A partially humanized monoclonal antibody to human IFN-gamma inhibits cytokine effects both in vitro and in vivo.
The mouse monoclonal antibody (MoAb) IGMB17 (muIGMB17) is a high-affinity antibody- neutralizing human interferon (IFN)-gamma and, accordingly, is a potential therapeutic agent for patients suffering from various diseases in which the cytokine is abnormally expressed. The clinical usefulness of mouse antibodies is limited, however, owing to their immunogenicity in humans. MuIGMB17 antibody was partially humanized by engrafting a small portion of mouse light chain (LC) in a human framework and by engineering its heavy chain (HC) in a chimeric version. The engineered IGMB17 (huIGMB17) was able to replicate a range of functional properties of the original muIGMB17, namely, specific binding to IFN-gamma, inhibition of histocompatibility complex (HLA-DR) expression in response to IFN-gamma induction, reversion of IFN-gamma antiproliferative activity on sensitive cell lines. We have hypothesized that as huIGMB17 was able to block IFN-gamma binding to its receptor as well as its murine counterpart, huIGMB17 could neutralize all cytokine activity, also in vivo. Indeed huIGMB17 was capable of interfering with delayed-type hypersensitivity reaction in humans, thus demonstrating its effectiveness in neutralizing IFN-gamma-mediated reactions in vivo.
Fiorentini
S
S
University of Brescia Medical School, Spedali Civili, piazzale Spedali Civili, Brescia, Italy.
De Panfilis
G
G
Pasolini
G
G
Bonfanti
C
C
Caruso
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004274:DNA, Recombinant / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D014373:Tuberculin / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D004274:DNA, Recombinant; D011993:Recombinant Fusion Proteins; D014373:Tuberculin; D007371:Interferon-gamma