The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results

Gail D. Lewis (), Guangmin Li, Jun Guo, Shang-Fan Yu, Carter T. Fields, Genee Lee, Donglu Zhang, Peter S. Dragovich, Thomas Pillow, BinQing Wei, Jack Sadowsky, Douglas Leipold, Tim Wilson, Amrita Kamath, Michael Mamounas, M. Violet Lee, Ola Saad, Voleak Choeurng, Alexander Ungewickell, Sharareh Monemi, Lisa Crocker, Kevin Kalinsky, Shanu Modi, Kyung Hae Jung, Erika Hamilton, Patricia LoRusso, Ian Krop, Melissa M. Schutten, Renee Commerford, Mark X. Sliwkowski and Eunpi Cho
Additional contact information
Gail D. Lewis: Discovery Oncology, Genentech
Guangmin Li: Discovery Oncology, Genentech
Jun Guo: Discovery Oncology, Genentech
Shang-Fan Yu: Translational Oncology, Genentech
Carter T. Fields: US Medical Affairs, Genentech
Genee Lee: Translational Oncology, Genentech
Donglu Zhang: DMPK, Genentech
Peter S. Dragovich: Discovery Chemistry, Genentech
Thomas Pillow: Discovery Chemistry, Genentech
BinQing Wei: Computational Chemistry, Genentech
Jack Sadowsky: Protein Chemistry, Genentech
Douglas Leipold: Preclinical and Translational Pharmacokinetics, Genentech
Tim Wilson: Oncology Biomarker Development, Genentech
Amrita Kamath: Preclinical and Translational Pharmacokinetics, Genentech
Michael Mamounas: Project Team Leadership, Oncology, Genentech
M. Violet Lee: Bioanalytical Sciences, Genentech
Ola Saad: Bioanalytical Sciences, Genentech
Voleak Choeurng: Data Sciences, Genentech
Alexander Ungewickell: Early Clinical Development, Oncology, Genentech
Sharareh Monemi: Early Clinical Development, Oncology, Genentech
Lisa Crocker: Translational Oncology, Genentech
Kevin Kalinsky: Winship Cancer Institute at Emory University
Shanu Modi: Memorial Sloan Kettering Cancer Center
Kyung Hae Jung: Asan Medical Center, University of Ulsan College of Medicine
Erika Hamilton: Sarah Cannon Research Institute/Tennessee Oncology
Patricia LoRusso: Yale Cancer Center, Yale University
Ian Krop: Yale Cancer Center, Yale University
Melissa M. Schutten: Safety Assessment Pathology, Genentech
Renee Commerford: Early Clinical Development, Oncology, Genentech
Mark X. Sliwkowski: Molecular Oncology, Genentech
Eunpi Cho: Early Clinical Development, Oncology, Genentech

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.

Date: 2024
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DOI: 10.1038/s41467-023-44533-z

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