Targeting weak antigens to CD64 elicits potent humoral responses in human CD64 transgenic mice.
Previous studies have documented that targeting foreign Ags to IgG FcgammaR leads to enhanced Ag-specific responses in vitro and in vivo. However, the ability to overcome immunologic nonresponsiveness by targeting poorly immunogenic Ags to FcgammaR has not been investigated. To address this question in a simple model, we immunized transgenic mice expressing human CD64 (FcgammaRI) and their nontransgenic littermates with Fab' derived from the murine anti-human CD64 mAb m22. The m22 Fab' served as both the targeting molecule and the Ag. We found that only CD64-expressing mice developed anti-Id titers to m22. Furthermore, chemically linked multimers of m22 Fab', which mediated efficient internalization of the human CD64, were significantly more potent than monomeric m22 F(ab')(2) at inducing anti-Id responses. In all cases, the humoral responses were specific for m22 Id and did not react with other murine IgG1 Fab' fragments. Chemical addition of a second murine Fab' (520C9 anti-human HER2/neu) to m22 Fab' multimers demonstrated that IgG1 and IgG2a anti-Id titers could be generated to 520C9 only in the CD64-expressing mice. These results show that targeting to CD64 can overcome immunological nonresponsiveness to a weak immunogen. Therefore, targeting to CD64 may be an effective method to enhance the activity of nonimmunogenic tumor vaccines.
Keler
T
T
Medarex, Inc., Annandale, NJ 08801, USA. tkeler@injersey.com
Guyre
P M
PM
Vitale
L A
LA
Sundarapandiyan
K
K
van De Winkel
J G
JG
Deo
Y M
YM
Graziano
R F
RF
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D000918:Antibody Specificity / Q000235:genetics; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000276:immunology*; D018448:Models, Immunological; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000941:Antigens; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG