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Results for “Integrin alphaVbeta3”

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PubMed2000

Mechanism of action in thalidomide teratogenesis.

In this commentary, we describe a model to explain the mechanism of the embryopathy of thalidomide. We propose that thalidomide affects the following pathway during development: insulin-like growth factor I (IGF-I) and fibroblast growth factor 2 (FGF-2) stimulation of the transcription of alphav and beta3 integrin subunit genes. The resulting alphavbeta3 integrin dimer stimulates angiogenesis in the developing limb bud, which promotes outgrowth of the bud. The promoters of the IGF-I and FGF-2 genes, the genes for their binding proteins and receptors, as well as the alphav and beta3 genes, lack typical TATA boxes, but instead contain multiple GC boxes (GGGCGG). Thalidomide, or a breakdown product of thalidomide, specifically binds to these GC promoter sites, decreasing transcription efficiency of the associated genes. A cumulative decrease interferes with normal angiogenesis, which results in truncation of the limb. Intercalation into G-rich promoter regions of DNA may explain why certain thalidomide analogs are not teratogenic while retaining their anti-tumor necrosis factor-alpha (TNF-alpha) activity, and suggests that we look elsewhere to explain the action of thalidomide on TNF-alpha. On the other hand, the anti-cancer action of thalidomide may be based on its antiangiogenic action, resulting from specific DNA intercalation. The tissue specificity of thalidomide and its effect against only certain neoplasias may be explained by the fact that various developing tissues and neoplasias depend on different angiogenesis or vasculogenesis pathways, only some of which are thalidomide-sensitive.

Animals↗

PubMed2006

Overexpression of laminin-8 in human dermal microvascular endothelial cells promotes angiogenesis-related functions.

This study examined the effects of endogenous overexpression of laminin-8 on angiogenesis and wound healing in primary human dermal microvascular endothelial cells (HDMECs). HDMECs expressed laminin-8 and laminin-10, but no other laminins, as determined by radioimmunoprecipitation assay using a panel of antibodies to individual laminin chains. To study laminin-8 function, full-length human laminin alpha4 cDNA was retrovirally transferred to HDMEC, and specific overexpression of laminin-8 was verified by Western blot. Laminin-8 overexpression promoted endothelial cell spreading and migration in scratch assays and accelerated angiogenic tubule formation in collagen gel overlay assays. Strong inhibitory effect of beta1 integrin and weak inhibition by alphavbeta3 integrin antibodies were observed in laminin-8-stimulated cell migration, but only beta1 integrin antibodies affected tubule formation. These studies suggest that laminin-8 overexpression may prove to be a useful method to engineer HDMECs to promote angiogenesis and wound repair.

Antibodies↗

PubMed2000

Regulation of differentiated osteoclasts.

Osteoclasts respond to many factors, including endocrines, cytokines, cell-cell interactions, and cell-matrix contacts. For mature osteoclasts, the first level of control occurs through signaling that follows binding to an appropriate substrate. Mononuclear and multinucleate osteoclasts are activated when cell surface integrins, notably but not exclusively alphavbeta3 integrins, bind to calcified matrices. The binding process results in actin ring formation and deployment of adhesive proteins into a ring shape such that a seal is formed. As this ring forms, components of the ruffled border assemble from diffuse distribution to form the resorption apparatus, which includes the vacuolar-ATPase, carbonic anhydrase, and other key molecules. This review focuses on the control of osteoclast activity, beginning with attachment and ruffled border assembly. Direct and indirect regulation by PTH/PTHrP, genomic and nongenomic effects of estrogen, and gene expression of ruffled border components, carbonic anhydrase, and vacuolar ATPase are reviewed. Finally, the need to understand complex signaling pathway interaction is discussed.

Animals↗

PubMed2005

Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity: generation of a new integrin inhibitor.

We investigated the interaction between the urokinase receptor (uPAR) and the integrin alphavbeta3. Vitronectin (VN) induces cell migration by binding to alphavbeta3, but expression of the uPAR boosts its efficacy. Thus, uPAR may regulate VN-induced cell migration by interacting laterally with alphavbeta3. In contrast, cells expressing a uPAR mutant lacking domain 2 do not migrate in response to VN. This effect is overcome by D2A, a synthetic peptide derived from the sequence of domain 2. In addition, D2A has chemotactic activity that requires alphavbeta3 and activates alphavbeta3-dependent signaling pathways such as the Janus kinase/Stat pathway. Moreover, D2A disrupts uPAR-alphavbeta3 and uPAR-alpha5beta1 co-immunoprecipitation, indicating that it can bind both of these integrins. We also identify the chemotactically active epitope harbored by peptide D2A. Mutating two glutamic acids into two alanines generates peptide D2A-Ala, which lacks chemotactic activity but inhibits VN-, FN-, and collagen-dependent cell migration. In fact, the GEEG peptide has potent chemotactic activity, and the GAAG sequence has inhibitory capacities. In summary, we have identified an integrin-interacting sequence located in domain 2 of uPAR, which is also a new chemotactic epitope that can activate alphavbeta3-dependent signaling pathways and stimulate cell migration. This sequence thus plays a pivotal role in the regulation of uPAR-integrin interactions. Moreover, we describe a novel, very potent inhibitor of integrin-dependent cell migration.

Adenoviridae↗

PubMed2005

New multifunctional molecular conjugate vector for targeting, imaging, and therapy of tumors.

We report the in vitro and in vivo characteristics of a new molecular conjugate vector for targeting and imaging of tumors. Its core is a cyclodecapeptide platform named RAFT, onto which two spatially independent functional domains can be covalently and stereospecifically linked: a cell-targeting domain for tumor targeting and a labeling domain able to carry two drugs and/or labeling agents. To prove the interest of this carrier, we used a well-known cRGD cyclopeptide, a ligand for the alphavbeta3 integrin. We demonstrate that this vector presenting four cRGD motifs very efficiently prevents alphavbeta3-mediated cell adhesion to vitronectin. Furthermore, it is actively endocytosed because of the multivalent cRGD presentation, a major advantage for drug delivery. In vivo experiments in nude mice reveal that repeated intratumoral injections of low doses of RAFT(cRGD)4 reduce tumor growth. Furthermore, RAFT(cRGD)4 significantly improves the targeting specificity of subcutaneous tumor masses as well as that of disseminated metastasis after intravenous injection. Thus, RAFT(cRGD)4 is specific, internalized, and perfectly controlled and can carry multiple biological functions on a single, spatially defined backbone, making it a powerful and versatile synthetic vector for drug delivery, molecular imaging, or both.

Animals↗

PubMed2005

Cyclic FEE peptide increases human gamete fusion and potentiates its RGD-induced inhibition.

BACKGROUND: Alpha6beta1 integrin has been proposed to act as a sperm receptor on the mouse oocyte by interacting with spermatozoon fertilin beta. We investigated, in humans, whether oocyte integrins could act similarly in gamete fusion, using a cyclic peptide containing the putative disintegrin-binding domain of human fertilin beta [cyclic FEE (cFEE)] and RGD peptide. METHODS: Zona-free eggs were inseminated in the absence or presence of peptides. To maintain the membrane protein pattern, the zona pellucida was removed by microdissection. Immunofluorescence and confocal microscopy were used to detect integrin subunits on the oocyte. RESULTS: Unexpectedly, cFEE alone increased human gamete fusion by 94% instead of inhibiting fertilization. Furthermore, cFEE together with RGD potentiated the RGD-induced inhibition of fertilization in a dose-dependent manner. The data suggested the hypothesis of integrin cross-talk, further supported by the co-localization of alpha6beta1 and alphavbeta3 integrins, the putative receptors of cFEE and RGD peptides, respectively. CONCLUSIONS: RGD-sensitive and -insensitive integrins may be associated in a multimolecular complex working as a sperm receptor on the human oocyte membrane. Supplementation of human IVF culture medium with cFEE peptide might improve fertilization rates in ART.

ADAM Proteins↗

PubMed1999

Macrophage and retinal pigment epithelium phagocytosis: apoptotic cells and photoreceptors compete for alphavbeta3 and alphavbeta5 integrins, and protein kinase C regulates alphavbeta5 binding and cytoskeletal linkage.

Noninflammatory monocyte macrophages use alphavbeta3 integrin to selectively bind apoptotic cells, initiating their phagocytic removal. In a related process, the retinal pigment epithelium (RPE) employs alphavbeta5 integrin to recognize spent photoreceptor outer segment particles (OS). Here, we show that apoptotic cells and OS compete for binding to these receptors, indicating that OS and apoptotic cells expose surface signals recognizable by alphavbeta3 and alphavbeta5. Particle binding to alphavbeta5 required protein kinase C (PKC) activation. In RPE, alphavbeta5 binding was maximally activated even before any phagocytic challenge and was reduced by PKC inhibitors. In macrophages, it was dormant but became activated upon PKC stimulation. PKC-activated alphavbeta5-mediated binding in macrophages differed from constitutive binding to the same integrin receptor in RPE cells in that the former followed much faster kinetics, similar to particle binding mediated by alphavbeta3. Activation of alphavbeta5 for particle binding correlated with its recruitment into a detergent-insoluble fraction, a process sensitive to pharmacological modulation of PKC in both types of phagocytes. Furthermore, alphavbeta5 but not alphavbeta3 particle binding required actin microfilaments. These data constitute the first evidence that noninflammatory phagocytes actively regulate the earliest phase of phagocytic clearance, particle binding, by controlling receptor activity.

Animals↗

PubMed2004

Human integrin alphavbeta5: homology modeling and ligand binding.

The recently reported crystal structures of the extracellular domains of the alphavbeta3 integrin in its unligated state and in complex with the peptide cyclo(-RGDf[NMe]V-) have dramatically increased our understanding of ligand binding to integrins. Nonetheless, ligand selectivity toward different integrin subtypes is still a challenging problem complicated by the fact that 3D structures of most of the integrin subtypes remain unknown. In this study, a three-dimensional model for the human alphavbeta5 integrin was obtained using homology modeling based on the crystal coordinates of alphavbeta3 in its bound conformation as template. The modeled receptor was refined using energy minimization and molecular dynamics simulations in explicit solvent. The refined alphavbeta5 model was used to explore the interactions between this integrin and alphavbeta3/alphavbeta5 dual and alphavbeta3-selective ligands in the attempt to provide a preliminary rationalization, at the molecular level, of ligand selectivity toward the two alphav integrins. It was found that, in the RGD binding site of the alphavbeta5 receptor, a partial "roof" composed mainly of the SDL residues Tyr179 and Lys180 is present and hampers the binding of compounds containing bulky substituents in the proximity of the carboxylate group. This study provides a testable hypothesis for alphav integrins subtype ligand binding selectivity, in line with both mutagenesis data and SARs studies.

Amino Acid Sequence↗

PubMed1998

Adenoviral transduction efficiency partly correlates with expression levels of integrin alphavbeta5, but not alphavbeta3 in human gastric carcinoma cells.

Adenovirus has attracted much attention as a vector for gene therapy. Integrin alphavbeta3 and alphavbeta5 mediate adenovirus internalization into cells. We examined adenoviral transduction efficiency and expression of integrin alphavbeta3 alphavbeta5 in 9 human gastric carcinoma cell lines. The percentage of -gal-positive cells was more than 85% 3 days after infection with recombinant adenovirus carrying the bacterial LacZ gene (AxCALacZ) at a dose of 25 MOI in 7 cell lines and the transduction efficiency was 32 and 42% in HSC-39 and MKN-28 cells, respectively. Adenoviral transduction efficiency did not correlate with the histological cell types. Flow cytometric analysis revealed relatively high expression of integrin alphavbeta5 in MKN-28 and OCUM-2M cells, followed by MKN-1, MKN-7, MKN-45, MKN-74, TMK-1 and KATO-III cells. HSC-39 cells minimally expressed integrin alphavbeta5. On the other hand, integrin alphavbeta3 was expressed only in MKN-1 cells. These results suggest that the adenovirus vector might be useful for gene transduction into human gastric carcinoma cells and the transduction efficiency partly correlates with the expression levels of integrin alphavbeta5 but not integrin alphavbeta3.

Adenoviridae↗

PubMed2005

A functional radioreceptor assay of alpha-V-beta-3 (alphavbeta3) inhibitors in plasma: application as an ex vivo pharmacodynamic model.

Development of alphavbeta3-integrin inhibitors has been hampered by a lack of pharmacodynamic endpoints to identify doses that inhibit alphavbeta3 in vivo. To address this need, we developed an alphavbeta3 radioreceptor assay (RRA) that could be performed in 100% plasma. The RRA was based on 125I-echistatin binding to plate-immobilized alphavbeta3. Small molecule alphavbeta3 inhibitors efficiently competed echistatin binding to alphavbeta3 when the assay was carried out in buffer. However, when carried out in 100% plasma, the RRA revealed a 45 to >3000-fold loss in compound potencies. The losses in potency reflected, in part, the high plasma protein binding by the compounds examined. The RRA was adapted as an ex vivo pharmacodynamic model. Echistatin binding was measured in the presence of plasma harvested at timed intervals from rats dosed with select compounds. Using this pharmacodynamic model, compound and dose selection was optimized for further testing in models of corneal angiogenesis. Moderate anti-angiogenic activity was achieved when rats were dosed sufficient to achieve sustained (>50%) plasma inhibition through the trough interval. Thus, the RRA provided a simple technique to rank order compound potency in plasma, and could find general use as an ex vivo pharmacodynamic assay to select compounds and doses for preclinical and clinical proof-of-principle studies.

Angiogenesis Inhibitors↗

PubMed2005

The mechanisms and dynamics of (alpha)v(beta)3 integrin clustering in living cells.

During cell migration, the physical link between the extracellular substrate and the actin cytoskeleton mediated by receptors of the integrin family is constantly modified. We analyzed the mechanisms that regulate the clustering and incorporation of activated alphavbeta3 integrins into focal adhesions. Manganese (Mn2+) or mutational activation of integrins induced the formation of de novo F-actin-independent integrin clusters. These clusters recruited talin, but not other focal adhesion adapters, and overexpression of the integrin-binding head domain of talin increased clustering. Integrin clustering required immobilized ligand and was prevented by the sequestration of phosphoinositole-4,5-bisphosphate (PI(4,5)P2). Fluorescence recovery after photobleaching analysis of Mn(2+)-induced integrin clusters revealed increased integrin turnover compared with mature focal contacts, whereas stabilization of the open conformation of the integrin ectodomain by mutagenesis reduced integrin turnover in focal contacts. Thus, integrin clustering requires the formation of the ternary complex consisting of activated integrins, immobilized ligands, talin, and PI(4,5)P2. The dynamic remodeling of this ternary complex controls cell motility.

Actins↗

PubMed2003

Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt.

Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (HUVEC) adhesion, migration, and survival, three events essential for angiogenesis. Zoledronate inhibited HUVEC adhesion mediated by integrin alphaVbeta3, but not alpha5beta1, blocked migration and disrupted established focal adhesions and actin stress fibers without modifying cell surface integrin expression level or affinity. Zoledronate treatment slightly decreased HUVEC viability and strongly enhanced tumor necrosis factor (TNF)-induced cell death. HUVEC treated with zoledronate and TNF died without evidence of enhanced annexin-V binding, chromatin condensation, or nuclear fragmentation and caspase dependence. Zoledronate inhibited sustained phosphorylation of focal adhesion kinase (FAK) and in combination with TNF, with and without interferon (IFN) gamma, of protein kinase B (PKB/Akt). Constitutive active PKB/Akt protected HUVEC from death induced by zoledronate and TNF/IFNgamma. Phosphorylation of c-Src and activation of NF-kappaB were not affected by zoledronate. Clodronate had no effect on HUVEC adhesion, migration, and survival nor did it enhanced TNF cytotoxicity. Taken together these data demonstrate that zoledronate sensitizes endothelial cells to TNF-induced, caspase-independent programmed cell death and point to the FAK-PKB/Akt pathway as a novel zoledronate target. These results have potential implications to the clinical use of zoledronate as an anti-angiogenic or anti-cancer agent.

Adenoviridae↗

PubMed1996

Transient functional expression of alphaVbeta 3 on vascular cells during wound repair.

During early granulation tissue formation of wound repair, new capillaries invade the fibrin clot, a process that undoubtedly requires an interaction of vascular cells with the wound provisional matrix composed mainly of fibrin, fibronectin, and vitronectin. Integrin alphaVbeta3 is the vascular cell receptor for these wound-associated adhesive proteins. Therefore, we investigated the expression of this receptor on new capillaries of healing full-thickness cutaneous porcine wounds. During granulation tissue formation, alphaVbeta3 was expressed specifically on capillary sprouts invading the central fibrin clot whereas the closely related integrin alphaVbeta5 failed to localize to these cells. Cyclic peptides or antibody antagonists of alphaVbeta3 specifically inhibited granulation tissue formation in a transient manner during the period of invasive angiogenesis. Immunolocalization studies revealed that alphaVbeta3 became aggregated and lost from sprouting vessels after treatment with a peptide antagonist. In contrast, beta 1 integrins were not modulated by this treatment. Once granulation tissue filled the wound and invasive angiogenesis terminated, the alphaVbeta3 showed little or no expression in the granulation tissue microvasculature. These data demonstrate that integrin alphaVbeta3 plays a fundamental, but transient, role during invasive angiogenesis and granulation tissue formation in a healing wound.

Analysis of Variance↗

PubMed2003

Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and alphavbeta3 complex.

Growth factor-induced neovascularization has received a great deal of attention because it is fundamental to the growth and metastasis of solid tumors. This multistep process requires extensive signaling through growth factor receptors and integrins. Among the integrins involved in this process, integrin alphavbeta3 is specific to basic fibroblast growth factor (bFGF)-induced angiogenesis. Here we show that junctional adhesion molecule 1/A (JAM-1/A) and alphavbeta3 form a complex in the absence of bFGF. JAM-1, which is normally localized at the cell-cell junctions of quiescent endothelial cells, redistributes to the cell surface on bFGF treatment. Blockage of the extracellular domain of JAM-1 inhibits bFGF-induced endothelial cell morphology, proliferation, and angiogenesis. Additionally, mutation in the JAM-1 cytoplasmic domain blocks bFGF-induced mitogen-activated protein (MAP) kinase activation and ablates its ability to induce endothelial cell tube formation, suggesting that signaling through JAM-1 is key to bFGF-induced signaling. Immunoprecipitation analysis suggests that bFGF signaling dissociates the JAM-1/ alphavbeta3 complex, allowing for signaling through JAM-1 and alphavbeta3. In addition, blockage of either JAM-1 or alphavbeta3 inhibits bFGF-induced MAP kinase activation. Thus, our results suggest that signaling through JAM-1 and alphavbeta3 is necessary for bFGF-induced angiogenesis.

Allantois↗

PubMed1998

Bone matrix proteins: isolation and characterization of a novel cell-binding keratan sulfate proteoglycan (osteoadherin) from bovine bone.

A small cell-binding proteoglycan for which we propose the name osteoadherin was extracted from bovine bone with guanidine hydrochloride-containing EDTA. It was purified to homogeneity using a combination of ion-exchange chromatography, hydroxyapatite chromatography, and gel filtration. The Mof the proteoglycan was 85, 000 as determined by SDS-PAGE. The protein is rich in aspartic acid, glutamic acid, and leucine. Two internal octapeptides from the proteoglycan contained the sequences Glu-Ile-Asn-Leu-Ser-His-Asn-Lys and Arg-Asp-Leu-Tyr-Phe-Asn-Lys-Ile. These sequences are not previously described, and support the notion that osteoadherin belongs to the family of leucine-rich repeat proteins. A monospecific antiserum was raised in rabbits. An enzyme-linked immunosorbent assay was developed, and showed the osteoadherin content of bone extracts to be 0.4 mg/g of tissue wet weight, whereas none was found in extracts of various other bovine tissues. Metabolic labeling of primary bovine osteoblasts followed by immunoprecipitation showed the cells to synthesize and secrete the proteoglycan. Digesting the immunoprecipitated osteoadherin with N-glycosidase reduced its apparent size to 47 kD, thus showing the presence of several N-linked oligosaccharides. Digestion with keratanase indicated some of the oligosaccharides to be extended to keratan sulfate chains. In immunohistochemical studies of the bovine fetal rib growth plate, osteoadherin was exclusively identified in the primary bone spongiosa. Osteoadherin binds to hydroxyapatite. A potential function of this proteoglycan is to bind cells, since we showed it to be as efficient as fibronectin in promoting osteoblast attachment in vitro. The binding appears to be mediated by the integrin alphavbeta3, since this was the only integrin isolated by osteoadherin affinity chromatography of surface-iodinated osteoblast extracts.

Amino Acid Sequence↗

PubMed2001

Contortrostatin, a homodimeric disintegrin, actively disrupts focal adhesion and cytoskeletal structure and inhibits cell motility through a novel mechanism.

Integrins play a major role in the regulation of cell motility. They physically link the extracellular environment to the cytoskeleton and participate in large protein complexes known as focal adhesions. In this report, it is demonstrated that treatment of tumor cells with the homodimeric disintegrin contortrostatin induces integrin-mediated tyrosine phosphorylation events and causes severe disruptions in the actin cytoskeleton and disassembly of focal adhesion structures without affecting cellular adhesion to a reconstituted basement membrane. Included in this disruption is the tyrosine phosphorylation and altered subcellular localization of FAK. Through use of transfected 293 cells with specific integrin expression profiles and anti-alphavbeta3 mAbs, we demonstrate that these events are mediated exclusively by the alphavbeta3 integrin and are likely the result of contortrostatin-mediated crosslinking of this receptor at the cell surface, since monovalent disintegrins, flavoridin or echistatin do not induce such effects. Further, it is shown that contortrostatin potently inhibits motility in cells expressing the alphavbeta33 integrin. The results of this study describe a novel integrin-mediated mechanism by which cell motility can be inhibited and suggest an alternative approach to therapeutic intervention for cancer invasion and metastasis.

Animals↗

PubMed2002

Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation.

Cysteine-rich repeats in the integrin beta subunit stalk region relay activation signals to the ligand-binding headpiece. The NMR solution structure and disulfide bond connectivity of Cys-rich module-3 of the integrin beta2 subunit reveal a nosecone-shaped variant of the EGF fold, termed an integrin-EGF (I-EGF) domain. Interdomain contacts between I-EGF domains 2 and 3 observed by NMR support a model in which the modules are related by an approximate two-fold screw axis in an extended arrangement. Our findings complement a 3.1 A crystal structure of the extracellular portion of integrin alphaVbeta3, which lacks an atomic model for I-EGF2 and a portion of I-EGF3. The disulfide connectivity of I-EGF3 chemically assigned here differs from the pairings suggested in the alphaVbeta3 structure. Epitopes that become exposed upon integrin activation and residues that restrain activation are defined in beta2 I-EGF domains 2 and 3. Superposition on the alphaVbeta3 structure reveals that they are buried. This observation suggests that the highly bent alphaVbeta3 structure represents the inactive conformation and that release of contacts with I-EGF modules 2 and 3 triggers a switchblade-like opening motion extending the integrin into its active conformation.

Amino Acid Motifs↗

PubMed2003

Integrin alphaIIbbeta3-specific synthetic human monoclonal antibodies and HCDR3 peptides that potently inhibit platelet aggregation.

The interaction of fibrinogen with integrin alphaIIbbeta3 (GPIIb/IIIa), in part mediated by an RGD tripeptide motif, is an essential step in platelet aggregation. Based on their inhibition of platelet aggregation, three integrin alphaIIbbeta3 inhibitors are clinically approved. The clinically most widely used integrin alphaIIbbeta3 inhibitor abciximab is a chimeric mouse/human antibody that induces thrombocytopenia, often severe, in 1-2% of patients due to a human anti-mouse antibody (HAMA) response. In addition, unlike other ligands mimicking small molecular drugs, abciximab cross-reacts with integrin alphavbeta3 and alphaMbeta2. Here we used phage display to select monoclonal antibodies specific to integrin alphaIIbbeta3 from a synthetic human antibody library based on the randomized HCDR3 sequence VGXXXRADXXXYAMDV. The selected antibodies revealed a strong consensus in HCDR3 (V(V/W)CRAD(K/R)RC) and high specificity toward integrin alphaIIbbeta3 but not to other RGD binding integrins such as alphavbeta3, alphavbeta5, and alpha5beta1. The selected antibodies as well as three synthetic peptides (VWCRADRRC, VWCRADKRC, and VVCRADRRC) whose sequences were derived from the HCDR3 sequences of the selected antibodies strongly inhibited the interaction between integrin alphaIIbbeta3 and fibrinogen and platelet aggregation ex vivo. To our knowledge, these are the first fully human monoclonal antibodies that are specific to integrin alphaIIbbeta3 and can potently inhibit platelet aggregation.

Amino Acid Motifs↗