Could Death Receptor 5 Antibodies Make A Comeback?

By Deborah Borfitz

May 4, 2021 | Big pharma has invested billions of dollars in developing antibodies targeting death receptor 5 (DR5) over the years in hopes of improving the survival of patients with cancer. The therapies all looked quite promising when tested on human tumors growing in immune-deficient mice in the lab. But when targeting solid tumors, they invariably failed to show efficacy during phase 2 clinical studies.

The issue may be that antibodies were inadvertently disabling the human immune system, according to Jogender Tushir-Singh, Ph.D., antibody engineer at the University of Virginia. His hunch is backed by findings of a study appearing in EMBO Molecular Medicine (DOI: 10.15252/emmm.202012716), where mice engineered to express the human death receptor unexpectedly reacted to human DR5 antibodies by activating the PD-L1 pathway. 

Only two years ago, the U.S. Food and Drug Administration (FDA) approved Genentech’s atezolizumab (Tecentriq) for PD-L1-positive, metastatic triple-negative breast cancer, Tushir-Singh notes. In combination with chemotherapy, it was found to extend the lives of patients by three to six months. 

If paired with DR5 antibodies, he wonders, might Tecentriq extend life by many more months—and perhaps even years? 

That is his suspicion. When Tushir-Singh and his team co-targeted their immune-sufficient mouse models with such a combination therapy, it “markedly” increased the effectiveness of T cells at shrinking tumors and improving survival of the rodents.

The Backstory 

The discovery marks an alternate but highly important direction in the field of DR5 research over the past two decades, says Tushir-Singh, who previously worked for both Boehringer Ingelheim and AbbVie. He is one of very few academic scientists in the country testing therapeutic targeting using antibodies he manufactures in his lab, he adds.

In the heyday of DR5-targeting antibody development in the early 2000s, multiple large companies—including Genentech, Abbott, Amgen, HGS, Sankyo, and Daiichi (merged in 2006 to form Daiichi Sankyo)—had candidates under study. Most such testing was done in nude mice lacking an immune system, says Tushir-Singh, noting that this was before the Nobel Prize-winning discovery that the human immune system has accelerators and brakes that could be leveraged to treat cancer.

The first DR5 antibody was produced at the University of Alabama at Birmingham (UAB) and licensed to Sankyo, according to Donald Buchsbaum, Ph.D., director of radiation biology at the university. It was initially used in arthritis research and later expanded to cancer. UAB researchers also led the studies on Daiichi Sankyo’s Tigatuzumab for DR5-positive, metastatic triple-negative breast cancer. 

Buchsbaum was part of the DR5 antibody program at UAB for about 10 years, he says, and investigated the original mouse DR5 antibody as well as the humanized version first produced by Sankyo that subsequently went into clinical trials at UAB and elsewhere for several types of solid tumors, including breast, pancreatic, and ovarian cancers.  Why clinical trials of the DR5 antibodies failed to demonstrate efficacy is not entirely clear, says Buchsbaum. 

Attempts have been made to rescue the DR5 antibodies by combining them with other, already FDA-approved therapies. But Tushir-Singh’s team was the first to pursue the idea that the antibodies might have some unnoticed negative impact with the job they were supposed to do. That is, along with killing cancer cells they were also applying the brakes on immune cells. 

It was a “big deal” that the new study allowed researchers to study both the cytotoxicity of DR5 and the host immune response, says Buchsbaum. “All of the work I did in preclinical models were done on human tumors grown in immune-deficient mice [prior to the discovery of checkpoint inhibitors], so we were relying on the DR5 death-inducing signaling complex and not an immune response.”

Currently, Buchsbaum adds, his immunotherapy research utilizes human organoids grown from human cancers. Investigating the immune component involves moving to a syngeneic mouse model with a retained and intact immune system.

The Big Idea

Tecentriq, like most checkpoint inhibitors, is effective in only a small subset of triple-negative breast cancer patients, says Buchsbaum. It is not completely understood why some patients respond while others do not, but the prevailing belief is that it is driven by the level of PD-L1 expression. 

Tushir-Singh’s idea to use a bi-specific antibody targeting the receptors for both PD-L1 and DR5 as a treatment for triple-negative breast cancer is based on market approval of Tecentriq, and positive signals seen in a phase 2 trial using a DR5 antibody manufactured by Daiichi Sankyo for the same indication, Buchsbaum says. “Tushir-Singh is relying on the concept that binding to DR5 leads to stabilization of PD-L1 and would make the anti-PD-L1 antibody more effective.” 

He might be right, says Buchsbaum. Companies could be motivated to fund that research if they have an immune checkpoint inhibitor with a low response rate and do not know how to pre-identify the responders or prevent toxicities in the nonresponders. “If they could increase the response rate from 10% to 15% to 50%, that would be extraordinarily good news.” 

On the other hand, he adds, “all the antibodies that have been used in clinical trials for checkpoint inhibitor therapy are intact antibodies… not bi-specific antibodies.” It remains to be seen if they would be as effective. 

Research on the role of DR5 in cancer originally relied almost exclusively on tumor necrosis factor-related apoptosis inducing ligand (TRAIL) but has been largely abandoned because the small-size ligand, naturally produced by the body to initiate cell death, is rapidly eliminated and thus had unfavorable pharmacokinetics and produced liver toxicity, Buchsbaum says. DR5 antibodies had a more favorable in vivo effect in immune-deficient tumor models because, once injected, they would “circulate for days and result in relatively higher localization within the tumor and didn’t produce systemic toxicity.” 

Daiichi Sankyo appears to be one of few companies that has recently investigated the therapeutic potential of DR5-targeting antibodies. As has been widely reported in recent years, it has also been embroiled in patent disputes with Seagen (formerly Seattle Genetics) over the antibody-drug conjugate technology that would likely be used for their study in clinical trials, says Buchsbaum. 

Tushir-Singh says he is confident the pharma industry will be testing the potential of the proposed combination therapy in patients with solid tumors. It could well extend the efficacy of CAR T-cell therapy and immune checkpoint inhibitors—potentially to the higher levels seen in patients with leukemia and melanoma, he adds, and make them less of a Hail Mary play near the end of life.

Chemotherapy drugs are currently one of the mainstays of cancer treatment because of their ability to break apart tumors so immune cells can infiltrate the mass and do their job. Immunotherapy could be a permanent, nontoxic alternative to chemo if super-activating, DR5-targeting antibodies (such as those in nanocages developed by David Baker at University of Washington) are shown in clinical trials to take on that role, Tushir-Singh says.