A new self-immolative
linker motif, Ortho Hydroxy-Protected Aryl
Sulfate (OHPAS), was devised, and OHPAS-containing antibody drug conjugates
(ADC) were tested in vitro and in vivo. Conveniently synthesized using
Sulfur Fluorine Exchange (SuFEx) chemistry, it is based structurally
on diaryl sulfate, with one aryl acting as a payload and the other
as a self-immolative sulfate unit having a latent phenol function
at the ortho position. The chemically stable OHPAS linker was stable
in plasma samples from 5 different species, yet it can release the
payload molecule smoothly upon chemical or biological triggering.
The payload release proceeds via intramolecular cyclization, producing
a cyclic sulfate coproduct that eventually hydrolyzes to a catechol
monosulfate. A set of OHPAS-containing ADCs based on Trastuzumab were
prepared with a drug to antibody ratio of ∼2, and were shown
to be cytotoxic in 5 different cancer cell lines in vitro and dose-dependently
inhibited tumor growth in a NCI-N87 mouse xenograft model. We conclude
that OHPAS conjugates will be of considerable use for delivering phenol-containing
payloads to tissues targeted for medical intervention.
Monolithic InGaAs/InAsPSb MQW LEDs have been demonstrated. The eSWIR light sources are fully strain-relaxed on the InAs
x
P1-
x
metamorphic virtual substrate. The novel InAsPSb barrier can successfully enhance the confinement of the electrons in QWs.
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