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Rational Design of a Humanized Antibody Inhibitor of Cathepsin B
journal contribution
posted on 2020-03-31, 19:39 authored by Zhefu Dai, Qinqin Cheng, Yong ZhangCathepsin
B (CTSB) is an abundant cysteine protease that functions
in both endolysosomal compartments and extracellular regions. A considerable
number of preclinical and clinical studies indicate that CTSB is implicated
in many human diseases. Expression levels and activity of CTSB significantly
correlate with disease progression and severity. Current inhibitors
of CTSB are lack of adequate specificity and pharmacological activities.
Through structure-guided rational design, we hereby designed and generated
a humanized antibody inhibitor targeting human CTSB. This was achieved
by genetically fusing the propeptide of procathepsin B, a naturally
occurring inhibitor of CTSB, into heavy chain complementarity-determining
region 3 (CDR3H) of Herceptin that is used in the clinic for the treatment
of breast cancer. The resulting antibody–propeptide fusion
displayed high specificity for inhibiting CTSB proteolytic activity
at nanomolar levels. Pharmacokinetic studies in mice revealed a plasma
half-life of approximately 42 h for this anti-CTSB antibody inhibitor,
comparable to that of the parental Herceptin scaffold. This study
demonstrates a new approach for the efficient generation of humanized
antibody inhibitors with high potency and specificity for human CTSB,
which may be extended to develop antibody inhibitors against other
disease relevant cathepsin proteases.
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nanomolar levelsprocathepsin B42 hHerceptin scaffoldhumanized antibody inhibitorhumanized antibody inhibitorsCathepsin B Cathepsin Bantibody inhibitorsCurrent inhibitorsCDR 3HHumanized Antibody Inhibitorchain complementarity-determining region 3anti-CTSB antibody inhibitorbreast cancerRational Designplasma half-lifePharmacokinetic studiescysteine proteaseextracellular regionsExpression levelsendolysosomal compartmentsspecificitydisease progressioncathepsin proteases
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