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*
Medarex, Inc., Annandale, NJ 08801;
Department of Physiology, Dartmouth Medical School, Lebanon, NH 08801; and
Department of Immunology and Medarex Europe, University Hospital Utrecht, Utrecht, The Netherlands
Previous studies have documented that targeting foreign Ags to IgG
Fc
R leads to enhanced Ag-specific responses in vitro and in vivo.
However, the ability to overcome immunologic nonresponsiveness by
targeting poorly immunogenic Ags to FcR has not been investigated.
To address this question in a simple model, we immunized transgenic
mice expressing human CD64 (FcRI) 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.
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