scholarly journals Discovery of a new class of integrin antibodies for fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji Zhang ◽  
Tao Wang ◽  
Ashmita Saigal ◽  
Josephine Johnson ◽  
Jennifer Morrisson ◽  
...  
Keyword(s):  
Treatment Options ◽  
Cross Reactivity ◽  
Lung Fibroblasts ◽  
Preclinical Model ◽  
Kidney Fibrosis ◽  
New Class ◽  
Medical Need ◽  
Lung Injury Model ◽  
Fibrotic Lung Diseases

AbstractLung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab’s yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated potent in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.

scholarly journals Discovery of A New Class of Integrin Antibodies for Fibrosis

2020 ◽  
Author(s):  
Ji Zhang ◽  
Tao Wang ◽  
Ashmita Saigal ◽  
Josephine Johnson ◽  
Jennifer Morrisson ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Treatment Options ◽  
Cross Reactivity ◽  
Lung Fibroblasts ◽  
Preclinical Model ◽  
Kidney Fibrosis ◽  
Medical Need ◽  
Lung Injury Model ◽  
Fibrotic Lung Diseases

AbstractLung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of all αv integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimab’s yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple αv integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGFβ activation. In IPF patient lung fibroblasts, TGFβ treatment induced profound αSMA expression in phenotypic imaging assays and Ab-31 demonstrated superior in vitro activity at inhibiting αSMA expression, suggesting that the integrin antibody is able to modulate TGFβ action though mechanisms beyond the inhibition of latent TGFβ activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases.One Sentence Summarytargeting integrin in lung fibrosis

scholarly journals Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

2016 ◽  
Vol 113 (45) ◽  
pp. 12786-12791 ◽  
Author(s):  
Fortunato Ferrara ◽  
Daniela I. Staquicini ◽  
Wouter H. P. Driessen ◽  
Sara D’Angelo ◽  
Andrey S. Dobroff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Options ◽  
Molecular Genetic ◽  
Preclinical Model ◽  
Dual Function ◽  
Castration Resistant Prostate Cancer ◽  
Candidate Target ◽  
Aggressive Variant

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

scholarly journals Organoid Cultures Derived From Patients With Papillary Thyroid Cancer

2021 ◽  
Author(s):  
Dong Chen ◽  
Yawen Tan ◽  
Zhichao Li ◽  
Wujiao Li ◽  
Lei Yu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Treatment Options ◽  
Estrogen Receptor Α ◽  
Patient Specific ◽  
Preclinical Model ◽  
Papillary Thyroid ◽  
Promote Cell Proliferation

Abstract Context Papillary thyroid cancer (PTC) has been one of the most frequent endocrine malignancies around the world. Although most PTC patients have a favorable prognosis, a subgroup of patients die, especially when disease recurrence occurs. There is a pressing need for clinically relevant preclinical thyroid cancer models for personalized therapy because of the lack of in vitro models that faithfully represent the biology of the parental tumors. Objective To understand thyroid cancer and translate this knowledge to clinical applications, patient-derived PTC organoids as a promising new preclinical model were established. Methods Surgically resected PTC primary tissues were dissociated and processed for organoid derivation. Tumor organoids were subsequently subjected to histological characterization, DNA sequencing, drug screen, and cell proliferation assay, respectively. Results We describe a 3-dimensional culture system for the long-term expansion of patient-derived PTC organoid lines. Notably, PTC organoids preserve the histopathological profiles and genomic heterogeneity of the originating tumors. Drug sensitivity assays of PTC organoids demonstrate patient-specific drug responses, and large correlations with the respective mutational profiles. Estradiol was shown to promote cell proliferation of PTC organoids in the presence of estrogen receptor α (ERα), regardless of the expression of ERβ and G protein–coupled ER. Conclusion These data suggest that these newly developed PTC-derived organoids may be an excellent preclinical model for studying clinical response to anticancer drugs in a personalized way, as well as provide a potential strategy to develop prevention and treatment options for thyroid cancer with ERα-specific antagonists.

scholarly journals Molecular Targets for Human Papillomaviruses: Prospects for Antiviral Therapy

1998 ◽  
Vol 9 (5) ◽  
pp. 359-377 ◽  
Author(s):  
WC Phelps ◽  
JA Barnes ◽  
DC Lobe
Keyword(s):  
Treatment Options ◽  
Human Papillomaviruses ◽  
Gene Products ◽  
Antiviral Therapies ◽  
Virus Life Cycle ◽  
Medical Need ◽  
Common Skin ◽  
Malignant Lesions ◽  
Made In

A substantial medical need exists for the development of antiviral medicines for the treatment of diseases associated with infection by human papillomaviruses (HPVs). HPVs are associated with various benign and malignant lesions including benign genital condyloma, common skin warts, laryngeal papillomas and anogenital cancer. Since treatment options are limited and typically not very satisfactory, the development of safe and effective antiviral drugs for HPV could have substantial clinical impact. In the last few years, exciting advances have been made in our understanding of papillomavirus replication and the effects that the virus has on growth of the host cell. Although still somewhat rudimentary, techniques have been developed for limited virion production in vitro offering the promise of more rapid advances in the dissection and understanding of the virus life cycle. Of the 8–10 HPV gene products that are made during infection, only one encodes enzymatic activities, the E1 helicase. Successful antiviral therapies have traditionally targeted viral enzymes such as polymerases, kinases and proteases. In contrast, macromolecular interactions which mediate the functions of E6, E7 and E2 are thought to be more difficult targets for small molecule therapy.

scholarly journals Pathology-specific experimental antivenoms for haemotoxic snakebite: The impact of immunogen diversity on the in vitro cross-reactivity and in vivo neutralisation of geographically diverse snake venoms

2021 ◽  
Vol 15 (8) ◽  
pp. e0009659
Author(s):  
Nessrin Alomran ◽  
Jaffer Alsolaiss ◽  
Laura-Oana Albulescu ◽  
Edouard Crittenden ◽  
Robert A. Harrison ◽  
...  
Keyword(s):  
Cross Reactivity ◽  
Preclinical Model ◽  
Protective Effects ◽  
Snake Venoms ◽  
Mortality And Morbidity ◽  
Binding Characteristics ◽  
Geographical Regions ◽  
The Impact

Background Snakebite is a neglected tropical disease that causes high global rates of mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Antivenoms are the mainstay therapeutic for treating the toxic effects of snakebite, but despite saving thousands of lives annually, these therapies are associated with limited cross-snake species efficacy due to venom variation, which ultimately restricts their therapeutic utility to particular geographical regions. Methodology/Principal findings In this study we explored the feasibility of generating globally effective pathology-specific antivenoms to counteract the haemotoxic signs of snakebite envenoming. Two different immunogen mixtures, consisting of seven and twelve haemotoxic venoms sourced from geographically diverse and/or medically important snakes, were used to raise ovine polyclonal antibodies, prior to characterisation of their immunological binding characteristics and in vitro neutralisation profiles against each of the venoms. Despite variability of the immunogen mixtures, both experimental antivenoms exhibited broadly comparable in vitro venom binding and neutralisation profiles against the individual venom immunogens in immunological and functional assays. However, in vivo assessments using a murine preclinical model of antivenom efficacy revealed substantial differences in venom neutralisation. The experimental antivenom generated from the seven venom immunogen mixture outperformed the comparator, by providing protective effects against venom lethality caused by seven of the eight geographically diverse venoms tested, including three distinct venoms that were not used as immunogens to generate this antivenom. These findings suggest that a core set of venom immunogens may be sufficient to stimulate antibodies capable of broadly neutralising a geographically diverse array of haemotoxic snake venoms, and that adding additional venom immunogens may impact negatively on the dose efficacy of the resulting antivenom. Conclusions/Significance Although selection of appropriate immunogens that encapsulate venom toxin diversity without diluting antivenom potency remains challenging and further optimisation is required, the findings from this pilot study suggest that the generation of pathology-specific antivenoms with global utility is likely to feasible, thereby highlighting their promise as future modular treatments for the world’s tropical snakebite victims.

scholarly journals Membrane particles from mesenchymal stromal cells reduce the expression of fibrotic markers on pulmonary cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248415
Author(s):  
Ana Merino ◽  
Martin J. Hoogduijn ◽  
Maria Molina-Molina ◽  
Elena G. Arias-Salgado ◽  
Sander S. Korevaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Fibrosis ◽  
Telomere Length ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Treatment Options ◽  
A549 Cells ◽  
Lung Fibroblasts ◽  
Pai 1

Background Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options in which the telomere shortening is a strong predictive factor of poor prognosis. Mesenchymal stromal cells (MSC) administration is probed in several experimental induced lung pathologies; however, MSC might stimulate fibrotic processes. A therapy that avoids MSC side effects of transformation would be an alternative to the use of living cells. Membranes particles (MP) are nanovesicles artificially generated from the membranes of MSC containing active enzymes involved in ECM regeneration. We aimed to investigate the anti-fibrotic role of MP derived from MSC in an in vitro model of pulmonary fibrosis. Methods Epithelial cells (A549) and lung fibroblasts, from IPF patients with different telomere length, were co-cultured with MP and TGF-β for 48h and gene expression of major pro-fibrotic markers were analyzed. Results About 90% of both types of cells effectively took up MP without cytotoxic effects. MP decreased the expression of profibrotic proteins such as Col1A1, Fibronectin and PAI-1, in A549 cells. In fibroblasts culture, there was a different response in the inhibitory effect of MP on some pro-fibrotic markers when comparing fibroblast from normal telomere length patients (FN) versus short telomere length (FS), but both types showed an inhibition of Col1A1, Tenascin-c, PAI-1 and MMP-1 gene expression after MP treatment. Conclusions MP conserve some of the properties attributed to the living MSC. This study shows that MP target lung cells, via which they may have a broad anti-fibrotic effect.

scholarly journals Engineered collagen-targeting therapeutics reverse lung and kidney fibrosis in mice

2022 ◽  
Author(s):  
MICHAEL John Victor WHITE ◽  
Michal Raczy ◽  
Erica Budina ◽  
Ani Solanki ◽  
Zheng Jenny Zhang ◽  
...  
Keyword(s):  
Mouse Models ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
The United States ◽  
Kidney Fibrosis ◽  
Fibrotic Diseases ◽  
Von Willebrand ◽  
Clinical Potential ◽  
Lung And Kidney

Fibrotic diseases are involved in 45% of deaths in the United States. In particular, fibrosis of the kidney and lung are major public health concerns due to their high prevalence and lack of existing treatment options. Here, we harness the pathophysiological features of fibrotic diseases, namely leaky vasculature and aberrant extracellular matrix (ECM) protein deposition (i.e. collagen), to target an anti-fibrotic biologic and a small molecule drug to disease sites of fibrosis, thus improving their therapeutic potential in mouse models of lung and kidney fibrosis. First, we identify and validate collagen-targeting drug delivery systems that preferentially accumulate in the diseased organs: von Willebrand Factor's A3 domain (VWF-A3) and decorin-derived collagen-binding peptide-conjugated micelles (CBP-micelles). We then engineer and recombinantly express novel candidate biologic therapies based on the anti-inflammatory cytokine IL-10: A3-IL-10 and A3-Serum Albumin-IL-10 (A3-SA-IL-10). Simultaneously, we stably encapsulate the potential anti-fibrotic water-insoluble drug, rapamycin, in CBP-micelles. We show that these novel formulations of therapeutics bind to collagen in vitro and that their efficacy in mouse models of lung and kidney fibrosis is improved, compared to free, untargeted drugs. Our results demonstrate that collagen-targeted anti-fibrotic drugs may be next generation therapies of high clinical potential.

scholarly journals Direct comparison of target-reactivity and cross-reactivity induced by CAR- and BiTE-redirected T cells for the development of antibody-based T-cell therapy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Masaki Maruta ◽  
Toshiki Ochi ◽  
Kazushi Tanimoto ◽  
Hiroaki Asai ◽  
Takashi Saitou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treatment Options ◽  
Cross Reactivity ◽  
Single Chain ◽  
Activated T Cells ◽  
T Cell Therapy ◽  
Myeloma Cells

Abstract The development of chimeric antigen receptor (CAR) and bispecific T-cell engager (BiTE) has led to the successful application of cancer immunotherapy. The potential reactivity mediated by CAR- and BiTE-redirected T cells needs to be assessed to facilitate the application of these treatment options to a broader range of patients. Here, we have generated CAR and BiTE possessing the same single chain fragment variable (scFv) specific for the HLA-A2/NY-ESO-1157-165 complex (A2/NY-ESO-1157). Using HLA-A2+NY-ESO-1+ myeloma cells and peptides presented by HLA-A2 molecules as a model, both sets of redirected T cells recognized and killed HLA-A2+NY-ESO-1+ myeloma cells in an A2/NY-ESO-1157-specific manner in vitro. Moreover, CAR- and BiTE-activated T cells showed similar functional avidity, as assessed by cytokine production and killing activity, both displaying antitumor reactivity against HLA-A2+NY-ESO-1+ myeloma cells in vivo. Interestingly, cross-reactivity for homologous peptides presented by HLA-A*02:01 and NY-ESO-1157 peptide presented by HLA-A2 alleles was not identical between CAR- and BiTE-redirected T cells, probably due to structural differences of modified antibodies. These results have demonstrated that both antitumor CAR- and BiTE-activated T cells have comparable potential to recognize tumors, while paying attention to unknown off-target reactivity that would differ for each antibody-based modality even if the same scFv was employed.

scholarly journals Liposomal doxorubicin-based treatment in a preclinical model of adrenocortical carcinoma

2012 ◽  
Vol 213 (2) ◽  
pp. 155-161 ◽  
Author(s):  
Constanze Hantel ◽  
Felicitas Lewrick ◽  
Martin Reincke ◽  
Regine Süss ◽  
Felix Beuschlein
Keyword(s):  
Adrenocortical Carcinoma ◽  
Association Studies ◽  
Treatment Options ◽  
Endocrine Tumor ◽  
Cytotoxic Agents ◽  
Preclinical Model ◽  
Promising Therapeutic Approach ◽  
Tumor Entity

Adrenocortical carcinoma (ACC) is a rare endocrine tumor entity with poor prognosis. Medical treatment is limited to common cytotoxic agents, which are associated with low treatment responses. Thus, lack of therapeutic efficacy demands innovative treatment options for patients with advanced ACC. Recently, we have developed and characterized anti-IGF1 receptor (IGF1-R) immunoliposomes (SSLD-1H7) for the treatment of neuroendocrine tumors of the gastroenteropancreatic system. As previous results indicated putative applicability also for other IGF1-R-overexpressing tumor entities, we initiated testing of liposomal preparations in in vitro and in vivo models of ACC. Adrenocortical NCIh295 cells were used for in vitro association studies with different liposomal formulations. Thereby, flow cytometry revealed high cellular association and internalization of anti-IGF1-R immunoliposomes (soy phosphatidylcholine (SPC)/cholesterol (Chol)–polyethyleneglycol (PEG)-1H7, 50.1±2.2%). Moreover, internalization of pegylated liposomes (SPC/Chol–PEG, 57.1±2.4%) and an even higher uptake of plain liposomes (84.6±0.8%; P<0.0001) were detectable in adrenocortical tumor cells. In vivo, liposomal treatments were investigated on NCIh295 tumor xenografts in pharmacokinetic and therapeutic experiments. A significant reduction in tumor size was detectable in NCIh295 tumor-bearing mice after a single treatment with SSLD-1H7 (0.89±0.15 cm; P=0.006) and a diminished efficacy for SSLD–PEG+ (1.01±0.19 cm; P=0.04) in comparison with untreated controls (1.5±0.0 cm). Thus, anti-IGF1-R immunoliposomes have been successfully tested in vitro and in vivo in a preclinical model for ACCs and could, therefore, represent a promising therapeutic approach for this tumor entity. Moreover, a combination of mitotane plus liposomally encapsulated cytostatic agents instead of free drugs could also be an interesting novel treatment option for ACC in the future.

scholarly journals Cannabinoid glycosides: In vitro production of a new class of cannabinoids with improved physicochemical properties

2017 ◽  
Author(s):  
Janee’ M. Hardman ◽  
Robert T. Brooke ◽  
Brandon J. Zipp
Keyword(s):  
Physicochemical Properties ◽  
Targeted Delivery ◽  
Treatment Options ◽  
Stevia Rebaudiana ◽  
Aqueous Solubility ◽  
In Vitro Production ◽  
New Class ◽  
Delivery Options ◽  
Arachidonoyl Glycerol

AbstractThe cannabinoid signaling system has recently garnered attention as a therapeutic target for numerous indications, and cannabinoids are now being pursued as new treatment options in diverse medical fields such as neurology, gastroenterology, pain management, and oncology. Cannabinoids are extremely hydrophobic and relatively unstable compounds, and as a result, formulation and delivery options are severely limited. Enzymatic glycosylation is a strategy to alter the physicochemical properties of small molecules, often improving their stability and aqueous solubility, as well as enabling site-specific drug targeting strategies. To determine if cannabinoids are a candidate for glycosylation, a library of glucosyltransferase (UGT) enzymes was screened for glycosylation activity towards various cannabinoids. The UGT76G1 enzyme from Stevia rebaudiana has been identified as having glucosyltransferase activity towards a broad range of cannabinoids. Compounds that were successfully glycosylated by UGT76G1 include the phytocannabinoids cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), cannabidivarin (CBDV), and cannabinol (CBN), and the human endocannabinoids anandamide (AEA), 2-arachidonoyl-glycerol (2AG), 1-arachidonoyl-glycerol (1AG), and synaptamide (DHEA). Interestingly, UGT76G1 is able to transfer primary, secondary, and tertiary glycosylations at each acceptor of most of the cannabinoids tested. Additionally, Os03g0702000p, a glycosyltransferase from Oryza sativa, was able to transfer secondary glucose residues onto cannabinoid monoglycosides previously established by UGT76G1. This new class of cannabinoid-glycosides has been termed cannabosides. The compounds have greatly improved solubility in aqueous solutions. This increased aqueous solubility may enable new oral pharmaceutical delivery options for cannabinoids, as well as targeted delivery and release of cannabinoids within the intestines through glycoside prodrug metabolism.

Sign in / Sign up

Export Citation Format

Share Document