The adsorption of serum proteins on biomaterial surfaces is a critical determinant for the outcome of medical procedures and therapies, which involve inserting materials and devices into the body. In Show more
The adsorption of serum proteins on biomaterial surfaces is a critical determinant for the outcome of medical procedures and therapies, which involve inserting materials and devices into the body. In this study, we aimed to understand how surface topography at the nanoscale influences the composition of the protein corona that forms on the (bio)material surface when placed in contact with serum proteins. To achieve that, we developed nanoengineered model surfaces with finely tuned topography of 16, 40, and 70 nm, overcoated with methyl oxazoline to ensure uniform outermost chemistry across all surfaces. Our findings revealed that within the studied height range, surface nanotopography had no major influence on the overall quantity of adsorbed proteins. However, significant alterations were observed in the composition of the adsorbed protein corona. For instance, clusterin adsorption decreased on all the nanotopography-modified surfaces. Conversely, there was a notable increase in the adsorption of ApoB and IgG gamma on the 70 nm nanotopography. In comparison, the adsorption of albumin was greater on surfaces that had a topography scale of 40 nm. Analysis of the gene enrichment data revealed a reduction in protein adsorption across all immune response-related biological pathways on nanotopography-modified surfaces. This reduction became more pronounced for larger surface nanoprotrusions. Macrophages were used as representative immune cells to assess the influence of the protein corona composition on inflammatory outcomes. Gene expression analysis demonstrated reduced inflammatory responses on the nanotopographically modified surface, a trend further corroborated by cytokine analysis. These findings underscore the potential of precisely engineered nanotopography-coated surfaces for augmenting biomaterial functionality. Show less
Interleukin (IL)-23 exists as a heterodimer consisting of p19 and p40 and is a key cytokine for promoting inflammatory responses in a variety of target organs. IL-23 plays a key role in the differenti Show more
Interleukin (IL)-23 exists as a heterodimer consisting of p19 and p40 and is a key cytokine for promoting inflammatory responses in a variety of target organs. IL-23 plays a key role in the differentiation and maintenance of T helper 17 cells, and deregulation of IL-23 can result in autoimmune pathologies of the skin, lungs, and gut. This study describes the generation and characterization of mirikizumab (miri), a humanized IgG4 monoclonal antibody directed against the p19 subunit of IL-23. Miri binds human and cynomolgus monkey IL-23 with high affinity and binds rabbit IL-23 weakly but does not bind to rodent IL-23 or the other IL-23 family members IL-12, IL-27, or IL-35. Miri effectively inhibits the interaction of IL-23 with its receptor, and potently blocks IL-23-induced IL-17 production in cell-based assays while preserving the function of IL-12. In both local and systemic in vivo mouse models, miri blocked IL-23-induced keratin mRNA or IL-17 production, respectively. These data provide a comprehensive preclinical characterization of miri, for which efficacy and safety have been demonstrated in human clinical trials for psoriasis, ulcerative colitis, and Crohn's disease. SIGNIFICANCE STATEMENT: This article describes the generation and characterization of mirikizumab, a high affinity, neutralizing IgG4 variant monoclonal antibody that is under development for the treatment of ulcerative colitis and Crohn's disease. Neutralization of interleukin (IL)-23 is achieved by preventing the binding of IL-23 p19 subunit to the IL-23 receptor and does not affect the IL-12 pathway. Show less