Antibodies are large, complex proteins used by the immune system to recognize and neutralize foreign invaders ranging from bacteria to viruses. The high binding affinity, exquisite binding specificity and low immunogenicity of human antibodies makes them attractive therapeutic agents for treating diverse disorders ranging from Parkinson’s disease to cancer. Nevertheless, there are several key unmet challenges in identifying, engineering, producing and formulating antibodies that are the focus of our research program.
The binding specificity and affinity of antibodies is governed by the sequence and conformation of their solvent-exposed peptide loops known as the complementarity-determining regions (CDRs). It has not been possible to design CDR loops in a rational manner to mediate specific and high affinity antibody binding. We have discovered that the loops of small antibodies can be designed to recognize aggregated proteins linked to Alzheimer’s and related diseases by mimicking the process of protein aggregation (see Section I of our research page for more detail).
Antibodies have attracted much interest for preventing toxic protein aggregation linked to disorders ranging from Parkinson’s disease to infectious prion diseases. Nevertheless, antibodies are generally poor (low potency) inhibitors of protein aggregation because near-stoichiometric antibody concentrations are required to arrest aggregation. We are developing methods of designing antibodies that potently inhibit amyloid formation linked to multiple human disorders (Alzheimer’s disease, Parkinson’s disease and type 2 diabetes; see Section II of our research page for more detail).
Antibodies commonly use hydrophobic residues in their CDRs to mediate high affinity binding, yet these solvent-exposed hydrophobic residues can also lead to poor antibody solubility. We have developed a novel mutational approach for engineering CDR loops that dramatically increases antibody solubility without reducing binding affinity (see Section III of research page for more detail). We have also sought to eliminate the need to re-engineer antibodies by improving the selection of highly soluble antibodies (early in antibody discovery) and formulation conditions (early in antibody development) that maximize antibody solubility. We have developed a novel high-throughput screening method (self-interaction nanoparticle spectroscopy, SINS) for identifying antibody mutants and/or solution conditions that minimize the propensity of antibodies to associate and aggregate (see Section IV of our research page for more detail).
