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Ontak-like human IL-2 fusion toxin
Zhaohui Wang1, Qian Zheng1, Huiping Zhang1
1Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
Ontak® is a FDA-approved diphtheria toxin-based recombinant fusion toxin for treatment of human CD25+ cutaneous T cell lymphoma (CTCL). However, it has been discontinued clinically due to the production issue related to the bacterial expression system with difficult purification. Recently we have developed monovalent and bivalent human IL-2 fusion toxins targeting human CD25+ cells using advanced unique diphtheria toxin resistant yeast Pichia Pastoris expression system. In vitro efficacy characterization using human CD25+ HUT102/6TG cells demonstrated that both monovalent and bivalent isoforms are potent and the bivalent isoform is approximately two logs more potent than the monovalent isoform. In this study, we further assessed the in vivo efficacy of the human IL-2 fusion toxins using human CD25+ HUT102/6TG tumor-bearing NSG mouse model. The data demonstrated that both monovalent and bivalent human IL-2 fusion toxins significantly prolonged the survival of the human CD25+ tumor-bearing NSG mice in a dose-dependent manner. Then we further assessed the residual tumor cells from the HUT102/6TG tumor-bearing NSG mice using the residual tumor cell bearing NSG mouse model. The results demonstrated that the residual tumor cells were still sensitive to the continual treatment with the human IL-2 fusion toxin. This yeast-expressed human IL-2 fusion toxin will be a promising candidate to replace the clinically discontinued Ontak®.
Insights
New IL-2 fusion toxins targeting CD25+ cells show promise for treating cutaneous T-cell lymphoma (CTCL). Developed using a yeast expression system, these toxins offer a potential replacement for the discontinued Ontak®.
Area of Science:
- Biotechnology
- Oncology
- Immunotherapy
Background:
- Ontak® (diphtheria toxin-based fusion toxin) was approved for CD25+ cutaneous T-cell lymphoma (CTCL) but was discontinued due to production issues.
- Bacterial expression systems for recombinant toxins like Ontak® present purification challenges.
Purpose of the Study:
- To develop and evaluate novel monovalent and bivalent human IL-2 fusion toxins for CD25+ CTCL treatment.
- To assess the in vivo efficacy and potential of yeast-expressed IL-2 fusion toxins as an alternative to Ontak®.
Main Methods:
- Developed monovalent and bivalent human IL-2 fusion toxins using a diphtheria toxin-resistant Pichia Pastoris yeast expression system.
- Characterized in vitro efficacy using human CD25+ HUT102/6TG cells.
- Assessed in vivo efficacy in human CD25+ HUT102/6TG tumor-bearing NSG mouse models, including evaluation of residual tumor cell sensitivity.
Main Results:
- Both monovalent and bivalent IL-2 fusion toxins demonstrated potent in vitro efficacy, with the bivalent form being significantly more potent.
- In vivo studies showed that both toxin isoforms significantly prolonged survival in tumor-bearing mice in a dose-dependent manner.
- Residual tumor cells remained sensitive to continued treatment, indicating sustained therapeutic potential.
Conclusions:
- Yeast-expressed human IL-2 fusion toxins are effective in vivo against CD25+ CTCL models.
- These novel toxins represent a promising alternative to the clinically discontinued Ontak®, addressing previous production limitations.
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