Use of the immunotoxin N901-blocked ricin in patients with small-cell lung cancer.
In patients with small-cell lung cancer (SCLC), relapse with resistant disease often causes death. N901-blocked ricin (N901-bR), a murine monoclonal antibody (MAb)-blocked ricin immunotoxin, is a potential therapeutic for SCLC. N901-bR targets CD56, present on SCLC and cells of neuro-ectodermal origin. N901-bR kills up to 5 logs of CD56-positive cells at a concentration of 0.25 nM, while CD56-negative cells require 1000-fold more drug to achieve similar cell kill. We treated 21 patients with relapsed or refractory SCLC with a single 7-day course of N901-bR as a continuous infusion. We determined the MTD and toxicity profile, demonstrated drug binding to tumor cells in biopsies of lung, liver and bone marrow, and determined the time to development of human anti-mouse and anti-ricin antibodies. One patient had a documented PR and 6 patients demonstrated stable disease. Toxicity included transient elevation of liver enzymes, mild thrombocytopenia, hypoalbuminemia, fever, malaise, and evidence of capillary leak syndrome. Toxicities were controllable and reversible. No apparent drug-related central- or peripheral-nervous-system toxicity was noted by serial neurologic examinations, EMGs, and nerve conduction studies. Trials of N901-bR are planned in SCLC patients achieving CR and PR following chemoradiotherapy, and in relapsed/refractory patients. Anti-B4-bR will be added as an immunosuppressant in order to permit delivery of multiple courses of N901-bR. Additional trials will investigate synergy with conventional chemotherapeutics and the use of N901-bR as a sensitizing agent for chemotherapy-resistant tumors.
Epstein
C
C
ImmunoGen, Inc., Boston, MA.
Lynch
T
T
Shefner
J
J
Wen
P
P
Maxted
D
D
Braman
V
V
Ariniello
P
P
Coral
F
F
Ritz
J
J
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001666:Binding Sites, Antibody; D001706:Biopsy; D019002:CD56 Antigen; D018288:Carcinoma, Small Cell / Q000473:pathology / Q000628:therapy*; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology; D004576:Electromyography / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity*; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D008252:Macaca fascicularis; D051379:Mice / Q000276:immunology; D009431:Neural Conduction / Q000187:drug effects; D012276:Ricin / Q000627:therapeutic use* / Q000633:toxicity*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D015816:Cell Adhesion Molecules, Neuronal; D007074:Immunoglobulin G; D000922:Immunotoxins; D012276:Ricin