P1317 Genetic factors influencing risk of anti-drug antibody formation in inflammatory bowel disease

Abstract Background Biological therapies have transformed the management of inflammatory bowel disease (IBD). However, many patients experience loss of response (LOR), often due to the development of anti-drug antibodies (ADA).1 The aim of the study was to explore association between genetic variations and ADA development in patients with IBD treated with biologics. Methods Systematic review of the literature using a predefined search string. We searched Medline, Embase, and the Cochrane Library and identified 1,944 records, of which 27 studies were included in the analysis. Articles were screened, and data extracted, by two independent persons. Results HLA-DQA105 carriage was consistently associated with increased risk of ADA, lower drug levels, treatment failure, and secondary LOR in both infliximab (IFX) and adalimumab (ADL) treated IBD patients, with strongest effects observed in IFX. With the high prevalence in Western populations (≈31–46%), HLA-DQA1*05 represents a clinically relevant risk factor.2 Outcomes varied with population, study design, and statistical approach across studies, preventing a pooled result or summary interval. Across four studies focusing on IFX, all demonstrated increased ADA risk in HLA-DQA1*05 carriers (HR 1.65, adjusted HR 7.29), including higher rates of treatment intensification, drug discontinuation and LOR.3 Other HLA alleles were also associated with increased risk of ADA, while some haplotypes appeared protective. FCGR3A variants were similarly strong predictors of ADA formation during IFX therapy with highest risk in V allele carriers (HR 7.3, OR 6.08), reduced trough levels and increased need for dose escalation. Frequencies for FCGR3A variants (F 66%, V 34%) further highlights their potential clinical impact.4 Combined carriage of FCGR3A and HLA-DQA1*05 additionally increased the ADA risk by 10-fold. For ADL, FCGR3A showed a weaker but allele-dose–dependent association with ADA formation. Other genetic variants including TNF-related SNPs, IGHG1 allotypes, NUDT15, and CD96, showed limited, inconsistent or context-specific associations. ADA rates for ustekinumab and vedolizumab were low and no genetic associations were detected. Immunomodulator co-therapy, disease type or age had inconsistent or minimal effects on ADA risk. Conclusion HLA-DQA1*05 and FCGR3A are the most consistent predictors of immunogenicity and are strongly associated with ADA formation, LOR and drug level reductions – particularly in IFX-treated patients. Given relatively high prevalence of the genetic variants, evaluating these polymorphisms is clinically relevant. Routine testing may guide treatment optimization and therapy selection. As commercial assays are available, implementation is feasible. References: 1. Nielsen OH, Hammerhøj A, Ainsworth MA, Gubatan J, D’Haens G. Immunogenicity of Therapeutic Antibodies Used for Inflammatory Bowel Disease: Treatment and Clinical Considerations. Drugs. 2025;85(1):67-85. doi:10.1007/s40265-024-02115-3 2. Navajas Hernández P, Mouhtar El Halabi S, González Parra AC, et al. Carriage of the HLA-DQA1⋆05 haplotype is associated with a higher risk of infratherapeutic drug concentration and higher immunogenicity in patients undergoing treatment with anti-TNF for inflammatory bowel disease. Therap Adv Gastroenterol. 2024;17:17562848241278145. doi:10.1177/17562848241278145 3. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology. 2020;158(1):189-199. doi:10.1053/j.gastro.2019.09.041 4. Mahaweni NM, Olieslagers TI, Rivas IO, et al. A comprehensive overview of FCGR3A gene variability by full-length gene sequencing including the identification of V158F polymorphism. Sci Rep. 2018;8(1):15983. doi:10.1038/s41598-018-34258-1 Conflict of interest: Mrs. Culmsee-Holm, Frederikke Bindseil: No conflict of interest Buhl, Emil: No conflict of interest Tjørnehøj Kraaer, Mads: No conflict of interest Steenholdt, Casper: Lectures for Takeda, MSD and Janssen-Cilag research grant from Takeda. Ainsworth, Mark Andrew: Other: None