Early Detection of Off-Target Binding Could Improve Drug Safety

Integral Molecular, a pioneer in antibody discovery and characterization, has published new findings in the journal mAbs, revealing that up to one-third of antibody-based drugs exhibit nonspecific binding to unintended targets. Off-target drug binding is a serious concern because it is a significant cause of adverse events in patients and has the potential to cause death.

Analysis of antibody off-target binding at various stages of clinical development suggests that this is a major cause of drug attrition. Early specificity testing may improve drug approval and patient safety.

In this study, Norden et al. quantify the frequency of off-target binding throughout the drug pipeline, providing the first empirical evaluation of antibody specificity.

They achieved this by conducting a prospective study of clinically administered antibody drugs (including those that are given to patients in advanced clinical trials, FDA-approved, or withdrawn) and retrospective specificity analyses of top antibody candidates from biopharmaceutical companies.

The Membrane Proteome Array™ (MPA), a cell-based protein array designed to test specificity and enhance drug safety, was used to evaluate the molecules. It represents the human membrane proteome.

Key Findings

  • Off-target interactions were seen in 18% of the 83 clinically administered antibody drugs examined
  • Nonspecific binding was seen in 22% of the antibody drugs that were taken off the market, frequently because of safety concerns
  • 33% of the 254 lead molecules that were examined exhibited nonspecific binding, which is indicative of development failure in later phases

These results cast doubt on the widely held notion that antibodies have perfect specificity and highlight the urgent need for more thorough 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™

Hundreds of customers worldwide rely on Integral Molecular’s Membrane Proteome Array™, the industry-leading technology for testing antibody specificity. The MPA evaluates binding to approximately 6,000 proteins, which encompasses the entire human membrane proteome. Every protein in the array is shown separately in its biological form.

The FDA and other international regulatory agencies have recognized the specificity data from MPA processes, which have earned ISO 9001 certification. The FDA is currently reviewing the MPA to determine whether or not it qualifies as an approved tool for drug development.

Source:
Journal reference:

Norden, D. M., et al. (2024) The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics. MAbs. doi.org/10.1080/19420862.2024.2393785

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