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Celltech Therapeutics Ltd., Slough, United Kingdom
Single chain Fv chimeric receptors, or T-bodies, are described with
intracellular sequences comprising the costimulatory signaling domain
of CD28 in series with the 
-chain from the TCR complex. Using an
engineered human single chain Fv derived from P67, an mAb with
specificity for human CD33, and a spacer comprising an Ab hinge region
with either Fc
or part of the CD28 extracellular region, fusion
molecules were constructed to test the ability of single chain designs
to mediate both primary signaling and costimulation from one
extracellular binding event. Constructs with the CD28 signaling domain
proximal and the -chain distal to the membrane were found to express
more efficiently in Jurkat than constructs with the opposite
orientation and were capable of mediating up to 20 times more IL-2
production on stimulation with solid phase Ag when compared with
transfectants expressing chimeric receptors with -chain
intracellular signaling domains only. IL-2 production was specific to
Ag challenge and was completely inhibited by incubation with free Ab of
the same specificity as the extracellular binding site of the
construct, but not by an isotype-matched control Ab. The CD28
intracellular domain of these fusion proteins was shown to be capable
of binding the p85 subunit of phosphatidylinositol 3'-kinase. These
constructs represent the first of a new generation of single gene
multidomain chimeric receptors capable of mediating both primary and
costimulatory signaling specifically from a single extracellular
recognition event.
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