Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of …

Z Eshhar, T Waks, G Gross… - Proceedings of the …, 1993 - National Acad Sciences
Z Eshhar, T Waks, G Gross, DG Schindler
Proceedings of the National Academy of Sciences, 1993National Acad Sciences
The generation of tumor-specific lymphocytes and their use in adoptive immunotherapy is
limited to a few malignancies because most spontaneous tumors are very weak or not at all
immunogenic. On the other hand, many anti-tumor antibodies have been described which
bind tumor-associated antigens shared among tumors of the same histology. Combining the
variable regions (Fv) of an antibody with the constant regions of the T-cell receptor (TCR)
chains results in chimeric genes endowing T lymphocytes with antibody-type specificity …
The generation of tumor-specific lymphocytes and their use in adoptive immunotherapy is limited to a few malignancies because most spontaneous tumors are very weak or not at all immunogenic. On the other hand, many anti-tumor antibodies have been described which bind tumor-associated antigens shared among tumors of the same histology. Combining the variable regions (Fv) of an antibody with the constant regions of the T-cell receptor (TCR) chains results in chimeric genes endowing T lymphocytes with antibody-type specificity, potentially allowing cellular adoptive immunotherapy against types of tumors not previously possible. To generalize and extend this approach to additional lymphocyte-activating molecules, we designed and constructed chimeric genes composed of a single-chain Fv domain (scFv) of an antibody linked with gamma or zeta chains, the common signal-transducing subunits of the immunoglobulin receptor and the TCR. Such chimeric genes containing the Fv region of an anti-trinitophenyl antibody could be expressed as functional surface receptors in a cytolytic T-cell hybridoma. They triggered interleukin 2 secretion upon encountering antigen and mediated non-major-histocompatibility-complex-restricted hapten-specific target cell lysis. Such chimeric receptors can be exploited to provide T cells and other effector lymphocytes, such as natural killer cells, with antibody-type recognition directly coupled to cellular activation.
National Acad Sciences