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.
The ortho-hydroxy-protected aryl sulfate (OHPAS) linker is composed of a diaryl sulfate backbone equipped with a latent phenol moiety at the ortho position of one of the aryl units. The Ar−OH released when the ortho phenol undergoes intramolecular cyclization and displaces the second aryl unit can be viewed as a payload. We have shown in the preceding paper that the OHPAS linkers are highly stable chemically and in various plasmas, yet release payloads when exposed to suitable triggering conditions. As an extension of the OHPAS system, we employed a para-hydroxy benzyl (PHB) spacer for coupling to nonphenolic payloads; this tactic again provided a highly stable system capable of smooth release of appended payloads. The PHB modification works beautifully for tertiary amine and N-heterocycle payloads.
Recently we have
reported that the ortho-hydroxy-protected aryl
sulfate (OHPAS) system can be exploited as a new self-immolative group
(SIG) for phenolic payloads. We extended the system to nonphenolic
payloads by simply introducing a para-hydroxy benzyl (PHB) spacer.
As an additional variation of the system, we explored a benzylsulfonate
version of the OHPAS system and found that it has two distinct breakdown
pathways, cyclization and 1,4-elimination, the latter of which implies
that para-hydroxy-protected (PHP) benzylsulfonate (BS) can also be
used as an alternative SIG. The PHP-BS system was found to be stable
chemically and in mouse and human plasma, having payload release rates
comparable to those of the original OHPAS conjugates.
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