Dual Inhibition of BLyS and APRIL in IgAN

Chee Kay Cheung, MBChB, MRCP, PhD: BLyS, …otherwise known as BAFF, and APRIL are 2 really important B-cell survival mediators that are produced in mucosal areas after exposure of dendritic cells and other cells to antigens, and they have a set of overlapping functions and shared sets of receptors on B cells. Both…these cytokines are really important in promoting B-cell survival and B-cell proliferation and plasma cell survival and plasma cells of cells that are responsible for the majority of antibody production, and also in class switch recombination. This is a process by which naïve cells, naïve B cells, switch to IgA-committed [or -] producing B cells. Both…these cytokines, both BLyS and APRIL, have been found in patients with IgA nephropathy [IgAN] to be increased. Overexpression of BLyS or BAFF was itself…shown to cause IgA-like disease in a mouse model, and the rationale for targeting both is to target their functions. And also it could avoid a compensatory increase in the other cytokine if you only target one. So targeting both theoretically could have beneficial outcomes, but we will need to await trial data…to see which is the most effective option to target B cells. Would it be APRIL only? Would it be BLyS and APRIL? Or will it be targeting plasma cells by using an anti-CD38 approach?

I think these agents that we discussed before that target both BLyS or BAFF and APRIL signaling are looking very promising in terms of being able to stop the production of galactose deficient IgA1 at its source and potentially reduce the autoantibodies that are formed against this so that we can target the disease at its initiating steps. I do think in the future that we are likely to need combinations of therapies to be used at different stages of the disease and to be able to work out which particular therapy might be most suitable for an individual patient. Regarding immunomodulatory therapies, clearly I think patients [who] would be most suitable are ones [who] do not suffer from other chronic infective conditions. They would be patients [who] have more preserved levels of kidney function and therefore have less of the irreversible scarring changes that we see in IgA nephropathy. But interestingly, in the phase 3 studies of sibeprenlimab, there will be patients enrolled with lower levels of kidney function compared [with patients in] other trials that are going on at the moment. And it’ll be interesting to see whether effects can be seen in patients with an eGFR [estimated glomerular filtration rate] between 20 [and] 30, for example. Although there are these cautions, I think the phase 2 data from these studies [are] providing reassurance about the safety of this approach regarding infective complications, but we’re not seeing any signal to date.

Transcript is AI-generated and edited for clarity and readability.