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Engineering a leucine zipper-TRAIL homotrimer with improved cytotoxicity in tumor cells
Dmitri V Rozanov1, Alexei Y Savinov, Vladislav S Golubkov
1Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA, USA.
Abstract:
Successful cancer therapies aim to induce selective apoptosis in neoplastic cells. The current suboptimal efficiency and selectivity drugs have therapeutic limitations and induce concomitant side effects. Recently, novel cancer therapies based on the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have emerged. TRAIL, a key component of the natural antitumor immune response, selectively kills many tumor cell types. Earlier studies with recombinant TRAIL, however, revealed its many shortcomings including a short half-life, off-target toxicity, and existence of TRAIL-resistant tumor cells. We improved the efficacy of recombinant TRAIL by redesigning its structure and the expression and purification procedures. The result is a highly stable leucine zipper (LZ)-TRAIL chimera that is simple to produce and purify. This chimera functions as a trimer in a manner that is similar to natural TRAIL. The formulation of the recombinant LZ-TRAIL we have developed has displayed high specific activity in both cell-based assays in vitro and animal tests in vivo. Our results have shown that the half-life of LZ-TRAIL is improved and now exceeds 1 h in mice compared with a half-life of only minutes reported earlier for recombinant TRAIL. We have concluded that our LZ-TRAIL construct will serve as a foundation for a new generation of fully human LZ-TRAIL proteins suitable for use in preclinical and clinical studies and for effective combination therapies to overcome tumor resistance to TRAIL.
Insights
Researchers developed a novel leucine zipper-tumor necrosis factor-related apoptosis-inducing ligand (LZ-TRAIL) chimera to enhance cancer therapy. This improved TRAIL formulation shows increased stability and efficacy, offering a promising foundation for new cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Current cancer therapies face limitations in efficiency and selectivity, leading to side effects.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for selective cancer cell apoptosis but has limitations like short half-life and resistance.
- Recombinant TRAIL has demonstrated shortcomings including poor stability and off-target toxicity.
Purpose of the Study:
- To engineer a more effective and stable variant of TRAIL for cancer therapy.
- To overcome the limitations of existing recombinant TRAIL formulations.
- To develop a foundation for a new generation of fully human TRAIL-based proteins.
Main Methods:
- Redesigning the structure of recombinant TRAIL to create a leucine zipper (LZ)-TRAIL chimera.
- Optimizing expression and purification procedures for the LZ-TRAIL chimera.
- Evaluating the chimera's stability, specific activity, and half-life in vitro and in vivo.
Main Results:
- A highly stable LZ-TRAIL chimera was successfully developed, functioning as a trimer.
- The recombinant LZ-TRAIL formulation demonstrated high specific activity in cell-based and animal studies.
- LZ-TRAIL exhibited an improved half-life exceeding 1 hour in mice, significantly longer than previous recombinant TRAIL formulations.
Conclusions:
- The developed LZ-TRAIL chimera represents a significant improvement over existing TRAIL therapies.
- This novel construct offers enhanced stability and efficacy, addressing key limitations of prior TRAIL versions.
- LZ-TRAIL provides a foundation for developing new fully human proteins for preclinical and clinical cancer treatment, potentially overcoming TRAIL resistance.
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