PHASE-I STUDY OF INTRAVENOUSLY APPLIED BISPECIFIC ANTIBODY IN RENAL-CELL CANCER-PATIENTS RECEIVING SUBCUTANEOUS INTERLEUKIN-2

In a phase I trial the toxicity and immunomodulatory effects of combined treatment with intravenous (i.v.) bispecific monoclonal antibody BIS-1 and subcutaneous (s.c.) interleukin 2 (IL-2) was studied in renal cell cancer patients. BIS-1 combines a specificity against CD3 on T lymphocytes with a specificity against a 40 kDa pancarcinoma-associated antigen, EGP-2. Patients received BIS-1 F(ab')(2) fragments intravenously at doses of 1, 3 and 5 mu g kg(-1) body weight during a concomitantly given standard s.c. IL-2 treatment. For each dose, four patients were treated with a 2 h BIS-1 infusion in the second and fourth week of IL-2 therapy. Acute BIS-1 F(ab')(2)-related toxicity with symptoms of chills, peripheral vasoconstriction and temporary dyspnoea was observed in 2/4 and 5/5 patients at the 3 and 5 mu g kg(-1) dose level respectively. The maximum tolerated dose (MTD) of BIS-1 F(ab')(2) was 5 mu g kg(-1). Elevated plasma levels of tumour necrosis factor a (TNF-alpha) and interferon gamma (IFN-gamma) were detected at the MTD. Flow cytometric analysis showed a dose-dependent binding of BIS-1 F(ab')(2) to circulating T lymphocytes. Peripheral blood mononuclear cells (PBMCs), isolated after treatment with 3 and 5 mu g kg(-1) BIS-1, showed increased specific cytolytic capacity against EGP-2(+) tumour cells as tested in an ex vivo performed assay. Maximal killing capacity of the PBMCs, as assessed by adding excess BIS-1 to the assay, was shown to be decreased after BIS-1 infusion at 5 mu g kg(-1) BIS-1 F(ab')(2). A BIS-1 F(ab')(2) dose-dependent disappearance of circulating mononuclear cells from the peripheral blood was observed. Within the circulating CD3(+)CD8(+) lymphocyte population. LFA-1 alpha-bright and HLA-DR(+) T-cell numbers decreased preferentially. It is concluded that i.v. BIS-1 F(ab')(2), when combined with s.c. IL-2, has a MTD of 5 mu g kg(-1). The treatment endows the T lymphocytes with a specific anti-EGP-2-directed cytotoxic potential.