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      Engineering of a bispecific affibody molecule towards HER2 and HER3 by addition of an albumin-binding domain allows for affinity purification and in vivo half-life extension.

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          Abstract

          Emerging strategies in cancer biotherapy include the generation and application of bispecific antibodies, targeting two tumor-associated antigens for improved tumor selectivity and potency. Here, an alternative format for bispecific molecules was designed and investigated, in which two Affibody molecules were linked by an albumin-binding domain (ABD). Affibody molecules are small (6 kDa) affinity proteins and this new format allows for engineering of molecules with similar function as full-length bispecific antibodies, but in a dramatically smaller size (around eight-fold smaller). The ABD was intended to function both as a tag for affinity purification as well as for in vivo half-life extension in future preclinical and clinical investigations. Affinity-purified bispecific Affibody molecules, targeting HER2 and HER3, showed simultaneous binding to the three target proteins (HER2, HER3, and albumin) when investigated in biosensor assays. Moreover, simultaneous interactions with the receptors and albumin were demonstrated using flow cytometry on cancer cells. The bispecific Affibody molecules were also able to block ligand-induced phosphorylation of the HER receptors, indicating an anti-proliferative effect. We believe that this compact and flexible format has great potential for developing new potent bispecific affinity proteins in the future, as it combines the benefits of a small size (e.g. improved tissue penetration and reduced cost of goods) with a long circulatory half-life.

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          Author and article information

          Journal
          Biotechnol J
          Biotechnology journal
          1860-7314
          1860-6768
          Sep 2014
          : 9
          : 9
          Affiliations
          [1 ] Division of Protein Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
          Article
          10.1002/biot.201400009
          24678002
          0965283d-7ca6-4d84-8f92-5e317dcd2501
          Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

          Affibody molecules,Albumin-binding domain,Bispecific,HER3,Half-life extension

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