Rational Design of a Humanized Antibody Inhibitor of Cathepsin B.,Biochemistry

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Rational Design of a Humanized Antibody Inhibitor of Cathepsin B.
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-31 , DOI: 10.1021/acs.biochem.0c00046
Zhefu Dai ₁ , Qinqin Cheng ₁ , Yong Zhang _{1,

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Affiliation

Cathepsin 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.

中文翻译：

组织蛋白酶B人源化抗体抑制剂的合理设计。

组织蛋白酶B（CTSB）是一种丰富的半胱氨酸蛋白酶，在溶酶体区室和细胞外区域均起作用。大量的临床前和临床研究表明CTSB与许多人类疾病有关。CTSB的表达水平和活性与疾病进展和严重程度显着相关。当前的CTSB抑制剂缺乏足够的特异性和药理活性。通过结构指导的合理设计，我们特此设计并生成了针对人CTSB的人源化抗体抑制剂。这是通过将自然存在的CTSB抑制剂procathepsin B的前肽遗传融合到Herceptin的重链互补决定区域3（CDR3H）中而实现的，该区域在临床上用于治疗乳腺癌。所得的抗体-肽融合物在纳摩尔水平上显示出抑制CTSB蛋白水解活性的高特异性。在小鼠中进行的药代动力学研究表明，这种抗CTSB抗体抑制剂的血浆半衰期约为42小时，与亲本赫赛汀支架的血浆半衰期相当。这项研究证明了一种有效产生对人CTSB具有高效力和特异性的人源化抗体抑制剂的新方法，该方法可以扩展以开发针对其他疾病相关组织蛋白酶的抗体抑制剂。

更新日期：2020-04-01

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