Genetic Variations May Explain Why Some Patients Don’t Respond to Antibody Therapies
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A new study reveals that even minor genetic differences can render certain antibody-based treatments ineffective, impacting therapies for conditions ranging from cancer to autoimmune diseases.
Antibody therapies, utilized in the treatment of a wide spectrum of illnesses including cancer, rheumatism, and multiple sclerosis, function by precisely targeting specific structures within the body. These therapies deliver active ingredients directly to the intended site, maximizing efficacy. However, groundbreaking research from the University of Basel in Switzerland suggests that the effectiveness of these treatments isn’t universal, and individual genetic makeup may play a critical role.
The Role of Genetic Differences in Treatment Response
Researchers at the University of Basel’s Biomedicine and Biocenter published their findings in the journal Science Translational Medicine, detailing how variations in an individual’s genetic makeup can prevent antibody-based therapies from working as intended. The team, led by Dr. Rosalba Lepore and Prof. Lukas Jeker, analyzed genetic sequences from thousands of individuals using computer-aided methods.
The core principle lies in the relationship between DNA and proteins. The DNA sequence dictates the order of amino acid building blocks that comprise proteins. Consequently, genetic variations can lead to alterations in the amino acid sequence. The researchers focused specifically on amino acids located at the epitopes – the specific regions of a protein that antibodies recognize and bind to.
A Single Amino Acid Can Disrupt Binding
“A single exchanged amino acid in the epitope can mean that the antibody can no longer dock,” explains a senior researcher involved in the study. The team meticulously examined the binding sites of 87 different therapeutic antibodies currently used in treatments for cancer and autoimmune diseases. Their analysis revealed a surprisingly high number of naturally occurring variants in the amino acid sequences within these epitopes.
Importantly, these variants don’t necessarily cause disease themselves. As one researcher emphasized, “The majority do not affect the function of the affected protein. But they can make the therapy ineffective.” This discovery highlights a previously underappreciated layer of complexity in personalized medicine.
Adapting Therapies to Genetic Profiles
The research team utilized computer modeling to predict which variants would hinder antibody binding. These predictions were then validated through laboratory experiments using four medically important target proteins and their corresponding antibodies. The results demonstrated that while one antibody might be unable to bind due to a genetic variation, another antibody – one that binds to a slightly different location on the target protein – could still be effective.
While the proportion of patients affected by these variants is currently considered relatively small – fewer than one in a hundred for most variations – Prof. Jeker believes it’s a crucial consideration for physicians. “It is important that doctors think about this aspect if a therapy does not work,” he stated.
The Cost-Benefit of Genetic Testing
The high cost of many antibody-based therapies, such as CAR T cells used in cancer treatment, further underscores the importance of this research. “A genetic test to see whether the therapy can work at all would be a small cost in comparison,” noted Marone, a co-first author of the study. This proactive approach could also be valuable in clinical trials, with Lepore suggesting that testing antibody binding sites in participants may be worthwhile.
Global Variations in Genetic Makeup
The study also revealed regional differences in the prevalence of these genetic variants. Certain variants rare in Europe are more common in other parts of the world, highlighting the need for a more global perspective in genetic research.
“There is still much less genetic sequence data for some regions of the world than for Europe or North America,” explained Lepore. “As a result, we may be overlooking an accumulation of such therapy-relevant variants in certain population groups.” This disparity in data emphasizes the need for increased genetic sequencing efforts in diverse populations to ensure equitable access to effective treatments.
This research underscores the growing importance of personalized medicine and the need to consider individual genetic profiles when selecting and administering antibody-based therapies, ultimately paving the way for more effective and targeted treatments.
