Novel CD7-specific nanobody-based immunotoxins potently enhanced apoptosis of CD7-positive malignant cells

• Published in: Oncotarget 2016-06, Vol.7 (23), p.34070-34083
• Main Authors: Tang, Jinle, Li, Jialu, Zhu, Xuejun, Yu, Yuan, Chen, Dan, Yuan, Lei, Gu, Zhenyang, Zhang, Xingding, Qi, Lin, Gong, Zhishu, Jiang, Pengjun, Yu, Juhua, Meng, Huimin, An, Gangli, Zheng, Huyong, Yang, Lin
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD7; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Humans; Immunotoxins - pharmacology; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Research Paper; Single-Domain Antibodies - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8710

Various CD7-targeting immunotoxins have been tested for its potential in treating CD7+ malignant patients but none of those immunotoxins was approved clinically because of lacking enough efficacy and safety. Here we successfully constructed the monovalent and bivalent CD7 nanobody-based immunotoxins PG001 and PG002, both conjugated with a truncated derivative of Pseudomonas exotoxin A respectively. The prokaryotic system expressed immunotoxins not only maintained their binding specificity for CD7-positive cells with a Kd of 16.74 nM and 3.6 nM for PG001 and PG002 respectively, but also efficiently promoted antigen-restricted apoptosis of the CD7-positive leukemia cell lines Jurkat and CEM, and primary T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) cells with an in vitro cytotoxic activity (EC50) in the range of 23-30 pM for PG002. In NOD/SCID mice transplanted with CEM cells, PG001 and PG002 prevented engraftment of the cells and markedly prolonged mouse survival. Owing to the efficient antigen-restricted anti-leukemic activity of PG002, this CD7 nanobody-based immunotoxin exhibited a superior anti-CD7 positive malignancies activity than previously reported immunotoxins, and may represent a promising therapeutic strategy in treating CD7-positive leukemia and lymphoma, which still remain a significant clinical challenge.