Dual targeting of B cell compartments using belatacept and daratumumab in highly sensitized kidney transplant candidates: A mechanistic proof-of-concept desensitization trial.

Highly sensitized kidney transplant candidates face limited access to compatible organs due to persistent anti-human leukocyte antigen (HLA) antibodies (Abs) and memory B cell (mBc) responses, which are generally not concomitantly targeted by current desensitization therapies. In this single-arm phase 1b/2 trial (NCT05145296), 5 highly sensitized kidney transplant candidates (calculated panel-reactive Ab >99%) were treated with belatacept and daratumumab to evaluate safety and mechanistic efficacy. Serum anti-HLA Ab levels, HLA-specific mBc, and bone marrow (BM)-residing long-lived plasma cells (PCs) were analyzed using single antigen beads, functional B cell assays, and spectral flow cytometry. The regimen was well-tolerated, with no serious adverse events attributable to study drugs. Three of 4 evaluable patients showed substantial serologic response by means of elimination and reductions in mean fluorescence intensity Abs and titers, mainly anti-HLA class I. HLA-specific mBc and CD38+ PC were significantly depleted in responders in peripheral blood and BM. Multidimensional profiling revealed depletion of CD38+ natural killer, T follicular helper, and PC in both peripheral blood and BM, which was accompanied by a reduction in calculated panel-reactive Ab levels, primarily in class I Abs. Dual targeting of T/B cell costimulation and PC using belatacept and daratumumab is a safe and mechanistically effective approach for desensitization in highly sensitized kidney transplant candidates. These findings support further investigation in larger trials.