1. Immunotherapy with human monoclonal antibodies. Fragment A specificity of polyclonal and monoclonal antibodies is crucial for full protection against tetanus toxin.
- Author
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Lang AB, Cryz SJ Jr, Schürch U, Ganss MT, and Bruderer U
- Subjects
- Antibody Affinity, Antibody Specificity, Humans, Hybridomas, Immunoglobulin Isotypes immunology, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Tetanus Toxin immunology
- Abstract
To investigate the feasibility of substituting human mAb (HmAb) for human polyclonal preparations in the treatment of infections, we employed anti-tetanus toxin (TT) as a model system. We established a large panel of hybridomas secreting anti-TT HmAb and compared their fine specificities and protectivity with those exhibited by tetanus immune globulin (TIG). Analysis of three different commercial TIG preparations indicated that the majority of anti-TT antibodies is directed against epitopes expressed by the A fragment, the L chain of TT. Absorption of TIG with purified A fragment completely abolished its protective capacity in mice. Absorption with C fragment, the carboxy-terminal portion of the H chain of TT, had no discernible effect, illustrating the crucial importance of anti-A fragment antibody. The vast majority of more than 100 generated TT-specific HmAb showed specificity for the A fragment. Six HmAb with significant neutralizing activity were identified and further characterized. Five of them recognized the A fragment, whereas one, ST12, bound to both the A fragment and the C fragment with equal affinity. ST12 by itself conferred long lasting protection against TT intoxication when singly administered, and the remainder mediated only a delayed death. ST12 conferred a protection of 13.2 IU/100 micrograms IgG. However, when individual HmAb were combined, synergistic effects were observed. Optimal potency (43 IU/100 micrograms IgG) was obtained with a combination of two HmAb. To obtain a 250-IU dose, only 0.7 mg of this mixture was required in contrast to 100 to 170 mg IgG for TIG.
- Published
- 1993