The immune system has many ways to protect the body against cells that grow out of control.
However, there are times when the rogue cells “overwhelm or evade” these natural defenses and give rise to cancer.
A new approach in cancer treatment, known as immunotherapy, is developing therapies that can give the immune system a helping hand.
Researchers from The Scripps Research Institute in Jupiter, FL, and the National Heart, Lung, and Blood Institute — of the National Institutes of Health (NIH) — in Bethesda, MD, have now engineered one in the form of a “two-pronged” anti-cancer antibody.
‘Two-pronged’ anti-cancer antibody
The first prong helps the antibody to locate a unique protein called receptor tyrosine kinase ROR1, which is present on the surface of cancer cells but not healthy cells.
When it finds the protein, the antibody binds to the cancer cell, effectively turning it into a target.
The second prong on the engineered antibody attracts and binds to killer T cells, which are a type of white blood cell in the immune system that kills cells that pose a threat. This event activates the killer T cell to release toxins that destroy the cancer cell.
The scientists report how they engineered and tested their “T cell engaging bi-specific antibody” in a paper that is now published in the Proceedings of the National Academy of Sciences.
“Once the T cells are recruited and activated,” explains senior study author Christoph Rader, an associate professor at The Scripps Research Institute, “they release cytotoxic molecules that penetrate the target cells and kill them.”
“Natural antibodies can’t do this,” he goes on to say. “You have to engineer them in a bi-specific fashion to do this.”
Bi-specific antibodies and cancer
Antibodies are proteins made by white blood cells. They patrol the bloodstream seeking bacteria, viruses, and other “non-self substances.” When they find their target, they bind to them.
Antibody engineering is now a well-established field of treatment development and there are dozens of approved antibody-based molecules.
The idea of bi-specific antibodies — that is, antibodies that can bind to two targets at the same time — is not new and the study authors note that it offers a “promising strategy for cancer immunotherapy.”
In fact, several bi-specific antibodies have already been developed that summon T cells to destroy tumor cells.
However, the challenge that remains is to find a protein target, or antigen, that is specific to cancer cells, so that healthy cells do not inadvertently get caught up in the battle.
ROR1 as cancer target
One reason for Prof. Rader deciding to engineer a bi-specific antibody based on receptor tyrosine kinase ROR1 is because, as he and his co-authors note in their paper, the protein “is expressed by numerous cancers and is largely absent from postnatal healthy cells and tissues.”
“ROR1 is expressed during embryogenesis, and then it is tightly down-regulated after birth,” Prof. Rader explains.
After birth, ROR1 re-emerges in cancer; the protein has been found on the surface of breast, lung, ovarian, and blood cancers, he adds.
Another reason that Prof. Rader decided to use ROR1 is because he has a particular interest in getting the antibody therapy to work for HER2-negative breast cancer, for which there are currently few treatment options.
“If you look at ROR1 expression in breast cancer,” he explains, “you see that the patients who are HER2 negative are often ROR1 positive.”
Antibody remains active for days
A significant part of the work was carried out by first Dr. Junpeng Qi, a research associate in Prof. Rader’s group. This involved the creation of a bi-specific antibody that remains active for days.
The single bi-specific antibody that has so far received regulatory approval in the United States only remains active for a few hours.
Dr. Qi “used a component of natural antibodies for this bi-specific antibody that gives it not only a larger size, but also the ability to be recycled and stay in the blood longer,” Prof. Rader explains.
While it is ideal for the antibodies to stay in the blood longer, to avoid toxic side effects, it is not ideal for them to linger for too long.
“One of the most unique aspects of this bi-specific antibody is that it can work in so many different cancer indications.”
Prof. Christoph Rader
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