B-cell-activating factor (BAFF) is a member of the tumour-necrosis factor (TNF) family. BAFF is a trimeric membrane-bound or soluble factor. BAFF binds to three receptors: BCMA (B-cell maturation antigen), TACI (transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor) and BAFF-R, which are all expressed on B cells. Importantly, BAFF is a survival factor for B cells that controls B-cell maturation. Therefore, BAFF-deficient mice lack mature B cells.

Interleukin-17A (IL-17A), a member of the IL-17 superfamily of cytokines. IL-17 is a key cytokine that links T cell activation to neutrophil mobilization and activation. As such, IL-17 can mediate protective innate immunity to pathogens or contribute to the pathogenesis of inflammatory diseases, such as psoriasis and rheumatoid arthritis. IL-17A was initially thought to be a “unique” cytokine, exclusively produced by T cells in psoriasis. On binding to a receptor, IL-17A upregulates inflammatory gene expression either by inducing de novo gene transcription or by stabilising mRNA of pro-inflammatory cytokines and chemokines.

Tibulizumab (LY 3090106) is a tetravalent bispecific monoclonal antibody targeting human BAFF and IL-17A.

Tibulizumab binds to human BAFF and IL-17, but only binds BAFF in mouse. In HT-29 cells, Tibulizumab antagonizes the IL-17-induced secretion of CXCL1 in a concentration-dependent manner. Besides, Tibulizumab blocks BAFF-induced proliferation of T1165 cells in a concentration-dependent manner. What’s more, Tibulizumab effectively antagonizes the biological effects induced by human BAFF and IL-17 in the mouse. In cynomolgus monkey, Tibulizumab suppresses B cell development and survival and remains functionally intact in circulation, with a prolonged half-life. Therefore,  Tibulizumab is effective against autoimmune diseases.

All in all, Tibulizumab, a tetravalent bispecific mAb targeting BAFF and IL-17A, is effective against autoimmune diseases.

References:

[1]. Mackay F, et, al. Nat Rev Immunol. 2002 Jul;2(7):465-75.

[2]. Benschop RJ, et, al. MAbs. 2019 Aug/Sep;11(6):1175-1190.