title: Enhanced tumor uptake of macromolecules induced by a novel vasoactive interleukin 2 immunoconjugate.
abstract: Low uptake of monoclonal antibodies (MAbs) in cancer lesions is a significant problem in cancer therapy. Recent studies have shown that antibody uptake in tumor is controlled in large part by the tumor blood flow and the vascular permeability of the tumor endothelium. We have hypothesized that these physiological properties of tumor vessels may be altered by pretreatment with vasoactive drugs or peptides linked to tumor-specific MAbs. To test this hypothesis, two MAbs, Lym-1 directed against human malignant lymphomas and B72.3 reactive with the TAG-72 antigen expressed in solid tumors, were chemically conjugated with human recombinant interleukin 2 (IL-2). IL-2 has been used in humans to activate lymphokine-activated killer cells for the treatment of cancer but is also known to produce a generalized vascular permeability by an unknown mechanism when used systemically. Chemical conjugation of IL-2 to MAbs appears to destroy its cytokine function as shown by T-cell proliferation studies in vitro. Despite this finding, MAb/IL-2 immunoconjugates retain their ability to produce an enhanced vascular permeability when injected i.v. into nude mice bearing relevant tumor models only. Biodistribution studies using 125I-labeled tracer Lym-1 have demonstrated that the Lym-1/IL-2 immunoconjugate can increase antibody uptake in tumor by a factor of 4 in a time (2.5-h pretreatment)- and dose (30 micrograms/mouse)-dependent manner. In contrast, treatment of mice with free IL-2 and antibody showed this effect in all organs of the mouse including the tumor. Bidirectional crossover imaging studies in individual tumor-bearing nude mice showed improved uptake and decreased blood pool when the MAb/IL-2 immunoconjugates were used compared to controls. Finally, tumor blood flow and vascular permeability studies demonstrate that the physiological effect of the MAb/IL-2 is due to a reversible and specific vascular leakage at the tumor site. These studies indicate that pretreatment with this novel immunoconjugate may enhance the diagnostic and therapeutic potential of MAbs, drugs, and other macromolecules for the treatment of cancer.
authors.affiliation: Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033.
authors.forename: B
authors.initials: B
authors.lastname: LeBerthon
authors.forename: L A
authors.initials: LA
authors.lastname: Khawli
authors.forename: M
authors.initials: M
authors.lastname: Alauddin
authors.forename: G K
authors.initials: GK
authors.lastname: Miller
authors.forename: B S
authors.initials: BS
authors.lastname: Charak
authors.forename: A
authors.initials: A
authors.lastname: Mazumder
authors.forename: A L
authors.initials: AL
authors.lastname: Epstein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism* / Q000627:therapeutic use; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012039:Regional Blood Flow; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2