In vivo neutralization of human IL-6 (hIL-6) achieved by immunization of hIL-6-transgenic mice with a hIL-6 receptor antagonist.
Neutralization of IL-6 represents an attractive therapeutic option in several diseases, including B cell neoplasia, osteoporosis, and autoimmunity. Therapeutic attempts in humans have shown that administration of injectable doses of a mAb to IL-6 does not provide efficient neutralization of the cytokine in vivo. Therefore, alternative approaches are needed. In this study, we evaluated whether the Ab response to human IL-6 (hIL-6) elicited by vaccination with Sant1 (a hIL-6 variant with seven amino acid substitutions) was able to fully correct in vivo the clinical and biological effects of a chronic endogenous overproduction of hIL-6 in the hIL-6-transgenic NSE/hIL-6 mice. Because of the overexpression of hIL-6, occurring since birth, with circulating levels in the nanogram per milliliter range, NSE/hIL-6 mice have a marked decrease in growth rate, associated with decrease in insulin-like growth factor I levels, and represent an animal model of the growth impairment associated with human chronic inflammatory diseases. Following immunization with Sant1, but not with hIL-6, NSE/hIL-6 mice developed high titers of polyclonal Abs to hIL-6. The Abs, acquired by transplacental transfer, effectively neutralized IL-6 activities in vivo as shown by the complete correction of the growth defect and normalization of insulin-like growth factor levels in the hIL-6-transgenic offspring. Immunization with Sant1 could therefore represent a novel and simple therapeutic approach for the specific neutralization of IL-6 in humans.
De Benedetti
F
F
Dipartimento di Scienze Pediatriche, Instituto di Ricerca e Cura a Carattere Scientifico Policlinico San Matteo, Universita' degli Studi di Pavia, Pavia, Italy.
Pignatti
P
P
Vivarelli
M
M
Meazza
C
C
Ciliberto
G
G
Savino
R
R
Martini
A
A
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D000917:Antibody Formation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D006130:Growth Disorders / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007112:Immunity, Maternally-Acquired; D007117:Immunization, Secondary; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000276:immunology*; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D014611:Vaccination / Q000379:methods*
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D010751:Phosphopyruvate Hydratase