Development and implementation of platforms to produce nanobodies and sybodies for use in antitumor immunotherapy.

• Grant number: 24/21826-9
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Health Sciences - Collective Health - Public Health
• Principal Investigator: Daniela Luz Hessel da Cunha
• Grantee: Daniela Luz Hessel da Cunha
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Andrea Balan Fernandes ; Débora Botéquio Moretti ; Lorena Itatí Ibañez ; Priscila Pini Zenatti Salles ; Roxane Maria Fontes Piazza ; Xavier Saelens

Abstract

Monoclonal antibodies (mAbs) have proven efficacy in the treatment of cancer, chronic and infectious diseases. Most mAbs available on the market are complete IgGs that use eukaryotic cells for their production, requiring more time and resources. It is worth noting that the nature of some antigens can make obtaining conventional mAbs challenging and costly.A promising alternative to the traditional use of mAbs are nanobodies (Nbs) and their synthetic version sybodies (Sybs), unique molecules derived from the plasma of camelids or cartilaginous fish. With the first Nbs recently approved as biopharmaceuticals, the market for these molecules, although still discreet, is expanding. Their differential lies in the conformational difference in the antigen interaction sites, which allow binding to cavities or crevices of molecules such as enzyme active sites or interaction pockets between proteins. They are highly resistant to protease activity and stable at high temperatures and pH variations. Their small size (15 kDa) makes them extremely effective in binding to membrane proteins, in addition to enabling their expression in microbial systems, a faster and cheaper alternative in the production of these molecules. Sybs, being synthetic, also allow the generation of molecules in a more controlled and personalized way for the target antigen, without the need for animal immunization. The Brazilian biopharmaceutical market is based on imports, burdening the public health system due to high prices, making it necessary to invest in initiatives that aim to produce this type of molecule domestically. Within this context, this proposal aims to establish nanobody and sybody platforms to generate tools of therapeutic interest against tumors, primarily targeting molecules from immune checkpoints such as TIM-3. These negative regulatory receptors serve as brakes for the immune system, maintaining self-tolerance and preventing tissue damage, and are expressed on immune cells under normal physiological conditions. However, these molecules also participate in immune escape mechanisms in tumor development. Therapies aimed at blocking these molecules are attractive in the treatment of various tumor types. Using the advantages of Nbs and Sybs, this proposal intends to offer simple and inexpensive biotechnological solutions for the treatment of tumors, targeting Brazilian and Latin American markets. (AU)