Therapies based on monoclonal antibodies (mAb) have revolutionized different medical fields, particularly, oncology.
By recognizing and targeting some checkpoints overexpressed on the surface of cancer cells, mAb can trigger an immune response that may result in cell apoptosis. Namely, Nivolumab (OPDIVO®) and Pembroluzimab (Keytruda®) disrupt the interaction between T cells (immune cells) and cancer cells by blocking a transmembrane protein called PD-L1, a checkpoint commonly overexpressed in tumors. As a result, T cells are no longer capable of recognizing these malignant cells.
mAb affinity towards certain receptors can also be harnessed to deliver cytotoxic payloads specifically to the tumor environment, thereby decreasing the off-target effect of the drug. As an example, Adcetris®, used in the treatment of certain lymphomas, consists of a mAb (brentuximab) chemically modified to incorporate a very potent antimitotic agent (Monomethyl auristatin E), which is delivered mainly in the tumor.
These mAbs are called Antibody Drug Conjugates (ADCs) and, so far there are 14 already approved by the FDA and around 100 are presently being tested.
However, some mAbs are currently failing in clinical trials due to its low tissue penetration. Their size (molecular weight over 100KDa) drastically reduces the diffusion within the tumor, which limits their efficacy as they only reach the surface of the tumor, while the inside is still growing.
In this sense, smaller proteins might be a solution as their diffusion is higher. Some constructions as nanobodies have been deeply studied to overcome mAb limitations. Nevertheless, these systems are fast cleared from the body, which also impact on their efficacy, as this fast removal may decrease the levels of drug reaching the tumor.
For all these reasons, finding a proper macromolecule that balances size and clearance remains a challenge and could be the key to achieve more effective treatment for cancer.
In this project, we envisioned the possibility of increasing the half-life of small proteins by stablishing a covalent bond with their targets. This covalent interaction would increase the tissue retention as these proteins, once bound to their receptors, would not be cleared that fast.
With this aim, we propose the chemical modification of small proteins to incorporate a relatively reactive motif able to interact only with receptor PD-L1.
