Chemical mutagenesis: a powerful tool for the creation of a library of nanobodies

Finding a non-aggressive treatment against Cancer is one of the most important challenges that medicine has nowadays. Immunotherapy has emerged as one of the best options to overcome the current problems of chemotherapy.

By the use of monoclonal antibodies (mAb), immunotherapy is able to block regulatory checkpoints and, therefore, the immune response against tumoral cells could be modulated.

Trastuzumab, pembrolizumab and nivolumab are some of the mAb approved by the Food and Drug Administration (FDA) for their use against several cancers.

Trastuzumab recognizes the overexpressed protein HER2 in breast cancer, whereas the pembrolizumab and the nivolumab recognize the Programmed Cell Death-1 (PD-1) receptor and are used in several cancers such as refractory melanoma.However, there are reported important issues concerning cancer resistance to these mAb, thus, modifying their characteristics became necessary.

Unlike it happens with small molecules, there are several limitations to functionalize an antibody to improve its characteristics.

In this context, chemical mutagenesis turns into a powerful tool because it allows the modification of an antibody directly with highly specific chemical reactions, and achieve changes onto its structure that would not be possible by using other techniques such as protein engineering and genetic encoding.In this proposal I envision the use of nanobodies able to recognize HER-2 protein and PD-1 receptor in order to improve their affinity to their targets by chemical mutagenesis via alanyl radical.

The success of this project would provide solutions to the cancer resistance to current immunotherapy.