Rituximab is a chimeric murine-human monoclonal IgG1 (human Fc) that binds to the CD20 molecule on normal and malignant B lymphocytes and is approved for the therapy of patients with CD20-positive large-B-cell diffuse non-Hodgkin’s lymphoma, and relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s lymphoma as a single agent or in combination with appropriate chemotherapy. It is approved for treatment of CLL in combination with chemotherapy. It is also approved for the treatment of rheumatoid arthritis in combination with methotrexate in patients for whom anti-TNF-α therapy has failed. The most recent indication for rituximab is for the treatment of Wegener’s granulomatosis and microscopic polyangiitis. The mechanism of action includes complement-mediated lysis, antibody-dependent cellular cytotoxicity, and induction of apoptosis in malignant lymphoma cells and in B cells involved in the pathogenesis of rheumatoid arthritis and granulomatosis and polyangiitis. In lymphoma this drug appears to be synergistic with chemotherapy (eg, fludarabine, CHOP; see Chapter 54). Anemia or neutropenia is an important adverse effect, which can be countered with granulocyte colony-stimulating factor (G-CSF). Other adverse effects include hypotension, rash, gastrointestinal disturbance, fever, and fatigue.
Trastuzumab is a recombinant DNA-derived, humanized monoclonal antibody that binds to the extracellular domain of HER-2/neu. This antibody blocks the natural ligand from binding and downregulates the receptor. Trastuzumab is approved for the treatment of HER-2/neu-positive tumors in patients with breast cancer and patients with metastatic gastric or gastroesophageal junction adenocarcinoma. As a single agent it induces remission in 15–20% of breast cancer patients; in combination with chemotherapy, it increases response rates and duration as well as 1-year survival. Trastuzumab is under investigation for other tumors that express HER-2/neu (see Chapter 54). Patients should be monitored for potential cardiomyopathy while taking this drug.
Mabs Used to Deliver Isotopes & Toxins to Tumors
Ado-trastuzumab emtansine is an antibody-drug conjugate in which the anti-HER-2/neu antibody, trastuzumab (see above), is chemically linked to the cytotoxic agent, mertansine, a micro-tubule disruptor. Ado-trastuzumab emtansine is approved for patients with HER-2/neu-positive breast cancer who have previously received trastuzumab and a taxane separately or in combination, and whose disease recurred or progressed during prior treatment. Toxicities are identical to trastuzumab alone and also include hepatotoxicity due to emtansine.
Arcitumomab is a murine Fab fragment from an anti-carcinoembryonic antigen (CEA) antibody labeled with technetium 99m (99mTc) that is used for imaging patients with metastatic colorectal carcinoma (immunoscintigraphy) to determine extent of disease. CEA is often upregulated in patients with gastrointestinal carcinomas. The use of the Fab fragment decreases the immunogenicity of the agent so that it can be given more than once; intact murine monoclonal antibodies would elicit stronger HAMA.