PHASE-I TRIAL OF 2B1, A BISPECIFIC MONOCLONAL-ANTIBODY TARGETING C-ERBB-2 AND FC-GAMMA-RIII

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificit y for the c-erbB-2 and Fc gamma RIII extracellular domains, This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-e rbB-2 gene product of the HER2/neu proto-oncogene by human natural kil ler cells and mononuclear phagocytes expressing the Fc gamma RIII A is oform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-o verexpressing tumors were treated with 1 h i.v. infusions of 2B1 on da ys 1, 4, 5, 6, 7, and 8 of a single course of treatment, Three patient s were treated with daily doses of 1.0 mg/m(2), while six patients eac h were treated with 2.5 mg/m(2) and 5.0 mg/m(2), respectively. The pri ncipal non-dose-limiting transient toxicities were fevers, rigors, nau sea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at t he 5.0 mg/m(2) dose level in two patients who had received extensive p rior myelosuppressive chemotherapy, Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding propert ies were retained. The pharmacokinetics of this murine antibody were v ariable and best described by nonlinear kinetics with an average t(1/2 ) of 20 h, Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor ne crosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma, Bris k human anti-mouse antibody responses were induced in 14 of 15 patient s. Several minor clinical responses were observed, with reductions in the thickness of chest mall disease in one patient with disseminated b reast cancer. Resolution of pleural effusions and ascites, respectivel y, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon canc er, Treatment with 2B1 BsMAb has potent immunological consequences. Th e maximum tolerated dose and Phase II daily dose for patients with ext ensive prior myelosuppressive chemotherapy was 2.5 mg/m(2). Continued dose escalation is required to identify the maximally tolerated dose f or patients who have been less heavily pretreated.