Two-pronged antibodies draw immune killers directly to cancer cells

May 30, 2018, The Scripps Research Institute
The structure of the ROR1-binding arm of the bi-specific antibody in complex with ROR1 was determined by X-ray crystallography. Credit: Rader lab, The Scripps Research Institute

Our immune system's arsenal of defenses usually protects us from cancer. But sometimes, cancer cells overwhelm or evade this elaborate defense system.

In the lab of biochemist and immunologist Christoph Rader, Ph.D., associate professor at The Scripps Research Institute in Florida, scientists have engineered a new type of anti-cancer antibody, one intended to enhance nature's cancer-fighting strategies by attracting killer T cells directly to cancer cells covered with a distinctive protein.

Dubbed "T-cell engaging bi-specific antibodies," these cancer combatants attack but leave untouched. That's thanks to their selective targeting system, which zeroes in on a protein found on the surface of several types of called ROR1, and also thanks to their talent for binding with T cells, the big guns of the immune system.

"Once the T cells are recruited and activated, they release cytotoxic molecules that penetrate the and kill them," Rader says. "Natural antibodies can't do this. You have to engineer them in a bi-specific fashion to do this."

The scientists' work is described in the article, "Potent and Selective Antitumor Activity of a T-Cell Engaging Bispecific Antibody Targeting a Membrane-Proximal Epitope of ROR1," appearing online May 29 in the journal Proceedings of the National Academy of Sciences.

Rader is particularly interested in applying his bi-specific antibodies to a type of with fewer treatment options, HER2-negative breast cancer.

"If you look at ROR1 expression in breast cancer, you see that the patients who are HER2 negative are often ROR1 positive," Rader says. "These might benefit."

Antibodies are proteins made by to attack specific targets like viruses, bacteria and cancers. A bi-specific antibody is a Y-shaped immune factor engineered to both bind with a specific disease target, and also to attract killer T cells, a type of white blood cell that destroys infected or dangerous cells.

ROR1 is an excellent target for a smart cancer-fighting system, Rader says, because it is seen only in mature cells that are malignant. Rader first discovered ROR1's activity in leukemia a decade ago while working at the National Cancer Institute.

"ROR1 is expressed during embryogenesis, and then it is tightly down-regulated after birth. It later reappears in both blood cancers and solid malignancies," Rader says.

It has been found on malignant cells including lung, breast, ovarian and blood-based cancers, Rader says.

"One of the most unique aspects of this bi-specific antibody is that it can work in so many different cancer indications," Rader says.

He credits first author Junpeng Qi, Ph.D., a postdoctoral associate at Scripps Research in Florida, with engineering a group of bi-specific antibodies that stay active in animal models for about five days—a feat compared with current approaches. The U.S. Food and Drug Administration has approved just one bi-specific antibody against cancer so far, against B-cell acute lymphoblastic leukemia. It stays active for a couple of hours, Rader says.

"Junpeng used a component of 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," Rader says. "They are not there eternally, though. You get rid of them eventually, which is important for avoiding systemic toxicity."

Explore further: 'Double decker' antibody technology fights cancer

More information: Junpeng Qi et al, Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1719905115

Related Stories

'Double decker' antibody technology fights cancer

October 25, 2017
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have created a new class of antibody-drug conjugates (ADCs), using a versatile "double decker" technology that ties antibodies and a drug together ...

Scientists develop new drug delivery method for cancer therapy

March 16, 2017
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have developed a new drug delivery method that produces strong results in treating cancers in animal models, including some hard-to-treat solid and ...

Researchers discover new approach to stimulate an immune response against tumor cells

January 30, 2018
New drugs that activate the immune system to target cancer cells have improved the lives of many patients with cancer. However, immunotherapies are not effective in all patients, and the success of these therapies depends ...

Scientists discover sweet spot of activity in immune system key to fighting cancer

April 18, 2018
Scientists at the University of Southampton have shown how stimulating a specific location on the surface of immune cells can be targeted with antibodies to help in their fight against cancer.

Developmental protein plays role in spread of cancer

June 14, 2013
A protein used by embryo cells during early development, and recently found in many different types of cancer, apparently serves as a switch regulating the spread of cancer, known as metastasis, report researchers at the ...

Recommended for you

Non-coding DNA reveals a route by which advanced prostate cancer resists treatment

June 15, 2018
Two research teams converge on epigenetic switches that feed treatment-resistant metastatic prostate tumors. This research highlights the value of exploring gene regulation and large-scale structural changes in the cancer ...

Researchers peer inside cells to spy on cancer's on-off switch

June 15, 2018
Forty years after researchers first discovered it in fruit flies, a once-obscure cluster of proteins called PRC2 has become a key target for new cancer-fighting drugs, due to its tendency—when mutated—to bind to and silence ...

PIM-2 protein kinase regulates T-cell activity differently than PIM-1 or PIM-3 isoform

June 15, 2018
The PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity, while PIM-1 and PIM-3 are positive regulators, report Medical University of South Carolina (MUSC) investigators in an article ...

Gene testing could identify men with prostate cancer who may benefit from immunotherapy

June 14, 2018
Scientists have identified a pattern of genetic changes that could pick out men with advanced prostate cancer who are likely to benefit from immunotherapy.

Without 'yoga and chardonnay' leukemia stem cells are stressed to death

June 14, 2018
Change is stressful. The change that a healthy blood stem cell undergoes to become a leukemia stem cell (LSC) is no exception—think of healthy blood stem cells as young professionals and the transformation into an LSC as ...

Statins found to enhance efficacy of chemotherapy drug in blood cancers

June 14, 2018
A team of researchers with members affiliated with several institutions in the U.S. has found that some statins could enhance the efficacy of a chemotherapy drug used to fight blood cancers in mouse models. In their paper ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.