Developing the sHIgM12 Human Antibody

"The most exciting thing about Lymph 12 is that it's a human antibody. And Mayo's huge patient base and vast collection of serum samples allowed us to develop it expediently." Larry Pease, Ph.D.

Larry Pease, Ph.D., has developed a powerful human antibody from stored blood serum that can promote a curative, immune response against established malignant melanoma and block inflammatory lung disease that resembles asthma in experimental animal models.

The antibody is formally known as sHIgM12, and its lab nickname is Lymph12. Dr. Pease was able to do that because of Mayo's unique and vast Mayo Clinic Serum Bank.

"This kind of bank, coupled with the extensive Mayo Clinic patient base from which to take samples, is just one of the many examples of the kind of resources that help make Mayo Clinic research the best of its kind," says Dr. Pease. "We wouldn't be where we are today with our research without my colleagues diligence in collecting such a vast resource of donated serum samples."

Developing a human antibody has significant advantages over antibodies produced from other species. That's because the animal-origin marks the antibody for detection in human immune systems. And that causes an undesirable immune response.

By contrast, the fact that Lymph 12 is a natural component of the human body favors rapid, effective development of new immunotherapeutic agents.

Says Dr. Pease: "To me, that's clearly the most exciting thing about Lymph 12 - that it's a human antibody that promotes powerful, curative changes in the immune response when administered to animals that have cancer of allergic asthma."

When Lymph 12 binds with Dendritic Cells Good Things Happen

In animal tests, Lymph12 has shown extraordinarily powerful health-giving effects when it binds to cells called dendritic cells. The effect on dendritic cells is to:

• Boost their survival
• Improve their ability to reach draining lymph cells
• Increase their ability to stimulate responses by T cells. T cells are the warriors of the immune system because they attack invaders. While dendritic cells are more like generals because they identify and select which T cells are suited for attacking a given pathogen, and then mobilize them to mount the attack.

How Dendritic Cells Initiate Immunity

Dendritic cells can be manipulated to stimulate immune responses to destroy tumor cells.

To fully appreciate these findings, it helps to understand the basic biological drama in which dendritic cells star as initiators of immunity. It works like this:

• Dendritic cells are located in tissues throughout the body. Their job is to pick up foreign antigens that arrive in the body and initiate the process that leads to their destruction. They pick the antigens up in many ways. They can engulf cells that are sick or dying. Or they can drink the environment in which the antigens are floating (called pinocytosis). As the immune response progresses, the lymph node sends chemical cues that summons both the dendritic cells and T cells.
• At the lymph node, dendritic cells then do their next trick - they display antigen fragments from just-engulfed invaders to the T cells. Together with a costimulatory signal, this activates T cells to mount an effective attack.

Lymph 12 + Dendritic Cells = Amazing Power

Why all the excitement over Lymph 12? Because when the antibody is given to animals that have established melanoma nodules in their lungs, the tumors in almost half of the mice disappear and far fewer tumor nodules remain in the rest of the animals.

Lymph 12 has newly-discovered, interesting, and important biologic effects when it binds to dendritic cells.

In animal experiments Lymph 12 has been shown to enhance the ability of the dendritic cells to:

1. Engulf, drink or otherwise take up antigens
2. Travel to the lymph nodes
3. Stimulate T cells

All three of these steps are key components of an effective immune response. The role of Lymph 12 is important because none of the steps are activated by the presence of a cancer tumor cell.

"Unfortunately, the body doesn't consider cancer tumor cells an infection," explains Dr. Pease. "So this multi-step process is not stimulated by them."

But if the laboratory results of Lymph 12 hold up in humans, physicians could be able to jumpstart the dendritic cells with Lymph 12, and that would "turn-on" the three-step immune response outlined above.

Says Dr. Pease: "Our lab results have demonstrated that the Lymph 12 antibody causes biological changes in human dendritic cells that are similar to those we have seen in the mouse.” This makes developing Lymph 12 as a drug for the treatment of human cancers an important possibility to consider.

A More Detailed Account of Lymph 12 Laboratory Findings

Lymph 12 appears to protect injured or "insulted" dendritic cells.

Researchers know this because in experiments, they can "insult" a dendritic cell and cause it to die by creating a hostile environment for it. However, when they add the Lymph12 antibody before the insult, the dendritic cells can withstand the insult and do not die.

Says Dr. Pease: "The antibody appears to prolong its ability to live in environmental stress."

This is important because learning how to therapeutically preserve dendritic cell function could be enlisted to boost the immune system to fight disease.

Lymph 12 appears to increase the number of transplanted dendritic cells that travel to the lymph nodes.

This is important because the lymph node is the site of interaction between dendritic cells and T cells in which the dendritic cells identify and mobilize the T cells best suited to attack the specific invader.

Says Dr. Pease: "It is exciting that the antibody not only helps the dendritic cells survive environmental stress, but also helps them get to the node."

Dendritic cells can control what kind of immune response the body marshals, and drive it toward an anti-tumor response.

To appreciate this point, it helps to keep in mind that there are several kinds of immune responses. For example:

• The TH2 immune response is suited for parasitic attack or allergic response in which antibodies are made.
• The TH1 immune response sends out T cells to attack viruses and cancer tumors.

A key attribute of Lymph 12 for immunotherapy purposes is that it prompts dendritic cells to secrete communicating chemicals that drive TH1 immunity - the kind that fights cancer cells. The therapeutic ability to control this would be enormously helpful for cancer patients who need a boost to fight tumors. Treatment with the antibody can also block allergic responses leading to in inflammatory lung diseases, such as seen in allergic asthma.

When Lymph 12 binds to dendritic cells, it increases their effectiveness in mobilizing T cells.

Says Dr. Pease: "When that happens, highly activated T cells can go out and do their job - and that's what we want so we can help the body kill cancer tumor cells."