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Antibody with Two Targets May Boost Immunotherapy Benefit

Antibody with Two Targets May Boost Immunotherapy Benefit

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 cytokines.

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 24 hours.

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.

 
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