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Engineering a therapeutic IgG molecule to address cysteinylation, aggregation and enhance thermal stability and expression

2013; Landes Bioscience; Volume: 5; Issue: 2 Linguagem: Inglês

10.4161/mabs.23392

1942-0870

Andrew Buchanan, Veronica Clementel, Rob Woods, Nicholas Harn, Michael A. Bowen, Wenjun Mo, Bojana Popovic, Steven M. Bishop, William F. Dall’Acqua, Ralph Minter, Lutz Jermutus, Vahe Bedian,

Protein purification and stability

Antibodies can undergo a variety of covalent and non-covalent degradation reactions that have adverse effects on efficacy, safety, manufacture and storage. We had identified an antibody to Angiopoietin 2 (Ang2 mAb) that neutralizes Ang2 binding to its receptor in vitro and inhibits tumor growth in vivo. Despite favorable pharmacological activity, the Ang2 mAb preparations were heterogeneous, aggregated rapidly and were poorly expressed. Here, we report the engineering of the antibody variable and constant domains to generate an antibody with reduced propensity to aggregate, enhanced homogeneity, 11°C elevated Tm, 26-fold improved level of expression and retained activity. The engineered molecule, MEDI-3617, is now compatible with the large scale material supply required for clinical trials and is currently being evaluated in Phase 1 in cancer patients. This is the first report to describe the stability engineering of a therapeutic antibody addressing non canonical cysteine residues and the design strategy reported here is generally applicable to other therapeutic antibodies and proteins.