Improving the efficacy of antibody-based cancer therapies

Five antibodies are now approved for cancer therapy with more approvals anticipated from among the 20 or so antibodies currently in oncology trials. The pressing clinical need to enhance the efficacy of anticancer antibodies is being met by the exploration of a plethora of strategies. Combination treatment of antibodies with chemotherapy is already benefiting some oncology patients. Chemically coupling antibodies to toxins or radionuclides is the most widely investigated means for increasing their antitumour activity. In Mylotarg, the anti-CD33–calicheamicin conjugate is already approved for cancer therapy, and two anti-CD20 radioimmunoconjugates, Bexxar (tositumomab; 131iodine) and Zevalin (ibritumomab tituxetan; 90yttrium), are poised for regulatory approval. Interactions between antibody Fc regions and their Fcγ receptors are crucial to the in vivo antitumour activity of at least four antitumour antibodies, including trastuzumab (Herceptin) and rituximab (Rituxan). Tumour-cell killing in vitro has been enhanced by point mutations in Fc that improve binding to FcγRIII and, alternatively, by cellular engineering of antibody production hosts to manipulate antibody glycoforms. Pre-targeting of radionuclides and prodrugs to tumours might greatly reduce the systemic toxicity of conventional radioimmunotherapy and cytotoxic chemotherapy, respectively. Pre-targeting strategies must overcome many remaining obstacles for them to provide significant new treatment options for cancer patients. Targeting tumour neovasculature and angiogenic growth factors (e.g. VEGF) and receptors are promising alternative and potentially complementary strategies to direct tumour targeting. A humanized anti-VEGF antibody, bevacizumab (Avastin), is now in Phase III oncology trials. Liposomal formulations of doxorubicin and daunorubicin have been approved in recent years for the treatment of Kaposi's sarcoma. Attaching antibody fragments to the surface of such liposomes allows them to be specifically targeted to tumours. Antibody–cytokine fusion proteins (immunocytokines) create high intratumour concentrations of cytokines to stimulate the antitumour immune response. An IL-2-containing immunocytokine eliminated established metastases in a syngeneic mouse tumour model, boding well for ongoing clinical studies with two different immunocytokines. Bispecific antibodies binding two different antigens might selectively deliver cytotoxic machinery, such as immune effector cells, radionuclides, drugs and toxins, to tumour cells in vivo. Any future clinical success with bispecific antibodies will probably require a deeper understanding of underwhelming clinical trial data combined with powerful new production technologies for these complex molecules.