ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade

Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes...

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Bibliographic Details
Published in:	mAbs Vol. 6; no. 2; pp. 523 - 532
Main Authors:	Silence, Karen, Dreier, Torsten, Moshir, Mahan, Ulrichts, Peter, Gabriels, Sofie ME, Saunders, Michael, Wajant, Harald, Brouckaert, Peter, Huyghe, Leander, Van Hauwermeiren, Tim, Thibault, Alain, De Haard, Hans J
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 01-03-2014 Landes Bioscience
Subjects:	Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - metabolism Antibody-Dependent Cell Cytotoxicity Antineoplastic Agents - immunology Antineoplastic Agents - metabolism ARGX-110 Camelids, New World CD27 Ligand - immunology CD70 Cell Cycle Checkpoints - immunology Cells, Cultured Humans immune checkpoint blockade Immunoglobulin G - immunology Immunoglobulin G - metabolism Immunotherapy - methods Lymphocyte Activation - drug effects Neoplasms - immunology Neoplasms - therapy POTELLIGENT Signal Transduction - drug effects T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology Tumor Necrosis Factor Receptor Superfamily, Member 7 - antagonists & inhibitors POTELLIGENT ARGX-110 CD70 immune checkpoint blockade
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Summary:	Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes CD70, the ligand of CD27. ARGX-110 was generated by immunization of outbred llamas. The antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assays. ARGX-110 binds CD70 with picomolar affinity. In depletion studies, ARGX-110 lyses tumor cells with greater efficacy than its fucosylated version. In addition, ARGX-110 demonstrates strong complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis activity. ARGX-110 inhibits signaling of CD27, which results in blocking of the activation and proliferation of Tregs. In a Raji xenograft model, administration of the fucosylated version of ARGX-110 resulted in a prolonged survival at doses of 0.1 mg/kg and above. The pharmacokinetics of ARGX-110 was tested in cynomolgus monkeys; the calculated half-life is 12 days. In conclusion, ARGX-110 is a potent blocking mAb with a dual mode of action against both CD70-bearing tumor cells and CD70-dependent Tregs. This antibody is now in a Phase 1 study in patients with advanced malignancies expressing CD70 (NCT01813539).
ISSN:	1942-0862 1942-0870 1942-0870 1942-0862
DOI:	10.4161/mabs.27398