Tolerance to rat monoclonal antibodies. Implications for serotherapy

Area of Science:

• Immunology
• Pharmacology

Background:

• Antiglobulin responses are a significant challenge in monoclonal antibody (mAb) therapy.
• Strategies like using humanized or chimeric mAbs, or inducing tolerance, have been proposed to mitigate this issue.

Purpose of the Study:

• To investigate the efficacy of tolerance induction to constant regions of rat IgG2b mAbs in mice.
• To determine if tolerance to constant regions prevents antiglobulin responses to therapeutic mAbs.

Main Methods:

• Tolerance was induced in mice using classical deaggregation methods and anti-L3T4 mAb therapy.
• Mice were immunized with rat IgG2b mAbs lacking mouse cell specificity and with cell-binding mAbs.

Main Results:

• Mice tolerant to IgG2b constant region determinants did not mount an antiglobulin response to non-cell-binding mAbs.
• However, these tolerant mice generated strong anti-idiotypic responses to cell-binding mAbs.
• Binding of mAbs to hematopoietic cells highlighted their idiotype determinants as major immunogens, even with constant region tolerance.

Conclusions:

• Tolerance to constant regions alone is insufficient to prevent antiglobulin responses to cell-binding mAbs.
• The immunogenicity of idiotype determinants on cell-binding mAbs remains a challenge.
• Further research into additional methods is necessary to overcome antiglobulin responses in mAb therapy.