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BioOncology Watch Timely Information for Practicing
Physicians |
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december 2001 Anti-CD20
Monoclonal Antibody Therapy Rituximab mechanism of action. Beatriz Bellosillo and colleagues
investigated the in vitro effect of
rituximab, a chimeric monoclonal antibody directed against CD20, on cells
from 55 patients with B-cell lymphoproliferative disorders. A cytotoxic effect was not observed when
cells were incubated with rituximab alone.
However, in the presence of human AB serum (as a source of
complement), rituximab induced complement-dependent cell death (R-CDC). Cytotoxic effects were observed in 4 of 4
patients with follicular lymphoma, 16 of 16 patients with mantle-cell lymphoma,
2 of 2 patients with hairy cell leukemia, and 9 of 33 patients with B-cell
chronic lymphocytic leukemia. The
development of R-CDC was directly correlated with the number of CD20
molecules per cell and pre-incubation with anti-CD59 enhanced the cytotoxic
effect of rituximab. R-CDC was not
found to activate caspase-3 or to cleave polyADP ribose polymerase. In addition, R-CDC was associated with a
rapid and intense production of reactive oxygen species (ROS) and was blocked
by ROS scavengers. These findings
indicate that the cytotoxic effect of rituximab is mediated by a
caspase-independent process involving the generation of superoxide radicals.
Furthermore, CD20, CD59, and complement all have roles in the in vitro cytotoxicity of
rituximab. (Bellosillo B, et al. Blood
2001;98:2771-2777) Pretargeted radioimmunotherapy (RIT). Encouraging results have been
seen with radiolabeled anti-CD20 monoclonal antibody treatments of patients
with relapsed B-cell lymphomas.
However, normal tissue is exposed to radiation during the period
required for the intravenously infused radioimmunoconjugate to circulate and
accumulate at tumor sites. Oliver
Press and coworkers investigated the ability of a "pretargeting"
approach to improve the biodistribution of radioactivity in mice bearing
Ramos lymphoma xenografts. This
approach comprised an initial infusion of pretargeted streptavidin-conjugated
anti-CD20 1F5 antibody followed 24 hours later by a biotinylated
N-acetyl-galactosamine-containing clearing agent, followed 3 hours later by 111Indium-labeled
DOTA-biotin. This pretargeting technique increased tumor/normal organ ratios
of adsorbed radioactivity from £ 6:1 with the infusion of conventional 111Indium-1F5
to 56:1. Further experiments
demonstrated that, while ³ 400 uCi of conventional 90Yttrium-1F5 was associated with
lethal toxicity in 100% of mice, up to 800 uCi of 90Yttrium-DOTA-biotin
could be safely administered with the pretargeting approach resulting in an
89% cure rate for the mice. These
data suggest that the pretargeting strategy has the potential to improve
anti-CD20 therapy and warrants further testing. (Press OW, et al. Blood
2001;98:2535-2543) Acute Myelogenous Leukemia (AML) Nuclear factor (NF)-kB expression. Previous
studies have shown that, while the transcriptional activator NF-kB is expressed in several malignant cell
types, normal unstimulated human CD34+ hematopoietic progenitor cells do not
express NF-kB. Monica Guzman and associates
isolated AML cells from patients and found NF-kB to be readily expressed by primary AML
CD34+ cells. Further detailed
analyses showed NF-kB to be active in the AML stem cell population
(CD34+/CD38-/CD123+). Exposure of AML
stem cells to the proteasome inhibitor MG-132, an inhibitor of NF-kB, induced rapid cell death (apoptosis),
whereas normal hematopoietic stem cells were unaffected. These preclinical data demonstrate that
AML stem cells aberrantly express active NF-kB, which may provide an opportunity to
devise leukemia-specific treatments. (Guzman ML, et al. Blood;
98:2301-2307) Metastatic
Melanoma
Phase I study of a chimeric
monoclonal antibody (mAb). The GD3 ganglioside antigen
has been previously been found to be highly expressed on malignant melanoma
cells. Andrew Scott et al conducted a
phase I dose-escalation study of KM871, a chimeric anti-GD3 mAb, in patients
with metastatic melanoma. Patients
received 3 infusions of KM871 at 2-week intervals and 17 patients were entered
into 5 dose levels (1, 5, 10, 20, and 40 mg/m2). In the initial infusion, KM871 was
trace-labeled with 111Indium for an assessment of biodistribution in vivo and biopsies of metastatic
sites were performed on days 7 and 10.
No dose-limiting toxicity was observed at any dose level. Uptake of 111Indium-KM871
was detected in all melanoma lesions >1.5 cm while no normal tissue uptake
was observed. None of the patients
developed human antichimeric antibody and the terminal plasma half-life of 111Indium-KM871
was 7.68 ± 2.94 days. One patient experienced
an objective clinical partial response of 11 months duration. These findings indicate that this anti-GD3
mAb represents a potentially safe and effective therapy for patients with
metastatic malignant melanoma. (Scott
AM, et al. J Clin Oncol 2001;19:3976-3987) |
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