An engineered IgM antibody targeting CD20 has enhanced complement-dependent cytotoxicity compared with an IgG.

Complement-dependent cytotoxicity (CDC) is one of the main mechanisms of action for approved therapeutic anti-CD20 IgG antibodies, including rituximab, ofatumumab, and ocrelizumab, in the treatment of B-cell lymphoma patients. However, resistance to these therapies inevitably develops in patients, and thus novel antibody approaches are needed. Here, we described the CDC activity of an anti-CD20 IgM in comparison to an anti-CD20 IgG. We applied live-cell imaging and kinetic analysis to measure CDC activity in real time. Through this imaging platform, we demonstrated that an IgM antibody exhibited more potent and faster target cell killing through CDC compared with an IgG antibody. Additionally, an IgM antibody was more effective at killing target cells with low antigen density, in low levels of complement, and in the presence of high complement inhibitor expression. An anti-CD20 IgM also showed superior CDC against ex vivo tumor samples from a patient with B-cell lymphoma. These preclinical studies demonstrated the potential of an anti-CD20 IgM-based therapeutic antibody having superior CDC in B-cell lymphoma compared with a traditional IgG antibody.