SMART-Ig® (Recycling antibody®)

The Recycling Antibody® is engineered so that a single antibody molecule can bind to an antigen multiple times. Binding to the neonatal Fc receptor (FcRn) after being taken up by vascular endothelial cells or other cells contributes to a long half-life for an antibody in plasma compared with other proteins by recycling the antibody back to plasma. However, when a conventional antibody binds to a membrane-bound antigen such as a cytokine receptor, the antibody-antigen complex is transferred to lysosome and degraded by protease. In the case of a soluble antigen such as a cytokine ligand, the antigen bound to the antibody is recycled back to plasma by FcRn as an antibody-antigen complex. Since antigens would be degraded by lysosome in the absence of the antibody, the antibody would accumulate the antigens in plasma, requiring administration of a large amount of antibodies for long-term blockade of the antigen function.

Conversely, the Recycling Antibody® has been engineered to dissociate from an antigen in acidic conditions within the cell. Since the antibody bound to a membrane-bound antigen dissociates from the antigen in a pH-dependent manner, a dissociated antibody would be recycled by FcRn while the antigen is transferred to lysosome and degraded, enabling the antibody to bind to other antigens repeatedly in plasma and reducing the antibody clearance.

Effect of Recycling Antibody® on Membrane-Bound Antigen

This antibody technology arose from an idea to prolong the duration of efficacy of tocilizumab. The engineering of tocilizumab led to the generation of SA237 (currently in phase III multinational clinical study). In preclinical studies, SA237 exhibited plasma persistence four times that of tocilizumab, and a phase I clinical trial has demonstrated significant improvement in the effective duration. SA237 is being developed as a subcutaneous formulation for the treatment of neuromyelitis optica with the potential to achieve the convenience of a dosing interval of longer than once a month.

Comparison of Plasma Persistence of SA237 and Tocilizumab
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