Compositions monovalent for CD40L binding and methods of use

Abstract

The invention relates to antibody polypeptides that monovalently bind CD40L. Antibody polypeptides that are monovalent for binding of CD40L can inhibit CD40L activity while avoiding potential undesirable effects that can occur with antibodies capable of divalent or multivalent binding of CD40L. In one aspect, a monovalent anti-CD40L antibody polypeptide consists of or comprises a single immunoglobulin variable domain that specifically binds and antagonizes the activity of CD40L, preferably without substantially agonizing CD40 activity. In another aspect, the monovalent anti-CD40L antibody polypeptide is a human antibody polypeptide. The invention further encompasses methods of antagonizing CD40 / CD40L interactions in an individual and methods of treating diseases or disorders involving CD40 / CD40L interactions, the methods involving administering a monovalent anti-CD40L antibody polypeptide to the individual.

Description

Background of the invention

[0001] CD40 is a 50kD cell surface glycoprotein molecule that is present on the surface of mature and immature B cells, macrophages, follicular dendritic cells, thymic epithelial cells, normal basal epithelial cells, and some tumor-derived cell lines on the expression. The CD40 molecule is a member of the TNF receptor family and has important signaling functions that elicit various downstream effects in many cell types. Early studies have shown that cross-linking of CD40 on the surface of B cells with antibodies leads to proliferation and activation of B cells. Antibodies crosslinked to CD40 in the presence of IL-4 induce in vitro proliferation and class switching, B cell recruitment by LFA-1 (Gordon et al., 1988, J. Immunol. 140:1425), and serine of many intracellular substances / threonine and tyrosine phosphorylation (Gordon et al., 1988, supra; Uckun et al., 1991, J. Biol. Chem. 266:17478). Anti-CD40 monoclonal antibodies also elicit B cell re...

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