MR1

When cells become tumor cells, their metabolism changes fundamentally. Researchers have now demonstrated that this change leaves traces that could provide targets for cancer immunotherapies. When cells become tumor cells, their metabolism changes fundamentally. Researchers at the University of Basel and the University Hospital Basel have now demonstrated that this change leaves traces that could provide targets for cancer immunotherapies. Cancer cells function in turbo mode: Their metabolism is programmed for rapid proliferation, whereby their genetic material is also constantly copied and translated into proteins. As researchers led by Professor Gennaro De Libero from the University of Basel and the University Hospital Basel now report, this turbo metabolism leaves traces on the surface of tumor cells that can be read by specific immune cells. The research team's findings have been published in the journal Science Immunology. The immunologists working with De Libero discovered the immune cells in question, known as MR1T cells, around ten years ago. This previously unknown type of T cell can attack and eliminate tumor cells. Since then, the team has been researching these cells as a potential tool for novel immunotherapies against a variety of different types of cancer. Modified DNA and RNA building blocks The team has now been able to decipher exactly how the T cells recognize the degenerated cells: The altered metabolism of the cancer cells produces a certain type of molecule that appears on the surface of these degenerated cells. "These molecules are chemically modified DNA and RNA building blocks that are the result of changes in three important metabolic pathways," explains De Libero. "The fact that cancer cells have a profoundly altered metabolism makes them recognizable to MR1T cells," adds Dr. Lucia Mori, who was involved in the research. In previous work, the researchers had already discovered that these T cells recognize a surface protein found on all cells, known as MR1. It acts as the proverbial silver platter and presents metabolic products from inside the cell on the cell surface so that the immune system can then check to see whether the cell is healthy or not. "Several metabolic pathways are altered in cancer cells. This produces particularly suspicious metabolic products and thus alert the MR1T cells," explains Dr. Alessandro Vacchini, the study's first author. As a next step, the researchers intend to examine in more detail just how these telltale metabolites interact with the MR1T cells. The long-term vision: Within the framework of future therapies, a patient's T cells could be reprogrammed and optimized to recognize and attack these cancer-typical molecules.

T-cell immune responses play a vital role in the control of tumors. To induce robust and durable T-cell immune responses, the initial requirement is a signal induced by T-cell receptor (TCR) activation (Signal 1). Signal 1 is antigen-specific and it is achieved via the interaction between the T-cell receptor and the peptide-major histocompatibility complex (MHC) on the antigen-presenting cell (APC). However, Signal 1 alone is not sufficient to effectively activate T-cell immune responses, and a sufficient co-stimulatory signal (Signal 2) is required. Unlike Signal 1, Signal 2 is not antigen-specific. Signal 2 is achieved through the interaction between the co-stimulatory signal molecules expressed on APCs and T cells. Costimulatory signals are necessary for T-cell proliferation, differentiation, and survival. Without costimulatory signals, there may be an unresponsive/low response T cells, cell death, or the emergence of immune tolerance. Common co-stimulatory molecule protein families include the IgSF (Immunoglobulin Superfamily), TNRSF (Tumor Necrosis Factor Receptor Superfamily), in addition to others derived from the TIM family, CD2/SLAM family of costimulatory factors. Due to the critical role of costimulatory factors in T-cell immune activation, they have been of particular interest in the field of tumor therapy. 4-1BB4-1BB (also known as CD137 or TNFRSF9) was first discovered in 1989 and is a critical co-stimulation receptor on T cells and other immune cells. It is a member of the TNRSF protein family mentioned earlier. In 1997, Melero and colleagues found that a monoclonal antibody against 4-1BB was able to induce anti-tumour activity in T cells in mice. The main effects of 4-1BB on T cell activation include cell proliferation, cytokine release, cytotoxicity, and the formation of long-term immune memory, among others. Most of T cell activation occurs in CD8+ T cells. Two second-generation CAR-T cell therapies, Kymriah (Novartis) and CARVYKTI (Johnson&Johnson), which have been approved by the FDA, utilise 4-1BB as their co-stimulation domain. Other second-generation CAR-T therapies use CD28 as their co-stimulatory domain. Although both have shown similar tumour control rates in cancer patients, some differences were found: CD28 appears to have a higher cytokine release effect and can better promote T cell proliferation, but it also has a higher risk of neurotoxicity, while 4-1BB can foster longer-term T cell persistence. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs, indications, organizations, clinical trials, clinical results, and drug patents related to this target. 4-1BB is a glycosylated type-I membrane protein. It has four functional domains (known as "CRD", cysteine-rich pseudo repeats domain). The 4-1BB ligand (4-1BBL) is the binding partner of 4-1BB, which is generally expressed on the cell surface as a homotrimeric complex. Upon antigen stimulation, effective binding between 4-1BB and 4-1BBL can activate rapid receptor activation. For optimal co-stimulation (signal 2), 4-1BB needs to cluster on the cell surface. The Application of 4-1BB in Antibody Drug DevelopmentThe First Generation of 4-1BB Agonist Drugs The clinical development of 4-1BB agonist antibodies began in 2005 with the antibody drug urelumab (BMS-663513) created by Bristol-Myers Squibb (BMS). Urelumab is a humanized anti-4-1BB IgG4 subtype antibody. The early development data was promising, but there were two serious adverse events due to hepatic toxicity. Subsequent research found that while the drug was effective, its potency was very limited when administered at a safe dose (0.1 mg/kg). The second 4-1BB antibody drug developed was Pfizer's utomilumab (PF-05082566). The antibody drug is a fully human IgG2 subtype antibody and entered clinical trials in 2011. Although it did not demonstrate the safety issues seen in urelumab, its effectiveness (whether used alone or in combination with rituximab) was very limited, leading to the discontinuation of its clinical development. Urelumab and utomilumab, as the first generation of 4-1BB antibodies, displayed different agonistic activities and liver toxicities. These differences are currently thought to be due to differences in the Fc effector functions and epitope binding of these two molecules. The Fc effector function, particularly binding to FcγRIIB, is generally believed to be associated with liver toxicity (FcγRIIB cross-linking in the liver). As an IgG4 subtype, urelumab has stronger FcγRIIB binding, which is likely why it differs in liver toxicity from utomilumab (IgG2 subtype). The epitope binding is another reason for the different activities between urelumab and utomilumab. Urelumab and 4-1BB bind through an epitope on CRD1, which does not interfere with the binding of 4-1BB to its natural ligand. Utomilumab binds to 4-1BB through epitopes on CRD2 and CRD3. This binding method results in a large amount of endogenous 4-1BB ligand competing with utomilumab for binding to the 4-1BB receptor, limiting the activity of 4-1BB receptor clustering (which promotes the agonist activity of 4-1BB). This explains why urelumab (which does not affect 4-1BB receptor clustering) has higher agonist activity than utomilumab (which does affect 4-1BB receptor clustering). Second Generation 4-1BB Agonist Drugs The mediocre performance of Urelumab and Utomilumab in clinical trials did not douse the interest of many pharmaceutical companies in further exploring the 4-1BB target. Since the beginning of 2017 to the present, more than 40 4-1BB agonist drugs have entered clinical trials. Although the clinical trials of 4-1BB drugs temporarily declined in 2020 due to the COVID-19 pandemic, they showed a strong rebound afterwards. There may be more and more 4-1BB agonist drugs entering the clinic in the future, as many pharmaceutical/biotech companies are actively conducting preclinical research on 4-1BB drugs. The 4-1BB drugs that appeared after Urelumab and Utomilumab are categorized as the second-generation 4-1BB agonist drugs in this article. The second-generation 4-1BB agonist drugs mainly fall into two categories: IgG type (mono-antibody structure) and bi/multi-antibody 4-1BB agonist drugs. The mechanism of action of the IgG type second-generation 4-1BB agonist drugs has some consistency with the first-generation drugs (Urelumab and Utomilumab): they mostly rely on the cross-linking effect of Fcγ receptors, but their binding epitopes have been modified compared to the first generation. For example, the drug ADG106 developed by Suzhou Tyvance Biotech, also adopts the IgG4 subtype like Urelumab, but it does not bind to Urelumab's epitope CRD1. The concept behind this design is to have the drug be effective while reducing its toxic side effects, achieving a more precise regulation of the balance between effectiveness and safety (“sweet point” of functionality). The second type of second-generation 4-1BB agonist drugs are bi/multi-antibody agonist drugs. These drugs bind to at least one other target in addition to 4-1BB. Adding another target can increase the specificity of the drug, its cross-linking effect, and confer additional stimulatory or inhibitory activity, endowing the drug with extra anti-tumor properties. Targets commonly paired with 4-1BB include: PD-L1 (e.g., I-MAB Biopharma's TJ-L14B, Nanjing Leads Biolabs's LBL-024, Biotheus' PM1003), FAP (e.g., Roche's RG7827, Boehringer Ingelheim's BI765179) etc. In addition, the Fc end of this type of drug has been engineered to eliminate the ability to bind with Fcγ receptors but maintain the ability to bind with neonatal Fc receptors (FcRn) to ensure the half-life of the drug in the body. The aim is to suppress the liver toxicity seen in Urelumab, improving the safety of the drug. Drugs adopting this design strategy include Roche's RG7827 and RG6076, Elpiscience Biopharma's ES101, I-MAB Biopharma's TJ-L14B etc. Immunotherapy, surgery, radiation therapy, and chemotherapy together constitute the four methods of cancer treatment. In order to enhance the efficacy, surgery/chemotherapy/radiation therapy can be combined with immunotherapy as a joint treatment strategy. Currently, the combination of 4-1BB with radiation therapy and chemotherapy has been shown to have a good synergistic effect. In addition, anti-4-1BB antibodies have also been shown to improve the efficacy of other antibodies. Joint treatment plans based on 4-1BB antibodies may be a direction for future advancements in cancer treatment.

Taking a significant leap in the field of vaccine development, Schulich School of Medicine & Dentistry researchers have discovered a potential 'super molecule' that can bolster the effectiveness of several vaccines against viral diseases, including influenza, COVID-19 and smallpox. Taking a significant leap in the field of vaccine development, Western researchers have discovered a potential 'super molecule' that can bolster the effectiveness of several vaccines against viral diseases, including influenza, COVID-19 and smallpox. A team led by Western professor Mansour Haeryfar found that a vitamin B2-derived molecule called 5-OP-RU, which is produced by bacteria, can enhance the efficacy of several vaccines for viral diseases. The study revealed the molecule binds to a protein called MR1 before stimulating a population of T lymphocytes called mucosa-associated invariant T (MAIT) cells -- essentially, one of the "first responders" that come rushing to fight off infection when a virus invades the body. The findings, recently published in PLOS Pathogens, could have significant implications for strengthening the global response to current and future viral threats. "We need better vaccines to combat viruses of pandemic potential, which are among the most vicious existential threats to human populations," said Haeryfar, professor of immunology at Western's Schulich School of Medicine & Dentistry. "Our strategy of targeting the MR1-MAIT cell axis using 5-OP-RU shows promise in generating strong antiviral immune responses in the body. This strategy could help develop more effective viral vaccines." For the study, the team of researchers used a combination of clinically relevant mouse models, human cell cultures and multiple vaccine platforms against various influenza, SARS-CoV-2 and smallpox. They found that 5-OP-RU worked in tandem with antiviral vaccines to expand MAIT cells and reprogram them to become more powerful antiviral entities. "MAIT cells are often found in the bloodstream and in mucosal tissues, including in our respiratory system, which is often the first place in which many viruses are encountered" said Haeryfar. When viruses like flu or SARS-CoV-2 get into our lungs, MAIT cells are already there and ready to fight. They respond quickly to infections, coordinate our immune response, and help destroy virus-infected cells. This makes them very attractive targets in vaccine design strategies." As for the next steps, Haeryfar and his team plan to extend their studies to test the efficacy of 5-OP-RU in several COVID vaccine candidates, including a promising Western-developed COVID-19 vaccine candidate and inhaled vaccines. "While mRNA vaccines were and remain potent in reducing the risk of severe morbidity and mortality due to COVID-19, we need more effective vaccines to prevent infection with SARS-CoV-2 variants of concern. We are now looking to investigate the possibility of using 5-OP-RU and potentially other MR1-binding molecules in inhaled vaccines," he added. The study also suggests that the unique characteristics of MAIT cells -- quick-acting entities with antibacterial and tissue repair properties -- could also help resolve secondary bacterial infections and tissue damage in the aftermath of viral infection. "It is also noteworthy that MAIT cells are evolutionarily conserved. Therefore, the results of preclinical studies are likely to be translatable to the clinic," said Haeryfar. "Everyone has the exact same MR1 protein. Therefore, immunization strategies that target MR1 and MAIT cells should work across diverse human populations, regardless of their genetic makeup." Supervised by Haeryfar, the study was spearheaded by Western graduate student Rasheduzzaman Rashu and a team of current and former Haeryfar Lab trainees including Marina Ninkov, Christine Wardell, Jenna Benoit, Nicole Wang and Courtney Meilleur. The research included contributions from Western professors David Hess, Stephen Barr, Ryan Troyer and Chil-Yong Kang, and researchers from McMaster University. This research was supported by a Canadian Institute of Health Research (CIHR) Project Grant awarded to Haeryfar.