Publications by authors named "E A Guarnera"
Allostery represents a fundamental mechanism in protein regulation, enabling modulation of protein function from sites distal to the active site. While traditionally explored in the context of small molecules, allosteric modulation is gaining traction as a main mode of action in the realm of antibodies, which offer enhanced specificity and reduced toxicity. This review delves into the rapidly growing field of allosteric antibodies, highlighting recent therapeutic advancements and novel druggability avenues.
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- The study focuses on humanizing camelid-derived variable domain heavy chain antibodies (VHHs), addressing challenges like immunogenicity, stability, and affinity reduction, especially through changes in crucial structural regions.
- Researchers systematically exchanged key residues in VHHs targeting NKp30 with human equivalents, then characterized the variants for binding affinity, yield, and purity using methods such as crystal structure determination and AlphaFold2 predictions.
- The study emphasizes the importance of specific sequence motifs and non-canonical disulfide bonds in VHHs, contributing to better understanding their structural determinants to aid in their design and optimization for therapeutic use.
Article Synopsis
- The study developed chimeric ultralong antibodies derived from cattle that specifically target tumor necrosis factor α (TNF-α) using immunization and yeast surface display techniques.
- One particular antibody variant was found to effectively neutralize TNF-α without losing potency when its structure was modified.
- The researchers also enhanced the antibody adalimumab by incorporating this structural change, resulting in a new antibody design that provides improved inhibition of TNF-α.
In this work, a theoretical-computational method is applied to study the deamidation reaction, a critical post-translational modification in proteins, using a simple model molecule in solution. The method allows one to comprehensively address the environmental effect, thereby enabling one to accurately derive the kinetic rate constants for the three main steps of the deamidation process. The results presented, in rather good agreement with the available experimental data, underline the necessity for a rigorous treatment of environmental factors and a precise kinetic model to correctly assess the overall kinetics of the deamidation reaction.
View Article and Find Full Text PDFIn this study, we demonstrate the feasibility of yeast surface display (YSD) and nextgeneration sequencing (NGS) in combination with artificial intelligence and machine learning methods (AI/ML) for the identification of de novo humanized single domain antibodies (sdAbs) with favorable early developability profiles. The display library was derived from a novel approach, in which VHH-based CDR3 regions obtained from a llama (Lama glama), immunized against NKp46, were grafted onto a humanized VHH backbone library that was diversified in CDR1 and CDR2. Following NGS analysis of sequence pools from two rounds of fluorescence-activated cell sorting we focused on four sequence clusters based on NGS frequency and enrichment analysis as well as in silico developability assessment.
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