Sequential Monoclonal Antibody Recycling Technology – Immunoglobulin – SMART-Ig

A conventional antibody derived from known technology, regardless of how high its affinity to a target antigen is, has two limitations:
1) The antibody can only bind to the antigen once; and
2) The antibody once bound to the antigen, cannot eliminate it from plasma.

SMART-Ig, developed by Chugai, is an entirely new technology that overcomes these two limitations. It enables the targeting of previously untargetable antigens and achieves a product profile that previously could not be realized with a conventional antibody.


The Recycling Antibody® is engineered so that a single antibody molecule can bind to an antigen multiple times, in contrast to conventional antibodies, which can only bind antigen once. Once conventional antibodies bind to a membrane anchored antigen such as a cytokine receptor, the antibody-antigen complex is internalized and degraded within the lysosome. This results in a shorter plasma half-life of the therapeutic antibody, necessitating frequent administration of the antibody drug or at higher doses to sustain efficacious plasma antibody concentration. Chugai’s proprietary SMART-Ig Recycling Antibody technology overcomes this problem by engineering the antibody to dissociate from the antigen at acidic pH within the endosome. Once dissociated, the recycling antibody is free to bind to the FcRn (neonatal Fc Receptor) within the endosome, which transports the antibody back into circulation to bind to more antigen.


The Sweeping Antibody® is a recycling antibody that has been further engineered to bind to FcRn at neutral pH. When conventional antibodies against a soluble antigen are administered, a stable antigen-antibody complex is formed which often persists in plasma. This is because the soluble antigen remains tightly bound to the antibody after internalization, and the antigen-antibody complex is recycled into circulation by the neonatal FcRn receptor in the endosome. As the recycled antigen does not reach the lysosome for degradation, this leads to an accumulation of the antigen in antibody bound form in the plasma, and in some cases, the concentration of antigen-antibody complexes can accumulate more than 1000-fold. A large amount of antibody is therefore required to ensure complete blockade of highly accumulated antigen.

This problem can be overcome by Chugai’s proprietary SMART-Ig sweeping Antibody technology. This enhances the uptake of antibody-bound soluble antigen into cells, accelerating antigen degradation by ‘sweeping’ the antigen from plasma. With these characteristics, a sweeping antibody can be administered in smaller doses with a longer dosing interval and can eliminate antigens present in large amounts in plasma that cannot be antagonized by conventional antibodies. Furthermore, even if sweeping antibodies do not completely block an antigen’s activity, they can still be effective by directly eliminating antigens from plasma. Moreover, by modulating the binding affinity for FcRn, the rate of antigen clearance by the sweeping antibody can be tailored to meet the therapeutic requirements of disease treatment. These properties confer the SMART-Ig technology with tremendous potential in a wide range of applications.

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Bispecific antibody can bind to two different antigens with the two arms of antibody. Chugai has established bispecific antibody technology to enable large scale manufacturing which was previously highly difficult. Bispecific antibody can be applied to antagonize two different antigens by single antibody molecule. Chugai was the first company in the world that successfully delivered humanized bispecific antibody to the patients by regulatory approval. Chugai discovered bispecific IgG antibody recognizing FIXa and FX, which mimics the function of FVIII, for the treatment of haemophilia A, and reported in Nature Medicine in 20126). Moreover, Chugai discovered that bispecific IgG antibody against tumor specific antigen and T cell antigen such as CD3 can redirect T cell to the cancer cell to kill tumor, and reported in Science Translational Medicine in 20176). We apply this T cell redirecting bispecific antibody platform to cancer immunotherapy aiming to eradicate tumor from the patients. Bispecific antibody allows us to develop more unique antibody therapeutics that overcome various unmet medical need.