(694f) Engineering Aggregation-Resistant Antibodies

A common challenge in the development and formulation of therapeutic antibodies is antibody self-association and oligomerization (i.e., formation of structures ranging from reversible dimers to irreversible aggregates). Importantly, different antibodies exhibit unique self-association behavior despite their high sequence similarity in their constant regions. We posit that hypervariable loops in variable domains of antibodies play a critical, yet poorly understood, role in regulating antibody self-association. To test this hypothesis, we have generated a library of homologous, single domain antibody variants that differ only in the sequence of their hypervariable loops. In this presentation we will discuss our findings that these antibody variants, which possess large variations in loop sequences, exhibit similar folding stabilities. Moreover, we will discuss how such sequence variation influences antibody self-association and solubility. We expect that insights gained in this work will improve the design and selection of aggregation-resistant antibodies.