Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA.
Protein Sci. 2020 Sep;29(9):1924-1930. doi: 10.1002/pro.3913. Epub 2020 Aug 7.
Cathepsin L (CTSL) is a cysteine protease involved in a variety of physiological and pathological processes. Potent inhibitors against CTSL have long been sought for drug development. Due to insufficient specificity and suboptimal pharmacological properties for current CTSL inhibitors, novel agents are still required for selectively blocking CTSL activity. Here we generated a humanized antibody inhibitor of CTSL by genetically fusing the inhibitory propeptide of procathepsin L to the N-terminus of the light chain of a humanized antibody. The resulting antibody fusion could be stably expressed and displays highly potent inhibition activity and specificity toward CTSL. This work demonstrates a new approach for the rapid generation of antibody inhibitors of CTSL. It can possibly be extended to create inhibitory antibodies targeting other cathepsin proteases, providing novel research and therapeutic tools.
组织蛋白酶 L（CTSL）是一种半胱氨酸蛋白酶，参与多种生理和病理过程。长期以来，人们一直在寻找针对 CTSL 的强效抑制剂用于药物开发。由于目前的 CTSL 抑制剂特异性不足和药理性质不理想，仍需要新型试剂来选择性阻断 CTSL 的活性。本研究通过将前体组织蛋白酶 L 的抑制性原肽与重链的 N 末端融合，从而构建了 CTSL 的人源化抗体抑制剂。该抗体融合物能够稳定表达，并对 CTSL 表现出高度有效的抑制活性和特异性。这项工作展示了一种快速生成 CTSL 抗体抑制剂的新方法。它可以扩展到创建针对其他组织蛋白酶蛋白酶的抑制性抗体，为研究和治疗提供新的工具。
