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Review
. 2022 Mar;36(2):95-103.
doi: 10.1007/s40259-022-00517-x. Epub 2022 Mar 22.

Enhancing the Response Rate to Recombinant Uricases in Patients with Gout

Naomi Schlesinger  1 , Lissa Padnick-Silver  2 , Brian LaMoreaux  3
Affiliations
Review

Enhancing the Response Rate to Recombinant Uricases in Patients with Gout

Naomi Schlesinger et al. BioDrugs. 2022 Mar.

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.

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Conflict of interest statement

NS has received grants from Amgen and is a consultant to and advisory board member for Horizon Therapeutics, Alnylam Pharmaceuticals, and JW Pharmaceutical Corporation. BL and LP-S are employees of and stockholders in Horizon Therapeutics.

Figures

Fig. 1
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
See this image and copyright information in PMC

References

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