Antibody-based therapeutic approaches have had a significant impact in the treatment of
non-Hodgkin's lymphoma (NHL).
Rituximab's development as an anti-CD20 antibody heralded a new era in treatment approaches for NHL. While
rituximab was first shown to be effective in the treatment of relapsed
follicular lymphoma, it is now standard monotherapy for front-line treatment of
follicular lymphoma, and is also used in conjunction with
chemotherapy for other indolent, intermediate and aggressive
B-cell lymphomas. The development of
rituximab has led to intense interest in this type of therapeutic approach and to development and approval of the
radioimmunoconjugates of
rituximab, (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, which have added to the repertoire of treatments for relapsed
follicular lymphoma and increased interest in developing other conjugated
antibodies. Since
rituximab is a chimeric antibody, there is a need to develop fully humanised
antibodies, such as
IMMU-106 (
hA20), in order to minimise infusion reactions and eliminate the development of human
antibodies against the
drug. Further clinical evaluation of
antibodies has been based largely on our knowledge of
antigen expression on the surface of
lymphoma cells and has led to the development of
antibodies against CD22 (unconjugated
epratuzumab and
calicheamicin conjugated
CMC-544 [
inotuzumab ozogamicin]), CD80 (
galiximab), CD52 (
alemtuzumab), CD2 (MEDI-507 [
siplizumab]), CD30 (SGN-30 and MDX-060 [
iratumumab]), and CD40 (SGN-40). Furthermore, the
VEGF (
vascular endothelial growth factor) inhibitor
bevacizumab, which was first approved for the treatment of
colon cancer is currently under investigation in NHL, and agonists rather than
antibodies to TRAIL (tumour
necrosis factor-related apoptosis-inducing
ligand) [rApo2L/TRAIL, HGS-ETR1{
mapatumumab}, HGS-ETR2] are currently being investigated as treatments for both advanced solid tumours and NHL. Knowledge of the ability of
cancer cells to become resistant to a targeted
therapy by activating an alternative pathway to evade apoptosis has driven studies that combine
antibodies such as
epratuzumab plus
rituximab (ER) or ER plus
chemotherapy with CHOP (
cyclophosphamide,
doxorubicin,
vincristine, and
prednisone) [ER-CHOP],
inotuzumab ozogamicin plus
rituximab,
alemtuzumab plus CHOP (CHOP-C),
bevacizumab plus
rituximab, and now the combination of rApo2L/TRAIL plus
rituximab. As a result of the expansion of research in this area, several treatment-specific adverse effects have been noted, including infusion-related reactions for
rituximab, myelosuppression secondary to (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, and immunosuppression leading to infectious complications for
alemtuzumab. Also, soluble forms of the
antigens (sCD30) are now being investigated as potential mechanisms of resistance to antibody treatments by binding the antibody before the
drug can bind to the
lymphoma cell. In addition, it has also become apparent that these
antibodies often have a dose-dependent half-life (
rituximab) or long half-lives of up to 2-3 weeks (
epratuzumab and
galiximab) with a consequent delay to a response, thus influencing how long we should wait for a response before declaring an antibody to be ineffective. Antibody-based therapeutic approaches have already had a profound impact on the treatment of NHL, and it is almost certain that, as their clinical development progresses, we will continue to refine the optimum methods of incorporating these drugs in NHL treatment in order to offer our patients the best clinical benefits.