1630. In vivo biomarker analysis of intranasally dosed PC945, a novel antifungal agent, in Aspergillus fumigatus infection in immunocompromised mice
Session: Poster Abstract Session: Mycology - There's a Fungus Among Us: Treatment
Friday, October 28, 2016
Room: Poster Hall
Background: PC945 is a novel antifungal agent developed as an inhalation therapy for the treatment of lung aspergillosis. In this study, we examined the effects of intranasally dosed PC945 on fungus load and cytokine biomarkers in Aspergillus fumigatus infected immunocompromised mice.

Methods: A/J mice (males, 5 weeks old) were dosed with hydrocortisone (125 mg/kg, sc,) on days 3, 2 and 1 before infection, and with cyclophosphamide (250 mg/kg, ip) 2 days before infection to induce temporary neutropenia. On day 0, animals were infected intranasally with 30µL of the spore suspension of Aspergillus fumigatus (ATCC 13073) at a concentration of 1.67 × 108 spores mL-1 of physiological saline. PC945 was treated intranasally on days 1, 2 and 3 and animals were culled 24 hours after the final treatment on day 3. Bronchoalveolar lavage fluid (BALF) and serum were collected for biomarker analysis. Bronchial epithelial lining fluid (ELF) was also collected using a synthetic absorptive matrix (SAM).

Results: Intranasal treatment of PC945 (0.016, 0.08, 0.4mg/ml isotonic saline suspension) was found to inhibit fungal load (culture and PCR) in the lung, and to decrease galactomannan (GM) concentrations in both BALF and serum in a dose-dependent manner. GM was also measurable in ELF collected by SAM strip, and PC945 inhibited it in a dose-dependent manner with ID50 value of 20.7µg/kg, in. PC945 also inhibited inflammatory cell accumulation into BALF, IL-17, CXCL1 and malondialdehyde (MDA, an oxidative stress marker) levels in BALF, and TNFα and IL-6 levels in serum, all of which were elevated by Aspergillus fumigatus infection.

Conclusion: Therapeutic intervention with intranasally dosed PC945 exhibited potent inhibitory effects of fungal load (culture and PCR), GM concentrations and A. fumigatus-dependent inflammation. Thus, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans. In addition, we were able to detect fungal biomarkers in ELF in bronchus collected by sampling with SAM strips, and this sampling method will be potentially less invasive and useful for biomarker analysis of respiratory fungal infection in humans.

Kazuhiro Ito, PhD1, Yasuo Kizawa, PhD2, Genki Kimura, PhD2, Takahiro Nakaoki, BSc2, Lindsey Cass, PhD1, Duncan Hunt, -3, Toby M. HUNT, BTECH3, Trevor L. HUNT, -3, Pete Strong, PhD1 and Garth Rapeport, MD1, (1)Pulmocide Ltd, London, United Kingdom, (2)Physiology and Anatomy, Nihon University School of Pharmacy, Funabashi, Japan, (3)Hunt Developments (UK) Ltd, West Sussex, United Kingdom

Disclosures:

K. Ito, Pulmocide Ltd: Employee , Salary

Y. Kizawa, Pulmocide Ltd: Collaborator , Research grant

G. Kimura, None

T. Nakaoki, None

L. Cass, Pulmocide Ltd: Employee , Salary

D. Hunt, Hunt Developments (UK) Ltd: Employee , Salary

T. M. HUNT, Hunt Developments (UK) Ltd: Employee , Salary

T. L. HUNT, Hunt Developments (UK) Ltd: Board Member and Employee , Salary

P. Strong, Pulmocide Ltd: Board Member and Employee , Salary

G. Rapeport, Pulmocide Ltd: Board Member and Employee , Salary

Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.