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Updated: Jun 20, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Nanotechnology-assisted intracellular delivery of antibody as a precision therapy approach for KRAS-driven tumors
Ana M López-Estévez1, Lucía Sanjurjo2, Ángela Turrero3
1Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; Health Research Institute of Santiago de Compostela, 15782 Santiago de Compostela, Spain; Department of Pharmacology, Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Abstract:
The Kirsten Rat Sarcoma Virus (KRAS) oncoprotein, one of the most prevalent mutations in cancer, has been deemed undruggable for decades. The hypothesis of this work was that delivering anti-KRAS monoclonal antibody (mAb) at the intracellular level could effectively target the KRAS oncoprotein. To reach this goal, we designed and developed tLyP1-targeted palmitoyl hyaluronate (HAC16)-based nanoassemblies (HANAs) adapted for the association of bevacizumab as a model mAb. Selected candidates with adequate physicochemical properties (below 150 nm, neutral surface charge), and high drug loading capacity (>10%, w/w) were adapted to entrap the antiKRASG12V mAb. The resulting antiKRASG12V-loaded HANAs exhibited a bilayer composed of HAC16 polymer and phosphatidylcholine (PC) enclosing a hydrophilic core, as evidenced by cryogenic-transmission electron microscopy (cryo-TEM) and X-ray photoelectron spectroscopy (XPS). Selected prototypes were found to efficiently engage the target KRASG12V and, inhibit proliferation and colony formation in KRASG12V-mutated lung cancer cell lines. In vivo, a selected formulation exhibited a tumor growth reduction in a pancreatic tumor-bearing mouse model. In brief, this study offers evidence of the potential to use nanotechnology for developing anti-KRAS precision therapy and provides a rational framework for advancing mAb intracellular delivery against intracellular targets.
Insights
Researchers developed novel nanoassemblies to deliver anti-KRAS monoclonal antibodies inside cancer cells, targeting the previously undruggable KRAS oncoprotein for precision therapy.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- KRAS mutations are prevalent in many cancers and historically difficult to target.
- Developing effective intracellular therapies for KRAS-mutated cancers remains a significant challenge.
Purpose of the Study:
- To design and develop nanotechnology-based drug delivery systems for intracellular delivery of anti-KRAS monoclonal antibodies.
- To evaluate the efficacy of these nanoassemblies in targeting KRAS oncoprotein and inhibiting cancer cell proliferation.
Main Methods:
- Fabrication of tLyP1-targeted palmitoyl hyaluronate (HAC16)-based nanoassemblies (HANAs) loaded with anti-KRAS G12V monoclonal antibody.
- Characterization of nanoassemblies' physicochemical properties (size, charge, drug loading) using techniques like cryo-TEM and XPS.
- In vitro evaluation of KRAS G12V engagement, inhibition of cancer cell proliferation, and colony formation.
- In vivo assessment of tumor growth inhibition in a pancreatic cancer mouse model.
Main Results:
- Developed HANAs with optimal physicochemical properties and high anti-KRAS G12V mAb loading capacity.
- Demonstrated efficient intracellular delivery and target engagement of KRAS G12V by the loaded nanoassemblies.
- Observed significant inhibition of proliferation and colony formation in KRAS G12V-mutated lung cancer cell lines.
- Showcased tumor growth reduction in a preclinical pancreatic cancer model.
Conclusions:
- This study validates the potential of nanotechnology for intracellular delivery of monoclonal antibodies against KRAS oncoprotein.
- The developed HANAs offer a promising platform for precision therapy in KRAS-mutated cancers.
- Provides a framework for advancing intracellular antibody delivery strategies for challenging intracellular targets.
