2 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
A Potent Anti-CD70 Antibody–Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology
A highly
cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD)
dimer with a valine-alanine dipeptide linker was conjugated to the
anti-CD70 h1F6 mAb either through endogenous interchain cysteines
or, site-specifically, through engineered cysteines at position 239
of the heavy chains. The h1F6<sub>239C</sub>-PBD conjugation strategy
proved to be superior to interchain cysteine conjugation, affording
an antibody–drug conjugate (ADC) with high uniformity in drug-loading
and low levels of aggregation. In vitro cytotoxicity experiments demonstrated
that the h1F6<sub>239C</sub>-PBD was potent and immunologically specific
on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma
(NHL) cell lines. The conjugate was resistant to drug loss in plasma
and in circulation, and had a pharmacokinetic profile closely matching
that of the parental h1F6<sub>239C</sub> antibody capped with N-ethylmaleimide
(NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models
showed pronounced antitumor activities at single or weekly doses as
low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These
results demonstrate that PBDs can be effectively used for antibody-targeted
therapy