Fractionated dosing improves preclinical therapeutic index of pyrrolobenzodiazepine-containing antibody drug conjugates

                Purpose:  To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBD) antibody drug conjugates (ADCs) without compromising anti-tumor activity.  <p>                Experimental design:   A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models.  The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast and gastric cancer by comparing anti-tumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer.  The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys).    </p> <p>Results:  Observations of similar anti-tumor activity in mice treated with single or fractionated dosing suggests that anti-tumor activity of PBD ADCs is more closely related to total exposure (AUC, area under the curve) than peak drug concentrations (C_max).  In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with C_max than AUC.  </p>                 Conclusions:  We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy.  These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further.

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