An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Maun, Henry R.; Jackman, Janet; Choy, David F.; Loyet, Kelly M.; Staton, Tracy; Jia, Guiquan; Dressen, Amy; Hackney, Jason A.; Bremer, Meire; Walters, Benjamin T.; Vij, Rajesh; Trivedi, Neil N.; Morando, Ashley; Lipari, Michael T.; Franke, Yvonne; Wu, Xiumin; Zhang, Juan; Liu, John; Wu, Ping; Chang, Diana; Orozco, Luz D.; Christensen, Erin; Wong, Manda; Corpuz, Racquel; Hang, Julie Q.; Lutman, Jeff; Sukumaran, Siddharth; Wu, Yan; Ubhayakar, Savita; Liang, Xiaorong; Schwartz, Lawrence B.; Babina, Magda; Woodruff, Prescott G.; Fahy, John V.; Ahuja, Rahul; Caughey, George H.; Kusi, Aija; Dennis, Mark S.; Kirchhofer, Daniel; Austin, Cary D.; Wu, Lawren C.; Koerber, James T.; Lee, Wyne P.; Yaspan, Brian L.; Alatsis, Kathila R.; Arron, Joseph R.; Lazarus, Robert A.; Yi, Tangsheng

doi:10.1016/j.cell.2020.01.003

Cited by 21 publications

(32 citation statements)

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“…57 establishing MC tryptase as a potential therapeutic target. 58 A detailed understanding if and how a-tryptase encoding TPSAB1 copy number gains contribute to the clonal expansion of KIT D816Vpositive neoplastic MC might provide new insight into the pathophysiology of SM and help to exploit novel targeting strategies.…”

Section: Discussionmentioning

confidence: 99%

Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis

Greiner

Sprinzl

Górska

et al. 2021

Blood

137

141

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Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital PCR in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (p<0.001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs. HαT- cases: 34.5 ng/mL, p=0.004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.

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Section: Discussionmentioning

confidence: 99%

Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis

Greiner

Sprinzl

Górska

et al. 2021

Blood

137

141

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“…Mast cells, present in strategic locations of human lung [ 19 , 20 , 26 , 32 ], are involved in several pulmonary diseases [ 22 , 31 ], lung remodeling [ 112 , 113 ], COPD [ 9 , 12 , 32 ], lung cancer [ 114 , 115 , 116 ], and asthma [ 17 , 19 ]. In recent years, the widespread use of ART has improved the survival of people with HIV [ 1 ], leading to the emergence of chronic inflammatory lung diseases as a noteworthy concern in this population [ 7 , 9 ].…”

Section: Discussionmentioning

confidence: 99%

HIV gp120 Induces the Release of Proinflammatory, Angiogenic, and Lymphangiogenic Factors from Human Lung Mast Cells

et al. 2020

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Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are involved in chronic pulmonary diseases occurring at high frequency among HIV-infected individuals. Immunoglobulin superantigens bind to the variable regions of either the heavy or light chain of immunoglobulins (Igs). Glycoprotein 120 (gp120) of HIV-1 is a typical immunoglobulin superantigen interacting with the heavy chain, variable 3 (VH3) region of human Igs. The present study investigated whether immunoglobulin superantigen gp120 caused the release of different classes of proinflammatory and immunoregulatory mediators from HLMCs. The results show that gp120 from different clades induced the rapid (30 min) release of preformed mediators (histamine and tryptase) from HLMCs. gp120 also caused the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HLMCs. Incubation (6 h) of HLMC with gp120 induced the release of angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The activating property of gp120 was mediated through the interaction with IgE VH3+ bound to FcεRI. Our data indicate that HIV gp120 is a viral superantigen, which induces the release of different proinflammatory, angiogenic, and lymphangiogenic factors from HLMCs. These observations could contribute to understanding, at least in part, the pathophysiology of chronic pulmonary diseases in HIV-infected individuals.

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“…The clinical efficacy of many of these agents is currently being explored in clinical trials. Finally, for patients with severe allergies and MCAS, and for those who are suffering from severe allergies, MCAS and/or additional aggravating MC conditions (like HAT and/or mastocytosis), application of antibodies removing IgE, such as omalizumab or ligelizumab, or targeting MC tryptase, may represent promising additional approaches 310 - 314 . Finally, a number of inhibitory receptors, such as Siglec-7, Siglec-8, or CD300a, have been identified on human MCs and are currently being validated for their role as therapeutic target sites 315 - 318 .…”

Section: New Treatment Concepts: Targeting Of MC Growth And/or Activamentioning

confidence: 99%

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts

et al. 2020

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The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.

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An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Cited by 21 publications

References 0 publications

Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis

Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis

HIV gp120 Induces the Release of Proinflammatory, Angiogenic, and Lymphangiogenic Factors from Human Lung Mast Cells

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts

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