This technology allows us to produce large amounts of pure antibodies in the following way: We can obtain cells that produce antibodies naturally; we also have available a class of cells that can grow continually in cell culture. If we form a hybrid that combines the characteristic of "immortality" with the ability to produce the desired substance, we would have, in effect, a factory to produce antibodies that worked around the clock.
In monoclonal antibody technology, tumor cells that can replicate endlessly are fused with mammalian cells that produce an antibody. The result of this cell fusion is a "hybridoma," which will continually produce antibodies. These antibodies are called monoclonal because they come from only one single antibody-producing B-cell.
Because selected hybrid cells produce only one specific antibody, they are more pure than the antibodies produced by conventional techniques. They are potentially more effective than conventional drugs in fighting disease, since drugs attack not only the foreign substance but the body's own cells as well, sometimes producing undesirable side effects such as nausea and allergic reactions. Monoclonal antibodies attack the target molecule and only the target molecule, with no or greatly diminished side effects.
History
This year represents the twenty-fifth anniversary of the discovery of monoclonal antibodies by Kohler and Milstein, a discovery resulting in their being awarded the Nobel Prize. Following on within five years of this discovery was the founding of a number of biotechnology companies focused on the application of this technology to the treatment of human ailments. Some of these companies experienced success in getting products to the marketplace and providing investors with significant returns. Others however took longer to realize their potential. Much of this delay was due to technical hurdles to making these genetically engineered mutants into pharmaceutical products while other delays came from their own poor choices in medical applications.
The next ten years of the monoclonal antibody era saw a shakeout and re-focusing of companies utilizing monoclonal antibody technologies. Virtually no new companies were formed and Wall Street all but ignored antibody technology. Despite the difficulties in financing, scientific progress continued and existing companies began to reach clinical and product development milestones. Wall Street saw fit to award those companies close to product approvals while not investing in start-ups.
This attitude in Wall Street however has dramatically changed in the last five years culminating with some of the largest private placements in the history of the Street for developmental stage companies. Monoclonal antibodies are now considered the driving success of the biotechnology industry. Wall Street estimates that this represents the largest segment of the biotechnology industry with 260 companies, private and public, working on 700 therapeutic antibody products. Evidence of this "New Age" is the high valuations of companies at various stages of clinical development.
Companies nearing or with pending market approvals have market capitalizations comparable to large pharmaceutical companies. The primary reason for these high valuations is that monoclonal antibodies will lead all other segments of the biotechnology industry for product introduction with 18 products already approved and an additional 18 pending approval. Furthermore, sales for antibody products have risen dramatically setting records for market introduction and penetration.
Monoclonal Antibodies: Evolving into the Mainstream of Pharmaceutical Drug Development
The rebirth of the monoclonal antibody industry has occurred for several reasons. First and foremost has been the achievement of many clinical and now market successes. Much of the early disappointment could be ascribed to the lack of market acceptance and poor revenue performance of the first antibody products approved, namely radio-imaging agents. (See Figure-First generation) Many of the follow-on radiotherapy agents proved too difficult to manufacture and were abandoned. The current success of the industry is owed primarily to therapeutic indications of un-conjugated antibodies. With the advent of human or genetically engineered, "humanized" forms, much of the remaining objection to monoclonal antibodies as pharmaceutical products have disappeared (See Figure-Second generation). Moreover, even conjugated forms of antibodies (toxins, drugs and isotopes) are finding the means around the significant limitations of toxicity and immunogenicity. More importantly, a whole Next generation (See Figure) of antibody products has evolved which involve the use of technology platforms aimed at improving the therapeutic properties and performance of antibodies. It is to this generation of antibody products that SuperAntibodies belong.
Monoclonal Antibodies: Evolving into the Mainstream
First Generation
Hybridoma generated murine Mabs-large scale fermentation
Enzymatically derived fragments
Second Generation
Yeast, bacteria, and plant derived human antibodies
"Humanized" murine Mabs
Selection of human ScFv by phage display
Selection of peptide mimetics by phage display
Next generation-improved therapeutic properties
SuperAntibodies*
Bispecific antibodies for ADCC and phagocytosis
Cell penetrating antibodies
Antibodies that can trigger signaling pathways
Anti-idiotypic vaccines
Toxin/Fusion proteins
*Kohler H. Superantibodies; synergy of innate and acquired immunity. Appl Biochem Biotechnol,;83;1-9,145-53. 2000
Monoclonal antibodies as a market segment have a virtually unlimited potential for generating new products. Combining the fine specificity of monoclonal antibodies with the numerous technologies for engineering an antibody into various forms allows the selection of a final product form almost as soon as an antibody of appropriate specificity is identified. Numerous companies currently exist with the ability to generate fully human or "humanized" antibodies, in full length, capable of long retention in the body and able to fix complement. Other forms represented by bi-specific or multi-specific antibodies represent fusions of two antibodies and are able to bind two or more targets simultaneously. At the other extreme are small, genetically engineered fragments representing only the portions of antibody that bind to the target antigen and having the property of rapid clearance from the circulation. Even peptides and organic molecules, which mimic the binding specificities of antibodies, can be generated from the information inherent within a selected antibody.
Equally important in the success of the current monoclonal antibody industry is the fact that antibodies can be scaled up in a cost-effective manner by several technologies. These technologies include traditional, large scale, fermentation of antibody-producing cells such as myeloma, yeast and bacteria. The antibody product is harvested from culture medium or from lysed cells and purified by established chromatographic methods. Alternatively, the genes for antibodies can be used to transfect species such as cows and goats and antibody harvested from milk. Antibodies can even be transfected into plants such as corn and harvested on large scale.
