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

MAbs. Mar-Apr 2014;6(2):523-32. doi: 10.4161/mabs.27398. Epub 2013 Dec 6.

Abstract

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).

Keywords: ARGX-110; CD70; POTELLIGENT®; immune checkpoint blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism*
  • Antibody-Dependent Cell Cytotoxicity
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / metabolism*
  • CD27 Ligand / immunology*
  • Camelids, New World
  • Cell Cycle Checkpoints / immunology
  • Cells, Cultured
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism*
  • Immunotherapy / methods*
  • Lymphocyte Activation / drug effects
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Signal Transduction / drug effects
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / antagonists & inhibitors

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CD27 Ligand
  • Immunoglobulin G
  • Tumor Necrosis Factor Receptor Superfamily, Member 7

Associated data

  • ClinicalTrials.gov/NCT01813539