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Neoplasia (New York, N.Y.) Nov 2008The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells and some cancer cells, but its expression on ovarian cancer cells and its potential as a...
The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells and some cancer cells, but its expression on ovarian cancer cells and its potential as a therapeutic target are unknown. In this study, expression of the alpha(v)beta(3) integrin on ovarian cancer cell lines and murine endothelial cells was tested, and the effect of a fully humanized monoclonal antibody against alpha(v)beta(3), Abegrin (etaracizumab), on cell invasion, viability, tumor growth, and the Akt pathway were examined in vitro and in vivo. We found that etaracizumab recognizes alpha(v)beta(3) on the ovarian cancer cell lines SKOV3ip1, HeyA8, and A2780ip2 (at low levels) but not on murine endothelial cells. Etaracizumab treatment decreased ovarian cancer proliferation and invasion. In vivo, tumor-bearing mice treated with etaracizumab alone gave variable results. There was no effect on A2780ip2 growth, but a 36% to 49% tumor weight reduction in the SKOV3ip1 and HeyA8 models was found (P < .05). However, combined etaracizumab and paclitaxel was superior to paclitaxel in the SKOV3ip1 and A2780ip2 models (by 51-73%, P < .001) but not in the HeyA8 model. Treatment with etaracizumab was then noted to decrease p-Akt and p-mTOR in SKOV3ip1, but not in HeyA8, which is Akt-independent. Tumors resected after therapy showed that etaracizumab treatment reduced the proliferating cell nuclear antigen index but not microvessel density. This study identifies tumor cell alpha(v)beta(3) integrin as an attractive target and defines the Akt pathway as a predictor of response to function-blocking antibody.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Cell Proliferation; Female; Flow Cytometry; Humans; Immunohistochemistry; Immunoprecipitation; Integrin alphaVbeta3; Mice; Neovascularization, Pathologic; Ovarian Neoplasms; Statistics, Nonparametric
PubMed: 18953435
DOI: 10.1593/neo.08740 -
Cancer Biology & Therapy Dec 2009We tested the efficacy of dual targeting of vascular endothelial growth factor (VEGF) and the alpha(V)beta(3) integrin in orthotopic mouse models of ovarian cancer.
PURPOSE
We tested the efficacy of dual targeting of vascular endothelial growth factor (VEGF) and the alpha(V)beta(3) integrin in orthotopic mouse models of ovarian cancer.
RESULTS
In the SKOV3ip1 model, both single-agent bevacizumab and etaracizumab reduced tumor growth by 52-63% (p < 0.05), while combined therapy reduced growth by 63-74% compared to either agent alone (p < 0.05). Furthermore, bevacizumab/paclitaxel was superior to paclitaxel alone (weight reduction by 53%, p < 0.05), but etaracizumab/paclitaxel was not. Combining all three agents was more effective than either agent with paclitaxel (p < 0.05). Significantly, both bevacizumab and etaracizumab each sensitized the taxane-resistant SKOV3TRip2 cells to paclitaxel, reducing growth by 56-73% (p < 0.05). Both agents decreased proliferation and microvessel density, and increased apoptosis, alone and in combination with paclitaxel. In the HeyA8 model, there was significantly reduced growth with bevacizumab treatment, but not with etaracizumab, and combination therapy was not superior to bevacizumab alone.
EXPERIMENTAL DESIGN
In vivo therapy experiments were conducted in chemo-sensitive (SKOV3ip1, HeyA8) and -resistant (SKOV3TRip2) ovarian cancer models. VEGF was targeted with bevacizumab and alpha(V)beta(3) with etaracizumab. Mice were treated with each agent alone, together, or in combination with paclitaxel for assessment of tumor growth. Tumor specimens were tested for proliferative index, microvessel density and apoptosis.
CONCLUSIONS
Bevacizumab and etaracizumab are more effective in combination than individually in some ovarian cancer models, but not all. Both can sensitize taxane-resistant ovarian cancer cells to paclitaxel, though bevacizumab was superior to etaracizumab in this regard. Further study of this dual anti-angiogenic therapy is warranted.
Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Apoptosis; Bevacizumab; Blotting, Western; Cell Proliferation; Disease Models, Animal; Drug Therapy, Combination; Female; Fluorescent Antibody Technique; Immunoenzyme Techniques; Immunoprecipitation; Integrin alphaVbeta3; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A
PubMed: 19829059
DOI: 10.4161/cbt.8.23.10134 -
Cancer Mar 2010The alpha (v) beta (3) (alpha(v)beta(3)) integrin is involved in intracellular signaling regulating cell proliferation, migration, and differentiation and is important... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The alpha (v) beta (3) (alpha(v)beta(3)) integrin is involved in intracellular signaling regulating cell proliferation, migration, and differentiation and is important for tumor-induced angiogenesis.
METHODS
This phase 2, randomized, open-label, 2-arm study was designed to capture safety data and evaluate the antitumor efficacy of etaracizumab (Abegrin), an IgG1 humanized monoclonal antibody against the alpha(v)beta(3) integrin, in patients with previously untreated metastatic melanoma. The objective was to evaluate whether etaracizumab + or - dacarbazine had sufficient clinical activity to warrant further study in a phase 3 clinical trial.
RESULTS
One hundred twelve patients were randomized to receive etaracizumab alone (N = 57) or etaracizumab + dacarbazine (N = 55). Safety of etaracizumab + or - dacarbazine was acceptable with infusion-related, gastrointestinal, and metabolic reactions being the most common adverse events (AEs). The majority of AEs were grade 1 or 2 in severity in both study arms; most events were not considered serious, except for cardiovascular (myocardial infarction, atrial fibrillation) and thromboembolic events, which occurred in 3 and 5 patients, respectively. None of the patients in the etaracizumab-alone study arm and 12.7% of patients in the etaracizumab + dacarbazine study arm achieved an objective response. The median duration of objective response in the etaracizumab + dacarbazine study arm was 4.2 months. Stable disease rate, time to progression (TTP), and progression-free survival (PFS) appeared to be similar between the 2 treatment arms. Stable disease occurred in 45.6% of patients in the etaracizumab-alone study arm and 40.0% of patients in the etaracizumab + dacarbazine study arm. Median TTP and median PFS were both 1.8 months in the etaracizumab-alone study arm and 2.5 and 2.6 months in the etaracizumab + dacarbazine study arm, respectively. Median overall survival was 12.6 months in the etaracizumab-alone study arm and 9.4 months in the etaracizumab + dacarbazine study arm.
CONCLUSIONS
The survival results in both treatment arms of this study were considered unlikely to result in clinically meaningful improvement over dacarbazine alone.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Female; Humans; Integrin alphaVbeta3; Male; Melanoma; Middle Aged; Skin Neoplasms
PubMed: 20108344
DOI: 10.1002/cncr.24821 -
Drugs in Context Nov 2012Melanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the... (Review)
Review
BACKGROUND
Melanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the last few decades many drugs have been developed but only in 2011 have new drugs demonstrated an impact on survival in metastatic melanoma.
METHODS
A systematic search of literature was conducted, and studies providing data on the effectiveness of current and/or future drugs used in the treatment of metastatic melanoma were selected for review. This review discusses the advantages and limitations of these agents, evaluating past, current and future clinical trials designed to overcome such limitations.
RESULTS
To date, there are four drugs approved by the Food and Drug Administration for melanoma (dacarbazine, interleukin-2, ipilimumab and vemurafenib). Despite efforts to develop new drugs, few of them have demonstrated any clinical benefits. Approved in 1975, dacarbazine remains the gold standard in chemotherapy, although ipilimumab and vemurafenib have raised many hopes in the last few years. Combining dacarbazine or other chemotherapy agents with new pharmacological agents may be a new way to achieve better clinical responses in patients with metastatic melanoma.
DISCUSSION
Advances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. However, heterogeneity amongst study populations, different approaches to treatment and the different melanoma types and localisations included in the trials makes their comparison difficult. New studies focusing on drugs developed in recent decades are warranted.
PubMed: 24432031
DOI: 10.7573/dic.212242 -
Methods and Findings in Experimental... Sep 2010Aclidinium bromide, AE-37, Alemtuzumab, AMA1-C1/ISA 720, Amlodipine besylate/atorvastatin calcium, Arachidonic acid, Arbaclofen placarbil, Aripiprazole, ARQ-621,...
Aclidinium bromide, AE-37, Alemtuzumab, AMA1-C1/ISA 720, Amlodipine besylate/atorvastatin calcium, Arachidonic acid, Arbaclofen placarbil, Aripiprazole, ARQ-621, Azelnidipine, Azilsartan medoxomil potassium; Bevacizumab, Biphasic insulin aspart, Bortezomib; Choriogonadotropin alfa, CTS-1027; Dapagliflozin, Dasatinib, Deforolimus, Degarelix acetate, Denufosol tetrasodium, Desvenlafaxine succinate, Dronedarone hydrochloride, Duloxetine hydrochloride, Dutasteride; Enfuvirtide, Entecavir, Etaracizumab, Everolimus, Exenatide, Ezetimibe; Ferric carboxymaltose, Fludarabine, Foretinib; Gefitinib, GFT-505, GSK-256066; HPV-6/11/16/18, HuM195/rGel, HyperAcute-Lung cancer vaccine; I5NP, Imatinib mesylate, Imexon, Insulin detemir, Insulin glargine, Ivabradine hydrochloride; L2G7, Lacosamide, Lapatinib ditosylate, Lenalidomide, Lidocaine/prilocaine, Liposomal vincristine, Liraglutide, Lixivaptan; Meningococcal (groups A, C, Y and W-135) oligosaccharide diphtheria CRM197 conjugate vaccine, Methoxy polyethylene glycol-epoetin-β, Mirabegron, Morphine/oxycodone, MR Vaccine, MSC-1936369B, Mycophenolic acid sodium salt; Narlaprevir, N-Desmethylclozapine; Ocriplasmin, Olaparib, Olmesartan medoxomil, Olmesartan medoxomil/azelnidipine, ONO-5334, ONO-8539; Palifermin, Panitumumab, Pardoprunox hydrochloride, PCV7, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pexelizumab, PF-337210, Pitavastatin calcium; Raltegravir potassium, Recombinant interleukin-7, Regadenoson, Reniale, Roflumilast, Rosuvastatin calcium; Safinamide mesilate, SB-1518, SCH-527123, Selumetinib, Sipuleucel-T, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talaporfin sodium, Tanespimycin, Technosphere/Insulin, Telaprevir, Telatinib, Telcagepant, Telmisartan/hydrochlorothiazide, Teriparatide, Testosterone transdermal gel, TH-302, Tiotropium bromide, Tocilizumab, Trabedersen, Tremelimumab; Valsartan/amlodipine besylate, Vernakalant hydrochloride, Visilizumab, Voreloxin, Vorinostat.
Topics: Clinical Trials as Topic; Humans
PubMed: 21069103
DOI: 10.1358/mf.2010.32.7.1549223 -
Annals of the Rheumatic Diseases Nov 2002A substantial and persuasive body of data now exists that supports the view that integrin alpha V beta 3 plays a critical part in activated macrophage dependent... (Review)
Review
A substantial and persuasive body of data now exists that supports the view that integrin alpha V beta 3 plays a critical part in activated macrophage dependent inflammation, osteoclast development, migration, and bone resorption, and inflammatory angiogenesis. All of these processes play an important part in the pathogenesis of rheumatoid arthritis (RA) and related arthropathies. Animal arthritis model data further support these concepts and also suggest that therapeutic antagonism of integrin alpha V beta 3 is worthy of further investigation in RA and related arthropathies. To this end, Vitaxin, also known as MEDI-522, has been developed. Vitaxin is a humanised monoclonal IgG1 antibody that specifically binds a conformational epitope formed by both the integrin alpha V and beta 3 subunits. It blocks the interaction of alpha V beta 3 with various ligands such as osteopontin and vitronectin. Clinical trials with Vitaxin in patients with RA are in progress.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Integrin alphaVbeta3; Rheumatic Diseases
PubMed: 12379637
DOI: 10.1136/ard.61.suppl_2.ii96 -
Structure (London, England : 1993) Nov 2017The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent...
The LM609 antibody specifically recognizes αβ integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for αβ-targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of αβ integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for αβ. Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the α chain and the βI domain of the β chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool.
Topics: Amino Acid Motifs; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antigens; Antiviral Agents; Binding Sites; Bone Density Conservation Agents; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli; Gene Expression; Genetic Vectors; Humans; Immunoglobulin Fab Fragments; Integrin alphaVbeta3; Ligands; Models, Molecular; Oligopeptides; Protein Binding; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Recombinant Proteins
PubMed: 29033288
DOI: 10.1016/j.str.2017.09.007 -
Proceedings of the National Academy of... May 1998A protein engineering strategy based on efficient and focused mutagenesis implemented by codon-based mutagenesis was developed. Vitaxin, a humanized version of the...
A protein engineering strategy based on efficient and focused mutagenesis implemented by codon-based mutagenesis was developed. Vitaxin, a humanized version of the antiangiogenic antibody LM609 directed against a conformational epitope of the alphav beta3 integrin complex, was used as a model system. Specifically, focused mutagenesis was used in a stepwise fashion to rapidly improve the affinity of the antigen binding fragment by greater than 90-fold. In the complete absence of structural information about the Vitaxin-alphav beta3 interaction, phage-expressed antibody libraries for all six Ig heavy and light chain complementarity-determining regions were expressed and screened by a quantitative assay to identify variants with improved binding to alphav beta3. The Vitaxin variants in these libraries each contained a single mutation, and all 20 amino acids were introduced at each complementarity-determining region residue, resulting in the expression of 2,336 unique clones. Multiple clones displaying 2- to 13-fold improved affinity were identified. Subsequent expression and screening of a library of 256 combinatorial variants of the optimal mutations identified from the primary libraries resulted in the identification of multiple clones displaying greater than 50-fold enhanced affinity. These variants inhibited ligand binding to receptor more potently as demonstrated by inhibition of cell adhesion and ligand competition assays. Because of the limited mutagenesis and combinatorial approach, Vitaxin variants with enhanced affinity were identified rapidly and required the synthesis of only 2,592 unique variants. The use of such small focused libraries obviates the need for phage affinity selection approaches typically used, permitting the use of functional assays and the engineering of proteins expressed in mammalian cell culture.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody Affinity; Binding Sites, Antibody; Binding, Competitive; Gene Library; Humans; Mutagenesis; Protein Engineering; Receptors, Vitronectin
PubMed: 9600913
DOI: 10.1073/pnas.95.11.6037 -
Molecular Imaging and Biology Feb 2011The cell adhesion molecule integrin α(v)β(3) is an important player in the process of tumor angiogenesis and metastasis. Abegrin™, a fully humanized anti-integrin...
PURPOSE
The cell adhesion molecule integrin α(v)β(3) is an important player in the process of tumor angiogenesis and metastasis. Abegrin™, a fully humanized anti-integrin α(v)β(3) monoclonal antibody, was currently in clinical trials for cancer therapy. Herein, we labeled Abegrin™ with (111)In, evaluated the in vitro and in vivo characteristics, and investigated whether the expression of integrin α(v)β(3) in tumors could be imaged with (111)In-labeled Abegrin™.
METHODS
The binding affinity and specificity of Abegrin™ was analyzed using U87MG glioblastoma cells. Abegrin™ was coupled with 1,4,7,10-tetraazadodecane-N,N',N",N'″-tetraacetic acid (DOTA) for (111)In radiolabeling. γ Imaging of (111)In-DOTA-Abegrin™ was carried out in nude mice bearing both integrin α(v)β(3)-positive U87MG and integrin α(v)β(3)-negative HT-29 tumors. Biodistribution and blocking studies of (111)In-DOTA-Abegrin™ were investigated in U87MG tumor-bearing nude mice.
RESULTS
Abegrin™ exhibited high-binding affinity to human integrin α(v)β(3) expressed on U87MG cells (K (d) of 0.35 ± 0.06 nM). The antibody retained antigen-binding affinity/specificity after DOTA conjugation. γ Imaging showed that the tumor uptake of (111)In-DOTA-Abegrin™ in integrin α(v)β(3)-positive U87MG tumors was much higher than that in integrin α(v)β(3)-negative HT-29 tumors. In the HT-29 tumors, Abegrin™ was mainly nonspecifically accumulated around the blood vessels, while in the U87MG tumors, besides the nonspecific tumor retention, Abegrin™ also specifically bound the human integrin α(v)β(3) expressed on the tumor cells. Biodistribution and blocking studies exhibited that the U87MG tumor uptake of (111)In-DOTA-Abegrin™ decreased from 14.12 ± 0.44 to 6.93 ± 0.94 percentage of injected dose per gram of tissue after coinjection of excess dose of cold Abegrin™, which confirmed the in vivo integrin α(v)β(3) binding specificity of (111)In-DOTA-Abegrin™.
CONCLUSIONS
Abegrin™ showed specific binding to human integrin α(v)β(3) expressed on the tumor cells. (111)In-DOTA-Abegrin™ can specifically target the human integrin α(v)β(3) expression in the nude mouse model. (111)In-DOTA-Abegrin™ has a potential for clinical translation as an agent for integrin α(v)β(3)-positive tumor imaging, evaluating tumor angiogenic status and monitoring the therapeutic efficacy of Abegrin™-based cancer therapy.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Female; Fluorescent Antibody Technique; Humans; Indium Radioisotopes; Integrin alphaVbeta3; Mice; Mice, Nude; Models, Animal; Tissue Distribution
PubMed: 20383594
DOI: 10.1007/s11307-010-0302-4 -
Blood Jan 2000Abnormal interaction of sickle red blood cells (SS RBC) with the vascular endothelium has been implicated as a factor in the initiation of vasoocclusion in sickle cell...
Abnormal interaction of sickle red blood cells (SS RBC) with the vascular endothelium has been implicated as a factor in the initiation of vasoocclusion in sickle cell anemia. Both von Willebrand factor (vWf) and thrombospondin (TSP) play important roles in mediating SS RBC-endothelium interaction and can bind to the endothelium via alphaVbeta3 receptors. We have used monoclonal antibodies (MoAb) directed against alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa) integrins to dissect the role of these integrins in SS RBC adhesion. The murine MoAb 7E3 inhibits both alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa), whereas MoAb LM609 selectively inhibits alphaVbeta3, and MoAb 10E5 binds only to alphaIIbbeta3. In this study, we have tested the capacity of these MoAbs to block platelet-activating factor (PAF)-induced SS RBC adhesion in the ex vivo mesocecum vasculature of the rat. Infusion of washed SS RBC in preparations treated with PAF (200 pg/mL), with or without a control antibody, resulted in extensive adhesion of these cells in venules, accompanied by frequent postcapillary blockage and increased peripheral resistance units (PRU). PAF also caused increased endothelial surface and interendothelial expression of endothelial vWf. Importantly, pretreatment ofthe vasculature with either MoAb 7E3 F(ab')(2) or LM609, but not 10E5 F(ab')(2), after PAF almost completely inhibited SS RBC adhesion in postcapillary venules, the sites of maximal adhesion and frequent blockage. The inhibition of adhesion with 7E3 or LM609 was accompanied by smaller increases in PRU and shorter pressure-flow recovery times. Thus, blockade of alphaVbeta3 may constitute a potential therapeutic approach to prevent SS RBC-endothelium interactions under flow conditions. (Blood. 2000;95:368-374)
Topics: Abciximab; Adult; Anemia, Sickle Cell; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cecum; Cell Adhesion; Endothelium, Vascular; Erythrocytes; Humans; Immunoglobulin Fab Fragments; Platelet Activating Factor; Platelet Glycoprotein GPIIb-IIIa Complex; Rats; Receptors, Vitronectin; Reference Values; Venules
PubMed: 10627437
DOI: No ID Found