Immunocytokine therapy for immune modulation in hemophilia
Active Project Grant Awarded Last action
- Award ID
- R33HL177497
- Recipient
-
Trustees Of Indiana University UEI SHHBRBAPSM35
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,272,128
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 96% complete
- Place of performance
- Indianapolis, IN 46202, USA
Award details come from USAspending.gov.
Description
- Abstract
- Clotting factor replacement therapy to manage bleeding in patients with hemophilia can lead to the development of neutralizing anti-drug antibodies called inhibitors, which complicate therapy. Current immune tolerance induction (ITI) protocols eradicate inhibitors only in a subset of patients and necessitates frequent intravenous (IV) infusions of clotting concentrates, placing a heavy burden on patients and generating high treatment costs. Further, patients with hemophilia B can develop anaphylactic reactions to chronic clotting factor exposure, discouraging healthcare providers from attempts at tolerization. Therefore, there is high interest in developing novel approaches to promote tolerance to the replacement protein. FOXP3+ regulatory T cells (TREGS) are essential for establishing and maintaining immune tolerance to inhibitor development against clotting factor replacement therapy in hemophilia. The cytokine IL-2 engages transmembrane signaling receptors in TREGS to mediate proliferation, differentiation, and expansion, thus promoting this tolerance effect. However, effector T cells and NK cells also express components of the IL-2 receptor complex, resulting in harmful off-target effects and toxicities. Additionally, the short half-life of cytokines necessitates frequent repetitive dosing for therapeutic effect, which increases the burden on patients. In this R33 product definition application, we will test a novel biotherapeutic IL-2 based immunocytokine, F5111- IC, which uses structure-based design to detarget IL-2 pleiotropy from non-TREGS. Pre-clinical assessments of F5111-IC has shown highly promising targeted immunosuppressive effects in models of autoimmune disease. We propose to investigate the F5111-IC treatment platform to suppress the formation of inhibitors in hemophilia. Our proposal seeks to validate this targeted immunomodulatory technology in multiple preclinical models of hemophilia a and B as part of our clinical translation strategy. We outline measurable milestones in the identification of an optimal treatment protocol for durable tolerance with acceptable safety profiles in small and large animal models of hemophilia. If successful, this technology is likely to be relevant to other biologic treatments that are complicated by anti-drug antibody formation and can also be applied other conditions such as antibody mediated hyperacute rejection in transplantation.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $524,214 | |
| Amendment | $0 | |
| Amendment | $582,638 | |
| Amendment | $582,638 | |
| Original award | $582,638 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| The Johns Hopkins University | $56,274 | |
| University Of North Carolina At Chapel Hill | $320,592 |
Quick answers
Who received award R33HL177497?
R33HL177497 was awarded to Trustees Of Indiana University by National Heart Lung and Blood Institute (National Institutes of Health) on January 1, 2025.
How much is award R33HL177497 worth?
$2,272,128 has been obligated on R33HL177497.
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