mAbs (Dec 2024)

The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics

  • Diana M. Norden,
  • Carmen T. Navia,
  • Jonathan T. Sullivan,
  • Benjamin J. Doranz

DOI
https://doi.org/10.1080/19420862.2024.2393785
Journal volume & issue
Vol. 16, no. 1

Abstract

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Specificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, leading to off-target binding going undetected. Here, we review the emergence of cell-based protein arrays as an alternative and improved assessment of mAb specificity. Cell-based protein arrays assess binding across the full human membrane proteome, ~6,000 membrane proteins each individually expressed in their native structural configuration within live or unfixed cells. Our own profiling indicates a surprisingly high off-target rate across the industry, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic mAbs in clinical development and currently on the market display off-target binding. Case studies and off-target rates at different phases of biotherapeutic drug approval suggest that off-target binding is likely a major cause of adverse events and drug attrition.

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