A5052615161- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Advanced Biosensing Techniques and Applications
- Nanofabrication and Lithography Techniques
- Cellular transport and secretion
- Liver physiology and pathology
- Molecular Junctions and Nanostructures
- Cancer Research and Treatments
- Radiopharmaceutical Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- Lipid Membrane Structure and Behavior
- Cancer Cells and Metastasis
- Chronic Lymphocytic Leukemia Research
- Innovative Microfluidic and Catalytic Techniques Innovation
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Chronic Myeloid Leukemia Treatments
- Renal and related cancers
- Phagocytosis and Immune Regulation
- Neuroscience and Neuropharmacology Research
- Virus-based gene therapy research
- Caveolin-1 and cellular processes
- Galectins and Cancer Biology
- Acute Lymphoblastic Leukemia research
- Pancreatic function and diabetes
Regeneron (United States)
2017-2023
Cornell University
2010-2019
Weill Cornell Medicine
2019
The properties of cell surface proteins targeted by antibody-drug conjugates (ADCs) have not been fully exploited; particular importance are the rate internalization and route intracellular trafficking. In this study, we compared trafficking HER2, which is target clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that prolactin receptor (PRLR), another potential in breast cancer. contrast to found PRLR rapidly constitutively internalized, traffics efficiently lysosomes, where it...
The basolateral recycling and transcytotic pathways of epithelial cells were previously defined using markers such as transferrin (TfR) polymeric IgA (pIgR) receptors. In contrast, our knowledge the apical pathway remains fragmentary. Here we utilize quantitative live-imaging mathematical modelling to outline Megalin (LRP-2), an receptor with key developmental renal functions, in MDCK cells. We show that, like TfR, is a long-lived fast-recycling receptor. enters polarized through segregated...
The coxsackie and adenovirus receptor (CAR) plays key roles in epithelial barrier function at the tight junction, a localization guided part by tyrosine-based basolateral sorting signal, 318 YNQV 321 . Sorting motifs of this type are known to route surface receptors into clathrin-mediated endocytosis through interaction with medium subunit (μ2) clathrin adaptor AP-2, but how they guide new recycling membrane proteins basolaterally is unknown. Here, we show that functions as canonical YxxΦ...
Most antibody-drug conjugates (ADC) approved for the treatment of cancer contain protease-cleavable linkers. ADCs that traffic to lysosomes traverse highly acidic late endosomes, while recycle plasma membrane through mildly sorting and recycling endosomes. Although endosomes have been proposed process cleavable ADCs, precise identity relevant compartments their relative contributions ADC processing remain undefined. Here we show a METxMET biparatopic antibody internalizes into rapidly...
Some native epithelia, for example, retinal pigment epithelium (RPE) and kidney proximal tubule (KPT), constitutively lack the basolateral sorting adaptor AP-1B; this results in many plasma membrane proteins being repositioned to apical domain, where they perform essential functions their host organs. We recently reported underlying polarity reversal mechanism: absence of AP-1B-mediated sorting, are shuttled through a transcytotic pathway mediated by plus-end kinesin KIF16B. Here, we...
Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating as a therapeutic target. Although antibody-mediated blockade of the pathway has not been successful in clinic, failures are likely result inadequate patient selection strategies well suboptimal antibody design. Thus, our goal was generate novel blocking with enhanced efficacy.Here, we describe...
Megalin (gp330, LRP-2) is a protein structurally related to the low-density lipoprotein receptor family that displays large luminal domain with multiligand binding properties. localizes apical surface of multiple epithelia, where it participates in endocytosis variety ligands performing roles important for development or homeostasis. We recently described recycling pathway megalin Madin-Darby canine kidney (MDCK) cells and found long-lived, fast turnover 15 min half-life 4.8 h. Previous work...
In spite of the many key cellular functions chloride channels, mechanisms that mediate their subcellular localization are largely unknown. ClC-2 is a ubiquitous channel usually localized to basolateral domain epithelia regulates cell volume, ion transport, and acid-base balance; mice knocked out for blind sterile. Previous work suggested CLC-2 sorted basolaterally by TIFS(812)LL, dileucine motif in CLC-2's C-terminal domain. However, our silico modeling this was buried within channel's...
Abstract Trastuzumab-emtansine (T-DM1) targets the well-characterized breast cancer oncogene HER2, and has shown success in clinic, but tumors expressing intermediate levels of HER2 remain resistant to T-DM1 therapy, apparently due insufficient lysosomal trafficking T-DM1. Here, we engineered bispecific HER2-DM1 conjugates that bridge with rapidly internalizing receptor APLP2. The high affinity arm HER2xAPLP2 antibodies mediates surface binding HER2+ tumor cells (but not HER2- normal cells)....
Trastuzumab-emtansine (T-DM1) targets the well-characterized breast cancer oncogene HER2, and has shown success in clinic, but tumors expressing intermediate levels of HER2 remain resistant to T-DM1 therapy, apparently due insufficient lysosomal trafficking T-DM1. Here, we engineered bispecific HER2-DM1 conjugates that bridge with rapidly internalizing receptor APLP2. The high affinity arm HER2xAPLP2 antibodies mediates surface binding HER2+ tumor cells (but not HER2- normal cells). After...
<p>Supplementary figure legends and methods</p>
<p>supplementary figures and tables</p>
<div>AbstractPurpose:<p>Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating as a therapeutic target. Although antibody-mediated blockade of the pathway has not been successful in clinic, failures are likely result inadequate patient selection strategies well suboptimal antibody design. Thus, our goal was generate novel blocking with...
<div>AbstractPurpose:<p>Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating as a therapeutic target. Although antibody-mediated blockade of the pathway has not been successful in clinic, failures are likely result inadequate patient selection strategies well suboptimal antibody design. Thus, our goal was generate novel blocking with...
<p>supplementary figures and tables</p>
<p>Supplementary figure legends and methods</p>
<p>HER2xPRLR bispecific antibodies with different HER2 and PRLR arms induced similar rates of degradation in T47D cells.</p>
<p>In T47D/HER2 cells, HER2xPRLR bsAb1 augments HER2 ADCinduced cell cycle arrest in G2M phase.</p>
<p>PRLR degradation was not significantly affected by PRLR antibody or Prolactin (PRL).</p>
<p>Supplementary Materials and Methods</p>