The Antibody Initiative -- Monoclonal Antibodies

Monoclonal Antibodies

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In the 1890s, German physician and bacteriologist Paul Erhlich coined the term “antibodies” to explain the substances found in blood serum which neutralized specific bacterial toxins. He recognized the potential of these unique molecules to act as “magic bullets” against disease. He envisioned drugs made from specific antibodies targeting only invading organisms or toxins while leaving the rest of the body unaffected.

The invention of monoclonal antibody (mAb) technology provided scientists with a tool to pursue that dream. In 1975, researchers César Milstein and Georges Köhler, working at the Laboratory for Molecular Biology in England, developed a technique for creating cells that could pump out streams of identical antibodies. Their invention built on years of scientific research on the immune system and cell culture (growing cells outside the body). It worked by merging two kinds of cells—cancerous human B cells and mouse spleen cells that had been induced to produce the desired antibody. These fused cells, called hybridomas, could be grown in culture. The identical antibodies they produced became known as monoclonal antibodies.

Previously, the antibodies for use in medicine and diagnostics were extracted from blood. Scientists exposed animals to the desired antigen (usually a bacteria, virus, or toxin), causing the body to produce antibodies. They then harvested blood from the animals and separated out the antibody-containing blood serum. However, due to variability in antibody production between individual animals, it was difficult to obtain consistent levels of antibodies in different batches of blood products. The blood also contained a variety of other antibodies, created by the animal’s immune system in reaction to everyday antigens. This made antibodies from serum sources variable in concentration and purity.

Anti-diphtheritic serums, 1898

Anti-diphtheritic serum, 1898

In contrast, mAb technology guaranteed a steady source of a single kind of antibody. The technique also eliminated the problem of variability of antibody concentration. Essentially, it allowed for a standardized product of known composition.

Antibodies have been used in diagnostics since the late 19th century. By 1985, ten years after Köhler and Milstein’s invention, the Food and Drug Administration (FDA) had approved more than 70 mAb-based diagnostic tests for use in the United States. By the late 1980s, one third of the approvals for mAb diagnostics were for pregnancy tests, which remain the most common at home diagnostic. Pregnancy tests use antibodies that bind to human chorionic gonadotrophin (hCG). The presence of this hormone in the urine indicates a woman is pregnant.

The QTest, a pregnancy test and ovulation predictor
The QTest, a pregnancy test and ovulation predictor
The QTest, a pregnancy test and ovulation predictor

mAbs were also used in ovulation prediction tests to help women either get pregnant or avoid pregnancy. The QTest by Beckton, Dickinson & Co. was available both as a pregnancy test and an ovulation predictor, seen in three views here.

The first mAb drug approved by the FDA was Orthoclone, in June 1986. The drug prevented kidney rejection in transplant patients. The mAb worked by binding to and disrupting the functioning of human T cells, which are largely responsible for organ rejection. However, Orthoclone provoked serious side effects, including allergic reactions to the mouse-cell derived antibodies.

Orthoclone OKT3

Orthoclone OKT3 (left) and Simulect, another immunosuppressant mAb drug. Orthoclone sometimes triggered severe reactions because it utilized mouse-cell derived antibodies. Simulect, approved for use in 1998, used genetically engineered antibodies that were part mouse, part human, thereby reducing allergic reactions to the drug.

Orthoclone approval came only seven years after its discovery, a relatively quick turnaround. Nevertheless, it would take until the late 1990s for mAb drug approvals to really take off. Unlike diagnostics, therapeutics actually entered the human body, creating larger safety concerns. Drugs also required larger numbers of mAbs. Companies had to find a way to scale-up mAb production, which proved challenging.

Rituxan (rituximab) for injection

Rituxan (rituximab) for injection. Two biotech companies, Idec and Genentech, formed a partnership to develop and market the drug.

In 1997, a milestone in mAb therapeutics was achieved with the FDA approval of Rituxan, the first mAb for cancer treatment. Rituxin is used to treat cancers such as leukemias and lymphomas, which are characterized by production of abnormal white blood cells. Rituxin binds to receptors on these cells, which helps the body to destroy them.

Cancer treatment had long been a goal for mAbs. Researchers hoped the targeted therapies would mean fewer side effects. Traditional treatments like chemotherapy and radiation damage both healthy and cancerous cells. Since Rituxan’s approval, approximately half of mAb drugs on the market have targeted cancer.

Today, mAbs are approved to treat a wide range of diseases and disorders, from breast cancer to psoriasis.