Development of a novel antibody molecule for redirected T cell immunity to tumor cells: The bispecific single chain antibody
Gruber, Meegan Minori
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Permalink
https://hdl.handle.net/2142/19278
Description
Title
Development of a novel antibody molecule for redirected T cell immunity to tumor cells: The bispecific single chain antibody
Author(s)
Gruber, Meegan Minori
Issue Date
1996
Doctoral Committee Chair(s)
Kranz, David M.
Department of Study
Biochemistry
Discipline
Biochemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Chemistry, Biochemistry
Health Sciences, Immunology
Health Sciences, Oncology
Language
eng
Abstract
Cancer is the one of the leading causes of death in the United States, and will affect one in three people in their lifetime. In addition to existing treatments, immunotherapy is emerging as a potential fourth tier of cancer therapy. The existence of tumor specific proteins and the production of monoclonal antibodies that bind them allow the specific targeting of cancer cells. A promising use for these anti-tumor antibodies involves redirecting a patient's own cytotoxic T cells (CTL) to specifically kill tumor cells by the use of a bispecific antibody. This approach is achieved through the use of bispecific antibodies that bind the T cell and the tumor cell, triggering the specific elimination of the tumor cell. Despite the success of bispecific antibodies and emergence into clinical trials the optimum method of preparing bispecifics has not been resolved.
To begin to engineer more effective bispecific antibodies, we have constructed a novel molecule for redirecting CTL lysis, the bispecific single chain antibody(scFv$\sb2$). scFv$\sb2$ were shown to redirect CTL lysis of tumor cells conjugated to a surrogate tumor antigen, the hapten fluorescein, as well as tumor cells that express a true tumor specific protein, erbB-2. In addition, we have demonstrated that a combination of interferon-$\gamma$ and tumor necrosis factor-$\alpha$, but neither agent alone, was effective at increasing the susceptibility of some erbB-2$\sp{+}$ tumors to CTL lysis mediated by scFv$\sb2$.
The lack of appropriate animal models has hindered the development of bispecific antibodies as in vivo reagents. In anticipation of testing scFv$\sb2$ in vivo, an animal model with optimal characteristics for testing immunotherapeutics was developed. These double transgenic mice express rearranged 2C T cell receptors (TCR) on a recombination activation gene knockout (RAG$\sp{-/-}$) background which yielded an immunodeficient strain of mice that contains a monoclonal population of CTLs. The TCR/RAG$\sp{-/-}$ mice accepted erbB-2$\sp{+}$ human tumor xenografts. However, the CTLs could be activated to kill target cells in vivo, and should be able to kill tumor cells by antibody redirection. Human tumor xenografts in TCR/RAG$\sp{-/-}$ mice, therefore, provide a system for evaluating the relative effectiveness of various bispecific antibodies that are currently in development.
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