The absence of a need for co-signaling through CD28 for these BiTEs might also be explained by the observation that among all T cell subtypes, CD8+ effector memory cells CD45RO+ (TEM) and CD8+ effector memory CD45RA+ (TEMRA) contribute the most to BiTE activity, whereas naïve T cells do not contribute at all to the killing efficiency.50 It is believed that memory T cells do not require CD28 costimulation for expansion during secondary responses, which could explain the efficiency of BiTEs. However, this dogma has recently been challenged.5

In the case of molecules targeting CD19 on B cells, one cannot exclude a possible co-signal triggered by the interaction between CD28 and B7, known to be expressed on normal and malignant B cells. However, BiTE molecules targeting EpCAM expressed on a variety of solid tumor of epithelial origin that do not express B7 show similar efficacy.