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Introduction

This is the second of five reports that are intended to give a layman’s overview, first of two technologies that created the biotechnology industry-recombinant DNA and monoclonal antibodies- and three that will importantly shape its future- RNA interference, gene therapy and stem cell therapy. In my last report, I wrote that recombinant DNA technology was the foundation upon which the modern biotechnology industry was built. However, the number of commercial, blockbuster drugs that were created by this technology was quite limited. The first meaningful product approved by the FDA from recombinant DNA technology was Humulin, a human insulin, approved in 1982. The next major technology platform created by the biotechnology industry was monoclonal antibodies (mABs) for which the first major commercial product was the oncology drug Rituxan, approved by the FDA in 1997.

The commercial impact of monoclonal antibody technology has been profound even though it is still in a relatively early phase of its development life cycle. It is now the major driver of worldwide sales growth for biopharma and is the central focus of industry research. There are over 110 FDA approved mAB products and more than 550 clinical trials are underway. The global monoclonal antibodies market was valued at about $135 billion in 2018 and is expected to grow at a CAGR of 12.0% to reach $215 billion by 2022. This compares to a worldwide pharmaceutical market that was $1.2 trillion in 2018. mABs currently account for about 11% of the worldwide biopharma sales. This will expand dramatically over the next decade so that by 2029, monoclonal antibody based products could account for 25% or more of worldwide biopharma sales.

Wikipedia has published a list of approved monoclonal antibodies and those under development which provides a clear visualization of the intense focus of the industry on mABs. Because monoclonal antibodies are ubiquitously embraced by the biopharma industry there are no companies that are dominant as was the case with Amgen, Biogen and Genentech in recombinant DNA.

Background on the Biology of Antibodies and Their Role in Fighting Disease

Antibodies are a key part of the adaptive immune system that evolved in humans to combat pathogens such as bacteria, viruses and parasites. They are produced from B-cells that form in the bone marrow and are secreted into the bloodstream. Upon receiving specific signals from other components of the immune system that the body is being attacked by a foreign life form, numerous B-cells are activated each to create one distinct antibody that can recognize and specifically target a protein (antigen) on the cell surface of pathogens. They attach to the antigens and signal other components of the immune system to join up to attack and destroy the cell on which it appears. The hall mark of antibodies is their exquisite ability to target antigens. This property has made them extremely valuable in treating a broad number of diseases beyond pathogenic infections.

It was recognized over 100 years ago that antibodies could be silver bullets to treat disease. In the case of cancer, an antibody targeted at an antigen on the surface of a cancer cell can bind to an antigen target and initiate an immune response involving complement proteins and T-cells (other key cells of the immune system) that act to destroy the cancer cell. However, an antigen that marks a cancer cell can also appear on normal cells, in which case the antibody would also try to destroy normal tissue. Hence, antigen targets must be highly specific to cancer cells to avoid unintended damage to normal cells. The first major commercial products were for treating cancer; they were Rituxan, Herceptin and Avastin.

The efficacy in treating disease extends far beyond cancer. Many proteins that play an important role in disease are secreted by cells or are located on the cell surface. Moreover, cells communicate through secreted factors and surface molecules. For example, there are a large number of autoimmune diseases that are caused by an over active immune system such as rheumatoid arthritis, asthma, Crohn’s disease and on and on. In these diseases certain immune system molecules are created in too great of quantities in reaction to the immune stimulus.

An example is the cytokine TNF alpha, a protein (cytokine) that normally conveys signals between elements of the immune system. If an overactive immune response results in its over production, it can cause rheumatoid arthritis. Antibodies against TNF alpha can reduce the amount in the body and are effective treatments for rheumatoid arthritis. The largest selling mAB in the world, AbbVie’s Humira targets TNF; it has worldwide sales of over $20 billion. There seem to be almost a limitless number of disease causing targets, treating everything from cancer to high cholesterol.

How Monoclonal Antibodies Are Made

Upon recognizing an antigen, the immune system activates a number of B-cells, each of which produces a distinct antibody and results in a heterogeneous mixture of antibodies. Each antibody has different specificities, i.e. they may recognize different antigens and different epitopes on one antigen. These mixtures are termed polyclonal antibodies. While polyclonal antibodies are very effective in the human body, they have significant limitations for use as therapeutics and diagnostics. What researchers needed was a way to create one highly specific monoclonal antibody that would bind to only one epitope on one antigen.

The breakthrough that enabled the production of monoclonal antibodies was hybridoma technology. This technique starts with the immunization of an animal, almost always a mouse. (It is interesting that a mice share about 98% of the human genome.) The mouse is injected several times with an antigen that is specific to a disease which stimulates the mouse’s B-cells to produce a polyclonal antibody response. Over several weeks, the final cells in the B-cell lineage producing different antibodies (referred to as plasma cells) are allowed to mature. The mouse is sacrificed and the spleen is removed. The various plasma cells can be separated from other cells in the spleen using mechanical and enzymatic stress. Each plasma cell produces a distinct antibody targeted at an epitope on the antigen that was injected.

B-cells or plasma cells have  a short life span in cell culture so it is necessary to extend their life cycle in order to produce large quantities needed for a commercial drug. To overcome this, the plasma cell is fused with a cell line of mutated multiple myeloma cells which can divide indefinitely in a culture (referred to as immortal). A mixture of cell types is formed in the culture of which some are hybrid cells formed by the fusion of an activated plasma cell and a multiple myeloma cell; they are called hybridomas. These hybridoma cells produce a monoclonal antibody that is specific for one epitope on the antigen. These hybridomas are isolated and grown individually and then screened to find those that are most specific.

Monoclonal antibodies produced by mice contain mouse proteins (murine) that are recognized by the human immune system as foreign and can cause an immune reaction. This limits effectiveness and can damage to organs that clear antibodies. In the early days of monoclonal antibodies this was thought to be an insurmountable stumbling block. However, over time genetic engineering of mice used in hybridoma production and manipulation of antibodies they produce has led to the production of humanized antibodies that significantly reduce, but do not completely eliminate the immune reaction.

After all of the engineering is done, the nucleotide sequence coding for the monoclonal antibody is incorporated into a vector as described in the previous section on recombinant DNA technology. As in the case of human insulin, host bacterial or other types of cells are turned into biological factories for producing huge amounts of the monoclonal antibody. I have skipped over the details of humanization and creating host cells that produce the monoclonal antibody. Frankly, the science is just so complex that most of it is over my head.

History

The production of monoclonal antibodies using hybridomas was based on research by César Milstein and Georges Köhler in 1975 for which they shared the Nobel Prize for Medicine and Physiology in 1984. Building on this technique scientists could engineer specifically targeted monoclonal antibodies. The first monoclonal antibody to be approved by the FDA was in 1986; this was OKT-3 for preventing kidney transplant rejection, which was a murine antibody. In 1988, Greg Winter pioneered the techniques to humanize monoclonal antibodies. This led to an explosion of drug development.

A San Diego company called IDEC was formed in 1985 to develop a monoclonal antibody for treating non-Hodgkin’s lymphoma called Rituxan. This product was approved by the FDA in 1997 and went on to become the first blockbuster monoclonal antibody. Genentech was the company that initially recognized the promise of monoclonal antibodies and really pioneered their development. It formed a collaboration with Idec in 1995 to develop and commercialize Rituxan. Then on its own, it developed the next two blockbuster drugs, which were also oncology drugs. Herceptin was approved by the FDA in 1998 and Avastin in 2004. Slowly at first, other companies recognized the promise of monoclonal antibodies and today they are the driving research and commercial force in the word pharmaceutical industry. Interestingly. Amgen and Biogen were much slower to jump into mAB product development.