8 research outputs found
Immolation of <i>p</i>‑Aminobenzyl Ether Linker and Payload Potency and Stability Determine the Cell-Killing Activity of Antibody–Drug Conjugates with Phenol-Containing Payloads
The valine-citrulline (Val-Cit) dipeptide
and <i>p</i>-aminobenzyl (PAB) spacer have been commonly
used as a cleavable
self-immolating linker in ADC design including in the clinically approved
ADC, brentuximab vedotin (Adcetris). When the same linker was used
to connect to the phenol of the cyclopropabenzindolone (CBI) (<b>P1</b>), the resulting <b>ADC1</b> showed loss of potency
in CD22 target-expressing cancer cell lines (e.g., BJAB, WSU-DLCL2).
In comparison, the conjugate (<b>ADC2</b>) of a cyclopropapyrroloindolone
(CPI) (<b>P2</b>) was potent despite the two corresponding free
drugs having similar picomolar cell-killing activity. Although the
corresponding spirocyclization products of <b>P1</b> and <b>P2</b>, responsible for DNA alkylation, are a prominent component
in buffer, the linker immolation was slow when the PAB was connected
as an ether (PABE) to the phenol in <b>P1</b> compared to that
in <b>P2</b>. Additional immolation studies with two other PABE-linked
substituted phenol compounds showed that electron-withdrawing groups
accelerated the immolation to release an acidic phenol-containing
payload (to delocalize the negative charge on the anticipated anionic
phenol oxygen during immolation). In contrast, efficient immolation
of <b>LD4</b> did not result in an active <b>ADC4</b> because
the payload (<b>P4</b>) had a low potency to kill cells. In
addition, nonimmolation of <b>LD5</b> did not affect the cell-killing
potency of its <b>ADC5</b> since immolation is not required
for DNA alkylation by the center-linked pyrrolobenzodiazepine. Therefore,
careful evaluation needs to be conducted when the Val-Cit-PAB linker
is used to connect antibodies to a phenol-containing drug as the linker
immolation, as well as payload potency and stability, affects the
cell-killing activity of an ADC
Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity
Antibody–drug
conjugates (ADCs) have become an important
therapeutic modality for oncology, with three approved by the FDA
and over 60 others in clinical trials. Despite the progress, improvements
in ADC therapeutic index are desired. Peptide-based ADC linkers that
are cleaved by lysosomal proteases have shown sufficient stability
in serum and effective payload-release in targeted cells. If the linker
can be preferentially hydrolyzed by tumor-specific proteases, safety
margin may improve. However, the use of peptide-based linkers limits
our ability to modulate protease specificity. Here we report the structure-guided
discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing
linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline
dipeptide linker is not. ADCs bearing the nonpeptidic linker are as
efficacious and stable in vivo as those with the dipeptide linker.
Our results strongly support the application of the peptidomimetic
linker and present new opportunities for improving the selectivity
of ADCs
Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity
Antibody–drug
conjugates (ADCs) have become an important
therapeutic modality for oncology, with three approved by the FDA
and over 60 others in clinical trials. Despite the progress, improvements
in ADC therapeutic index are desired. Peptide-based ADC linkers that
are cleaved by lysosomal proteases have shown sufficient stability
in serum and effective payload-release in targeted cells. If the linker
can be preferentially hydrolyzed by tumor-specific proteases, safety
margin may improve. However, the use of peptide-based linkers limits
our ability to modulate protease specificity. Here we report the structure-guided
discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing
linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline
dipeptide linker is not. ADCs bearing the nonpeptidic linker are as
efficacious and stable in vivo as those with the dipeptide linker.
Our results strongly support the application of the peptidomimetic
linker and present new opportunities for improving the selectivity
of ADCs
Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity
Antibody–drug
conjugates (ADCs) have become an important
therapeutic modality for oncology, with three approved by the FDA
and over 60 others in clinical trials. Despite the progress, improvements
in ADC therapeutic index are desired. Peptide-based ADC linkers that
are cleaved by lysosomal proteases have shown sufficient stability
in serum and effective payload-release in targeted cells. If the linker
can be preferentially hydrolyzed by tumor-specific proteases, safety
margin may improve. However, the use of peptide-based linkers limits
our ability to modulate protease specificity. Here we report the structure-guided
discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing
linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline
dipeptide linker is not. ADCs bearing the nonpeptidic linker are as
efficacious and stable in vivo as those with the dipeptide linker.
Our results strongly support the application of the peptidomimetic
linker and present new opportunities for improving the selectivity
of ADCs