The dark side of treating COVID-19 with monoclonal antibodies

A recent study conducted as part of the ORCHESTRA project has shed new light on the treatment of COVID-19 infections with mAbs. Published in the Journal of Clinical Investigation, the research reveals that patients treated with different mAbs may develop SARS-CoV-2 mutations in certain cases. The scientists developed a score that identifies patients at high risk of developing mutations owing to mAb treatment.

mAbs are lab-made proteins engineered to act like human antibodies in the immune system, attacking unwanted cells. They offer a treatment option for patients undergoing cancer treatment and other individuals with a weakened immune system who have a high risk of developing severe COVID-19 and for whom vaccination does not offer sufficient protection.

However, as reported in a news item posted on the website of ORCHESTRA project partner University of Antwerp, Belgium, the scientists "have now discovered that treatment with mAbs comes with a serious trade-off; SARS-CoV-2 mutates in response to the immune-pressure created under mAb-treatment along with host immune responses. This also means that the virus can develop resistance to mAbs—similar to resistance emergence under antibiotic treatments in bacterial infections."

Speedy mutations

In a clinical trial held at ORCHESTRA project coordinator University of Verona, Italy, the team collected biological samples from high-risk COVID-19 patients treated with various mAbs. The University of Antwerp research team then performed a viral variant analysis that "showed that approximately 8% of mAb-treated patients developed evasive SARS-CoV-2 spike mutations with remarkable speed and high specificity for the targeted mAb binding sites." Moreover, while most patients gradually cleared the virus, patients with weakened immune systems "had significantly higher viral loads for prolonged periods and had 3-fold higher chance to develop SARS-CoV-2 escape mutations."

Study lead author Prof. Samir Kumar-Singh of the University of Antwerp comments in the same news item, "It was intriguing to see that not only the mAb neutralizing capacity and host immunity, but also host-healing responses played a crucial role in development of SARS-CoV-2 escape mutants."

The researchers also developed an index that identifies patients who have a high risk of developing escape mutations to mAb treatment. Boasting more than 96% accuracy, the index uses a combination of circulating immune and growth factors-related biomarkers (CIB) measured in the blood at first contact with the patient before mAb treatment. The CIB index could reduce the risk of mAb treatment failure by helping doctors to determine if other treatment options such as antiviral treatments and convalescent plasma could be more effective.

The index is useful even if patients have already undergone mAb treatment, according to the news item, since "knowledge of this CIB index can still improve mitigation strategies to avoid possible spread of SARS-CoV-2 escape mutants, especially to individuals at high-risk in the same clinical or close contact setting."

ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic: ORCHESTRA) project coordinator Prof. Evelina Tacconelli of the University of Verona concludes: "The study provides innovative data to select high risk patients for early treatment. We believe this will reduce not only COVID-19 mortality but also Long COVID."