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

• 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
• DOI: 10.4161/mabs.27398
• EISSN: 1942-0870; 1942-0862
• ISSN: 1942-0862; 1942-0870

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).