Suppression of anti-drug antibody formation against coagulation factor VIII by oral delivery of anti-CD3 monoclonal antibody in hemophilia A mice

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School of Dental Medicine::Departmental Papers (Dental)
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Dentistry
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Forkhead Transcription Factors
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2023-03
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Bertolini, Thais B.
Herzog, Roland W.
Kumar, Sandeep R.P.
Sherman, Alexandra
Rana, Jyoti
Kaczmarek, Radoslaw
Yamada, Kentaro
Arisa, Sreevani
Lillicrap, David
Terhorst, Cox
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Abstract

Active tolerance to ingested dietary antigens forms the basis for oral immunotherapy to food allergens or autoimmune self-antigens. Alternatively, oral administration of anti-CD3 monoclonal antibody can be effective in modulating systemic immune responses without T cell depletion. Here we assessed the efficacy of full length and the F(ab’)2 fragment of oral anti-CD3 to prevent anti-drug antibody (ADA) formation to clotting factor VIII (FVIII) protein replacement therapy in hemophilia A mice. A short course of low dose oral anti-CD3 F(ab’)2 reduced the production of neutralizing ADAs, and suppression was significantly enhanced when oral anti-CD3 was timed concurrently with FVIII administration. Tolerance was accompanied by the early induction of FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+ populations of CD4+ T cells in the spleen and mesenteric lymph nodes. FoxP3+LAP+ Tregs expressing CD69, CTLA-4, and PD1 persisted in spleens of treated mice, but did not produce IL-10. Finally, we attempted to combine the anti-CD3 approach with oral intake of FVIII antigen (using our previously established method of using lettuce plant cells transgenic for FVIII antigen fused to cholera toxin B (CTB) subunit, which suppresses ADAs in part through induction of IL-10 producing FoxP3-LAP+ Treg). However, combining these two approaches failed to improve suppression of ADAs. We conclude that oral anti-CD3 treatment is a promising approach to prevention of ADA formation in systemic protein replacement therapy, albeit via mechanisms distinct from and not synergistic with oral intake of bioencapsulated antigen. © 2023 Elsevier Inc.

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2023-03
Journal title
Cellular Immunology
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Elsevier
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10.1016/j.cellimm.2023.104675
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