Perspective | Published:

Roadmap and strategy for overcoming infusion reactions to nanomedicines

Nature Nanotechnologyvolume 13pages11001108 (2018) | Download Citation

Abstract

Infusion reactions (IRs) are complex, immune-mediated side effects that mainly occur within minutes to hours of receiving a therapeutic dose of intravenously administered pharmaceutical products. These products are diverse and include both traditional pharmaceuticals (for example biological agents and small molecules) and new ones (for example nanotechnology-based products). Although IRs are not unique to nanomedicines, they represent a hurdle for the translation of nanotechnology-based drug products. This Perspective offers a big picture of the pharmaceutical field and examines current understanding of mechanisms responsible for IRs to nanomedicines. We outline outstanding questions, review currently available experimental evidence to provide some answers and highlight the gaps. We review advantages and limitations of the in vitro tests and animal models used for studying IRs to nanomedicines. Finally, we propose a roadmap to improve current understanding, and we recommend a strategy for overcoming the problem.

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References

  1. 1.

    Joerger, M. Prevention and handling of acute allergic and infusion reactions in oncology. Ann. Oncol. 23(Suppl. 10), x313–x319 (2012).

  2. 2.

    Johansson, S. G. et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 56, 813–824 (2001).

  3. 3.

    Jutel, M. et al. International consensus on allergy immunotherapy. J. Allergy Clin. Immunol. 136, 556–568 (2015).

  4. 4.

    Lenz, H. J. Management and preparedness for infusion and hypersensitivity reactions. Oncologist 12, 601–609 (2007).

  5. 5.

    Simons, F. E. et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J. 8, 32 (2015).

  6. 6.

    Rosello, S., Blasco, I., Garcia Fabregat, L., Cervantes, A. & Jordan, K. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann. Oncol. 28(Suppl. 4), iv100–iv118 (2017). Describes clinical approaches for addressing infusion reactions commonly experienced in response to oncology drugs.

  7. 7.

    Torres, M. J. et al. Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America. Clin. Transl. Allergy 7, 7 (2017).

  8. 8.

    The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.5) (US DDepatartment of Health and Human Services, 2017).

  9. 9.

    Gell, P. G. H. & Coombs, R. R. A. in Clinical Aspects of Immunology (eds Gell, P. G. H. & Coombs, R. R. A.) 575–596 (Blackwell, Oxford, 1963). Provides classification of allergic reactions based on the underlying mechanisms. It is still among the most commonly used classifications of allergy.

  10. 10.

    Khan, D. A. Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist. Ann. Allergy Asthma Immunol. 117, 115–120 (2016).

  11. 11.

    Patel, S. V. & Khan, D. A. Adverse reactions to biologic therapy. Immunol. Allergy Clin. North Am. 37, 397–412 (2017).

  12. 12.

    Sampson, H. A. et al. Second symposium on the definition and management of anaphylaxis: Summary Report. Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J. Allergy Clin. Immunol. 117, 391–397 (2006).

  13. 13.

    Lorenzo-Abalde, S. & Gonzalez-Fernandez, A. in Handbook of Immunological Properties of Engineered Nanomaterials (eds Dobrovolskaia, M. A. & McNeil, S. E.) 517–546 (World Scientific, Singapore, 2013).

  14. 14.

    Szebeni, J. et al. A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. Adv. Drug Deliv. Rev. 64, 1706–1716 (2012).

  15. 15.

    Szebeni, J., Bedőcs, P., Dézsi, L. & Urbanics, R. A porcine model of complement activation-related pseudoallergy to nanopharmaceuticals: pros and cons of translation to a preclinical safety test. Precision Nanomed. 1, 63–75 (2018). Most recent review of the porcine CARPA model, highlighting the model’s pros and cons and the fact that it is a disease model (that of hypersensitivity), rather than a model of normal human response to IV-administered nanoparticles.

  16. 16.

    Markman, M. et al. Paclitaxel-associated hypersensitivity reactions: experience of the gynecologic oncology program of the Cleveland Clinic Cancer Center. J. Clin. Oncol. 18, 102–105 (2000).

  17. 17.

    Postmarketing Safety Review (FDA, 2005); https://www.fdagov/ohrms/dockets/ac/05/briefing/2005-4095B1_02_15-FDA-Tab-7-10pdf

  18. 18.

    Szebeni, J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol. Immunol. 61, 163–173 (2014). A comprehensive summary of the CARPA theory proposing that the phenomenon represents a stress reaction in blood, an universal acute defense mechanism against foreign microbes along the immuno-circulatory axis.

  19. 19.

    Szebeni, J., Muggia, F., Gabizon, A. & Barenholz, Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv. Drug Deliv. Rev. 63, 1020–1030 (2011).

  20. 20.

    Canna, S. W. & Behrens, E. M. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr. Clin. North Am. 59, 329–344 (2012).

  21. 21.

    DeFrancesco, L. CAR-T cell therapy seeks strategies to harness cytokine storm. Nat. Biotechnol. 32, 604 (2014).

  22. 22.

    Tyrsin, D. et al. From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis. Clin. Exp. Rheumatol. 34(Suppl. 98), 45–48 (2016).

  23. 23.

    Rupaimoole, R. & Slack, F. J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 16, 203–222 (2017).

  24. 24.

    Chousterman, B. G., Swirski, F. K. & Weber, G. F. Cytokine storm and sepsis disease pathogenesis. Semin. Immunopathol. 39, 517–528 (2017).

  25. 25.

    Dobrovolskaia, M. A. Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: challenges, considerations and strategy. J. Control. Release 220, 571–583 (2015).

  26. 26.

    D'Mello, S. R. et al. The evolving landscape of drug products containing nanomaterials in the United States. Nat. Nanotech. 12, 523–529 (2017).

  27. 27.

    Granot, Y. & Peer, D. Delivering the right message: challenges and opportunities in lipid nanoparticles-mediated modified mRNA therapeutics — an innate immune system standpoint. Semin. Immunol. 34, 68–77 (2017). Provides a comprehensive summary of the current literature regarding immunological recognition of and inflammation in response to lipid nanocarriers commonly used in drug delivery.

  28. 28.

    Landesman-Milo, D. & Peer, D. Altering the immune response with lipid-based nanoparticles. J. Control. Release 161, 600–608 (2012).

  29. 29.

    Szebeni, J. et al. Prevention of infusion reactions to PEGylated liposomal doxorubicin via tachyphylaxis induction by placebo vesicles: a porcine model. J. Control. Release 160, 382–387 (2012).

  30. 30.

    Wibroe, P. P. et al. Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes. Nat. Nanotech. 12, 589–594 (2017). The pulmonary hypertensive effect of polystyrene nanoparticles is shown to depend on particle shape, macrophage phagocytosis and erythrocyte binding, but not on the complement activation. The study initiated hot debates regarding the mechanism underlying infusion reactions.

  31. 31.

    Moghimi, S. M. Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions. Drug Discov. Today 23, 1034–1042 (2017). A position paper proposing that IRs are due to the robust nanoparticle clearance from the blood by macrophages, regardless of complement activation (‘rapid phagocytic response’ hypothesis). The concept is debated in refs 32 and 38.

  32. 32.

    Szebeni, J. Mechanism of nanoparticle-induced hypersensitivity in pigs: complement or not complement? Drug Discov. Today 23, 487–492 (2018). Review of the evidence for complement activation to play a causal role in infusion reactions and the pitfalls of complement assays. This position paper challenges the rapid phagocytic response hypothesis proposed by refs 30 and 31.

  33. 33.

    Jackman, J. A. et al. Comparison of complement activation-related pseudoallergy in miniature and domestic pigs: foundation of a validatable immune toxicity model. Nanomedicine 12, 933–943 (2016).

  34. 34.

    Schneberger, D., Aharonson-Raz, K. & Singh, B. Pulmonary intravascular macrophages and lung health: what are we missing? Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L498–L503 (2012).

  35. 35.

    Winkler, G. C. Pulmonary intravascular macrophages in domestic animal species: review of structural and functional properties. Am. J. Anat. 181, 217–234 (1988).

  36. 36.

    Brain, J. D., Molina, R. M., DeCamp, M. M. & Warner, A. E. Pulmonary intravascular macrophages: their contribution to the mononuclear phagocyte system in 13 species. Am. J. Physiol. 276, L146–L154 (1999). (1 Pt 1).

  37. 37.

    Csukás, D., Urbanics, R., Wéber, G., Rosivall, L. & Szebeni, J. Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA. Eur. J. Nanomed. 7, 27–36 (2015).

  38. 38.

    Mészáros, T. et al. Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: unique surface properties underlying alternative pathway activation and instant opsonization. Int. J. Nanomed. (in the press). Evidence that complement activation plays a role in the pulmonary reactivity of polystyrene nanospheres in pigs. The study highlights the relevance of the porcine CARPA model in preclinical safety testing of nanomedicines.

  39. 39.

    Beutier, H. et al. Platelets expressing IgG receptor FcgammaRIIA/CD32A determine the severity of experimental anaphylaxis. Sci. Immunol. 3, eaan5997 (2018). This study demonstrates the contribution of platelets to drug-mediated anaphylaxis in a mouse model engineered to express human receptor for immunoglobulin G, FcγIIA (CD32A).

  40. 40.

    Patko, Z. & Szebeni, J. Blood cell changes in complement activation-related pseudoallergy. Eur. J. Nanomed. 7, 233–244 (2015).

  41. 41.

    Song, S., Yang, L., Trepicchio, W. L. & Wyant, T. Understanding the supersensitive anti-drug antibody assay: unexpected high anti-drug antibody incidence and its clinical relevance. J. Immunol. Res. 2016, 3072586 (2016).

  42. 42.

    Szebeni, J. et al. Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J. Liposome Res. 17, 107–117 (2007).

  43. 43.

    Johansson, S. G. et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 113, 832–836 (2004).

  44. 44.

    Doessegger, L. & Banholzer, M. L. Clinical development methodology for infusion-related reactions with monoclonal antibodies. Clin. Transl. Immunol. 4, 1–9 (2015).

  45. 45.

    Szebeni, J., Wassef, N. M., Rudolph, A. S. & Alving, C. R. Complement activation in human serum by liposome-encapsulated hemoglobin: the role of natural anti-phospholipid antibodies. Biochim. Biophys. Acta 1285, 127–130 (1996).

  46. 46.

    Chen, B. M. et al. Measurement of pre-existing IgG and IgM antibodies against polyethylene glycol in healthy individuals. Anal. Chem. 88, 10661–10666 (2016).

  47. 47.

    Hashimoto, Y., Shimizu, T., Abu Lila, A. S., Ishida, T. & Kiwada, H. Relationship between the concentration of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) and the intensity of the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes in mice. Biol. Pharm. Bull. 38, 417–424 (2015).

  48. 48.

    Dezsi, L. et al. Features of complement activation-related pseudoallergy to liposomes with different surface charge and PEGylation: comparison of the porcine and rat responses. J. Control. Release 195, 2–10 (2014).

  49. 49.

    Kozma, G. T. et al. Variable association of complement activation by rituximab and paclitaxel in cancer patients in vivo and in their screening serum in vitro with clinical manifestations of hypersensitivity: a pilot study. Eur. J. Nanomed. 7, 289–301 (2015).

  50. 50.

    Lozano-Fernandez, T. et al. Potential impact of metal oxide nanoparticles on the immune system: the role of integrins, L-selectin and the chemokine receptor CXCR4. Nanomedicine 10, 1301–1310 (2014).

  51. 51.

    Savi, E., Peveri, S., Cavaliere, C., Masieri, S. & Montagni, M. Laboratory tests for allergy diagnosis. J. Biol. Regul. Homeost. Agents 32(1 Suppl. 1), 25–28 (2018).

  52. 52.

    Chanan-Khan, A. et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann. Oncol. 14, 1430–1437 (2003).

  53. 53.

    Kozma Gergely, T. et al. Variable association of complement activation by rituximab and paclitaxel in cancer patients in vivo and in their screening serum in vitro with clinical manifestations of hypersensitivity: a pilot study. Eur. J. Nanomed. 7, 289–301 (2015).

  54. 54.

    Morgan, B. P. & Harris, C. L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14, 857–877 (2015).

  55. 55.

    Szebeni, J. et al. Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model for pseudoallergic cardiopulmonary reactions to liposomes. Role of complement and inhibition by soluble CR1 and anti-C5a antibody. Circulation 99, 2302–2309 (1999).

  56. 56.

    Baranyi, L. et al. Complement-dependent shock and tissue damage induced by intravenous injection of cholesterol-enriched liposomes in rats. J. Appl. Res. 3, 221–231 (2003).

  57. 57.

    Picard, M. & Galvao, V. R. Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J. Allergy Clin. Immunol. Pract. 5, 600–609 (2017).

  58. 58.

    VYXEOS: warning and precautions (accessed 18 August 2018); https://vyxeospro.com/?gclid=EAIaIQobChMIvJurn4jt3AIVx1mGCh3pSwXhEAAYASAAEgK1RvD_BwE.

  59. 59.

    Onyvide: important safety information (accessed 18 August 2018); https://www.onivyde.com/important-safety-information

  60. 60.

    Corominas, M., Gastaminza, G. & Lobera, T. Hypersensitivity reactions to biological drugs. J. Investig. Allergol. Clin. Immunol. 24, 212–225 (2014).

  61. 61.

    Szebeni, J. Hemocompatibility testing for nanomedicines and biologicals: predictive assays for complement mediated infusion reactions. Eur. J. Nanomed. 5, 33–53 (2012).

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Acknowledgements

The study was supported in part (M.A.D.) by federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract HHSN261200800001E, and by NIH grants CA194058 (D.S.) and EB022040 (D.S.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. J.S. acknowledges support by the European Union Seventh Framework Program grants NMP-2012-309820 (NanoAthero) and NMP-2013-602923 (TheraGlio), and by the Applied Materials and Nanotechnology Center of Excellence at Miskolc University, Hungary. Y.B. acknowledges the partial support of the Barenholz Fund, which was established by the Hebrew University with royalties obtained from Y.B.’s inventions and is used to support research in the Barenholz Lab. The work of A.G.F. was funded by Xunta de Galicia (Grupo de referencia competitiva ED431C 2016041). We thank A. L. Chun of Science Story Lab for comments.

Author information

Affiliations

  1. Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary

    • Janos Szebeni
  2. SeroScience Ltd, Budapest, Hungary

    • Janos Szebeni
  3. Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary

    • Janos Szebeni
  4. Translational Bio-Nanosciences Laboratory, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA

    • Dmitri Simberg
  5. Immunology, Centro de Investigaciones Biomédicas (CINBIO), Centro de Investigación Singular de Galicia, Instituto de Investigación Sanitaria Galicia Sur (IIS-GS), University of Vigo, Vigo, Spain

    • África González-Fernández
  6. Department of Biochemistry, Institute for Medical Research Israel–Canada, Hebrew University–Hadassah Medical School, Jerusalem, Israel

    • Yechezkel Barenholz
  7. Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, USA

    • Marina A. Dobrovolskaia

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Contributions

All authors wrote the paper.

Competing interests

J.S. is involved in SeroScience Ltd’s CRO activity providing immune toxicology services. J.S. and Y.B. are co-inventors on US patent 9,078,812B2, 14 July 2015, relevant to the use of liposomal carrier as desensitizing agent and co-owned by Semmelweis University, Hungary and Hebrew University, Israel. Y.B. is one of the inventors of two patents relevant to Doxil: US Patent 5,192,549, 9 March 1993, and US Patent 5,316,771, 31 May 1994. Both patents expired in March 2010. The Hebrew University received royalties from Doxil sales until the patent expiration. The Barenholz Fund, established with a portion of these royalties, is used to support research in Y.B.’s laboratory, including this study. The other authors declare no competing interests related to the subject described in the manuscript.

Corresponding author

Correspondence to Marina A. Dobrovolskaia.

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DOI

https://doi.org/10.1038/s41565-018-0273-1