Past, present and future of monoclonal antibodies

Monoclonal antibodies: the discovery
In 1975, Köhler and Millstein discovered how to prepare hybridoma's: a new cell type, resulting from the fusion of B-lymphocytes (immune cells of a mouse) with a myeloma (cancer) cell. The hybridoma combines two characteristics of the parent cells: immortality of the cancer cell and specific antibody production of the B-lymphocyte. Since all hybridoma cells derived of this fusion product make the same cell antibody type, these antibodies are called monoclonal (coming from one clone) antibodies.

Optimism and hype about usefulness
The monoclonal antibody technology was quickly adopted by scientists in both industry and academia and led to a hype in industry and academia about the almost unlimited usefulness of monoclonal antibodies. Their usefulness in research and diagnostics has by now been proven: it is difficult to find a research laboratory where monoclonal antibodies are not generated for research purposes, in particular for selection of compounds. Industrially, they are used to recognize proteins from a culture broth and thereby assist in purification processes. In diagnostics, numerous test kits are on the market featuring monoclonal antibodies that specifically recognize certain molecules. Among the over the counter products featuring monoclonal antibodies, easy-to-use pregnancy or fertility tests are best known among the public. This widespread use of monoclonal antibodies was based on such inherent characteristics as

- safety,
- a broad range of potential targets,
- high selectivity,
- high affinity and,
- ease of preparation (easy to generate).

Therapeutic disappointments in the 1980s
In the early 1980s, the hype about monoclonal antibodies extended to the field of therapeutics. The concept of the 'magic bullet' was born: a combination of a specific drug or toxin, bound to a monoclonal antibody that specifically zeroes in on its target and delivers the drug or toxin there where it is needed. However, in the mid and late 1980s the development of therapeutic monoclonal antibodies suffered a number of serious disappointments, which reduced faith in the therapeutic applicability of monoclonal antibodies considerably. These disappointments were caused by

- the need for high therapeutic doses,
- poor penetration in solid tumors,
- potential cross reactivity with other tumors,
- high production costs,
- potential viral safety problems,
- technical difficulties in large scale production and,
- relatively poor patent protection.

In addition, all monoclonal antibodies were derived from rodent cells, and these rodent-derived monoclonal antibodies suffered from

- a very short half life,
- poor recognition of the rodent IgG constant region by human effector function,
- HAMA response (generation of human anti-mouse antibodies).

Strategies to overcome drawbacks
All these drawbacks led to sophisticated technological developments and improvements, primary consisting of strategies to generate human(ized) monoclonal antibodies (mAbs). There are 5 such strategies:

- generation of true human mAbs (but these are instable and have only a limited number of targets),
- chimerization (the resulting monoclonal antibodies are 60-70% human),
- humanization (the resulting monoclonal antibodies are 90-95% human),
- use of phage display (resulting in fully human monoclonal antibodies),
- use of transgenics (resulting in fully human monoclonal antibodies).

Shortly, technological progress led to the development and approval of an increasing number of initially chimeric, then humanized therapeutic mononclonal antibodies.

Monoclonal antibodies in development (mainly based on Dimitrov DS, Marks JD 2009)
Regardless recurring throwbacks, technological developments and better understanding of physiological pathways and valid targets have led to a whole series of new projects in industry, resulting in an increasing number of monoclonal antibodies in clinical trials.
Currently about 200 different antibody-based candidate therapeutics are in clinical trials targeting about 70 different molecules. At least 1-3 antibodies against each relevant target are developed concurrently at different companies. A notable exception is IGF-IR, which is actually targeted by more than 10 different monoclonal antibodies.

Monoclonal antibodies approved for therapeutic use
In total, 22 mAbs are approved by the United States and Drug Administration  (FDA) for therapeutic use. The table below gives a listing.

FDA approved monoclonal antibodies for therapeutic use:

- TheraCIM, a therapeutic humanized mAb, developed by CIM/CIMAB/YM Biosciences, targeting EGFR has been approved in China and Cuba for nasopharyngeal carcinomas and in Argentina, Colombia and Cuba for head and neck tumors in 2005. Clinical trials for approval by the FDA and the EMEA are ongoing.
- Cotara, an Iodine-131 radiolabeled TNT monoclonal antibody developed by Peregrine Pharmaceuticals, has been launched in China in 2003 to treat lung cancer. EMEA and FDA granted Orphan Drug status, a phase III clinical trial is currently ongoing.
- Actemra, a humanized anti-interleukin-6 receptor monoclonal antibody developed by In 2005, Chugai Pharmaceuticals, the Japanese subsidiary of Roche, has been launched in Japan. The FDA approval is expected for later in 2009.
- Removab®, a trifunctional antibody developed by TRION Pharma for the intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas, has been approved by EMEA in 2009.

Polyclonal antibody preparations for therapeutic us:
Also polyclonal antibody preparations for therapeutic use, as for example CroFab developed by Protherics PLC. and Savage Laboratories to treat rattlesnake evenomation, or GAMMAGARD® by Baxter International Inc. were approved by the FDA.

Monoclonal antibodies are also used as highly specific diagnostic tools:
CEA-Scan® (Immunomedics, Inc.) is an example for a monoclonal, technetinum-99 labeld antibody approved as imaging agent in metastatic colorectoral cancer.

Further challenges — no highly effective drugs without severe adverse events?

In 2005, as major challenges seemed to be overcome, Tysabri® was withdrawn from the US market only 3 month after its first approval to treat relapsing multiple sclerosis. 3 patients treated with Tysabri® developed PML (Progressive Multifocal Leukoencephalopathy) that occurs almost exclusively in people with severe immune deficiency. As no further cases of PML were observed, Tysabri® was re-launched in US and first approved for Europe in 2006. To this day, approx. 60.000 humans were medicated with Tysabri® in US and Europe and 4 further cases of PML were registered.
In March 2006, the confidence in antibody drugs was shaken again by the horrible outcome of the TGN1412 phase I clinical trial. Tegenero tested a superagonistic monoclonal antibody that stimulates T-cell generation in healthy volunteers. However, the trial was immediately suspended by the MHRA after all six subjects that took TGN-1412 developed a life-threatening inflammatory reaction. In July 2006, the company filed for insolvency and all development by the company was discontinued.
More recently, in March 2009, Actemra, a monoclonal antibody developed and launched by Chugai Pharmaceuticals, caused tongues to wag: 15 subjects suffering from rheumatoid arthritis died after being treated with Actemra. A causal connection between the administration of the drug and the cases of deaths was neither proven nor could it be excluded until yet.
Raptiva, developed and launched by Genentech and Xoma and approved in the EU in 2004 to treat chronic moderate-to-severe plaque psoriasis, was voluntarily withdrawn due to increased risk of progressive multifocal leukoencephalopathy (PML) in April 2009.

Regulatory authorities such as FDA and EMEA react: the prescription and the administration of monoclonal antibody drugs is strictly regulated as soon as particular risks are suspected. Distributers are obliged to apply formal warnings; healthcare professionals are to inform patients properly. For some drugs, use is restricted to patients that meet well defined demands.
But in many cases the medical benefit for the individual is to rate much higher than the related risk. Thousands of patients suffering from a wide variety of diseases already benefit from the possibility of the treatment with mAbs, were formerly no medication was available.

Sales improving:

The mAb market is expected to continue its strong growth pattern, with a number of already marketed products forecast to perform strongly in addition to key product launches that will further boost the market. Revenue expansion will be driven by a number of key individual products recording peak sales growth and the launch of new products. Revenue growth will be enhanced further by horizontally broadening the indications in a number of key mAbs.
The biggest sales growth generator over the next years is expected to be Avastin (Genentech/Roche). Avastin is subject to an extensive horizontally broadening strategy and, as detailed on Genentech’s website, by May 2009 the compound is in 17 Phase III clinical trials, the FDA submission is already in preparation in one further indication.

Sales volume and forecast (billion USD)

If not otherwise indicated: data from Biocentury, January 12, 2009
1Datamonitor: Monoclonal Antibodies: Update 2008
2Global Monoclonal Antibodies Market Review 2008 (World Top Ten mAbs)

Foundation for optimism
Currently, the climate for the development of monoclonal antibodies is much better than it has been foreseen 10 years ago. Knowledge increase, technological improvements and growing experience with marketed mAbs as well as promising sales volumes may accelerate the development of therapeutic mAbs. Not only small Biotech companies, but also the global players in “Big Pharma” push the development of these promising therapeutic tools.

Groundbreaking elements for successful future development:
the availability of human(ized) mAbs,
proven financial success,
more experience in the selection of good targets,
more experience in the selection of good antibodies,
improvements in manufacturing (cheaper, larger scale),
well established registration procedures.

Reference List
Dimitrov, D. S. and J. D. Marks. "Therapeutic antibodies: current state and future trends - is a paradigm change coming soon?" Methods Mol.Biol. 525 (2009): 1-27.

Additional Sources:
Datamonitor (2008): Monoclonal Antibodies Update 2008 (www.datamonitor.com)
Thomson Pharma (www.Thomsonpharma.com)
Krishan Maggon: Global Monoclonal Antibodies Market Review 2008 (http://knol.google.com/k/krishan-maggon/global-monoclonal-antibodies-market/3fy5eowy8suq3/11#)
AdisIinsight (http://bi.adisinsight.com)
Clinical trials (http://www.clinicaltrials.gov/)
Biocentury: (http://Biocentury.com)