Immunological Safety

Immunological safety studies are vital to ensure patient safety throughout development release

Many of the immunomodulatory effects of mAbs are desirable and clinically efficious. However, activation or suppression/depletion of non-target immune cells and mediators, or permanent non-reversible changes to immune target cells/pathways, or any unintended sequelae of the intended pharmacology, e.g., cell and tissue injury, inflammation, 'cytokine storms,' tumor lysis syndrome, infection and cancer, autoimmunity, hypersensitivity, would be considered to be or reflect immunotoxicity. These often adverse consequences can result from exaggerated or prolonged activity of the mAb binding to the desired target antigen on the desired target cells/mediators, modulating a target with pleiotropic immune functions, including those whose modification is not required for therapeutic benefit, or modulating a target that is also expressed on non-immune cells or other immune cells besides those that are the intended therapeutic focus. Some of these immunological safety concerns can be reduced or circumvented by rational mAb design, e.g., through the use of an 'inert' IgG isotype with little or no effector function, or by screening mAb candidates for reduced cytokine release, DC activation and immunogenicity potential.

In Vitro Cytokine Release Syndrome (CRS) assay

  • Assay to predict side effects from uncontrolled release of cytokines
  • PBMC or whole blood based assay (depending on the biologic)
  • Large number of donors required for the assay (>20)
  • Assay can be validated with antibodies e.g. Cetuximab (low-risk), Infliximab(low-risk), Alemtuzumab (high-risk).

Immunogenicity risk assessment assay

  • Assay to assess the risk of generation of anti-drug antibodies (ADA)
  • Can be performed with PBMCs or DC-T Cells (depending on the biologic activity of the molecule tested)
  • Requires a large number of donors (~20-50 donors) that can cover >80% of HLA-DRB of world population

Immunosuppression risk assessment assay

  • Assay to predict immunosuppression induced by therapeutics
  • Identical to the antigen specific T-cell activation assay
  • Proof of concept using infliximab, dexamethasone, methotrexate and nivolumab
  • For a risk assessment assay, a large number of donors might be requested by clients