Monobody for Renal Inflammaton

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 1R43AI094830-01
Agency Tracking Number: R43AI094830
Amount: $241,123.00
Phase: Phase I
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIAID
Solicitation Number: PA10-050
Small Business Information
DUNS: 556962439
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (415) 264-6311
Business Contact
Phone: (408) 747-5201
Research Institution
DESCRIPTION (provided by applicant): Monobody for Renal Inflammation End stage renal disease (ESRD) affects gt485,000 Americans, including over 341,000 hemodialysis patients with an estimated 90,000 new cases per year. The annual cost of treating Americanssuffering from some form of kidney failure is about 23 billion. Progression of kidney disease is characterized by a persistent inflammatory response that causes irreversible renal glomerulosclerosis and tubulointerstitial fibrosis eventually leading to ESRD (reviewed in Kanamaru, 2008). Monovalent targeting of Fc alphaRI (CD89) inhibits responses triggered by co-expressed ITAM-activated receptors (Pasquier, 2005). The inhibitory mechanism involves activation of SHP-1 likely by neutralizing receptor-activated phosphorylation responses. A substantial body of data supports the hypothesis (Fig. 1) that monovalent engagement of Fc-alphaRI attenuates inflammation (Monteiro, 2010). For example, the anti-Fc-alphaRI Fab A77 blocks renal inflammation induced by ureteral obstruction or anti-glomerular basement membrane antibodies (Kanamaru 2007a,b; 2008). Fab therapy suffers significant drawbacks related to pharmacokinetics, dose and production costs. To address this problem PRI has invented monobodies, facilely produced mono-specific antibody-based molecules which bind to the FcRN giving a substantial serum half-life and dose/cost reduction. The overall goal of this project is to create and evaluate an A77-based monobody as a novel therapy for renal disease. In phase1 an A77-based monobody will be prepared, purified and its in vitro binding to Fc alphaRI measured. Next the in vitro functional activity of the monobody will be evaluated. Finally, the A77 monobody will be compared to A77 Fab in two models of renal pathology: one induced by anti- glomerular basement antibody and the other by ureteral obstruction. Successful demonstration of protection in these models will merit submission of a phase 2 application focused on expanded animal studies, PK/PD, toxicology and production optimization to support submission of an IND. PUBLIC HEALTH RELEVANCE: Effective treatments to slow the progression of chronic kidney disease are badly needed to reduce the number of patients who progress into end-stage renal disease and who eventually require hemodialysis or kidney transplantation. Inflammation has recently been shown to contribute to the decay of renal function. A novel antibody which inhibits inflammation by binding to FcaR1 will be developed as an immunotherapeutic for kidney disease.

* information listed above is at the time of submission.

Agency Micro-sites

SBA logo
Department of Agriculture logo
Department of Commerce logo
Department of Defense logo
Department of Education logo
Department of Energy logo
Department of Health and Human Services logo
Department of Homeland Security logo
Department of Transportation logo
Environmental Protection Agency logo
National Aeronautics and Space Administration logo
National Science Foundation logo
US Flag An Official Website of the United States Government