Preliminary Investigation and Therapeutic Efficacy Determination of a Novel Anti-IL-17A Antibody, Indikizumab.

Purpose: The study aimed to develop and characterize Indikizumab, a novel humanized anti-IL-17A monoclonal antibody (mAb), for potential therapeutic use in inflammatory indications such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. Methods: The research involved the purification of IL-17 isoforms, epitope mapping, affinity ranking, and comparative binding assessment of anti-IL-17 antibodies. The study also included cell-based neutralization assays and in vivo studies using mouse models to evaluate the efficacy of Indikizumab. Results: Indikizumab demonstrated a high binding affinity (KD=27.2 pM) and specificity for IL-17A, with comparable potency to Secukinumab. In cell-based neutralization assays, Indikizumab effectively neutralized the effects of IL-17A and demonstrated a statistically significant reduction in plasma KC (Keratinocyte) levels in a mouse model. In imiquimod-induced psoriasis mouse model, Indikizumab showed potential in reducing the psoriasis index. Conclusion: Indikizumab represents a promising therapeutic option for inflammatory indications with its high binding affinity, specificity for IL-17A, and effectiveness in neutralizing IL-17A effects in vivo.

Impact of novel N-aryl piperamide NO donors on NF-κB translocation in neuroinflammation: rational drug-designing synthesis and biological evaluation.

NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NF-κB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3'K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3'k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively.

PEGylation of an osteoclast inhibitory peptide: suitable candidate for the treatment of osteoporosis.

Osteoporosis is a condition of bone loss due to excessive osteoclastic activity. Several protein factors, such as receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), have been identified that are important in the pathogenesis of osteoporosis. RANKL binds to RANK and activates the NF-κB pathway by interaction of its cytoplasmic domain with an intracellular adapter protein, TNF receptor associated factors 6 (TRAF 6). This interaction can be inhibited by cell-permeable peptides that prevent RANK-TRAF 6 interaction. However, similar to the peptides/proteins used in clinical setting, the effective application of this TRAF 6 Inhibitory peptide as a therapeutic agent is marred by several limitations for instance short half-life, rapid renal clearance and immunogenicity. In the present study, we have developed PEGylated TRAF 6 Inhibitory peptide by conjugating TRAF 6 Inhibitory peptide to linear PEG backbone that exhibits longer bioavailability in plasma in the animal model. Besides, it has an enhanced uptake at its site of action, i.e., bone marrow.