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 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).
arGEN-X; Zwijnaarde, Belgium.
Karen
K
Silence
arGEN-X; Zwijnaarde, Belgium.
Torsten
T
Dreier
arGEN-X; Zwijnaarde, Belgium.
Mahan
M
Moshir
arGEN-X; Zwijnaarde, Belgium.
Peter
P
Ulrichts
arGEN-X; Zwijnaarde, Belgium.
Sofie M E
SM
Gabriels
arGEN-X; Zwijnaarde, Belgium.
Michael
M
Saunders
Division of Molecular Internal Medicine; Department of Internal Medicine II; University Hospital Würzburg; Würzburg, Germany.
Harald
H
Wajant
VIB Department for Molecular Biomedical Research; Ghent University; Zwijnaarde, Belgium.
Peter
P
Brouckaert
VIB Department for Molecular Biomedical Research; Ghent University; Zwijnaarde, Belgium.
Leander
L
Huyghe
arGEN-X; Zwijnaarde, Belgium.
Tim
T
Van Hauwermeiren
arGEN-X; Zwijnaarde, Belgium.
Alain
A
Thibault
arGEN-X; Zwijnaarde, Belgium.
Hans J
HJ
De Haard
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism*; D053282:CD27 Ligand / Q000276:immunology*; D002161:Camelids, New World; D059447:Cell Cycle Checkpoints / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000187:drug effects; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053282:CD27 Ligand; D007074:Immunoglobulin G; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
ARGX-110; CD70; POTELLIGENT®; immune checkpoint blockade