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Gregson, Stephen J.; Pugh, Kathryn; Patel, Neki; Afif-Rider, Shameen; Vijayakrishnan, Balakumar; Santos, Kathleen; Riedl, Jitka; Hutchinson, Ian; Kang, Gyoung-Dong; Chooi, K. Phin; Beard, Rhiannon; Adams, Lauren; Barry, Conor S.; Ball, Kathryn; Masterson, Luke A.; McFarlane, Mary; Hartley, John A.; Howard, Philip W.

Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody–Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer

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  • Media type: E-Article
  • Title: Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody–Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer
  • Contributor: Gregson, Stephen J.; Pugh, Kathryn; Patel, Neki; Afif-Rider, Shameen; Vijayakrishnan, Balakumar; Santos, Kathleen; Riedl, Jitka; Hutchinson, Ian; Kang, Gyoung-Dong; Chooi, K. Phin; Beard, Rhiannon; Adams, Lauren; Barry, Conor S.; Ball, Kathryn; Masterson, Luke A.; McFarlane, Mary; Hartley, John A.; Howard, Philip W.
  • imprint: American Association for Cancer Research (AACR), 2022
  • Published in: Molecular Cancer Therapeutics
  • Language: English
  • DOI: 10.1158/1535-7163.mct-22-0145
  • ISSN: 1535-7163; 1538-8514
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>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 hematologic (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 hematologic and solid tumors are warranted.</jats:p>
  • Access State: Open Access