Belatacept suppresses B-cell subset alloresponses

Belatacept-treated kidney transplant recipients (KT) experience a lower incidence of de novo donor-specific anti-HLA antibody (DSA) formation despite their higher risk of acute cellular rejection. In vitro studies show that concentrations associated with half-maximal suppression (EC50) of target cells correlate with therapeutic trough concentrations (C0).

To determine whether belatacept inhibits B-cell alloantigen presentation and B-cell alloresponse at known therapeutic C0.

Peripheral blood leukocytes (PBL) from healthy adults were cultured with HLA-mismatched PBL or fluorochrome-labeled alloantigenic lysate and increasing belatacept concentrations. EC50 was calculated with best-fit four-parameter log-logistic function under a Poisson assumption, as described.

After overnight allostimulation, frequencies of alloreactive CD154 + B-cells and their subsets decreased with increasing belatacept concentrations (n = 10). Median (range) EC50s were 1.3 (0.01-37) µg/ml for unfractionated B-cells, 2 (0.03-50) µg/ml for naïve, 3.6 (0.2-92) µg/ml for unswitched memory, 6.2 (0.05-32) µg.ml for transitional, and 7.8 (0.01-101) µg/ml for plasmablasts. Median EC50s were highest at 19 and 31 µg/ml, respectively for CD27- and CD27 + isotype-switched memory B-cells. No effect was seen on B-cell presentation of alloantigen.

At lower C0 levels of < 10 µg/ml, belatacept suppresses alloresponses of B-cells and most B-cell subsets, thereby explaining lower levels of DSA in kidney transplant patients.