FUTURE DEVELOPMENTS

Over the years, the technological focus of antibody engineering has shifted as new and better strategies were adopted throughout the antibody R&D community. Originally, mAbs were murine, constructed through a slow, laborious process of immunizing mice and fusing lymphocytes with myeloma cell lines. Thousands of such events were screened by hand, and the best representatives were cloned and recloned in order to develop the most specific antibodies. These antibodies were chimerized or humanized in order to build pharmacologically effective products. But today, newer approaches, such as phage display libraries and transgenic mice, have proven much more successful in generating fully human antibodies, and there is every indication that continuing advances in these protocols will make the process even more user-friendly (5).

Screening of large numbers of potential antibody producing clones is now performed with robotics technology. Antibody Solutions and Guava Technologies (acquired by Millipore) are among numerous companies that have developed automated work stations to identify unique antibody-producing clones. Using flow cytometry and the Guava EasyCyte cell analysis platform, the system can screen 10–20 96-well plates in a 24-hour period. Positive clones can be simultaneously tested for specificity using the ELISA method. Such automatic, robotic approaches have revolutionized labor-intensive antibody isolation protocols.

Perhaps the most striking change in antibody strategy is the rise of ADCs. Effective ADCs could profoundly affect the demand for large quantities of antibodies, since they are effective at a fraction of the dose required by naked antibodies. While Adcetris has been approved and T-DM1 is expected to enter the market in 2013, both Seattle Genetics and Immunogen have several more ADCs in their clinical pipeline. Currently, around 100 ADCs are in active development, including 39 in clinical trials.

The pace of research pertaining to the identification of bispecific, bitargeted, and multifunctional antibodies and their clinical development should allow the introduction of more functionally versatile antibodies. This level of progress will provide better treatment possibilities for diseases beyond cancer and inflammation, such as those of the central nervous system and nosocomial infections. While the development of immunomodulatory antibodies, such as Yervoy has been one of the most significant advances in cancer therapy in the past decade, new and alternative approaches to creating immunomodulatory antibodies for the treatment of cancer and nonmalignant diseases, including rheumatoid arthritis and multiple sclerosis, will continue to be vigorously pursued.

The antibody R&D community is also tussling with a variety of challenges, the most pressing of which may be the concept of the rise of biosimilars and their potential market impact. One way to move beyond this issue is to develop, in some instances, polyethylene glycol-conjugated (PEGylated) antibodies, which may allow for extension of patent protection. There is a substantial literature establishing their extended halflife while at the same time retaining their potency and binding ability (6). UCB Group's Cimzia is a PEGylated anti-TNFα antibody that was approved in 2008 for the treatment of Crohn's disease and rheumatoid arthritis. The PEGylation method involves expressing antibody fragments in a bacterial system such as Escherichia coli, and then site-specifically PEGylating the fragment in a manner that avoids the loss of antigen-binding activity.

It should be noted that Amunix has developed an alternative technology to PEGylation, called XTENylation that utilizes a long, hydrophilic, and unstructured amino acid polymer (XTEN). When attached to molecules of interest, it greatly increases their effective size, thereby prolonging their presence in serum by slowing kidney clearance in a manner analogous to that of PEG. Because it can be recombinantly engineered into the organism producing an antibody of interest, thereby resulting exceptionally long half-lives and often monthly dosing of the therapeutic molecule, it offers an alternative to PEG.

Other systems that bear potential promise for generating high-potency products include ultrapotent antibodies produced through affinity maturation and replacement of crucial amino acids, bispecific antibodies and antibody fragments, glycoengineered antibodies, and innovative engineering of the Fc portion of the molecule, allowing expanded modifications and novel functions.

While it is always challenging to offer forecasts concerning the future, based upon the late-stage clinical trials of a large number of antibody therapeutic candidates as well as the recent deal-making activities involving newer antibodies, the authors believe that both the near- and long-term outlook for the antibody industry is quite positive. Consequently, the authors foresee the major contribution of antibody therapeutics to pharma revenues should continue.

K. John Morrow, Jr., PhD, is president of Newport Biotechnology Consultants, Newport, KY, and a member of BioPharm International's editorial advisory board, kjohnmorrowjr@insightbb.com
, and Rathin C. Das, PhD, is chief executive officer of Synergys Biotherapeutics, Walnut Creek, CA, rathindas2009@gmail.com
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4. J. Baselga et al., N. Engl. J. Med. 366 (2), 109–119 (2012).

5. M. A. and G. Gellerman, J Hematol. Oncol. 5, 70–86 (2012).

6. Ducreux et al., Bioconj. Chem. 20 (2), 295–303 (2009).