After scientists discover promising anti-cancer drugs, they typically partner with a biotech or pharmaceutical company that can develop the compound and pay for the necessary clinical trials. But Xingxing Zang, Ph.D., has taken a completely different route.
Despite an impressive history of attracting pharmaceutical-industry support for his previous compounds, Dr. Zang decided that the best commercial path for one of his most promising experimental anti-cancer compounds would be a start-up company focused on his discovery.
“Going with a large pharmaceutical company has both good and bad aspects,” says Dr. Zang, a member of the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC), and professor of microbiology & immunology, of oncology, of medicine, and of urology and the Louis Goldstein Swan Chair in Cancer Research at Albert Einstein College of Medicine.
Those companies have the resources to invest millions of dollars on an experimental compound, against overwhelming odds that it will ever make it to market, Dr. Zang noted. On the other hand, such compounds can gather dust when large companies don’t prioritize them.
“I reasoned that being involved in a start-up, we would be able to control the development of this new compound, ensuring it gets the attention it deserves,” Dr. Zang says. “And because we have equity in the new company, it also allows more of the revenue to go to Einstein.”
With his new anti-cancer molecule—a novel first-in-class immune checkpoint inhibitor (ICI) called NPX267—Dr. Zang is pursuing his own path.
I reasoned that being involved in a start-up, we would be able to control the development of this new compound, ensuring it gets the attention it deserves.
Xingxing Zang, Ph.D.
A Better Way to Treat Cancer
The immune system has a mechanism for preventing T cells and other immune cells from straying beyond their usual “enemy” targets and attacking healthy cells instead. That mechanism features proteins called inhibitory, or “checkpoint” receptors, which stud the surface of immune cells. When normal cells and immune cells come in contact with each other, proteins on the normal cells bind with immune cells’ inhibitory checkpoint receptors, triggering a signal that prevents, or “checks,” immune cells from attacking the cells they’ve encountered. Unfortunately, most cancers cleverly express surface proteins that can stimulate immune cells’ inhibitory receptors, tricking immune cells into standing down and not attacking.
Some 30 years ago, James P. Allison, Ph.D.—Dr. Zang’s mentor—realized that cancer treatment could be improved by preventing cancer cells from putting the brakes on T cells. He envisioned a strategy that called for using ICIs—monoclonal antibodies that would short-circuit immune-cell/cancer-cell interactions by blocking either the tumor proteins or the immune-cell receptors. With no brakes to impede them, immune cells would be free to attack and destroy cancer cells. Dr. Allison’s ground-breaking research earned him the 2018 Nobel Prize in Physiology or Medicine; and today, ICIs, such as Keytruda®, Yervoy®, and Opdivo®, have completely revolutionized cancer therapy and are used to treat a wide range of human cancers.
The Pros and Cons of Today’s ICIs
ICIs are remarkably effective—in some cases curing previously incurable cancers such as advanced melanomas and far less likely to cause the debilitating side effects typically associated with traditional chemotherapy. ICIs have been approved for treating several other cancer types as well, including lung cancer, breast cancer, colorectal cancer, bladder cancer, cervical cancer, kidney cancer, head and neck cancer, liver cancer, gastric cancer, and Hodgkin and non-Hodgkin lymphoma.
In 2008, Dr. Zang set up his own research lab at Einstein. Since then, he has been motivated by the need to find new checkpoints and develop better ICIs. “As remarkable as they are,” says Dr. Zang, “the ICIs now available don’t work in the majority of cancer patients.”
One of the main challenges for ICI therapy is that they are designed to inhibit only one checkpoint signaling pathway: the PD-1/PD-L1 pathway, involving the T-cell checkpoint receptor PD-1 and the tumor-cell protein PD-L1. Moreover, since PD-1 is found mainly on T cells, today’s ICIs fail to liberate other immune cells capable of attacking tumors, such as natural killer (NK) cells.
In sharp contrast, Dr. Zang’s new compound, NPX267, targets a checkpoint pathway completely different from PD-1/PD-L1. And since that pathway occurs in both T cells and NK cells, NPX267 can potentially boost the cancer fighting ability of both types of immune cells. For those reasons, Dr. Zang is hopeful that his new compound may work against cancers that don’t respond to current checkpoint inhibitors.
How a New Pathway Led to a New Drug
![At left: A T cell has recognized a tumor cell as foreign (T cell receptor has bound to tumor cell antigen) but fails to attack because checkpoint proteins have interacted: The tumor’s PD-L1 protein has bound to the T cell’s PD-1 protein, putting the brakes on T cell activity. At right: In immunotherapy, monoclonal antibodies block checkpoint protein interactions so that T cells remain active to kill tumor cells. Here, one type of monoclonal antibody (Anti-PD-L1) has been designed to bind to the tumor’s PD-L1 protein, and another type (Anti-PD-1) works by binding to the T cell’s PD-1 protein.]()
Click to enlarge
In a 2013 paper in the Proceedings of the National Academy of Sciences, Dr. Zang reported that—in addition to PD-L1—tumors express a previously unknown immune checkpoint protein called HHLA2. He soon found that HHLA2 was over-expressed in a broad spectrum of human cancers including breast, lung, thyroid, skin, pancreatic, ovarian, liver, bladder, colon, prostate, kidney, and esophageal. Further research by Dr. Zang and colleagues revealed that most cancers that don’t express PD-L1 do express high levels of HHLA2.
These findings indicated that Dr. Zang had discovered an important new pathway, involving HHLA2, that could be targeted using new checkpoint inhibitors. Targeting this pathway could be especially helpful for treating the many patients whose cancers do not express PD-L1 and therefore usually don’t respond to current ICIs. All that remained was to identify HHLA2’s “binding partner,” or inhibitory receptor, on immune cells.
In a 2021 paper in Science Immunology, Dr. Zang and colleagues characterized HHLA2’s inhibitory receptor, which they called KIR3DL3, and found that it was present on both T cells and NK cells. The researchers next developed anti-KIR3DL3 monoclonal antibodies that successfully interfered with the interaction between KIR3DL3 and HHLA2. Most importantly, those monoclonal antibodies, termed NPX267, bolstered the activity of T cells and NK cells and inhibited tumor growth in humanized mice.
Making Contact With a Matchmaker
Dr. Zang was ready to translate NPX267 into a clinical therapy, preferably in a homegrown biotechnology company. For help in realizing this venture, Dr. Zang turned to Janis Paradiso, M.B.A., director of Einstein’s office of biotechnology and business development. Ms. Paradiso put him in touch with Einstein alumnus Elizabeth Stoner, M.D. ’77, M.S., and executive partner at MPM BioImpact, a Boston-based biotechnology investment firm. It was an excellent match.
Dr. Stoner, a pediatric endocrinologist, started her career at Weill Cornell Medicine. After a few years in academic medicine, she joined Merck & Co. as a physician-scientist, developing drugs including Proscar®, a treatment for enlarged prostates. Twenty-three years later, she moved to MPM BioImpact, where she remained firmly planted in the scientific world.
“Venture capital is about funding companies,” she says, “but it’s also about understanding the science of what you fund and being able to guide a discovery to the next level. Every day I remind myself that I’m a physician, even if I don’t touch patients.”
At MPM, Dr. Stoner would check in periodically with Ms. Paradiso about promising, investment-worthy research being conducted at Einstein.
“I’m not an immunologist or oncologist, but Dr. Zang’s work on HHLA2 looked very interesting,” Dr. Stoner recalls. Her MPM colleagues were also intrigued, since they’d previously worked with immunotherapy pioneer Gordon Freeman, Ph.D., of Boston’s Dana-Farber Cancer Institute, who had discovered the HHLA2/KIR3DL3 pathway independently of Dr. Zang.
Ultimately, all three parties—Dr. Zang, Dr. Freeman, and MPM—decided to join forces to launch NextPoint Therapeutics, with a focus on drugs that target this new pathway. They have the field mostly to themselves, since most pharmaceutical companies are still focused on developing drugs that disrupt the PD-1/PD-L1 signaling pathway.
In January of 2023, NextPoint announced that it had raised $80 million to move HHLA2/KIR3DL3-related cancer immunotherapies to clinical trials. Seven months later, the company announced the launch of a Phase 1a/1b clinical trial to evaluate the safety, tolerability, and pharmacokinetics of Dr. Zang’s NPX267 in 131 patients affected by 12 different types of treatment-resistant metastatic solid tumors. Patients are currently being enrolled at six medical centers around the United States, including MECCC.
NextPoint will soon start another clinical trial with its second drug, the monoclonal antibody NPX887 targeting HHLA2. This antibody is directly aimed at disrupting the HHLA2/KIR3DL3 pathway. While NPX267 targets KIR3DL3 on immune cells, NPX887 targets HHLA2 on tumor cells.
Wanted: More Alumni Connections
“I’m proud to have made the introductions that helped make NextPoint happen,” says Dr. Stoner. “NPX267 is a novel therapy with the potential to transform immunotherapy. We have lots of room for improvement in cancer treatment.”
Ms. Paradiso says that “it would be great” if more Einstein alumni established connections with Einstein through the office of development and alumni relations and the office of biotechnology and business development. “Not all of our graduates go into medical practice, but they may have other expertise that could contribute to medicine and to Einstein,” she notes. “If there are other graduates out there who could help move our technologies forward, please get in touch with us.”
Posted on: Thursday, February 15, 2024