Tiny antibody therapy could be ‘breakthrough’ in CF treatment
Researchers develop nanobody to repair defective protein
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A therapy created using a miniaturized antibody can correct the functionality of the defective CFTR protein in people with cystic fibrosis (CF) caused by the F508del mutation.
Preclinical data indicate that this nanobody can act in synergy with Trikafta (ivacaftor/tezacaftor/elexacaftor), an approved treatment for CF. In combination, the nanobody and Trikafta restored CFTR activity to near-normal levels.
“Since the nanobodies bind directly in the region of the F508del mutation, they enable even more targeted treatment of the maturation defect in CFTR channels,” study co-author Marcus Mall, MD, director of pediatric respiratory medicine at Charité – Universitätsmedizin Berlin, said in a university press release. “This new mechanism of action allows CFTR function to be corrected significantly better in combination with [Trikafta]. Our results suggest that this new approach may even enable complete normalization of CFTR function. This would be another breakthrough for the treatment of cystic fibrosis.”
The study, “A cell-permeable nanobody to restore F508del cystic fibrosis transmembrane conductance regulator activity,” was published in Nature Chemical Biology.
Making antibodies smaller
Antibodies are proteins produced by the immune system that bind with extremely high specificity to a particular molecular target. This feature has made antibodies a useful tool for developing therapies, as scientists can engineer purified antibodies that bind to specific disease targets.
One of the biggest drawbacks of using antibodies in medicine is that, at the molecular level, antibodies are gigantic. Because of their bulk, their use is limited by their inability to penetrate tissues and enter cells. As a result, antibody therapies have mainly been used for diseases in which the intended target is outside the cell or on the cell membrane.
CF is caused by mutations in the gene that encodes the CFTR protein. Normally, the CFTR protein is made inside cells and then transported to the cell membrane, where it plays a vital role in regulating mucus production. F508del, the most common CF-causing mutation, destabilizes this protein within cells, so it falls apart before it can reach the membrane and carry out its function.
A team led by scientists in Germany set out to create an antibody-based treatment to stabilize the mutated CFTR protein. To design an antibody-based therapy that can get inside cells, the researchers used two key approaches. First, instead of using a full-sized antibody, they used a nanobody, an antibody that’s been stripped down to the bare essentials, so it’s as small as it can be while still retaining its ability to stick to the intended target. Second, they attached a specific molecular signaling sequence to the nanobody, designed to act like a skeleton key, allowing it to pass through cellular membranes into the cell interior.
The researchers showed that this new nanobody therapy boosted the activity of the mutated CFTR protein in cell models and in lung cells isolated from CF patients. “Our data demonstrate that … a functional CFTR-binding nanobody can modulate the fate of misfolded intracellular F508del-CFTR to restore its physiological function in a translational model of CF,” the team wrote.
In addition to testing the nanobody on its own, the researchers also tested it in combination with Trikafta.
Trikafta is an oral therapy containing CFTR modulators that stabilize the mutated CFTR protein so it can reach the membrane and function correctly. In principle, the new nanobody and Trikafta aim to work similarly, and the researchers’ data indicate the two therapies may work even better together than alone.
Data showed that Trikafta alone increased CFTR protein function to slightly more than half that seen in healthy cells. But when both Trikafta and the nanobody were used in combination, CFTR protein function increased to almost 90% of normal.
“The nanobody exerts a synergistic effect when combined with the clinically approved triple combination CFTR modulator therapy [Trikafta],” the researchers wrote. “Of note, this combination achieved near-normal levels of CFTR function in primary airway cultures from patients with CF, highlighting the potential of nanobody-based therapies to address the limitations of partial functional correction achieved by currently available CFTR modulator drugs.”
The scientists noted that this is the first published example of a cell-penetrating antibody with potential therapeutic effects, so this study may lay the groundwork for further work to develop new antibody-based therapies for a range of diseases.
Trikafta is sold by Vertex Pharmaceuticals. The company wasn’t directly involved in the study.
