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Anti-Drug Antibody Formation Against Biologic Agents in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

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Abstract

Background and aims

Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment.

Methods

MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated.

Results

Data from 68 studies were analyzed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug-sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52; 95% CI 0.44–0.62), adalimumab (RR 0.31; 95% CI 0.14–0.69), golimumab (RR 0.29; 95% CI 0.10–0.83), certolizumab pegol (RR 0.30; 95% CI 0.14–0.67) and natalizumab (RR 0.20; 95% CI 0.11–0. 39). ADA to infliximab were associated with lower clinical response rates (RR 0.75; 95% CI 0.61–0.91) and higher rates of infusion reactions (RR 2.36; 95% CI 1.85–3.01).

Conclusions

Differences in analytical methods to detect ADA hamper comparison of true ADA rates across biologics in IBD. Use of combination therapy with immunomodulators appeared to reduce ADA positivity for most biologics. For infliximab, ADA were associated with reduced drug efficacy and increased adverse events.

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Acknowledgements

We would like to thank John MacDonald (Alimentiv Inc, London, Ontario, Canada) for his assistance in the writing process.

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Authors and Affiliations

  1. Amsterdam University Medical Center, Amsterdam, The Netherlands

    Steven J. Bots, Johannan F. Brandse, Mark Löwenberg & Geert D’Haens

  2. Division of Gastroenterology, Department of Medicine, School of Medicine, IBD Center, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA

    William J. Sandborn & Niels Vande Casteele

  3. Alimentiv Inc, London, ON, Canada

    Claire E. Parker, Brian G. Feagan, William J. Sandborn, Vipul Jairath, Geert D’Haens & Niels Vande Casteele

  4. Department of Medicine, Western University, London, ON, Canada

    Brian G. Feagan & Vipul Jairath

  5. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada

    Brian G. Feagan & Vipul Jairath

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  1. Steven J. Bots
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Correspondence to Niels Vande Casteele.

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Grant support

NVC holds a Research Scholar Award from the American Gastroenterological Association. WJS and NVC are supported in part by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515).

Disclosures

SB has served as speaker for Abbvie, Merck, Sharp & Dome, Takeda, Jansen Cilag, Pfizer and Tillotts. CEP is an employee of Robarts Clinical Trials, Inc. JFB has served as speaker for Abbvie, Merck, Sharp & Dome, Takeda and Tillotts. ML has served as speaker and/or principal investigator for Abbvie, Celgene, Covidien, Dr Falk, Ferring Pharmaceuticals, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist Therapeutics, Receptos, Takeda, Tillotts, Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Achmea Healthcare and ZonMW. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGeniX and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, ActoGeniX, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, gIcare Pharma Inc. and Sigmoid Pharma; and speaker bureau fees from UCB, AbbVie and J&J/Janssen. WJS has received research grants from Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from Abbvie, Abivax, AdMIRx, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), BeiGene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Prometheus Laboratories Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences; and is an employee at Shoreline Biosciences. Spouse: Iveric Bio (consultant, stock options); Progenity (stock); Oppilan Pharma (consultant, stock options); Prometheus Biosciences (employee, stock, stock options); Prometheus Laboratories (stock, stock options, consultant); Ventyx Biosciences (stock, stock options); Vimalan Biosciences (stock, stock options). VJ has received scientific advisory board fees from Janssen, Takeda, Pfizer, Sandoz, Abbvie and Merck; and speaker bureaux fees from Takeda, Ferring, Janssen, Pfizer and Shire. GDH has served as advisor for Abbvie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronic, Ferring, Dr Falk Pharma, Eli Lilly, enGene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp & Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, TiGenix, Tillotts, Topivert, Versant and Vifor; received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp & Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts and Vifor. NVC has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from Alimentiv, Inc. (formerly Robarts Clinical Trials, Inc.), Celltrion and Prometheus.

Availability of data and material

All data will be made available.

Writing assistance

No funding was received for writing assistance.

Author contributions

Study concept and design: SB, GDH, NVC; acquisition of data: SB, JFB, NVC; analysis and interpretation of data: SB, CEP, NVC; draft of the manuscript: SB, CEP, NVC; critical revision of the manuscript for important intellectual content: SB, JFB, ML, BGF, WJS, RK, VJ, GDH, NVC; study supervision: GDH, NVC. All authors have approved the final version of this manuscript.

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Bots, S.J., Parker, C.E., Brandse, J.F. et al. Anti-Drug Antibody Formation Against Biologic Agents in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. BioDrugs 35, 715–733 (2021). https://doi.org/10.1007/s40259-021-00507-5

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