Comparative Studies of a Humanized Anti-glycoprotein IIb/IIIa Monoclonal Antibody, YM337, and Abciximab on in Vitro Antiplatelet Effect and Binding Properties.

Suzuki, Kenichi; Sato, Kazuo; Kamohara, Masazumi; Kaku, Seiji; Kawasaki, Tomihisa; Yano, Shinya; Iizumi, Yuichi

doi:10.1248/bpb.25.1006

Cited by 10 publications

(3 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these microfluidics-based experiments, abciximab at a final concen- tration of 136 nM was preincubated with purified platelets for at least 30 min before dendrimer exposure to platelets. On the basis of reports in the literature of abciximab having a K d in platelet-rich plasma of 6.65 ± 1.45 nM, 49 it is unlikely that the abciximab would unbind from its receptor to interact with the dendrimer. These results may seem inconsistent with previously published reports in which the platelet α llb β 3 receptor blockade by abciximab did not hinder aggregation.…”

Section: ■ Discussionmentioning

confidence: 99%

Cationic PAMAM Dendrimers Disrupt Key Platelet Functions

et al. 2012

View full text Add to dashboard Cite

Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, in vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood.

show abstract

Section: ■ Discussionmentioning

confidence: 99%

Cationic PAMAM Dendrimers Disrupt Key Platelet Functions

et al. 2012

View full text Add to dashboard Cite

show abstract

“…However, if not accompanied by framework fine-tuning based on detailed structural information of the antibody, this CDR grafting strategy often yields antibodies with greatly reduced affinity to the antigen as in the case of anti-integrin α ΙΙb β 3 monoclonal antibody YM337, which is currently evaluated in clinical trials (38). As the RAD antibodies are entirely composed of human sequences, except for the synthetic HCDR3, they are expected to be less immunogenic than chimeric or humanized antibodies (39,40). However, the induction of human anti-idiotypic antibodies by our RAD antibodies is possible.…”

Section: Discussionmentioning

confidence: 99%

Integrin αIIbβ3 specific synthetic human monoclonal antibodies and HCDR3 peptides that potently inhibit platelet aggregation

et al. 2003

View full text Add to dashboard Cite

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.

show abstract

“…The samples were incu bated for 30 min at 37°C without any additions or in the presence of monoAB CRC54, Monafram, or antibody AK2, which were added into the medium before incuba tion. Non adherent platelets were washed off with Tyrode/Hepes and the level of platelet adhesion was eval uated by measuring endogenous acid phosphatase activi ty according to the method described by Suzuki et al [23]. Phosphatase substrate, 4 nitrophenol phosphate, was added into the wells at 4 mg/ml in 250 µl of 50 mM citrate buffer, pH 5.5, containing 0.1% Triton X 100.…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

Ability of Different Glycoprotein IIb-IIIa Ligands to Support Platelet Aggregation Induced by Activating Antibody CRC54

Naimushin

Мазуров

2005

Biochemistry (Moscow)

View full text Add to dashboard Cite

The ability of different ligands of glycoprotein (GP) IIb-IIIa (alphaIIb/beta3-integrin) to support platelet aggregation stimulated by activating anti-GP IIb-IIIa monoclonal antibody (monoAB) CRC54 has been investigated. Antibody CRC54 stimulated aggregation of washed platelets not only in the presence of fibrinogen, the main GP IIb-IIIa ligand, but also in the presence of von Willebrand factor (vWF). Unlike these ligands, fibronectin failed to support CRC54-induced aggregation. Fibrinogen and vWF dependent platelet aggregation was completely suppressed by GP IIb-IIIa antagonists--preparations Monafram (F(ab')2 fragments of monoAB that blocked GP IIb-IIIa receptor activity) and aggrastat (RGD-like peptidomimetic). However, aggregation stimulated in the presence of vWF was also completely inhibited by monoAB AK2 directed against GP Ib and capable of blocking its binding with vWF. CRC54-induced aggregation of platelets from patient with GP Ib deficiency in the presence of vWF was significantly lower than aggregation of platelets from normal donors and was not inhibited by anti-GP Ib antibody but still blocked by GP IIb-IIIa antagonist Monafram. Monafram also suppressed CRC54-stimulated platelet adhesion to plastic-adsorbed fibrinogen, vWF, and fibronectin. Unlike CRC54-induced platelet aggregation supported by fluid phase vWF, CRC54-induced adhesion to adsorbed vWF was not affected by anti-GP Ib antibody. Aggregation induced by CRC54 in the presence of fibrinogen and vWF was only partially suppressed by prostaglandin E1, an inhibitor of platelet activation, and was associated with serotonin release from platelet granules only when Ca2+ concentration was decreased from 1 mM (physiological level) to 0.1 mM. The data indicate that vWF supports CRC54-induced platelet aggregation via interaction with two receptors--GP IIb-IIIa and GP Ib. Aggregation induced by CRC54 in the presence of vWF or fibrinogen is only partially dependent on platelet activation and is accompanied with granule secretion only at low Ca2+ concentrations.

show abstract

Comparative Studies of a Humanized Anti-glycoprotein IIb/IIIa Monoclonal Antibody, YM337, and Abciximab on in Vitro Antiplatelet Effect and Binding Properties.

Cited by 10 publications

References 29 publications

Cationic PAMAM Dendrimers Disrupt Key Platelet Functions

Cationic PAMAM Dendrimers Disrupt Key Platelet Functions

Integrin αIIbβ3 specific synthetic human monoclonal antibodies and HCDR3 peptides that potently inhibit platelet aggregation

Ability of Different Glycoprotein IIb-IIIa Ligands to Support Platelet Aggregation Induced by Activating Antibody CRC54

Contact Info

Product

Resources

About