title: Novel CD7-specific nanobody-based immunotoxins potently enhanced apoptosis of CD7-positive malignant cells.
abstract: 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.
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Jinle
authors.initials: J
authors.lastname: Tang
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Jialu
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Medicine, Jiangsu Provincial Traditional Chinese Medical Hospital, Nanjing, Jiangsu Province, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Suzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Zhenyang
authors.initials: Z
authors.lastname: Gu
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Suzhou, China.|The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xingding
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Suzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: The Medical Group of Zhengzhou First People's Hospital, Zhengzhou, China.
authors.forename: Zhishu
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Division of Hematology, Department of Medicine, Jiangsu Provincial Traditional Chinese Medical Hospital, Nanjing, Jiangsu Province, China.
authors.forename: Pengjun
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Division of Hematology, Department of Medicine, Jiangsu Provincial Traditional Chinese Medical Hospital, Nanjing, Jiangsu Province, China.
authors.forename: Juhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Meng
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
authors.forename: Gangli
authors.initials: G
authors.lastname: An
authors.affiliation: Beijing 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.
authors.forename: Huyong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: The Cyrus Tang Hematology Center, Soochow University, Suzhou, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.|Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Suzhou, China.|The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D019011:Antigens, CD7; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D061905:Single-Domain Antibodies / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019011:Antigens, CD7; D000970:Antineoplastic Agents; D000922:Immunotoxins; D061905:Single-Domain Antibodies
keywords: VHH; immunotoxin; leukemia; nanobody; target delivery drug