Bispecific antibodies (BsAb) are hybrid antibodies constructed from two parent monoclonal antibodies (mAbs): one specific for tumor cells and the other specific for immune effector cells. Tumor cells can be killed when specific """"""""trigger molecules"""""""" including CD64 (FcgRl) on monocytes, monocyte-derived macrophages (MAK) and IFNg-activated neutrophils are engaged by BsAb during the interaction of an effector cell with a tumor cell. Effector cell targeting with BsAb may overcome natural and pathological barriers to immunotherapy with mAbs. The applicant developed a BsAb anti-FcgRl x anti-HER-2/neu (MDX-210) that effectively targets human monocytes, MAK and neutrophils to phagocytose and kill tumor cells that over express the proto-oncogene-HER-2neu. HER-2/neu is over expressed in many cancers including approximately 30% of breast cancers. A phase 1 trial demonstrated that MDX-210 is well tolerated and is immunologically active. Tumor regressions were observed. The optimal biological dose (OBD) and maximum tolerated dose (MTD) was between 7 and 10mg/m2. The anti-FcgRl mAb 22 has been humanized and a BsAb designated MDX-H210 was constructed. MDX-210 and MDX H210 are virtually identical in preclinical testing. The applicant anticipates that MDX-H210 will induce less human anti-mouse antibodies than did MDX-210. In this application the applicant proposes to perform a phase I trial of MDX- H210 plus IFNg. This combination was chosen because IFNg has multiple actions including increased expression of FcgRl and activation of effector cells that may increase effectiveness of treatment with MDX- H210. Patients will be treated with IFNg 0.1 mg/m2 on days 1 and 3 and with MDX-H210 on day 2. Treatment is repeated weekly. The dose of MDX-H210 will be increased for cohorts of 3 patients until the MTD is determined. The immunological efficacy of MDX-H210 will be assessed by determining: 1) binding of MDX-H210 to monocytes and PMNs and to tumor cells in vivo; 2) stimulation of T cell and B cell responses to HER-2/neu; 3) changes in plasma concentration of cytokines (TNF, Il-1, Il-6, G-CSF, neopterin); and 4) tumor infiltration by effector cells. He anticipates that the MTD and OBD will be identical. A phase II trial will then be performed to determine the therapeutic efficacy of MDX-H210 plus IFNg given at this optimal dose for treatment of breast cancer. MDX-210 has shown potent immunological activity and promising clinical efficacy in phase I testing when given alone. The combination of IFNg and MDX-H210 may increase the efficacy of this promising BsAb by enhancing effector cell activity.
| Lewis, Lionel D; Beelen, Andrew P; Cole, Bernard F et al. (2002) The pharmacokinetics of the bispecific antibody MDX-H210 when combined with interferon gamma-1b in a multiple-dose phase I study in patients with advanced cancer. Cancer Chemother Pharmacol 49:375-84 |
| Wallace, P K; Kaufman, P A; Lewis, L D et al. (2001) Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo. J Immunol Methods 248:167-82 |
