In November 2013, the US FDA approved the glycoengineered, type II anti-CD20 antibody obinutuzumab (also known as GA101) in combination with chlorambucil chemotherapy for the treatment of people with previously untreated chronic lymphocytic leukemia (CLL). Obinutuzumab is the first drug approved under the FDA’s breakthrough therapy designation, created in 2012 to quicken the pace of development and review of drugs for serious conditions. The Fc portion of obinutuzumab was glycoengineered to reduce fucosylation of the Fc carbohydrate, resulting in increased FcγRIIIa affinity and antibody-dependent cellular cytotoxicity (ADCC) potency. As expected for a type II antibody, obinutuzumab demonstrated lower complement-mediated cytotoxicity, more potent mediation of cell death via the nonclassical apoptosis pathway and increased ADCC as compared with rituximab in preclinical studies. In addition, obinutuzumab induced a stronger antitumor effect in mouse xenograft models of human lymphoma than rituximab and ofatumumab, supporting clinical investigation of this third generation anti-CD20 antibody.
