High-affinity antibodies are critical for numerous detection and therapeutic applications, yet their utility is limited by their propensity to aggregate. Therefore, determining the sequence and structural features that differentiate aggregation-resistant antibodies from aggregation-prone ones is critical to improving their activity. Our hypothesis is that the complementarity determining regions (CDRs) � which commonly contain solvent-exposed hydrophobic residues to mediate high binding affinity � contribute disproportionately to the aggregation propensity of antibodies. Consistent with this hypothesis, we find that the aggregation behavior of several human VH domain antibodies is governed primarily by their CDRs, and this poor solubility can often be localized to a single CDR loop. Moreover, we find that charged mutations within or near hydrophobic CDRs greatly increases antibody solubility. We will present multiple examples of how antibodies can be engineered in a systematic manner to resist aggregation without altering their binding affinity.

Engineering aggregation-resistant, high-affinity antibodies

243rd National Meeting (2012)

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