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Paris, March 20, 2025. Sanofi and Dren Bio, Inc., a private clinical-stage biopharmaceutical company, have entered into a definitive agreement under which Sanofi has agreed to acquire DR-0201, a targeted bispecific myeloid cell engager (MCE) that has shown robust B-cell depletion in pre-clinical and early clinical studies. DR-0201 is a potential first-in-class CD20-directed bispecific antibody that targets and engages specific tissue-resident and trafficking myeloid cells to induce deep B-cell depletion via targeted phagocytosis. Recent early clinical study data in autoimmune diseases suggest that deep B-cell depletion might have the potential to reset the adaptive immune system, leading to sustained treatment-free remission in patients with refractory B-cell mediated autoimmune diseases such as lupus, where significant unmet medical needs remain. Deep B-cell depletion is at the frontier of treating autoimmune diseases and using the myeloid cell engager DR-0201 has the potential to elevate the treatment effect for patients, in particular patients refractory to existing treatments. This is yet another important step in Sanofi’s ambition to bring breakthrough medicines to patients, and further strengthens our robust pipeline focused on the immune system. Through our own research and strategic licensing and acquisitions, we continue to advance our goal of becoming the leader in immunology. Dren Bio is committed to redefining treatment possibilities in immunology, oncology, and other therapeutic areas with our targeted myeloid engager and phagocytosis platform. It has been a privilege to advance our lead platform program, DR-0201 into clinical development and evaluate its potential to achieve potent B-cell depletion. As a leader in immunology, Sanofi is ideally positioned to unlock the power of deep B-cell depletion and immune reset for autoimmune patients with this novel myeloid cell engager. DR-0201 is the first bispecific antibody from Dren Bio’s targeted myeloid engager and phagocytosis platform, which acts by engaging tissue-resident and trafficking myeloid cells to induce deep B-cell depletion. DR-0201 is being evaluated in two ongoing phase 1 studies and has shown deep and robust B-cell depletion in non-clinical and clinical settings. Under the terms of the merger agreement, Sanofi will acquire DR-0201 through the acquisition of the Dren Bio affiliate Dren-0201 for an upfront payment of $600 million and potential future payments totaling $1.3 billion upon achievement of certain development and launch milestones. After the acquisition of Dren-0201, Dren Bio will continue to operate independently to advance its pipeline of antibody therapeutics that selectively deplete pathogenic cells and other disease-causing agents. Sanofi’s acquisition of Dren-0201 is subject to closing conditions, including receipt of regulatory approvals. The companies expect the transaction to close during Q2 2025. Sanofi expects to finance the transaction with available cash resources.

A protein in the immune system programmed to protect the body from fungal infections is also responsible for exacerbating the severity of certain autoimmune diseases such as irritable bowel disease (IBS), type 1 diabetes, eczema and other chronic disorders, new research has found.  The discovery could pave the way for new and more effective drugs, without the nasty side effects of existing treatments. In addition to helping to manage severe autoimmune conditions, the breakthrough could also help treat all types of cancer.   A protein in the immune system programmed to protect the body from fungal infections is also responsible for exacerbating the severity of certain autoimmune diseases such as irritable bowel disease (IBS), type 1 diabetes, eczema and other chronic disorders, new research from The Australian National University (ANU) has found. The discovery could pave the way for new and more effective drugs, without the nasty side effects of existing treatments. In addition to helping to manage severe autoimmune conditions, the breakthrough could also help treat all types of cancer. The scientists have discovered a previously unknown function of the protein, known as DECTIN-1, which in its mutated state limits the production of T regulatory cells or so-called 'guardian' cells in the immune system. These guardian cells are crucial to preventing autoimmune disease because they suppress the effects of a hyperactive immune system, which can be extremely dangerous if not properly regulated. The immune system is designed to protect the body from infection, but in severe cases it becomes overactivated and turns the body's natural defences against itself. "When this happens, the immune system wrongly perceives healthy cells as a threat, causing it to attack the body and promote the onset of autoimmune disease," lead author Dr Cynthia Turnbull, from ANU, said. "Although the DECTIN-1 protein helps to fight fungal infections, in its mutated state it's also responsible for exacerbating severe autoimmune disease. "Understanding how and why the mutated version of this protein causes autoimmunity in patients brings us a step closer to developing more effective drugs and offers new hope to more than one million Australians who suffer from some form of autoimmune disease." The scientists believe they can control the immune system by turning the DECTIN-1 protein on and off, like a light switch. "Turning on the protein would lower the intensity of the immune system's defensive response which would help to treat conditions such as autoimmune disease," Professor Carola Vinuesa, from the Francis Crick Institute, said. "On the other hand, turning off the protein could give the immune system a boost, sending its defensive mechanisms into overdrive and allowing the body to treat an entirely different set of diseases. "The findings are exciting because there haven't been many discoveries of so-called modifier proteins such as DECTIN-1, which can change the way the immune system behaves to the extent it can either cause a disease or prevent it." According to Dr Turnbull, this means DECTIN-1 could play a key role in treating cancer. "Cancer cells can disguise themselves by releasing certain proteins and chemicals into the body that essentially render them invisible from the immune system's natural defences," she said. "We think that by using drugs to turn off the DECTIN-1 protein, in combination with existing therapies, we can activate the immune system and help it identify and attack the cancerous cells." Current treatments for autoimmune?disease aren't very effective and have a lot of damaging side effects. This is because the majority of existing treatments suppress the entire immune system rather than targeting a specific area. "That means it might not fix the exact problem behind the patient's disease and could inadvertently make them vulnerable to infections. Many people on these kinds of treatments also get bacterial, fungal and viral infections which can make their autoimmunity worse," Professor Vinuesa said. By examining the DNA of a Spanish family, the researchers discovered the DECTIN-1 mutation was responsible for exacerbating the severity of a chronic autoimmune disease suffered by the family's only child. "We found the family was also carrying a mutated version of another immune system protein known as CTLA-4. The CTLA-4 mutation prevents guardian cells from working properly and is known to cause severe autoimmune disease in about 60 to 70 per cent of people who carry it in their DNA," Dr Pablo Canete, from the University of Queensland, said. "Strangely, the remaining 30 to 40 per cent of the population who carry this mutated protein don't develop disease. "We discovered?the family's only child had both the DECTIN-1 mutation and the CTLA4 mutation, while his parents had only one of each. This helped us identify why the child, who is now in his twenties, was the only person in the family to develop severe autoimmunity, ending a 20-year-long mystery behind the cause of his disease. "By discovering the existence of mutated versions of modifier proteins such as DECTIN-1, we finally have an explanation for why some people develop severe autoimmune diseases while others don't, even if they inherit gene mutations passed down from family members."

Immunotherapy has revolutionized cancer treatment, but its effectiveness is often limited by the presence of immunosuppressive myeloid cells, including tumor-associated macrophages (TAMs). TAMs are among the most abundant immune cells observed in colorectal cancer, and their infiltration into the tumor microenvironment has been linked to poor prognosis. TAMs can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, and M2-TAMs are known to suppress cytotoxic T cells, leading to T-cell exhaustion. Tumor-associated macrophages (TAMs) and their ambivalent role in shaping the tumor microenvironment.Restoring anti-tumour immunityA new study published in the journal Gut has revealed a potential new target on TAMs for cancer immunotherapy. The study, led by researchers from Southern Medical University in China, found that targeting a protein called MS4A4A on TAMs could restore CD8+ T-cell-mediated antitumor immunity and enhance the efficacy of immune checkpoint inhibitor (ICI) therapy in colorectal cancer.  The researchers used public databases and bioinformatic analysis to identify MS4A4A, a transmembrane protein selectively highly expressed in TAMs. They found that MS4A4A promotes M2 polarization of macrophages by activating the PI3K/AKT pathway and JAK/STAT6 pathway, leading to CD8+ T-cell dysfunction. MS4A4A was highly expressed in tumour-associated macrophages and associated with a poor prognosis in patients with cancer.To investigate the potential of targeting MS4A4A in cancer immunotherapy, the researchers used murine subcutaneous tumour or orthotopic transplanted models and assessed the inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth. They found that in vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. MS4A4A promotes M2 macrophage polarisation and induces CD8+ T-cell dysfunction.The researchers concluded that targeting MS4A4A could enhance the efficacy of ICI therapy and represent a new anticancer immunotherapy. The Synapse database demonstrates that there’s only one drug (HG-1299) targeting MS4A4A currently available, with the clinical trial status listed as pending, since the role of MS4A4A in immune system’s response to tumor has only recently been elucidated.  MS4A4A enhances NK cell–mediated resistance to metastasisA previous study published in the journal Nature Immunology has shed light on the role of MS4A4A in the immune system's response to cancer metastasis. The findings suggest that MS4A4A plays a critical role in activating natural killer (NK) cells, which are essential in fighting the spread of cancer cells. The study was conducted by a team of researchers from the Humanitas Clinical and Research Center in Italy, along with collaborators from several other institutions around the world. Their research focused on the interplay between MS4A4A and Dectin-1, a receptor that is involved in the recognition of fungal pathogens and other microbial invaders. MS4A4A expression and its regulation in human macrophages.The researchers discovered that MS4A4A is expressed selectively by cells of the monocyte-macrophage lineage and is induced during monocyte-to-macrophage differentiation, but not in dendritic cells. Additionally, M2 or M2-like signals, including IL-4 and dexamethasone, upregulate MS4A4A in macrophages. In vivo, MS4A4A is expressed by human tissue resident macrophages, macrophages infiltrating the inflamed synovium in rheumatoid arthritis patients, and tumor-associated macrophages, and is induced in monocytes in patients treated with methylprednisolone. When macrophages engage with Zymosan, an agonist of the β-glucan receptor Dectin-1, MS4A4A colocalizes with Dectin-1 in the lipid rafts. The absence of MS4A4A leads to an impairment in the activation of the Syk pathway downstream Dectin-1, resulting in reduced production of cytokines and reactive oxygen species. It is important to note that MS4A4A deficiency in macrophages has no impact on primary tumor growth, but it does compromise Dectin-1-driven NK cell-mediated resistance to metastasis. To test the role of MS4A4A in cancer metastasis, the researchers utilized a mouse model of mesenchymal carcinogenesis and transplanted tumor growth. They found that macrophage-selective genetic inactivation of Ms4a4a had no impact on primary tumor growth. Conversely, Ms4a4a-deficient macrophages were impaired in their ability to support Dectin-1-dependent cross-talk with NK cells, which resulted in uncontrolled metastatic spread. These findings shed new light on the critical role that MS4A4A plays in activating NK cells, and highlight the potential of MS4A4A as a therapeutic target for cancer immunotherapy. Ms4a4a is expressed in murine TAM but is dispensable for primary tumor growth.The identification of MS4A4A as a key regulator of tumor-associated macrophages represents an important step forward in cancer immunotherapy. By targeting MS4A4A, researchers were able to reshape the tumor immune microenvironment to be more immunostimulatory, enhancing the efficacy of immune checkpoint inhibitors. The studies provide critical insights into how modulating macrophages can unleash the potential of the immune system against cancer.  References: 1.Li Y, Shen Z, Chai Z, et al. Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity, Gut, 2023;0:1–14. 2.Mattiola, I., Tomay, F., De Pizzol, M. et al. The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell–mediated resistance to metastasis. Nat Immunol 20, 1012–1022 (2019).