A single-domain i-body, AD-114, attenuates renal fibrosis through blockade of CXCR4.

The G protein-coupled CXC chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define its renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, TGF-ß1 expression, and fibroblast activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-ß1-induced upregulated expression of ECM, matrix metalloproteinase-2, and downstream p38 mitogen-activated protein kinase (p38 MAPK) and PI3K/AKT/mTOR signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.

Perpetual complexity: predicting human CD8+ T-cell responses to pathogenic peptides.

The accurate prediction of human CD8+ T-cell epitopes has great potential clinical and translational implications in the context of infection, cancer and autoimmunity. Prediction algorithms have traditionally focused on calculated peptide affinity for the binding groove of MHC-I. However, over the years it has become increasingly clear that the ultimate T-cell recognition of MHC-I-bound peptides is governed by many contributing factors within the complex antigen presentation pathway. Recent advances in next-generation sequencing and immunnopeptidomics have increased the precision of HLA-I sub-allele classification, and have led to the discovery of peptide processing events and individual allele-specific binding preferences. Here, we review some of the discoveries that initiated the development of peptide prediction algorithms, and outline some of the current available online tools for CD8+ T-cell epitope prediction.