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ABSTRACT: The purpose of the study was to evaluate safety, effects on platelet aggregation and pharmacokinetics of F(ab') 2 fragments of anti-glycoprotein (GP) IIb-IIIa murine monoclonal antibody FRaMon (F(ab') 2 FRaMon) upon its intravenous administration in patients undergoing high-risk coronary angioplasty. Patients were treated before angioplasty with F(ab') 2 FRaMon at 0.2 mg/kg ( n = 17) and 0.25 mg/kg ( n = 12) bolus or with abciximab at 0.25 mg/kg bolus + 12 h infusion at 0.125 w g/kg per min ( n = 29). F(ab') 2 FRaMon at both doses decreased platelet aggregation induced by 20 w M ADP to <10, <20, <40 and <70% of the predrug level at 1, 12, 24 and 72 h after injection, respectively. No significant differences were observed between F(ab') 2 FRaMon and abciximab antiaggregatory effects. In none of the patients did F(ab') 2 FRaMon cause allergic reactions, major bleedings or deep thrombocytopenia. Antibodies against F(ab') 2 FRaMon were detected in one patient. Free F(ab') 2 FRaMon was cleared from plasma within 12 h, while platelet-bound preparation occupied >95, 70-80 and 40-50% of GP IIb-IIIa at 1 and 12-24 h and 3 days after injection, respectively. Thrombotic complications within the first month after angioplasty in groups treated with F(ab') 2 FRaMon and abciximab were observed in one and two patients, respectively. The data obtained have shown that F(ab') 2 FRaMon at bolus administration to patients undergoing coronary angioplasty caused no serious side effects and at comparative dosage inhibited platelet aggregation with the same efficacy as abciximab at bolus + infusion administration.
07/2009; 13(8):465-477.
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ABSTRACT: The purpose of the study was to evaluate safety, effects on platelet aggregation and pharmacokinetics of F(ab')(2) fragments of anti-glycoprotein (GP) IIb-IIIa murine monoclonal antibody FRaMon (F(ab')(2) FRaMon) upon its intravenous administration in patients undergoing high-risk coronary angioplasty. Patients were treated before angioplasty with F(ab')(2) FRaMon at 0.2 mg/kg (n = 17) and 0.25 mg/kg (n = 12) bolus or with abciximab at 0.25 mg/kg bolus + 12 h infusion at 0.125 microg/kg per min (n = 29). F(ab')(2) FRaMon at both doses decreased platelet aggregation induced by 20 microM ADP to <10, <20, <40 and <70% of the predrug level at 1, 12, 24 and 72 h after injection, respectively. No significant differences were observed between F(ab')(2) FRaMon and abciximab antiaggregatory effects. In none of the patients did F(ab')(2) FRaMon cause allergic reactions, major bleedings or deep thrombocytopenia. Antibodies against F(ab')(2) FRaMon were detected in one patient. Free F(ab')(2) FRaMon was cleared from plasma within 12 h, while platelet-bound preparation occupied >95, 70-80 and 40-50% of GP IIb-IIIa at 1 and 12-24 h and 3 days after injection, respectively. Thrombotic complications within the first month after angioplasty in groups treated with F(ab')(2) FRaMon and abciximab were observed in one and two patients, respectively. The data obtained have shown that F(ab')(2) FRaMon at bolus administration to patients undergoing coronary angioplasty caused no serious side effects and at comparative dosage inhibited platelet aggregation with the same efficacy as abciximab at bolus + infusion administration.
Platelets 01/2003; 13(8):465-77. · 1.85 Impact Factor
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ABSTRACT: To study the effects of F(ab')2 fragments of the monoclonal antibody (monAB) FRaMon against glycoproteins (GP) IIb-IIIa on platelet aggregating activity in vitro and after injection to healthy volunteers.
In vitro experiments were performed to study effects of F(ab')2 and Fab fragments of FRaMon on platelet aggregation (PA) and 14C-serotonin secretion and characteristics of 125I-labelled F(ab')2 and Fab FRaMon binding to platelets. In vivo effects of F(ab')2 FRaMon (preparation FRAMON) were studied upon its bolus i.v. injection to 10 healthy volunteers at the doses of 0.025-0.2 mg/kg. PA was registered before and 1, 6, 12, 24 hours and 3 and 12-15 days after FRAMON injection. FRAMON binding to platelets in the vascular bed was evaluated by inhibition of 125I-FRAMON in vitro binding to platelets obtained from volunteers. Development of antibodies against FRAMON was evaluated by ELISA two weeks after FRAMON injection.
In vitro F(ab')2 FRaMon completely blocked PA induced by ADP and thrombin at the concentrations < 4 and < 7.5 mcg/ml, respectively, and revealed higher inhibitory capacity than Fab FRaMon. F(ab')2 FRamon also inhibited 14C-serotonin secretion from ADP-activated platelets. F(ab')2 FRamon interacted with two GP IIb-IIIa molecules on one platelet and bound to platelets more tightly than Fab FRaMon. F(ab')2 FRaMon (preparation FRAMON) bolus i.v. injection to healthy volunteers at the doses of 0.025-0.2 mg/kg did not induce any signs of individual intolerance, including allergic reactions, bleeding and thrombocytopenia. FRAMON at 0.2 mg/kg almost completely inhibited ADP-induced PA of volunteer's platelets 1 h after injection and by more than 70% at 12 h and by more than 50% at 24 h after injection. PA ability recovered to normal 3 days after injection. Antibodies against FRAMON were detected in 1 out of 10 volunteers.
F(ab')2 fragments of monAB FRaMon effectively inhibited aggregating ability both in vitro and after injection to healthy volunteers and could be suggested as a basis for development of a new GP IIb-IIIa antagonist.
Terapevticheskii arkhiv 01/2001; 73(9):66-73. · 0.14 Impact Factor
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ABSTRACT: Platelet glycoprotein (GP) IIb-IIIa complex (alpha IIb beta 3-integrin) changes its conformation upon platelet activation that results in binding of RGD-containing ligands and expression of ligand-induced binding site (LIBS) neoepitopes. Anti-GIIb-IIIa monoclonal antibody (monAB) CRC54 bound to < or = 10% of GPIIb-IIIa on resting platelets but binding was enhanced by the occupation of GPIIb-IIIa with RGDS peptide and by platelet activation indicating that CRC54 is directed against LIBS epitope. The epitope was located within the first 100 N-terminal residues of GPIIIa and differed from other LIBS epitopes. CRC54 as well as its Fab fragments were able to induce platelet aggregation. CRC54 also stimulated interaction of GPIIb-IIIa with its ligands (fibrinogen and fibronectin) and conformation-dependent antibodies. The results indicated that changes of GPIIb-IIIa conformation, binding of ligands and platelet aggregation could be stimulated via interaction of anti-LIBS antibody with the N-terminal part of GPIIIa.
FEBS Letters 09/1996; 391(1-2):84-8. · 3.54 Impact Factor
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ABSTRACT: Low density lipoproteins (LDL) enhance the entry of Ca2+ and other bivalent cations via receptor-operated channels. The use of a synthetic peptide and antibodies blocking the glycoproteins IIb and IIIa interaction with ligands revealed that fibrinogen receptor antagonists prevent platelet aggregation without any effect on the ability of LDL to increase the cytoplasmic Ca2+ level. These data indicate that glycoproteins IIb-IIIa are not involved in the activation of the second messenger system by LDL but play a role in the proaggregant effect of LDL by providing cell-to-cell interactions.
Biokhimii͡a (Moscow, Russia) 09/1995; 60(8):1187-94.
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ABSTRACT: Monoclonal antibody (MAb) CRC81 against P-selectin, a membrane cell adhesion protein of platelets and endothelial cells (EC), has been obtained and characterized. The antibody selectively interacted with the surface of activated platelets and EC due to the redistribution of P-selectin from intracellular organelles onto the surface by activation. MAb CRC81 could recognize not only human but also rabbit and dog P-selectins. MAb CRC81 was used to establish the heterogeneity of human aorta EC with regard to the P-selectin content. Some of the cells in culture did not contain this protein but were nevertheless positively stained for von Willebrand factor, a specific marker for EC which, similar to P-selectin, is localized in Weibel-Palade's bodies. The proportion of P-selectin negative EC increased dramatically in the course of cell passaging: in primary cultures of aortic EC their content was about 15%, while after the 6th passage it exceeded 90%.
Biokhimii͡a (Moscow, Russia) 09/1995; 60(8):1292-301.
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Biulleten' eksperimental'noĭ biologii i meditsiny 11/1994; 118(10):402-5.
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ABSTRACT: Monoclonal antibodies CRC64 are obtained against Ca2+-dependent glycoprotein IIb–IIIa complex of the platelet membrane which possess the ability to inhibit completely fibrinogen-dependent
platelet aggregation. CRC64 is directed against the epitope formed by the glycoprotein IIb–IIIa complex and does not interact
with proteins isolated after platelets are treated with ethylenediamine tetraacetate. Complete, reproducible blockade of platelet
aggregation caused by 5 μM adenosine diphosphate is noted in an MCA concentration of 3 μg/ml, while in the case of a stronger
inductor, namely 1 U/ml thrombin, platelet aggregation is inhibited in a concentration of 5 μg/ml. F(ab′)2 fragments are also able to inhibit platelet aggregation completely and are usually effective in concentrations lower than
native monoclonal antibodies.
Bulletin of Experimental Biology and Medicine 09/1994; 118(4):1102-1105. · 0.27 Impact Factor
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ABSTRACT: Glycoproteins (GPs) IIb and IIIa form a Ca(2+)-dependent complex in platelet membrane and change their conformation upon platelet activation and dissociation of the complex. A new anti-GPIIIa monoclonal antibody (mAb), CRC54, is described which could distinguish different conformational states of GPIIIa. This antibody (i) precipitated GPIIb-IIIa from platelet Triton X-100-lysate, (ii) recognized the GPIIIa band in Western blotting of platelet SDS-lysate, and (iii) did not react with platelets from a Glanzmann's thrombasthenia patient lacking GPIIb-IIIa. Immunoblotting of chymotryptic digestion products of purified GPIIb-IIIa has shown that CRC54 epitope is located within residues 1-100 at the N-terminus of GPIIIa. CRC54 bound weakly to platelets in the presence of Ca2+ and Mg2+, 2.34 +/- 0.28 x 10(3) molecules per platelet at saturation. The same level of binding was observed without any divalent cations in the medium. However, binding of CRC54 was increased by several times after treatment of platelets with EDTA, 10.04 +/- 0.28 x 10(3) molecules per platelet. Increase of CRC54 binding correlated with the dissociation of GPIIb-IIIa complex which was followed by the decrease of the binding of another mAb, CRC64, directed against complex-specific epitope of GPIIb-IIIa. Binding of CRC54 to platelets was changed neither by platelet activation in suspension with thrombin or ADP nor by the occupancy of GPIIb-IIIa ligand binding site with GRGDSR peptide. However, binding was significantly stimulated by platelet adhesion to polystyrene plastic. As measured using 51Cr-labelled platelets, binding of 125I-CRC54 to adherent platelets in the presence of divalent cations was about 4 times higher than to platelets in suspension, 8.68 +/- 0.48 x 10(3) per platelet. This increase was not due to the dissociation of GPIIb-IIIa since complex-specific antibody CRC64 still bound effectively to the surface of adherent platelets. The data obtained indicated that: (1) CRC54 recognized an epitope specific for the dissociated form of GPIIIa; (2) the CRC54-reactive epitope of GPIIIa is also expressed on the surface of adherent platelets.
British Journal of Haematology 11/1993; 85(2):332-40. · 4.94 Impact Factor
