MD Anderson and Xencor enter strategic collaboration to develop novel T cell-engaging bispecific antibodies for potential treatment of patients with cancer
The University of Texas MD Anderson Cancer Center and Xencor, Inc. announced a strategic research collaboration and commercialization agreement to develop novel CD3 bispecific antibody therapeutics for the potential treatment of patients with cancer. This collaboration joins Xencor’s innovative XmAb® technology and protein engineering expertise to create bispecific antibodies with MD Anderson’s expertise in the research and discovery of novel therapeutic antibodies, including the Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, part of MD Anderson’s Therapeutics Discovery division.
The University of Texas MD Anderson Cancer Center and Obsidian Therapeutics, Inc. today announced a multi-year strategic collaboration designed to expedite the research and development of novel engineered tumor infiltrating lymphocytes (TILs) for the treatment of solid tumors. The agreement pairs Obsidian and its novel cytoDRiVE™ technology platform with MD Anderson’s extensive experience and state-of-the-art capabilities in TIL cell therapy, led by the Biologics Development platform, within the Therapeutics Discovery division.
The collaboration is focused on developing TIL armored with regulated membrane-bound IL15 (referred to as cytoTIL™) with the potential to enhance anti-tumor efficacy and reduce tumor burden in patients suffering from different types of solid tumors. The teams will collaborate to accelerate the development of cytoTIL, including process and analytical development and clinical readiness activities.
“TIL therapy has emerged as a promising option for treating patients with solid tumors, though its widespread use today is limited by safety and efficacy challenges,” said Rodabe Amaria, M.D., associate professor of Melanoma Medical Oncology at MD Anderson. “We are pleased to work with Obsidian to advance their novel cytoTIL program, which has the potential to drive more durable treatment responses and expand TIL therapy to a broader group of our patients.”
The cytoTIL therapy is engineered using Obsidian's cytoDRiVE platform technology, which precisely and reversibly controls protein expression and activity using FDA-approved orally bioavailable drugs. By leveraging regulated membrane-bound IL15 to drive antigen-independent expansion of T cells and transactivation of NK cells, cytoTIL therapy is anticipated to improve patient response to TIL treatment and expand patient eligibility to those who currently cannot benefit from this transformative therapy.
“We are delighted to work with MD Anderson’s Biologics Development team to build upon the success of first generation TIL therapies and bring the first controllable TIL therapy to patients as rapidly as possible,” said Paul Wotton, Ph.D., CEO of Obsidian Therapeutics. “Through its cell therapy research platforms, deep clinical development experience, and industrial manufacturing capabilities, MD Anderson is a best-in-class collaborator to advance and accelerate cutting-edge cell therapies.”
MD Anderson’s Biologics Development
platform is built around an experienced team focused on pioneering
impactful biologic therapeutics, including antibodies and cell
therapies. With a state-of-the-art 60,000 sq. foot GMP cell-therapy
manufacturing facility, the platform joins MD
Anderson expertise with the rigor of industrial development.
Biologics Development offers a strong starting point for early-stage
companies to access the breadth of MD
Anderson capabilities in cell therapy development.
MD Anderson is implementing an Institutional Conflict of Interest Management and Monitoring Plan for any research related to this relationship.
The University of Texas MD Anderson Cancer Center and Taiho Pharmaceutical Co., Ltd., today announced a three-year strategic collaboration to accelerate the development of treatments for significant unmet medical needs in oncology, including patients with brain metastases and those with cancers refractory to available therapies.
This collaboration will bring Taiho’s unique portfolio of preclinical and clinical brain-penetrant therapies together with both the translational research capabilities of MD Anderson’s Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform as well as insights and clinical development infrastructure from MD Anderson’s Brain Metastasis Clinic.
“Our collaboration with MD Anderson exemplifies a direct line of sight from target development to therapies for patients with limited treatment options,” said Teruhiro Utsugi, Ph.D., managing director at Taiho. “Investigating our novel portfolio of drug candidates in this innovative research structure will enable us to more rapidly identify and develop effective treatment strategies.”
According to the American Brain Tumor Association, metastases to the brain and spine are diagnosed in more than 200,000 patients annually in the US. However, the development of effective treatment approaches for these patients has been hampered because they often are excluded from clinical trials. However, recent studies in melanoma, lung and breast cancers have demonstrated that patients with brain metastases can gain significant clinical benefit from immunotherapy and targeted therapies, leading to improvements in quality of life and survival.
MD Anderson’s Brain Metastasis Clinic is a patient-focused, multidisciplinary center designed to reduce the time from a diagnosis to treatment for patients with brain metastases while improving access to clinical trials. The TRACTION platform, an industry-scale translational research unit within MD Anderson’s Therapeutics Discovery division, has established a robust integrated research framework with the Brain Metastasis Clinic to identify innovative treatment approaches and execute novel clinical trials.
“MD Anderson’s commitment to delivering novel therapeutic strategies to patients with unmet clinical needs is exemplified in the development of the Brain Metastasis Clinic and its close collaboration with the TRACTION platform,” said Timothy Heffernan, Ph.D., executive director of TRACTION at MD Anderson. “Our alliance with Taiho combines outstanding drug discovery with expertise in translational research and clinical development to advance new treatment options for patients diagnosed with brain metastases.”
First emerging almost three decades ago, monoclonal antibodies are changing the way doctors treat cancer and other illnesses, including COVID-19. These drugs mimic the immune system’s natural ability to fight off infection.
But how do monoclonal antibodies work to treat cancer? What are their side effects? And how are doctors using them to treat COVID-19? We spoke with Ecaterina Ileana Dumbrava, M.D., and Dongxing Zha, Ph.D., to learn more.
What are monoclonal antibodies?
The immune system creates millions of y-shaped proteins called antibody receptors – or antibodies. Each antibody is floating through the body looking for a unique target that’s on the surface of a foreign cell called an antigen. When an antibody finds its target, it binds with the antigen and helps the immune system kill the diseased cell.
“An antibody is like a key that’s matched to a specific door,” says Dumbrava.
Monoclonal antibodies are drugs that are designed to copy the benefit of natural antibodies and their ability to fight off cancer and other illness, adds Zha.
How monoclonal antibodies are used to treat cancer
Monoclonal antibodies are used to treat many cancer types. They’re given to patients through an infusion and can be used alone or in combination with other cancer treatments. Each monoclonal antibody works in one or multiple ways, depending on the antigen that it’s targeting.
Some monoclonal antibodies directly bind to the cancer cells to kill them. Because they’re targeting specific receptors in the cells, these monoclonal antibodies are referred to as targeted therapies. An example is trastuzumab (Herceptin), which is used to treat HER2-positive breast cancer and stomach cancer.
“Trastuzumab attaches to the HER2 receptors on the cancer cells and prevents them from multiplying, which stops growth and slows cancer progression,” Dumbrava says.
Other monoclonal antibodies help ramp up the immune system’s white blood cells. “By enhancing white blood cells, monoclonal antibodies can make your immune system more effective in killing the tumor,” Zha says. An example is nivolumab, which targets the PD-1 receptor. Nivolumab is a type of immunotherapy that’s used to treat colorectal cancer, lung cancer, kidney cancer, melanoma, lymphoma and some head and neck cancers.
Immunotherapy drugs like nivolumab can sometimes cause severe side effects like inflammation in the colon or the lungs. “The immune system becomes too boosted and it attacks normal tissue,” Dumbrava says.
To manage the inflammation, the patient stops the immunotherapy and is given steroids. If the steroids don’t work, some patients may receive a different monoclonal antibody to bring the inflammation down. “It’s fascinating that we use monoclonal antibodies to treat side effects from other monoclonal antibodies,” Dumbrava says.
Engineering monoclonal antibodies to treat cancer more effectively
“A lot of times, monoclonal antibodies are still not enough to kill the tumor cells by themselves,” Zha says. So, they can be further modified to be even more effective, he adds. One approach is to create bi-specific antibodies. “One end of the y-shaped antibody is bound to the tumor cell and the other end is fused to a white blood cell,” Zha says. “Then the white blood cells kill the tumor.”
Another approach is to attach a chemotherapy drug to a monoclonal antibody. These are called antibody-drug conjugates. “With this approach, chemotherapy is delivered to the cancer cells while avoiding healthy cells,” Dumbrava says. “It’s sort of like a trojan horse.” An example is trastuzumab emtansine, which combines the HER2 monoclonal antibody trastuzumab with the chemotherapy drug emtansine. When trastuzumab connects with HER2 antigen expressed on the cancer cells, emtansine enters inside the cancer cell and kills it.
CAR T cell therapy is also built off a monoclonal antibody known as chimeric antigen receptor (CAR). A type of white blood cell called a T cell is removed from a patient through a process like a blood draw. In the lab, Dumbrava says, the T cells are modified to produce the CAR monoclonal antibody, which allows the T cells to attach to specific antigens on the tumor cells. The engineered CAR T cells are then reinfused back into the patient. “With CAR T cell therapy, we’re using a monoclonal antibody to more specifically target your immune system to the tumor to kill it,” Zha says.
Although only currently approved by the Food and Drug Administration (FDA) to treat some types of B-cell lymphoma and acute lymphoblastic leukemia, studies are underway to explore the use of CAR T cell therapy or similar therapies in solid tumors such as lung, breast or liver cancer.
Monoclonal antibody side effects vary, but are usually mild
When compared to chemotherapy, monoclonal antibodies are precise in the way they attack cancer cells. “Because they’re more targeted, they’re typically safer for patients,” Zha says. Fewer normal cells are being affected by the therapy, which results in fewer side effects.
However, Dumbrava says, there are still risks. Some of the most common mild side effects are fatigue, nausea, diarrhea and skin rashes. Some patients also have an allergic reaction to the infusion, so they may break out in hives or experience itching.
Side effects of monoclonal antibodies can be severe. Although it’s rare, the allergic reaction to the infusion can become life-threatening. Other rare but severe concerns include decreased blood cell counts, bleeding or problems with the heart or lungs.
How do monoclonal antibodies treat COVID-19?
Cancer isn’t the only disease treated with monoclonal antibodies. They’re also used to treat chronic inflammatory diseases like Crohn’s disease and rheumatoid arthritis, as well as other diseases like graft-versus-host disease.
Currently, it’s being explored as a treatment option for the coronavirus (COVID-19). “Just like we identify an antibody for cancer, we have the same approach to identify the antibody against the virus,” says Zha, who is the institute head of MD Anderson’s Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, which specializes in the development of monoclonal antibodies. Part of our Therapeutics Discovery division, ORBIT’s researchers, drug developers and clinicians work together to bring new, more effective therapies to patients faster than ever. “We call it ‘bench at bedside,’” says Zha.
Because of ORBIT’s unique structure, Zha and his team have been working to develop a treatment for the coronavirus using antibodies from patients who have recovered from the virus. Through sophisticated technology called single B-cell cloning, the ORBIT team can sort through a recovered patient’s B-cells and identify the antibody that’s matched with the COVID-19 protein.
“The hope is these antibodies can neutralize the virus and prevent it from infecting more normal tissue,” Zha says. Using mouse models, they’ve already identified the COVID-19 target and established the methodology for next steps in the drug’s development.
Zha is hopeful for the future. “It’s a very good time for antibody drug discovery and for patients,” he says.
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New preclinical research from The University of Texas MD Anderson Cancer Center and BridgeBio Pharma, Inc. affiliate Navire Pharma, Inc., finds that the novel SHP2 inhibitor IACS-13909 is able to overcome multiple therapeutic-resistance mechanisms in non-small cell lung cancer (NSCLC), suggesting a possible new approach to treating cancers that have developed resistance to the targeted EGFR inhibitor osimertinib.
The data is published today in Cancer Research, a journal of the American Association for Cancer Research. IACS-13909 is a potent and selective allosteric SHP2 (Src homology 2 domain-containing phosphatase) inhibitor developed through collaboration between Navire and MD Anderson’s Therapeutics Discovery division. Based on these data, Navire plans to launch a clinical study of SHP2 inhibitors by the end of 2020 at multiple US sites, including MD Anderson.
IACS-13909 was initially discovered as an SHP2 inhibitor by a team of scientists in MD Anderson’s Institute for Applied Cancer Science (IACS) and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within the Therapeutics Discovery division.
“Tyrosine kinase inhibitors, like osimertinib, appear initially effective in suppressing tumor growth, but multiple mechanisms of resistance can develop while a patient is still receiving treatment,” said Nancy Kohl, Ph.D., a senior author of the study and member of Navire’s scientific advisory board. “This study shows that IACS-13909’s ability to inhibit a protein downstream of multiple signaling pathways is a promising approach in overcoming these common tumor-resistance mechanisms.”
Osimertinib is a targeted EGFR inhibitor used as a front-line option for treating patients with NSCLC harboring specific EGFR mutations. However, NSLCs frequently develop osimertinib resistance over time, either through additional mutations in EGFR that block activity of the drug, or by activating compensatory signaling pathways.
SHP2 is a protein that acts downstream in these pathways, and it is required for full activation of the MAPK signaling pathways, which is known to fuel tumor growth, proliferation and survival.
“Our findings show that IACS-13909 is capable of suppressing tumor cell proliferation in vitro and causing tumor regression in vivo for lung cancers harboring a variety of activated kinases as the oncogenic driver,” said lead author Yuting Sun, Ph.D., co-project lead and senior research scientist with TRACTION at MD Anderson. “These data suggest that targeting SHP2 could provide a viable strategy for overcoming osimertinib resistance occurring through a variety of mechanisms.”
These results were consistent when IACS-13909 was used as a single agent and in combination with osimertinib in vivo. The combination treatment in vitro led to prolonged, more durable responses in tumors that were sensitive to osimertinib and stimulated tumor regression in osimertinib-resistant models.
“Through our collaboration with the Therapeutics Discovery team at MD Anderson, we continue to uncover SHP2’s critical role in activating multiple different pathways related to cancer’s onset and growth,” said Eli Wallace, chief scientific officer of oncology at BridgeBio, Navire’s parent company. “This study further supports the very reason that Navire was founded – to develop novel SHP2 insights into targeted medicines for patients in need. We look forward to advancing our lead SHP2 inhibitor into the clinic later this year.”
The ongoing research is supported by Navire through a global licensing and development agreement, and the Therapeutics Discovery division is supported in part by MD Anderson’s Moon Shots Program®. MD Anderson has an institutional financial conflict of interest with Navire, and the research is managed according to MD Anderson’s Institutional Conflict of Interest Management and Monitoring Plan. A complete list of study co-authors and their disclosures can be found with the full paper here.