Abstract
Herein, we describe the synthesis of a chemically defined anti-CD3 Fab-folate conjugate that targets cytotoxic T cells to folate receptor positive (FR+) tumors. The unnatural amino acid pacetylphenylalanine (pAcPhe) was site-specifically incorporated into an anti-CD3 Fab and conjugated to folate via the formation of a stable oxime linkage. The anti-CD3 Fab-folate conjugate was able to promote T cell mediated killing of FR+ cancer cells in culture. Moreover, the anti-CD3 Fab-folate conjugate potently eliminates tumor xenografts in mice. This approach can likely be generalized to other ligands that bind cancer and other pathogenic cells.
Keywords:
T cells; bispecific antibody; cancer; folate receptor; immunotherapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD3 Complex / immunology
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Cell Line, Tumor
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Coculture Techniques
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Folate Receptors, GPI-Anchored / metabolism*
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Folic Acid / chemistry
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Humans
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / immunology
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Immunoglobulin Fc Fragments / chemistry
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Immunoglobulin Fc Fragments / immunology
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Immunoglobulin G / chemistry
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Immunoglobulin G / immunology
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Immunotherapy
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Leukocytes, Mononuclear / cytology
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplasms / therapy
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Rats
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Rats, Sprague-Dawley
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology*
Substances
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CD3 Complex
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Folate Receptors, GPI-Anchored
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Immunoglobulin Fab Fragments
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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immunoglobulin Facb fragment
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Folic Acid