A CHIMERIC LYM-1 INTERLEUKIN-2 FUSION PROTEIN FOR INCREASING TUMOR VASCULAR-PERMEABILITY AND ENHANCING ANTIBODY UPTAKE/

A murine antihuman B-cell monoclonal antibody, Lym-1, has shown consid erable promise for the treatment of human malignant lymphomas. To enha nce its clinical potential, a genetically engineered fusion protein co nsisting of a chimeric Lym-1 (chLym-1) and interleukin 2 (IL-2) was te sted for mediating cytotoxicity, increasing vasopermeability, and enha ncing antibody uptake in human malignant lymphomas. The chLym-1/IL-2 f usion protein, which was expressed initially in a baculovirus system a nd more recently in the glutamine synthetase gene amplification system , was shown to be processed and assembled into a normal immunoglobulin monomer with two IL-2 molecules per antibody. It was found to be equi valent to the chLym-1 antibody in antigen-binding specificity and rela tive affinity. In addition, it maintains IL-2 cytokine activity as dem onstrated by support of T-cell proliferation. Moreover, in antibody-de pendent cellular cytotoxicity assays against Raji target cells, chLym- 1/IL-2 had approximately 2-fold and 4-fold higher cytotoxicity than ch Lym-1 and murine Lym-1, respectively. Used as a pretreatment, chLym-1/ IL-2 enhances the uptake of chLym-1 at the tumor site by altering the permeability of tumor vessels producing tumor:normal organ ratios of 4 20:1 for blood and 1708:1 for muscle at 3 days. The in vitro and in vi vo activities of chLym-1/IL-2, therefore, suggest that this geneticall y engineered antibody fusion protein may represent a new immunotherape utic reagent for the treatment of human malignant lymphomas.