Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies.

Journal article

The antiglobulin (anti-Ig) response to therapeutic monoclonal antibodies (mAbs) poses a significant obstacle to their routine application in man. Whilst humanization has lessened the problem, repeated courses of humanized mAbs still sensitise some patients. Previous work suggested that unresponsiveness to cell-binding (therapeutic) mAbs could not be achieved due to an unexpected immunogenicity of their idiotypes (ids). The current work examines this phenomenon in more detail using CBA/Ca mice receiving rat antimouse CD8 mAbs as a model system. It is shown that the anti-Ig response is dependent on CD4+ T-cells. Furthermore, for at least some mAbs, most helper epitopes appear to reside within the mAb c-region. Consequently, when tolerance is induced to c-region (isotype), the anti-id response is extremely weak (induced helplessness). For one (weakly immunogenic) CD8 mAb concomitant administration of a CD4 mAb was sufficient to induce tolerance, whereas for another (more immunogenic) CD8 mAb, tolerance could only be achieved by prior concomitant exposure to both a CD4 mAb and an isotype-matched non-cell-binding mAb. The general applicability of these results is discussed and extrapolated to the clinical situation. Non-cell-binding variants of therapeutic mAbs could be usefully exploited to generate therapeutic unresponsiveness to any clinically useful mAb.

Authors: Isaacs, J; Waldmann, H

• Journal: Therapeutic immunology
• Volume: 1
• Issue: 6
• Pages: 303-312
• Publication date: 1994-12-01
• ISSN: 0967-0149
• Language: English
• Keywords: Immune Tolerance; Animals; T-Lymphocytes; Antibodies, Anti-Idiotypic; Antigens, CD4; Mice, Inbred CBA; Immunoglobulin Idiotypes; Antibodies, Monoclonal; Male; Antigens, CD8; Peptides; Mice; T-Lymphocytes, Helper-Inducer; Lymphocyte Cooperation; Female