A major problem in the treatment of hemophilia A patients with factor VIIII (FVIII) is that up to 30% of these patients produce antibodies to therapeutic FVIII. These antibodies block (inhibit) the pro- coagulant function of FVIII and thus are termed inhibitors. The focus of our lab has been to develop novel approaches for the induction of tolerance so that it can be applied to the prevention or reversal of undesirable immune responses, including the formation of hemophilia inhibitors. We have used immunoglobulin (Ig) fusion proteins expressed in B lymphocytes for the induction of tolerance in animal models of hemophilia. This technology is based on the well-known tolerogenicity of IgG carriers, onto which we engineer multiple epitope-containing polypeptides in frame at the N-terminus. We know that CD4+CD25+ regulatory T cells (Tregs) are required in our tolerogenic protocol and have shown that that the IgG scaffold increases the efficacy of this tolerance process. Independent data suggests that IgG domains contain epitopes, termed Tregitopes, which can activate Tregs. Indeed, recent clinical studies with FVIII-Fc fusion proteins designed for longer half-life appear to be less immunogenic, and may be tolerogenic. We hypothesize that the presence of Tregitopes and IgG processing mechanisms promote tolerogenic presentation. We focus in this proposal to take advantage of B-cell tolerogenic presentation of IgG fusion proteins (including a B-cell directed soluble fusion protein using a single chain anti-CD20) that can be utilized to induce tolerance to FVIII and prevent/reverse inhibitor formation. Moreover, T-cell receptors (TCR) from hemophilia patients will be used to create antigen-specific effector and regulatory CD4 T cells in analogy to the CAR19 T cells designed to treat B-cell leukemias. These will be used to test novel tolerogenic therapy and the efficacy of engineered human Tregs to prevent and reverse inhibitor formation. Our ultimate Aims, thus, are: (1) to use B-cell targeted fusion proteins to modulate anti-FVIII responsiveness, and finally (2) to express human TCR specific for FVIII in expanded human regulatory T cells to effectively suppress inhibitor responses to FVIII. Elucidating the mechanisms of these tolerogenic approaches will enhance our ability to optimize the efficacy and safety of this approach for translation in humans.

Public Health Relevance

Hemophilia A is a life-threatening blood clotting disorder caused by mutations in factor VIII, a clotting factor. The current therapy for this disorder is to administer functional factor VIII intravenously, but a significant number of patients produce antibodies to the treatment, making it ineffective. Our goal is to develop and translate novel therapeutic protocols to prevent and reverse this undesirable antibody formation by inducing tolerance to therapeutic factor VIII.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126727-02
Application #
9064200
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
2015-05-06
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Sicard, Antoine; Levings, Megan K; Scott, David W (2018) Engineering therapeutic T cells to suppress alloimmune responses using TCRs, CARs, or BARs. Am J Transplant 18:1305-1311
Kim, Yong Chan; Kim, Kee Kwang; Yoon, Jeongheon et al. (2018) SAMHD1 Posttranscriptionally Controls the Expression of Foxp3 and Helios in Human T Regulatory Cells. J Immunol 201:1671-1680
Zhang, Ai-Hong; Yoon, Jeongheon; Kim, Yong Chan et al. (2018) Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells. J Immunol 201:1434-1441
Blumberg, Richard S; Lillicrap, David; IgG Fc Immune Tolerance Group (2018) Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia Blood 131:2205-2214
Parvathaneni, Kalpana; Abdeladhim, Maha; Pratt, Kathleen P et al. (2017) Hemophilia A inhibitor treatment: the promise of engineered T-cell therapy. Transl Res 187:44-52
Yoon, Jeongheon; Schmidt, Anja; Zhang, Ai-Hong et al. (2017) FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood 129:238-245
Adair, Patrick R; Kim, Yong Chan; Zhang, Ai-Hong et al. (2017) Human Tregs Made Antigen Specific by Gene Modification: The Power to Treat Autoimmunity and Antidrug Antibodies with Precision. Front Immunol 8:1117
Adair, Patrick; Kim, Yong Chan; Pratt, Kathleen P et al. (2016) Avidity of human T cell receptor engineered CD4(+) T cells drives T-helper differentiation fate. Cell Immunol 299:30-41