title: Immunotherapy with human monoclonal antibodies. Fragment A specificity of polyclonal and monoclonal antibodies is crucial for full protection against tetanus toxin.
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.
authors.affiliation: Swiss Serum and Vaccine Institute, Berne.
authors.forename: A B
authors.initials: AB
authors.lastname: Lang
authors.forename: S J
authors.initials: SJ
authors.lastname: Cryz
authors.forename: U
authors.initials: U
authors.lastname: Schürch
authors.forename: M T
authors.initials: MT
authors.lastname: Ganss
authors.forename: U
authors.initials: U
authors.lastname: Bruderer
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D000915:Antibody Affinity; D000918:Antibody Specificity; D006801:Humans; D006825:Hybridomas; D007132:Immunoglobulin Isotypes / Q000276:immunology; D013744:Tetanus Toxin / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007132:Immunoglobulin Isotypes; D013744:Tetanus Toxin