Teplizumab

Scientists say that an experimental monoclonal antibody drug called mAb43 appears to prevent and reverse the onset of clinical type 1 diabetes in mice, and in some cases, to lengthen the animals' lifespan. Scientists at Johns Hopkins Medicine say that an experimental monoclonal antibody drug called mAb43 appears to prevent and reverse the onset of clinical type 1 diabetes in mice, and in some cases, to lengthen the animals' lifespan. The drug is unique, according to the researchers, because it targets insulin-making beta cells in the pancreas directly and is designed to shield those cells from attacks by the body's own immune system cells. The drug's specificity for such cells may enable long-term use in humans with few side effects, say the researchers. Monoclonal antibodies are made by cloning, or making identical replicas of, an animal (including human) cell line. The findings, reported online recently and in the May issue of Diabetes, raise the possibility of a new drug for type 1 diabetes, an autoimmune condition that affects about 2 million American children and adults and has no cure or means of prevention. Unlike type 2 diabetes, in which the pancreas makes too little insulin, in type 1 diabetes, the pancreas makes no insulin because the immune system attacks the pancreatic cells that make it. The lack of insulin interferes with the body's ability to regulate blood sugar levels. "People with type 1 diabetes face lifelong injections of insulin and many complications, including stroke and eyesight problems if the condition is not managed properly," says Dax Fu, Ph.D., associate professor of physiology at the Johns Hopkins University School of Medicine and leader of the research team. Fu says mAb43 binds to a small protein on the surface of beta cells, which dwell in clusters called islets. The drug was designed to provide a kind of shield or cloak to hide beta cells from immune system cells that attack them as "invaders." The researchers used a mouse version of the monoclonal antibody, and will need to develop a humanized version for studies in people. For the current study, the researchers gave 64 non-obese mice bred to develop type 1 diabetes a weekly dose of mAb43 via intravenous injection when they were 10 weeks old. After 35 weeks, all mice were non-diabetic. One of the mice developed diabetes for a period of time, but it recovered at 35 weeks, and that mouse had early signs of diabetes before the antibody was administered. In five of the same type of diabetes-prone mice, the researchers held off giving weekly mAb43 doses until they were 14 weeks old, and then continued dosages and monitoring for up to 75 weeks. One of the five in the group developed diabetes, but no adverse events were found, say the researchers. In the experiments in which mAb43 was given early on, the mice lived for the duration of the monitoring period of 75 weeks, compared with the control group of mice that did not receive the drug and lived about 18-40 weeks. Next, the researchers, including postdoctoral fellows Devi Kasinathan and Zheng Guo, looked more closely at the mice that received mAb43 and used a biological marker called Ki67 to see if beta cells were multiplying in the pancreas. They said, after treatment with the antibody, immune cells retreated from beta cells, reducing the amount of inflammation in the area. In addition, beta cells slowly began reproducing. "mAb43 in combination with insulin therapy may have the potential to gradually reduce insulin use while beta cells regenerate, ultimately eliminating the need to use insulin supplementation for glycemic control," says Kasinathan. The research team found that mAb43 specifically bound to beta cells, which make up about 1% or 2% of pancreas cells. Another monoclonal antibody drug, teplizumab, was approved by the U.S. Food and Drug Administration in 2022. Teplizumab binds to T cells, making them less harmful to insulin-producing beta cells. The drug has been shown to delay the onset of clinical (stage 3) type 1 diabetes by about two years, giving young children who get the disease time to mature and learn to manage lifelong insulin injections and dietary restrictions. "It's possible that mAb43 could be used for longer than teplizumab and delay diabetes onset for a much longer time, potentially for as long as it's administered," says Fu. "In an ongoing effort, we aim to develop a humanized version of the antibody and conduct clinical trials to test its ability to prevent type 1 diabetes, and to learn whether it has any off-target side effects," says Guo. Other scientists who contributed to the research include Dylan Sarver, G. William Wong and Maria Golson from Johns Hopkins; Shumei Yun from the University of Maryland, Aaron Michels and Liping Yu from the University of Colorado; and Chandan Sona and Matthew Poy from Johns Hopkins All Children's Hospital. Funding for the research was provided, in part, by the National Institutes of Health (R01DK125746, P30DK116073, R01DK110183, R01 DK135688 and RO1DK084171).

NEW YORK, April 23, 2024 (GLOBE NEWSWIRE) -- Tiziana Life Sciences, Ltd. (Nasdaq: TLSA) (“Tiziana” or the “Company”), a biotechnology company developing breakthrough immunomodulation therapies via novel routes of drug delivery, today announced that the U.S. Food and Drug Administration (FDA) has allowed its intranasal foralumab non-active Secondary Progressive Multiple Sclerosis (na-SPMS) Expanded Access (EA) Program to expand from 10 patients to a total of 30 patients. To date, of the 10 participating patients, two patients have been dosed for more than one year and eight additional patients have been dosed for six months, all without serious side effects. All patients have either stabilized or improved on treatment with foralumab, and no patients have declined in key clinical measures. Additionally, 70% of these patients have seen a measurable improvement in fatigue. These data are the first to combine PET imaging with a novel ligand, immune-biomarkers, clinical measures and comprehensive safety data endpoints in patients receiving long-term intranasal foralumab. In November 2023 Tiziana initiated a Phase 2a trial in na-SPMS. Patients not eligible for the Phase 2a trial may now be considered for this expanded EA program. The September 2023 release of FDA guidance entitled “Guidance on Substantial and Confirmatory Evidence of Efficacy and Safety” addresses the use of EA programs to be considered as part of confirmatory evidence. As per FDA guidance, “Expanded access refers to the use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition rather than to obtain the kind of information about the drug that is generally derived from clinical trials.” Gabriele Cerrone, Chairman, acting CEO and founder of Tiziana Life Sciences commented, “Tiziana is glad to provide patients with na-SPMS who do not qualify to be enrolled on our Phase 2 trial (NCT06292923) the possibility to receive open-label treatment with our intranasal fully human anti-CD3 monoclonal-antibody, foralumab. As there are no FDA approved treatments for na-SPMS, an EA program gives these patients access to this novel drug.” “I am grateful to be allowed to dose 20 additional patients that do not meet the inclusion criteria for the ongoing intranasal foralumab Phase 2a, randomized, double-blind placebo-controlled, multicenter dose-ranging study multiple sclerosis trial potential access to this treatment,” stated Dr. Tanuja Chitnis, M.D., Professor of Neurology at Harvard Medical School and senior neurologist at Brigham and Women’s Hospital, a founding member of Mass General Brigham Healthcare System. “The EA program has allowed us to obtain important information about dosing, and drug use, including patient feedback which was critical for the design of the current Phase 2a trial.” About Foralumab Activated T cells play an important role in the inflammatory process. Foralumab, the only fully human anti-CD3 monoclonal antibody (mAb), binds to the T cell receptor and dampens inflammation by modulating T cell function, thereby suppressing effector features in multiple immune cell subsets. This effect has been demonstrated in patients with COVID and with multiple sclerosis, as well as in healthy normal subjects. The na-SPMS intranasal foralumab Phase 2 trial began screening patients in November of 2023. Immunomodulation by nasal anti-CD3 mAb represents a novel avenue for treatment of neuroinflammatory and neurodegenerative human diseases.[1], [2] About Tiziana Life Sciences Tiziana Life Sciences is a clinical-stage biopharmaceutical company developing breakthrough therapies using transformational drug delivery technologies to enable alternative routes of immunotherapy. Tiziana’s innovative nasal approach has the potential to provide an improvement in efficacy as well as safety and tolerability compared to intravenous (IV) delivery. Tiziana’s lead candidate, intranasal foralumab, which is the only fully human anti-CD3 mAb, has demonstrated a favorable safety profile and clinical response in patients in studies to date. Tiziana’s technology for alternative routes of immunotherapy has been patented with several applications pending and is expected to allow for broad pipeline applications. Forward-Looking Statements Certain statements made in this announcement are forward-looking statements. These forward-looking statements are not historical facts but rather are based on the Company's current expectations, estimates, and projections about its industry, its beliefs, and assumptions. Words such as 'anticipates,' 'expects,' 'intends,' 'plans,' 'believes,' 'seeks,' 'estimates,' and similar expressions are intended to identify forward-looking statements. These statements are not guarantees of future performance and are subject to known and unknown risks, uncertainties, and other factors, some of which are beyond the Company's control, are difficult to predict, and could cause actual results to differ materially from those expressed or forecasted in the forward-looking statements. The Company cautions security holders and prospective security holders not to place undue reliance on these forward-looking statements, which reflect the view of the Company only as of the date of this announcement. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the uncertainties related to market conditions and other factors described more fully in the section entitled ‘Risk Factors’ in Tiziana’s Annual Report on Form 20-F for the year ended December 31, 2022, and other periodic reports filed with the Securities and Exchange Commission. The forward-looking statements made in this announcement relate only to events as of the date on which the statements are made. The Company will not undertake any obligation to release publicly any revisions or updates to these forward-looking statements to reflect events, circumstances, or unanticipated events occurring after the date of this announcement except as required by law or by any appropriate regulatory authority. For further inquiries: Tiziana Life Sciences LtdPaul Spencer, Business Development and Investor Relations+44 (0) 207 495 2379email: info@tizianalifesciences.com Investors:Irina KofflerLifeSci Advisors, LLC646.970.4681ikoffler@lifesciadvisors.com [1] https://www.pnas.org/doi/10.1073/pnas.2220272120 [2] https://www.pnas.org/doi/10.1073/pnas.2309221120