The chimeric monoclonal anli-CD20 antibody rituximab has significant activity against follicular lymphoma and CLL. Both the in vivo mechanisms of action and resistance of rituximab are not well characterized. Induction of apoptosis, complement mediated lysis, and ADCC are all proposed mechanisms by which antibodies eliminate CLL cells. To investigate the role of complement mediated lysis, we measured CH50 and C3 levels in 12 patients(pts) on days 1 and 3 of rituximab treatment as part of a recently completed clini cal trial of thrice weekly rituximab therapy for CLL. Plasma was obtained before and immédiat ely following antibody treatment. Significant decreases in CH50 and C3 levels were founc in all pts. Day 1 CH50 pre-Rx 41.9 to post-Rx 32.25 (p=0.001 ) and Day 3 CH50 pre-Rx 37.5 to post-Rx 24.2 (p=0.02). Day l C3 pre-Rx 79.7mg/dl to post-Rx 69.7mg/dl (p=0.001) and Day 3 C3 pre-Rx 74.9mg/dl to post-Rx 64.2mg/dl (p=0.01 ). Complement mediated cell 1; sis in vivo appears to be important for clearance of CLL cells by rituximab. We assessed b 3th pre-treatment and sequential expression of the cell surface complement inhibitors CD55 ; md CD59 during rituximab therapy. Quantibrite-PE beads and 1:1 dilution PE labeled a itiCD55 or CD59 antibody were used to quantitate CD55 or CD59 expression on CLL cdls. Wide variability was seen in pretreatment expression of CD55 (3,478 to 13,233 molecu es/ cell) and CD59 (1,851 to 9,707 molecules/cell) in 20 pts examined. Although there was no significant correlation of CD55 or CD59 expression with response to rituximab therapy on this trial, non-responders tended to have higher expression than responders. In pts v iho failed to have clearance of CLL cells in blood at 8 weeks post-treatment, CD59 significai itly increased from baseline in all 7 pts (pre-Rx 3,587 to post-Rx 5,724 molecules/cell; p=0.()2). CD55 expression also increased with rituximab therapy in 6 of 7 of these same pts (pre Rx 5,992 to post-Rx 7,503 molecules/cell; p=0.3). These data demonstrate variabilit; in pretreatment expression of CD55 and CD59, an initial partial depletion of complement after treatment, and an increase in CD55 and CD59 in pts failing to clear CLL cells from bl od following rituximab therapy. These findings suggest complement mediated cell lysis contributes to the elimination of CLL cells in vivo by rituximab therapy. Alternative dos ing schedules for rituximab and/or the addition of treatments to block complement proteci ing factors (i.e. anti-CD55 or anti-CD59 antibodies) may be required to reduce this mechan sm of drug resistance.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology