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Target cell‐induced T cell activation with bi‐ and trispecific antibody fragments

Previously we proposed a concept for tumor immunotherapy in which two different bispecific antibody conjugates, an anti‐target × anti‐CD3 and an anti‐target × anti‐CD28 conjugate, induce the activation of resting human T cells upon binding to the respective tumor target cells. After in vivo application of these reagents, this model of a “target cell‐induced T cell activation” envisages the destruction of target cells by in situ activated T cells. Obviously however, for in vivo application, the use of Fc‐free antibody fragments is mandatory to prevent binding of the conjugates to Fc receptor‐positive cells which would lead to Fc‐mediated T cell activation. Here we report a simplification of published procedures for the generation of bispecific Fab‐hybrid fragments, univalent for each antigen. We demonstrate that an anti‐target × anti‐CD3/anti‐target × anti‐CD28 combination of such hybrids, as well as an identical combination of covalently coupled F(ab')2 fragments, mediate “target cell‐induced T cell activation” in an in vitro test system. Thus, these reagents may be capable of inducing an in situ activation of human T cells upon systemic in vivo application according to the concept outlined above. A trispecific conjugate with anti‐target, anti‐CD3‐and anti‐CD28 specificity appears to be unsuitable for this purpose because it activates resting T cells in soluble form without requiring immobilization through binding via its anti‐target portion.