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 sever al diseases, including B cell neoplasia, osteoporosis, and autoimmunity. Th erapeutic attempts in humans have shown that administration of injectable d oses of a mAb to IL-6 does not provide efficient neutralization of the cyto kine in vivo. Therefore, alternative approaches are needed. In this study, we evaluated whether the Ab response to human IL-6 (hIL-6) elicited by vacc ination with Sant1 (a hIL-6 variant with seven amino acid substitutions) wa s able to fully correct in vivo the clinical and biological effects of a ch ronic 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 c irculating 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 impair ment associated with human chronic inflammatory diseases. Following immuniz ation 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, e ffectively neutralized IL-6 activities in vivo as shown by the complete cor rection of the growth defect and normalization of insulin-like growth facto r levels in the hIL-6-transgenic offspring. Immunization with Sant1 could t herefore represent a novel and simple therapeutic approach for the specific neutralization of IL-6 in humans.