Skip to main content

Advertisement

SpringerLink
Log in

Anti-Drug Antibody Incidence Comparison of Therapeutic Proteins Administered Via Subcutaneous vs. Intravenous Route

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Subcutaneous (SC) administration of therapeutic proteins is perceived to pose higher risk of immunogenicity when compared with intravenous (IV) route of administration (RoA). However, systematic evaluations of clinical data to support this claim are lacking. This meta-analysis was conducted to compare the immunogenicity of the same therapeutic protein by IV and SC RoA. Anti-drug antibody (ADA) data and controlling variables for 7 therapeutic proteins administered by both IV and SC routes across 48 treatment groups were analyzed. RoA was the primary independent variable of interest while therapeutic protein, patient population, adjusted dose, and number of ADA samples were controlling variables. Analysis of variance was used to compare the ADA incidence between IV and SC RoA, while accounting for controlling variables and potential interactions. Subsequently, 10 additional therapeutic proteins with ADA data published for both IV and SC administration were added to the above 7 therapeutic proteins and were evaluated for ADA incidence. RoA had no statistically significant effect on ADA incidence for the initial dataset of 7 therapeutic proteins (p = 0.55). The only variable with a significant effect on ADA incidence was the therapeutic protein. None of the other controlling variables, including their interactions with RoA, was significant. When all data from the 17 therapeutic proteins were pooled, there was no statistically significant effect of RoA on ADA incidence (p = 0.81). In conclusion, there is no significant difference in ADA incidence between the IV and SC RoA, based on analysis of clinical ADA data from 17 therapeutic proteins.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

Data are available upon request.

References

  1. National Cancer Institute at the National Institute of Health. Definition of biotherapy. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/biotherapy. Accessed 17 Feb 2023.

  2. United States Food and Drug Administration. Center for Drug Evaluation and Research. 21 CFR 600. 2020–03505. Definition of the term biological product. 2020;85(35):10057–63. https://www.federalregister.gov/documents/2020/02/21/2020-03505/definition-of-the-term-biological-product. Accessed 17 Feb 2023.

  3. Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides – harmonized terminology and tactical recommendations. AAPS J. 2014;16(4):658–73. https://doi.org/10.1208/s12248-014-9599-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hamuro L, Kijanka G, Kinderman F, Kropshofer H, Bu DX, Zepeda M, et al. Perspectives on subcutaneous route of administration as an immunogenicity risk factor for therapeutic proteins. J Pharm Sci. 2017;106(10):2946–54. https://doi.org/10.1016/j.xphs.2017.05.030.

    Article  CAS  PubMed  Google Scholar 

  5. United States Food and Drug Administration, Center for Drug Evaluation and Research. Guidance document: Immunogenicity assessment for therapeutic protein products. 2014. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/immunogenicity-assessment-therapeutic-protein-products. Accessed 17 Feb 2023.

  6. United States Food and Drug Administration, Center for Drug Evaluation and Research. Guidance document: Immunogenicity testing of therapeutic protein products – developing and validating assays for anti-drug antibody detection. 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/immunogenicity-testing-therapeutic-protein-products-developing-and-validating-assays-anti-drug. Accessed 17 Feb 2023.

  7. Pitiot A, Heuzé-Vourc’h N, Sécher T. Alternative routes of administration for therapeutic antibodies-state of the art. Antibodies (Basel). 2022;11(3):56. https://doi.org/10.3390/antib11030056.

    Article  CAS  PubMed  Google Scholar 

  8. Davis JD, Padros MB, Conrado DJ, Ganguly S, Guan X, Hassan HE, et al. Subcutaneous administration of monoclonal antibodies: pharmacology, delivery, immunogenicity, and learnings from applications to clinical development. Clin Pharmacol Ther. 2024;115(3):422–39. https://doi.org/10.1002/cpt.3150.

    Article  CAS  PubMed  Google Scholar 

  9. Davda J, Declerck P, Hu-Lieskovan S, Hickling TP, Jacobs IA, Chou J, et al. Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics. J Immunother Cancer. 2019;7:105. https://doi.org/10.1186/s40425-019-0586-0.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Genovese MC, Covarrubias A, Leon G, Mysler E, Keiserman M, Valente R, et al. Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum. 2011;63(10):2854–64. https://doi.org/10.1002/art.30463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (Columba): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370–80. https://doi.org/10.1016/s2352-3026(20)30070-3.

    Article  PubMed  Google Scholar 

  12. Simponi (golimumab). Highlights of prescribing information. Janssen Biotech, Inc. 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125289s000lbl.pdf. Accessed 17 Feb 2023.

  13. Simponi Aria (golimumab). Highlights of prescribing information. Janssen Biotech, Inc. 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125433s032lbl.pdf. Accessed 17 Feb 2023.

  14. Schreiber S, Ben-Horin S, Leszczyszyn J, Dudkowiak R, Lahat A, Gawdis-Wojnarska B, et al. Randomized controlled trial: subcutaneous vs intravenous infliximab ct-p13 maintenance in inflammatory bowel disease. Gastroenterology. 2021;160(7):2340–53. https://doi.org/10.1053/j.gastro.2021.02.068.

    Article  CAS  PubMed  Google Scholar 

  15. Ortega HG, Liu MC, Pavord ID, Brusselle GG, Fitzgerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–207. https://doi.org/10.1056/nejmoa1403290.

    Article  PubMed  Google Scholar 

  16. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97. https://doi.org/10.1056/nejmoa1403291.

    Article  PubMed  Google Scholar 

  17. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (Musca): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5(5):390–400. https://doi.org/10.1016/s2213-2600(17)30125-x.

    Article  PubMed  Google Scholar 

  18. Omontys (peginesatide). Highlights of prescribing information. Affymax, Inc. and Takeda Pharmaceuticals America, Inc. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202799s000lbl.pdf. Accessed 17 Feb 2023.

  19. Neelakantan S, Oemar B, Johnson K, Rath N, Salganik M, Berman G, et al. Safety, tolerability, and pharmacokinetics of pf-06823859, an anti-interferon β monoclonal antibody: a randomized, phase I, single- and multiple-ascending-dose study. Clin Pharmacol Drug Dev. 2021;10(3):307–16. https://doi.org/10.1002/cpdd.887.

    Article  CAS  PubMed  Google Scholar 

  20. MabThera (rituximab). Summary of product characteristics. Roche Pharma. 2009. https://www.ema.europa.eu/en/documents/product-information/mabthera-epar-product-information_en.pdf. Accessed 17 Feb 2023.

  21. Johnson ML, Braiteh F, Grilley-Olson JE, Chou J, Davda J, Forgie A, et al. Assessment of subcutaneous vs intravenous administration of anti-pd-1 antibody pf-06801591 in patients with advanced solid tumors: a phase 1 dose-escalation trial. JAMA Oncol. 2019;5(7):999–1007. https://doi.org/10.1001/jamaoncol.2019.0836.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Birbara C, Dabezies EJ, Burr AM, Fountaine RJ, Smith MD, Brown MT, et al. Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis. J Pain Res. 2018;11:151–64. https://doi.org/10.2147/jpr.s135257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Actemra (tocilizumab). Highlights of prescribing information Genentech, Inc. 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125276lbl.pdf. Accessed 17 Feb 2023.

  24. Ogata A, Tanimura K, Sugimoto T, Inoue H, Urata Y, Matsubara T, et al. Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res. 2014;66(3):344–54. https://doi.org/10.1002/acr.22110.

    Article  CAS  Google Scholar 

  25. Herceptin (trastuzumab). Summary of product characteristics. Genentech, Inc. 2010. https://www.ema.europa.eu/en/documents/product-information/herceptin-epar-product-information_en.pdf. Accessed 17 Feb 2023.

  26. Sandborn WJ, Baert F, Danese S, Krznaric Z, Kobayashi T, Yao X, et al. Efficacy and safety of vedolizumab subcutaneous formulation in a randomized trial of patients with ulcerative colitis. Gastroenterology. 2020;158(3):562-572.e12. https://doi.org/10.1053/j.gastro.2019.08.027.

    Article  CAS  PubMed  Google Scholar 

  27. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on immunogenicity assessment of therapeutic proteins. 2017. https://www.ema.europa.eu/en/immunogenicity-assessment-biotechnology-derived-therapeutic-proteins-scientific-guideline.

Download references

Acknowledgements

Yazdi K. Pithavala, Pfizer, also contributed suggestions for the analyses. David Potter, Pfizer, advised on the optimal statistical analysis method and aided in explanation of statistical results.

Funding

This work was sponsored by Pfizer Inc. and funded by a grant from the University of California, San Diego Skaggs School of Pharmacy Summer Research Program.

Author information

Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA

    Jacob Felderman

  2. Global Pathology & Drug Safety, Pfizer Inc, Pearl River, New York, USA

    Lila Ramaiah

  3. Clinical Immunogenicity, Pfizer Research and Development, Pfizer Inc, Cambridge, Massachusetts, USA

    Maria-Dolores Vazquez-Abad

  4. BioMedicine Design, Pfizer Inc, Cambridge, Massachusetts, USA

    Dean Messing

  5. Clinical Pharmacology, Pfizer Inc, 10555 Science Center Dr., San Diego, California, 92121, USA

    Ying Chen

Authors
  1. Jacob Felderman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lila Ramaiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria-Dolores Vazquez-Abad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dean Messing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.F. and Y.C. wrote the manuscript. J.F. collected and analyzed the data. L.R., M.D.V.A, D.M., and Y.C. provided the basis for the project, contributions to the analyses, as well as revisions to the manuscript.

Corresponding author

Correspondence to Ying Chen.

Ethics declarations

Conflict of Interest

J.F. is a student at the University of California, San Diego Skaggs School of Pharmacy and was a summer intern at Pfizer when this work was conducted who declared no competing interests for this work. M.D.V.A., D.M., and Y.C. are employees of Pfizer Inc. and own stock in Pfizer.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Felderman, J., Ramaiah, L., Vazquez-Abad, MD. et al. Anti-Drug Antibody Incidence Comparison of Therapeutic Proteins Administered Via Subcutaneous vs. Intravenous Route. AAPS J 26, 60 (2024). https://doi.org/10.1208/s12248-024-00930-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-024-00930-w

Keywords

Search

Navigation