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EDITOR'S LETTER
 

The seven among the top ten selling drugs in 2013 and 2014 worldwide are bio-therapeutics represented by antibody drugs. This continues to be expected due to their prominent clinical effects. They can block protein-protein interaction efficiently and specifically, which is generally hard to achieve with conventional small molecule drugs.

Smaller antibody formats are gaining more and more interest because of their higher tissue penetration, lower cost, and higher ability to sweep antigen (higher mol/mg ratio). However, there are various obstacles in the course of antibody drug discovery [1]. The topic of this month covers the basic technologies developed by academia in Japan. They are expected to eliminate the obstacles of current antibody drug discovery, and to promote related research area.

A fundamental problem is the difficulty in obtaining lead antibodies against membrane proteins. Hamakubo et al. have developed a method to display membrane proteins on a viral envelope for antigen immunization. Another problem is the difficulty in lead antibody optimization. Lead antibodies should be optimized in multiple aspects including higher affinity, better biological activity, longer PK, better stability, lower aggregation, higher expression, lower viscosity, etc. Although in silico optimization methods including our work [2] have been reported, more powerful algorithms are necessary. Tsuchiya and Mizuguchi have carried out informatics research on known antibody structures. They found some rules of antibody-antigen interactions. Those rules would be good hints for optimization.

Higher concentration antibody solutions are necessary for the switch from intravenous to self-injecting subcutaneous administration. Krayukhina and Uchiyama overviewed antibody solution viscosity and intermolecular interactions. They also highlighted the importance of taking the packaging material into consideration. Smaller antibody formats are expected to penetrate well to reach antigens that are normally hard to be reached by normal antibody in patients. A typical small antibody format is single chain variable fragment (scFv). It is a single polypeptide composed of heavy chain and light chain in variable domain connected by a linker. However, this modality is usually unstable. To combat this, Hoshino et al. developed a method to enhance stability of a scFv with amino acid substitutions by using a super-computer. VHH antibody is another example of small antibody. It is the variable domain of camelid heavy-chain antibody. Akazawa-Ogawa and Hagihara could enhance the thermal stability on VHH antibodies. Ito’s group used VHH and carried out high-throughput sequencing on next generation sequencer to identify specific VHH binders from the phage library.

References:

  1. Shirai H, Prades C, Vita R, et al. Antibody informatics for drug discovery. Biochim Biophys Acta 2014; 1844:2002-2015.
  2. Kiyoshi M, Caaveiro JM, Miura E, et al. Affinity improvement of a therapeutic antibody by structure-based computational design: generation of electrostatic interactions in the transition state stabilizes the antibody-antigen complex. PloS One 2014; 9:e87099
Hiroki Shirai, PhD, executive fellow, Bioscience Research Laboratories, Astellas Pharma Inc.
Guest Editor for APBN August issue 2016

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