Module 9 2021

22/03/2021

Immunogenicity – Anti-drug antibodies (ADA) : Large molecules are proteinaceous and can be seen as “foreign” thus ADA analysed in all repeat dose studies : • Presence of ADA often leads to marked decrease/absence of drug in blood • 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 any animal can still predict toxicity Preclinical testing of biologics Repeat dose toxicology study design

1000

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

Preclinical testing of Biologics – March 22 nd 2021

The Organisation for Professionals in Regulatory Affairs

13

Preclinical testing of biologics Defined case-by-case

Immunotoxicology : Immune system changes related to pharmacology 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.TT) • Assess effects on host defence against infection & cancer • Cytokine Release : • Cytokine release testing conducted on high risk molecules only • Measure cytokine release in ex vivo human blood by biologic alone or when another immunoglobulin Fc is present

Preclinical testing of Biologics – March 22 nd 2021

The Organisation for Professionals in Regulatory Affairs

14

7