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

Project description

Improving nanobodies’ affinity via chemical mutagenesis

Cancer immunotherapy has emerged as one of the best alternatives to current chemotherapy treatments. Nanobodies (VHH antibodies) are antibodies with a single variable domain located on a heavy chain. Conventional antibodies have VH and VL variable domains, which provide stability and binding specificity. Nanobodies have VHH domains and lack VL domains and occur naturally in camelids and sharks. Nanobodies have found use in such medical fields as oncology, infection and immunity. The EU-funded Chemical Mutagenesis project proposes the development of nanobodies able to recognise HER-2 protein and PD-1 receptors in cancer cells. The objective is to improve the nanobodies’ affinity to their targets using chemical mutagenesis via alanyl radicals, with a goal of resolving the challenges of cancer resistance in the context of immunotherapy.

Objective

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.

Coordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Net EU contribution
€ 212 933,76
Address
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 212 933,76