2 research outputs found
All-Organic, Stimuli-Responsive Polymer Composites with Electrospun Fiber Fillers
Stimuli-responsive materials are desired for a wide range
of applications.
Here, we report the design and fabrication of all-organic, stimuli-responsive
polymer composites using electrospun nanofibers as the filler. The
incorporation of 4 wt % of filler into the polymer matrix increased
the tensile storage modulus by 2 orders of magnitude. Upon exposure
to water, the filler fibers plasticize and no longer provide mechanical
reinforcement. The tensile storage modulus subsequently diminishes
2 orders of magnitude to the value of the neat matrix polymer
Efficient Preparation of Site-Specific Antibody–Drug Conjugates Using Phosphopantetheinyl Transferases
Post-translational
modification catalyzed by phosphopantetheinyl
transferases (PPTases) has previously been used to site-specifically
label proteins with structurally diverse molecules. PPTase catalysis
results in covalent modification of a serine residue in acyl/peptidyl
carrier proteins and their surrogate substrates which are typically
fused to the N- or C-terminus. To test the utility of PPTases for
preparing antibody–drug conjugates (ADCs), we inserted 11 and
12-mer PPTase substrate sequences at 110 constant region loop positions
of trastuzumab. Using Sfp-PPTase, 63 sites could be efficiently labeled
with an auristatin toxin, resulting in 95 homogeneous ADCs. ADCs labeled
in the CH1 domain displayed in general excellent pharmacokinetic profiles
and negligible drug loss. A subset of CH2 domain conjugates underwent
rapid clearance in mouse pharmacokinetic studies. Rapid clearance
correlated with lower thermal stability of the particular antibodies.
Independent of conjugation site, almost all ADCs exhibited subnanomolar
in vitro cytotoxicity against HER2-positive cell lines. One selected
ADC was shown to induce tumor regression in a xenograft model at a
single dose of 3 mg/kg, demonstrating that PPTase-mediated conjugation
is suitable for the production of highly efficacious and homogeneous
ADCs