Module 9 2024

03/09/2024

Immunogenicity – Anti-drug antibodies (ADA) : Monoclonal antibodies are proteinaceous and, even though humanised, can be seen as “foreign” by the immune system Nonclinical testing of biologics Repeat dose toxicology study design

Thus ADA analysed in all repeat dose studies:

• Presence of ADA can lead to marked decrease/absence of drug in blood (enhanced clearance) 1000

• VERY IMPORTANT – Incidence in primate does not predict incidence in human → Biologics are humanised, so foreign to a primate anyway! • However, understanding immunogenicity is vital to interpret any loss of exposure to the drug observed during the study….and whether that individual animal can still predict toxicity….

100

10

1

mAb ug/ml

0.1

0.01

-1 8 17 26 35 44 53 62 71 80 89 98 107 116 125 134 143

Days

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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Nonclinical testing of biologics Defined case-by-case

Immunotoxicology :

Immune system changes often anticipated, as related to pharmacology/pharmacodynamics, but can be unexpected • Assessments focus on specific cells/immune pathways targeted using a tiered approach • Effects on immune cell counts (T-cells, B-cells etc) • Effects on immune function (e.g. immune response following antigen eg.Tetanus Toxoid) • Assess effects on host defence against infection & cancer

Cytokine Release :

•

• Cytokine release testing usually conducted on high-risk molecules only • Measured in ex vivo PBMCs or whole human blood induced by treatment with biologic alone or when another immunoglobulin Fc is present

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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