Epitope-driven deimmunization of Factor VIII

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$528,313.00
Award Year:
2007
Program:
SBIR
Phase:
Phase I
Contract:
1R43HL088834-01
Award Id:
85833
Agency Tracking Number:
HL088834
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
146 CLIFFORD STREET, PROVIDENCE, RI, 02903
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
135531015
Principal Investigator:
ANNE DEGROOT
(401) 272-2123
ANNIED@EPIVAX.COM
Business Contact:
JULIE MCMURRY
() -
grants@epivax.com
Research Institution:
n/a
Abstract
DESCRIPTION (provided by applicant): Hemophilia A patients are prone to develop inhibitory immune responses to the very therapy they require: Factor VIII protein replacement. Up to 30% of all hemophiliacs and greater than 50% of severe hemophiliacs produce antibodies (inhibitors) in response to treatment. Immunogenicity to Factor VIII (FVIII) is its most significant complication: immunogenicity not only reduces or eliminates the therapeutic efficacy, but also requires that FVIII be delivered by invasive rou tes since less invasive routes are known to further increase the immunogenicity of therapeutic proteins. To address this problem, it is necessary to develop a less immunogenic FVIII that will provide hemophiliacs with the benefits of prophylactic Factor VI II therapy without the interference of neutralizing antibodies. Neutralizing antibody formation, the root cause of FVIII therapy failure, is a process dependent on antigen presenting cell signaling to helper T cells. We thus propose to develop a de- imm unized version of FVIII by T-cell epitope modification. FVIII contains highly immunogenic T- cell epitopes that are excellent targets for mutation in order to prevent T cell-dependent antibody formation. The aims of this Phase I SBIR are to (1) identify an d select the key immunodominant T-cell epitopes in FVIII that are responsible for its immunogenicity, (2) strategically modify those epitopes using point amino acid changes as guided by EpiVax' validated immunoinformatics tools and techniques and (3) to de monstrate that reengineered individual FVIII domains have reduced immunogenicity in a mouse model of hemophilia. A series of FVIII domain variants bearing single epitope modifications will be produced and their immunogenicity will be evaluated. The focus o f a Phase II SBIR will be studies of FVIII constructs bearing multiple epitope modifications (combinations of the modifications identified during Phase I). These research and development programs will lead to the development of a commercially available and fully functional Factor VIII protein that has significantly reduced immunogenicity as confirmed in HLA transgenic mice and Factor VIII deficient mice. Epitope-driven deimmunization of factor VIII 12,000 Americans have the blood clotting disorder Hemophili a A, and as such are susceptible to a host of complications from chronic bleeding of the joints to life threatening blood loss due to traumatic injury. This proposal describes a plan to produce an improved clotting protein (Factor VIII) that could be used to treat hemophiliacs since the current treatment is often rejected by the body. The proposed reengineered protein will be evaluated in a mice that have a hemophilia as well as in mice that have a human- like immune system.

* information listed above is at the time of submission.

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