Module 9 2024

03/09/2024

Nonclinical testing of biologics Defined case-by-case

Cytokine Release Syndrome (CRS) : Not always a stop on the development as mild CRS can be managed in the clinic (risk-benefit assessment) However, it can have serious consequences if not understood and managed correctly • TGN1412 → A CD28 super-agonist monoclonal antibody that preferentially activated regulatory T cells in the absence of other costimulation • Cynomolgus monkey CD28 has 100% sequence homology with human, TGN1412 affinity was similar in human and monkey and was well tolerated in nonclinical studies • However, first patients dosed in Phase 1 clinical trial showed extensive, life-threatening CRS (2006) • Later research showed human T effector memory cells expressed CD28, but primate T effector memory cells didn’t. • The primate could not predict the effects seen in the clinic

● Human starting dose actually had ~90% target occupancy

● TGN1412 incident had significant impact on FIM trial conduct worldwide...

● Sentinel dosing now compulsory

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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Nonclinical testing of biologics Repeat dose toxicology study design

Tissue Cross Reactivity Study :

• TCR study = Immunohistochemistry to detect potential expected and unexpected binding to human and nonclinical species tissues • Binding in human should identify any key organs that may require more extensive evaluation in repeat dose toxicology study

• If binding observed in human tissue, then should check binding also seen in nonclinical species → Often human and NHP conducted together

• Unexpected binding in monkey and/or human indicates potential for off-target or unknown binding

Key to note : TCR studies cannot be used to justify species selection

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

20

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