RD-05, a novel anti-CD154 antibody, efficiently inhibits generation of anti-drug antibody without the risk of thrombus formation in non-human primates.

Abstract

Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies. For this, we attempted to derive an idea as to how this major complication can be eliminated. Consequently, we developed a novel anti-CD154 chimeric antibody, which was made by genetic modification of a portion of human IgG4 Fc. This antibody has an almost comparable antigen binding affinity to a previously developed 5C8 clone and near completely inhibited CD40-CD154 interaction and T cell-dependent B cell activation in vitro. Even under the condition, where we injected immune complexes comprised of RD-05 and CD154 antigen, the formation of thromboembolism was not seen in human FcγRIIA-transgenic mice, whereas the converse was exactly true in the case of 5C8 antibody. Notably, just two injections of RD-05 antibody was sufficient to inhibit the antibody formation against adalimumab during 3-4 months in cynomolgus macaques, in which adalimumab was repeatedly injected for 12 weeks. Based on these findings, we suggest that this RD-05 antibody can be applied to antibody-mediated autoimmune diseases, including systemic lupus erythematosus and immune thrombocytopenic purpura.

• Authors: Jae-Il Lee, Yun-Jung Choi, Hi-Jung Park, Kyeong Cheon Jung, Seong Hoe Park
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 498 Issue 4 Pg. 996-1001 (04 15 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29550477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Anti-Idiotypic
• CD40 Ligand
• Factor VIII
• Adalimumab

Topics

• Adalimumab (immunology)
• Animals
• Antibodies, Anti-Idiotypic (pharmacology, therapeutic use)
• Antibody Formation (drug effects)
• Autoimmune Diseases (drug therapy, immunology)
• CD40 Ligand (immunology)
• Factor VIII (immunology)
• Humans
• Macaca
• Mice
• Mice, Transgenic
• Thrombosis (etiology)