bc9b00777_si_001.pdf (706.23 kB)
Site-Specific Conjugation of the Indolinobenzodiazepine DGN549 to Antibodies Affords Antibody–Drug Conjugates with an Improved Therapeutic Index as Compared with Lysine Conjugation
journal contribution
posted on 2019-12-10, 17:42 authored by Chen Bai, Emily E. Reid, Alan Wilhelm, Manami Shizuka, Erin K. Maloney, Rassol Laleau, Lauren Harvey, Katie E. Archer, Dilrukshi Vitharana, Sharlene Adams, Yelena Kovtun, Michael L. Miller, Ravi Chari, Thomas A. Keating, Nicholas C. YoderAntibody–drug conjugates have elicited great interest
recently
as targeted chemotherapies for cancer. Recent preclinical and clinical
data have continued to raise questions about optimizing the design
of these complex therapeutics. Biochemical methods for site-specific
antibody conjugation have been a design feature of recent clinical
ADCs, and preclinical reports suggest that site-specifically conjugated
ADCs generically offer improved therapeutic indices (i.e., the fold
difference between efficacious and maximum tolerated doses). Here
we present the results of a systematic preclinical comparison of ADCs
embodying the DNA-alkylating linker-payload DGN549 generated with
both heterogeneous lysine-directed and site-specific cysteine-directed
conjugation chemistries. Importantly, the catabolites generated by
each ADC are the same regardless of the conjugation format. In two
different model systems evaluated, the site-specific ADC showed a
therapeutic index benefit. However, the therapeutic index benefit
is different in each case: both show evidence of improved tolerability,
though with different magnitudes, and in one case significant efficacy
improvement is also observed. These results support our contention
that conjugation chemistry of ADCs is best evaluated in the context
of a particular antibody, target, and linker-payload, and ideally
across multiple disease models.