AACR 2022: Generation of a Novel Humanized TLR8 Mouse Model for the Evaluation of Human TLR8 Agonists and Antibody-Conjugated TLR8 Agonists
Conclusions
- mRNA expression analysis: Mouse Tlr8 mRNA was detectable in wild-type C57BL/6 mice (+/+). Human TLR8 mRNA was detectable only in heterozygote B-hTLR8 but not in wild-type mice.
- Protein expression analysis: Mouse TLR8 was detectable in WT mice and homozygous B-hTLR8 due to the cross-reactivity of anti-mouse TLR8 antibody with human TLR8. Human TLR8 was exclusively detectable in homozygous B-hTLR8 but not WT mice.
- Functional assay: TNFα, IFNγ and IL12p40 secretion were enhanced in homozygous B-hTLR8 mice compared to wild-type mice due to the selectively high binding affinity to human TLR8.
- Leukocyte cell subpopulation analysis: TLR8 humanized does not change the overall development, differentiation or distribution of immune cell types in spleen, thymus and blood.
- In vivo efficacy study: anti-human TROP2 antibody-conjugated TLR8 agonists were efficacious in controlling tumor growth in B-hTLR8 mice, demonstrating that B-hTLR8 mouse model is a promising model for preclinical in vivo studies to evaluate antibody-conjugated TLR8 agonists.
