Abstract
PURPOSE: ABP 654 is the first FDA-approved interchangeable biosimilar for ustekinumab reference product (RP). To support the totality of evidence (TOE), in vitro pharmacology studies were conducted in peripheral blood mononuclear cells (PBMCs) from healthy human donors and Crohn's disease (CD) patients to evaluate IL-23 and IL-12 inhibition by ABP 654 and ustekinumab RP relevant to the mechanism of action of chronic inflammation. METHODS: ABP 654 and ustekinumab RP were assessed using inhibition of IL-23 and IL-12-mediated IFN-γ release, signal transducer and activator of transcription (STAT)3 and STAT4 phosphorylation, and IL-17 release. IFN-γ levels were determined using homogenous time-resolved fluorescence (HTRF). STAT3 and STAT4 phosphorylation were measured by flow cytometry. IL-17 was measured using a Cisbio IL-17 detection kit. IC(50) values were calculated to assess the relative potency of ABP 654 and ustekinumab RP. RESULTS: ABP 654 and ustekinumab RP demonstrated similar inhibition and relative potency of IL-23 and IL-12-mediated IFN-γ release, and no difference in inhibition of IL-23/IL-12-mediated STAT3/STAT4 phosphorylation in healthy donor PBMCs, as evidenced by the overlapping standard deviation (SD). In CD PBMCs, ABP 654 and ustekinumab RP also showed no difference in IC(50) values for inhibition of IL-23/IL-12-mediated STAT3/STAT4 phosphorylation. ABP 654 and ustekinumab RP showed no difference in IC(50) values for IL-23-induced IL-17 release, in either healthy (ABP 654, 458.7±110.8 pM; ustekinumab (EU), 514.6±48.7 pM) or CD (ABP 654, 260.8±88.5 pM; ustekinumab (EU), 256.9±96.8 pM) donor cells with overlapping SD. CONCLUSION: These studies demonstrated similar inhibition of IL-23 and IL-12 function by ABP 654 and ustekinumab RP in both healthy and CD PBMCs. Overall, these assays support the conclusion that ABP 654 and ustekinumab RP are functionally similar, thereby contributing to the TOE supporting a demonstration of biosimilarity.