A chimeric Lym-1/interleukin 2 fusion protein for increasing tumor vascular permeability and enhancing antibody uptake.

Abstract

A murine antihuman B-cell monoclonal antibody, Lym-1, has shown considerable promise for the treatment of human malignant lymphomas. To enhance its clinical potential, a genetically engineered fusion protein consisting of a chimeric Lym-1 (chLym-1) and interleukin 2 (IL-2) was tested for mediating cytotoxicity, increasing vasopermeability, and enhancing antibody uptake in human malignant lymphomas. The chLym-1/IL-2 fusion protein, which was expressed initially in a baculovirus system and 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 equivalent to the chLym-1 antibody in antigen-binding specificity and relative affinity. In addition, it maintains IL-2 cytokine activity as demonstrated by support of T-cell proliferation. Moreover, in antibody-dependent cellular cytotoxicity assays against Raji target cells, chLym-1/IL-2 had approximately 2-fold and 4-fold higher cytotoxicity than chLym-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 420:1 for blood and 1708:1 for muscle at 3 days. The in vitro and in vivo activities of chLym-1/IL-2, therefore, suggest that this genetically engineered antibody fusion protein may represent a new immunotherapeutic reagent for the treatment of human malignant lymphomas.

• Authors: P Hu, J L Hornick, M S Glasky, A Yun, M N Milkie, L A Khawli, P M Anderson, A L Epstein
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 21 Pg. 4998-5004 (Nov 01 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8895756 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Immunoconjugates
• Interleukin-2
• Recombinant Fusion Proteins

Topics

• Animals
• Antibodies, Monoclonal (immunology, metabolism, pharmacology)
• Antibody-Dependent Cell Cytotoxicity
• Base Sequence
• Capillary Permeability (drug effects)
• Humans
• Immunoconjugates (pharmacology)
• Interleukin-2 (metabolism, pharmacology)
• Lymphoma (therapy)
• Mice
• Molecular Sequence Data
• Recombinant Fusion Proteins (immunology, metabolism, pharmacology)
• Tissue Distribution