Antibody with Two Targets May Boost Immunotherapy Benefit

Early trials of an antibody engineered to target two differentantigens suggest that the approach may improve the effectivenessof immunotherapy in selected malignancies.

Researchers at Norris Cotton Cancer Center, Dartmouth HitchcockMedical Center, are studying MDX-210, a bispecific antibody ofmurine 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 Dartmouthand director of the Clinical Therapeutics Research Program atNorris Cotton Cancer Center, Lebanon, NH, reported on phase Istudies of the antibody (developed by Medarex, Annandale, NJ)at the symposium of the Chemotherapy Foundation.

"One explanation for the low level of therapeutic benefitseen with monoclonal antibodies in the treatment of human malignanciesis the inability of many murine and human MoAbs to activate immuneeffector pathways," he said. Another problem is that nonspecificimmunoglobulins often compete with MoAbs for binding to certainreceptors on immune effector cells.

Bispecific antibodies are constructed from two parent moleculeswith two distinct specificities, he explained. By linking theantibody to an effector cell and a target (tumor) cell, it ishoped that immunologic effectiveness will be increased.

"It is an indirect way of vaccinating patients against theirtumor," 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 placewithout competition from nonspecific Igs.

In vitro studies showed that MDX-210 facilitates antibody-dependentcell mediated cytotoxicity and phagocytosis of HER-2/neu-positivetargets, and stimulates release of monocyte/macrophage-derivedcytokines.

Phase I Trials

Based on those observations, phase I trials of MDX-210 were undertakenin patients with breast and ovarian cancers, Dr. Ernstoff said.Patients were treated with either a single injected dose or multipledoses (three times a week or weekly for 3 weeks) ranging from0.35 mg/m² to 10 mg/m².

Treatment has been well tolerated, with transient grade 1 to 2fevers, malaise, and hypotension, all of which persisted for nomore than 6 hours at low doses, and between 12 and 20 hours athigh doses. Mild reversible hepatic enzyme elevations occurred,as did transient monocytopenia, which was fully resolved within24 hours.

The dose-limiting toxicity appears to be transient grade 3 hypotension,which developed in a number of patients. Prophylactic measuresmay be undertaken to avoid this event, Dr. Ernstoff said.

The biologic effects of MDX-210 were confirmed in the clinicalstudies. It was immunologically active, and localization in tumortissues was demonstrated by biopsies in two patients.

Of 10 evaluable patients in the single-dose study, one patientwith metastatic breast cancer showed a partial response; a mixedresponse was seen in one patient with ovarian cancer. In the multidosestudy, eight patients were evaluable, and one with metastaticbreast cancer was stable for 5 months.

Phase 1 studies are ongoing with multidose schedules in metastaticprostate cancer and with a combination of gamma interferon andMDX-210 in metastatic breast cancer. Although this work is inits earliest stages, Dr. Ernstoff expressed optimism about thisnew immunotherapeutic tool.