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Human Anti-IgG1 Hinge Autoantibodies Reconstitute the Effector Functions of Proteolytically Inactivated IgGs¹

Discovery Research, Centocor R&D Inc., Radnor, PA 19087

A number of proteases of potential importance to human physiology possess the ability to selectively degrade and inactivate Igs. Proteolytic cleavage within and near the hinge domain of human IgG1 yielded products including Fab and F(ab')₂ possessing full Ag binding capability but absent several functions needed for immune destruction of cellular pathogens. In parallel experiments, we showed that the same proteolytically generated Fabs and F(ab')₂s become self-Ags that were widely recognized by autoantibodies in the human population. Binding analyses using various Fab and F(ab')₂, as well as single-chain peptide analogues, indicated that the autoantibodies targeted the newly exposed sequences where proteases cleave the hinge. The point of cleavage may be less of a determinant for autoantibody binding than the exposure of an otherwise cryptic stretch of hinge sequence. It was noted that the autoantibodies possessed an unusually high proportion of the IgG3 isotype in contrast to Abs induced against foreign immunogens in the same human subjects. In light of the recognized potency of IgG3 effector mechanisms, we adopted a functional approach to determine whether human anti-hinge (HAH) autoantibodies could reconstitute the (missing) Fc region effector functions to Fab and F(ab')₂. Indeed, in in vitro cellular assays, purified HAH autoantibodies restored effector functions to F(ab')₂ in both Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays. The results indicate that HAH autoantibodies selectively bind to proteolytically cleaved IgGs and can thereby provide a surrogate Fc domain to reconstitute cell lytic functions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a post-doctoral fellowship grant from Johnson & Johnson Corporate Office of Science and Technology (to R.J.B.).

² Address correspondence and reprint requests to Centocor R&D Inc., 145 King of Prussia Road, Radnor, PA 19087. E-mail address: rbrezski{at}cntus.jnj.com

³ Abbreviations used in this paper: MMP, matrix metalloproteinase; IdeS, IgG-degrading enzyme of Streptococcus pyogenes; HNE, human neutrophil elastase; ADCC, Ab-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; HAH, human anti-hinge.

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