Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation-Associated Thrombotic Microangiopathy.

PURPOSE: Hematopoietic stem-cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. METHODS: In this single-arm open-label pivotal trial (NCT02222545), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed. RESULTS: The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern. CONCLUSION: In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

Lectins from the Edible Mushroom Agaricus bisporus and Their Therapeutic Potentials.

The mushroom Agaricus bisporus secretes biologically active compounds and proteins with benefits for human health. Most reported proteins from A. bisporus are tyrosinases and lectins. Lectins are of therapeutic or pharmaceutical interest. To date, only limited information is available on A. bisporus lectins and lectin-like proteins. No therapeutic products derived from A. bisporus lectin (ABL) are available on the market despite its extensive exploration. Recently, A. bisporus mannose-binding protein (Abmb) was discovered. Its discovery enriches the information and increases the interest in proteins with therapeutic potential from this mushroom. Furthermore, the A. bisporus genome reveals the possible occurrence of other lectins in this mushroom that may also have therapeutic potential. Most of these putative lectins belong to the same lectin groups as ABL and Abmb. Their relationship is discussed. Particular attention is addressed to ABL and Abmb, which have been explored for their potential in medicinal or pharmaceutical applications. ABL and Abmb have anti-proliferative activities toward cancer cells and a stimulatory effect on the immune system. Possible scenarios for their use in therapy and modification are also presented.

Mannose-Binding Lectin: A Potential Therapeutic Candidate against Candida Infection.

Mannose-binding lectin (MBL) is one of the key players in the innate immune system. It has the ability to identify a broad range of pathogens based on recognition of carbohydrate repeats displayed on microbial surfaces. Since mannans make about 40% of the total polysaccharide content of cell wall of Candida species (spp.) and MBL is capable of high-affinity binding to the mannan fraction of their cell wall component, this study has investigated the direct influence of MBL on Candida in vitro. Candida (C.) albicans and C. glabrata were in vitro exposed to different doses of recombinant human MBL for various time points to assess MBL influence on the production of hyphae and on the yeast forms. Moreover, the direct effect of MBL on the growth of C. albicans was measured by a cell proliferation assay. MBL induced agglutination of yeast forms as well as hyphal forms of Candida spp. and significantly reduced proliferation of C. albicans in vitro. MBL can be used as a potential antifungal candidate against Candida infection.

Mannose-Binding Lectin: Biologic Characteristics and Role in the Susceptibility to Infections and Ischemia-Reperfusion Related Injury in Critically Ill Neonates.

The mannose-binding lectin (MBL) is a member of the collectin family, belonging to the innate immunity system. Genetic, biologic, and clinical properties of MBL have been widely investigated throughout the last decades, although some interesting aspects of its potential clinical relevance are still poorly understood. Low circulating concentrations of MBL have been associated with increased risk of infection and poor neurologic outcome in neonates. On the other hand, an excessive and uncontrolled inflammatory response by the neonatal intestine after the exposure to luminal bacteria, leading to an increased production of MBL, may be involved in the onset of necrotizing enterocolitis. The purpose of the present review is to summarize the current knowledge about genetic and biologic characteristics of MBL and its role in the susceptibility to infections and to ischemia-reperfusion related tissue injuries to better explore its clinical relevance during the perinatal period and the possible future therapeutic applications.

Restoration of MBL-deficiency: redefining the safety, efficacy and viability of MBL-substitution therapy.

MBL-deficiency is a commonly occurring deficiency of the innate immune system, affecting a substantial part of the population and has been extensively studied. MBL appears to function as a disease modifier. The role of MBL in different conditions is context-dependent. Many clinical studies show conflicting results, which can be partially explained by different definitions of MBL-deficiency, including phenotype- and genotype-based approaches. In this review we give an overview of literature of MBL, its role in different pathologies, diseases and patient populations. We review MBL replacement studies, and discuss the potential of MBL substitution therapy. We finally suggest that new MBL substitution trials should be conducted within a predefined patient population. MBL-deficiency should be based on serum levels and confirmed by genotyping.

Does treatment of the laryngeal mucosa reduce dystonic symptoms? A prospective clinical cohort study of mannose binding lectin and other immunological parameters with diagnostic use of phonatory function studies.

This study examined efficacy of the innate immune defence via the mannose binding lectin (MBL) in a cohort of 55 dystonic patients prospectively referred to the clinic with laryngeal mucosal complaints, who were placed on local steroids (budesonid inhaler, 400 µg 2 times daily) and antihistamines (fexofenadin 180 mg mostly 3 times daily) with adjuvant lifestyle corrections. Treatment efficacy of the larynx was assessed based on mucosal findings of the vocal folds examined with phonatory function studies (PhFS) comprising simultaneous high-speed digital images, kymography, electroglottography and voice acoustics combined with a visual score of arytenoids oedema, as these measures are indicative of the magnitude of laryngitis. Lactose and gluten intolerance and immunological analyses of the innate system were made systematically. Results showed that the genetic aspects of immunology did not reveal a role for the innate immune system, represented by the MBL. But an unexpected positive effect of the larynx treatment on dystonia symptoms was found evidenced by reduction of dystonic complaints and more normative results of PhFS, and a reduction of oedema of the inter arytenoids region. Symptoms relieve and better quality of life was observed on follow-up for the dystonia complaints.

Efficacy of recombinant human mannose binding lectin alone and in combination with itraconazole against murine Candida albicans vaginitis.

Mannan binding lectin (MBL) deficiency has been associated with increased susceptibility to vaginitis in humans due to Candida albicans. In these studies we assessed the utility of recombinant human MBL (rhMBL) as a therapeutic against experimental C. albicans vaginitis. After intravenous treatment of uninfected mice with 75 µg of rhMBL, rhMBL was detected in the serum and peritoneal lavage fluid; rhMBL was detected in the serum of infected mice 2 and 24 hours post-dose, and at very low concentrations in vaginal lavage fluid. Intravenous treatment with rhMBL alone or in combination with oral itraconazole enhanced the clearance of C. albicans from the vagina of wild-type or MBL gene knockout (KO) mice; rhMBL was modestly effective alone. However, rhMBL in combination with itraconazole was not better than itraconazole alone. Topical administration of rhMBL in a cream appeared more effective than rhMBL in a gel and both were inferior to commercial clotrimazole cream. Topical rhMBL cream in combination with itraconazole resulted in a 3-fold improvement in clearance of the yeast compared with sole itraconazole therapy. Overall, these data indicate that rhMBL may have utility in the treatment of candidal vaginitis when used as an adjunctive therapy.

Mannan-binding lectin and healing of a radiation-induced chronic ulcer--a case report on mannan-binding lectin replacement therapy.

Mannan-binding lectin is an important component of innate immunity, and insufficiency is associated with several clinical disorders. Recently, experimental replacement therapy with plasma-derived mannan-binding lectin has become an option. The current article presents the case of a patient with an insufficient level of mannan-binding lectin and a chronic radiation-induced ulcer following the treatment of breast cancer. After 15 months of initially conservative treatment and thereafter plastic surgery, the healing was still impaired with necrosis in the periphery of the ulcer. Immunological work-up of the patient revealed pronounced insufficiency of mannan-binding lectin. Following a 6-week experimental intravenous treatment with mannan-binding lectin purified from human plasma, that is, 0.2-0.3 mg mannan-binding lectin per kg body weight twice a week, the defect was completely healed. We suggest that deficiency of mannan-binding lectin can explain cases of otherwise unexplained impaired healing, and that replacement therapy is considered in such cases.

Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: A review and meta-analysis.

Mannose-binding lectin (MBL) is an innate immune protein produced by the liver. MBL binds to glycoconjugates containing mannose, fucose or N-acetylglucosamine that are present in a wide variety of bacteria, viruses and fungi. Upon binding, MBL may active the lectin pathway of complement or directly opsonize organisms to enhance phagocytosis. MBL is primarily a serum protein but accumulates in the lung during acute inflammation. Recent evidence suggests an important role for MBL in a variety of infectious disorders. Cystic fibrosis (CF) is a multisystem disease caused by mutations in the gene encoding the CF transmembrane regulator (CFTR). The course of CF lung disease is highly variable even in patients with the same CFTR genotype, suggesting that other modulator genes are important for prognosis. MBL has been proposed as a possible modulator of clinical severity in CF. In this review and meta-analysis, we found that MBL2 genotypes associated with MBL insufficiency were associated with earlier acquisition of Pseudomonas aeruginosa (P < 0.0001), reduced pulmonary function among adult patients (P < 0.0001 for forced expiratory volume), and an increased rate of death or requirement for lung transplantation (odds ratio 3.69; P = 0.02). The available evidence therefore suggests that MBL insufficiency is associated with the severity of CF lung disease. The possible future prophylactic or therapeutic application of MBL replacement is discussed.

Potential therapeutic efficacy of a bactericidal-immunomodulatory fusion peptide against methicillin-resistant Staphylococcus aureus skin infection.

To enhance the potential therapeutic efficacy of an antimicrobial peptide human beta-defensin 3, two fusion peptides, a bactericidal-immunomodulatory fusion peptide human beta-defensin 3-mannose-binding lectin and a bactericidal-bactericidal fusion peptide human beta-defensin 3-lysozyme were synthesized and the bactericidal activities in vitro and in vivo against methicillin-resistant Staphylococcus aureus N315 were demonstrated in this study. Peptide human beta-defensin 3-lysozyme showed the best bactericidal activity in vitro, but human beta-defensin 3-mannose-binding lectin showed a significant improvement in angiogenesis and tissue reconstruction. Our results illustrated that outstanding bactericidal activity in vitro is not essential in the development of antimicrobial peptides. Fusion strategy and immunomodulatory factors should be utilized in novel antimicrobial peptide development.

Therapeutic role for mannose-binding lectin in cigarette smoke-induced lung inflammation? Evidence from a murine model.

Defective efferocytosis in the airway may perpetuate inflammation in smokers with/without chronic obstructive pulmonary disease. Mannose-binding lectin (MBL) improves efferocytosis in vitro; however, the effects of in vivo administration are unknown. MBL circulates in complex with MBL-associated serine proteases (MASPs), and efferocytosis involves activation of cytoskeletal-remodeling molecules, including Rac1/2/3. We hypothesized that MBL would improve efferocytosis in vivo, and that possible mechanisms for this effect would include up-regulation of Rac1/2/3 or MASPs. We used a smoking mouse model to investigate the effects of MBL on efferocytosis. MBL (20 microg/20 g mouse) was administered via nebulizer to smoke-exposed mice. In lung tissue (disaggregated) and bronchoalveolar lavage (BAL), we investigated leukocyte counts, apoptosis, and the ability of alveolar and tissue macrophages to phagocytose apoptotic murine epithelial cells. In human studies, flow cytometry, ELISA, and RT-PCR were used to investigate the effects of MBL on efferocytosis, Rac1/2/3, and MASPs. Smoke-exposed mice showed significantly reduced efferocytosis in BAL and tissue. Efferocytosis was significantly improved by MBL (BAL: control, 26.2%; smoke-exposed, 17.66%; MBL + smoke-exposed, 27.8%; tissue: control, 35.9%; smoke-exposed, 21.6%; MBL + smoke-exposed, 34.5%). Leukocyte/macrophage counts were normalized in smoke-exposed mice treated with MBL. In human studies, MBL was reduced in chronic obstructive pulmonary disease and in smokers, and was significantly correlated with reduced efferocytosis ex vivo. MASPs were not detected in BAL, and were not produced by alveolar or tissue macrophages. MBL significantly increased macrophage expression of Rac1/2/3. We provide evidence for Rac1/2/3 involvement in the MBL-mediated improvement in efferocytosis, and a rationale for investigating MBL as a supplement to existing therapies in smoking-related lung inflammation.

Second-generation nanofiltered plasma-derived mannan-binding lectin product: process and characteristics.

BACKGROUND AND OBJECTIVES: Mannan-binding lectin (MBL) is an important component of the innate immune defence; it binds to carbohydrate structures on pathogenic micro-organisms resulting in complement activation and opsonization. Individuals with low MBL levels are at risk of recurrent and severe infections. Substitution therapy with plasma-derived MBL is a promising treatment of diseases associated with MBL deficiency. A first-generation MBL product has been shown to be safe and well tolerated, and patients have benefited from MBL treatment. Following is a description of the development of a nanofiltered second-generation MBL product from Cohn fraction III, with the use of a new affinity matrix for MBL purification and the characteristics of this improved product. MATERIALS AND METHODS: Carbohydrate-based gels were comparatively screened as affinity matrices. MBL was extracted from fraction III, and affinity purified on a Superdex 200 pg column. The eluted material underwent two virus reduction steps: filtration through Planova 20N and solvent/detergent treatment. It was further purified by anion-exchange and gel-filtration chromatography. The affinity eluate and the final MBL fraction were characterized by protein chemical, immunological, and functional assays. RESULTS: In production scale, Superdex 200 pg was found to be superior to other carbohydrate-based matrices, and MBL was affinity purified from fraction III with a yield of 70%. The viral safety was increased by performing a nanofiltration of the affinity eluate through Planova 20N with a minimal loss of MBL. The purity of the final MBL fraction was 53% excluding the MBL-associated serine proteases (MASP). The product consisted of high-oligomeric MBL, with two dominating forms, and with MASP-1, -2, -3 and 19 kDa MBL-associated protein (MAp19). Only a few protein impurities were present, the major being alpha2-macroglobulin. MBL formed complexes with alpha2-macroglobulin bridged by MASP-1 covalently attached to the latter. The functional activity, assessed by mannan-binding activity and opsonic function, was intact, whereas half of the C4 activating capacity was lost during the production process. CONCLUSION: A second-generation MBL process was developed with an average yield of 50%. It was possible to nanofilter the MBL-MASP complexes through Planova 20N with only a minor loss resulting in an increased safety profile of this MBL product.

Protective role of mannan-binding lectin in a murine model of invasive pulmonary aspergillosis.

Innate immune molecules such as lung collectins and serum pentraxins have evolved as important host defence proteins against Aspergillus fumigatus, a medically important opportunistic fungal pathogen. Mannan-binding lectin (MBL), an opsonin and lectin complement pathway activator, constitutes another vital player of innate immunity against several pathogenic organisms in the serum. Studies have reported significant binding of MBL to A. fumigatus; however, the protective role of MBL against A. fumigatus-mediated invasive disease remains elusive. Henceforth, we investigated the contribution of externally administered recombinant human (rh) MBL towards anti-fungal defence in invasive pulmonary aspergillosis (IPA) by in vivo and in vitro studies. In murine models of IPA with corticosteroid-induced immunosuppression, rhMBL-treated mice showed 80% survival compared to untreated IPA mice with no survivors. Treated IPA mice also showed a marked increase in tumour necrosis factor (TNF)-alpha and interleukin (IL)-1alpha and a significant decrease in pulmonary fungal hyphae and IL-10. In vitro, rhMBL-bound A. fumigatus conidia showed a dose-dependent increase in the deposition of C4b, the first product of the lectin pathway. There was an enhanced uptake of A. fumigatus conidia by the polymorphonuclear cells (PMNs) in the presence of rhMBL that increased further in the presence of MBL supplemented with MBL-deficient serum. However, an increase in the oxidative burst of PMNs and A. fumigatus killing were observed only when MBL was supplemented with MBL-deficient serum. The study suggests a therapeutic role of ex vivo-administered MBL in host defence against aspergillosis, possibly through MBL-mediated complement activation and other protective mechanisms aimed both directly at the pathogen, and indirectly through modulation of the host inflammatory responses.

Potential of lung surfactant proteins, SP-A and SP-D, and mannan binding lectin for therapy and genetic predisposition to allergic and invasive aspergillosis.

A significant proportion of bronchial asthma patients have underlying pulmonary fungal infections that contribute to persistent inflammation and allergic reactions. Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen causing a spectrum of allergic and infectious diseases. Currently, oral corticosteroids form the first line of treatment for allergic aspergillosis and use of antifungals such as itraconazole has been indicated in non-responders. In view of the protective role of innate immunity in host defense against Aspergillus fumigatus, we aimed to identify the relevant innate immune proteins In a series of studies, we identified and established the therapeutic potential of pulmonary collectins SP-A and SP-D and serum collectin MBL in murine models of allergic and invasive aspergillosis. Use of SP-D for diagnosis and therapy of lung disorders and MBL for therapy of various infections including invasive aspergillosis has been patented. Genetic polymorphisms in these genes may result in partial or total loss of function and may increase the host's susceptibility to aspergillosis. Candidate gene association studies showed SNPs in SP-A2 and MBL significantly associate with patients of allergic bronchopulmonary aspergillosis and bronchial asthma with rhinitis. The patients carrying either one or both of GCT and AGG alleles of SP-A2 and patients with A allele at position 1011 of MBL had markedly higher eosinophilia, total IgE antibodies and lower FEV1 (the clinical markers of ABPA). These SNPs may be useful for predicting susceptibility to allergic aspergillosis and bronchial asthma with allergic rhinitis and have been patented. Elucidation of the immunoregulatory role of SP-A, SP-D and MBL in mechanisms of allergy and inflammation suggests that they may also be potentially useful for predisposition diagnosis and therapy of non-fungal bronchial asthma.

Lectina de unión a manosa: actividad biológica y significado / Manosse-binding lectin: biological activity and significance

La lectina de unión a la manosa (MBL) es una colectina que se sintetiza en el hígado y es secretada al torrente sanguíneo, la cual es capaz de unirse con estructuras repetidas de azúcares presentes en una amplia variedad de bacterias y otros microorganismos promoviendo su eliminación mediante la activación del complemento a través de serín proteasas asociadas. A las deficiencias de MBL se les considera como un importante factor de riesgo de infecciones en niños y en individuos inmunosuprimidos. Se discute la evidencia de que la MBL contribuye de forma importante a la inmunidad innata con el incremento de la susceptibilidad a determinadas enfermedades o la incidencia en el curso de estas. Estudios preliminares del empleo de terapias sustitutivas con MBL han arrojado resultados prometedores, los que deben ofrecer evidencias acerca del significado fisiológico de esta proteína

Lectina de unión a manosa: actividad biológica y significado / Manosse-binding lectin: biological activity and significance

La lectina de unión a la manosa (MBL) es una colectina que se sintetiza en el hígado y es secretada al torrente sanguíneo, la cual es capaz de unirse con estructuras repetidas de azúcares presentes en una amplia variedad de bacterias y otros microorganismos promoviendo su eliminación mediante la activación del complemento a través de serín proteasas asociadas. A las deficiencias de MBL se les considera como un importante factor de riesgo de infecciones en niños y en individuos inmunosuprimidos. Se discute la evidencia de que la MBL contribuye de forma importante a la inmunidad innata con el incremento de la susceptibilidad a determinadas enfermedades o la incidencia en el curso de estas. Estudios preliminares del empleo de terapias sustitutivas con MBL han arrojado resultados prometedores, los que deben ofrecer evidencias acerca del significado fisiológico de esta proteína(AU)

Clinical manifestations of mannan-binding lectin deficiency.

Mannan-binding lectin (MBL) is a plasma protein of the innate immune system with the ability to initiate antimicrobial and inflammatory actions. MBL deficiency is common. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. Ongoing research attempt to illuminate at which conditions MBL deficiency may lead to disease. With examples, this review illustrates the diversity of results obtained so far.

Mannose-binding lectin: biology and clinical implications.

The innate host defence molecule mannose-binding lectin (MBL) has attracted great interest as a potential candidate for passive immunotherapy to prevent infection. MBL is a multimeric lectin that recognizes a wide array of pathogens independently of specific antibody, and initiates the lectin pathway of complement activation. The basic structural unit is a triple helix of MBL peptides, which aggregate into complement-fixing higher-order structures (tetramers, pentamers and hexamers). The gene encoding MBL, MBL2, contains several common polymorphisms that influence transcription and assembly of the molecule into multimers. MBL2 coding alleles associated with low blood levels are present in up to 40% of Caucasoids, with up to 8% having genotypes associated with profound reduction in circulating MBL levels. Low-producing MBL2 variants and low MBL levels are associated with increased susceptibility to and severity of a variety of infective illnesses, particularly when immunity is already compromised--for example, in infants and young children, patients with cystic fibrosis, and after chemotherapy and transplantation. These observations suggest that administration of recombinant or purified MBL may be of benefit in clinical settings where MBL deficiency is associated with a high burden of infection. This review provides a background to MBL biology and disease associations, and identifies the exciting therapeutic possibilities of MBL replacement.

Introduction to mannan-binding lectin.

Mannan-binding lectin (MBL) was first discovered as a plasma opsonin for baker's yeast and was independently characterized biochemically. It belongs to the small subfamily of collectins: C-type lectins possessing a collagen-like domain. MBL is synthesized by the liver and secreted into the bloodstream. It is believed to be an important component of innate immunity, acting as an ante-antibody and/or as a disease modifier. It is thought to influence disorders as diverse as meningococcal disease, rheumatoid arthritis, cystic fibrosis and recurrent miscarriage. Lack of MBL may be most relevant in the context of a co-existing secondary immune deficiency. Replacement therapy, first carried out 30 years ago with unfractionated plasma, appears promising. The development of a recombinant product should permit the extension of MBL therapy to randomized clinical trials of sufficient size to provide clear evidence about the physiological significance of this intriguing glycoprotein.