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EBioMedicine
Feb, 2020;52 102625.

DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing.

Patrick J Engelberts, Ida H Hiemstra, Bart de Jong, Danita H Schuurhuis, Joyce Meesters, Irati Beltran Hernandez, Simone C Oostindie, Joost Neijssen, Edward N van den Brink, G Jean Horbach, Sandra Verploegen, Aran F Labrijn, Theodora Salcedo, Janine Schuurman, Paul W H I Parren, Esther C W Breij
Author Information
  1. Patrick J Engelberts: Genmab, Utrecht, The Netherlands.
  2. Ida H Hiemstra: Genmab, Utrecht, The Netherlands.
  3. Bart de Jong: Genmab, Utrecht, The Netherlands.
  4. Danita H Schuurhuis: Genmab, Utrecht, The Netherlands.
  5. Joyce Meesters: Genmab, Utrecht, The Netherlands.
  6. Irati Beltran Hernandez: Genmab, Utrecht, The Netherlands.
  7. Simone C Oostindie: Genmab, Utrecht, The Netherlands; Dept of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
  8. Joost Neijssen: Genmab, Utrecht, The Netherlands.
  9. Edward N van den Brink: Genmab, Utrecht, The Netherlands.
  10. G Jean Horbach: Genmab, Utrecht, The Netherlands.
  11. Sandra Verploegen: Genmab, Utrecht, The Netherlands.
  12. Aran F Labrijn: Genmab, Utrecht, The Netherlands.
  13. Theodora Salcedo: Genmab, Utrecht, The Netherlands.
  14. Janine Schuurman: Genmab, Utrecht, The Netherlands.
  15. Paul W H I Parren: Genmab, Utrecht, The Netherlands; Dept of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
  16. Esther C W Breij: Genmab, Utrecht, The Netherlands. Electronic address: EBJ@genmab.com.
PMID: 31981978 DOI: 10.1016/j.ebiom.2019.102625

Abstract

BACKGROUND: DuoBody®-CD3xCD20 (GEN3013) is a full-length human IgG1 bispecific antibody (bsAb) recognizing CD3 and CD20, generated by controlled Fab-arm exchange. Its Fc domain was silenced by introduction of mutations L234F L235E D265A.
METHODS: T-cell activation and T-cell-mediated cytotoxicity were measured by flow cytometry following co-culture with tumour cells. Anti-tumour activity of DuoBody-CD3xCD20 was assessed in humanized mouse models in vivo. Non-clinical safety studies were performed in cynomolgus monkeys.
FINDINGS: DuoBody-CD3xCD20 induced highly potent T-cell activation and T-cell-mediated cytotoxicity towards malignant B cells in vitro. Comparison of DuoBody-CD3xCD20 to CD3 bsAb targeting alternative B-cell antigens, or to CD3xCD20 bsAb generated using alternative CD20 Ab, emphasized its exceptional potency. In vitro comparison with other CD3xCD20 bsAb in clinical development showed that DuoBody-CD3xCD20 was significantly more potent than three other bsAb with single CD3 and CD20 binding regions and equally potent as a bsAb with a single CD3 and two CD20 binding regions. DuoBody-CD3xCD20 showed promising anti-tumour activity in vivo, also in the presence of excess levels of a CD20 Ab that competes for binding. In cynomolgus monkeys, DuoBody-CD3xCD20 demonstrated profound and long-lasting B-cell depletion from peripheral blood and lymphoid organs, which was comparable after subcutaneous and intravenous administration. Peak plasma levels of DuoBody-CD3xCD20 were lower and delayed after subcutaneous administration, which was associated with a reduction in plasma cytokine levels compared to intravenous administration, while bioavailability was comparable.
INTERPRETATION: Based on these preclinical studies, a clinical trial was initiated to assess the clinical safety of subcutaneous DuoBody-CD3xCD20 in patients with B-cell malignancies.
FUNDING: Genmab.

Keywords

B cell malignancy Bispecific antibody CD20 CD3 Subcutaneous administration T cell redirection

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MeSH Term

Animals
Antibodies, Bispecific
Antibody Specificity
Antibody-Dependent Cell Cytotoxicity
Antigens, CD20
Antineoplastic Agents, Immunological
CD3 Complex
Cell Line, Tumor
Cytotoxicity, Immunologic
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Humans
Leukemia, B-Cell
Lymphocyte Activation
Lymphoma, B-Cell
Macaca fascicularis
Mice
Mutation
Recombinant Proteins
T-Lymphocytes
Xenograft Model Antitumor Assays

Chemicals

Antibodies, Bispecific
Antigens, CD20
Antineoplastic Agents, Immunological
CD3 Complex
Recombinant Proteins
Journal Article

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