Thymosin Alpha-1

Aging and Thymosin Alpha-1.

Aging is characterized by immune decline, mainly due to thymic involution-the age-related shrinkage of the thymus gland. This leads to reduced T-cell production, chronic inflammation, and increased susceptibility to age-related diseases. Thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, exhibits potent immunomodulatory, anti-inflammatory, and antioxidant properties. It helps restore immune function by stimulating T-cell differentiation, enhancing thymic output, and modulating dendritic cell and macrophage activity. Preclinical and clinical studies show that Tα1 can improve vaccine response in the elderly and mitigate immunosenescence. The hybrid drug Refnot (a fusion of tumor necrosis factor alpha (TNFα) and Tα1) combines Tα1's immunomodulation with TNF's antitumor activity but has reduced toxicity. It represents a promising therapeutic approach to counteract age-related immune dysfunction and inflammation, potentially by slowing the aging process. Further research is needed to validate its long-term efficacy and safety in geriatrics.

Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy.

Although oncolytic adenoviruses are widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains to be studied. Here, we demonstrate that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, thymosin alpha 1 (Tα1) reprograms "M2-like" TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 is constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing oncolytic engineered adenoviruses.

Thymosin alpha-1 treatment in chronic hepatitis B.

Stimulating a successful host immune response may be a promising helpful therapy to achieve elimination of hepatitis B virus (HBV) infection in chronic hepatitis B (CHB). Thymosin α-1 (Tα-1), as an immunomodulatory agent, can enhance T-cell response in CHB patients and has been widely studied either alone or in combination with nucleos(t)ide analogs. This editorial reviews these articles to present the efficacy of Tα-1 in CHB. English and Chinese articles in MEDLINE, EMBASE, the Cochrane Controlled Trial Registry, Chinese periodical full-text database of science and technology, Chinese periodical full-text database and Wan-fang database by thesis search were collected and reviewed. In CHB, Tα-1monotherapy is effective in suppressing viral replication compared with untreated control or conventional interferon. Most of the combination therapy of Tα-1 plus either lamivudine or IFN-α showed better effects on HBV DNA suppression and HBeAg seroconversion. Presently, clinical studies of Tα-1 combined with entecavir on the treatment of HBV-cirrhosis are ongoing.

Structures of Thymosin Proteins.

The thymosin proteins are all short, highly charged, intrinsically unstructured proteins under natural conditions. However, structure can be induced in many of the thymosin proteins by providing charge neutralization at low pH or by the addition of Zn(2+) ions, organic reagents such as trifluoroethanol, hexafluoropropanol, or n-dodecyltrimethylammonium bromide, or interactions with their natural binding partner proteins. The differing structures of thymosin alpha and thymosin beta proteins have been studied by circular dichroism, nuclear magnetic resonance, and crystallographic methods in order to better understand the role of these proteins. In this structural biology review the structures of prothymosin, parathymosin, thymosin alpha-1, and several beta thymosin proteins, in both native states and under secondary structure-inducing conditions are discussed.

A Pilot Trial of Thymalfasin (Thymosin-α-1) to Treat Hospitalized Patients With Hypoxemia and Lymphocytopenia Due to Coronavirus Disease 2019 Infection.

Thymosin-α-1 (Tα1) may be a treatment option for coronavirus disease 2019 (COVID-19), but efficacy and safety data remain limited. Prospective, open-label, randomized trial assessing preliminary efficacy and safety of thymalfasin (synthetic form of Tα1), compared with the standard of care, among hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19. A total of 49 patients were included in this analysis. Compared with control patients, the incidence of clinical recovery was higher for treated patients with either baseline low-flow oxygen (subdistribution hazard ratio, 1.48 [95% confidence interval, .68-3.25]) or baseline high-flow oxygen (1.28 [.35-4.63]), although neither difference was significant. Among patients with baseline low-flow oxygen, treated patients, compared with control patients, had an average difference of 3.84 times more CD4+ T cells on day 5 than on day 1 (P = .01). Nine serious adverse events among treated patients were deemed not related to Tα1. Tα1 increases CD4+ T-cell count among patients with baseline low-flow oxygen support faster than the standard of care and may have a role in the management of hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19. NCT04487444.

Clinical applications of thymosin alpha-1.

Utility of thymosin alpha-1 (Zadaxin) as a co-adjuvant in influenza vaccines: a review.

Influenza constitutes a serious problem for healthcare and social services worldwide, owing to its pattern and the severity of its complications in some categories of subjects at risk, such as the elderly and immunocompromised individuals. The only really effective means of combating influenza is vaccination. The elderly and immunocompromised subjects are refractory or low responders to vaccination. The need for ever more immunogenic and efficacious influenza vaccines, especially for subjects at risk, has prompted the development of adjuvated vaccines. With a view to enhancing the immune response in the elderly and in subjects at risk, the possibility of co-administering immunostimulants as Thymosin alpha-1 (Talpha1) with influenza vaccines has been investigated. Talpha1 is a biologically active peptide made up of 28 amino acids that can enhance T-cells, dendritic cell and antibody responses, modulate cytokines and chemokines production. Several studies were conducted and showed that Talpha1 ameliorate the performanc of influenza vaccination in elderly and subjects at risk. Although further studies on co-adjuvants are necessary, the future prospects of producing ever more efficacious influenza vaccines appear very promising.

Thymosin-alpha 1 (Zadaxin) enhances the immunogenicity of an adjuvated pandemic H1N1v influenza vaccine (Focetria) in hemodialyzed patients: a pilot study.

Although influenza vaccination is widely recommended for immunosuppressed people, the same immune dysfunction that can increase the risk of contracting influenza might also compromise vaccine effectiveness, especially during pandemics. Clinical data have highlighted the role of adjuvants in improving vaccine efficacy. As uremic patients are especially vulnerable to infections, it is recommended that they should be vaccinated yearly against influenza. This paper presents the results of a pilot clinical trial, conducted in hemodialyzed patients with an adjuvated pandemic H1N1v influenza vaccine alone and combined with Thymosin-alpha 1. Subjects were subdivided into 3 treatment groups receiving: the adjuvated pandemic influenza vaccine (Focetria) only (first treatment group), and the Vaccine+Thymosin alpha 1 (Zadaxin) at a dose of 3.2 and 6.4 mg (second and third treatment groups respectively). The immunoresponse was assessed on days 0, 21, 42, 84 and 168 after vaccine administration by means of Hemagglutination Inhibition (HI), Microneutralization (MN) and Single Radial Hemolysis (SRH) assays. The CHMP regards HI as the gold standard test to evaluate the immune response to influenza vaccines before influenza vaccines are licensed. The CHMP criteria are slightly different in adults (18-60-year-old subjects) and the elderly (>60 years old). Indeed, 40% of seroconversion, 70% of subjects seroprotected 21 days after vaccination, and a 2.5-fold increase in GMR (Geometric Mean Ratio) are required in adults, while in the elderly, the corresponding threshold values are: 30%, 60% and a 2-fold increase. All these criteria must be met for the licensing of a pandemic influenza vaccine. Safety evaluation was performed by means of Adverse Event (AE) recording, laboratory assays (hematology and chemistry), electrocardiogram, and assessment of vital signs. Three populations were considered: Intention-To-Treat (ITT) (94 patients), Per Protocol (PP) (82 patients), and Safety population (99 patients). With regard to the Geometric Mean Titer (GMT) and the Geometric Mean Ratio (GMR) of HI on Day 21 in the ITT population, both "Vaccine+Thymosin alpha 1" groups presented better results than the "Vaccine only" group. A large proportion of ITT patients in the two Vaccine+Thymosin alpha 1 groups achieved seroconversion by Day 21. On Day 42, the decrease in the GMT of HI was greater in the Vaccine+Thymosin alpha 1 groups than in the vaccine only group. Similar results were obtained in the PP population. The CHMP criteria were fully met in the groups treated with Vaccine+Thymosin alpha 1. No AE was found to be related to Thymosin alpha 1 nor to the Focetria vaccine. Although further studies in larger hemodialyzed populations are necessary, it can be concluded that Thymosin alpha 1 enhanced the immunogenicity of the pandemic influenza vaccine used. Moreover, it proved safe and well tolerated, and did not affect hematology or blood-chemistry values.

Thymosin alpha 1: A comprehensive review of the literature.

Thymosin alpha 1 is a peptide naturally occurring in the thymus that has long been recognized for modifying, enhancing, and restoring immune function. Thymosin alpha 1 has been utilized in the treatment of immunocompromised states and malignancies, as an enhancer of vaccine response, and as a means of curbing morbidity and mortality in sepsis and numerous infections. Studies have postulated that thymosin alpha 1 could help improve the outcome in severely ill corona virus disease 2019 patients by repairing damage caused by overactivation of lymphocytic immunity and how thymosin alpha 1 could prevent the excessive activation of T cells. In this review, we discuss key literature on the background knowledge and current clinical uses of thymosin alpha 1. Considering the known biochemical properties including antibacterial and antiviral properties, time-honored applications, and the new promising findings regarding the use of thymosin, we believe that thymosin alpha 1 deserves further investigation into its antiviral properties and possible repurposing as a treatment against severe acute respiratory syndrome coronavirus-2.

Thymosin alpha 1 treatment for patients with sepsis.

Sepsis is a life-threatening organ dysfunction caused by host immune response to infection. In this regard, modifying host immune response may help to eliminate systemic infection and restore organ function. Thymosin alpha 1 (Tα1), acting as an immune modulator, exerts great biological influence in activating and restoring the dysregulated immune response for patients with sepsis. In this review, we summarize the clinical studies of Tα1 treatment alone and in combination with anti-inflammatory for patients with sepsis or septic shock. Clinical studies were collected from available English and Chinese databases. In previous studies, single or combined treatment with Tα1 reduced the mortality rate of sepsis, improved the expression of HLA-DR on monocyte, and diminished the incidence of secondary infection. Based on the existing studies, Tα1 seems to be a promising alternative adjuvant therapy for sepsis. However, sepsis is a remarkably heterogeneous clinical syndrome, so much so that it is impossible to generalize the clinical results to all septic patients. Also, the present studies on Tα1 treatment are not able to focus on the immunosuppressive individuals. We believe that selecting septic patients with immunosuppression will be more likely to reveal the efficacy of Tα1 in future trials.

Immune Modulation with Thymosin Alpha 1 Treatment.

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines. Due to the immune stimulating effects of Ta1, the compound would be expected to show utility for treatment of immune suppression, whether related to aging or to diseases such as infection or cancer. Extensive studies in both the preclinical and clinical setting will be summarized in the subsequent sections. These studies have demonstrated improvements in immune system cell subsets and the potential of Ta1 for the treatment of a range of diseases.

Phenotypic drug discovery: a case for thymosin alpha-1.

Phenotypic drug discovery (PDD) involves screening compounds for their effects on cells, tissues, or whole organisms without necessarily understanding the underlying molecular targets. PDD differs from target-based strategies as it does not require knowledge of a specific drug target or its role in the disease. This approach can lead to the discovery of drugs with unexpected therapeutic effects or applications and allows for the identification of drugs based on their functional effects, rather than through a predefined target-based approach. Ultimately, disease definitions are mostly symptom-based rather than mechanism-based, and the therapeutics should be likewise. In recent years, there has been a renewed interest in PDD due to its potential to address the complexity of human diseases, including the holistic picture of multiple metabolites engaging with multiple targets constituting the central hub of the metabolic host-microbe interactions. Although PDD presents challenges such as hit validation and target deconvolution, significant achievements have been reached in the era of big data. This article explores the experiences of researchers testing the effect of a thymic peptide hormone, thymosin alpha-1, in preclinical and clinical settings and discuss how its therapeutic utility in the precision medicine era can be accommodated within the PDD framework.

Thymalfasin (thymosin-alpha 1) therapy in patients with chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its worldwide distribution and potential adverse sequelae. Globally, there are approximately 350 million people infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct antiviral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory, particularly in perinatally infected patients, patients with lower ALT levels and those with HBeAg-negative chronic hepatitis B. Thymalfasin (thymosin-alpha1) is an immunoregulatory agent able to enhance Th1 response. It has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. Studies are underway in both monotherapy and combination therapy with thymalfasin and interferon and results are promising.

Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection.

The complex alterations of the immune system and the immune-mediated multiorgan injury plays a key role in host response to SARS-CoV-2 infection and in the pathogenesis of COVID-19, being also associated with adverse outcomes. Thymosin alpha 1 (Tα1) is one of the molecules used in the treatment of COVID-19, as it is known to restore the homeostasis of the immune system during infections and cancer. The use of Tα1 in COVID-19 patients had been widely used in China and in COVID-19 patients, it has been shown to decrease hospitalization rate, especially in those with greater disease severity, and reduce mortality by restoring lymphocytopenia and more specifically, depleted T cells. Persistent dysregulation with depletion of naive B and T cell subpopulations and expansion of memory T cells suggest a chronic stimulation of the immune response in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Our data obtained from an ex vivo study, showed that in PASC individuals with a chronically altered immune response, Tα1 improve the restoration of an appropriate response, most evident in those with more severe illness and who need respiratory support during acute phase, and in those with specific systemic and psychiatric symptoms of PASC, confirming Tα1 treatment being more effective in compromised patients. The results obtained, along with promising reports on recent trials on Tα1 administration in patients with COVID-19, offer new insights into intervention also for those patients with long-lasting inflammation with post-infectious symptoms, some of which have a delayed onset.

Thymosin alpha 1 and HIV-1: recent advances and future perspectives.

In spite of the consistent benefits for HIV-1 infected patients undergoing antiretroviral therapy, a complete immune reconstitution is usually not achieved. Actually, antiretroviral therapy may be frequently accompanied by immunological unresponsiveness, persistent inflammatory conditions and inefficient cytotoxic T-cell response. Thymosin alpha 1 is a thymic peptide that demonstrates a peculiar ability to restore immune system homeostasis in different physiological and pathological conditions (i.e., infections, cancer, immunodeficiency, vaccination and aging) acting as multitasking protein depending on the host state of inflammation or immune dysfunction. This review reports the present knowledge on the in vitro and in vivo studies concerning the use of thymosin alpha 1 in HIV-1 infection. Recent findings and future perspectives of therapeutic intervention are discussed.

Thymalfasin (thymosin-alpha 1) therapy in patients with chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection is a serious clinical problem because of its world-wide distribution and potential adverse sequelae. Globally, there are approximately 350 million people infected with chronic HBV, 75% of whom live in the Asia-Pacific region. Interferon-alfa and direct anti-viral agents such as lamivudine and adefovir are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory, particularly in perinatally infected patients, patients with lower ALT levels and those with HBeAg-negative chronic hepatitis B. Thymalfasin (thymosin-alphal) is an immunoregulatory agent able to enhance Thl response. It has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. Studies are underway in both monotherapy and combination therapy with thymalfasin and interferon and results are promising.

Historical review of thymosin α 1 in infectious diseases.

Thymosin α 1 (Tα1) is a peptidic biological response modifier, which plays a significant role in activating and regulating various cells of the immune system. For the above-mentioned activities it is expected to exert a clinical benefit in the treatment of diseases where the immune system is altered. Several clinical trials have been carried out with Tα1 for treatment or prevention of many different infectious diseases such as hepatitis B and C, sepsis and Aspergillosis in bone marrow-transplanted patients. Data available on the use of Tα1 in infectious disease as well as a vaccine enhancer will be reviewed to possibly generate new working hypothesis. Tα1 has been widely used in thousands of patients. Nevertheless, there are some issues that have not yet been properly addressed (i.e., dose, schedule, combination treatments, end-points to be evaluated in clinical trials). In the most recent clinical trials Tα1 has been used at higher doses than those commonly used in the past showing a direct proportionality between the dose and the effect. The safety profile of Tα1 is excellent and it is virtually devoid of toxicity.

Thymosin Alpha 1 Mitigates Cytokine Storm in Blood Cells From Coronavirus Disease 2019 Patients.

Coronavirus disease 2019 (COVID-19) is characterized by immune-mediated lung injury and complex alterations of the immune system, such as lymphopenia and cytokine storm, that have been associated with adverse outcomes underlining a fundamental role of host response in severe acute respiratory syndrome coronavirus 2 infection and the pathogenesis of the disease. Thymosin alpha 1 (Tα1) is one of the molecules used in the management of COVID-19, because it is known to restore the homeostasis of the immune system during infections and cancer. In this study, we captured the interconnected biological processes regulated by Tα1 in CD8+ T cells under inflammatory conditions. Genes associated with cytokine signaling and production were upregulated in blood cells from patients with COVID-19, and the ex vivo treatment with Tα1-mitigated cytokine expression, and inhibited lymphocyte activation in a CD8+ T-cell subset specifically. These data suggest the potential role of Tα1 in modulating the immune response homeostasis and the cytokine storm in vivo.

Therapeutic applications of thymosin peptides: a patent landscape 2018-present.

Thymosins are small proteins found mainly in the thymus. They are involved in several biological processes, including immunoregulation, angiogenesis, and anti-inflammatory activity. Due to these multiple activities, thymosins are widely used as therapeutics. In fact, these peptides have shown interesting results in the treatment of eye disorders, anticancer therapy, and dysregulated immune disorders. We analyzed the thymosins therapeutic patent landscape describing the most significant patents published after 2018 and originally written in English, classified according to the different type of functions and diseases. We searched 'Thymosin' on Patentscope and Espacenet. Thymalfasin (Zadaxin) is the only FDA-approved thymosine-based drug used to treat chronic hepatitis B and C and as a chemotherapy inducer. This outcome demonstrates how thymosins can be exploited as therapeutics, especially in immunological and anti-cancer therapies. However, the development of modified thymosins could expand their therapeutic interest and application in different diseases. In fact, by chemical modifications, it is possible to increase proteolytic stability in the biological environment, enhance cell permeability, and stabilize the secondary structure of the peptide. Finally, the development of shorter sequences could reduce the cost and production time of these thymosin-based drugs.

Comprehensive Review of the Safety and Efficacy of Thymosin Alpha 1 in Human Clinical Trials.

This study aims to assess the safety and efficacy of Thymosin Alpha 1 (Tα1) through a comprehensive narrative review of clinical studies involving over 11 000 human subjects in more than 30 trials. The focus was on Tα1's application in COVID-19, autoimmune conditions, and cancer treatment, with implications for future considerations. We systematically searched articles relevant to critical studies on COVID-19, infectious diseases, cancer, and autoimmune diseases indexed on Pubmed, Google Scholar, and Cochrane Library. Our focus was on evaluating the safety and efficacy of Tα1 in human subjects. Clinical trials conducted worldwide involving diverse populations were analyzed to assess the safety and effectiveness of Tα1. The review examines explicit outcomes in over 11 000 human subjects, emphasizing its role in addressing COVID-19, autoimmune conditions, and cancer treatment. Contrary to the FDA's restriction on Tα1 and 21 additional peptides in 2023, our analysis reveals consistent evidence of Tα1's safety and efficacy. The peptide has demonstrated significant effectiveness in treating various conditions, including COVID-19, autoimmune disorders, and cancer. This review summarizes conclusions drawn from a comprehensive examination of clinical trials worldwide. Based on substantial evidence from clinical trials, Tα1 emerges as a well-tolerated and effective immune modulator. The FDA›s restriction appears unfounded, as Tα1 has shown safety and efficacy beyond the initially specified conditions. Urgent attention and intervention are warranted to ensure the continued availability of this life-saving peptide through prescription. Therefore, it is recommended that the FDA permits 503A compounding pharmacies to compound Tα1, considering its potential to treat a variety of conditions effectively.

Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial.

Infected pancreatic necrosis (IPN) is a highly morbid complication of acute necrotising pancreatitis (ANP). Since there is evidence of early-onset immunosuppression in acute pancreatitis, immune enhancement may be a therapeutic option. This trial aimed to evaluate whether early immune-enhancing Thymosin alpha 1 (Tα1) treatment reduces the incidence of IPN in patients with predicted severe ANP. We conducted a multicentre, double-blind, randomised, placebo-controlled trial involving ANP patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 8 and a computed tomography (CT) severity score ≥ 5 admitted within 7 days of the advent of symptoms. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebos (normal saline). The primary outcome was the development of IPN during the index admission. A total of 508 patients were randomised, of whom 254 were assigned to receive Tα1 and 254 placebo. The vast majority of the participants required admission to the intensive care unit (ICU) (479/508, 94.3%). During the index admission, 40/254(15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95% CI - 7.4 to 5.1%]; p = 0.48). The results were similar across four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15%), bleeding (6.3% vs. 3.5%), and gastrointestinal fistula (2% vs. 2.4%). The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.

Interferon-α and thymosin-α1 plus tislelizumab enhance CD8+ T cell cytotoxicity toward pancreatic ductal adenocarcinoma.

The strong immunosuppression and immune evasion of pancreatic ductal adenocarcinoma (PDAC) result in poor efficacy of immune checkpoint blockade. In this study, the PD-1 level on CD8+ T cells in the peripheral blood of patients with PDAC was significantly greater than that in the peripheral blood of healthy individuals. To enhance the anticancer activity of adoptive CD8+ T cells toward PDAC, interferon-α (IFN-α) and thymosin-α1 (Tα1) plus tislelizumab were preclinically explored. Compared with those of tislelizumab monotherapy, the proliferation and cytokine secretion of CD8+ T cells and the cytotoxic activity toward PDAC cells were significantly greater with the combination treatment of IFN-α and Tα1 plus tislelizumab. Moreover, the growth of PDAC tumors was inhibited by CD8+ T cells with high efficacy under the combination treatment. Thus, IFN-α and Tα1 plus tislelizumab enhance the anticancer activity of CD8+ T cells toward PDAC, representing an alternative strategy for improving cancer immunotherapy.

Construction, expression, and characterization of thymosin alpha 1 tandem repeats in Escherichia coli.

Thymosin alpha 1 (T α 1), which is composed of 28 amino acids, has been commercialized worldwide for its immune-modulatory and antitumor effects. T α 1 can stimulate T cell proliferation and differentiation from bone marrow stem cells, augment cell-mediated immune responses, and regulate homeostasis of immune system. In this study, we developed a novel strategy to produce T α 1 concatemer (T α 1③) in Escherichia coli and compared its activity with chemically synthesized T α 1. Results showed that T α 1③ can more effectively stimulate T cell proliferation and significantly upregulate IL-2 receptor expression. We concluded that the expression system for T α 1 concatemer was constructed successfully, which could serve as an efficient tool for the production of large quantities of the active protein.

Thymosin α-1 in cancer therapy: Immunoregulation and potential applications.

Thymosin α-1 (Tα-1) is an immunomodulating polypeptide of 28 amino acids, which was the first peptide isolated from thymic tissue and has been widely used for the treatment of viral infections, immunodeficiencies, and especially malignancies. Tα-1 stimulates both innate and adaptive immune responses, and its regulation of innate immune cells and adaptive immune cells varies under different disease conditions. Pleiotropic regulation of immune cells by Tα-1 depends on activation of Toll-like receptors and its downstream signaling pathways in various immune microenvironments. For treatment of malignancies, the combination of Tα-1 and chemotherapy has a strong synergistic effect by enhancing the anti-tumor immune response. On the basis of the pleiotropic effect of Tα-1 on immune cells and the promising results of preclinical studies, Tα-1 may be a favorable immunomodulator to enhance the curative effect and decrease immune-related adverse events of immune checkpoint inhibitors to develop novel cancer therapies.

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia.

In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. Considering the numerous effects of the F508del mutation on the assembly and processing of CFTR protein, combination therapy with several pharmacological correctors is likely to be required to treat CF patients. Recently, it has been reported that thymosin α-1 (Tα-1) has multiple beneficial effects that could lead to a single-molecule-based therapy for CF patients with F508del. Such effects include suppression of inflammation, improvement in F508del-CFTR maturation and gating, and stimulation of chloride secretion through the calcium-activated chloride channel (CaCC). Given the importance of such a drug, we aimed to characterize the underlying molecular mechanisms of action of Tα-1. In-depth analysis of Tα-1 effects was performed using well-established microfluorimetric, biochemical, and electrophysiological techniques on epithelial cell lines and primary bronchial epithelial cells from CF patients. The studies, which were conducted in 2 independent laboratories with identical outcome, demonstrated that Tα-1 is devoid of activity on mutant CFTR as well as on CaCC. Although Tα-1 may still be useful as an antiinflammatory agent, its ability to target defective anion transport in CF remains to be further investigated.

Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis.

The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5'-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer. Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.

Neoadjuvant immunochemotherapy plus thymalfasin in locally advanced gastric cancer: a prospective clinical trial.

Neoadjuvant immunochemotherapy has emerged as a promising strategy for locally advanced gastric and gastroesophageal junction (G/EGJ) adenocarcinoma, but a substantial proportion of patients derive limited benefit. Thymalfasin is an immunomodulatory peptide that may amplify antitumor immunity while attenuating toxicity. We conducted a phase II trial to evaluate anti-PD-1 plus SOX (S-1 and oxaliplatin) immunochemotherapy combined with thymalfasin as neoadjuvant treatment for G/EGJ adenocarcinoma. The prospective trial enrolled patients aged 18-75 with cStage III G/EGJ adenocarcinoma, ECOG 0-1, and adequate organ function. Treatment included three 21-day cycles of serplulimab (anti-PD-1) plus SOX (S-1 and oxaliplatin) and 9 weeks of thymalfasin, followed by curative gastrectomy. The primary endpoint was pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), safety, survival, and other efficacy measures. Peripheral immune remodeling was assessed by flow cytometry, and bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs) interrogated thymalfasin-associated transcriptional programs. Thirty patients were enrolled and all underwent curative-intent minimally invasive gastrectomy. pCR was achieved in 30.0% (9/30), and MPR in 56.7% (17/30). ypN0 status was observed in 63.3% (19/30), with N-stage downstaging in 80.0% (24/30). At a median follow-up of 14.0 months (range 10.0-17.2), only one retroperitoneal nodal relapse had occurred at 14.4 months after diagnosis; no deaths were documented. Any-grade adverse events (AEs) occurred in 93.3% of patients, grade ≥ 3 AEs in 26.7%, and immune-related AEs in 23.3%. Flow cytometry showed expansion of CD8⁺ T cells with increased CD69 expression and a concurrent reduction in HLA-DR-positive T cells, suggesting dynamic remodeling from broad systemic activation toward a more focused effector or memory response. RNA-seq revealed thymalfasin-associated upregulation of genes involved in antigen processing and presentation, type I interferon signaling, and identified immune co-expression modules linked to treatment and response. Neoadjuvant serplulimab, SOX, and thymalfasin produced encouraging pathological response, substantial nodal clearance, and an acceptable safety profile in stage III G/EGJ adenocarcinoma. Peripheral immune and transcriptomic profiling are consistent with a hypothesis in which thymalfasin may help preserve and coordinate systemic antitumor immunity without excessive toxicity. These findings warrant further larger randomized trials. ClinicalTrials.gov, NCT06461910, 2024-06-14.

Thymosin alpha 1 does not promote growth or oncogenic transformation.

Thymosin alpha 1 (T alpha 1) is an immune modulatory peptide which has been evaluated in a variety of clinical trials. Although no in vivo adverse effects, including enhancement of tumor growth, have been noted, in vitro studies suggesting a role for T alpha 1 in cell growth have been reported. The studies presented in this report evaluated both exogenously added T alpha 1 and endogenously expressed T alpha 1 as factors which could either promote growth of tumor cells or induce transformation. No effect of exogenous T alpha 1 on cell growth was found. NIH-3T3 cells transfected with cDNA for the precursor ProThymosin alpha (Pro T alpha) expressed elevated levels of authentic T alpha 1 but did not demonstrate either enhanced proliferation in liquid culture or transformation as defined by the loss of contact inhibition or anchorage independent growth in soft agar. Thus these studies argue against the hypothesis that T alpha 1 is either an intracellular or extracellular growth promoter.

Identification and determination of structurally related peptide impurities in thymalfasin by liquid chromatography-high-resolution mass spectrometry.

Thymalfasin is an important peptide drug widely used for the single or combination treatment of hepatitis, sepsis, cancer, and immunodeficiency. Accurate purity assessment of thymalfasin material is essential for thymalfasin certified reference materials (CRMs) production and analytical method validation, in which comprehensive determination of thymalfasin-related impurities is required to avoid quantitative bias. In this study, liquid chromatography-high-resolution mass spectrometry (LC-hrMS) methods have been established to comprehensively characterize and quantify thymalfasin-related impurities using a thymalfasin China Pharmacopoeia (ChP) standard and then successfully applied to three commercial thymalfasin materials. A total of twenty-three thymalfasin-related impurities (> 0.1 mg/g) were separated, identified, and quantified in the ChP standard analyzed. The major impurities existing in thymalfasin ChP standard and commercial materials include deamination, amination, succinimide, amino acid insertion/deletion, dimers, and isomers at different mass fraction levels. In particular, over half of the thymalfasin-related impurities were found directly or indirectly arising from the labile C-terminal asparagine (Asn) residue. Given the 28th Asn residue at the C-terminus is not necessary for the biological activity of thymalfasin as reported previously, thus deletion, replacement, or modification of thymalfasin C-terminal Asn residue is proposed for new drug research and development. In summary, these results provide a further complement to the thymalfasin-related impurity profile and issue a warning for protection or processing of the thymalfasin C-terminal Asn residue.

Thymalfasin: an immune system enhancer for the treatment of liver disease.

Thymalfasin (thymosin-alpha 1) is an immunomodulating agent able to enhance the Th1 immune response. It has been evaluated for its immunomodulatory activities and related therapeutic potential in several diseases, including chronic hepatitis B and C, AIDS, primary immunodeficiency diseases, depressed response to vaccination and cancer. The basis for effectiveness in these conditions is primarily through modulation of immunological responsiveness, as thymalfasin has been shown to have beneficial effects on numerous immune system parameters and to increase T-cell differentiation and maturation. Thymalfasin is responsible for reconstitution of immune function when thymic tissue is given back to thymectomized animals. In addition, thymalfasin has been shown to have efficacy in multiple experimental models of immune dysfunction, mainly, infectious diseases such as hepatitis (woodchuck) and influenza (mouse), and cancer such as melanoma (mouse) and colorectal carcinoma (rat) where thymalfasin has shown antitumor effects.

Thymalfasin therapy accelerates COVID-19 pneumonia rehabilitation through anti-inflammatory mechanisms.

Thymosin drugs are commonly used for the treatment of viral infections due to their immunomodulatory effects. The comprehensive clinical efficacy of Thymalfasin therapy for COVID-19 associated pneumonia is not yet fully researched, another issue, whether the use of thymosin drugs can reduce the rate of COVID-19 progression to severe pneumonia has not been well documented. The aim of the present study was to multi-angle evaluate the clinical efficacy of Thymalfasin therapy for COVID-19 pneumonia by retrospective review of the clinical data of 338 inpatients with common COVID-19 infection who received treatment in our hospital. The primary index of observation was whether progression to severe pneumonia occurred within a week after admission, and the secondary indexes were the length of hospital stay, time of negative conversion of COVID-19 antigen, the number of peripheral lymphocytes and white blood cells (WBC), and C-reactive protein (CRP) and procalcitonin (PCT) levels,and the control of pneumonia related symptoms, for example, fever, listlessness, inflammatory exudate area shown on lung CT (%). The length of hospital stay of patients in Thymalfasin group was significantly shorter than that of patients in the control group (p&#x2009;<&#x2009;0.01). The proportion of relief of pneumonia related symptoms (fever, fatigue) in the Thymalfasin therapy group was significantly higher than that in the control group, and the inflammatory exudate area shown on CT was significantly lower than that in the control group (p&#x2009;<&#x2009;0.05). Multivariate logistic regression analysis showed that the use of Thymalfasin was an independent protective factor affecting the progression to severe pneumonia. Multifactorial Cox model analysis indicated that negative conversion of COVID-19 antigen was significantly faster in patients using Thymalfasin and younger patients. Thymalfasin therapy has shown excellent clinical efficacy in the treatment of COVID-19 pneumonia, it can reduce inflammatory reactions, promote the relief of COVID-19 pneumonia related symptoms such as fever and fatigue, facilitate effusion absorption, and accelerate COVID-19 pneumonia recovery. Thymalfasin can prevent progression of common COVID-19 infection to severe pneumonia via multiple immunity-enhancing and anti-inflammatory protective mechanisms.

Thymosin alpha1. SciClone Pharmaceuticals.

Thymosin alpha1 (Talpha1), a synthetic 28-amino acid peptide with multiple biological activities primarily directed towards immune response enhancement, was originally developed by Alpha 1 Biomedicals for the treatment of hepatitis B virus (HBV) infection. SciClone developed and launched Talpha1, under the trade name Zadaxin, for the treatment of HBV and hepatitis C virus (HCV) infections. The drug is also being developed for the treatment of non-small cell lung cancer (NSCLC), hepatocellular carcinoma, AIDS and malignant melanoma. Talpha1 is able to potentiate the action of cytokines and also reduce the hematological toxicity of cytotoxic drug therapy (cyclophosphamide-, 5-fluorouracil-, dacarbazine- or ifosfamide-based regimens). These studies also demonstrated the mechanism of action of Talpha1 and its role as an immune system enhancer. By July 2001, it was in phase III trials in the US in combination with PEGylated interferon-alpha, and later the same month it was approved in the Philippines. SciClone received expanded approval for HBV and HCV infection in Mexico in July 2001. Talpha1 has been launched in Argentina, China, Peru, the Philippines and Singapore for the treatment of chronic HBV infection. The product subsequently received expanded approval for the treatment of both HBV and HCV infection in Argentina. Marketing approval was granted in India for HBV infection in February 2001. The company was working to expand this approval to include HCV infection. In March 2000, approval for treatment of HBV infection was granted in Thailand, Laos and Malta. Approval was also granted in Sri Lanka and Brunei in August 1999. In September 2000, SciClone announced that approval had been expanded to include the treatment of HCV infection as well as the previously approved HBV indication in both Peru and Sri Lanka. In January 1999, SciClone received approval for Talpha1 in Venezuela for the treatment of HBV and HCV infection. The company also filed a marketing application in New Zealand for Talpha1 to treat HBV infection. The drug was approved in South Korea in April 2000, as an influenza vaccine adjuvant and this was expected to be expanded to indude use for treatment of both HBV and HCV infections. In July 2001, it was approved in In September and October 2000, SciClone was granted patents in Mexico and Canada, respectively, for the use of Talpha1 for the treatment of HCV infection. In June 2000, SciClone was issued a Notice of Allowance by the US Patent and Trademark Office for use of Talpha1 in the treatment of HBV infection. The EPO granted a patent, exclusively licensed to SciClone, for the use of Talpha1 as a monotherapy or in combination with interferon, to treat for HCV infection. In April 2001, SciClone received a Notice of Allowance for a US patent covering newly described analogs of Talpha1. The patent gave the Philippines as an adjuvant to chemotherapy for the treatment of various cancers. In December 2001, Talpha1 entered a phase 1 trial program in Europe, with patient enrolment planned for 2002. SciClone exclusive composition-of-matter rights to several families of Talpha1 analogs that could have proprietary therapeutic or biologic distinctions from Talpha1. The company was issued US patents covering the use of Talpha1 for the treatment of HCV infection in August 1998 and the treatment of HBV infection in September 1999. A Notice of Allowance for a second US patent covering the use of Talpha1 was issued in October 1999. In April 1999, SciClone received allowance of a patent from the EPO covering the use of Talpha1 in small cell and non-small cell lung cancer. In August 2001, SciClone received a notice of allowance for patent protection in Japan covering the use of Talpha1. The patent, which extends until 2012, also covers the use of Talpha1 in combination with interferon-alpha for the treatment of HCV infection. SciClone was previously granted a Japanese patent for the use of Talpha1 in the treatment of HBV infection.

Thymalfasin: an immune system enhancer for the treatment of liver disease.

Thymalfasin (thymosin-alpha 1) is an immunomodulating agent able to enhance the Thl immune response. It has been evaluated for its immunomodulatory activities and related therapeutic potential in several diseases, including chronic hepatitis B and C, AIDS, primary immunodeficiency diseases, depressed response to vaccination and cancer. The basis for effectiveness in these conditions is primarily through modulation of immunological responsiveness, as thymalfasin has been shown to have beneficial effects on numerous immune system parameters and to increase T-cell differentiation and maturation. Thymalfasin is responsible for reconstitution of immune function when thymic tissue is given back to thymectomized animals. In addition, thymalfasin has been shown to have efficacy in multiple experimental models of immune dysfunction, mainly, infectious diseases such as hepatitis (woodchuck) and influenza (mouse), and cancer such as melanoma (mouse) and colorectal carcinoma (rat) where thymalfasin has shown antitumor effects.

Mechanism and clinical application of thymosin in the treatment of lung cancer.

Cancer is one of the leading causes of death worldwide. The burden of cancer on public health is becoming more widely acknowledged. Lung cancer has one of the highest incidence and mortality rates of all cancers. The prevalence of early screening, the emergence of targeted therapy, and the development of immunotherapy have all significantly improved the overall prognosis of lung cancer patients. The current state of affairs, however, is not encouraging, and there are issues like poor treatment outcomes for some patients and extremely poor prognoses for those with advanced lung cancer. Because of their potent immunomodulatory capabilities, thymosin drugs are frequently used in the treatment of tumors. The effectiveness of thymosin drugs in the treatment of lung cancer has been demonstrated in numerous studies, which amply demonstrates the potential and future of thymosin drugs for the treatment of lung cancer. The clinical research on thymosin peptide drugs in lung cancer and the basic research on the mechanism of thymosin drugs in anti-lung cancer are both systematically summarized and analyzed in this paper, along with future research directions.

Thymosin &#x3b1;1-induced secretion of the IL-15/RA complex by THP-1-derived dendritic cells restrains HIV latency in vitro.

Viral reservoir presents a significant challenge in HIV-1 cure. We previously observed that Thymosin &#x3b1;1 (T&#x3b1;1) may restrict the reservoir through the IL-15 pathway. However, the precise mechanism remains to be fully elucidated. Peripheral blood mononuclear cells (PBMCs) were obtained from people living with HIV-1 (PLWH). In vitro, THP-1 cells were differentiated into mature monocyte-derived dendritic cells (MoDCs) and co-cultured with PBMCs under various conditions. Intracellular HIV-1 p24 levels, CD8+ T and NK cell functionality, and reservoir size were evaluated. In vitro, T&#x3b1;1 stimulation of MoDCs resulted in significant immune response and secretion of IL-15/RA complex (p&#x2009;<&#x2009;0.001). This interaction with IL-2&#x2009;R&#x3b2;/&#x3b3; receptors on T cells enhanced the intracellular secretion of CCL3/5, IFN-&#x3b3;, and TNF-&#x3b1; in CD8+ T cells (p&#x2009;<&#x2009;0.05), which inhibited p24 levels in CD4+ T cells (p&#x2009;=&#x2009;0.002), and reduced HIV-1 integrated DNA levels (p&#x2009;=&#x2009;0.012). Furthermore, the secretion levels of IFN-&#x3b3;, TNF-&#x3b1;, and GZMB in NK cells and proportion of CD8+ TVM cells significantly increased following co-culture. These alterations were found to be markedly inversely associated with reservoir size and reactivation. However, these effects were observed in PBMCs from immunological responders (CD4+ T cell count&#x2009;>&#x2009;350 cells/&#xb5;L) rather than nonresponders. T&#x3b1;1 enhances CD8+ T cell function, promotes TVM proliferation, and suppresses reservoir size and reactivation via IL-15 pathway activation in dendritic cells, which warrants testing in functional cure trials in the future.

Thymalfasin in the treatment of hepatitis B and C.

Thymalfasin exhibited an immunomodulatory and a direct antiviral mechanism of action. The low rate of sustained response of chronic hepatitis with current therapies, underscores the need for new therapeutic options. It has been suggested that thymalfasin may have efficacy in the treatment of chronic hepatitis B and C. Pilots studies in patients with chronic hepatitis B treated with thymalfasin in combination with interferon or nucleoside analogue, showed a 70% complete sustained response rate. Studies in chronic hepatitis C patients, would indicate that thymalfasin in combination with standard or pegylated interferon with ribavirin may improve response rate in hepatitis C virus (HCV) na&#xef;ve and nonresponder patients. However, a large phase-III randomized study conducted in Europe in HCV patients nonresponder to Peg-interferon with ribavirin, demonstrated that thymalfasin did not improve the rate of sustained virologic responses, but, in patients who completed therapy, thymalfasin significantly diminished the relapse rate. In conclusion, thymalfasin, in combination with the standard of care, may be helpful as an adjuvant in the treatment of patients with chronic hepatitis B and C.

Prothymosin alpha: a ubiquitous polypeptide with potential use in cancer diagnosis and therapy.

The thymus is a central lymphoid organ with crucial role in generating T cells and maintaining homeostasis of the immune system. More than 30 peptides, initially referred to as "thymic hormones," are produced by this gland. Although the majority of them have not been proven to be thymus-specific, thymic peptides comprise an effective group of regulators, mediating important immune functions. Thymosin fraction five (TFV) was the first thymic extract shown to stimulate lymphocyte proliferation and differentiation. Subsequent fractionation of TFV led to the isolation and characterization of a series of immunoactive peptides/polypeptides, members of the thymosin family. Extensive research on prothymosin &#x3b1; (proT&#x3b1;) and thymosin &#x3b1;1 (T&#x3b1;1) showed that they are of clinical significance and potential medical use. They may serve as molecular markers for cancer prognosis and/or as therapeutic agents for treating immunodeficiencies, autoimmune diseases and malignancies. Although the molecular mechanisms underlying their effect are yet not fully elucidated, proT&#x3b1; and T&#x3b1;1 could be considered as candidates for cancer immunotherapy. In this review, we will focus in principle on the eventual clinical utility of proT&#x3b1;, both as a tumor biomarker and in triggering anticancer immune responses. Considering the experience acquired via the use of T&#x3b1;1 to treat cancer patients, we will also discuss potential approaches for the future introduction of proT&#x3b1; into the clinical setting.

Modified Thymosin Alpha 1 Distributes and Inhibits the Growth of Lung Cancer in Vivo.

Targeted therapy of tumors is an effective method for treating cancer. Thymosin alpha 1 (T&#x3b1;1), a hormone that contains 28 amino acids, is already approved for cancer treatment. However, its clinical application is limited because of the lack of tumor targeting. Considering that RGD can specifically bind to integrin, the anticancer drug can have a targeted therapeutic effect on tumors when it combines with a peptide containing an RGD sequence. We produced a polypeptide, T&#x3b1;1-RGDR, by binding T&#x3b1;1 to RGDR. The RGDR can combine with the &#x3b1;v&#x3b2;3 and NRP-1 domains, which are highly expressed on the surface of the tumor, to achieve the effect of tumor targeting. This work aimed to investigate the difference of antitumor activity and tumor targeting between T&#x3b1;1 modified by RGDR and T&#x3b1;1 by using H460 and LLC tumor models. Results showed that T&#x3b1;1-RGDR had remarkable antitumor effects, and its tumor targeting was better than that of T&#x3b1;1. Hence, T&#x3b1;1-RGDR is a promising antitumor drug.

Combination therapy of thymalfasin (thymosin-alpha 1) and peginterferon alfa-2a in patients with chronic hepatitis C virus infection who are non-responders to standard treatment.

The worldwide spread of hepatitis C virus is enormous; chronic hepatitis C virus infection is a leading cause of liver cirrhosis and hepatocellular carcinoma. While treatment options have improved substantially over the last decade, responses are still disappointing, particularly in certain difficult-to-treat groups such as patients who are immunosuppressed or have decompensated disease. Preliminary studies have indicated that combined treatment strategies may provide effective approaches for the future. The combination of thymalfasin with pegylated interferon is currently a promising option for the treatment of patients with chronic hepatitis C virus infection. An ongoing phase 3 study in the USA should provide much needed data to improve the outcome for these patients.

A pilot trial of Thymalfasin (Ta1) to prevent covid-19 infection and morbidities in renal dialysis patients: Preliminary report.

Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are considered particularly susceptible to infection with SARS-CoV2 on the basis of the immunodeficiency associated with advanced age, comorbidity burden, medication use, and need for frequent visits to dialysis clinics. In prior studies, thymalfasin (thymosin alpha 1, Ta1) has been shown to enhance antibody response to influenza vaccine and reduce influenza infection in geriatric populations, including hemodialysis patients, when used as an adjunct to influenza vaccine. Early in the COVID-19 pandemic we speculated that administration of Ta1 to HD patients would result in reduced rate and severity of COVID-19 infection. We also hypothesized that HD patients treated with Ta1 who did become infected with COVID-19 would have a milder course of infection in terms of hospitalization rates, requirement for and length of ICU stays, requirement for mechanical ventilation, and survival. Further, we proposed that patients who avoided COVID-19 infection during the study would have decreased non-COVID-19 infections and hospitalizations compared to controls. The study launched in January 2021 and, as of July 1, 2022, 254 ESRD/ HD patients from five dialysis centers in Kansas City, MO have been screened. Of these, 194 patients have been randomized 1:1 to either Group A (1.6&#xa0;mg Ta1 given subcutaneously twice weekly for 8&#xa0;weeks), or Group B (control group not receiving Ta1). After the 8-week treatment period, subjects were followed for an additional 4&#xa0;months and monitored for safety and efficacy. A data safely monitoring board reviewed all reported adverse effects and commented on study progress. To date, only 3 deaths have occurred in subjects treated with Ta1 (Group A), compared to 7 in the control (Group B). There have been 12 COVID-19 related serious adverse effects (SAEs; 5 in Group A, and 7 in Group B). The majority of patients have received a COVID-19 vaccine (91 patients in group A, and 76 patients in Group B) at various times throughout the study. Nearing completion of the study, blood samples have been collected and antibody responses to COVID-19 will be analyzed along with safety and efficacy endpoints when all subjects have completed the study.