SBIR-STTR Award

The overall goal is to develop monoclonal antibody-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. Three pathways have been described for complement activation: the classical, alternative and lectin pathways. 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. Recent studies indicate that the lectin pathway may have a critical role in triggering complement activation in many tissue injury settings, especially when there is no evident role for the classical pathway in the disease pathogenesis. A mouse genetically-deficient in the MASP-2 protein has been developed. The availability of the MASP-2 (-/-) mouse and the genetically-matched MASP-2 (+/+) mouse provides a powerful research tool to directly evaluate the pathogenic role of MASP-2 and the lectin-dependent complement system in murine models of CNV and AMD. The specific objectives in this SBIR grant application are to compare and contrast the results obtained when MASP-2 (-/-) and MASP-2 (+/+) mice are evaluated in the course of laser-induced CNV, an accelerated model of neovascular AMD. A successful outcome in the Phase I studies would indicate that MASP-2 is an attractive therapeutic target for the treatment of the CNV (wet) form of AMD. A Phase II application would focus on the development of blocking monoclonal antibody-based compounds specific for MASP-2 as potential therapeutic agents for AMD. Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 and 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 in mice deficient in MASP-2 to determine their susceptibility to AMD and would provide support for this as a novel target in AMD medication development.

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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.

Thesaurus Terms:
Accounting; Affect; Age; Age Related Macular Degeneration; Aged 65 And Over; Animals; Antibodies; Applications Grants; Area; Atrophic Amd; Atrophic Age-Related Macular Degeneration; Automobile Driving; Blindness; Blood Plasma; Body Tissues; Bruch Membrane; Bruch's Basal Membrane Structure; Choroid; Choroidal Neovascularization; Cicatrix; Clinical; Clinical Evaluation; Clinical Testing; Complement; Complement Activation; Complement Inactivators; Complement Inhibitors; Complement Proteins; Complex; Country; Development; Diabetic Retinopathy; Disease; Disorder; Dose; Drivings, Automobile; Drugs; Dry Amd; Elderly; Elderly, Over 65; Electromagnetic, Laser; Emotional; Evaluation; Food; Foundations; Gfac; Glaucoma; Goals; Government; Grant; Grant Proposals; Grants, Applications; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Host Defense Mechanism; Human; Human, General; Immune; Impairment; Individual; Inflammatory; Inflammatory Response; Injury; Investigation; Investigators; Ischemia-Reperfusion Injury; Kentucky; Knockout Mice; Laboratories; Lamina Basalis Choroideae; Laser Injury; Lasers; Lectin; Left; Licensing; Lucentis; Masp Protease; Masp-2 Protein, Human; Masp-2 Protein, Mouse; Masp2 Protein, Human; Map19 Protein, Mouse; Mbl-Associated Serine Protease 2, Human; Mbl-Associated Serine Protease-2, Mouse; Mbl-Associated Serine Proteases; Mbp-Associated Serine Protease; Macular Degeneration; Macular Degenerative Disease; Maculopathy, Age-Related; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Masp2 Protein, Mouse; Mediating; Medication; Medicine; Mice; Mice, Knock-Out; Mice, Knockout; Moab, Clinical Treatment; Modeling; Monoclonal Antibodies; Murine; Mus; National Eye Institute; Neovascularization, Choroid; Nonexudative Age-Related Macular Degeneration; Null Mouse; Organ System; Outer Pigmented Layer Of Retina; Pathogenesis; Pathology; Pathway Interactions; Patients; Peripheral; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Pigment Cell Layer Of Retina; Pigmented Layer Of Retina; Plasma; Play; Population; Programs (Pt); Programs [publication Type]; Radiation, Laser; Reading; Recovery; Regulation; Reperfusion Damage; Reperfusion Injury; Reporting; Research; Research Personnel; Researchers; Reticuloendothelial System, Serum, Plasma; Retina; Retinal Pigment Epithelium; Retinal Pigment Epithelial Cells; Risk; Rodent; Rodentia; Rodentias; Role; Sbir; Sbirs (R43/44); Subgp; Safety; Scars; Science Of Medicine; Serine Endopeptidases; Serine Protease; Serine Protein Hydrolases; Serine Proteinases; Serum, Plasma; Side; Sight; Small Business Innovation Research; Small Business Innovation Research Grant; Solid; Strategic Planning; Structure Of Bruch's Basal Membrane; Structure Of Retinal Pigment Epithelium; Subgroup; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Tissue Donors; Tissues; Toxic Effect; Toxicities; United States; Universities; Vegfs; Validation; Vascular Endothelial Growth Factors; Vegf; Vision; Wild Type Mouse; Work; Advanced Age; Base; Biomarker; Body System; Clinical Effect; Clinical Test; College; Complement Pathway; Complement Pathway Regulation; Complement System; Design; Designing; Disease/Disorder; Driving; Drug Development; Drug/Agent; Effective Therapy; Elders; Geriatric; Glaucomatous; Human Masp2 Protein; Human Disease; In Vivo; Inhibitor; Inhibitor/Antagonist; Interest; Intervention Therapy; Late Life; Later Life; Macula; Macular; Mannan-Binding Lectin Serine Protease 2, Human; Mannan-Binding Lectin Serine Protease 2, Mouse; Mannan-Binding Lectin Serine Proteases; Mannan-Binding Lectin-Associated Serine Protease 2, Human; Mannan-Binding Protein-Associated Serine Protease-2, Human; Mannose-Binding Protein-Associated Serine Protease 2, Human; Mannose-Binding Protein-Associated Serine Proteases; Mouse Masp2 Protein; Mouse Model; Neovascular; New Therapeutics; Next Generation Therapeutics; Non-Human Primate; Nonhuman Primate; Novel Therapeutics; Older Adult; Older Person; Ophthalmic Drug; Pathogen; Pathway; Phase 1 Study; Pre-Clinical; Preclinical; Preclinical Study; Prevent; Preventing; Programs; Public Health Relevance; Research Clinical Testing; Senile Macular Disease; Senior Citizen; Social Role; Socioeconomic; Socioeconomically; Socioeconomics; Therapeutic Target; Tool; Web Site