Diphtheria toxin‐based anti‐human CD19 immunotoxin for targeting human CD19+ tumors

• Published in: Molecular oncology Vol. 11; no. 5; pp. 584 - 594
• Main Authors: Zheng, Qian, Wang, Zhaohui, Zhang, Huiping, Huang, Qi, Madsen, Joren C., Sachs, David H., Huang, Christene A., Wang, Zhirui
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2017; John Wiley and Sons Inc
• Subjects: Animals; Antibody-toxin conjugates; Antigens, CD19 - immunology; B cells; CD19+ tumor; Cell Survival - drug effects; diphtheria toxin; Diphtheria Toxin - genetics; Diphtheria Toxin - therapeutic use; DNA - genetics; Dose-Response Relationship, Drug; human CD19; Humans; immunotoxin; Immunotoxins - pharmacology; Immunotoxins - therapeutic use; Killer cells; Lymphomas; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms - therapy; Pichia Pastoris; Time Factors; Tumor Cells, Cultured; CD19+ tumor; diphtheria toxin; immunotoxin; Pichia Pastoris; human CD19
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12056

CD19 is expressed on normal and neoplastic B cells and is a promising target for immunotherapy. However, there is still an unmet need to further develop novel therapeutic drugs for the treatment of the refractory/relapsing human CD19+ tumors. We have developed a diphtheria toxin‐based anti‐human CD19 immunotoxin for targeting human CD19+ tumors. We have constructed three isoforms of the CD19 immunotoxin: monovalent, bivalent, and foldback diabody. In vitro binding affinity and efficacy analysis demonstrated that the bivalent isoform had the highest binding affinity and in vitro efficacy. The in vivo efficacy of the CD19 immunotoxins was assessed using human CD19+ JeKo‐1 tumor‐bearing NOD/SCID IL‐2 receptor γ−/− (NSG) mouse model. In these animals, CD19 immunotoxins significantly prolonged the median survival from 31 days in controls to 34, 36, and 40 days in animals receiving the monovalent isoform, foldback diabody isoform, and bivalent isoform, respectively. The bivalent CD19 immunotoxin is a promising therapeutic drug candidate for targeting relapsing/refractory human CD19+ tumors. A novel recombinant anti‐human CD19 immunotoxin was developed using a unique diphtheria toxin‐resistant yeast Pichia Pastoris expression system. The in vivo efficacy was characterized using a human CD19+ tumor‐bearing immunodeficient NSG mouse model. This anti‐human CD19 immunotoxin is a promising therapeutic drug candidate for targeting relapsing/refractory human CD19+ tumors.