A5102858762- Angiogenesis and VEGF in Cancer
- Cancer, Hypoxia, and Metabolism
- Axon Guidance and Neuronal Signaling
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Lipids, and Metabolism
- Lymphatic System and Diseases
- RNA Interference and Gene Delivery
- Protein purification and stability
- Advanced Proteomics Techniques and Applications
- Fibroblast Growth Factor Research
- Drug Transport and Resistance Mechanisms
- DNA and Nucleic Acid Chemistry
- Chemotherapy-induced cardiotoxicity and mitigation
- Receptor Mechanisms and Signaling
- Mass Spectrometry Techniques and Applications
- Glycosylation and Glycoproteins Research
- Signaling Pathways in Disease
- Cell Adhesion Molecules Research
- Hippo pathway signaling and YAP/TAZ
- Endoplasmic Reticulum Stress and Disease
- Alzheimer's disease research and treatments
- Osteoarthritis Treatment and Mechanisms
- Spinal Fractures and Fixation Techniques
- Autophagy in Disease and Therapy
- Pectus Deformity Diagnosis and Treatment
Denali Therapeutics (United States)
2016-2024
Kaiser Permanente South San Francisco Medical Center
2023
Chinese University of Hong Kong
2023
Molecular Oncology (United States)
2016
University of Colorado Cancer Center
2012
The Barbara Ann Karmanos Cancer Institute
2012
South Texas Accelerated Research Therapeutics
2012
Wayne State University
2012
University of Colorado Denver
2012
Wageningen University & Research
2011
Bispecific antibodies engineered to both bind the primate transferrin receptor and inhibit β-secretase are taken up by nonhuman brain reduce β-amyloid.
The antibody Fc region regulates cytotoxic activities and serum half-life. In a therapeutic context, however, the effector function of an is often not desirable can create safety liabilities by activating native host immune defenses against cells expressing receptor antigens. Several amino acid changes in have been reported to silence or reduce antibodies. These earlier studies focused primarily on interaction human antibodies with Fc-γ receptors, it remains largely unknown how such might...
Engineering human IgG1 Fc binding to a brain endothelial cell–enriched receptor allows enhanced exposure of biotherapeutics in multiple species.
Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific variants mouse and show reducing TfR binding affinity improves not only brain but also peripheral exposure profile these antibodies. identify seek to address targeting with antibodies,...
Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need be delivered intrathecally central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, oligonucleotide transport vehicle (OTV), tool ASO across BBB in TfR knockin (TfR mu/hu KI) mice nonhuman primates. Intravenous injection systemic delivery of...
Neuropilin-1 (NRP1) was first described as a receptor for the axon guidance molecule, Semaphorin3A, regulating development of nervous system. It later shown that NRP1 is an isoform-specific vascular endothelial growth factor (VEGF), specifically VEGF165. Much interest has been placed on role various VEGF isoforms in biology. Here we report blocking function, using recently antibody inhibits VEGF165 binding to NRP1, surprisingly reduces VEGF121-induced migration and sprout formation cells....
Rationale: Collagen- and calcium-binding EGF domains 1 (CCBE1) has been associated with Hennekam syndrome, in which patients have lymphedema, lymphangiectasias, other cardiovascular anomalies. Insight into the molecular role of CCBE1 is completely lacking, mouse models for disease do not exist. Objective: deficient mice were generated to understand function development, recombinant protein was used both vivo vitro settings gain insight CCBE1. Methods Results: Phenotypic analysis murine Ccbe1...
No going back The mammalian spinal cord coordinates neuronal systems across the body. Axons that cross midline during development first need permission to and then instruction not keep crossing forth. Jaworski et al. studied axonal guidance receptor ROBO3 found a ligand NELL2 in mice appears help this process. Science , issue p. 961
Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed a potential treatment for obesity-linked disorders. Here, we describe the generation humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/βKlotho complex, common FGF21 and FGF19. Using this molecule, show antibody-mediated activation FGFR1/βKlotho complex in mice induces sustained energy expenditure BAT, browning white tissue,...
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report engineering and characterization a BBB transport vehicle targeting CD98 heavy chain (CD98hc or SLC3A2) heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic biodistribution properties CD98hc antibody (ATVCD98hc) are assessed in humanized knock-in mice cynomolgus monkeys. Compared to most existing platforms transferrin receptor, peripherally...
Abstract Antisense oligonucleotides (ASO) are promising therapies for neurological disorders, though they unable to cross the blood-brain barrier (BBB) and must be delivered directly central nervous system (CNS). Here, we use a human transferrin receptor (TfR)-binding molecule transport ASO across BBB in mice non-human primates, termed oligonucleotide vehicle (OTV). Systemically OTV drives significant, cumulative, sustained knockdown of target multiple CNS regions all major cell types....
Abstract Vascular permeability and neovascularization are implicated in many diseases including retinopathies diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown −/− mice develop hyperpermeability, but how signals remained unclear. Here we show deletion enhances revascularization oxygen-induced retinopathy (OIR) accelerates cutaneous To determine signalling pathways, generated transgenic expressing a truncated lacking...
Abstract Although the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem this class drugs. Here, we report an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) brain delivery amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in mouse model deposition. Asymmetrical Fc mutations (ATV cisLALA )...
MNRP1685A is a monoclonal antibody to neuropilin-1 (NRP1). We evaluated blood-based pharmacodynamic biomarkers of in two phase I studies assess exposure/response relationships inform target dose and regimen selection.The escalating doses as single agent or combination with bevacizumab. Plasma placental growth factor (PlGF), VEGF, circulating NRP1 (cNRP1) were at multiple time points using meso-scale discovery (MSD) assays ELISA, respectively. PlGF was also measured I/II trial bevacizumab...
The primary objective of this study was to utilize MR molecular imaging compare the 3-dimensional spatial distribution Robo4 and αVβ3-integrin as biosignatures angiogenesis, in a rapidly growing, syngeneic tumor. B16-F10 melanoma-bearing mice were imaged with magnetic resonance (MR; 3.0 T) 11 d postimplantation before after intravenous administration either Robo4- or αVβ3-targeted paramagnetic nanoparticles. percentage signal-enhanced voxels throughout tumor volume low increased animals...
This study was conducted to investigate the therapeutic effect of allogeneic adipose-derived MSCs on dogs with hip osteoarthritis (OA). Twenty bilateral coxofemoral (hip) joint, diagnosed by a veterinarian through physical examination and radiographs were randomly allocated into four groups. Group 1 served as placebo control injected 0.9% sodium chloride (saline) (n=4). 2 single dose 5 million (n=5). 3 received 25 (n=6) 4 50 Intra-articular administration multiple joints did not result in...
Bispecific antibodies offer a clinically validated platform for drug discovery. In generating functionally active bispecific antibodies, it is necessary to identify unique parental antibody pair merge into single molecule. However, technologies that allow high-throughput production of immunoglobulin Gs (BsIgGs) screening purposes are limited. Here, we describe novel format termed tethered-variable CLBsIgG (tcBsIgG) allows robust intact BsIgG in cell line, concurrently ensuring cognate light...
Adolescent idiopathic scoliosis is a common condition that affects children between the age of 10 and young adulthood. Rigid brace treatment an effective to control progression spinal deformity. However, it limits mobility causes discomfort, which leads low compliance. In this study, we developed characterized kirigami-inspired CT/MRI compatible spring could be employed modify our previously designed exoskeleton hinge vertebrae provide immediate in-brace correction, good wear comfort, one...
Abstract Transferrin receptor (TfR)-mediated transcytosis across the blood-brain barrier (BBB) is a promising strategy to improve delivery of biologics central nervous system (CNS). However, it remains unclear whether age and aging-related diseases impact TfR expression and/or BBB transport capacity. Here, we used TfR-targeted antibody vehicle (ATV ) enhance CNS in healthy mice 5xFAD mouse model Alzheimer’s disease (AD). Healthy neonates exhibited highest vascular ATV brain exposure, whereas...