Individual differences in genetic material can impair the effectiveness of antibody-based therapies against cancer, rheumatism or multiple sclerosis. This is reported by researchers at the University of Basel in Science Translational Medicine and shows how natural amino acid variations in the binding sites of target proteins can prevent antibodies from docking.

The team led by Rosalba Lepore and Lukas Jeker analyzed genome sequences of thousands of people from public studies. They examined binding sites of 87 therapeutic antibodies and found a surprisingly high number of variants that are not disease-causing, but can sabotage the therapy.

Computer models and laboratory tests on four key proteins showed that an antibody often no longer binds, but an alternative one with a different binding site does. The proportion of affected patients is usually less than one percent, but varies regionally – rarely in Europe, more common in other regions.

Doctors should take this aspect into account if a therapy does not work, says Jeker. Co-author Romina Marone advocates genetic testing before expensive treatments such as CAR-T cells. Lepore calls for more genomic data from underrepresented regions so as not to miss variants.

Original Paper:

Romina Marone, Erblin Asllanaj, Giuseppina Capoferri, Torsten Schwede, Lukas T. Jeker, & Rosalba Lepore.
Single-amino acid variants in target epitopes can confer resistance to antibody-based therapies
Science Translational Medicine (2025), doi: 10.1126/scitranslmed.ady4877

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