates that target the high affinity folate receptors on tumor cells. We have shown that combinations of folate/anti-TCR antibodies and folate/anti-CD28 antibodies are synergistic in stimulating T cell activity in vitro. The induced activity was completely dependent on the presence of the tumor, suggesting that there will be minimal side effects due to systemic cytokine release by non-specific T cell activating agents. In a complementary approach, monovalent forms of an anti-CTLA-4 antibody (Fab and scFv) were produced and shown to further sustain the activity of T cells in vitro. Finally, folatelanti-TCR antibody agents were tested in an in vivo animal model of an endogenously arising tumor of the choroid plexus. Treated animals had extensive T cell infiltration into the site of the tumor and significant increases in survival. Further studies will explore the use of the T cell stimulating agents described above, in this animal model.