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Updated: Jun 1, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Targeting intracellular cancer proteins with tumor-microenvironment-responsive bispecific nanobody-PROTACs for
Changping Deng1,2, Jiacheng Ma3, Yuping Liu4
1State Key Laboratory of Bioreactor Engineering East China University of Science and Technology Shanghai P. R. China.
Abstract:
Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, their non-specificity can lead to systemic toxicity due to protein degradation in normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged the tumor microenvironment to enhance drug specificity. In this study, we engineered BumPeD, a novel bispecific nanobody-targeted PROTACs-like platform, by fusing two nanobodies with a Furin protease cleavage site (RVRR) and a degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling the tumor microenvironment to direct the degradation of intracellular proteins. We utilized KN035 and Nb4A to target PD-L1 (programmed death ligand 1) on the cell surface and intracellular Survivin, respectively. In vitro experiments showed that BumPeD triggers Survivin degradation via the ubiquitin-proteasome pathway, inducing tumor apoptosis and suppressing bladder tumor cell proliferation and migration. In vivo experiments further confirmed BumPeD's robust anti-tumor efficacy, underscoring its potential as a precise protein degradation strategy for cancer therapy. Our platform provides a systematic approach to developing effective and practical protein degraders, offering a targeted theoretical basis and experimental support for the development of novel degradative drugs, as well as new directions for cancer therapy.
Insights
We developed BumPeD, a novel cancer therapy platform that uses nanobodies and the tumor microenvironment to precisely degrade tumor proteins. This targeted approach enhances efficacy and reduces toxicity for improved cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Proteolysis targeting chimeras (PROTACs) offer targeted protein degradation for cancer therapy.
- Non-specificity of traditional PROTACs can cause systemic toxicity in normal cells.
- Leveraging the tumor microenvironment can enhance drug specificity.
Purpose of the Study:
- To engineer a novel bispecific nanobody-targeted PROTACs-like platform, named BumPeD.
- To utilize the tumor microenvironment for directed intracellular protein degradation.
- To evaluate BumPeD's efficacy in targeting PD-L1 and intracellular Survivin for cancer therapy.
Main Methods:
- Engineered BumPeD by fusing nanobodies with a Furin protease cleavage site and degron sequences.
- Utilized KN035 and Nb4A nanobodies to target cell surface PD-L1 and intracellular Survivin.
- Conducted in vitro and in vivo experiments to assess protein degradation, apoptosis, and anti-tumor effects.
Main Results:
- BumPeD successfully triggered Survivin degradation via the ubiquitin-proteasome pathway in vitro.
- Demonstrated induction of tumor apoptosis and suppression of bladder tumor cell proliferation and migration.
- Confirmed robust anti-tumor efficacy in vivo, highlighting precise protein degradation potential.
Conclusions:
- BumPeD represents a precise protein degradation strategy for cancer therapy.
- The platform offers a systematic approach to developing effective and practical degradative drugs.
- Provides a targeted theoretical basis and experimental support for novel cancer therapeutics.
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