Immunocytokine therapy for immune modulation in hemophilia

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.

Grant Number: 5R33HL177497-02
NIH Institute/Center: NIH
Principal Investigator: Moanaro Biswas