Abstract
Uricase (UOX) is effective for treating refractory gout but is limited by antidrug antibody (ADA) formation, which leads to loss of efficacy and infusion reactions. Here, we demonstrate that a single coadministration of erythrocyte-conjugated UOX (UOX-Ery) with an immunosuppressant such as cyclophosphamide (CTX) induces robust and durable antigen-specific immune tolerance. This one-time intervention effectively prevented ADA formation in mice and rats, even after repeated challenges with UOX-Ery or free UOX protein, an outcome not achieved by CTX or UOX plus CTX. This tolerogenic effect relied on splenic uptake of UOX-Ery by myeloid cells, particularly macrophages, and was associated with the expansion of a distinct subset of effector regulatory T cells. Functionally, this immune tolerance enhanced the pharmacokinetics of UOX, sustained long-term control of serum uric acid levels, and attenuated local inflammation within tophus-like lesions. Together, these findings demonstrate that UOX-Ery, combined in a single dose with clinically used immunosuppressants, can effectively treat gout by inducing antigen-specific immune tolerance.