Over the past few decades, antibody-based therapies have revolutionized
modern medicine and are now widely used to treat cancer, autoimmune diseases,
inflammatory disorders and even infectious diseases. Despite their success,
however, antibodies have a significant limitation: They struggle to penetrate
cells and are therefore largely limited to targeting molecules located on the
cell surface or outside the cell.
In addition, antibody-based drugs have difficulty crossing the blood-brain
barrier, restricting their use in treating diseases such as Parkinson's and
Alzheimer's. Now, researchers at Tel Aviv University, together with colleagues,
have developed a new technology that could overcome these barriers, enabling
antibodies to reach key targets located inside cells.
The technology was developed through a collaboration between research
groups from Cornell University in the United States, Tel Aviv University and
the Technion. The study was led by Prof. Chris A. Alabi and Prof. Matthew P.
DeLisa from Cornell, collaborating with Prof. Avi Schroder from the Technion
and TAU's Prof. Ben Maoz of the Fleischman Faculty of Engineering and the Sagol
School of Neuroscience and Prof. Uri Ashery of the Wise Faculty of Life
Sciences and the Sagol School of Neuroscience, together with Prof. Alabi of
Cornell. The findings are published in the Proceedings
of the National Academy of Sciences.
Masking antibodies for cell entry
In the study, the researchers developed an innovative approach based on
temporarily "masking" the antibody using a synthetic molecule called
SL4. This masking alters the antibody's chemical properties in a controlled
manner, allowing it to be encapsulated in lipid nanoparticles (LNPs), similar
to the technology used to develop mRNA vaccines against COVID-19. Once the
nanoparticles enter the cell, the antibody is released and regains its original
structure and activity.
According to the researchers, this represents a significant breakthrough
because approximately 80% of the proteins involved in human disease are located
inside cells, making them inaccessible to most antibody-based therapies. The
ability to deliver active antibodies into the cell cytoplasm opens new
possibilities for treating diseases that have long been considered inaccessible
to drug-based interventions.
Stronger delivery, preserved function
The study demonstrated that the masking process significantly improves the
efficiency with which antibodies can be encapsulated within lipid
nanoparticles. Whereas unmodified antibodies were incorporated into the
nanoparticles with relatively low efficiency, the masked antibodies achieved
substantially higher encapsulation rates while retaining their stability and
ability to recognize the molecular target associated with the disease.
The researchers tested the technology using a series of therapeutic
antibodies targeting key biological pathways involved in disease development.
The antibodies successfully entered cells and altered important signaling
pathways associated with various types of cancer and inflammatory diseases.
Following treatment, the activity of these pathways was significantly reduced,
indicating that the antibodies had reached their intended targets and remained
active inside the cells.
Early signs in Parkinson's and lung injury
One of the study's most promising findings emerged from a research model of
Parkinson's disease. The researchers used an antibody targeting
alpha-synuclein, a protein whose accumulation in the brain is one of the
hallmark features of the disease. Following delivery of the antibody via the
nanoparticles, they observed a significant reduction in the pathological aggregates of the
protein in nerve cells, a finding that suggests the technology could pave the way
for new treatments for neurodegenerative diseases.
The technology was also evaluated in a model of acute inflammatory lung
injury. The researchers found that delivering antibodies via the lipid
nanoparticles reduced inflammatory markers and improved pathological features
of lung tissue. These findings highlight the potential for developing targeted
therapies for severe inflammatory conditions.
A long path beyond preclinical work
Prof. Ben Maoz said, "For many years, delivering antibodies into cells
has been considered one of the greatest challenges in the field of biologic
therapies. We have succeeded in developing a system that enables antibodies to
cross the cellular barrier and reach targets that were previously beyond their
reach. We believe this is an important step toward expanding the therapeutic
toolbox of modern medicine and paving the way for more precise treatments for
complex diseases that still lack adequate therapeutic solutions."
The researchers emphasize that the technology is still at the preclinical stage. Nevertheless, they believe the platform could lay the foundation for a new generation of biologic therapies. If it successfully progresses through development and clinical trials, it could, for the first time, enable the widespread use of antibodies against intracellular targets, a goal widely regarded in the pharmaceutical industry as the next frontier of personalized medicine.
Source: Masked antibodies may open intracellular treatment route for Parkinson's disease
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