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 x anti-CD3 and an anti-target x 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 x anti-CD3/anti-target x 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.
Jung
G
G
Medizinische Klinik III, Universität München, FRG.
Freimann
U
U
Von Marschall
Z
Z
Reisfeld
R A
RA
Wilmanns
W
W
D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D018106:CD28 Antigens; D017252:CD3 Complex; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology; D016853:Muromonab-CD3 / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D007140:Immunoglobulin Fab Fragments; D016853:Muromonab-CD3; D011948:Receptors, Antigen, T-Cell