The overall goal is to develop monoclonal antibody (MoAb)-based compounds capable of blocking human MASP-2 function as potential therapeutic agents for the treatment of age-related macular degeneration (AMD). MASP-2 is a plasma serine protease uniquely required for complement activation via the lectin pathway and may be an attractive target for the development of novel therapeutics for inflammatory disorders. The complement system is an important host defense mechanism, however excessive or uncontrolled complement activation can trigger an intense inflammatory response that is thought to significantly contribute to undesired tissue damage in many disease states. Recent results implicate a central role for complement activation in the pathogenesis of AMD, and especially of choroidal neovascularization (CNV), the most serious form of AMD. To treat AMD it would be desirable to develop pathway-specific inhibitors which would target only the complement pathway causing the particular pathology without completely shutting down the immune defense capabilities of complement. Immunohistological studies of human donor tissues indicate that the classical pathway does not play a major role in triggering complement activation in AMD. Results from the Phase I studies have shown inhibition of CNV by MASP-2 MoAbs and now have provided definitive proof for an important role of MASP-2 in mediating CNV caused by laser injury to the retina. In addition, we have confirmed that laser injury-induced increases in VEGF are prevented in the lectin pathway deficient MASP-2 (-/-) mice. These findings further provide very convincing evidence that MASP-2 is an attractive therapeutic target for this indication.
The Specific Aims for year 1 include: 1) Establishment of the pharmacology and protective mechanisms of anti-MASP-2 MoAb in the mouse model of AMD by evaluating the therapeutic effects on CNV, lectin pathway biomarkers and the disease-relevant growth factor, VEGF, in choroid/ RPE tissue. The other specific aim for year 1 includes: 2) Evaluation of an anti-MASP-2 MoAb clinical candidate on local and systemic pharmacodynamics in the non-human primate.
The specific aims for year 2 include: 3) Establishment of the efficacy of the anti-MASP-2 MoAb clinical candidate in a non-human primate AMD model and 4) Evaluation of the local ocular and global safety and toxicity of a single dose administration of the anti- MASP-2 MoAb.

Public Health Relevance

Age-related macular degeneration (AMD) is the leading cause of blindness after age 55. It is estimated that 1.75 million individuals suffer from this disease in the United States, with another 7 million """"""""at risk"""""""". In this SBIR grant, studies will evaluate a potential new target called MASP-2 for treatment of AMD. Studies will be conducted with anti-MASP- 2 monoclonal antibodies to determine their potential as novel therapeutic agents in models of AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44EY018017-03
Application #
8035293
Study Section
Special Emphasis Panel (ZRG1-ETTN-E (12))
Program Officer
Wujek, Jerome R
Project Start
2007-05-01
Project End
2013-07-31
Budget Start
2011-05-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$173,661
Indirect Cost
Name
Omeros Corporation
Department
Type
DUNS #
033364923
City
Seattle
State
WA
Country
United States
Zip Code
98119