Lyso, a metalloendopeptidase that is bacteriolytic for S. aureus, is a potential systemic therapy for treating methicillin-resistant S. aureus (MRSA) mediated infections including endocarditis, osteomyelitis, catheter related infections, and MRSA-mediated community acquired furunculosis and pneumonia. However, the short half-life of this enzyme in vivo has precluded its development thus far as a systemic therapy, despite positive clinical trial data. Our company, PharmaIN, has developed a nanocarrier, Protected Graft Copolymers (PGC), that can reversibly bind peptides and/or proteins (US patent #7,138,105) with measurable dissociation constant (Kd). Importantly, because of its size, PGC nanocarrier concentrates at sites of increased vascular permeability and thus can potentially concentrate lyso at the site of infection. Our goal is to develop a formulation of lyso to provide life-saving treatment against MRSA and to suppress the emergence of resistance. Our preliminary data demonstrates that PGC can reversibly associate with lyso, increase blood half-life 14-fold, and increase its in vivo efficacy against MRSA by 100-fold. We propose to prepare endotoxin- free lyso and create a "master cell-line bank" (E. coli expressing lyso) that will be used for: 1) this project to supply our lyso needs, and 2) as reference cells for the planned post-SBIR IND filing and clinical trial. We will also optimize the structure of PGC by synthesizing variations (at least 10) of the effective PGC shown in the preliminary data with the intention to further extend the half-life to at least 30 fold. This is important before we put a lot of resource towards IND. To this end, we will continue the development of PGC-lyso formulation by doing binding studies of at least 10 new carrier variations. We will do PKs and biodistribution studies on at least 6 selected lyso formulations. We will determine and compare with commercially available antibiotics the effectiveness of our lyso formulation in vivo against MRSA. PharmaIN Corp. Confidential

Public Health Relevance

We will develop a formulation of lysostaphin (lyso) to provide a life-saving treatment against MRSA and to suppress the emergence of resistance. To this end, we will optimize the structure of PGC to extend lyso blood residence time by 30 fold and effectiveness in vivo against MRSA by more than 100-fold. We also propose to prepare endotoxin-free lyso and create a master cell-line bank (E. coli expressing lyso) that will be used for: 1) this project to supply our lyso needs, and 2) as reference cells for the planned post-SBIR IND filing and clinical trial. PharmaIN Corp. Confidential

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
5R43AI098130-02
Application #
8468113
Study Section
Special Emphasis Panel (ZRG1-IDM-U (10))
Program Officer
Xu, Zuoyu
Project Start
2012-05-09
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$300,000
Indirect Cost
Name
Pharmain Corporation
Department
Type
DUNS #
167580682
City
Bothell
State
WA
Country
United States
Zip Code
98011