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Targeting tumor cells with bispecific antibodies and T cells
D M Kranz1, T C Manning, L A Rund
1Department of Biochemistry, University of Illinois, Urbana 61801, USA. d-kranz@uiuc.edu
Abstract:
It has been known for some time that mammalian immune systems are capable of eliminating large tumor burdens. Redirecting the immune response of a patient to an established tumor has now become the focus of various therapeutic strategies. In this report, two projects toward this goal are described. The first project involves the development of a transgenic mouse model for T cell directed therapeutics. These mice express specific T cell receptor alpha and beta transgenes on a background in which the recombinational-activating-gene-1 (RAG) has been knocked out. The mice express cytotoxic T cells but not either T helper cells or B cells. Despite these deficiencies, the animals are capable of eliminating tumors that express the appropriate peptide/major histocompatibility complex ligand that is recognized by the alphabeta transgenic T cell receptor. Human tumors grow as transplants in these mice, thereby allowing various agents that redirect the endogenous T cells against human tumors to be tested. The second project involves a description of such agents: bispecific antibodies that simultaneously bind to an immune effector cell and a tumor cell. The bispecific antibody described here consists of folate attached to anti-T cell receptor antibodies, or their fragments. A single-chain Fv coupled with folate can redirect the lysis of human tumor cells that bear the high affinity folate receptor. Preliminary in vivo data showed that the folate/antibody conjugates were also capable of mediating rejection of the human tumor. This transgenic mouse model should now allow the evaluation and optimization of bispecific agents that can redirect a patient's own T cell response.
Insights
Researchers developed a new mouse model and bispecific antibodies to redirect T cells for cancer immunotherapy. This approach enhances the immune system's ability to target and eliminate tumors, offering a promising new therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Mammalian immune systems can eliminate large tumor burdens.
- Redirecting patient immune responses to established tumors is a key therapeutic goal.
Purpose of the Study:
- To develop a transgenic mouse model for T cell-directed cancer therapeutics.
- To describe bispecific antibodies for redirecting T cells against human tumors.
Main Methods:
- Created RAG-knockout mice expressing specific T cell receptor transgenes.
- Developed bispecific antibodies (folate-conjugated anti-TCR antibodies) to target tumor cells.
Main Results:
- Transgenic mice with cytotoxic T cells rejected human tumors expressing specific ligands.
- Folate/antibody conjugates redirected T cell lysis of human tumor cells expressing folate receptors.
- Preliminary in vivo data demonstrated tumor rejection mediated by conjugates.
Conclusions:
- The developed transgenic mouse model enables testing and optimization of T cell-redirecting agents.
- Bispecific antibodies show potential for redirecting endogenous T cell responses against tumors.