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

Eur J Immunol. 1991 Oct;21(10):2431-5. doi: 10.1002/eji.1830211020.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Neoplasm / immunology
  • Antigens, CD / immunology*
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • CD28 Antigens
  • CD3 Complex
  • Humans
  • Immunoglobulin Fab Fragments / immunology
  • In Vitro Techniques
  • Lymphocyte Activation*
  • Melanoma / immunology
  • Muromonab-CD3 / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Structure-Activity Relationship
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neoplasm
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD28 Antigens
  • CD3 Complex
  • Immunoglobulin Fab Fragments
  • Muromonab-CD3
  • Receptors, Antigen, T-Cell