CCR2

Researchers have developed a new nanoparticle that can 'hitch a ride' on immune cells, or monocytes. Because of its tiny size, the particle can tag along directly into lymph nodes and help metastasis show up on MRIs where it would otherwise be too hard to detect. The process offers game-changing benefits for the early detection of cancer metastasis in the lymph nodes. While previously, metastasis could only be assessed by an increase in lymph node size; the new particles could lead to MRI contrast agents that can highlight metastatic cells in lymph nodes that may otherwise appear normal. Our lymph nodes are the canaries in the coal mine of our immune system -- firing into gear at the first indication of illness, then sending immune cells where they're needed in the body to fight infection and disease. For the nearly 20 million patients around the world diagnosed with cancer each year, the lymph nodes are an invaluable early indicator of whether their cancer has metastasized -- when cancer cells begin to spread to another organ. Catching metastasis as early as possible means that the patient can be administered the necessary chemotherapy and immune therapies that will vastly improve their prognosis. Researchers at USC's Alfred E. Mann Department of Biomedical Engineering have developed a new nanoparticle that can "hitch a ride" on immune cells, or monocytes. Because of its tiny size, the particle can tag along directly into lymph nodes and help metastasis show up on MRIs where it would otherwise be too hard to detect. The results could lead to more advanced contrast agents that can be injected into patients to improve MRI cancer screenings of the lymph nodes. The work has been published in ACS Nano and was led by Eun Ji Chung, the Dr. Karl Jacob Jr. and Karl Jacob III Early-Career Chair, and Noah Trac, a Ph.D. student in the Chung Lab. While lymph nodes are an essential factor in cancer detection, screening them via biopsy is painful and invasive, and can lead to unwanted side effects like infection, lymphedema and thrombosis. Imaging tools such as MRI detection are non-invasive. Still, they also have significant shortcomings when it comes to screening lymph nodes, "MRIs will look at the lymph node's size, but that does not have a great connection and correlation to the fact that it is metastatic," Chung said. "Even if you have a cold, your lymph nodes will start inflaming." "The major issue with current MRI techniques is not that they don't detect the immune cells," Trac said. "A major issue with current contrast agents is that there is no cancer-targeting mechanism, so most lymph nodes are lit up equally, regardless of whether or not there is cancer." To address this challenge, Chung, Trac and their co-authors developed a nanoparticle that targets a receptor present on both tumor cells and immune cell monocytes -- cells that travel to the lymph nodes and are increasingly prevalent under disease conditions. "The idea behind this nanoparticle is to try and direct the delivery of the gadolinium contrast agent to lymph nodes that have cancer, so that they show up brighter on the MRI than healthy lymph nodes," Trac said. The diagnostic tool would also offer strong clinical value for doctors to not only catch first-time metastasis during an initial cancer diagnosis, but it will also allow clinicians to keep track of cancer recurrence. "Just say a primary tumor has been removed, but perhaps they didn't get all of it, or the cancer comes back and it's metastatic for the second time. Recurrent metastasis is much harder to detect and can lead to worse outcomes for the patient," Chung said. Hitching a ride to light up cancer The nanoparticles work by targeting a protein expressed by cancer cells, known as C-C chemokine receptor 2 (CCR2). The particles "hitchhike" onto the immune cell monocytes that the body produces that also express this same receptor in response to the cancer. The monocytes then give the particles a free ride into the lymph nodes, where the particles can effectively highlight the metastatic cancer cells and enable clearer detection via MRI. "The reason why this mechanism works, in addition to the targeting elements, is because our particle size is also very unique, and it can reach the lymph nodes," Chung said. "We found there's a size cut-off and our particle type is able to pass into the lymph nodes and target cancer cells that have gotten there, along with the monocytes that express this receptor." The process offers game-changing benefits for the early detection of cancer metastasis in the lymph nodes. While previously, metastasis could only be assessed by an increase in lymph node size; the new Chung Lab particles could lead to MRI contrast agents that can highlight metastatic cells in lymph nodes that may otherwise appear normal. In experiments using a mouse model, the team demonstrated that the particles increased the signal detected by MRI by up to 50%. "The particles are amplifying the signal, and we can see that at points where the lymph nodes haven't yet changed in size, and the metastasis is very early. We're providing this benefit where, clinically, you wouldn't be able to see metastasis at all," Chung said. The next step for the research team is to get their work closer to clinical applications for MRI contrast agents. The work has been submitted to the Nanoparticle Characterization Laboratory at the National Institutes of Health, where a third party will assess and validate the work to enable it to move closer to human trials.

The absence of a single immune cell receptor has been linked to both fewer defenses against mycobacterial infections, such as TB, and damaging buildup of sticky residue in the lungs. The macrophage is one of the body's most important inhabitants. Meaning "big eater" in Greek, this immune cell consumes and digests problematic elements from microbes and cancer cells to dust and debris. Macrophages are especially important in the lungs, where they both fight bacterial infection and clear the lungs of excess surfactant, a protein- and lipid-rich layer that's essential to healthy function but can create a sticky buildup if not controlled. In a recent study, investigators from Rockefeller University and other institutions have discovered a never-before-documented genetic disorder that causes the improper functioning of these cells. The researchers made their discovery by drawing an unexpected connection between a select group of sick children. Throughout their lives, these nine children had battled severe diseases such as pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent bacterial and viral infections that left them gasping for breath from often cyst-plagued lungs. But as genomic data revealed, the children shared another characteristic: the absence of a chemical receptor that is supposed to call alveolar macrophages into action. It's the first time that this missing receptor, called CCR2, has been linked to disease. The researchers, including Rockefeller's Jean-Laurent Casanova and Institut Imagine's Anna-Lena Neehus, recently published their results in Cell. The study also found that the children are missing half of their alveolar macrophages, which are located in the air sacs of the lungs. "It was surprising to find that CCR2 is so essential for alveolar macrophages to properly function," says Casanova. "When it comes to lung defense and cleanup, people without it are operating at a double loss." Chemical communication More formally known as C-C motif chemokine receptor 2, CCR2 sits on the surface of alveolar macrophages, a kind of monocyte (or white blood cell). It responds to the presence of a chemical ligand, or binding molecule, known as CCL-2, which is also expressed by monocytes. The receptor and ligand work together to summon macrophages to the site of an infection, and to maintain the appropriate level of surfactant; too little can lead to collapsed lung tissue, and too much can result in narrowed airways. It was among these immune cells that first author Neehus, of Casanova's lab at the Institut Imagine in Paris, was seeking evidence of genetic deficiencies that might alter their behavior. While combing through the genomic data on 15,000 patients in a database, she found two Algerian sisters, then aged 13 and 10, who'd been diagnosed with severe PAP, a syndrome in which surfactant builds up and the gas exchange that takes place in alveoli is hindered. About 90% of PAP cases are caused by antibodies that cripple a protein that stimulates the growth of infection-fighting white blood cells. The girls, however, didn't have the PAP autoantibodies. Instead, they had no CCR2 -- a newly identified genetic mutation. Perhaps its lack was connected to their pulmonary conditions, Neehus thought. "It looked interesting and promising," she recalls. She soon found seven other children in the cohort who had the same CCR2 mutation and serious lung conditions: two more pairs of siblings, and one trio of siblings. They were from the United States and Iran. Diminished capacity To explore the impact the variant might have on the children, the researchers analyzed the children's clinical histories, lung tissue samples, and genetic data. Several key findings emerged. "First we discovered that these patients have only half the normal counts of pulmonary alveolar macrophages, which explains the different types of lesions they have across the pulmonary tissues," says Casanova. With only half a crew, the reduced cleanup unit couldn't keep up with its workload, leading to tissue injury. The macrophages were otherwise normal, as were the children's other immune cells. Without CCR2 signaling, monocytes have no idea where they're needed. In the study, a live-imaging analysis of the monocytes from the lungs of a 10-year-old girl with CCR2 deficiency showed the cells milling about aimlessly, unsure where to go. (See gif at top.) In contrast, live imaging of monocytes from a healthy control patient shows them migrating in the same direction, summoned by the teamwork of CCR2 and CCL-2. A troubled inheritance This directionlessness also makes those with a CCR2 deficiency more susceptible to mycobacterial infections, because the macrophages can't find their way to the tissue clusters where mycobacteria take up residence, and thus digest the invaders. This had dire effects for three of the children in the study, who developed bacterial infections after being vaccinated with a live-attenuated substrain of Mycobacterium bovis, an agent of tuberculosis. Their immune systems failed to assemble a legion of macrophages at the vaccination site in the shoulder, causing tissue destruction or hard nodes that had to be surgically removed, or lymph node infections. (All of the children were effectively treated with antibiotics.) The children inherited the deficiency from their parents -- and yet their parents were healthy. "Each of the parents carries one disease copy of the gene, and both parents gave the affected copy to their children," says Neehus. "The parents aren't affected because they each only have one copy, whereas the kids have two." Several children were the result of consanguineous marriages, in which the parents are related. The offspring of such pairings have a higher risk of inheriting the mutation that causes CCR2 to disappear. The diagnostic test The absence of CCR2 leads to another effect: an excess of the chemokine CCL-2. Lacking its receptor, CCL-2 builds up in the blood and plasma. This outcome may provide a diagnostic test for screening patients with unexplained lung or mycobacterial disease; the detection of high CCL-2 levels could provide some clarity about the condition's genetic underpinnings. In future research, Casanova and his team will mine their database of genomes for patients with gene mutations in CCL-2 rather than in its receptor, CCR2, to understand how such errors may influence the development of disease. Neehus says, "With more follow-up studies, we could potentially cure the patients by using gene therapy to correct the mutation."

LA JOLLA, Calif., Aug. 15, 2023 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the Standard Market of the Tokyo Stock Exchange (Code Number: 4875), today announced it has received a Decision to Grant from the European Patent Office for a new patent which covers MN-001 (tipelukast) for the treatment of scleroderma and/or systemic sclerosis. This patent is expected to expire no earlier than June 2035. The allowed claims cover the use of MN-001 (tipelukast) for inhibiting or treating scleroderma and/or systemic sclerosis. The allowed claims cover oral administration, including tablets and capsules, as well as liquid dosage forms. The allowed claims cover a wide range of doses and a range of different dosing frequencies. Kazuko Matsuda, M.D. Ph.D., MPH., Chief Medical Officer, MediciNova, Inc., commented, “This new patent is based on positive results from a systemic sclerosis animal model study conducted recently. The Canadian Intellectual Property Office granted a similar patent earlier this year. We are very pleased to receive notice of this new patent which covers Europe, and we believe it could increase the potential value of MN-001.” About MN-001 (tipelukast) MN-001 (tipelukast) is a novel, orally administered, small molecule compound with multiple mechanisms of action which has been in clinical development for the treatment of chronic inflammatory and fibrotic diseases, among others, due to its anti-inflammatory and anti-fibrosis effects. Based on the finding that MN-001 (tipelukast) reduces triglycerides (TG) in the blood from our previous clinical trials, we conducted a Phase 2 clinical trial in patients with hypertriglyceridemia and NASH or NAFLD. Based on the findings from the in-vitro mechanistic study of MN-001 (tipelukast), a subgroup analysis of the Phase 2 clinical trial showed a stronger improvement in lipid profile in the NASH/NAFLD patients with a history of diabetes. Therefore, a new Phase 2 clinical trial was initiated to investigate the effect of MN-001 (tipelukast) in NAFLD patients with type 2 diabetes and hypertriglyceridemia. The molecular mechanism of action of MN-001 (tipelukast) includes leukotriene receptor antagonism and inhibition of phosphodiesterase (mainly 3 and 4) and 5-lipoxygenase (5-LO) and these multiple mechanisms are believed to reduce inflammation and prevent fibrosis. We have also confirmed that MN-001 (tipelukast) suppresses fibrosis-promoting genes such as LOXL2, Collagen Type 1, and TIMP-1 and suppresses inflammation-promoting genes such as CCR2 and MCP-1 in a fibrosis disease model study. Although the direct mechanism of action of MN-001 (tipelukast) on TG reduction in blood has not yet been fully clarified, we are conducting joint research with Juntendo University with the aim of elucidating this mechanism of action. In various animal models of fibrosis disease, MN-001 (tipelukast) has been shown to improve fibrosis on histopathological examination, and the FDA has granted Fast Track status to MN-001 (tipelukast) for the treatment of NASH with fibrosis. MN-001 (tipelukast) has also been granted Fast Track status and Orphan Drug designation for the treatment of idiopathic pulmonary fibrosis. In the past, we have conducted clinical trials for MN-001 (tipelukast) for the treatment of bronchial asthma and interstitial cystitis, and more than 600 patients have been treated with MN-001 (tipelukast) to date, confirming its good safety and tolerability profile. About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety profiles, MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in glioblastoma, Long COVID, and substance dependence. MN-001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by, or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2022 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT: Geoff O'BrienVice PresidentMediciNova, Inc.info@medicinova.com