Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity

Zelig Eshhar's group at the Weizmann Institute of Science asked whether the specificity of a T cell could be designed rather than selected. They built chimeric T-cell receptor genes in which the variable domains of the heavy and light chains of an anti-trinitrophenyl antibody (SP6) were spliced to the constant regions of the T-cell receptor alpha or beta chain, and expressed them in a cytotoxic T-cell hybridoma.

The transfectants expressed a functional receptor carrying the antibody's idiotope, and responded to trinitrophenyl-bearing targets without major histocompatibility complex restriction, killing them and producing interleukin-2 across strain and species barriers. They also responded to immobilised trinitrophenyl-protein conjugates, which means cellular processing and presentation were bypassed entirely. Because the binding site of this particular antibody lies almost wholly in the heavy chain, a construct containing only the heavy-chain variable domain fused to either constant region was enough.

Eshhar called the construct a T-body. Everything that followed, the single-chain variable fragment format, the CD28 and 4-1BB costimulatory domains added by Michel Sadelain, Carl June and Dario Campana, and the manufacturing that turns the idea into a product, is built on this experiment.