Researchers in Switzerland have conducted the first systematic study that demonstrated that even small variations in a person’s genome can disrupt the therapeutic effects of monoclonal antibodies.

Reporting in the journal Science Translational Medicine, investigators at the University of Basel demonstrated on a broader scale what researchers in Japan first reported in 2014: A single genetic mutation in a gene encoding one complement protein, C5, can block the therapeutic effect of a monoclonal antibody, in this case eculizumab.

“We found that even the smallest possible change in a protein sequence, namely a substitution of one single amino acid, can be sufficient to reduce or completely abolish the binding of a therapeutic monoclonal antibody,” study co-senior author Lukas Jeker, MD, of University Hospital Basel and the University of Basel, Switzerland, told Medscape Medical News. 

“This essentially means that if a target protein happens to contain a mutation exactly where the antibody is supposed to bind, it can no longer bind and loses its ability to block the antigen.”

Study Design 

The researchers retrieved therapeutic antibody sequences from the Therapeutic Structural Antibody Database, which tracks antibody- and nanobody-based therapeutics recognized by the World Health Organization, then used corresponding Protein Data Bank files to link them to isotype-specific profiles. They mapped variants onto available three-dimensional structures of monoclonal antibody antigen complexes along with other computational and experimental analyses to identify variants resistant to specific monoclonal antibodies. 

Among the therapeutic antibodies the study identified that can be neutralized by this genetic canceling is rituximab, one of the seven monoclonal antibodies they selected for a more detailed analysis. They concluded that single nucleotide variants in the gene encoding CD20 in the MS4A1 genomic regioncan affect the binding of B-cell depleting antibodies such as rituximab. The research focused on antibodies mostly used in oncology, immunology, hematology, and neurology.

“For clinicians, the key message is that even highly effective therapies can fail if the patient target is genetically different,” said co-senior author of the study, Rosalba Lepore, PhD, MSc, also at University Hospital Basel and the University of Basel. 

The findings can also be useful in drug development in that it can help identify patients who would otherwise be nonresponsive to the therapy, she added. 

“At this point, the most immediate impact is that physicians should be aware that this can happen,” Jeker said. “It’s not something you typically think about when you prescribe an antibody.”

Presently, no specific genetic tests exist to identify these genetic resistances, he said. And currently, if a monoclonal antibody that is supposed to work does not work in a patient, a physician can try an alternative monoclonal antibody targeting the same antigen if one is available, but it is right now mostly an empirical process, Jeker said. 

Their laboratory analysis found that both rituximab and ofatumumab bind to CD20, but the latter binds to variants that are resistant to the former. 

Future Outlook 

Testing for these variants is not currently practical in the clinic, Lepore said. “However, from a technical standpoint this would require to basically detect the variants, and this can be done by standard sequencing technologies that are widely available,” she said. 

“We still need more evidence that a genetic test can change clinical decision-making and lead to measurable benefits for patients,” Lepore said, “but from a technical point of view, I think we have all the tools available.”

For clinical practice, Jeker said, “you also need some standardization and the approval of the diagnostic test.”

Strengths of the study were its computational analysis along with the experimental validations of the selected antibodies, he said. “Together they make a very strong case.”

The key limitation is that “continuously more variants are being found because more individuals are being sequenced, so this a moving target,” he said. “In fact, we think we underestimated the variants.”

Future prospective clinical trials would be needed to validate the findings in clinical practice, Lepore said. “This is substantial information to establish clinical relevance beyond the experimental validation,” she said of their study. 

It would also be important to integrate these findings with a genetic test’s cost effectiveness and measurable clinical benefit, she said. 

Jeker added that he would hope that clinicians would test patients who do not respond to monoclonal antibody therapy for resistant variants. “That could be easily done and that would be great for clinical validation,” he said. 

Jeker and Lepore are cofounders of and hold equity in Cimeio Therapeutics and hold patents and patent applications related to immune cell engineering. Jeker is also a Cimeio board member and reported having financial relationships with Novartis and Kyowa Kirin. Lepore is a consultant for Memo Therapeutics. 

Richard Mark Kirkner is a medical journalist based in Philadelphia.