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  • American Association for the Advancement of Science (AAAS)  (4)
  • 1
    Online Resource
    Online Resource
    Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Translational Medicine Vol. 12, No. 545 ( 2020-05-27)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 12, No. 545 ( 2020-05-27)
    Abstract: Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aay1163
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Immunology Vol. 6, No. 56 ( 2021-02-12)
    Details
    In: Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 6, No. 56 ( 2021-02-12)
    Abstract: Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14 + monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E 2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE 2 , which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.
    Type of Medium: Online Resource
    ISSN: 2470-9468
    URL: Article
    DOI: 10.1126/sciimmunol.abd6279
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Translational Medicine Vol. 12, No. 549 ( 2020-06-24)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 12, No. 549 ( 2020-06-24)
    Abstract: Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti–PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of “costimulatory bispecifics” that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti–PD-1 approach and endow responsiveness—as well as long-term immune memory—against tumors that otherwise do not respond to anti–PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and “off the shelf” combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aba2325
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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    Online Resource
  • 4
    Online Resource
    Online Resource
    A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Translational Medicine Vol. 12, No. 525 ( 2020-01-08)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 12, No. 525 ( 2020-01-08)
    Abstract: T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide–major histocompatibility complexes (“signal 1”); activation is enhanced by engagement of a second “costimulatory” receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell (“signal 2”). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized. Here, we introduce a class of bispecific antibodies that mimic signal 2 by bridging TSA to the costimulatory CD28 receptor on T cells. We term these TSAxCD28 bispecifics and describe two such bispecific antibodies: one specific for ovarian and the other for prostate cancer antigens. Unlike CD28 superagonists, which broadly activate T cells and resulted in profound toxicity in early clinical trials, these TSAxCD28 bispecifics show limited activity and no toxicity when used alone in genetically humanized immunocompetent mouse models or in primates. However, when combined with TSAxCD3 bispecifics, they enhance the artificial synapse between a T cell and its target cell, potentiate T cell activation, and markedly improve antitumor activity of CD3 bispecifics in a variety of xenogeneic and syngeneic tumor models. Combining this class of CD28-costimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aaw7888
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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