In vivo properties of an IgG3-IL-2 fusion protein. A general strategy for immune potentiation.
In this report, we describe a strategy for enhancing the immunogenicity of a wide variety of Ags by linking them to IL-2 via an IgG3-IL-2 fusion protein with high affinity for a convenient hapten Ag, dansyl (DNS; N,N-dimethyl-1-aminonaphthalene-5-sulfonyl chloride). This fusion protein, anti-DNS-IgG3-IL-2, combines the functional characteristics of its constituents and has pharmacokinetic properties that are greatly improved over those of IL-2 and a previously described IgG1-IL-2 fusion. The molecule is intact and recoverable from the blood of mice hours after i.p. injection and reaches distant organs throughout the animal. The 7-h in vivo half-life of this molecule is much longer than that of IL-2, addressing a major obstacle in the application of IL-2 to human diseases, including cancer and AIDS. Additionally, the Ab's specificity for the hapten dansyl and the convenient chemistry of dansyl provide a means to link IL-2 to virtually any molecule of interest without the complexities and uncertainties of making IL-2 fusions with each molecule individually. Using hapten-conjugated-BSA (DNS-BSA) as a model Ag we show that the Ab response elicited by anti-DNS-IgG3-IL-2-bound DNS-BSA-Sepharose injected into mice is increased over that of DNS-BSA-Sepharose or anti-DNS-IgG3-bound DNS-BSA-Sepharose. Anti-DNS-IgG3-IL-2 also increased the Ab response to soluble DNS-BSA after a booster injection. This system should be useful in testing the ability of IL-2 to potentiate the immune response to Ag and in screening a large number of potential Ags for use in vaccines. The dramatically improved pharmacokinetics should also overcome one of the major difficulties in applying IL-2 to the treatment of human disease, its short half-life.
Harvill
E T
ET
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.
Fleming
J M
JM
Morrison
S L
SL
D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000917:Antibody Formation; D003619:Dansyl Compounds; D005260:Female; D006207:Half-Life; D006241:Haptens / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology* / Q000633:toxicity; D007376:Interleukin-2 / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D012685:Sepharose; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000276:immunology; D014018:Tissue Distribution
D000276:Adjuvants, Immunologic; D003619:Dansyl Compounds; D006241:Haptens; D007074:Immunoglobulin G; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D012710:Serum Albumin, Bovine; D012685:Sepharose; C029038:dansyl chloride