A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu

Abstract

A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of the study were to define the maximal tolerated dose (MTD) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics of MDX-H210 when administered with G-CSF, and to determine the toxicity, biological effects and possible therapeutic effect of MDX-H210 with G-CSF. MDX-H210 is a F(ab)' x F(ab)' humanized bispecific murine antibody that binds to both HER2/neu and the FcgammaR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The beta-elimination half-life varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor alpha was observed after administration of bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.

Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcγRI × anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer

“…Furthermore, G-CSF might contribute to an enhanced antiinflammatory cytokine response (Hartung et al, 1995). Concomitant administration of MDX-H210 and G-CSF seems to be safe in our study as well as in a multidose trial with MDX-H210 (Pullarkat et al, 1999). Interestingly, the side effects in our study were similar to other MDX-H210 studies, with other cytokines such as IFN-g or GM-CSF (Posey et al, 1999;Lewis et al, 2001).…”

“…Strikingly less side effects were noted in these patients. This desensitisation phenomenon was also reported in other clinical trials with BsAb or mAb (Maloney et al, 1997;Dillman, 1999;Posey et al, 1999;Pullarkat et al, 1999).…”

Immature Neutrophils Mediate Tumor Cell Killing via IgA but Not IgG Fc Receptors

“…Additionally, stimulation of neutrophils with G-CSF (or IFN-␥) induces expression of the high affinity Fc␥RI (CD64), which represents the predominant cytotoxic Fc␥R on neutrophils (16). These data stimulated the evaluation of a combined therapy of G-CSF and Fc␥RI-specific BsAb in a number of clinical trials (17)(18)(19). These trials, however, only showed limited therapeutic effects, indicating that improvement of neutrophil-mediated Ab therapy is required.…”

The CY Domain of the FcγRIa α-Chain (CD64) Alters γ-Chain Tyrosine-based Signaling and Phagocytosis

“…Targeting of tumors to Fc␥RI with bispecific mAbs 1 can facilitate tumor killing via Fc␥RI-expressing macrophages, and therapeutic humanized bispecific reagents targeting human Fc␥RIa are currently in clinical trials (13)(14)(15)(16)(17)(18)(19). Bispecific mAb-based antigen targeting to Fc␥RI can also enhance antigen presentation by dendritic cells with clear applications to enhanced immunization strategies (20).…”