Engaging the lysosomal compartment to combat B cell malignancies

Abstract

The combination of rituximab, a type I anti-CD20 mAb, with conventional chemotherapy has significantly improved the outcome of patients with B cell malignancies. Regardless of this success, many patients still relapse with therapy-resistant disease, highlighting the need for the development of mAbs with higher capacity to induce programmed cell death. The so-called type II anti-CD20 mAbs (e.g., tositumomab) that trigger caspase-independent B cell lymphoma cell death in vitro and show superior efficacy as compared with rituximab in eradicating target cells in mouse models are emerging as the next generation of therapeutic anti-CD20 mAbs. In this issue of the JCI, Ivanov and colleagues identify the lysosomal compartment as a target for type II mAbs (see the related article beginning on page 2143). These data encourage the further clinical development of type II mAbs as well as other lysosome-targeting drugs in the treatment of B cell malignancies.

Figure 1. The effector mechanisms of type I and type II anti-CD20 mAbs.

Whereas type I anti-CD20 mAbs induce cytotoxicity in B cells mainly via complement-dependent cytotoxicity and Ab-dependent cellular cytotoxicity (ADCC), type II anti-CD20 mAbs are weaker at activating complement-dependent cytotoxicity. Instead, type II anti-CD20 mAbs are potent inducers of actin-dependent homotypic adhesions between B cells. In this issue of the JCI, Ivanov and colleagues demonstrate that these adhesions are associated with localization of lysosomes to the proximity of cell-cell contacts, lysosomal swelling, and lysosomal membrane permeabilization (17). Importantly, the lysosomal hydrolases leaked into the cytosol can then induce nonapoptotic cell death even in highly apoptosis-resistant and rituximab-resistant B cell malignancies. Thus, type II mAbs may provide new treatment options even in aggressive B cell tumors resistant to current therapies.