WALTHAM, MA, United States

Nkt Therapeutics, Inc.

www.nktrx.com
WALTHAM, MA, United States
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Waters E.K.,Cambridge Healthcare | Waters E.K.,Archemix | Genga R.M.,Cambridge Healthcare | Genga R.M.,Archemix | And 9 more authors.
Journal of Thrombosis and Haemostasis | Year: 2013

Background: Tissue factor pathway inhibitor (TFPI) is a multidomain protein that negatively regulates the coagulation cascade. TFPI inhibits the tissue factor (TF)-activated factor VII-activated FX (FXa) complex during TF-mediated coagulation initiation. The aptamer BAX 499 binds specifically to TFPI and inhibits its function, mediating a procoagulant effect in both in vitro and in vivo models of hemophilia. Objectives: This study sought to identify the regions of TFPI that are critical for BAX 499 binding, and to determine how binding mediates aptamer inhibition of TFPI. Methods and Results: In vitro biochemical methods were used to evaluate the BAX 499 interaction with and inhibition of TFPI. Binding experiments indicated that the full-length TFPI protein is required for tight aptamer binding. Binding-competition experiments implicated the Kunitz 1, Kunitz 3 and C-terminal domains of TFPI in aptamer binding, a finding that is supported by hydrogen-deuterium exchange experiments, and indicated that aptamer and FXa can bind simultaneously to TFPI. In enzymatic assays, BAX 499 inhibited TFPI in a manner that is distinct from domain-specific antibodies, and aptamer inhibitory activity is reduced in the presence of the TFPI cofactor protein S. Conclusions: These studies demonstrate that BAX 499 binds to TFPI via multiple domains of the protein in a manner that is distinct from other TFPI inhibitors, mediating a mechanism of inhibition that does not involve direct competition with FXa. With this unique inhibitory mechanism, BAX 499 provides a useful tool for studying TFPI biology in health and disease. © 2013 International Society on Thrombosis and Haemostasis.


PubMed | University of Western Ontario and Nkt Therapeutics, Inc.
Type: | Journal: The Journal of infectious diseases | Year: 2016

During toxic shock syndrome (TSS), bacterial superantigens trigger a polyclonal T cell response leading to a potentially catastrophic cytokine storm. Whether innate-like invariant natural killer T(iNKT) cells, with remarkable immunomodulatory properties, participate in TSS is unclear. Using genetic and cell depletion approaches, we generated iNKT cell-deficient, superantigen-sensitive HLA-DR4-transgenic (DR4tg) mice, which were compared with their iNKT-sufficient counterparts for responsiveness to staphylococcal enterotoxin B(SEB). Both approaches indicate that iNKT cells are pathogenic in TSS. Importantly, treating DR4tg mice with a T


Scheuplein F.,Nkt Therapeutics, Inc. | Thariath A.,Nkt Therapeutics, Inc. | Macdonald S.,Nkt Therapeutics, Inc. | Truneh A.,Nkt Therapeutics, Inc. | And 2 more authors.
PLoS ONE | Year: 2013

Invariant Natural Killer T (iNKT) cells are a subset of T cells recognizing glycolipid antigens presented by CD1d. Human iNKT cells express a conserved T cell receptor (TCR)-α chain (Vα24-Jα18) paired with a specific beta chain, Vβ11. The cells are both innate-like, with rapid cytokine release, and adaptive-like, including thymic positive selection. Over activation of iNKT cells can mediate tissue injury and inflammation in multiple organ systems and play a role in mediating the pathology associated with clinically important inflammatory diseases. At the same time, iNKT cell activation can play a role in protecting against infectious disease and cancer or modulate certain autoimmune diseases through its impact on both the innate and adaptive immune system. This suggests that approaches to cause iNKT cell reduction and/or depletion could treat inflammatory diseases while approaches to promote activation may have therapeutic potential in certain infections, cancer or autoimmune disease. This report summarizes the characterization of a humanized monoclonal depleting antibody (NKTT120) in the cynomolgus macaque. NKTT120 is being developed to treat iNKT mediated inflammation that is associated with chronic inflammatory conditions like sickle cell disease and asthma. NKTT120 binds to human iTCRs and to FCγRI and FCγRIII and has been shown to kill target cells in an ADCC assay at low concentrations consistent with the FCγR binding. iNKT cells were depleted within 24 hours in cynomolgus macaques, but T cell, B cell, and NK cell frequencies were unchanged. iNKT cell recovery was dose and time dependent. T cell dependent antigen responses were not impaired by NKTT120 mediated iNKT depletion as measured by response to KLH challenge. NKTT120 administration did not induce an inflammatory cytokine release at doses up to 10 mg/kg. These data support the use of NKTT120 as an intervention in inflammatory diseases where iNKT reduction or depletion could be beneficial. © 2013 Scheuplein et al.


Scheuplein F.,Nkt Therapeutics, Inc. | Lamont D.J.,The Jackson Laboratory | Poynter M.E.,University of Vermont | Boyson J.E.,University of Vermont | And 4 more authors.
PLoS ONE | Year: 2015

Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. The cells have both innate-like rapid cytokine release, and adaptive-like thymic positive selection. iNKT cell activation has been implicated in the pathogenesis of allergic asthma and inflammatory diseases, while reduced iNKT cell activation promotes infectious disease, cancer and certain autoimmune diseases such as Type 1 diabetes (T1D). Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have potential in certain infectious diseases, cancer or autoimmunity. Thus, we developed invariant TCR-specific monoclonal antibodies to better understand the role of iNKT cells in disease. We report here the first monoclonal antibodies specific for the mouse invariant TCR that by modifying the Fc construct can specifically deplete or activate iNKT cells in vivo in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1D. As demonstrated previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively accelerated and retarded T1D onset. In BALB/c mice, ovalbumin (OVA) mediated airway hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation. © 2015 Scheuplein et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | University of Vermont, Nkt Therapeutics, Inc. and The Jackson Laboratory
Type: Journal Article | Journal: PloS one | Year: 2015

Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. The cells have both innate-like rapid cytokine release, and adaptive-like thymic positive selection. iNKT cell activation has been implicated in the pathogenesis of allergic asthma and inflammatory diseases, while reduced iNKT cell activation promotes infectious disease, cancer and certain autoimmune diseases such as Type 1 diabetes (T1D). Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have potential in certain infectious diseases, cancer or autoimmunity. Thus, we developed invariant TCR-specific monoclonal antibodies to better understand the role of iNKT cells in disease. We report here the first monoclonal antibodies specific for the mouse invariant TCR that by modifying the Fc construct can specifically deplete or activate iNKT cells in vivo in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1D. As demonstrated previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively accelerated and retarded T1D onset. In BALB/c mice, ovalbumin (OVA) mediated airway hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.


Patent
Nkt Therapeutics, Inc. | Date: 2014-11-05

Pharmaceutical compositions and treatments involving iNKT cell activation are provided.


Patent
Nkt Therapeutics, Inc. | Date: 2015-07-28

Pharmaceutical compositions and treatments involving iNKT cell activation are provided.


Patent
Nkt Therapeutics, Inc. | Date: 2012-10-26

Methods of treatment to suppress an immune response are provided. The method comprises administering to a subject in need of treatment a naked blocking antibody that binds selectively iNKT cells in an amount effective to suppress the subjects iNKT cell function. Compositions comprising, an isolated, humanized antibody that binds selectively iNKT cells are also provided.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.95K | Year: 2014

There is a central role for iNKT cells in mediating inflammatory responses in sickle cell disease. NKT Therapeutics has developed a humanized monoclonal antibody (NKTT120) that can specifically mediate iNKT cell depletion by antibody and complement directed cellular cytotoxicity. We are currently engaged in a safety/PK Phase 1 study in stable sickle cell disease patients. Although the use of specific murine SCD models has helped in defining the role of iNKT cells in SCD, the fact that NKTT120 does not crossreact with murine iNKT cells has limited our ability to assess the short and long term impact of iNKT cell depletion on the pathology of SCD. Our recent identification of a monoclonal antibody (NKT-14) that binds to the mouse NKT cell to mediate murine iNKT cell depletion provides us with a unique opportunity to directly explore the impact of iNKT cell depletion in mediating the pathology of SCD. The antibody is specific for the mouse iTCR and, when bound, promotes a rapid and long lasting (gt 14 days) dep


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