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Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody–Drug Conjugate SYD985
Antibody–drug conjugates (ADCs)
that are currently on the
market or in clinical trials are predominantly based on two drug classes:
auristatins and maytansinoids. Both are tubulin binders and block
the cell in its progression through mitosis. We set out to develop
a new class of linker-drugs based on duocarmycins, potent DNA-alkylating
agents that are composed of a DNA-alkylating and a DNA-binding moiety
and that bind into the minor groove of DNA. Linker-drugs were evaluated
as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced
interchain disulfides. Duocarmycin <b>3b</b>, bearing an imidazoÂ[1,2-<i>a</i>]Âpyridine-based DNA-binding unit, was selected as the drug
moiety, notably because of its rapid degradation in plasma. The drug
was incorporated into the linker-drugs in its inactive prodrug form, <i>seco</i>-duocarmycin <b>3a</b>. Linker attachment to the
hydroxyl group in the DNA-alkylating moiety was favored over linking
to the DNA-binding moiety, as the first approach gave more consistent
results for in vitro cytotoxicity and generated ADCs with excellent
human plasma stability. Linker-drug <b>2</b> was eventually
selected based on the properties of the corresponding trastuzumab
conjugate, SYD983, which had an average drug-to-antibody ratio (DAR)
of about 2. SYD983 showed subnanomolar potencies against multiple
human cancer cell lines, was highly efficacious in a BT-474 xenograft
model, and had a long half-life in cynomolgus monkeys, in line with
high stability in monkey and human plasma. Studies comparing ADCs
with a different average DAR showed that a higher average DAR leads
to increased efficacy but also to somewhat less favorable physicochemical
and toxicological properties. Fractionation of SYD983 with hydrophobic
interaction chromatography resulted in SYD985, consisting of about
95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an
average DAR of about 2.8. SYD985 combines several favorable properties
from the unfractionated ADCs with an improved homogeneity. It was
selected for further development and recently entered clinical Phase
I evaluation