Unlabeled monoclonal antibodies (MoAbs) are attractive for the treatment of non-Hodgkin’s lymphoma (NHL) as they may: (1) mediate cytotoxicity with complement (complement-dependent cytotoxicity [CDC]) or effector cells (antibody-dependent cellular cytotoxicity [ADCC]); (2) effect apoptosis; (3) be less toxic, less immunogenic, and more effective than toxin- or drug-conjugated MoAbs; (4) not require the complex procedures needed for radiolabeled MoAb therapy (RIT); and (5) not produce the myelosuppression typical of high-dose RIT.
The anti-CD20 MoAb, rituximab(Drug information on rituximab) (Rituxan) has low toxicity and significant activity. It is approved for the treatment of relapsed or refractory, low-grade or follicular NHL. In a single-agent study of 166 patients with refractory, low-grade or follicular NHL treated with rituximab at 375 mg/m² weekly for four infusions, the overall response rate was 48% (6% complete response [CR] and 42% partial response [PR]). Median time to progression for responders was 13.2 months and duration of response 11.6 months.
Median circulating B-lymphocyte counts dropped to 0 following the first dose. CD3, CD4, CD8, and natural killer (NK) cell counts remained unchanged. B-cell recovery in peripheral blood began at 6-9 months and was complete by 9-12 months. No significant changes in serum complement levels were noted.
The mechanism of action remains unresolved, with CDC, ADCC, apoptosis, and/or other mechanisms being considered. Humanized and chimeric antibodies are more likely to mediate/activate human effector functions. We have observed a correlation between higher absolute NK cell count at baseline and response to the MoAb.
CONCLUSION: ADCC may be an important mechanism for the clinical activity seen in patients treated with rituximab. Agents that increase effector cell number and function may enhance the MoAb’s clinical activity. Studies of rituximab in combination with interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (INF), and other agents are in progress.
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