Protective factors identified against anti-drug antibody formation to adalimumab in psoriasis

The development of anti-drug antibodies (ADA) against adalimumab is an important cause of treatment failure in patients with psoriasis. In a genome-wide association study, certain amino acid variations within the human leukocyte antigens (HLA)-DR peptide-binding groove showed to be protective against ADA formation. Thus, pre-treatment HLA-DRB1 genotyping might be a promising option for patient selection.

An analysis of the BADBIR registry enrolling more than 50% of patients with psoriasis in the United Kingdom revealed that the major reason for stopping biologic therapy is ineffectiveness [1]. “We know that at least some of this ineffectiveness is driven by drug immunogenicity, the ability of therapeutic proteins to trigger the development of ADA,” Dr Teresa Tsakok (King’s College London, UK) explained. ADA drive drug ineffectiveness by reducing levels of a functional drug. In a UK cohort, 65% of patients developed ADA over 3 years. ADA-positive patients were more than twice as likely to stop treatment compared with ADA-negative patients. Until now, it was not clear why some patients on adalimumab treatment developed ADA and some did not. “Genetic predictors of developing ADA at baseline may have clinical utility in decision making even before treatment has started, such as using a more immunogenic biologic and whether to consider co-therapy with an immunosuppressant such as methotrexate, which is known to reduce the development of ADA,” Dr Tsakok suggested.

With their genome-wide association study, Dr Tsakok and her team aimed to identify genetic predictors of developing ADA in psoriasis patients on their first course of adalimumab. They used data within the BSTOP bioresource. Genotyping data was available of 1,732 patients exposed to adalimumab. The discovery cohort comprised 784 psoriasis patients with ADA data available 6­–36 months after starting adalimumab. In the replication cohort, 232 patients had ADA data available of <6 months after starting adalimumab, and the treatment cohort had 716 psoriasis patients with only clinical data but no ADA data available. All in all, they measured genetic variations of single nucleotide polymorphisms in 10,917,604 samples.

In the discovery cohort, a genome-wide significant association was identified with ADA within the major histocompatibility complex (MHC). This complex is responsible for antigen presentation, which initiates the adaptive immune response. Dr Takok pointed out that the presence of tryptophan at position 9 and lysine at position 71 each conferred about 2.8-fold protection against ADA. This result was also shown in the replication cohort. Amino acid positions 9 and 71 are centrally located in the peptide-binding groove of the HLA-DR protein. “In fact, these HLA-DR positions are well known in terms of susceptibility to immune-mediated diseases such as rheumatoid arthritis or inflammatory bowel disease, but they have not been robustly described in the context of developing an immune response against a drug,” Dr Tsakok explained. An assessment of the treatment cohort underscored the clinical relevance of these findings: both HLA-DRB1 residues (position 9 and 71) were also protective against treatment failure (HR 0.73; 95% CI 0.57–0.94; P=0.013) with patients having 2 protective residues being most likely to remain on adalimumab treatment (see Figure). Thus, Dr Tsakok concluded that pre-treatment HLA-DRB1 genotyping holds the potential to direct clinical decision-making in terms of biologic selection and immunosuppressant co-therapy.

Figure: HLA-DRB1 residues 9W and 71K protect against treatment failure [2]

1. 
   
   1. Yiu ZZN, et al. Br J Dermatol 2020;183:294–302.
   2. Tsakok T, et al. Development of antidrug antibodies to adalimumab is associated with amino acid variation within the HLADRB1 peptide-binding groove. FC-15. Psoriasis form gene to clinic 2021, 9–11. December.

Copyright ©2021 Medicom Medical Publishers



Posted on 2 February 20222 February 2022