Review
The Current Status and Prospects of Antibody Engineering for Therapeutic Use: Focus on Glycoengineering Technology

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ABSTRACT:

Monoclonal antibodies have demonstrated enormous potential as new classes of drugs that confer great benefits to patients, and more than 40 therapeutic antibodies have already been approved for clinical use. In particular, the past 5 years might be recognized as the period guiding the new era for “engineered antibodies,” with the successful approval of numerous antibody–drug conjugates, bispecific antibodies, and glyco-engineered antibodies for clinical applications. In this review, we summarize the development of antibody engineering technologies that are proving their concepts in the clinic, mainly focusing on the latest trends in defucosylated antibody technologies.

Section snippets

CURRENT STATUS AND ISSUES ASSOCIATED WITH THERAPEUTIC ANTIBODIES

Since the late 1990s, monoclonal antibodies have demonstrated enormous potential as new classes of drugs that confer great benefits to patients, and more than 40 therapeutic antibodies have been approved for clinical use (Table 1). Therapeutic antibodies have led to improvements in the overall survival, as well as the time to disease progression, in a variety of human malignancies, such as breast, colon and hematological cancers.1., 2., 3., 4. Compared with conventional small molecule drugs,

THE BASIC STRUCTURE AND FUNCTIONS OF THERAPEUTIC ANTIBODIES

Among the five classes [IgG (immunoglobulin G), IgA, IgM, IgE, and IgD] and multiple subclasses (two for IgA and four for IgG) of immunoglobulins in humans, the human IgG1 isotype is primarily employed as a therapeutic antibody. IgG1 has a long half-life in blood (~ 2 weeks) and stronger effector functions compared with those of other classes and subclasses. The basic structure of human IgG1 is a heterotetramer of approximately 150 kDa, consisting of two immunoglobulin heavy chains and two light

CLINICAL MECHANISMS OF THERAPEUTIC ANTIBODIES

Therapeutic antibodies are classified into different types according to their mode of action. The first group functions as neutralizing agents against specific pathogens or target molecules causing diseases. The leading examples include several of the marketed anti-TNF-α antibodies and an antivascular endothelial growth factor A (VEGF-A) antibody, bevacizumab (Avastin®). TNF-α is closely related to the pathologies of rheumatoid arthritis and inflammatory bowel diseases, such as ulcerative

Principle Features and the Manufacture of the Defucosylated Antibodies: ADCC Enhancement by Removal of the Fucose from Fc Oligosaccharides

As discussed above, ADCC has been proven to be an important mode of action of therapeutic antibodies within the last decade, and this notion has greatly motivated many biotech and pharmaceutical companies to develop engineered antibodies with enhanced FcγRIIIa binding capacity.

The majority of IgG antibody oligosaccharides are known to have fucosylated glycoforms in human serum.42., 43. Two groups, including the authors’ group, reported that the removal of α̛1,6 fucose from oligosaccharides

LANDSCAPE FOR ENGINEERED ANTIBODIES AND THEIR CLINICAL DEVELOPMENT

Many attempts to improve the clinical efficacy are ongoing, including the development of ADCs, bsAbs, Fc amino acid mutations that improve various effector functions or pharmacokinetics, and antibody glycoengineering. Among these approaches, bsAb, ADC, and glycoengineering approaches have recently succeeded, with different therapeutic agents obtaining approval for marketing in the past 5 years. In 2009, catumaxomab (Removab®), an anti-CD3/EpCAM bsAb, was approved as the first therapeutic bsAb in

FUTURE DIRECTIONS

The past 5 years might be recognized as the period guiding the new era for “engineered antibodies,” as exemplified by the approval of the first bsAb, catumaxomab, in 2009, followed by two ADCs (brentuximab vedotin in 2010 and trastuzumab emtansine in 2012) and two glycoengineered antibodies (mogamulizumab and obinutuzumab).

One of the major issues that must be overcome for these new antibody therapeutics might be the establishment of methodologies for selecting the most suitable disease and

ACKNOWLEDGMENT

The authors are employees of Kyowa Hakko Kirin Co., Ltd.

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