Anti-FK-506 monoclonal antibody, clone C247M

Tacrolimus, also known as FK506, with the molecular formula C₄₄H₆₉NO₁₂, is a novel immunosuppressant of the neutral hydrophobic macrolide class. The drug was first isolated from the fermentation product of Streptomyces tsukubaenis. As a representative drug of second-generation immunosuppressant, tacrolimus has 10-100 times stronger immunosuppressive effect than cyclosporine A. It has the advantages of high graft survival rate, low toxicity, low incidence of acute rejection, and relative non-dependence on steroidal alcohols, which has a wide range of applications in the clinic. However, its blood concentration in the body is susceptible to a variety of factors, such as race, genetic differences, gender, age, health status, etc., of which genetic differences are the main cause of individual differences, therefore, the clinic advocates an individualized approach to drug administration, adjusting the dosage of the drug according to the changes in drug concentration.

FK506 is metabolized in vivo primarily by demethylation or hydroxylation of FK506 by the hepatic cytochrome P450-3A enzyme system of the CYP3A gene family. Oral FK506 is mainly absorbed in the jejunum and duodenum, the average oral bioavailability is 20%, and there is a large individual variation, and its absorption is affected by food, especially high-fat diets, and the peak concentration of fasting is 2 times that of taking the drug after meals. Tacrolimus, similar to cyclosporine A, is a calcineurin inhibitor. It inhibits early calcium-dependent phenomena in signaling after T-cell stimulation and binds to FK506 receptor-binding protein-12 (FKBP-12) in the cytoplasm of T-lymphocytes in vivo to form the FK506-FKBP-12 complex. Subsequent inhibition of the phosphatase activity of calmodulin phosphatase inhibits Ca²⁺ inward flow, prevents dephosphorylation of T-cell nuclear factors, and deters transcription of a range of cytokine genes, including interleukin-2 and its receptor and IFN-γ. In this process the production of several cytokines such as IL-1, IL-2 and IL-9 is inhibited, in addition it inhibits the production of cytotoxic CD8⁺ T cells, the activation of specific CD4⁺ T helper cells and T helper cell-dependent B-cell proliferation, which in turn inhibits the anti-host response and delayed-onset metamorphosis.

Figure 1. Schematic drawings of calcineurin inhibitor pathways
(Source: Lee H, et al. 2023)

FK506 has strong immunosuppressive effects and is safe and effective. It is currently used clinically mainly in organ transplantation, but has also been found to have value in other applications. Some studies have shown that dynamic monitoring of cytokines, immunoglobulin, complement and T-cell indicators during the treatment of paraquat poisoning patients can grasp the immune status of patients, supplemented with immune preparations when necessary, and play an auxiliary therapeutic role in the recovery of patients. However, there is a lack of sufficient evidence-based medical evidence for the use of tacrolimus in the treatment of poisoning and further research is needed.

Anti-tacrolimus monoclonal antibody