About Monoclonal Antibodies

Monoclonal Antibodies Defined

An antibody is a component of the body’s immune system. It is a Y-shaped protein that binds specifically to a foreign substance (antigen) and marks it for destruction and/or removal. Monoclonal antibodies (mAbs) can be directed to bind to a single, specific structure on the surface of a cell. The inherent selectivity of monoclonal antibodies makes them ideally suited for targeting specific cells, such as cancer cells, while bypassing most normal tissue.

Once bound to the targeted site, monoclonal antibodies can block the growth of the tumor, recruit the body’s immune system to attack the target, sensitize a cancer cell to chemotherapy and/or be used as a carrier of payloads, such as cell-killing drugs. A monoclonal antibody can be used as a therapeutic either on its own or in combination with chemotherapy.

Realizing the Potential of Monoclonal Antibodies

Monoclonal antibodies were first discovered in 1975 when British scientists Milstein and Kohler invented a process for generating large quantities of uniform mouse antibodies designed to target specific proteins. They earned a Nobel Prize in medicine for this pioneering work in 1984. However, initial clinical studies found monoclonal antibodies to be of limited therapeutic value, predominantly because early mouse-derived (murine) monoclonal antibodies often resulted in an immune system response by patients. When injected into humans, a mouse mAb is usually recognized by the body’s immune system as being foreign. The human immune system therefore responds by rapidly neutralizing the mouse mAb and rendering it ineffective for further therapy, a reaction referred to as a Human Anti-Mouse Antibody (“HAMA”) response.

Over the years, researchers have developed a number of approaches to make mouse mAbs appear more human-like to a patient’s immune system, thereby lowering the risk of immune responses and allowing for longer duration of treatment. These technologies have enabled scientists to develop antibody products that can be administered to patients repeatedly over time, or on a chronic basis, with reduced adverse responses by the human immune system. A therapeutic mAb can be chimeric, humanized or fully human. A chimeric mAb contains a mixture of both mouse and human sequences, usually a 30/70 split, respectively, where the mouse components are responsible for binding to the antigen and the human components are involved in inducing a therapeutic effect. Humanized mAbs contain over 90 percent human sequences, while fully-human mAbs contain 100 percent human sequences.

Another limitation of the early work in this antibody field was that, although monoclonal antibodies are capable of targeting specific cell structures, most are not potent enough on their own to induce cell death. Advances in technology to arm mAbs with cell-killing payloads have helped scientists overcome this constraint. Seattle Genetics has developed leading technology to increase the potency of mAbs, whether the antibody internalizes or stays on the surface of the targeted cell (see Strategies for Monoclonal Antibodies as Therapeutics.)

The ability to identify mAbs with sufficient potency, or to increase potency through the addition of payloads, and to limit immune system response have led to a large number of monoclonal antibodies currently undergoing clinical and preclinical investigation. The Food and Drug Administration (FDA) has approved more than fifteen therapeutic antibodies to date, over ten of which were approved in the last five years. Eight antibody-based products for the treatment of cancer are currently sold commercially, with combined sales measured in the billions of dollars.

Strategies for Monoclonal Antibodies as Therapeutics

Monoclonal antibodies can be used alone or in combination with other therapies, such as chemotherapeutic drugs. Seattle Genetics employs two approaches in its research and development of mAb-based therapeutics:

Genetically Engineered Monoclonal Antibodies
Genetically engineered monoclonal antibodies describe those mAbs that have cell-killing properties on their own. Sometimes referred to as “naked” or “unlabeled” antibodies, these mAbs do not require a cell-killing payload such as a drug, toxin or radioactive material in order to induce death (apoptosis) in the targeted cell.

The FDA has approved five genetically engineered antibodies for the treatment of cancer. Rituxan, the first mAb approved for cancer therapy, is marketed by Genentech and Biogen IDEC for the treatment of patients with non-Hodgkin’s lymphoma; Herceptin, marketed by Genentech, is a mAb for patients with breast cancer; Campath, marketed by Genzyme, treats patients suffering from B-cell chronic lymphocytic leukemia; Erbitux, marketed by Imclone and Bristol-Myers Squibb, for patients with colon cancer; and, Avastin, marketed by Genentech, for patients with colon cancer.

Seattle Genetics is currently developing three genetically engineered mAb product candidates. Dacetuzumab (SGN-40) is in multiple clinical trials both as a single agent and in combination with standard regimens for patients with non-Hodgkin lymphoma or multiple myeloma. Lintuzumab (SGN-33) is in phase I and phase II clinical trials for acute myeloid leukemia and myelodysplastic syndromes. SGN-70, which is in a phase I clinical trial, is being developed as a novel agent for the treatment of autoimmune diseases.

Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates are comprised of monoclonal antibodies linked to cell-killing drugs. The high affinity and selectivity of antibodies to tumor cells makes them ideally suited for delivering potent cell-killing agents. ADCs generally are comprised of mAbs that enter, or internalize, within cells. The specific environment and/or factors inside the cell cause the drug to be released from the mAb, allowing it to have the desired cell-killing effect on the target cell, while sparing most normal tissue.

ADCs are an emerging therapeutic strategy for monoclonal antibodies because they empower antibodies that have specificity for tumor cells but no cell-killing capabilities. By employing an ADC strategy, it is possible to deliver potent, cytotoxic drug in a targeted manner to a tumor as compared to systemically injected drugs. Systemic administration of cytotoxic drugs is typically limited by toxicity resulting from exposure of normal tissues. By utilizing an ADC, it may be possible to achieve a higher concentration of drug at the tumor while minimizing exposure to normal tissues.

A crucial component of ADCs are the linkers that hold and then release the drugs from the mAbs once inside of target cells. Seattle Genetics has developed leading ADC technology that utilizes highly potent, proprietary drugs and novel linkers that have been shown in preclinical models to be much more stable in the bloodstream than conventional linkers. The Seattle Genetics drug-linker system is synthetic, making it readily scalable and representing an improvement over natural product drug systems that are often more difficult to produce.

The FDA approved the first ADC for cancer, Mylotarg®, in 2000. Mylotarg, marketed by Wyeth, links an antibody with the drug calicheamicin for the treatment of patients with acute myeloid leukemia.

Seattle Genetics'  lead ADC product candidates are SGN-35, which is in phase I clinical trials for Hodgkin lymphoma and other CD30-positive hematologic malignancies, and SGN-75 and SGN-19A, which are in preclinical development.