5 research outputs found
Design and Synthesis of Tesirine, a Clinical Antibody–Drug Conjugate Pyrrolobenzodiazepine Dimer Payload
Pyrrolobenzodiazepine
dimers are an emerging class of warhead in
the field of antibody–drug conjugates (ADCs). Tesirine (SG3249)
was designed to combine potent antitumor activity with desirable physicochemical
properties such as favorable hydrophobicity and improved conjugation
characteristics. One of the reactive imines was capped with a cathepsin
B-cleavable valine-alanine linker. A robust synthetic route was developed
to allow the production of tesirine on clinical scale, employing a
flexible, convergent strategy. Tesirine was evaluated <i>in vitro</i> both in stochastic and engineered ADC constructs and was confirmed
as a potent and versatile payload. The conjugation of tesirine to
anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T),
currently under evaluation for the treatment of small cell lung cancer
Pyrrolobenzodiazepine Dimer Antibody–Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers
Three rationally designed pyrrolobenzodiazepine
(PBD) drug-linkers
have been synthesized via intermediate <b>19</b> for use in
antibody–drug conjugates (ADCs). They lack a cleavable trigger
in the linker and consist of a maleimide for cysteine antibody conjugation,
a hydrophilic spacer, and either an alkyne (<b>6</b>), triazole
(<b>7</b>), or piperazine (<b>8</b>) link to the PBD.
In vitro IC<sub>50</sub> values
were 11–48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (<b>7</b> inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and
0.10–1.73 μg/mL (<b>7</b> inactive) in CD22 3+
BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive
at low doses). In vivo antitumor efficacy for the anti-HER2 ADCs in
Founder 5 was observed with tumor stasis at 0.5–1 mg/kg, 1
mg/kg, and 3–6 mg/kg for <b>6</b>, <b>8</b>, and <b>7</b>, respectively. Tumor stasis at 2 mg/kg was observed for
anti-CD22 <b>6</b> in WSU-DLCL2. In summary, noncleavable PBD-ADCs
exhibit potent activity, particularly in HER2 models
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