Early specificity testing crucial for antibody drug safety

Integral Molecular, a leader in antibody discovery and characterization, has published new research in the journal mAbs, revealing that as many as one-third of antibody-based drugs exhibit nonspecific binding to unintended targets.

A serious concern, off-target drug binding is a significant cause of adverse events in patients, with the potential to even cause death. Analysis of antibody off-target binding across different phases of clinical development suggests this to be a major cause of drug attrition. Early specificity testing could improve drug approvals and patient safety.

In this study, Norden et al. present the first empirical assessment of antibody specificity, quantifying the prevalence of off-target binding across the drug pipeline. They accomplished this through retrospective specificity analyses of leading antibody candidates from biopharmaceutical companies and a prospective study of clinically administered antibody drugs (including those that are given to patients in advanced clinical trials, FDA-approved, or withdrawn). The molecules were tested using the Membrane Proteome Array™ (MPA), a cell-based protein array representing the human membrane proteome, that was developed to test specificity and improve drug safety.

Key Findings (Norden et al., mAbs)

• 18% of the 83 clinically administered antibody drugs tested showed off-target interactions.
• 22% of the antibody drugs withdrawn from the market, often due to safety issues, showed nonspecific binding.
• 33% of the 254 lead molecules tested showed nonspecific binding, a predictor of failure in future stages of development.

These findings challenge the long-held belief in the absolute specificity of antibodies and underscore the critical need for more rigorous testing.

Nonspecific drug binding can lead to adverse events or even death. The presumption that every antibody confers absolute specificity is simply not accurate. New technologies like the MPA provide a detailed assessment of antibody specificity and can significantly de-risk drug development."

Diana Norden, PhD, Study Lead Author, Senior Research and Communications Scientist, Integral Molecular

About the Membrane Proteome Array™

Integral Molecular's Membrane Proteome Array™ is the industry-leading technology for antibody specificity testing used by hundreds of customers worldwide. The MPA assesses binding across ~6,000 proteins, representing the full human membrane proteome. Each protein within the array is individually presented in its biological conformation. MPA processes are ISO 9001 certified, and its specificity data has been accepted by regulatory bodies globally, including the FDA. The MPA is currently under review by the FDA for qualification as an accepted Drug Development Tool.