Treatment of advanced solid tumors with immunotoxin LMB–1: An antibody linked to Pseudomonas exotoxin

Abstract

Immunotoxin LMB-1 is composed of monoclonal antibody B3 chemically linked to PE38, a genetically engineered form of Pseudomonas exotoxin. B3 recognizes a carbohydrate antigen (Le(Y)) present on many human solid tumors. LMB-1 has excellent antitumor activity in nude mice bearing Le(Y)-positive tumors. We conducted a phase I study of 38 patients with solid tumors who failed conventional therapy and whose tumors expressed the Le(Y) antigen. Objective antitumor activity was observed in 5 patients, 18 had stable disease, 15 progressed. A complete remission was observed in a patient with metastatic breast cancer to supraclavicular nodes. A greater than 75% tumor reduction and resolution of all clinical symptoms lasting for more than six months was observed in a colon cancer patient with extensive retroperitoneal and cervical metastasis. Three patients (two colon, one breast cancer) had minor responses. The maximum tolerated dose of LMB-1 is 75 microgram/kg given intravenously three times every other day. The major toxicity is vascular leak syndrome manifested by hypoalbuminemia, fluid retention, hypotension and, in one case, pulmonary edema. Although immunotoxins have been evaluated in clinical studies for more than two decades, this is the first report of antitumor activity in epithelial tumors.

Antibody-Based Immunotoxins for the Treatment of Cancer

“…B3 reacts with the carbohydrate antigen Lewis Y and with several closely related carbohydrate antigens found in carcinomas of the breast, colon, stomach, esophagus, ovary and lung [79]. In a phase I study carried out between 1993-1996 and conducted on 38 patients with malignant solid tumors expressing Lewis Y antigen, 1 patient showed CR and 1 patient showed PR [54]. Further development of LMB-1 was not pursued; instead, other recombinant immunotoxins (LMB-7, LMB-9, BR96-sFv-PE40) that targeted the Lewis Y antigen were produced and evaluated in clinical trials of patients with Lewis Y-expressing malignancies [15,55].…”

F protein induced fusion of Sendai viral envelopes with mouse teratocarcinoma cells through LeX‐LeX interaction

“…These structures have also been suggested to be involved in the activation of platelets by tumor cells which in turn is correlated with malignancy [4,5]. A monoclonal antibody against carbohydrate antigen Le y (al ~ 2 fucosylated derivative of LeX), chemically linked to a genetically engineered form of Pseudomonas exotoxin, has been recently demonstrated to have excellent anti-tumor activity against LeY-positive tumors [6]. The possibility of targeted anti-tumor chemotherapy using Le x as a ligand is recognized widely.…”

The Therapeutic Potential of Fungal Ribotoxins

“…Within this idea, a singlechain immunotoxin composed of the variable domains of the B5 monoclonal antibody bound to α-sarcin through a peptide containing a furin cleavage site (scFv-IMTXαS) (Fig. 3) [130,135].…”