Monoclonal Antibodies, the Immune System, and Lupus

Monoclonal antibodies are lab-made molecules. They help the immune system to target and attack foreign invaders. And, when it comes to managing lupus, they offer hope for new treatments.

The immune system works by sending specialized cells after targets that the body has marked with “flags” called antibodies. Every person has millions of different antibodies, each one unique and able to bind to different targets. In overall healthy people, antibodies that flag the body’s own cells for attack, called “autoantibodies” (“auto,” in this case, means “self”) are caught and destroyed by a sort of internal “quality control.”

However, in systemic lupus erythematosus (SLE) and other autoimmune diseases, the body doesn’t perform this quality control properly. As a result, healthy cells are misidentified and attacked throughout the body.

When the immune system attacks the body, it generates inflammation. Inflammation can cause pain, interfere with the proper function of organs, and can even cause lasting damage. In addition, it convinces the body that there is a threat to it, encouraging the production of more autoantibodies!

Because of this, Lupus Warriors may feel like their own immune system is the enemy. After all, the immune system is the root of their disease and the source of flares! Usually, lupus medications focus on regulating or almost turning it off completely (as in the case of immunosuppressants). But, what if the immune system could be used to fight the very lupus it causes? What if it could be manipulated in order to fix itself?

These are exactly the questions that a class of medications called monoclonal antibodies hope to answer.

What are Monoclonal Antibodies?

Monoclonal antibodies are molecules made in a laboratory to act like antibodies targeting specific substances in the body. Typically, they are administered intravenously (through the vein using an IV setup) in hospital or in an appropriately equipped home setting.

Essentially, monoclonal antibodies mark cells which causes the marked cells to be attacked by the immune system, destroying them. The targets, also known as antigens, can be anything. Specifically speaking, antigens that monoclonal antibodies target are engineered to target specific types of cells.

In their most prevalent use for treating cancer, monoclonal antibodies can be directed to mark:

• substances found on the surfaces of cancer cells
• proteins in the cell membranes of cancer cells
• signaling proteins involved in cell growth
• key proteins that control the development of blood vessels
• proteins that hold back immune system cells from attacking cancer cells

Once marked, these proteins are attacked by the immune system, slowing the growth of tumors or even destroying them.

Since monoclonal antibodies can be made to bind to targets only found on specific cells, they can also act as highly-specific delivery molecules. If something is attached to them, they can carry drugs, toxins, or radioactive substances directly to the cells of concern. This can increase the effectiveness of the treatment and reduce the impact on non-targeted cells. The fewer non-target cells that are affected by a treatment, the more precise the therapeutic delivery is.

While all of these features of monoclonal antibodies are of interest for lupus, the feature that most current monoclonal antibody treatments for lupus focus on is “mark-and-destroy.” Through these monoclonal antibodies, people with lupus and their treatment teams can potentially re-tune their immune systems.

B Cells and Monoclonal Antibodies

B-cells are very important targets for monoclonal antibodies. If they are disrupted or destroyed, B cells can no longer produce cytokines. (One role of cytokines is telling immune system cells to ramp up inflammation.)

Destroying B cells and preventing cytokines from being produced turns down the alarm level of the cells, and reduces lupus symptoms, making B-cells common targets for lupus. You can read more about B-cells and lupus here.

Monoclonal Antibodies (mABs) for Lupus

Today, there are limited pharmacologic options when it comes to treating lupus. mABs add more options and new strategies for development. This makes it a lot more likely that a lupus treatment team could tailor a medical strategy to that person.

Of the monoclonal antibodies, Rituximab is the most used monoclonal antibody or mAB for lupus. It acts on the membrane protein CD20, which is found on B lymphocytes. In studies, it improved symptoms. While it was not more effective than more conventional treatments, it was able to work in patients resistant or non-responsive to corticosteroids.

Belimumab, also known as Benlysta, targets a cytokine (BLyS) of the tumor-necrosis factor ligand and inhibits its activity. Epratuzumab and other mABs target other parts of the immune system.

Anifrolumab targets type-1 interferon (IFN,) which is continuously active in lupus and encourages inflammation. When IFN is blocked and turned off, inflammation is reduced. In trials, anifrolumab was able to reduce disease activity and symptoms even when the steroid dose was reduced.

A few other notable targets of monoclonal antibodies include:

• CD20
  • An antigen found on the membranes of all B cells, but not on other plasma cells, which makes it an ideal and relatively harmless target for monoclonal antibodies.
  • Several monoclonals, including veltuzumab and ocrelizumab target CD20.
• CD22
  • A receptor in the membranes of B-Cells that bind to sialic acid and act as inhibitors (limiters of B-cell activity). Targeting CD22 would target B cells too, but a delivery monoclonal antibody could deliver sialic acid right to it.
• BLyS, or the B-Lymphocyte Stimulator Protein
  • Controls whether B-cells self-destruct. If they are allowed to self-destruct, this can help reduce the immune response and SLE symptoms.

Also, the monoclonal antibody Eclulizumab targets C5, a protein that normally would bind two other proteins together. These two proteins combined create a compound, C5b-C9, that regulates inflammation in podocytes and glomeruli, the key cell types in the kidney. This makes Eclulizimab potentially very useful for the treatment of lupus nephritis.

Side Effects of Monoclonal Antibodies

For the most part, monoclonal antibodies have relatively mild side effects related to the activation of the immune system or the IV itself. This is a part of why monoclonal therapies are so promising as a treatment! However, these side effects can include:

• Allergic reactions, including hives or itching
• Irritation such as skin rashes
• Flu-like symptoms
• Nausea and Vomiting
• Lowered blood pressure
• Diarrhea

Subacute cutaneous lupus (SCLE) is a form of mild cutaneous lupus that might be caused by monoclonal antibodies. There are other side effects are specific to monoclonal antibodies for lupus, as well. Like all immune system suppressing drugs, some monoclonal antibodies can make people more vulnerable to infection.

In general, however, these symptoms are mild, and monoclonals are a viable medication for lupus.