1 research outputs found
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