Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous infusions of large volumes of immunoglobulin in a swine model

Abstract

Many patients with primary immunodeficiency disease (PIDD) require lifelong immunoglobulin (Ig) replacement therapy. Home-based subcutaneous (SC) infusion provides advantages to patients with PIDD compared to hospital-based intravenous infusion. One limitation of current practice with SCIg infusion is the need for small-volume infusions at multiple injection sites on a frequent basis. A method was developed for large-volume SC infusion that uses preinfusion of recombinant human hyaluronidase (rHuPH20) to facilitate fluid dispersion. Miniature swine was used as a preclinical model to assess the effects of rHuPH20-facilitated infusions, of a single monthly dose, on fluid dispersion, infusion-related pressure, swelling, induration, and tissue damage. Preinfusion of vehicle (control) or rHuPH20 (75 U/g Ig) was performed simultaneously on contralateral abdominal sites on each animal, followed by infusion of 300 mL 10 % Ig (30 g) at each site. Compared to control infusions, rHuPH20 significantly reduced infusion pressure and induration (p < 0.05) and accelerated postinfusion Ig dispersion. Histological evaluation of infusion site tissue showed moderate to severe swelling for the control. Swelling after rHuPH20-facilitated infusion was mild on day 1 and had completely resolved shortly thereafter. Laser Doppler imaging of control infusion sites revealed local cutaneous hypoperfusion during Ig infusion, which was reduced almost 7-fold (p < 0.05) with the use of rHuPH20. These results demonstrate that rHuPH20-facilitated Ig infusion is associated with improved dispersion of Ig, resulting in reduced tissue pressure, induration, and reduced risk of tissue damage from mechanical trauma or local ischemia, thus enabling SC administration of large volumes of Ig at a single site.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Rezaei N, Hedayat M, Aghamohammadi A, Nichols KE. Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. J Allergy Clin Immunol. 2011;127(6):1329–41.

    PubMed  Article  Google Scholar 

  2. 2.

    Moise A, Nedelcu FD, Toader MA, Sora SM, Tica A, Ferastraoaru DE, Constantinescu I. Primary immunodeficiencies of the B lymphocyte. J Med Life. 2010;3(1):60–3.

    PubMed  Google Scholar 

  3. 3.

    Gardulf A. Immunoglobulin treatment for primary antibody deficiencies. BioDrugs. 2007;21:105–16.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Kittner JM, Grimbacher B, Wulff W, Jäger B, Schmidt RE. Patients’ attitude to subcutaneous immunoglobulin substitution as home therapy. J Clin Immunol. 2006;26(4):400–5.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Gardulf A, Nicolay U. Replacement Ig therapy and self-therapy at home improve the health-related quality of life in patients with primary antibody deficiencies. Curr Opin Allergy Clin Immunol. 2006;6(6):434–42.

    PubMed  Article  Google Scholar 

  6. 6.

    Misbah S, Sturzenegger MH, Borte M, Shapiro RS, Wasserman RL, Berger M, Ochs HD. Subcutaneous immunoglobulin: opportunities and outlook. Clin Exp Immunol. 2009;158 Suppl 1:51–9.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Gustafson R, Gardulf A, Hansen S, Leibl H, Engl W, Lindén M, Müller A, Hammarstrӧm L. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol. 2008;152:274–9.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M, Subcutaneous Ig Study Group. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006;26(3):265–73.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Borte M, Bernatowska E, Ochs HD, Roifman CM, Vivaglobin Study Group. Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies. Clin Exp Immunol. 2011;164(3):357–64.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Gardulf A, Nicolay U, Math D, Asensio O, Bernatowska E, Böck A, Costa-Carvalho BT, Granert C, Haag S, Hernández D, Kiessling P, Kus J, Matamoros N, Niehues T, Schmidt S, Schulze I, Borte M. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous Ig self-infusions at home. J Allergy Clin Immunol. 2004;114(4):936–42.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Nicolay U, Kiessling P, Berger M, Gupta S, Yel L, Roifman CM, Gardulf A, Eichmann F, Haag S, Massion C, Ochs HD. Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous Ig self-infusions at home. J Clin Immunol. 2006;26(1):65–72.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Hizentra Package Insert. Available at http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM203150.pdf.

  13. 13.

    Bookbinder LH, Hofer A, Haller MF, Zepeda ML, Keller GA, Lim JE, Edgington TS, Shepard HM, Patton JS, Frost GI. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Contr Release. 2006;114(2):230–41.

    Article  CAS  Google Scholar 

  14. 14.

    Frost GI. Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Exp Opin Drug Deliv. 2007;4:427–40.

    Article  CAS  Google Scholar 

  15. 15.

    NCT00814320 at ClinicalTrials.gov. Gammagard Liquid and rHuPH20 in PID. Available at http://www.clinicaltrials.gov/ct2/show/NCT00814320?term=NCT00814320&rank=1.

  16. 16.

    Melamed I, Wasserman RL, Stein M, Rubinstein A, McCoy B, Engl W, Leibl H, Gelmont D, Grossman WJ, Schiff RI, and the IGSC, 10 % rHuPH20 Study Group. Tolerability of human immunoglobulin 10 % (Ig) administered subcutaneously (SC) or facilitated with recombinant human hyaluronidase (rHuPH20) in patients with primary immunodeficiency disease (PIDD). Presented at the Annual Meeting of the Clinical Immunology Society, May 19–22, 2011. Abstract #28.

  17. 17.

    Wasserman RL, Melamed I, Stein M, Rubinstein A, McCoy B, Engl W, Leibl H, Gelmont D, Grossman WJ, Schiff RI, and the IGSC, 10 % rHuPH20 Study Group. Pharmacokinetics (PK) of human immunoglobulin 10 % (Ig) administered intravenously (IV), subcutaneously (SC) or facilitated with recombinant human hyaluronidase (rHuPH20) in patients with primary immunodeficiency disease (PIDD). Presented at the Annual Meeting of the Clinical Immunology Society, May 19–22, 2011. Abstract #53.

  18. 18.

    Svendsen O. The minipig in toxicology. Exp Toxicol Pathol. 2006;57:335–9.

    PubMed  Article  Google Scholar 

  19. 19.

    van der Laan JW, Brightwell J, McAnulty P, Ratky J, Stark C, Steering Group of the RETHINK Project. Regulatory acceptability of the minipig in the development of pharmaceuticals, chemicals and other products. J Pharm Toxicol Methods. 2010;62(3):184–95.

    Article  Google Scholar 

  20. 20.

    Mahl JA, Vogel BE, Court M, Kolopp M, Roman D, Nogués V. The minipig in dermatotoxicology: methods and challenges. Exp Toxicol Pathol. 2006;57(5–6):341–5.

    PubMed  Article  Google Scholar 

  21. 21.

    Nunoya T, Shibuya K, Saitoh T, Yazawa H, Nakamura K, Baba Y, Hirai T. Use of miniature pig for biomedical research, with reference to toxicologic studies. J Tox Pathol. 2007;20:125–32.

    Article  CAS  Google Scholar 

  22. 22.

    Golla S, Madihally S, Robinson Jr RL, Gasem KA. Quantitative structure–property relationship modeling of skin sensitization: a quantitative prediction. Toxicol Vitro. 2009;23(3):454–65.

    Article  CAS  Google Scholar 

  23. 23.

    Porter CJ, Edwards GA, Charman SA. Lymphatic transport of proteins after s.c. injection: implications of animal model selection. Adv Drug Deliv Rev. 2001;50(1–2):157–71.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Supersaxo A, Hein WR, Steffen H. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm Res. 1990;7(2):167–9.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol. 2004;112:1–7.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Berger M. Subcutaneous administration of IgG. Immunol Allergy Clin North Am. 2008;285(4):779–802.

    Article  Google Scholar 

  27. 27.

    Chouksey A, Duff K, Wasserbauer N, Berger M. Subcutaneous immunoglobulin-g replacement therapy with preparations currently available in the United States for intravenous or intramuscular use: reasons and regimens. Allergy Asthma Clin Immunol. 2005;1(3):120–30.

    PubMed  Google Scholar 

  28. 28.

    Singh S. Acute compartment syndrome. Curr Orthop. 2004;18:468–76.

    Article  Google Scholar 

  29. 29.

    Steinberg BD. Evaluation of limb compartments with increased interstitial pressure. An improved noninvasive method for determining quantitative hardness. J Biomech. 2005;38(8):1629–35.

    PubMed  Article  Google Scholar 

  30. 30.

    Mars M, Hadley GP. Raised intracompartmental pressure and compartment syndrome. Injury. 1998;29(6):403–11.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Kalns J, Cox J, Baskin J, Santos A, Odland R, Recura Jr S. Threshold model for extremity compartment syndrome in swine. J Surg Res. 2011;167(1):13–9.

    Article  Google Scholar 

  32. 32.

    Leu AJ, Leu HJ, Franzeck UK, Bollinger A. Microvascular changes in chronic venous insufficiency—a review. Cardiovasc Surg. 1995;3(3):237–45.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Laferrière A, Millecamps M, Xanthos DN, Xiao WH, Siau C, de Mos M, Sachot C, Ragavendran JV, Huygen FJ, Bennett GJ, Coderre TJ. Cutaneous tactile allodynia associated with microvascular dysfunction in muscle. Mol Pain. 2008;4:49.

    PubMed  Article  Google Scholar 

  34. 34.

    Uhlmann D, Armann B, Gaebel G, Ludwig S, Hess J, Pietsch UC, Escher E, Fieldler M, Tannapfel A, Hauss J, Witzigmann H. Endothelin A receptor blockade reduces hepatic ischemia/reperfusion injury after warm ischemia in a pig model. J Gastrointest Surg. 2003;7(3):331–9.

    PubMed  Article  Google Scholar 

  35. 35.

    Reddy NP, Cochran GV. Interstitial fluid flow as a factor in decubitus ulcer formation. J Biomech. 1981;14(12):879–81.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Ghia Bacani for formulation support, James Skipper and Adrian Radi for assistance with the preclinical studies, Rebecca Symons for histology support, Dr. Michael J. Tomlinson for histopathological assessment, Dr. Ping Jiang for statistical analysis of the histopathological assessment, and Drs. Daniel C. Maneval, David A. Gold, Curtis B. Thompson, and H. Michael Shepard for critical review of the manuscript. Medical writing support, funded by Baxter BioScience, was provided by Roland Tacke, Candace Lundin, and Josh Collis of Gardiner-Caldwell Communications.

Author information

Affiliations

Authors

Corresponding author

Correspondence to David W. Kang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kang, D.W., Jadin, L., Nekoroski, T. et al. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous infusions of large volumes of immunoglobulin in a swine model. Drug Deliv. and Transl. Res. 2, 254–264 (2012). https://doi.org/10.1007/s13346-012-0065-3

Download citation

Keywords

  • Recombinant human hyaluronidase
  • Subcutaneous infusion
  • Immunoglobulin
  • Primary immunodeficiency disease
  • Induration
  • Miniature swine