Site-specific antibody masking enables conditional activation with different stimuli

Roberta Lucchi, Maria C. Lucana, Montserrat Escobar-Rosales, Cristina Díaz-Perlas, Benjamí Oller-Salvia

Producció científica: Article en revista indexadaArticleAvaluat per experts

1 Citació (Scopus)

Resum

Antibody therapeutics show great potential to treat a variety of diseases. Often, the dose that can be safely administered is limited by side effects that arise from the interaction with the target outside the diseased tissue. Conditionally-active antibodies provide an additional layer of selectivity to improve safety. Distinct external stimuli or internal cues enable different control strategies and applications. However, current antibody masking strategies have low transferability across stimuli. Here we propose a versatile approach to conditionally mask antibody derivatives and its application to a single chain variable fragment (scFv) against a receptor expressed on cancer stem cells in several tumours. Our strategy relies on the site-specific conjugation of a polymer to an engineered cysteine residue through a chemically-synthesised linker that can be cleaved in response to the target stimulus. We show that the masking efficiency depends on the conjugation site and the size of the mask. An optimised mask decreases antigen binding by up to 20-fold and affinity can be fully recovered upon activation by exposure to light at 365 nm or by incubation with matrix metalloproteinases overexpressed in solid tumours. This approach opens up the possibility to rapidly engineer antibodies activatable with any internal or external stimulus.

Idioma originalAnglès
Pàgines (de-a)76-83
Nombre de pàgines8
RevistaNew Biotechnology
Volum78
DOIs
Estat de la publicacióPublicada - 25 de des. 2023

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