Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors.

TLDR

Tumor‑specific lymphocytes are limited to a few cancers because most tumors are weakly immunogenic, yet many antibodies bind shared tumor antigens, and fusing antibody variable regions to T‑cell receptor constant regions creates chimeric genes that could enable adoptive immunotherapy for previously untreatable tumors. The authors aimed to broaden this strategy by designing chimeric genes that fuse a single‑chain antibody variable domain to the gamma or zeta signal‑transducing subunits of the immunoglobulin receptor and the TCR. These chimeric genes encode a single‑chain Fv domain linked to the common signal‑transducing subunits, allowing expression as functional surface receptors on lymphocytes. The resulting receptors were expressed on a cytolytic T‑cell hybridoma, triggered interleukin‑2 secretion upon antigen encounter, and mediated non‑MHC‑restricted hapten‑specific lysis, showing that antibody‑type recognition can be directly coupled to lymphocyte activation.

Abstract

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.