Early trials of an antibody engineered to target two different
antigens suggest that the approach may improve the effectiveness
of immunotherapy in selected malignancies.
Researchers at Norris Cotton Cancer Center, Dartmouth Hitchcock
Medical Center, are studying MDX-210, a bispecific antibody of
murine origin that binds to both CD64 and the HER-2/neu oncogene,
in breast, ovarian, and prostate cancers.
Marc S. Ernstoff, MD, associate professor of medicine at Dartmouth
and director of the Clinical Therapeutics Research Program at
Norris Cotton Cancer Center, Lebanon, NH, reported on phase I
studies of the antibody (developed by Medarex, Annandale, NJ)
at the symposium of the Chemotherapy Foundation.
"One explanation for the low level of therapeutic benefit
seen with monoclonal antibodies in the treatment of human malignancies
is the inability of many murine and human MoAbs to activate immune
effector pathways," he said. Another problem is that nonspecific
immunoglobulins often compete with MoAbs for binding to certain
receptors on immune effector cells.
Bispecific antibodies are constructed from two parent molecules
with two distinct specificities, he explained. By linking the
antibody to an effector cell and a target (tumor) cell, it is
hoped that immunologic effectiveness will be increased.
"It is an indirect way of vaccinating patients against their
tumor," he said. Binding to CD64 enables activation of monocytes,
macrophages, dendritic cells, and cytokine-stimulated neutrophils.
Because the binding site is outside the Ig ligand, it takes place
without competition from nonspecific Igs.
In vitro studies showed that MDX-210 facilitates antibody-dependent
cell mediated cytotoxicity and phagocytosis of HER-2/neu-positive
targets, and stimulates release of monocyte/macrophage-derived
Phase I Trials
Based on those observations, phase I trials of MDX-210 were undertaken
in patients with breast and ovarian cancers, Dr. Ernstoff said.
Patients were treated with either a single injected dose or multiple
doses (three times a week or weekly for 3 weeks) ranging from
0.35 mg/m² to 10 mg/m².
Treatment has been well tolerated, with transient grade 1 to 2
fevers, malaise, and hypotension, all of which persisted for no
more than 6 hours at low doses, and between 12 and 20 hours at
high doses. Mild reversible hepatic enzyme elevations occurred,
as did transient monocytopenia, which was fully resolved within
The dose-limiting toxicity appears to be transient grade 3 hypotension,
which developed in a number of patients. Prophylactic measures
may be undertaken to avoid this event, Dr. Ernstoff said.
The biologic effects of MDX-210 were confirmed in the clinical
studies. It was immunologically active, and localization in tumor
tissues was demonstrated by biopsies in two patients.
Of 10 evaluable patients in the single-dose study, one patient
with metastatic breast cancer showed a partial response; a mixed
response was seen in one patient with ovarian cancer. In the multidose
study, eight patients were evaluable, and one with metastatic
breast cancer was stable for 5 months.
Phase 1 studies are ongoing with multidose schedules in metastatic
prostate cancer and with a combination of gamma interferon and
MDX-210 in metastatic breast cancer. Although this work is in
its earliest stages, Dr. Ernstoff expressed optimism about this
new immunotherapeutic tool.