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A Formal Toxicology Study of Inhaled rhGM-CSF in Healthy, Non-Human Primates
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A3115 - A Formal Toxicology Study of Inhaled rhGM-CSF in Healthy, Non-Human Primates
Author Block: B. C. Carey1, P. Terse2, S. Haugabook2, L. Toney2, K. Balakrishnan2, G. Sittampalam2, C. Chalk1, B. C. Trapnell1; 1Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, 2NIH/NCATS, Rockville, MD, United States.
Rationale: Clinical studies of inhaled recombinant human granulocyte/macrophage-colony stimulating factor (rhGM-CSF) show promise as therapy of autoimmune PAP (aPAP) and have not identified safety concerns. However, the effects of inhaled rhGM-CSF in the lungs are poorly defined. This study was done to better understand the biological responses to administration of inhaled rhGM-CSF.
Methods: Healthy non-human primates (NHPs) received rhuGM-CSF daily at 0, 1, 5, 25 mcg/kg (Groups: placebo, low, mid, high-dose (n=10/group)) by daily inhalation for 28 days (D) followed by a 28D recovery period and were evaluated using standard toxicology methods under good laboratory practice conditions under contract at Battelle, Inc.
Results: All animals tolerated rhGM-CSF with respiratory findings (cough, rapid, and/or labored breathing) only occurring at mid-dose (n=3; D11-D28) and high-dose (n=8; D15-D28). Toxicokinetics revealed dose-related systemic exposure in rhGM-CSF-treated NHPs: maximal mean(±SEM) plasma concentrations were 153±96, 449±113, and 1928±623pg/ml and area under the curves were 543±251, 1,669±385, 30,029±15,024hr*pg/ml), respectively. Transient dose-related systemic eosinophilia was observed only at mid-dose and high-dose (mean±SEM) on D2 (0.04±0.02, 0.11±0.02, 0.23±0.07, and 0.45±0.15 x10^3cells/mcl) and D16 (0.07±0.1, 0.19±0.03, 1.25±0.32, and 3.6±1.01 x10^3cells/mcl). Anti-drug antibodies (ADAs) developed in all rhuGM-CSF-treated NHPs by D15. On D29, BAL fluid contained increased GM-CSF (217±128, 2177±889, 2647±1080pg/ml) and increased ADA titer (27±12, 15±5, 30±11) compared to corresponding placebo values, respectively, (18.8±4.6 pg/ml and 0). On D29, eosinophils were increased in BAL in dose-dependent fashion (5.7±2.1, 30.8±7.7, and 28.3±5.3cells/mcl) compared to placebo (0.2±0.2cells/mcl). Microscopic examination of lung histology revealed minimal, dose-dependent, multifocal, peribronchiolar, interstitial eosinophilic (33%, 66%, 100%) and histiocytic (66%, 100%, 100%) infiltrates in the lung parenchyma. Alveolar epithelial cell (AEC) hyperplasia was noted in 33% of NHPs in the high-dose but not other groups. Dose-dependent lymphoid hyperplasia was observed (33%, 66%, and 100%) in the lung parenchyma. Upon recovery, plasma GM-CSF levels, hematologic parameters, and the incidence of the cellular infiltrates and AEC and lymphoid hyperplasia were noted to have resolved. Pulmonary GM-CSF was detectable in all treated animals and ADA titers were detectable at low levels in low-dose and mid-dose groups.
Conclusion: Aerosol inhalation of rhGM-CSF by healthy NHPs caused transient alterations in transient systemic and pulmonary eosinophilia, development of ADAs, and histopathologic changes in the lung and lymphoid tissue, all of which, except ADAs, resolved upon withdrawal of rhGM-CSF. These results should be interpreted in the context of the knowledge that GM-CSF autoantibodies present in autoimmune PAP will neutralize some of the administered rhGM-CSF.
Author Block: B. C. Carey1, P. Terse2, S. Haugabook2, L. Toney2, K. Balakrishnan2, G. Sittampalam2, C. Chalk1, B. C. Trapnell1; 1Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, 2NIH/NCATS, Rockville, MD, United States.
Rationale: Clinical studies of inhaled recombinant human granulocyte/macrophage-colony stimulating factor (rhGM-CSF) show promise as therapy of autoimmune PAP (aPAP) and have not identified safety concerns. However, the effects of inhaled rhGM-CSF in the lungs are poorly defined. This study was done to better understand the biological responses to administration of inhaled rhGM-CSF.
Methods: Healthy non-human primates (NHPs) received rhuGM-CSF daily at 0, 1, 5, 25 mcg/kg (Groups: placebo, low, mid, high-dose (n=10/group)) by daily inhalation for 28 days (D) followed by a 28D recovery period and were evaluated using standard toxicology methods under good laboratory practice conditions under contract at Battelle, Inc.
Results: All animals tolerated rhGM-CSF with respiratory findings (cough, rapid, and/or labored breathing) only occurring at mid-dose (n=3; D11-D28) and high-dose (n=8; D15-D28). Toxicokinetics revealed dose-related systemic exposure in rhGM-CSF-treated NHPs: maximal mean(±SEM) plasma concentrations were 153±96, 449±113, and 1928±623pg/ml and area under the curves were 543±251, 1,669±385, 30,029±15,024hr*pg/ml), respectively. Transient dose-related systemic eosinophilia was observed only at mid-dose and high-dose (mean±SEM) on D2 (0.04±0.02, 0.11±0.02, 0.23±0.07, and 0.45±0.15 x10^3cells/mcl) and D16 (0.07±0.1, 0.19±0.03, 1.25±0.32, and 3.6±1.01 x10^3cells/mcl). Anti-drug antibodies (ADAs) developed in all rhuGM-CSF-treated NHPs by D15. On D29, BAL fluid contained increased GM-CSF (217±128, 2177±889, 2647±1080pg/ml) and increased ADA titer (27±12, 15±5, 30±11) compared to corresponding placebo values, respectively, (18.8±4.6 pg/ml and 0). On D29, eosinophils were increased in BAL in dose-dependent fashion (5.7±2.1, 30.8±7.7, and 28.3±5.3cells/mcl) compared to placebo (0.2±0.2cells/mcl). Microscopic examination of lung histology revealed minimal, dose-dependent, multifocal, peribronchiolar, interstitial eosinophilic (33%, 66%, 100%) and histiocytic (66%, 100%, 100%) infiltrates in the lung parenchyma. Alveolar epithelial cell (AEC) hyperplasia was noted in 33% of NHPs in the high-dose but not other groups. Dose-dependent lymphoid hyperplasia was observed (33%, 66%, and 100%) in the lung parenchyma. Upon recovery, plasma GM-CSF levels, hematologic parameters, and the incidence of the cellular infiltrates and AEC and lymphoid hyperplasia were noted to have resolved. Pulmonary GM-CSF was detectable in all treated animals and ADA titers were detectable at low levels in low-dose and mid-dose groups.
Conclusion: Aerosol inhalation of rhGM-CSF by healthy NHPs caused transient alterations in transient systemic and pulmonary eosinophilia, development of ADAs, and histopathologic changes in the lung and lymphoid tissue, all of which, except ADAs, resolved upon withdrawal of rhGM-CSF. These results should be interpreted in the context of the knowledge that GM-CSF autoantibodies present in autoimmune PAP will neutralize some of the administered rhGM-CSF.
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