Development of an ICOSL and BAFF bispecific inhibitor AMG 570 for systemic lupus erythematosus treatment

Clin Exp Rheumatol. Nov-Dec 2019;37(6):906-914. Epub 2019 Feb 15.


Objectives: Systemic lupus erythematous (SLE) is a heterogeneous disease lacking highly effective treatment options. Here we tested if targeting both BAFF and ICOSL has superior efficacy than single target inhibition in the mouse arthritis and lupus models. We also generated AMG 570, an ICOSL and BAFF bispecific inhibitory molecule, for potential treatment of autoimmune diseases such as SLE.

Methods: Murine BAFF/ICOSL bispecific, combination of BAFF and ICOSL inhibitors or single inhibitor was evaluated in the sheep red blood cell (SRBC) challenge model, mouse collagen induced arthritis (CIA) model, or NZB/NZW lupus models. AMG 570 was tested for human and cyno BAFF and ICOSL binding affinities by Kinexa A. AMG 570 dual target blocking activities was evaluated in human and cyno BAFF and ICOSL mediated B cell and T cell assay, respectively. Pharmacodynamics effect of AMG 570 was evaluated in cynomolgus monkey.

Results: Treatment with murine ICOSL/BAFF bispecific or combination therapy was more efficacious than single ICOSL or BAFF inhibitor in mouse NZB/NZW lupus model. Dual ICOSL and BAFF inhibition was also more effective in the mouse collagen induced arthritis (CIA) model. AMG 570 was developed as the clinical bispecific lead. AMG 570 inhibits human and cynomolgus monkey ICOSL and BAFF. B cell reduction was observed after AMG 570 treatment in cynomolgus monkeys, consistent with the pharmacological effect of BAFF inhibition.

Conclusions: By targeting both ICOSL and BAFF, AMG 570 has the potential to achieve superior efficacy in treatment of autoimmune diseases such as SLE and rheumatoid arthritis.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / immunology
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Arthritis, Rheumatoid* / drug therapy
  • B-Cell Activating Factor
  • B-Lymphocytes
  • Humans
  • Immunosuppressive Agents* / therapeutic use
  • Inducible T-Cell Co-Stimulator Ligand / immunology*
  • Lupus Erythematosus, Systemic* / drug therapy
  • Lupus Erythematosus, Systemic* / immunology
  • Macaca fascicularis
  • Mice
  • Sheep
  • Treatment Outcome


  • AMG 557
  • Antibodies, Monoclonal, Humanized
  • B-Cell Activating Factor
  • Immunosuppressive Agents
  • Inducible T-Cell Co-Stimulator Ligand