The Janus kinase (JAK) family of protein-tyrosine kinase has four members: JAK1, JAK2, JAK3, and TYK2. The Janus kinases share seven distinct JAK homology (JH1-JH7) domains. These proteins possess an inactive pseudokinase domain (JH2) adjacent to an active carboxyterminal protein kinase domain (JH1). JAK3 associates with the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Signal transduction mediated by JAK3 is obligatory for lymphocyte activation, differentiation and homeostasis. After binding of the interleukin to its specific type I or II receptor, JAKs will associate with the receptor and activate downstream proteins, STATs. While JAKs are typically present in many tissues, JAK3 expression is largely restricted to hematopoietic cells. In this study, Tofacitinib is a JAK3 inhibitor and it binds JAK3 and JAK1 with roughly equivalent affinity, and JAK2 to a much lesser extent.

Tofacitinib is an orally available JAK3/2/1 inhibitor with IC50s of 1, 20, and 112 nM, respectively. It also binds potentially at JAK3 and JAK2 as 2.2 nM and 5 nM (Kd). Tofacitinib inhibits specific IgG1 antibody responses to immunized proteins in mice. It also inhibits the production of antigen-specific immunoglobulin isotypes after repeated immunizations of proteins. Tofacitinib reduces numbers of CD127+ pro-B cells. Furthermore, it specifically reduced anti-drug antibodies, thus preserving the potential efficacy of biological therapeutics. In addition, Tofacitinib is a pan-JAK inhibitor, and it has the potential for the research of rheumatoid arthritis.

In summary, Tofacitinib is an orally available JAK3/2/1 inhibitor. It suppresses antibody responses to protein therapeutics in murine hosts and it is also for the research of rheumatoid arthritis.


Onda M, et al. J Immunol. 2014;193(1):48-55.