Road tripping treatments

Sometimes the journey isn’t half the battle, it’s the whole battle. And if that’s the case, you better take a good hard look at your wingman.

Antibody drug conjugates (ADCs) have this road trip down. They focus on the journey, aiming to deliver a treatment only to the cells that need it. In oncology, an ADC aims to deliver chemotherapy to destroy cancer cells while not damaging nearby healthy tissue. AbbVie researchers are now looking at using this same ADC technology to help patients with immune-mediated diseases by investigating delivering targeted immunology treatments, specifically steroids.

“We’re not trying to kill these target cells in immunology, we are trying to get them to change their minds and not be so angry,” says Lisa Olson, Ph.D., vice president, immunology, AbbVie. “It’s a big question - could we get an antibody to deliver the steroid inside an immune cell and after delivery, would the steroid work appropriately inside a cell?"

A dedicated team of about 10 AbbVie scientists grew to 50 scientists in order to figure it all out.

Immune-mediated diseases are caused by abnormal activity within a body’s immune system and while genetics and environment could play a role, no one really knows why. After all, the immune system is supposed to defend us – against everything from colds to serious diseases. But for some people, their immune systems overreact or start attacking the body, leading to diseases such as rheumatoid arthritis, psoriasis and Crohn’s disease.

Steroids can be highly effective anti-inflammatory drugs but affect many cells throughout the entire body and not just one area. Introduced in the 1950s as a treatment for immune-mediated diseases, steroids mimic the effects of hormones our bodies produce naturally, and they work by suppressing a patient’s immune system, which can help control symptoms.

While steroids are good at helping to stop inflammation, at the same time, they can have a negative impact on normal, healthy cells, says Marek Honczarenko, M.D., Ph.D., vice president, global immunology development, AbbVie.

“Steroids work like a hammer inside the body, paralyzing multiple cells,” Honczarenko says. “They do not discriminate between pathogenic cells causing immune disease and normal cells in the body as they bind to a cell’s glucocorticoid receptor, which is present on many different cell types in the human body.”

Immunology scientists have a deep molecular understanding of the immune system and why, for some, it goes haywire attacking a person’s joints, skin or gut. AbbVie’s immunology team of scientists knew steroids helped some patients, but the medicine applied broadly to the entire body was not tolerable for others. If they could figure out a way to direct where steroids should go it might lead to a new treatment approach.

Here’s where your road tripping ADCs come in.

In oncology, ADCs are mostly known for delivering treatment to the cancer cells they aim to kill. These ADCs have three parts – the antibody, which targets a particular protein; the payload, which is a toxin meant to attack the cancer cell; and a linker that connects the two. For ADCs in immune-mediated diseases, the antibody and linkers are similar; however, the payload is not a toxin but an immunomodulator, which is meant to help normalize the response of immune cells.

The immunology team learned two important lessons from ADCs in oncology. The first was the stability of the ADC in the body and the attachment site chemistry. An immunology ADC needs to be rock solid so that it will stay together in the bloodstream and get to the targeted cells. Instability leads to early release of the payload and side effects through non-targeted mechanisms. The second was choosing the right payload mechanism, and a steroid was chosen for further research.

Normally, immune cells are pretty quiet and circulate throughout the body, but once they encounter a foreign antigen or become dysregulated in autoimmune diseases they become activated and secrete cytokines like tumor necrosis factor (TNF) which is a protein in your body that causes inflammation, says Bob Stoffel, senior director, discovery immunology, AbbVie.

“We discovered that during the activation of immune cells, TNF is expressed on the cell surface and that antibodies that bind TNF will internalize,” Stoffel says. “This realization helped our immunology scientists target the activated or inflamed immune cells to deliver the steroid payload.”

A linker acts as the glue between the medicine and the antibody. A linker also allows the payload to be released only once it reaches the target cell. Linkers take years to develop since they must keep the medicine attached to the antibody while in the bloodstream, but then release the medicine inside the immune cell. It took AbbVie’s immunology team more than five years to study more than 100 linker combinations and 200 steroid payloads to find the right combination off all three.

“The magic sauce to get this all to work in the linker technology to build a molecule that is stable in blood and knows just when to release the payload,” Olson says. “We identified a linker-payload combination that gave us a wide therapeutic index.”

Unwanted activity of steroids on certain tissues can be measured with blood biomarkers, so the team used steroid biomarkers to lead them to the right linker-payload combination.

“This research is important for patients living with immune-related diseases such as RA, because many of these patients fail to achieve remission. Our scientists are committed to investigating new options for these patients and hope for a better future,” Honczarenko says.