The strategy of using monoclonal antibodies for cancer treatment was first described in the late 1970s with the promise that they could be developed into therapies that were highly specific to cancer cells, killing them with few or no side effects. For several types of cancer, monoclonal antibodies have already offered this advantage to patients. For other cancer types, they have provided an additional therapeutic weapon, but with smaller benefits and sometimes new side effects.

"The first efforts for monoclonal antibody cancer therapy were to find antibodies that would home in on tumors and bind to proteins on the surface of cancer cells," explained physician-scientist David A. Scheinberg. "We looked for unique proteins that were specific only to cancer cells. The idea was that the antibody would be used to stimulate an immune response in the body, which would kill the cancer cell." Dr. Scheinberg, who is Chair of Memorial Sloan-Kettering's Experimental Therapeutics Center and the Molecular Pharmacology and Chemistry Program within the Sloan-Kettering Institute, developed an antibody called M195, which targets a protein on leukemia cells, when working as a research fellow in collaboration with Memorial Sloan-Kettering immunologist Lloyd Old in the 1980s.

This approach further evolved when researchers realized they could use the antibody as a carrier to deliver a radioactive isotope or a toxic drug directly to the cancer cell, where it would kill the cell while sparing nearby healthy tissue.

Antibodies are proteins that help the immune system to identify foreign substances by binding to them and marking them as foreign. Monoclonal antibodies are manufactured using a type of cell called a hybridoma. The hybridoma -- which is engineered in the laboratory by fusing an antibody-producing immune cell called a B cell to a tumor cell -- multiplies to produce a continuous supply of a specific antibody. Early monoclonal antibodies were made exclusively from mouse cells, but because the immune system can recognize these antibodies as foreign, leading to unwanted reactions, most monoclonal antibodies used today are either chimeric, consisting of both mouse and human parts, or fully human.

Improving Survival for Lymphoma

The first monoclonal antibody approved for cancer was rituximab (Rituxan®) in 1997. It was initially developed by Ronald Levy at the Stanford School of Medicine to treat follicular lymphoma, the most common type of indolent (slow-growing) non-Hodgkin's lymphoma. "When rituximab was developed, everyone working in the field thought it was going to be a marginal drug that would benefit a small number of patients with relapsed and refractory disease," remembered Andrew D. Zelenetz, Chief of Memorial Sloan-Kettering's Lymphoma Service. "But it turned out we were all wrong. For patients with follicular lymphoma, a combination of rituximab with chemotherapy has resulted in improved disease control and prolonged survival. In patients with diffuse large B cell lymphoma, the most common lymphoma subtype worldwide, the addition of rituximab to the standard chemotherapy protocol known as CHOP increased the cure rate by about 15 percent."

Rituximab, which binds to the protein CD20 on the surface of B cells, has three different mechanisms of action. Its primary way of killing cancer cells is by eliciting an immune response, drawing what are known as effector cells (various types of killer white blood cells) to the tumor and activating them. This process is called antibody-dependent cell-mediated cytotoxicity (ADCC). Another mechanism is directly causing the cells to undergo apoptosis (programmed cell death). The third mechanism is by activation of what are called complement proteins. These proteins form a membrane-attack complex and poke holes in the membranes of cells, killing them.

Because CD20 is present on the surface of normal B cells as well as leukemia cells, normal B cells are killed as well. "We make 10 million B cells a day, and most of them die anyway," Dr. Zelenetz said. "So when we target B cells and knock them out, they are easily replaced. It's possible that long-term use of rituximab could lead to an increased risk of some types of infections, but it's something we really haven't seen as a frequent problem."

Two other drugs for lymphoma make use of antibodies as carriers for radioactive isotopes. Ibritumomab tiuxetan (Zevalin®), developed by a small pharmaceutical company, contains an antibody similar to rituximab linked to yttrium-90, a radioisotope that emits a cell-blasting beta particle. Tositumomab (Bexxar®), developed by Mark Kaminski and Richard Wahl, then at the University of Michigan, is an antibody that carries the beta-emitting isotope iodine-131. Both antibodies also target CD20.

Less Toxic Treatments for Leukemia

Another tactic for using antibodies as delivery devices is attaching them to a cytotoxic agent, such as a chemotherapy drug. Gemtuzumab (Mylotarg®), a drug that is used to treat acute myelogenous leukemia (AML), consists of an antibody connected to calicheamicin, a highly toxic antibiotic. Gemtuzumab, developed at the Fred Hutchinson Cancer Research Center, targets CD33, a protein found on the surface of leukemia cells.

"The average age for AML patients is 68," said Joseph G. Jurcic, Acting Chief of Memorial Sloan-Kettering's Leukemia Service…