European Medical Journal Hematology (Aug 2018)
Making Rituximab Directly Cytotoxic for Substantial Improvement in Therapeutic Efficacy
Abstract
The humanised anti-CD20 antibody (Ab) rituximab (RTX) has significantly improved the prognosis of B cell non-Hodgkin’s lymphomas (BNHL). However, major challenges remain: a) RTX is often used with toxic chemotherapy that not only causes serious side effects but may also compromise RTX activity and host antitumour immunity, predisposing patients to relapse; b) indolent low-grade BNHL remain largely incurable; c) a significant percentage of aggressive BNHL do not respond to RTX-based therapy; and d) a significant number of responders may eventually relapse in long-term follow-up. The data suggest that the limit in the efficacy may result from the inability of RTX to directly kill lymphoma cells. RTX primarily relies on indirect mechanisms to attack lymphoma cells, which include complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity, induction of apoptosis, and immune activation. These mechanisms could be readily compromised by various situations, such as chemotherapy. The new generation of anti-CD20 Ab have not been found to be directly cytotoxic. Cytotoxic radioactive isotope-conjugated anti-CD20 Ab appeared to be highly effective, but serious radiotoxicity prohibited their clinical application. Increasing Ab valency augments activity; a recent study has demonstrated drastic improvement in activity by non-covalently associating RTX with nanomaterial graphene oxide (GO). The multivalent Ab product RTX/GO is highly cytotoxic, capable of directly killing BNHL cells in vitro and rapidly eliminating established xenograft lymphoma in vivo in the absence of toxic chemo-agents. While further studies are needed to determine the mechanism of activity and clinical efficacy, the current data suggest a significant possibility that RTX/GO might constitute nontoxic but effective therapy for BNHL.
