After washing, the plates were incubated with patient sera. (RIA), and a newly developed bridging enzyme linked immunosorbent assay (ELISA) was used to measure anti-allotype antibodies against adalimumab. The association between AAA and the G1m3 and the G1m17 allotypes was determined. For differences between groups we used the independent or paired samples t-test, Mann-Whitney test or Chi square/Fisher’s exact test as appropriate. To investigate the influence of confounders on the presence or absence of AAA a multiple logistic regression-analysis was used. == Results == Adalimumab carries the G1m17 allotype. No anti-allotype antibodies against adalimumab were detected. Thirty-nine out of 249 patients had anti-idiotype antibodies against adalimumab (16%). IgG allotypes of RA patients were associated with the frequency of AAA: patients homozygous for G1m17 had the highest frequency of AAA (41%), patients homozygous for G1m3 the lowest frequency (10%), and heterozygous patients’ AAA frequency was 14% (P= 0.0001). == Conclusions == An allotype mismatch between adalimumab and IgG in adalimumab-treated patients did not lead to a higher frequency of AAA. On the contrary, patients who carried the same IgG allotype as present on the adalimumab IgG molecule, had the highest frequency of anti-adalimumab antibodies compared to patients whose IgG allotype differed from adalimumab. This suggests that the allotype of adalimumab may not be highly immunogenic. Furthermore, patients carrying the G1m17-allotype might be more prone to antibody responses. == Introduction == Treatment with monoclonal antibodies (mAbs) is known to induce anti-mAb antibodies, leading to a diminished treatment response [1-5]. The general structure of all antibodies is very similar; it consists of a constant and a variable region, the variable region determines the idiotype. The anti-adalimumab antibodies (AAA) measured in previous studies are anti-idiotype antibodies, directed against the idiotype of adalimumab [1,6]. The constant region is almost identical in all antibodies of the same isotype, but differs in antibodies of different isotypes (for example, IgA, IgM, IgG, IgE, IgD). However, within an immunoglobulin of a certain isotype, allotypes represent slight differences in the amino acid sequences of the constant heavy or light chains of different individuals (Figure1) [7]. There are different allotypes for IgG1, IgG2 and IgG3 and no allotypes have been found for IgG4. Allotypes are inherited in a codominant Mendelian way, in fixed combinations called haplotypes. Allotypes expressed on the constant region of IgG heavy chain are designated as Gm (Genetic markers) together with the subclass. Allotypes of heavy 1 chains are defined as G1m allotypes, allotypes of heavy 2 chains as G2m allotypes, and of heavy 3 chains as G3m allotypes. The Gm system is unique in its ability to characterize human populations by specific sets of haplotypes. Specific Gm haplotypes are found in African, Caucasian and Mongoloid populations. In a Caucasian population the G1m1,17 (or G1m(a,z)) allotype is much less frequent (0.15 to 0.35) than G1m3 (or G1m(f)) (0.65 to 0.85) [8]. Therefore, serologically defined allotypes differ widely within Yunaconitine and between population groups [9]. == Figure 1. == Basic immunoglobulin structure and IgG1 allotypes.(a). Basic immunoglobulin structure. CH1, 2 and 3 are the constant heavy Yunaconitine chains. CL is the constant light chain. VH is the variable heavy chain and VL the variable light chain which together form the variable domain of the immunoglobulin, a specific antigen binding site, also referred to as the idiotype.(b). IgG1 allotypes [7]. The white residues in the constant parts are those residues which differ by allotype in human IgG1. There is a Lys (G1m17) for Arg (G1m3) change at codon 214 in the CH1 domain, an Asp 356 Leu 358 (G1m1) for Glu 356 Met 358 (nG1m1) in the CH3 domain and a Gly 431 (G1m2) for Ala (nG1m2) also in the CH3 domain. The nG1m1 and nG1m2 are not “true” allotypes because these amino acid residues are present in other IgG subclasses and are not expected to be immunogenic in the individual. Allotypic markers can therefore differ between individuals and immunoglobulins with Yunaconitine certain allotypes can be immunogenic when injected into individuals whose immunoglobulins lack the allotype. Treatment with monoclonal antibodies with a certain allotype can lead to the formation of anti-allotype antibodies. The allotypes of a panel of licensed mAbs was determined and adalimumab expresses the G1m1,17-allotype [9]. The risk to provoke antibody responses as a result of TSPAN7 allo-immunization has been described in a review [9]. MAb treatment of patients may lead to both allo-immunization and/or xeno-immunization that result in antisera that may recognize isotypic, allotypic and idiotypic epitopes. The association.