From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis

• Published in: Clinical and experimental rheumatology Vol. 34; no. 4 Suppl 98; pp. 45 - 48
• Main Authors: Tyrsin, Dmitry, Chuvpilo, Sergey, Matskevich, Alexey, Nemenov, Daniil, Römer, Paula S, Tabares, Paula, Hünig, Thomas
• Format: Journal Article
• Language: English
• Published: Italy 01.07.2016
• Subjects: Animals; Antibodies, Monoclonal, Humanized - adverse effects; Antirheumatic Agents - adverse effects; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; CD28 Antigens - antagonists & inhibitors; CD28 Antigens - immunology; CD28 Antigens - metabolism; Cytokines - immunology; Cytokines - metabolism; Disease Models, Animal; Humans; Lymphocyte Activation - drug effects; Molecular Targeted Therapy; Risk Assessment; Signal Transduction - drug effects; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0392-856X

CD28 superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study.