Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study

Abstract

Introduction: The human monoclonal antibody adalimumab is known to induce an anti-globulin response in some adalimumab-treated patients. Antibodies against adalimumab (AAA) are associated with non-response to treatment. Immunoglobulins, such as adalimumab, carry allotypes which represent slight differences in the amino acid sequences of the constant chains of an IgG molecule. Immunoglobulins with particular IgG (Gm) allotypes are racially distributed and could be immunogenic for individuals who do not express these allotypes. Therefore, we investigated whether a mismatch in IgG allotypes between adalimumab and IgG in adalimumab-treated patients is associated with the development of AAA.

Methods: This cohort study consisted of 250 adalimumab-treated rheumatoid arthritis (RA) patients. IgG allotypes were determined for adalimumab and for all patients. Anti-idiotype antibodies against adalimumab were measured with a regular radio immunoassay (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.

Figure 1

Basic immunoglobulin structure and IgG1 allotypes. (a). Basic immunoglobulin structure. CH1, 2 and 3 are the constant heavy 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.