ArticleProtein science : a publication of the Protein Society2019
Reducing proteolytic liability of a MMP-14 inhibitory antibody by site-saturation mutagenesis.
Article in Protein science : a publication of the Protein Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 11 citations in OpenAlex.
- Monoclonal antibodies inhibiting MMP-9 activity alleviate peripheral neuropathy in diabetic mice.Science translational medicine · 2026Article
- Achieving protease substrate-specific inhibition by mAb dual functional selections.Protein science : a publication of the Protein Society · 2026Article
- Generation of Protease Inhibitory Antibodies by Functional In Vivo Selection.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Substrate derived sequences act as subsite-blocking motifs in protease inhibitory antibodies.Protein science : a publication of the Protein Society · 2023Article
- Engineering sigma factors and chaperones for enhanced heterologous lipoxygenase production in Escherichia coli.Biotechnology for biofuels and bioproducts · 2022Article
- Peptide barcoding for one-pot evaluation of sequence-function relationships of nanobodies.Scientific reports · 2021Article
- Improving enzyme activity of glucosamine-6-phosphate synthase by semi-rational design strategy and computer analysis.Biotechnology letters · 2020Article
- Protease Inhibition Mechanism of Camelid-like Synthetic Human Antibodies.Biochemistry · 2020Article
- Functional selection of protease inhibitory antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Inhibitory Antibodies Designed for Matrix Metalloproteinase Modulation.Molecules (Basel, Switzerland) · 2019Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Playing pivotal roles in tumor growth and metastasis, matrix metalloproteinase-14 (MMP-14) is an important cancer target. Potent inhibitory Fab 3A2 with therapy-desired high selectivity has been isolated from a synthetic antibody library carrying long CDR-H3s. However, like many standard mechanism protease inhibitors, Fab 3A2 can be cleaved by high concentrations of MMP-14 after extended incubation at acidic pH. Edman sequencing of generated 3A2 fragments indicated that cleavage occurred within its CDR-H3 between residues N100h (P1) and L100i (P1'). To improve proteolytic stability of 3A2, three positions adjacent to its cleavage site (P1, P1', and P3') were subjected to site-saturation mutagenesis (SSM). Mutations at P1' (L100i) resulted in loss of inhibition function, while screening of 3A2 Fab mutants at P1 (N100h) or P3' (A100k) positions identified four clones exhibiting improvements in both stability and inhibition potency. The majority of these mutants with improved stability were substitutions to either hydrophobic (Lue, Trp) or basic residues (Arg, Lys, His). Combinations of these beneficial mutations resulted in a double mutant N100hR/A100kR, which prolonged half-life twofold with an inhibition potency K
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