Single coadministration of erythrocyte-uricase conjugate and immunosuppressant induces durable immune tolerance for gout therapy.

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.