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Recycling Reagents to Improve Antibody Therapy

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Science Translational Medicine  24 Nov 2010:
Vol. 2, Issue 59, pp. 59ec184
DOI: 10.1126/scitranslmed.3001944

It might not be absolutely true that all we really need to know we learned in kindergarten. But sometimes the application of simple tenets to sophisticated pursuits yields fruit. Recent generations of children have been taught to recycle in order to save the planet by reducing unnecessary waste. Now, Igawa et al. set out to use recycling to save therapeutic antibodies from unnecessary degradation.

One way that antibodies serve as therapeutic agents is by binding to disease-promoting cellular receptors or ligands and blocking harmful physiological processes. An example of this phenomenon is the antibody drug tocilizumab (TCZ), which binds to the plasma-soluble or cell-surface interleukin-6 receptor (IL-6R) and is used to treat rheumatoid arthritis. After binding, the TCZ–IL-6R complex is internalized, transported to a lysosome, and destroyed by the cell, leading to a reduction in inflammation and arthritis symptoms. However, in this degradation process the antibody itself is also destroyed, reducing the prolonged effectiveness of the drug and causing the patient to require either high doses or frequent injections to achieve a long-term therapeutic effect. Taking the lead of environmentalists, Igawa et al. sought to develop a way to recycle the antibody so that it could be reused, improving the effectiveness of the drug.

To this end, the authors modified the amino acid composition of TCZ to endow it with pH-dependent receptor-binding properties. With this modification, the antibody bound tenaciously to the IL-6R in the extracellular environment, but then dissociated from the receptor in the acidic environment of the liposome and returned to the extracellular milieu for reuse. As shown in a preclinical monkey model, modifying TCZ in this fashion resulted in ~75% of the drug being recycled and reused. Further, a typical dose of 2 mg/kg TCZ effectively neutralized IL-6R for 4 weeks, up from 1 week for the unmodified version. It is likely that this approach can be recycled for use with other currently approved antibody therapeutics so as to reduce their dose or frequency of administration—a change that could reduce costs and side effects for patients who receive these medications.

T. Igawa et al., Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat. Biotechnol. 28, 1203–1207 (2010). [Abstract]

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