Glucagon‐like peptide‐2 (GLP‐2) is a member of the glucagon multigene family that is produced by intestinal enteroendocrine cells in response to food intake. GLP‐2 stimulates growth of the intestinal epithelium, enhances its barrier functions, and increases nutrient uptake. Therefore, a GLP‐2 agonist may be efficacious in human diseases characterized by malabsorption or injury to the gastrointestinal epithelium. MIMETIBODY™ refers to a proprietary scaffold developed to extend the half‐life of rapidly cleared peptides. It consists of a peptide linked to a scaffold that contains sequence elements from a human immunoglobulin G including those that allow recycling through the FcRn. The GLP‐2 sequence was engineered into the MIMETIBODY™ scaffold. The primary state of both GLP‐2 and the GLP‐2 MIMETIBODY™ in DPBS was a noncovalently associated dimer indicative of self‐interaction. The increased heterogeneity and the decreased lot‐to‐lot reproducibility caused by the self‐interaction of therapeutic proteins are a challenge to drug development. A similar protein, GLP‐1 MIMETIBODY™, contains the related GLP‐1 peptide and does not form a dimer under similar conditions. Therefore, to minimize or abrogate dimerization, several variants were made by substituting GLP‐2 amino acids with the corresponding amino acids from GLP‐1. Molecular weight and secondary structure analyses reveal that substituting leucine for glutamine at position 17 (L17Q) reduces dimerization and α‐helix content yet retains bioactivity. Copyright © 2012 John Wiley & Sons, Ltd.