Novel CD7-specific nanobody-based immunotoxins potently enhanced apoptosis of CD7-positive malignant cells
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Jinle Tang1, Jialu Li1, Xuejun Zhu3, Yuan Yu1, Dan Chen2, Lei Yuan4, Zhenyang Gu4, Xingding Zhang1,2,6, Lin Qi2, Zhishu Gong7, Pengjun Jiang3, Juhua Yu3, Huimin Meng1, Gangli An1, Huyong Zheng5,*, Lin Yang1,2,6,*
1The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
2Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Suzhou, China
3Division of Hematology, Department of Medicine, Jiangsu Provincial Traditional Chinese Medical Hospital, Nanjing, Jiangsu Province, China
4Department of Hematology, Chinese PLA General Hospital, Beijing, China
5Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, Beijing, China
6The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
7The Medical Group of Zhengzhou First People’s Hospital, Zhengzhou, China
*These authors contributed equally to this work
Lin Yang, email: [email protected]
Huyong Zheng, email: [email protected]
Keywords: immunotoxin, nanobody, VHH, leukemia, target delivery drug
Received: November 23, 2015 Accepted: March 28, 2016 Published: April 12, 2016
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.
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