The challenge with cancer treatments is finding a balance between effectiveness and side effects. A recent study by scientists has proposed a potential solution by using antibody-peptide inhibitor conjugates to target specific cell types and inhibit the activity of cancer-promoting enzymes known as cathepsins. Tumor cells often manipulate normal physiological processes to aid their growth by exploiting proteins responsible for essential cell functions. It is important to block the activity of these proteins only in cancer cells without affecting their important roles in healthy tissues. This is why traditional methods using small.
Molecules that cause widespread inhibition in the body can result in serious side effects.
Cancer cells often take control of important proteins such as cathepsins, a group of enzymes responsible for breaking down other proteins and changing the tissues in the body. Cathepsins are involved in various types of cancer, osteoporosis, and autoimmune diseases. However, attempts to use small molecule inhibitors to target cathepsins in clinical trials have not been successful, either because they didn’t work well or because they were toxic.
But now, a group of researchers at EPFL, led by Elisa Oricchio and Bruno Correia, has come up with a new way to deal with this problem.
These limitations gave rise to a modular drug platform that combines non-natural peptide inhibitors (NNPIs) with antibodies to form antibody-peptide inhibitor conjugates (APICs). This approach ensures targeted delivery of the inhibitors to cancer cells, reducing systemic side effects and improving therapeutic effectiveness.
The researchers initially developed NNPIs designed to covalently bind to and inhibit cathepsins. They modified the peptide sequences to include a Michael acceptor, a chemical moiety that facilitates the formation of a stable bond with cathepsins.
The Michael acceptor reacts with the cysteine residue inThe cathepsin’s active site, which is the part of the enzyme responsible for its main job, is targeted by creating a stable, covalent linkage to effectively inhibit the cathepsin. To improve the peptides’ specificity and potency, the team used saturation mutagenesis screening, a method that systematically changes each amino acid in a protein to find the best variants with desired properties.
The researchers found several strong inhibitors for four different cathepsins: cathepsin S, B, K, and L. These inhibitors were then attached to antibodies that recognize CD22, CD79, HER2, and Siglec15, allowing for precise delivery.The NNPIs have been found to have an impact on lymphoma cells, breast cancer cells, and osteoclasts. This takes advantage of antibodies’ natural ability to be absorbed by target cells, guiding the inhibitors to where they are needed.
Subsequently, the APICs were put to the test: they demonstrated significant therapeutic effects in both cell lines and animal models. For instance, in lymphoma models, treatment with APICs targeting cathepsin S resulted in tumor reduction and activation of the immune response against cancer cells. In breast cancer models, APICs targeting cathepsin B impeded tumor invasiveness and cell migration, highlighting the potential of APICs to prevent metastasis.The APIC approach delivers specific inhibitors to cancer cells, which helps to avoid or reduce the side effects commonly associated with other treatments like chemotherapies. Additionally, the modular design of APIC allows for adaptation to target different proteases involved in various diseases, potentially transforming the treatment of conditions beyond cancer.
The APIC project is progressing from the laboratory to the clinical arena. Elisa Oricchio stated, “We filed two patent applications based on this project.” Aaron Petruzzella, the PhD student who is involved in this project, is leading the way towards making APIC a clinical reality.The project leader has recently been awarded the SNF Bridge Proof of Concept fellowship to further develop these inhibitors, lay the groundwork for a new start-up, and attract potential investors.”
