Safety of inhaled proteins for therapeutic use.

The use of the inhalation route for delivery of inhaled proteins has received increasing attention recently. The purpose of this article is to review the available information related to the safety aspects of inhaled proteins. The review focuses primarily on possible toxicity to the respiratory tract, because usually one is either considering an agent to treat the lung or an agent for which the systemic toxicity has been investigated following subcutaneous (s.c.) administration in its clinical use as a therapeutic agent. Some background is provided on mechanisms of absorption and reasons why inhalation delivery is considered for many proteins. Available data are summarized from clinical trials of proteins and protein-like biomolecules, generally showing minimal, if any, adverse respiratory effects. The results of the animal toxicology studies that have been published are presented. In general, the observed lung toxicity has been relatively low, and it has been difficult to interpret in cases where the animal protein differs considerably from the human protein. Discussion is presented on the possibility of adverse immune reactions, suggesting that this is not likely to be any greater issue than it is for subcutaneously injected materials. Although the safety information is relatively sparse at present, the available data suggest that the inhalation route can be an attractive route to consider for many therapeutic proteins.

[1]  J. Crapo,et al.  Allometric relationships of cell numbers and size in the mammalian lung. , 1992, American journal of respiratory cell and molecular biology.

[2]  C. Jefcoate P450 Cytochromes and Hormonal Regulation: An Overview , 1996 .

[3]  Y. Chien,et al.  Systemic delivery of peptides and proteins across absorptive mucosae. , 1996, Critical reviews in therapeutic drug carrier systems.

[4]  E. Weibel Morphometry of the Human Lung , 1965, Springer Berlin Heidelberg.

[5]  J. Patton,et al.  Drug delivery via the respiratory tract. , 1994, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[6]  G. Smaldone,et al.  Quantitative deposition of aerosolized gentamicin in cystic fibrosis. , 1987, The American review of respiratory disease.

[7]  K. Bensch,et al.  Absorption of Intact Protein Molecules across the Pulmonary Air-Tissue Barrier , 1967, Science.

[8]  E. G. Erdös,et al.  Neutral metalloendopeptidase in human lung tissue and cultured cells. , 1985, The American review of respiratory disease.

[9]  P. Byron Respiratory Drug Delivery , 1989 .

[10]  W. Thurlbeck The internal surface area of nonemphysematous lungs. , 2015, The American review of respiratory disease.

[11]  J. Patton,et al.  Mechanisms of macromolecule absorption by the lungs , 1996 .

[12]  R. Boucher Human airway ion transport. Part one. , 1994, American journal of respiratory and critical care medicine.

[13]  A. Sant'annaGandra Aerosols in medicine , 1957 .

[14]  H. Folkesson,et al.  Permeability of the respiratory tract to different-sized macromolecules after intratracheal instillation in young and adult rats. , 1990, Acta physiologica Scandinavica.

[15]  J. Dosman,et al.  Characterization of health effects of grain dust exposures. , 1990, American Journal of Industrial Medicine.

[16]  J. Brain,et al.  Respiratory Defense Mechanisms , 1977 .

[17]  B. Zinman The Physiologic Replacement of Insulin , 1989 .

[18]  J. Jones,et al.  Rapid improvement in abnormal pulmonary epithelial permeability after stopping cigarettes , 1981, British medical journal.

[19]  R. Elliott,et al.  Parenteral absorption of insulin from the lung in diabetic children , 1987, Australian paediatric journal.

[20]  S. Walford,et al.  A Fifteen‐month Double‐blind Cross‐over Study of the Efficacy and Antigenicity of Human and Pork Insulins , 1984, Diabetic medicine : a journal of the British Diabetic Association.

[21]  D H Bowden,et al.  Dose response of the pulmonary macrophagic system to various particulates and its relationship to transepithelial passage of free particles. , 1981, Experimental lung research.

[22]  D. Borson Roles of neutral endopeptidase in airways. , 1991, The American journal of physiology.

[23]  J. Whisstock,et al.  Conformational Changes in Serpins and the Mechanism of α1-Antitrypsin Deficiency , 1994 .

[24]  P. Holt,et al.  Suppression of IgE responses by antigen inhalation: studies on the role of genetic and environmental factors. , 1987, Immunology.

[25]  L. Lazarus,et al.  Identification and characterization of specific growth hormone receptors in cultured human fibroblasts. , 1983, The Journal of clinical endocrinology and metabolism.

[26]  R. Baumal,et al.  Animal model of grain worker's lung. , 1986, Environmental health perspectives.

[27]  J. Mauderly,et al.  Particle Overload in Toxicological Studies: Friend or Foe? , 1990 .

[28]  John F. Murray,et al.  Textbook of Respiratory Medicine , 1988 .

[29]  J. Patton,et al.  (D) Routes of delivery: Case studies , 1992 .

[30]  M. Karnovsky,et al.  THE ULTRASTRUCTURAL BASIS OF ALVEOLAR-CAPILLARY MEMBRANE PERMEABILITY TO PEROXIDASE USED AS A TRACER , 1968, The Journal of cell biology.

[31]  G. Fick,et al.  Protein clearance from the air spaces and lungs of unanesthetized sheep over 144 h. , 1989, Journal of applied physiology.

[32]  R. Bick,et al.  Clinical Use of Intrapulmonary Heparin , 1985, Seminars in thrombosis and hemostasis.

[33]  M. Matthay,et al.  Long-term clearance of liquid and protein from the lungs of unanesthetized sheep. , 1985, Journal of applied physiology.

[34]  R. Crystal,et al.  Aerosol α1 -antitrypsin treatment for cystic fibrosis , 1991, The Lancet.

[35]  P. Holt Immunoprophylaxis of atopy: light at the end of the tunnel? , 1994, Immunology today.

[36]  L. Deftos,et al.  Alveolar epithelial cells express and secrete parathyroid hormone-related protein. , 1994, American journal of respiratory cell and molecular biology.

[37]  J. Crapo,et al.  Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. II. Morphometric analysis. , 1997, Journal of applied physiology.

[38]  P. Morrow,et al.  Dust overloading of the lungs: update and appraisal. , 1992, Toxicology and applied pharmacology.

[39]  G. K. Adams,et al.  Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients. , 1993, JAMA.

[40]  W. Solomon Aerobiology of pollinosis. , 1984, The Journal of allergy and clinical immunology.

[41]  R. Martin,et al.  The effects of inhaled interferon gamma in normal human airways. , 1993, The American review of respiratory disease.

[42]  Green Jd Pharmaco-toxicological expert report Pulmozyme rhDNase Genentech, Inc. , 1994 .

[43]  H. Folkesson,et al.  Alveolar epithelial clearance of protein. , 1996, Journal of applied physiology.

[44]  R. Wolff,et al.  Toxicologic testing of inhaled pharmaceutical aerosols. , 1993, Critical reviews in toxicology.

[45]  K. Cantell,et al.  Effect of inhaled natural interferon-alpha on diffuse bronchioalveolar carcinoma. , 1990, European journal of cancer.

[46]  Y. Sibille,et al.  Alpha-2-macroglobulin, monomeric and polymeric immunoglobulin A, and immunoglobulin M in bronchoalveolar lavage. , 1985, The American review of respiratory disease.

[47]  H. Reynolds,et al.  Analysis of proteins and respiratory cells obtained from human lungs by bronchial lavage. , 1974, The Journal of laboratory and clinical medicine.

[48]  M. Jaurand,et al.  Immunoelectron microscopic and immunochemical demonstrations of serum proteins in the alveolar lining material of the rat lung. , 1976, The American review of respiratory disease.

[49]  J. Davidson,et al.  Factors Influencing the Absorption, Serum Insulin Concentration, and Blood Glucose Responses After Injections of Regular Insulin and Various Insulin Mixtures , 1981, Diabetes Care.

[50]  M. Perricaudet,et al.  In vivo adenovirus-mediated transfer of human CFTR cDNA to rhesus monkey airway epithelium: efficacy, toxicity and safety. , 1994, Gene therapy.

[51]  T. Platts-Mills,et al.  How environment affects patients with allergic disease: indoor allergens and asthma. , 1994, Annals of allergy.

[52]  R. Crystal,et al.  Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis , 1994, Nature Genetics.

[53]  T. Sweeney Exposing Animals to Aerosols: Considerations That Influence Regional Lung Deposition , 1990 .

[54]  R. Crystal,et al.  Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. , 1986, Journal of applied physiology.

[55]  W. Busse,et al.  Asthma and Rhinitis , 1995 .

[56]  M. Newhouse,et al.  Sulfur dioxide and tracheobronchial clearance in man. , 1975, Archives of environmental health.

[57]  D. Curiel,et al.  Gene therapy approaches for inherited and acquired lung diseases. , 1996, American journal of respiratory cell and molecular biology.

[58]  F. Morén,et al.  Aerosols in Medicine: Principles, Diagnosis and Therapy , 1993 .

[59]  J. Brain,et al.  Pathways of clearance in mouse lungs exposed to iron oxide aerosols , 1975, The Anatomical record.

[60]  D. Valeyre,et al.  Glucose, K+, and albumin concentrations in the alveolar milieu of normal humans and pulmonary sarcoidosis patients. , 1991, The American review of respiratory disease.

[61]  M. Matthay,et al.  Clearance of different-sized proteins from the alveolar space in humans and rabbits. , 1992, Journal of applied physiology.

[62]  M. Williams,et al.  Endocytosis in alveolar type II cells: effect of charge and size of tracers. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Palmer,et al.  Insulin antibodies in insulin-dependent diabetics before insulin treatment. , 1983, Science.

[64]  R. Effros,et al.  Rapidly reversible alterations of pulmonary epithelial permeability induced by smoking. , 1983, Chest.

[65]  Wear Ll Recent progress in protein and peptide delivery by noninvasive routes. , 1991 .

[66]  Effros Rm,et al.  Measurements of pulmonary epithelial permeability in vivo. , 1983, The American review of respiratory disease.

[67]  C. Hall Aerosolized Treatment of Acute Pulmonary Infections , 1989 .

[68]  R. S. Pillai,et al.  The effect of pulmonary-delivered insulin on blood glucose levels using two nebulizer systems. , 1996, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[69]  M. Welsh,et al.  Safety and efficacy of repetitive adenovirus–mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats , 1994, Nature Genetics.

[70]  M. Newhouse,et al.  Deposition and fate of aerosolized drugs. , 1978, Chest.

[71]  J. Caillon,et al.  Lung distribution and pharmacokinetics of aerosolized tobramycin. , 1993, The American review of respiratory disease.

[72]  T. Ahmed,et al.  Variability of hypoxic pulmonary vasoconstriction in sheep. Role of prostaglandins. , 2015, The American review of respiratory disease.

[73]  R. Niven,et al.  Delivery of biotherapeutics by inhalation aerosol. , 1995, Critical reviews in therapeutic drug carrier systems.