SBIR-STTR Award

Monobody For Renal Inflammaton
Award last edited on: 10/7/11

Sponsored Program
SBIR
Awarding Agency
NIH : NIAID
Total Award Amount
$241,123
Award Phase
1
Solicitation Topic Code
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Principal Investigator
James W Larrick

Company Information

Panorama Research Inc

1230 Bordeaux Drive
Sunnyvale, CA 94089
   (408) 747-5201
   admin@pano.com
   www.pano.com
Location: Single
Congr. District: 17
County: Santa Clara

Phase I

Contract Number: 1R43AI094830-01
Start Date: 5/1/11    Completed: 4/30/12
Phase I year
2011
Phase I Amount
$241,123
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.

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.

Thesaurus Terms:
Aram;Address;Affect;Affinity;Ag Recognition Activation Motif;American;Animal Model;Animal Models And Related Studies;Animals;Anti-Gbm Disease;Anti-Glomerular Basement Membrane Disease;Antibodies;Antigen-Antibody Complex;Attenuated;Balb/C;Binding;Binding (Molecular Function);Blood;Blood Serum;Blood Monocyte;Bright Disease;Ccl2;Ccl2 Gene;Cd89 Antigen;Cells;Chemotaxis;Chronic Kidney Failure;Chronic Renal Disease;Data;Dose;Drug Kinetics;Elisa;Esrd;End Stage Renal Failure;End-Stage Kidney Disease;Enzyme-Linked Immunosorbent Assay;Fc Alpha Ri;Fc(Alpha) Receptor;Fibrosis;Gdcf-2;Gdcf-2 Hc11;Glomerular Basement Membrane Antibody;Glomerulonephritis;Goals;Grafting, Kidney;Hc11;Hcp;Hcph;Hptp1c;Half-Life;Half-Lifes;Hemodialyses;Hemodialysis;Heymann Nephritis;Human;Human, General;Iga Fc Receptor;Inflm;Itam;Iga;Igafc (T Alpha) Receptor;Immune;Immune Complex;Immune System;Immunoglobulin A;Immunoglobulin V;Immunoglobulin Variable Region;Immunoreceptor Tyr-Based Activation Motif;Immunoreceptor Tyrosine-Based Activation Motif;Immunotherapeutic Agent;In Vitro;Inbred Balb C Mice;Indirect Immunofluorescence;Indirect Immunofluorescences;Inflammation;Inflammatory;Inflammatory Response;Kidney;Kidney Diseases;Kidney Failure;Kidney Failure, Chronic;Kidney Insufficiency;Kidney Transplantation;Kidney Transplants;Lead;Mcaf;Mcp-1;Mcp1;Mgc9434;Mammals, Rabbits;Man (Taxonomy);Man, Modern;Marrow Monocyte;Measures;Mediating;Mice, Inbred Balb C;Modeling;Molecular Interaction;Mono-S;Monos;Mouse, Balb C;Myeloid Cells;Nephritis;Nephropathy;Oryctolagus Cuniculus;Ptp-1c;Ptpn6;Ptpn6 Gene;Pathology;Patients;Pb Element;Pharmacokinetics;Phase;Phosphatases;Phosphohydrolases;Phosphomonoesterases;Phosphoric Monoester Hydrolases;Phosphorylation;Process;Production;Protein Phosphorylation;Rabbit, Domestic;Rabbits;Receptor Activation;Receptor Protein;Renal Disease;Renal Disease, End-Stage;Renal Failure;Renal Failure, Chronic;Renal Insufficiency;Renal Transplantation;Renal Transplants;Renal Function;Reticuloendothelial System, Blood;Role;Scya2;Sh-Ptp1;Shp-1;Shp-1l;Smc-Cf;Serum;Specificity;Time;Toxicology;Transgenic Mice;Ureteral Obstruction;Urinary System, Kidney;Variable Region;Variable Region, Ig;Work;Anti-Gbm;Antibody;Antiglomerular Basement Membrane Antibody;Base;Body System, Allergic/Immunologic;Chronic Kidney Disease;Chronic Renal Failure;Cost;Cross-Link;Crosslink;Effective Therapy;Enzyme Linked Immunosorbent Assay;Glomerular Sclerosis;Glomerulosclerosis;Heavy Metal Pb;Heavy Metal Lead;Immunologic Preparation;Immunotherapeutics;Kidney Disorder;Kidney Function;Model;Model Organism;Monocyte;Mouse Model;Novel;Organ System, Allergic/Immunologic;Receptor;Renal;Renal Disorder;Response;Social Role;Ureter Obstruction

Phase II

Contract Number: ----------
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
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Phase II Amount
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