Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Ping Tsui is active.

Publication


Featured researches published by Ping Tsui.


The International Journal of Biochemistry & Cell Biology | 2008

Hyper-responsiveness of IPF/UIP fibroblasts: Interplay between TGFβ1, IL-13 and CCL2

Lynne Murray; Rochelle L. Argentieri; Francis X. Farrell; Michelle Bracht; Hai Sheng; Brian Whitaker; Heena Beck; Ping Tsui; Karyn Cochlin; Holly L. Evanoff; Cory M. Hogaboam; Anuk Das

One of the hallmarks of idiopathic pulmonary fibrosis with a usual interstitial pneumonia histological pathology (IPF/UIP) is excess collagen deposition, due to enhanced fibroblast extracellular matrix synthetic activity. Studies using murine models of lung fibrosis have elucidated a pro-fibrotic pathway involving IL-13 driving CCL2, which in turn drives TGFbeta1 in lung fibroblasts. Therefore, we sought to determine whether this pathway exists in the human fibrotic setting by evaluating human IPF/UIP fibroblasts. IPF/UIP fibroblasts have an increased baseline fibrotic phenotype compared to non-fibrotic fibroblasts. Interestingly, non-fibrotic fibroblasts responded in a pro-fibrotic manner to TGFbeta1 but were relatively non-responsive to IL-13 or CCL2, whereas, IPF/UIP cells were hyper-responsive to TGFbeta1, IL-13 and CCL2. Interestingly, TGFbeta1, CCL2 and IL-13 all upregulated TGFbeta receptor and IL-13 receptor expression, suggesting an ability of the mediators to modulate the function of each other. Furthermore, in vivo, neutralization of both JE and MCP5, the two functional orthologs of CCL2, during bleomycin-induced pulmonary fibrosis significantly reduced collagen deposition as well as JE and CCR2 expression. Also in the bleomycin model, CTGF, which is highly induced following TGFbeta stimulation, was attenuated with anti-JE/anti-MCP5 treatment. Overall this study demonstrates an interplay between TGFbeta1, IL-13 and CCL2 in IPF/UIP, where these three mediators feedback on each other, promoting the fibrotic response.


Science Translational Medicine | 2014

Selective Targeting of TGF-β Activation to Treat Fibroinflammatory Airway Disease

Shunsuke Minagawa; Jianlong Lou; Robert Seed; Anthony Cormier; Shenping Wu; Yifan Cheng; Lynne A. Murray; Ping Tsui; Jane Connor; Ronald Herbst; Cedric Govaerts; Tyren Barker; Stephanie Cambier; Haruhiko Yanagisawa; Amanda Goodsell; Mitsuo Hashimoto; Oliver J. Brand; Ran Cheng; Royce Ma; Kate J. McKnelly; W. Wen; Arthur Hill; David M. Jablons; Paul J. Wolters; Hideya Kitamura; Jun Araya; Andrea J. Barczak; David J. Erle; Louis F. Reichardt; James D. Marks

Therapeutic targeting of an extended-closed conformation of the integrin αvβ8 inhibits TGF-β activation and ameliorates symptoms of experimental airway disease in mice. Breathing Freely Narrowing of the airways through accumulation of scar tissue and inflammation results from chronic injury in common diseases such as chronic obstructive pulmonary disease (COPD) and severe chronic asthma. Such airway narrowing causes the obstruction responsible for the breathlessness that these patients experience, and there are no available treatments that ameliorate fibroinflammatory airway narrowing. In a new study, Minagawa et al. engineered a monoclonal antibody that locks in a specific inactive conformation of a protein named integrin αvβ8. This protein is a crucial receptor required for activation of transforming growth factor–β, a central mediator of pathological inflammation and fibrosis. This antibody, when administered to mice engineered to express only human and not mouse αvβ8, reduced airway inflammation and fibrosis in response to a variety of injurious agents including cigarette smoke and allergens that are involved in the pathogenesis of COPD. Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor–β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human αvβ8 (B5) inhibited TGF-β activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases.


Journal of Biological Chemistry | 2015

pH-dependent Binding Engineering Reveals an FcRn Affinity Threshold That Governs IgG Recycling

M. Jack Borrok; Yanli Wu; Nurten Beyaz; Xiang-Qing Yu; Vaheh Oganesyan; William F. Dall'Acqua; Ping Tsui

Background: FcRn controls the serum persistence of antibodies. Results: A panel of novel Fc mutations reveals sites controlling pH dependence and FcRn affinity. Conclusion: FcRn affinity thresholds determine IgG recycling efficiency. Significance: Knowledge of the relationship between FcRn binding and serum persistence can aid in designing better therapeutic antibodies. The Fc domain of IgG has been the target of multiple mutational studies aimed at altering the pH-dependent IgG/FcRn interaction to modulate IgG pharmacokinetics. These studies have yielded antibody variants with disparate pharmacokinetic characteristics, ranging from extended in vivo half-life to those exhibiting extremely rapid clearance. To better understand pH-dependent binding parameters that govern these outcomes and limit FcRn-mediated half-life extension, we generated a panel of novel Fc variants with high affinity binding at acidic pH that vary in pH 7.4 affinities and assessed pharmacokinetic outcomes. Pharmacokinetic studies in human FcRn transgenic mice and cynomolgus monkeys showed that multiple variants with increased FcRn affinities at acidic pH exhibited extended serum half-lives relative to the parental IgG. Importantly, the results reveal an underappreciated affinity threshold of neutral pH binding that determines IgG recycling efficiency. Variants with pH 7.4 FcRn affinities below this threshold recycle efficiently and can exhibit increased serum persistence. Increasing neutral pH FcRn affinity beyond this threshold reduced serum persistence by offsetting the benefits of increased pH 6.0 binding. Ultra-high affinity binding to FcRn at both acidic and neutral pH leads to rapid serum clearance.


Journal of Immunological Methods | 2010

Antibody Fab display and selection through fusion to the pIX coat protein of filamentous phage

Mark Tornetta; Scott Baker; Brian Whitaker; Jin Lu; Qiang Chen; Eileen Pisors; Lei Shi; Jinquan Luo; Raymond Sweet; Ping Tsui

Fab antibody display on filamentous phage is widely applied to de novo antibody discovery and engineering. Here we describe a phagemid system for the efficient display and affinity selection of Fabs through linkage to the minor coat protein pIX. Display was successful by fusion of either Fd or Lc through a short linker to the amino terminus of pIX and co-expression of the counter Lc or Fd as a secreted, soluble fragment. Assembly of functional Fab was confirmed by demonstration of antigen-specific binding using antibodies of known specificity. Phage displaying a Fab specific for RSV-F protein with Fd linked to pIX showed efficient, antigen-specific enrichment when mixed with phage displaying a different specificity. The functionality of this system for antibody engineering was evaluated in an optimization study. A RSV-F protein specific antibody with an affinity of about 2nM was randomized at 4 positions in light chain CDR1. Three rounds of selection with decreasing antigen concentration yielded Fabs with an affinity improvement up to 70-fold and showed a general correlation between enrichment frequency and affinity. We conclude that the pIX coat protein complements other display systems in filamentous phage as an efficient vehicle for low copy display and selection of Fab proteins.


mAbs | 2015

Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding

M.J Borrok; Luheshi Nm; Beyaz N; Davies Gc; Legg Jw; Herren Wu; William F. Dall'Acqua; Ping Tsui

Fc effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) are crucial to the efficacy of many antibody therapeutics. In addition to IgG, antibodies of the IgA isotype can also promote cell killing through engagement of myeloid lineage cells via interactions between the IgA-Fc and FcαRI (CD89). Herein, we describe a unique, tandem IgG1/IgA2 antibody format in the context of a trastuzumab variable domain that exhibits enhanced ADCC and ADCP capabilities. The IgG1/IgA2 tandem Fc format retains IgG1 FcγR binding as well as FcRn-mediated serum persistence, yet is augmented with myeloid cell-mediated effector functions via FcαRI/IgA Fc interactions. In this work, we demonstrate anti-human epidermal growth factor receptor-2 antibodies with the unique tandem IgG1/IgA2 Fc can better recruit and engage cytotoxic polymorphonuclear (PMN) cells than either the parental IgG1 or IgA2. Pharmacokinetics of IgG1/IgA2 in BALB/c mice are similar to the parental IgG, and far surpass the poor serum persistence of IgA2. The IgG1/IgA2 format is expressed at similar levels and with similar thermal stability to IgG1, and can be purified via standard protein A chromatography. The tandem IgG1/IgA2 format could potentially augment IgG-based immunotherapeutics with enhanced PMN-mediated cytotoxicity while avoiding many of the problems associated with developing IgAs.


Molecular Cancer Therapeutics | 2016

A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response

Zhan Xiao; Rosa A. Carrasco; Kevin Schifferli; Krista Kinneer; Ravinder Tammali; Hong Chen; Ray Rothstein; Leslie Wetzel; Chunning Yang; Partha S. Chowdhury; Ping Tsui; Philipp Steiner; Bahija Jallal; Ronald Herbst; Robert E. Hollingsworth; David A. Tice

HER3/ERBB3 is a kinase-deficient member of the EGFR family receptor tyrosine kinases (RTK) that is broadly expressed and activated in human cancers. HER3 is a compelling cancer target due to its important role in activation of the oncogenic PI3K/AKT pathway. It has also been demonstrated to confer tumor resistance to a variety of cancer therapies, especially targeted drugs against EGFR and HER2. HER3 can be activated by its ligand (heregulin/HRG), which induces HER3 heterodimerization with EGFR, HER2, or other RTKs. Alternatively, HER3 can be activated in a ligand-independent manner through heterodimerization with HER2 in HER2-amplified cells. We developed a fully human mAb against HER3 (KTN3379) that efficiently suppressed HER3 activity in both ligand-dependent and independent settings. Correspondingly, KTN3379 inhibited tumor growth in divergent tumor models driven by either ligand-dependent or independent mechanisms in vitro and in vivo. Most intriguingly, while investigating the mechanistic underpinnings of tumor response to KTN3379, we discovered an interesting dichotomy in that PTEN loss, a frequently occurring oncogenic lesion in a broad range of cancer types, substantially blunted the tumor response in HER2-amplified cancer, but not in the ligand-driven cancer. To our knowledge, this represents the first study ascertaining the impact of PTEN loss on the antitumor efficacy of a HER3 mAb. KTN3379 is currently undergoing a phase Ib clinical trial in patients with advanced solid tumors. Our current study may help us optimize patient selection schemes for KTN3379 to maximize its clinical benefits. Mol Cancer Ther; 15(4); 689–701. ©2016 AACR.


Journal of Immunology | 2015

TGF-β-dependent dendritic cell chemokinesis in murine models of airway disease

Mitsuo Hashimoto; Haruhiko Yanagisawa; Shunsuke Minagawa; Debasish Sen; Royce Ma; Lynne A. Murray; Ping Tsui; Jianlong Lou; James D. Marks; Jody L. Baron; Matthew F. Krummel; Stephen L. Nishimura

Small airway chronic inflammation is a major pathologic feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Dendritic cells (DCs) accumulate around small airways in COPD. DCs are critical mediators of Ag surveillance and Ag presentation and amplify adaptive immune responses. How DCs accumulate around airways remains largely unknown. We use 2-photon DC imaging of living murine lung sections to directly visualize the dynamic movement of living DCs around airways in response to either soluble mediators (IL-1β) or environmental stimuli (cigarette smoke or TLR3 ligands) implicated in COPD pathogenesis. We find that DCs accumulate around murine airways primarily by increasing velocity (chemokinesis) rather than directional migration (chemotaxis) in response to all three stimuli. DC accumulation maximally occurs in a specific zone located 26–50 μm from small airways, which overlaps with zones of maximal DC velocity. Our data suggest that increased accumulation of DCs around airways results from increased numbers of highly chemokinetic DCs entering the lung from the circulation with balanced rates of immigration and emigration. Increases in DC accumulation and chemokinesis are partially dependent on ccr6, a crucial DC chemokine receptor, and fibroblast expression of the integrin αvβ8, a critical activator of TGF-β. αvβ8-Mediated TGF-β activation is known to enhance IL-1β–dependent fibroblast expression of the only known endogenous ccr6 chemokine ligand, ccl20. Taken together, these data suggest a mechanism by which αvβ8, ccl20, and ccr6 interact to lead to DC accumulation around airways in response to COPD-relevant stimuli.


Journal of Controlled Release | 2018

Tumor uptake of pegylated diabodies: Balancing systemic clearance and vascular transport

Qing Li; Jason B. White; Norman C. Peterson; Keith W. Rickert; Chris Lloyd; Kevin L. Allen; Kim Rosenthal; Xizhe Gao; Herren Wu; William F. Dall'Acqua; M. Jack Borrok; Ping Tsui

ABSTRACT The accumulation, dissemination and clearance of monoclonal antibody‐based therapeutics or imaging reagents targeting tumor associated antigens is governed by several factors including affinity, size, charge, and valency. Tumor targeting antibody fragments have distinct advantages over intact monoclonal antibodies such as enhanced penetration within the tumor and rapid accumulation but are subject to rapid clearance. Polyethylene glycol (PEG)‐modified antibody fragments can provide a way to balance tumor penetration and accumulation with improved serum persistence. In this study, we use a diabody, the dimeric antibody fragment, targeting the 5T4 antigen to assess the impact of PEGs of distinct size and shape on tumor accumulation and pharmacokinetics (PK). We show that PEG‐modified diabodies improved the PK of the parental diabody from a half‐life of 40min to over 40h for the higher molecular weight PEG conjugated diabodies. This improvement correlates with the increasing hydrodynamic size of pegylated diabodies, and can serve as a better predictor of the PK behavior of pegylated molecules than molecular weight alone. Tumor uptake profiles determined by quantitative PET imaging differed significantly based on PEG size and shape with diabody‐PEG5K showing peak accumulation early on, but with the larger diabody‐PEG20K showing better sustained tumor uptake at later time points. In addition, we demonstrate that a diabody‐PEG20K‐B with a hydrodynamic radius (Rh) of 6nm had superior tumor uptake than the larger diabody‐PEG40K‐B with Rh of 12nm, indicating that beyond 6nm, larger pegylated diabodies have a slower tumor uptake rate while having comparable clearance kinetics. Our data demonstrate that pegylated diabodies with Rh of ˜6nm have an optimal size and PK profile for tumor uptake. Understanding the impact of pegylation on PK and tumor uptake could facilitate the development of pegylated diabodies as therapeutics.


JCI insight | 2018

Enhancing IgG distribution to lung mucosal tissue improves protective effect of anti–Pseudomonas aeruginosa antibodies

M. Jack Borrok; Antonio DiGiandomenico; Nurten Beyaz; Gabriela M. Marchetti; Arnita S. Barnes; Kristen Lekstrom; Sandrina Phipps; Michael P. McCarthy; Herren Wu; William F. Dall’Acqua; Ping Tsui; Ruchi Gupta

IgG antibodies are abundantly present in the vasculature but to a much lesser extent in mucosal tissues. This contrasts with antibodies of the IgA and IgM isotype that are present at high concentration in mucosal secretions due to active delivery by the polymeric Ig receptor (pIgR). IgG is the preferred isotype for therapeutic mAb development due to its long serum half-life and robust Fc-mediated effector function, and it is utilized to treat a diverse array of diseases with antigen targets located in the vasculature, serosa, and mucosa. As therapeutic IgG antibodies targeting the luminal side of mucosal tissue lack an active transport delivery mechanism, we sought to generate IgG antibodies that could be transported via pIgR, similarly to dimeric IgA and pentameric IgM. We show that an anti-Pseudomonas aeruginosa IgG fused with pIgR-binding peptides gained the ability to transcytose and be secreted via pIgR. Consistent with these results, pIgR-binding IgG antibodies exhibit enhanced localization to the bronchoalveolar space when compared with the parental IgG antibody. Furthermore, pIgR-binding mAbs maintained Fc-mediated functional activity and promoted enhanced survival compared with the parental mAb in a P. aeruginosa acute pneumonia model. Our results suggest that increasing IgG accumulation at mucosal surfaces by pIgR-mediated active transport can improve the efficacy of therapeutic mAbs that act at these sites.


mAbs | 2017

The TGF-β inhibitory activity of antibody 37E1B5 depends on its H-CDR2 glycan

Ping Tsui; Daniel R. Higazi; Yanli Wu; Rebecca Dunmore; Emilie Solier; Toyin Kasali; Nicholas J. Bond; Catherine Huntington; Alan Carruthers; John Hood; M. Jack Borrok; Arnita Barnes; Keith W. Rickert; Sandrina Phipps; Lena Shirinian; Jie Zhu; Michael A. Bowen; William Dall'acqua; Lynne A. Murray

ABSTRACT Excessive transforming growth factor (TGF)-β is associated with pro-fibrotic responses in lung disease, yet it also plays essential roles in tissue homeostasis and autoimmunity. Therefore, selective inhibition of excessive and aberrant integrin-mediated TGF-β activation via targeting the α-v family of integrins is being pursued as a therapeutic strategy for chronic lung diseases, to mitigate any potential safety concerns with global TGF-β inhibition. In this work, we reveal a novel mechanism of inhibiting TGF-β activation utilized by an αvβ8 targeting antibody, 37E1B5. This antibody blocks TGF-β activation while not inhibiting cell adhesion. We show that an N-linked complex-type Fab glycan in H-CDR2 of 37E1B5 is directly involved in the inhibition of latent TGF-β activation. Removal of the Fab N-glycosylation site by single amino acid substitution, or removal of N-linked glycans by enzymatic digestion, drastically reduced the antibodys ability to inhibit latency-associated peptide (LAP) and αvβ8 association, and TGF-β activation in an αvβ8-mediated TGF-β signaling reporter assay. Our results indicate a non-competitive, allosteric inhibition of 37E1B5 on αvβ8-mediated TGF-β activation. This unique, H-CDR2 glycan-mediated mechanism may account for the potent but tolerable TGF-b activation inhibition and lack of an effect on cellular adhesion by the antibody.

Collaboration


Dive into the Ping Tsui's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Anuk Das

Queen Mary University of London

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge