Unlabeled monoclonal antibodies (MoAbs) are attractive for the
treatment of non-Hodgkins 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
The anti-CD20 MoAb, 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 MoAbs
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.