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

  • Nat Commun. 2024 Jan 11;15(1):466. doi: 10.1038/s41467-023-44533-z.
Gail D Lewis  1 ,  Guangmin Li  2 ,  Jun Guo  2 ,  Shang-Fan Yu  3 ,  Carter T Fields  4 ,  Genee Lee  3 ,  Donglu Zhang  5 ,  Peter S Dragovich  6 ,  Thomas Pillow  6 ,  BinQing Wei  7 ,  Jack Sadowsky  8  9 ,  Douglas Leipold  10 ,  Tim Wilson  11 ,  Amrita Kamath  10 ,  Michael Mamounas  12 ,  M Violet Lee  13 ,  Ola Saad  13 ,  Voleak Choeurng  14 ,  Alexander Ungewickell  15 ,  Sharareh Monemi  15 ,  Lisa Crocker  3 ,  Kevin Kalinsky  16 ,  Shanu Modi  17 ,  Kyung Hae Jung  18 ,  Erika Hamilton  19 ,  Patricia LoRusso  20 ,  Ian Krop  20 ,  Melissa M Schutten  21  22 ,  Renee Commerford  15  23 ,  Mark X Sliwkowski  24 ,  Eunpi Cho  15
Affiliations
  • 1. Discovery Oncology, Genentech, South San Francisco, CA, USA. [email protected].
  • 2. Discovery Oncology, Genentech, South San Francisco, CA, USA.
  • 3. Translational Oncology, Genentech, South San Francisco, CA, USA.
  • 4. US Medical Affairs, Genentech, South San Francisco, CA, USA.
  • 5. DMPK, Genentech, South San Francisco, CA, USA.
  • 6. Discovery Chemistry, Genentech, South San Francisco, CA, USA.
  • 7. Computational Chemistry, Genentech, South San Francisco, CA, USA.
  • 8. Protein Chemistry, Genentech, South San Francisco, CA, USA.
  • 9. Carmot Therapeutics, Berkeley, CA, USA.
  • 10. Preclinical and Translational Pharmacokinetics, Genentech, South San Francisco, CA, USA.
  • 11. Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
  • 12. Project Team Leadership, Oncology, Genentech, South San Francisco, CA, USA.
  • 13. Bioanalytical Sciences, Genentech, South San Francisco, CA, USA.
  • 14. Data Sciences, Genentech, South San Francisco, CA, USA.
  • 15. Early Clinical Development, Oncology, Genentech, South San Francisco, CA, USA.
  • 16. Winship Cancer Institute at Emory University, Atlanta, GA, USA.
  • 17. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 18. Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 19. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
  • 20. Yale Cancer Center, Yale University, New Haven, CT, USA.
  • 21. Safety Assessment Pathology, Genentech, South San Francisco, CA, USA.
  • 22. SeaGen, South San Francisco, CA, USA.
  • 23. Gilead Sciences, Foster City, CA, USA.
  • 24. Molecular Oncology, Genentech, South San Francisco, CA, USA.
PMID: 38212321 DOI: 10.1038/s41467-023-44533-z
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.

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