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Innovations in Monoclonal Antibody Development

Medical & Biological Laboratories Co., Ltd. (MBL) was established in 1969 as the first Japanese company to manufacture antibodies. Since then, MBL has been involved in the research, development, manufacture, and sales of a broad range of diagnostics and research reagents. MBL has been engaged not only in the worldwide sales of over 8,000 antibodies developed in-house or marketed by foreign and domestic alliance partners but also in the contract manufacturing of custom-made polyclonal and monoclonal antibodies. In addition, MBL has extended its business to sales of in vitro diagnostic reagents for autoimmune diseases, cancers, and aberrant metabolic disorders. In Japan, MBL is the leading manufacturer of products involved in the diagnosis of autoimmune diseases. The core technology of MBL includes monoclonal antibody (mAb) development. In order to further reinforce our core competence, we constantly work towards the advancement and challenge of antibody development technology by improving the quality of antibodies. Moreover, we actively adopt novel techniques that have originally been developed by Japanese immunologists. By focusing on innovative and unique technologies of antibody production, MBL's business opportunities will expand beyond the continuous improvement of the quality of our own products, towards the development of novel antibodies for diagnostics, therapeutic antibodies, and revenue generating of license agreements.

Mouse mAb Development

Artificial Lymph Node Technology

Artificial lymph nodeIn Nature Biotechnology in 2004, artificial lymph node technology was reported by Dr. Takeshi Watanabe, a unit leader (Present: Visiting Professor, Kyoto University Graduate School of Medicine), and colleagues at RIKEN1). MBL has been involved in technological development for producing high-performance antibodies based on this artificial lymph node technology. The “artificial lymph node technology,” as indicated by the name, was used to create artificial lymph nodes in the kidney of a mouse that naturally has no lymph nodes. The artificial lymph nodes have a distinct feature in that it consists of only target antigen-specific immune cells, while cells responsive to various antigens are present in normal lymph nodes. By transplanting an artificial lymph node constructed in a mouse immunized with antigen to a mouse with severe combined immunodeficiency disease (SCID), a mouse is produced with an immune system active only against the target antigen. When this mouse is stimulated with the antigen, antibody titer in blood of the mouse is 10 to 100 times higher than that in normal mice1).

When this technology was applied to monoclonal antibody production, the number of target monoclonal antibodies obtained per mouse became more than 10 times greater than that obtained by conventional methods. In addition, these monoclonal antibodies contained various ultra-high affinity clones. This means that diverse, high-quality monoclonal antibodies can be obtained at one time by using the artificial lymph node technology, as well as that this technology can possibly be used as an antibody production technology to create innovative monoclonal antibodies. Currently, we are engaging in improvements of the technology to produce more high-quality antibodies, while trying to develop new technologies for producing antibodies that are very difficult or impossible to obtain by the conventional methods.

1) Suematsu S and Watanabe T, Generation of synthetic lymphoid tissue-like organoid in mice. Nature Biotechnology. 22: 1539-1545, 2004 (PubMed: 15568019)

Immunogenicity-enhancing Antigen Technology

The IEA (Immunogenicity-Enhancing Antigen) is our innovation in which genetic engineering of the target proteins (antigens) used for immunization is employed to enhance immunogenicity in mice. We used such modified antigens to successfully produce a dramatic increase in the mAb titer and the establishment of mAbs for proteins, which is difficult to accomplish by conventional methods. When combined with artificial lymph node technology, synergistic effects facilitate the isolation of a variety of mAbs. This technology has many applications and is particularly useful for the establishment of high-quality antibodies for any proteins.

Human mAb Development

In recent years, chimeric, humanized, and fully human antibodies have been used as therapeutic antibodies. Of these, fully human antibodies are regarded as highly safe antibodies for therapeutic use because they are not antigenic in human. The efficient methods of preparation of fully human antibodies include: phage display of cloned human antibody genes, antibody generation by immunization of transgenic mice with human immunoglobulin genes, immortalization of human antibody-producing cells by Epstein-Barr virus, and fusion of human peripheral blood mononuclear cells with fusion partners. The MBL group is well equipped to develop fully human antibodies by using methods such as the fusion partner method and the phage display method.

Phage Display Technology

In human antibody production technologies using a phage display method, antibodies can be isolated in vitro. Using this method, substances that are difficult to produce in the living body, and toxic molecules and low molecular weight compounds that cannot be used as immunogens because of lethality can be used as antigens. MBL possesses several human immunized libraries and naïve libraries with the size of 1010 to 1011 for these antigens and develops fully human antibodies based on phage display technology. In addition, we have established a unique screening method, “ICOS,”1) which can discriminate antibodies responsive to molecules on the surface of cells. We have also identified more than 30 cancer-related molecules and have succeeded to isolate more than 600 clones of antibodies against these molecules. Furthermore, we have successfully isolated antibodies that neutralize infectious disease viruses, and anti-sugar chain antibodies, which have attracted attention of major pharmaceutical manufacturers.

1) Kubota-Koketsu, R. et al. Isolation of antigen/antibody complexes through organic solvent (ICOS) method. Biochem Biophys Res Commun. 387:180-5, 2009 (PubMed: 19580789)

mAb Development Using Rabbits and Chickens

Since antibodies developed in animals are based on the immune systems of those animals, antibody titers against the proteins of the immunized animals (i.e., "autoantigens") may not increase due to immunological tolerance. Since mice and humans are conventionally subjects of research, the need for antibodies against their proteins accounts for the majority of the antibody requirement in research. Mice are representative immunized animals in which mAb development technologies have been established. Consequently, it is difficult to obtain antibodies against proteins that are highly homologous to mouse counterparts. In other words, if laboratory animals that are phylogenetically distant from human and mouse are used, the problem of immune tolerance can be avoided and a broader range of antibodies can be obtained. To this end, we are developing techniques for the acquisition of rabbit and chicken mAbs. In particular, chickens are very useful to generate antibodies against target proteins in human, mouse, and by extension, all mammals in general. Since we have a chicken fusion partner, MBL is the only company that can develop chicken mAbs based on the hybridoma method. mAbs are currently used as therapeutic antibodies, diagnostic agents, and research reagents, and their roles in the post-genome era will further expand in the future. Meanwhile, "depletion of targets" is a frequently used phrase in the field of therapeutic mAb development, wherein certain researchers hold the extreme viewpoint that since mAbs have been developed actively worldwide, almost all possible antibodies that can be obtained using ordinary methods have already been obtained. However, the development of novel and original methods such as the ones stated above, which include antibody development technologies using artificial lymph nodes, have enabled the generation of high-quality antibodies with higher sensitivity than those obtained with conventional techniques, and antibodies with unique properties and functions that have not yet been reported elsewhere. We believe that the numerous proprietary technologies owned by MBL can help overcome this situation, contribute to healthcare and related research, and lead to further technological developments.