Monobody for Renal Inflammation End stage renal disease (ESRD) affects >485,000 Americans, including over 341,000 hemodialysis patients with an estimated 90,000 new cases per year. The annual cost of treating Americans suffering 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 phase 1 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.
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.
