Protein aggregation is a significant challenge in developing safe and effective therapeutic antibodies. We are investigating how antibody fragments can be engineered to possess extremely high solubility without altering binding activity. Our studies have focused on poorly soluble antibody fragments with clusters of hydrophobic residues in their complementarity-determining regions (CDRs). We have developed a mutational approach for engineering the edges of hydrophobic CDRs with charged residues that dramatically increases antibody solubility without reducing binding affinity. Our studies reveal that the location of charged mutations within CDRs as well as the polarity of such mutations dramatically impact their solubilizing activity. We also find that similar charged mutations in the antibody scaffold and non-CDR loops are ineffective at preventing aggregation. Our current work is aimed at extending this mutational approach to poorly soluble multidomain antibody fragments and full-length antibodies.

Engineering aggregation-resistant antibody fragments

247th National Meeting (2014)

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