USE OF THE IMMUNOTOXIN N901-BLOCKED RICIN IN PATIENTS WITH SMALL-CELLLUNG-CANCER

In patients with small-cell lung cancer (SCLC), relapse with resistant disease often causes death. N901-blocked ricin (N901-bR), a murine mo noclonal antibody (MAb)-blocked ricin immunotoxin, is a potential ther apeutic for SCLC. N901-bR targets CD56, presents on SCLC and cells of neuro-ectodermal origin, N901-bR kills up to 5 logs of CD56-positive c ells at a concentration of 0.25 nM, while CD56-negative cells require 1000-fold more drug to achieve similar cell kill. We treated 21 patien ts with relapsed or refractory SCLC with a single 7-day course of N901 -bR as a continuous infusion. We determined the MTD and toxicity profi le, demonstrated drug binding to tumor cells in biopsies of lung, live r and bone marrow, and determined the time to development of human ant i-mouse and anti-ricin antibodies. One patient had a documented PR and 6 patients demonstrated stable disease. Toxicity included transient e levation of liver enzymes, mild thrombocytopenia, hypoalbuminemia, fev er, malaise, and evidence of capillary leak syndrome. Toxicities were controllable and reversible. No apparent drug-related central- or peri pheral-nervous-system toxicity was noted by serial neurologic examinat ions, EMGs, and nerve conduction studies. Trials of N901-bR are planne d in SCLC patients achieving CR and PR following chemoradiotherapy, an d in relapsed/refractory patients. Anti-B4-bR will be added as an immu nossuppressant in order to permit delivery of multiple courses of N901 -bR. Additional trials will investigate synergy with conventional chem oterapeutics and the use of N901-bR as a sensitizing agent for chemoth erapy-resistant tumors. (C) 1994 Wiley-Liss, Inc.