H2020Индивидуална стипендия2021–2023

Lipobodies · Targeting intracellular proteins and protein-protein interactions with site-specific lipobodies: a new approach for intracellular antibodies

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-10-01 → 2023-09-30
Финансиране от ЕС: 224 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Добавянето на мазнини (липиди) към антитела, като тези срещу HER2, помага на тези молекули да проникват по-лесно в клетките. Това е важно за подобряване на терапиите при рак и други заболявания, при които трябва да се достигнат протеини вътре в клетката.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Targeting intracellular proteins and protein-protein interactions with site-specific lipobodies: a new approach for intracellular antibodies

The main scientific problem addressed during this project was the lack of effective delivery strategies for antibodies and antibody fragments. It proposed that the development of a practical, general, and modular strategy for the efficient delivery and cell uptake of antibodies and antibody fragments could help further optimize these therapeutics, which have already proven high value in the treatment of cancer and many other diseases. As the outcomes of this project could positively impact the development of next-generation therapeutics, they could be of high interest not only to the scientific community but to the general society. The main strategy proposed by this project was to study the covalent lipidation of antibodies or antibody fragments as a tool to efficiently boost their cell internalization. To assemble different lipo-antibodies bearing a variable number of lipid chains as well as labels for intracellular monitoring and suitable handles for bioconjugation, a unique combination between multicomponent reactions (MCRs) and site-selective conjugation chemistries was projected (Figure 1). During this period, I developed and optimized the conditions for both the assembly of modular systems for the modification of the antibody fragments and their final conjugation. The utilization of MCRs allowed me to generate a library of constructs, including fluorescently labeled molecules for cell internalization and trafficking monitoring. Lipidation of therapeutics such as the engineered antibody THIOMAB V205C, different anti-HER2 affibodies, and anti-mesothelin nanobodies, proved efficient at increasing their cell permeability properties, without strongly affecting their target binding capacity. As a follow-up to this work, I also aim to study lipidation of therapeutics as a strategy to foster half-life extension, which has been described as one of the main drawbacks of antibody fragments. In addition to this work, I designed and developed a new multicomponent process based on the combination of the isonitrile-tetrazine (4+1) cycloaddition and the Ugi four-component reaction (Ugi-4CR) which allowed me to access a new chemical space of pyrazole amide derivatives and has been already well received by the scientific community.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The RAS family of GTPases is associated with important signalling events responsible for cell growth, proliferation and survival. Mutated RAS are, nevertheless, associated with uncontrolled cell proliferation in 30% of human cancers. Intracellular antibodies targeting oncogenic RAS proteins constitute promising anticancer therapeutics. Nevertheless, their intrinsic cytosolic instability as well as the lack of methods enabling their proper cellular uptake and localization highly limit their use and further development. This proposal describes the multicomponent synthesis of lipidic scaffolds (lipo-TAGs) for the permanent or temporal site-selective lipidation of anti-RAS antibody fragments. Lipidic antibodies (lipobodies) are novel constructs that could share the properties of any lipid-drug conjugate which includes oral bioavailability, enhanced lymphatic/tumour targeting and reduced toxicity. This project also aims to build amphiphilic lipobodies with the ability to experiment cellular uptake and endosomal escape, thus avoiding lysosomal degradation, and eventually experimenting cytosolic processing to generate the active antibody fragment. These unique features will be relevant not only at targeting RAS but any other intracellular protein or protein-protein interaction targets.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство