Enhancing the Response Rate to Recombinant Uricases in Patients with Gout

Abstract

Refractory, or uncontrolled, gout is a chronic, progressive, inflammatory arthropathy resulting from continued urate deposition after failed attempts to lower serum uric acid below the therapeutic threshold with oral urate-lowering therapies such as allopurinol and febuxostat. Recombinant uricase is increasingly being used to treat refractory gout; however, the immunogenicity of uricase-based therapies has limited the use of these biologic therapies. Antidrug antibodies against biologic therapies, including uricase and PEGylated uricase, can lead to loss of urate-lowering response, increased risk of infusion reactions, and subsequent treatment failure. However, co-therapy with an immunomodulator can attenuate antidrug antibody development, potentially increasing the likelihood of sustained urate lowering, therapy course completion, and successful treatment outcomes. This review summarizes evidence surrounding the use of immunomodulation as co-therapy with recombinant uricases.

Fig. 1

Immunologic response to uricase-based biologics in the presence and absence of immunomodulation [, , –68]. (a) Uricase antigen uptake facilitates dendritic cell (DC) differentiation and maturation. In response to antigen presentation by DCs, T cells facilitate B-cell antidrug antibody production, followed by neutralization and proteolysis of uricase. (b) Exposure to a co-formulated system (e.g., PEGylated uricase enzyme encapsulated with SVP-rapamycin) induces DC tolerization to PEGylated uricase antigen. Tolerogenic DCs facilitate the production of anergic (or regulatory) T cells, dampening immunogenicity and prolonging PEGylated uricase activity. (c) Exposure to a PEGylated uricase enzyme with immunomodulation (IMM) co-therapy (e.g., oral methotrexate) increases T-cell sensitivity to apoptosis, disrupting the pathway to immunogenicity. Figure adapted from Brunn et al. 2021 [55]. Molecular images of uricase and PEGylated uricase enzymes are not representative of molecule shape or structure and are for illustration purposes only