Abstract
Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.
Highlights
Monoclonal antibodies are central components in the diagnosis, imaging and treatment of cancers and autoimmune diseases, among other diseases (Weiner et al, 2012; Baker & Isaacs, 2017)
Our recent discovery of meditope, a cyclic peptide that binds to a Fab cavity of cetuximab, can serve as an alternative, noncovalent method to modify antibodies, with a precise ratio of two meditopes to one IgG
We wondered whether it was possible to reach through the other side of the Fab hole by extending the side chain of Arg8, increasing the surface area to improve the affinity of the meditope–Fab interaction
Summary
Monoclonal antibodies (mAbs) are central components in the diagnosis, imaging and treatment of cancers and autoimmune diseases, among other diseases (Weiner et al, 2012; Baker & Isaacs, 2017). ‘Naked’ mAbs inhibit ligand binding of the target receptor and block cell signaling, lead to down-regulation of receptors on the cell surface, recruit other components of the immune system through antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), or a combination of all three (Bakema & van Egmond, 2014; Stasiłojcet al., 2016) Their specificity has led to the development of antibody–drug conjugates, where they act as targeting moieties to deliver cytotoxic cargo to the site of the disease. Our recent discovery of meditope, a cyclic peptide that binds to a Fab cavity of cetuximab, can serve as an alternative, noncovalent method to modify antibodies, with a precise ratio of two meditopes to one IgG To use this interaction for delivery, we have focused on enhancing the lifetime of the interaction. We investigate the possibility of increasing the affinity of this interaction by reaching through to the other side of the Fab hole (Fig. 1)
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