6 research outputs found
Conditional Nuclear Import and Export of Yeast Proteins Using a Chemical Inducer of Dimerization
Assessment of genetic diversity in Vigna unguiculata L. (Walp) accessions using inter-simple sequence repeat (ISSR) and start codon targeted (SCoT) polymorphic markers
Development of Anti-CD74 Antibody–Drug Conjugates to Target Glucocorticoids to Immune Cells
Glucocorticoids (GCs)
are excellent anti-inflammatory drugs but
are dose-limited by on-target toxicity. We sought to solve this problem
by delivering GCs to immune cells with antibody–drug conjugates
(ADCs) using antibodies containing site-specific incorporation of
a non-natural amino acid, novel linker chemistry for in vitro and
in vivo stability, and existing and novel glucocorticoid receptor
(GR) agonists as payloads. We directed fluticasone propionate to human
antigen-presenting immune cells to afford GR activation that was dependent
on the targeted antigen. However, mechanism of action studies pointed
to accumulation of free payload in the tissue culture supernatant
as the dominant driver of activity and indeed administration of the
ADC to human CD74 transgenic mice failed to activate GR target genes
in splenic B cells. Suspecting dissipation of released payload, we
designed an ADC bearing a novel GR agonist payload with reduced permeability
which afforded cell-intrinsic activity in human B cells. Our work
shows that antibody-targeting offers significant potential for rescuing
existing and new dose-limited drugs outside the field of oncology