Abstract
Human Papillomavirus 16-associated cancer, affecting primarily the uterine cervix but, increasingly, other body districts, including the head–neck area, will long be a public health problem, despite there being a vaccine. Since the virus oncogenic activity is fully ascribed to the viral E6 and E7 oncoproteins, one of the therapeutic approaches for HPV16 cancer is based on specific antibodies in single-chain format targeting the E6/E7 activity. We analyzed the Complementarity Determining Regions, repositories of antigen-binding activity, of four anti-HPV16 E6 and -HPV16 E7 scFvs, to highlight possible conformity to biophysical properties, recognized to be advantageous for therapeutic use. By epitope mapping, using E7 mutants with amino acid deletions or variations, we investigated differences among the anti-16E7 scFvs in terms of antigen-binding capacity. We also performed computational analyses to determine whether length, total net charge, surface hydrophobicity, polarity and charge distribution conformed well to those of the antibodies that had already reached clinical use, through the application of developability guidelines derived from recent literature on clinical-stage antibodies, and the Therapeutic Antibodies Profiler software. Overall, our findings show that the scFvs investigated may represent valid candidates to be developed as therapeutic molecules for clinical use, and highlight characteristics that could be improved by molecular engineering.
Highlights
Recombinant monoclonal antibodies are among the classes of therapeutic drugs that convey most of the large funds from the biotechnology industry
Our findings show that the scFvs investigated may represent valid candidates to be developed as therapeutic molecules for clinical use, and highlight characteristics that could be improved by molecular engineering
Bearing in mind the possible use of our scFvs for the treatment of HPV16 lesions, we evaluated the scFv specificity based on the charge of the aa residues that form their Complementarity Determining Regions (CDRs), and investigated by Therapeutic Antibody Profiler (TAP) the properties potentially favoring their therapeutic development
Summary
Recombinant monoclonal antibodies (mAbs) are among the classes of therapeutic drugs that convey most of the large funds from the biotechnology industry. Since 1986 up until to May 2020, the European Medicines Agency and the US Food and Drug Administration have approved ninety-four antibody therapies for the European or US market, while sixteen are under review [1] Among the different formats of recombinant antibodies, single-chain variable antibody fragments (scFvs), consisting of the variable domains of the heavy (VH) and light (VL) immunoglobulin chains joined by a flexible linker, have probably the primacy of versatility. They can be engineered by molecular biology techniques according to the purpose; e.g., grafted to different scaffolds, expressed as intracellular antibodies (intrabodies) by eukaryotic viral or non-viral vectors
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