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Publication Detail
Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody-Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Gregson SJ, Pugh K, Patel N, Afif-Rider S, Vijayakrishnan B, Santos K, Riedl J, Hutchinson I, Kang G-D, Chooi KP, Beard R, Adams L, Barry CS, Ball K, Masterson LA, McFarlane M, Hartley JA, Howard PW
  • Publisher:
    American Association for Cancer Research
  • Publication date:
    06/07/2022
  • Journal:
    Molecular Cancer Therapeutics
  • Status:
    Published online
  • Country:
    United States
  • Print ISSN:
    1535-7163
  • PII:
    706895
  • Language:
    eng
Abstract
Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low cLogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematological (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC-MS/MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematological and solid tumors are warranted.
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