title: Immunogenicity in rabbits and mice of an antibody-chelate conjugate: comparison of (S) and (R) macrocyclic enantiomers and an acyclic chelating agent.
abstract: The macrocyclic bifunctional chelating agent 2-(p-bromoacetamidobenzyl)-1,4,7,10-tetraazacyclododecanetetraa cetic acid (BAD), forms inert metal complexes ideal for radioimmunotherapy. Kosmas et al. (Cancer Res., 52: 904-911, 1992) found 2-imminothiolane linker-(S)-BAD monoclonal antibody HMFG1 highly immunogenic in patients. We studied the immunogenicity of (S) and (R) enantiomers of 2-imminothiolane linker-BAD rabbit IgG, monoclonal antibody Lym-1, and Lym-1 2-imminothiolane linker-(S)-bromoacetamidobenzyl-EDTA in 15 rabbits. Five groups of three each were given 0.1, 1.0, or 10 mg of 111In conjugate i.v., blood samples were taken daily for 14 days and biweekly for 70 days, and the plasma T1/2 was calculated. A drop in plasma 111In at 6-8 days coincided with the appearance of antibody on enzyme-linked immunosorbent assay. Specific anti-(S)-BAD, anti-(R)-BAD, anti-(S)-bromoacetamidobenzyl-EDTA, and anti-mouse IgG were measured. Rabbit IgG conjugates did not elicit an immune response. Mouse IgG conjugates were immunogenic on the first exposure, with both anti-1,4,7,10-tetraazacylododecane N,N',N'',N'''-tetraacetic acid and anti-mouse responses. Anti-1,4,7,10-tetraazacylododecane N,N',N'',N'''-tetraacetic acid was specific for the (S) or (R) enantiomer, but cross-reaction appeared with reboosting. A second injection of the opposite enantiomer gave a response to that enantiomer. Lym-1 bromoacetamidobenzyl-EDTA produced anti-bromoacetamidobenzyl-EDTA and anti-mouse response.
authors.affiliation: Nuclear Medicine Service, VA Medical Center, Palo Alto 94304.
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
authors.forename: D A
authors.initials: DA
authors.lastname: Goodwin
authors.forename: C F
authors.initials: CF
authors.lastname: Meares
authors.forename: M
authors.initials: M
authors.lastname: McTigue
authors.forename: W
authors.initials: W
authors.lastname: Chaovapong
authors.forename: C M
authors.initials: CM
authors.lastname: Ransone
authors.forename: O
authors.initials: O
authors.lastname: Renn
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D002614:Chelating Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004492:Edetic Acid / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D006241:Haptens / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D013237:Stereoisomerism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D006241:Haptens; D006433:Hemocyanins; D004492:Edetic Acid; C032808:keyhole-limpet hemocyanin