Scientific Publications by FDA Staff

Blood 2005 May 1;105(9):3707-13

Hodgkin's lymphoma therapy with interleukin-4 receptor-directed cytotoxin in an infiltrating animal model.

Kawakami M, Kawakami K, Kioi M, Leland P, Puri RK

Kawakami K, US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapeut, Lab Mol Tumor Biol, Bldg 29B-2E08, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapeut, Lab Mol Tumor Biol, Bethesda, MD 20892 USA

Hodgkin's lymphoma represents unique clinicopathological features because Hodgkin and Reed-Sternberg (H-RS) cells produce a variety of cytokines, express a variety of cytokine receptors, and are surrounded by numerous non-malignant immunoreactive cells. We found that receptors for interleukin-4 (IL-4R) are highly expressed in H-RS cells. To target IL-4R, we utilized a recombinant protein fusing circularly permuted human IL-4 and Pseudomonas exotoxin termed IL4(38-37)-PE38KDEL or IL-4 cytotoxin. The cytotoxic effect of IL-4 cytotoxin on H-RS cell lines was determined to be moderate to high in vitro. We developed an infiltrating model of Hodgkin's disease by injecting an adherent population of HD-MyZ cells subcutaneously into the flanks of beige/nude/X-linked immunodeficient mice. The animal model exhibited spontaneous metastasis of H-RS cells to lymph nodes as well as dissemination to vital organs including the lungs. Intraperitoneal or intratumoral treatment of these mice with IL-4 cytotoxin resulted in regression of the primary tumor mass and a decrease in the incidence of lymph node metastasis. Mice injected with HD-MyZ cells demonstrated 203% prolonged survival (mean survival, 63 days) compared to control (mean survival, 31 days) when they received systemic IL-4 cytotoxin treatment. Because a variety of H-RS cell lines express receptors for IL-4, IL-4 cytotoxin may be a unique agent for the treatment of Hodgkin's lymphoma.