Hodgkin lymphoma therapy with interleukin-4 receptor-directed cytotoxin in an infiltrating animal model.
Hodgkin lymphoma represents unique clinicopathologic 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 nonmalignant immunoreactive cells. We found that receptors for interleukin-4 (IL-4R) are highly expressed in H-RS cells. To target interleukin-4 receptor (IL-4R), we used 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 disease (HD) 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 and 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 with control (mean survival, 31 days) when they received systemic IL-4 cytotoxin treatment. Because numerous H-RS cell lines express receptors for IL-4, IL-4 cytotoxin may be a unique agent for the treatment of Hodgkin lymphoma.
Kawakami
Mariko
M
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapeutics, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Bldg 29B/2E08, Bethesda, MD 20892, USA. kawakami-k@umin.ac.jp
Kawakami
Koji
K
Kioi
Mitomu
M
Leland
Pamela
P
Puri
Raj K
RK
D000818:Animals; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D015847:Interleukin-4 / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D019948:Receptors, Interleukin-4 / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D015996:Survival Rate; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D047368:Tumor Burden
D003603:Cytotoxins; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4