Abstract
Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes’ cofactors, such as heme. Here, by using a set of 113 samples with variable region sequences matching clinical-stage antibodies, we demonstrated that a considerable number of these antibodies interact with heme. Antibodies that interact with heme possess specific sequence traits of their antigen-binding regions. Moreover they manifest particular physicochemical and functional qualities i.e. increased hydrophobicity, higher propensity of self-binding, higher intrinsic polyreactivity and reduced expression yields. Thus, interaction with heme is a strong predictor of different molecular and functional qualities of antibodies. Notably, these qualities are of high importance for therapeutic antibodies, as their presence was associated with failure of drug candidates to reach clinic. Our study reveled an important facet of information about relationship sequence-function in antibodies. It also offers a convenient tool for detection of liabilities of therapeutic antibodies.
Highlights
Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes’ cofactors, such as heme
Our results obtained with 113 samples with V region sequences corresponding to the clinical-stage therapeutic monoclonal Abs expressed on the human IgG1 framework, revealed that interaction with heme correlated with specific sequence characteristics of the antigen-binding site
We demonstrated that a considerable fraction of monoclonal therapeutic Abs recognizes heme
Summary
Immunoglobulin repertoires contain a fraction of antibodies that recognize low molecular weight compounds, including some enzymes’ cofactors, such as heme. Human Abs recognize a xenogenic disaccharide molecule, i.e., galactosyl-(1-3)-galactose (α-Gal)[15,16,17] These studies suggested that the binding of cofactors or other low molecular weight molecules occurs in the variable regions of Abs. Of note, the interaction of Abs with some cofactors results in a dramatic effect on their functions. Our results obtained with 113 samples with V region sequences corresponding to the clinical-stage therapeutic monoclonal Abs expressed on the human IgG1 framework, revealed that interaction with heme correlated with specific sequence characteristics of the antigen-binding site.
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