0774: HLA-DQ2 Is Associated with Anti-drug Antibody Formation to Infliximab Across Immune-mediated Inflammatory Diseases

Marthe K. Brun¹, Kristin Hammersbøen Bjørlykke², Marte Kathrine Viken³, Grete-Elisabeth Stenvik¹, Rolf Klaasen³, Johanna Elin Gehin³, David Warren³, Joe Sexton¹, Espen Haavardsholm¹, Jørgen Jahnsen², Benedicte Alexandra Lie³, Nils Bolstad³, Kristin Kaasen Jørgensen², Guro Løvik Goll¹ and Silje Watterdal Syversen¹, ¹Diakonhjemmet Hospital, Oslo, Norway, ²Akershus University Hospital, Oslo, Norway, ³Oslo University Hospital, Oslo, Norway

Background/Purpose: Immunogenicity is a leading cause of treatment failure to TNF inhibitors, and also affects drug safety. Variations in HLA class II genes have been suggested to predispose to anti-drug antibody formation (ADA), but characterization of biologically relevant HLA haplotypes, based on high-resolution genotyping, is lacking. The aim was to assess associations between HLA loci and formation of ADA to infliximab across different immune mediated inflammatory diseases.

Methods: Patients with immune mediated inflammatory diseases on infliximab therapy (N=612; 181 spondyloarthritis, 120 rheumatoid arthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 80 Crohn's disease and 45 psoriasis) participating in the Norwegian Drug Monitoring (NOR-DRUM) trials (1, 2) were included in the present analyses. Neutralizing ADA were assessed with an automated fluorescence assay at each infusion. Next generation sequencing-based HLA typing was performed (Histogenetics®). Associations with ADA formation were assessed at locus, allele, haplotype and amino acid level. Peptide binding predictions for infliximab were performed.

Results: ADA were detected in 147 patients (24%). Significant associations were shown between ADA and several HLA loci, whereas conditional analyses indicated HLA-DQB1 (p=1.4x10-6) as the primary risk locus. Highest risk of ADA formation was seen for patients carrying at least one of the HLA-DQ2 haplotypes; DQB1*02:01~DQA1*05:01 and DQB1*02:02~DQA1*02:01 (OR 3.18, 95% CI 2.15 to 4.69, p=5.9x10-9) (Figure). These findings were consistent across diagnoses (Table), and remained significant when adjusting for other possible predictors of ADA. Computational predictions indicated that both these HLA-DQ2 haplotypes could strongly bind two peptide motifs (INTVESEDI and VYACEVTHQ) in the infliximab heavy and light chain.

Conclusion: The risk of ADA to infliximab was three-fold higher in patients carrying the HLA-DQ2 risk haplotypes across diseases. A biological role for the HLA-DQ2 molecules encoded by the two different HLA-DQ2 risk haplotypes in the formation of ADA was further supported by peptide binding predictions. These novel findings provide promise for future incorporation of HLA-DQ2 testing to facilitate personalized treatment decisions.

1. Syversen SW et al. Jama. 2021;326(23):2375-84.

2. Syversen SW et al. Jama. 2021;325(17):1744-54.

Table. HLA-DQ2 Carrier Frequencies According to the Different Disease Phenotypes and for All Diagnosis Combined


Disclosures: M. Brun, None; K. Bjørlykke, Akershus University Hospital; M. Viken, None; G. Stenvik, None; R. Klaasen, GE Healthcare; J. Gehin, None; D. Warren, None; J. Sexton, None; E. Haavardsholm, Pfizer, AbbVie, Eli Lilly, UCB, Boehringer-Ingelheim, Gilead; J. Jahnsen, AbbVie/Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb(BMS), Janssen, Gilead, Pfizer, Roche, Sandoz, Takeda, Galapagos; B. Lie, None; N. Bolstad, None; K. Jørgensen, Roche, Bristol-Myers Squibb(BMS); G. Goll, Galapagos, AbbVie/Abbott, Pfizer, UCB; S. Syversen, None.