Anti-idiotypes

Geha R, Quinti I, Austen K, Cicardi M, Sheffer A, Rosen F Acquired Cl-inhibitor deficiency associated with anti-idiotypic antibody to monoclonal immunoglobuhns. N Engl J Med 1985 312 534-540. Donaldson V, Hess E, McAdams A Lupus-erythe-matosus-like disease in three umelated women with hereditary angioneurotic edema. Arm Intern Med 1977 86 312-313. 

Idiotypic network. Idiotypic determinants (idiotypes) are unique antigenic epitopes characteristic of the antigen receptors on the surface of T and B cells. They are associated with the variable regions of these receptors. Antibodies produced by B cells as the result of antigenic stimulation can themselves stimulate the production of auto-anti-idiotypic antibodies which have the ability to combine with the B-cell receptor (Ig) and thus can dampen down the immune response. Idiotypes may likewise stimulate the production of T cells specific for idiotypic determinants. Jerne (1974) postulated his... 

Ab2 S Anti-idiotype antibody which binds to the antigen binding region Ab3 Anti-anti-idiotype antibody Abcc Antibody dependent cellular cytotoxicity... 

Hypersensitivity to foreign epitopes Anti-idiotypic response to normal cells Immune complex disease Potential MPS toxicity D. Specific specificity... 

Garcia, K.C., Ronco, P.M., Verroust, P.J., Briinger, AT. and Mazel, L.M. (1992) Three-dimensional structure of an angiotensin II-Fab complex at 3 A hormone recognition by an anti-idiotypic antibody, Science, 257, 502-507. 

Szabo, J., Kruger, S.R., and Beall, G.N. (1989) Detection of cells producing anti-idiotypic antibody to thyroid stimulating hormone-reactive antibodies. Immunol. Invest. 18, 879-884. 

Mercuric chloride in the BN rat gives a lymphoproliferation in spleen and lymph nodes, including B and T helper cells, an increase in the number of Ig containing cells resulting in a rise in all serum Ig isotypes and an early thymic atrophy [196]. The kinetics of the increase in the serum level of various Ig isotypes were similar to that observed for IgE, suggesting spontaneous autoregulation, which could involve suppressor T cells [ 197, 198] and/or auto-anti-idiotypic antibodies [ 199]. 

Monoclonal antibody (or component) Hybridoma human cell line Probably predictable anitgenicity Moderate Anti-tumor antibody for imaging anti-idiotype antibody as vaccine... 

Igarashi, K., Kaneda, M., Yamaji, A., Saido, T.C., Kikkawa, U., Qno, Y., Inoue, K., and Umeda, M., 1995, A novel phosphatidylserine-binding peptide motif defined by an anti-idiotypic monoclonal antibody. Localization of phosphatidylserine-specific binding sites on protein kinase C and phosphatidylserine decarboxylase. J. Biol. Chem. 270 29075-29078. 

Figure 26 Production of abzymes using the anti-idiotypic antibodies method.

The most outstanding example illustrating this strategy came from the team of Alain Friboulet and Daniel Thomas, who produced anti-idiotype antibodies against a monoclonal antibody AE2 that was a competitive inhibitor of acetylcholine esterase. One of the selected antibodies, 9A8, catalyzes the hydrolysis of acetylthio-choline with a pseudo first-order rate constant /feat = 81 and a factor of acceleration of 4.2 x 10 . These remarkable parameters, which are only two orders of magnitude lower when compared to those of the enzyme, make abzyme 9A8 the most powerful abzyme known until now. 

Immunogenicity Low titers of anti-idiotype antibodies to daclizumab were detected in the adult patients treated with daclizumab with an overall incidence of 14%. The incidence of anti-daclizumab antibodies observed in the pediatric patients was 34%. No antibodies that affected efficacy, safety, serum daclizumab levels or any other clinically related parameter were detected. 

Assay Systems Based on Anti-idiotype Antibodies. 158... 

The invention of B cell hybridoma technology (K3) has allowed the generation of various kinds of useful antibodies, even very minor or rare antibody species elicited in serum by the conventional procedure, as a pure immunochemical reagent in almost unlimited amounts. Among such new-generation monoclonal antibodies, anti-idiotype antibodies and anti-immune complex (anti-metatype) antibodies have been successfully introduced as key reagents enabling noncompetitive hapten immunoassays (Fig. 11). 

Fig. 11. Schematic representation of the binding properties of anti-idiotype antibodies and antimetatype antibodies. V, hapten a-Id, a-type anti-idiotype antibody /i-Id, /i-type anti-idiotype antibody Met, anti-metatype antibody anti-C-region, antibodies recognizing the constant region of a primary antibody (recognizing isotype or allotype).

Fig. 12. Noncompetitive hapten immunoassay procedures (A and B) using a combination of the a-type and j6-type anti-idiotype antibodies, each recognizing the framework and paratope of the anti-hapten antibody. Anti-hap, anti-hapten antibody (primary antibody) a-Id, a-type anti-idiotype antibody /J-Id, /i-type anti-idiotype antibody S, signal-generating group B, biotin SA, streptavidin.

Self (S4) first proposed the concept of noncompetitive assay for haptens utilizing an adequate combination of an a-type and a jS-type anti-idiotype antibody, in which he used the term, selective antibody for the a-type antibodies. Then, Barnard and Cohen (Bl) applied this assay principle for the determination of serum E2, naming the assay system an idiometric assay. Figure 12A illustrates the assay procedure of the idiometric assay of E2. The target hapten is captured by excess anti-E2 antibody immobilized on microtiter strips by incubation at room temperature for 1 h (step i). After washing the strips, the /3-type anti-idiotype antibody was added in order to saturate (or block) the unoccupied paratope of the anti-E2 antibody (incubation, room temperature for 30 min) (step ii). The a-type anti-idiotype antibody, which has been labeled with a europium chelate (H4), was then added to the plate and incubated at room temperature for a further 2 h (step iii). Finally, fluorescence intensity due to bound europium was measured with a time-resolved fluorometer. Because of large steric hindrance around the bound jS-type antibody (MW 150,000), the labeled a-type antibody would. 

We (K1) attempted to develop a noncompetitive assay based on the anti-idiotype antibodies for a conjugated bile acid metabolite, ursodeoxycholic acid 7-A-acetyl-glucosaminide (UDCA 7-NAG), which is expected to serve as a diagnostic index for an autoimmune disease, primary biliary cirrhosis. In our assay, the hapten UDCA 7-NAG, a /3-type antibody, and a biotin-labeled a-type antibody were simultaneously added to a microtiter plate coated with an F(ab )2 fragment of a specific anti-UDCA 7-NAG antibody, then incubated at room temperature for 8 h. Bound biotin was then detected with HRP-labeled streptavidin, whose enzyme activity was measured using o-phenylenediamine/H202 as a substrate. This noncompetitive assay system provided a subfemtomole-order sensitivity (detection limit 118 amol) that was 7 times lower than the competitive immunoassay using the same anti-hapten antibody (K2), even with a common colorimetric detection (Fig. 13). Somewhat improved specificity was also obtained namely, better... 

Development of such idiotype-dependent assays requires much labor and a long period because two-step antibody production is necessary first, immunization with a hapten-carrier conjugate to produce a specific anti-hapten antibody, then a second immunization with the anti-hapten antibody for generating two types of anti-idiotype antibodies. Furthermore, a suitable combination between a-type and /3-type antibodies, whose binding to the anti-hapten antibody is competitive, has to be found. 

The assay principle should, however, be applicable to any target hapten, unlike assays based on a chemical modification. Cloning efficiency of the hybridoma-secreting anti-idiotype antibodies would be in a practical range, and much higher than that of anti-metatype antibodies. We (Kl) established four kinds of a-type and two kinds of /3-type anti-idiotype antibodies after three fusion experiments, each using spleen cells from one immunized mouse. Barnard et al. (Bl, B3, B4)... 

Kl. Kobayashi, N., Oiwa, H., Kubota, K., Sakoda, S., and Goto, J., Monoclonal antibodies generated against an affinity-labeled immune complex of an anti-bile acid metabolite antibody An approach to noncompetitive hapten immunoassays based on anti-idiotype or anti-metatype antibodies. J. Immunol. Methods 245, 95-108 (2000). 

Schick, M. R., and Kennedy, R. C., Production and characterization of anti-idiotypic antibody reagents. Methods Enzymol. 178,36-48 (1989). 

Figure 1. A general scheme of idiotypes and anti-idiotypes. Depicted here are immunoglobulin proteins whose antigencombining site expresses unique conformations or epitopes, that are termed idiotopes. A collection of idiotopes constitute what is termed idiotype. Some idiotypes are shared by many immunoglobulins with the same antigenic specificity.

Anti-idiotypes are antibodies with specificity for idiotypes. The antibodies can be made in the same species or in other species. Often the interaction of anti-idiotypes to idiotypes is inhibited by free antigen. 

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