Patient-related: |
Genetic factors |
IL-10 gene polymorphism (fundamental in AB synthesis) in patients with rheumatoid arthritis (RA) treated with the anti-tumor necrosis factor (anti-TNF). Specific human leukocyte antigen (HLA) haplotypes: - HLA DRB1 in antigen-presenting dendritic cells in patients with hidradenitis suppurativa (HS) and adalimumab (ADL), inflammatory bowel disease (IBD), and infliximab (IFX). - HLA DBbeta-11, HLA-DQ-03, and HLA DQ-05 anti-NF alleles. V158F functional polymorphism in one of the FcgammaR genes that affects the AB binding capacity to the drug (eg. IFX in EC) (11. Vaisman-Mentesh A, Gutierrez-Gonzalez M, DeKosky BJ, Wine Y. The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment with Monoclonal Antibodies. Front Immunol. 2020;11:1951. https://doi.org/10.3389/fimmu.2020.01951 https://doi.org/10.3389/fimmu.2020.01951...
). |
Disease type and activity |
Immune system (IS) activation: - Due to immunoreactivity of the disease itself. - High expression of costimulatory molecules in dendritic cells that accelerate the production of anti-drug antibodies (ADAs). - B lymphomas in patients with RA treated with rituximab (RTX): ADA in 1-4% Type of inflammatory diseases: - Primary Sjörgen syndrome + ANCA (+) vasculitis: ADA in 25% of the patients - LES: ADA up to 40% - ADA anti-IFX in patients with RA (+) versus RA (-) = 62.5% versus 37.5%, respectively Reduced disease activity allows higher levels of circulating monoclonal antibodies (mcABs), which may promote immune tolerance |
Drug-related: |
Drug dose (and plasma concentration) |
Lower doses>higher doses: Higher doses of the drug reduce immunogenicity and induce tolerance by depletion of the immune response (1414. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552-63. https://doi.org/10.1002/1529-0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W https://doi.org/10.1002/1529-0131(199809...
) |
Route of administration |
Intradermal or SBC>intravenous: Favor the uptake and presentation by antigen-presenting cells (APCs) |
Frequency of administration |
Intermittent treatment>continuous therapy: Continuous administration allows the development of immune tolerance |
Chemical formulation |
Molecular structure not identical to endogenous immunoglobulin (Ig) even in fully human mcAB (new epitopes in complementarity determining region (CDR) sequences) due to idiotype/anti-idiotype interactions (11. Vaisman-Mentesh A, Gutierrez-Gonzalez M, DeKosky BJ, Wine Y. The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment with Monoclonal Antibodies. Front Immunol. 2020;11:1951. https://doi.org/10.3389/fimmu.2020.01951 https://doi.org/10.3389/fimmu.2020.01951...
). Severe anaphylactic reactions to cetuximab due to non-human carbohydrate residues that cross- react in red meat proteins sensitized patients (beef, pork, or lamb) that induce the formation of IgE-type ADA (1515. Yamaguchi K, Watanabe T, Satoh T, Ishiguro M, Izawa M, Inoshiri S, et al. Severe infusion reactions to cetuximab occur within 1 h in patients with metastatic colorectal cancer: results of a nationwide, multicenter, prospective registry study of 2126 patients in Japan. Jpn J Clin Oncol. 2014;44(6):541-6. https://doi.org/10.1093/jjco/hyu049 https://doi.org/10.1093/jjco/hyu049...
). |
Post-translational modifications |
Removal of N-terminal glycosylation of the Fc fragments chains decreases the immunogenicity of mcAB. Impurities in the formulation processes. Danger model: IS responds more to substances that cause harm than exogenous ones. For example, impurities or residues in the processing of biologicals agents (11. Vaisman-Mentesh A, Gutierrez-Gonzalez M, DeKosky BJ, Wine Y. The Molecular Mechanisms That Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment with Monoclonal Antibodies. Front Immunol. 2020;11:1951. https://doi.org/10.3389/fimmu.2020.01951 https://doi.org/10.3389/fimmu.2020.01951...
). |
Target molecules |
Anti-IL-6 mcAB, tocilizumab, has low incidence of ADA formation because interleukin (IL)-6 participates in modulating the humoral immune response. mcAB directed at certain target molecules on cell surfaces, would induce greater immunogenicity than those directed against soluble molecules, since the latter require more processing to be finally presented as antigens Rituximab, chimeric anti-CD20 mcAB, selectively depletes CD20 (+) B lymphocytes, but does not affect pre-B or immature B cells lymphocytes, nor does it affect the maturation of memory plasma cells, which prevents the production of ADAs (1616. Schmidt E, Hennig K, Mengede C, Zillikens D, Kromminga A. Immunogenicity of rituximab in patients with severe pemphigus. Clin Immunol. 2009;132(3):334-41. https://doi.org/10.1016/j.clim.2009.05.007 https://doi.org/10.1016/j.clim.2009.05.0...
). |
Treatment-related: |
Treatment duration |
Short>long treatments: - ADA titers decrease over time in prolonged treatments by inducing immunological tolerance due to continuous exposure to the drug. |
Treatment interruption |
Variable response: - Greater development of ADA after temporary suspension of IFX versus continuous administration, without interruptions (39% versus 16%), in patients with Crohn's disease (CD) and ulcerative colitis (UC) (1717. Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11:1756283X17750355. https://doi.org/10.1177/1756283X17750355 https://doi.org/10.1177/1756283X17750355...
). - Repeated cycles with several interruptions of omalizumab in patients with UC showed complete remission without development of ADA (1818. Matucci A, Nencini F, Rossi O, Pratesi S, Parronchi P, Maggi E, et al. The percentage of patients achieving complete remission of urticaria increases with repeated courses of treatment. J Allergy Clin Immunol Pract. 2019;7(1):339-40. https://doi.org/10.1016/j.jaip.2018.06.011 https://doi.org/10.1016/j.jaip.2018.06.0...
). |
Concomitant use of immunosuppressants |
Methotrexate (MTX) favors the elimination of antigen-activated lymphocytes and/or stimulates the activity of regulatory T cells lymphocytes, avoiding clonal expansion of B cells. Dose-dependent effect on RA (1919. Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71(11):1914-5. https://doi.org/10.1136/annrheumdis-2012-201544 https://doi.org/10.1136/annrheumdis-2012...
). The addition of azathioprine (AZA) in patients with inflammatory bowel disease (IBD) and loss of response to a first anti-TNF, favors the pharmacokinetic profile of a second anti-TNF (2020. Roblin X, Williet N, Boschetti G, Phelip JM, Del Tedesco E, Berger AE, et al. Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Gut. 2020;69(7):1206-12. https://doi.org/10.1136/gutjnl-2019-319758 https://doi.org/10.1136/gutjnl-2019-3197...
). |