Mode of action of otlertuzumab (TRU-016) in CLL. Otlertuzumab represents a SMIP with an antibody-derived scFv specific for CD37 linked to an immunoglobulin constant domain (Fc). After ligation of CD37 by otlertuzumab, proapoptotic SHP1 molecules are recruited that finally result in B-cell lymphoma 2 interacting mediator of cell death upregulation and cell death. In contrast, CD37 ligation also results in prosurvival signals via the PI3K pathway via activation of β-catenin. Therefore, PI3K blockade by specific inhibitor, for example, idelalisib, might foster proapoptotic effects in the CLL cell.