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Diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors
Qian Zheng1, Zhaohui Wang1, Huiping Zhang1
1Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
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.
Insights
A novel diphtheria toxin-based immunotoxin targeting CD19+ tumors shows promise. The bivalent CD19 immunotoxin demonstrated the highest efficacy in preclinical models, offering a potential new treatment for relapsing/refractory cancers.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD19 is a key target for B-cell immunotherapy.
- Existing treatments for relapsing/refractory CD19+ tumors have limitations.
- Novel therapeutic strategies are needed for CD19-expressing malignancies.
Purpose of the Study:
- To develop and evaluate novel diphtheria toxin-based immunotoxins targeting human CD19.
- To compare the efficacy of different CD19 immunotoxin isoforms (monovalent, bivalent, foldback diabody).
- To assess the therapeutic potential of CD19 immunotoxins in a preclinical model of human CD19+ tumors.
Main Methods:
- Construction of three CD19 immunotoxin isoforms: monovalent, bivalent, and foldback diabody.
- In vitro assessment of binding affinity and cellular efficacy.
- In vivo efficacy evaluation in a human CD19+ JeKo-1 tumor xenograft model in NSG mice.
Main Results:
- The bivalent CD19 immunotoxin exhibited the highest in vitro binding affinity and efficacy.
- All tested CD19 immunotoxin isoforms significantly prolonged median survival in tumor-bearing mice compared to controls.
- The bivalent isoform provided the greatest survival benefit, extending median survival to 40 days.
Conclusions:
- The bivalent CD19 immunotoxin is a potent therapeutic candidate for CD19+ tumors.
- This diphtheria toxin-based immunotoxin demonstrates significant preclinical efficacy.
- Further development is warranted for treating relapsing/refractory human CD19+ malignancies.
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