Danica Stanimirovic

Danica Stanimirovic
National Research Council Canada | NRC · Human Health Therapeutics Portfolio

MD, PhD

About

281
Publications
30,088
Reads
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11,001
Citations
Citations since 2016
53 Research Items
4192 Citations
20162017201820192020202120220200400600800
20162017201820192020202120220200400600800
20162017201820192020202120220200400600800
20162017201820192020202120220200400600800
Additional affiliations
June 2012 - present
National Research Council Canada
Position
  • Director Research, Translational Bioscience
June 2001 - December 2012
National Research Council Canada
Position
  • Director Research, Neurobiology
June 1998 - June 2001
National Research Council Canada
Position
  • Group Leader, Cerebrovascular Research

Publications

Publications (281)
Article
Full-text available
The blood-brain barrier (BBB) prevents the access of therapeutic antibodies to central nervous system (CNS) targets. The engineering of bispecific antibodies in which a therapeutic "arm" is combined with a BBB-transcytosing arm can significantly enhance their brain delivery. The BBB-permeable single-domain antibody FC5 was previously isolated by ph...
Article
Full-text available
The cerebral vasculature ensures proper cerebral function by transporting oxygen, nutrients, and other substances to the brain. Distribution of oxygenated blood throughout the neuroaxis takes place at the level of the circle of Willis (CW). While morphologic and functional alterations in CW arteries and its main branches have been reported in cereb...
Article
Full-text available
Background Aβ transport (flux) across the blood-brain barrier (BBB) is thought to contribute to the pathogenesis of Alzheimer’s disease as well as to elimination of toxic amyloid from the brain by immunotherapy. Several BBB transporters have been implicated in Aβ exchange between brain parenchyma and the circulation, including efflux transporters P...
Article
Full-text available
The identification of molecular biomarkers in CSF from individuals affected by Huntington disease may help improve predictions of disease-onset, better define disease progression, and could facilitate evaluation of potential therapies. The primary objective of our study was to investigate novel CSF protein candidates and replicate previously report...
Article
Pathologies of the central nervous system impact a significant portion of our population, and the delivery of therapeutics for effective treatment is challenging. The insulin-like growth factor receptor (IGF1R) has emerged as a target for receptor-mediated transcytosis, a process by which antibodies are shuttled across the blood-brain barrier (BBB)...
Article
Full-text available
Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises concerns about safety and developmental burden. Here,...
Conference Paper
The identification of molecular biomarkers in CSF from individuals affected by Huntington disease may help improve prediction of disease onset, better define disease progression, and could facilitate evaluation of potential therapies. The primary objective of our study was to assess previously reported changes in CSF protein markers and investigate...
Article
Full-text available
The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way to increase drug delivery to the brain. In this study, w...
Article
Full-text available
Purpose We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer’s disease (AD). F...
Article
Full-text available
Human blood brain barrier (BBB) models derived from induced pluripotent stem cells (iPSCs) have become an important tool for the discovery and preclinical evaluation of central nervous system (CNS) targeting cell and gene-based therapies. Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary form of gene-modified cell-based immunotherap...
Chapter
Brain delivery of therapeutic antibodies and biologics is restricted due to the presence of the blood-brain barrier (BBB). However, their delivery can be improved with the use of “carrier” antibodies that target receptors on the luminal surface of the BBB which initiate a process termed receptor-mediated transcytosis (RMT). This review describes ke...
Preprint
Full-text available
Human blood brain barrier (BBB) models derived from induced pluripotent stem cell (iPSC) have become an important tool for discovery and preclinical evaluation of central nervous system (CNS) targeting cell and gene-based therapies. Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary form of gene-modified cell-based immunotherapy with...
Article
Full-text available
The blood‐brain barrier (BBB) prevents the majority of drugs from crossing into the brain and reaching neurons. To overcome this challenge, safe and non‐invasive technologies targeting receptor‐mediated pathways have been developed. In this study, three single‐domain antibodies (sdAbs; IGF1R3, IGF1R4, and IGF1R5) targeting the extracellular domain...
Chapter
Automated high-throughput immunoassays are emerging as reliable analytic techniques for the quantitative detection of proteins from a variety of sample types. Herein, we describe a method using the Protein Simple Wes capillary-based automated immunoassays platform for the quantification of His- and HA-tagged antibody transcytosis across an in vitro...
Article
Full-text available
Interrogation of the molecular makeup of the blood–brain barrier (BBB) using proteomic techniques has contributed to the cataloguing and functional understanding of the proteins uniquely organized at this specialized interface. The majority of proteomic studies have focused on cellular components of the BBB, including cultured brain endothelial cel...
Article
Full-text available
In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer’s disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used i...
Article
Full-text available
Synthetic grafts have been developed for vascular bypass surgery, however, the risks of thrombosis and neointimal hyperplasia still limit their use. Tissue engineering with the use of adipose-derived stem cells (ASCs) has shown promise in addressing these limitations. Here we further characterized and optimized the ASC differentiation into smooth m...
Article
Background and Objectives The prediction of pharmacokinetics of monoclonal antibodies (mAbs) exhibiting non-linear pharmacokinetics in preclinical species to human is challenging, and very limited scientific work has been published in this field of research. Therefore, we have conducted an elaborate comparative assessment to determine the most reli...
Chapter
The development of translational and predictive models in vitro for assessing blood–brain barrier (BBB) delivery has become an important requirement in preclinical testing of CNS-targeting therapeutics. Here we describe a directed monolayer differentiation strategy to generate a population of brain endothelial-like cells (BECs) from human induced p...
Article
Full-text available
Ligand-activated signaling through the type 1 insulin-like growth factor receptor (IGF1R) is implicated in many physiological processes ranging from normal human growth to cancer proliferation and metastasis. IGF1R has also emerged as a target for receptor-mediated transcytosis, a transport phenomenon that can be exploited to shuttle biotherapeutic...
Article
We have developed a blood‐brain barrier (BBB) crossing anti‐amyloid fusion protein KG207 as a potential AD therapeutic. This humanized bi‐functional molecule was generated by fusing an Aß oligomer (AßO)‐ binding peptide (ABP) with a BBB carrier FC5 via IgG‐1 Fc fragment. Present study shows that KG207 crosses the BBB in vitro and in vivo (mouse, ra...
Article
Full-text available
Receptor-mediated transcytosis (RMT) is a principal pathway for transport of macromolecules essential for brain function across the blood-brain barrier (BBB). Antibodies or peptide ligands which bind RMT receptors are often co-opted for brain delivery of biotherapeutics. Constitutively recycling transferrin receptor (TfR) is a prototype receptor ut...
Article
Full-text available
Introduction: In vivo imaging technologies have become integral and essential component of drug discovery, development, and clinical assessment for central nervous system (CNS) diseases. Near-infrared (NIR) fluorescence imaging in the range of 650–950 nm is widely used for pre-clinical in vivo imaging studies. The recent expansion of NIR imaging in...
Preprint
Full-text available
Receptor-mediated transcytosis (RMT) is a principal pathway for transport of macromolecules essential for brain function across the blood-brain barrier (BBB). Antibodies or peptide ligands which bind RMT receptors are often co-opted for brain delivery of biotherapeutics. A constitutively recycling transferrin receptor (TfR) is a prototype receptor...
Preprint
Full-text available
Receptor-mediated transcytosis (RMT) is a principal pathway for transport of macromolecules essential for brain function across the blood-brain barrier (BBB). Antibodies or peptide ligands which bind RMT receptors are often co-opted for brain delivery of biotherapeutics. Constitutively recycling transferrin receptor (TfR) is a prototype receptor ut...
Chapter
Protein-protein interactions play key roles in leukocyte extravasation process into the brain and have been attractive therapeutic targets for inhibiting brain inflammation using blocking (or neutralizing) antibodies. These targets include protein-protein interactions between cytokines (or chemokines) and their receptors on leukocytes and between a...
Article
Full-text available
Antibodies have become one of the most successful therapeutics for a number of oncology and inflammatory diseases. So far, central nervous system (CNS) indications have missed out on the antibody revolution, while they remain ‘hidden’ behind several hard to breach barriers. Among the various antibody modalities, single-domain antibodies (sdAbs) may...
Article
Full-text available
Antibody, immuno- and gene therapies developed for neurological indications face a delivery challenge posed by various anatomical and physiological barriers within the central nervous system (CNS); most notably, the blood–brain barrier (BBB). Emerging delivery technologies for biotherapeutics have focused on trans-cellular pathways across the BBB u...
Data
Table S1. Peptide ‘signature’ used for nanoLC‐SRM analysis of early endosome and late endosome/lysosome markers. Table S2. Peptides used for nanoLC‐SRM detection of antibody variants used in the study. Table S3. Relative abundance of various proteins involved in intracellular trafficking and receptor‐mediated transcytosis among low‐density (LDFs;...
Article
Full-text available
The blood‐brain barrier (BBB) is a formidable obstacle to the delivery of therapeutics to the brain. Antibodies that bind transferrin receptor, which is enriched in brain endothelial cells, have been shown to cross the BBB and are being developed as fusion proteins to deliver therapeutic cargos to brain targets. Various antibodies have been develop...
Conference Paper
Objectives: Detecting and treating diseases of the central nervous system is extremely limited by the capacities of imaging agents and drugs to cross the blood brain barrier (BBB). Our groups have developed high-diversity libraries of human antibodies and protocols to select and evaluate in vitro BBB-crossing antibodies. The aim of this project was...
Article
Full-text available
Zika virus (ZIKV) is a flavivirus that is highly neurotropic causing congenital abnormalities and neurological damage to the central nervous systems (CNS). In this study, we used a human induced pluripotent stem cell (iPSC)-derived blood brain barrier (BBB) model to demonstrate that ZIKV can infect brain endothelial cells (i-BECs) without compromis...
Article
The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargos into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies...
Article
Full-text available
We have developed a renewable, scalable and transgene free human blood-brain barrier model, composed of brain endothelial cells (BECs), generated from human amniotic fluid derived induced pluripotent stem cells (AF-iPSC), which can also give rise to syngeneic neural cells of the neurovascular unit. These AF-iPSC-derived BECs (i-BEC) exhibited high...
Chapter
Brain vessels display a distinct phenotype that includes tight junctions and barrier properties of brain endothelial cells, as well as their close association with glial cells and neurons that enable tight coupling of blood flow with brain tissue energy demand. Brain vessels undergo profound molecular, physiological, and anatomical changes and reor...
Article
Current methods for examining antibody trafficking are either non-quantitative such as immunocytochemistry or require antibody labeling with tracers. We have developed a multiplexed quantitative method for antibody ‘tracking’ in endosomal compartments of brain endothelial cells. Rat brain endothelial cells were co-incubated with blood-brain barrier...
Conference Paper
Full-text available
Infiltrated glioblastoma (GBM) cells into the brain parenchyma cause recurrences after tumor resection and there is presently no efficient non-invasive method to detect these infiltrated cells. One obstacle is the blood-brain barrier (BBB), which limits the passage of specific radiolabeled antibodies targeting infiltrated cells to the central nervo...
Article
Key points: It is unclear precisely how macromolecules (e.g. endogenous proteins and exogenous immunotherapeutics) access brain tissue from the cerebrospinal fluid (CSF). We show that transport at the brain-CSF interface involves a balance between Fickian diffusion in the extracellular spaces at the brain surface and convective transport in periva...
Article
Physiological and pathological processes that increase or decrease the central nervous system's need for nutrients and oxygen via changes in local blood supply act primarily at the level of the neurovascular unit (NVU). The NVU consists of endothelial cells, associated blood-brain barrier tight junctions, basal lamina, pericytes, and parenchymal ce...
Article
Full-text available
Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in A-induced/neuroinflammation were investigated in this study usi...
Article
Cerebrovascular insufficiency appears years prior to clinical symptoms in Alzheimer's disease. The soluble, highly toxic amyloid-β species, generated from the amyloidogenic processing of amyloid precursor protein, are known instigators of the chronic cerebrovascular insufficiency observed in both Alzheimer's disease patients and transgenic mouse mo...
Chapter
In the last decade, amniotic fluid (AF) has gained extensive attention as a source of stem cells with potential applications in pharmaceutical screening, disease modeling and cell-based therapies. In particular, the routine collection of AF through amniocentesis in the clinic has facilitated its availability for isolating amniotic fluid stem cells...
Article
Full-text available
Objective: Diabetic ketoacidosis in children is associated with vasogenic cerebral edema, possibly due to the release of destructive polymorphonuclear neutrophil azurophilic enzymes. Our objectives were to measure plasma azurophilic enzyme levels in children with diabetic ketoacidosis, to correlate plasma azurophilic enzyme levels with diabetic ke...
Article
Receptor mediated transcytosis harnessing the cellular uptake and transport of natural ligands across the blood-brain barrier (BBB) has been identified as a means for antibody delivery to the CNS. In this study, we characterized bispecific antibodies in which a BBB-crossing antibody fragment FC5 was used as a BBB carrier. "Cargo" antibodies were ei...