scholarly journals Clot lysis induced by a monoclonal antibody against alpha 2-plasmin inhibitor

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2692-2697 ◽  
Author(s):  
Y Sakata ◽  
Y Eguchi ◽  
J Mimuro ◽  
M Matsuda ◽  
Y Sumi
Keyword(s):  
Monoclonal Antibody ◽  
Therapeutic Agent ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Plasma Clot ◽  
Partial Digestion ◽  
Tissue Plasminogen ◽  
Dose Dependent ◽  
Plasmin Inhibitor

Abstract A monoclonal antibody (MoAb) to alpha 2-plasmin inhibitor designated JTPI-1 inhibited antiplasmin activity by interfering with formation of alpha 2-plasmin inhibitor (alpha 2-PI)-plasmin complex. With this MoAb, we observed plasma clot lysis in vitro and evaluated the potential of JTPI-1 to serve as a new therapeutic agent for thrombolysis. After adding 125I-labeled fibrinogen to plasma, clots were made by adding thrombin and calcium and were then resuspended in normal plasma containing various concentrations of JTPI-1. The presence of JTPI-1 enhanced release of the soluble 125I-labeled fibrin degradation fragment from the clots in a dose-dependent manner. With tissue plasminogen activator (t-PA)-depleted plasma, we showed that induction of clot lysis by JTPI-1 was dependent on fibrin-bound endogenous t-PA. Regulation of fibrinolysis initiated on the fibrin surface by fibrin- bound t-PA and plasminogen is mediated by alpha 2-PI cross-linked to fibrin by activated factor XIII. JTPI-1 bound to this cross-linked alpha 2-PI neutralized its activity and induced partial digestion of fibrin by plasmin. This resulted in additional binding of Glu- plasminogen to fibrin during the incubation. When 1.2 mumol/L JTPI-1 and 5 U/mL exogenous t-PA were present in the suspending plasma, the rate of clot lysis was essentially the same as that induced by 60 U/mL exogenous t-PA alone. These results suggest that JTPI-1 may be useful in reducing the amount of t-PA administered for thrombolytic therapy.

scholarly journals Clot lysis induced by a monoclonal antibody against alpha 2-plasmin inhibitor

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2692-2697
Author(s):  
Y Sakata ◽  
Y Eguchi ◽  
J Mimuro ◽  
M Matsuda ◽  
Y Sumi
Keyword(s):  
Monoclonal Antibody ◽  
Therapeutic Agent ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Plasma Clot ◽  
Partial Digestion ◽  
Tissue Plasminogen ◽  
Dose Dependent ◽  
Plasmin Inhibitor

A monoclonal antibody (MoAb) to alpha 2-plasmin inhibitor designated JTPI-1 inhibited antiplasmin activity by interfering with formation of alpha 2-plasmin inhibitor (alpha 2-PI)-plasmin complex. With this MoAb, we observed plasma clot lysis in vitro and evaluated the potential of JTPI-1 to serve as a new therapeutic agent for thrombolysis. After adding 125I-labeled fibrinogen to plasma, clots were made by adding thrombin and calcium and were then resuspended in normal plasma containing various concentrations of JTPI-1. The presence of JTPI-1 enhanced release of the soluble 125I-labeled fibrin degradation fragment from the clots in a dose-dependent manner. With tissue plasminogen activator (t-PA)-depleted plasma, we showed that induction of clot lysis by JTPI-1 was dependent on fibrin-bound endogenous t-PA. Regulation of fibrinolysis initiated on the fibrin surface by fibrin- bound t-PA and plasminogen is mediated by alpha 2-PI cross-linked to fibrin by activated factor XIII. JTPI-1 bound to this cross-linked alpha 2-PI neutralized its activity and induced partial digestion of fibrin by plasmin. This resulted in additional binding of Glu- plasminogen to fibrin during the incubation. When 1.2 mumol/L JTPI-1 and 5 U/mL exogenous t-PA were present in the suspending plasma, the rate of clot lysis was essentially the same as that induced by 60 U/mL exogenous t-PA alone. These results suggest that JTPI-1 may be useful in reducing the amount of t-PA administered for thrombolytic therapy.

Thrombin activatable fibrinolysis inhibitor (TAFI) affects fibrinolysis in a plasminogen activator concentration-dependent manner

2004 ◽  
Vol 91 (03) ◽  
pp. 473-479 ◽  
Author(s):  
Ana Guimarães ◽  
Dingeman Rijken
Keyword(s):  
Plasminogen Activator ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Retardation Factor ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Plasma Clot ◽  
Concentration Dependent Manner ◽  
Plasmin Inhibitor

SummaryTAFIa was shown to attenuate fibrinolysis. In our in vitro study, we investigated how the inhibitory effect of TAFIa depended on the type and concentration of the plasminogen activator (PA). We measured PA-mediated lysis times of plasma clots under conditions of maximal TAFI activation by thrombin-thrombomodulin in the absence and presence of potato carboxypeptidase inhibitor. Seven different PAs were compared comprising both tPA-related (tPA, TNK-tPA, DSPA), bacterial PA-related (staphylokinase and APSAC) and urokinase-related (tcu-PA and k2tu-PA) PAs. The lysis times and the retardation factor were plotted against the PA concentration. The retardation factor plots were bell-shaped. At low PA concentrations, the retardation factor was low, probably due to the limited stability of TAFIa. At intermediate PA concentrations the retardation factor was maximal (3-6 depending on the PA), with TNK-tPA, APSAC and DSPA exhibiting the strongest effect. At high PA concentrations, the retardation factor was again low, possibly due to inactivation of TAFIa by plasmin or to a complete conversion of glu-plasminogen into lys-plasminogen. Using individual plasmas with a reduced plasmin inhibitor activity (plasmin inhibitor Enschede) the bell-shaped curve of the retardation factor shifted towards lower tPA and DSPA concentrations, but the height did not decrease. In conclusion, TAFIa delays the lysis of plasma clots mediated by all the plasminogen activators tested. This delay is dependent on the type and concentration of the plasminogen activator, but not on the fibrin specificity of the plasminogen activator. Furthermore, plasmin inhibitor does not play a significant role in the inhibition of plasma clot lysis by TAFI.

PLASMA-CLOT LYSIS INDUCED BY MONOCLONAL ANTIBODY AGAINST α2-PLASMIN INHIBITOR

1987 ◽  
Author(s):  
Y Sakata ◽  
J Mimuro ◽  
Y koike
Keyword(s):  
Clot Lysis ◽  
Blood Collection ◽  
Plasma Clot ◽  
Specific Patient ◽  
Lysis Time ◽  
Pi Deficiency ◽  
Dose Dependent ◽  
Plasmin Inhibitor

A Monoclonal antibody (MCA) against α2-plasmin inhibitor α2-Pl) designated as JTP-1 inhibited antiplasmin act ivity and complex formation of a2-PI with plasmin. By using this MCA we tried to observe plasma-clot lysis (CL) in vitro and to estimate the level of total fibrinolytic capacity in plasma. As reported previously (Blood 55: U83, 1980) spontaneous CL is a striking feature of the plasma derived from a patient with α2-PI deficiency. We showed that this abnormally increased fibrinolysis was solely due to the deficiency of α2-PI. However, the contribution of plasminogen activator (PA) and its inhibitor to this specific patient' plasma -CL has been under discussion. Therefore, to test whether similar CL can be found in normal plasma without an addition of PA, plasma clots were made after incubation of plasma from normal volunteers containing 125i fibrinogen with various concentration of JTP-1, and fibrinolysis was measured by counting the soluble radioactivity. The addition of JTP-1 to plasma led to a dose-dependent enhancement of the soluble 125i fragment-release from the clot. However, JTP-1 had no effect on a2-PI-deficient plasma-CL. Other anti-a2-PI MCAs whose epitopes were not involved in the reactive site of a2-PI had no effect on CL and rabbit anti-mouse immunoglobulin IgG neutralized this JTP-l-inducing CL completely. Immunodepletion of tissue PA (tPA) or plasminogen from plasma decreased the rate of CL but that of prourokinase did not. To determine the role of PA inhibitor (PAl) released from platelets (pits) in the regulation of CL in vitro, plasma clots were made from pits poor plasma (PPP) and pits rich plasma (PRP), and CL was observed in the presence of JTP-1. There was almost no difference of the lysis time between PPP clot and PRP clot, although plasma clot from pregnant woman was lysed slowly. These results strongly suggest that endogenous t-PA in plasma is still functionally active after blood collection and CL is mainly prevented by a2-PI in vitro.-plasmin inhibitor (a2-Pl) designated as JTP-1 inhibited antiplasmin act ivity and complex formation of a2-PI with plasmin. By using this MCA we tried to observe plasma-clot lysis (CL) in vitro and to estimate the level of total fibrinolytic capacity in plasma. As reported previously (Blood 55: U83, 1980) spontaneous CL is a striking feature of the plasma derived from a patient with a2-PI deficiency. We showed that this abnormally increased fibrinolysis was solely due to the deficiency of a2-PI. However, the contribution of plasminogen activator (PA) and its inhibitor to this specific patient' plasma -CL has been under discussion. Therefore, to test whether similar CL can be found in normal plasma without an addition of PA, plasma clots were made after incubation of plasma from normal volunteers containing 125i fibrinogen with various concentration of JTP-1, and fibrinolysis was measured by counting the soluble radioactivity. The addition of JTP-1 to plasma led to a dose-dependent enhancement of the soluble 125i fragment-release from the clot. However, JTP-1 had no effect on a2-PI-deficient plasma-CL. Other anti-a2-PI MCAs whose epitopes were not involved in the reactive site of a2-PI had no effect on CL and rabbit anti-mouse immunoglobulin IgG neutralized this JTP-l-inducing CL completely. Immunodepletion of tissue PA (tPA) or plasminogen from plasma decreased the rate of CL but that of prourokinase did not. To determine the role of PA inhibitor (PAl) released from platelets (pits) in the regulation of CL in vitro, plasma clots were made from pits poor plasma (PPP) and pits rich plasma (PRP), and CL was observed in the presence of JTP-1. There was almost no difference of the lysis time between PPP clot and PRP clot, although plasma clot from pregnant woman was lysed slowly. These results strongly suggest that endogenous t-PA in plasma is still functionally active after blood collection and CL is mainly prevented by a2-PI in vitro.-plasmin inhibitor (a2-Pl) designated as JTP-1 inhibited antiplasmin act ivity and complex formation of a2-PI with plasmin. By using this MCA we tried to observe plasma-clot lysis (CL) in vitro and to estimate the level of total fibrinolytic capacity in plasma. As reported previously (Blood 55: U83, 1980) spontaneous CL is a striking feature of the plasma derived from a patient with α2-PI deficiency. We showed that this abnormally increased fibrinolysis was solely due to the deficiency of a2-PI. However, the contribution of plasminogen activator (PA) and its inhibitor to this specific patient' plasma -CL has been under discussion. Therefore, to test whether similar CL can be found in normal plasma without an addition of PA, plasma clots were made after incubation of plasma from normal volunteers containing 125i fibrinogen with various concentration of JTP-1, and fibrinolysis was measured by counting the soluble radioactivity. The addition of JTP-1 to plasma led to a dose-dependent enhancement of the soluble 125i fragment-release from the clot. However, JTP-1 had no effect on a2-PI-deficient plasma-CL. Other anti-a2-PI MCAs whose epitopes were not involved in the reactive site of a2-PI had no effect on CL and rabbit anti-mouse immunoglobulin IgG neutralized this JTP-l-inducing CL completely. Immunodepletion of tissue PA (tPA) or plasminogen from plasma decreased the rate of CL but that of prourokinase did not. To determine the role of PA inhibitor (PAl) released from platelets (pits) in the regulation of CL in vitro, plasma clots were made from pits poor plasma (PPP) and pits rich plasma (PRP), and CL was observed in the presence of JTP-1. There was almost no difference of the lysis time between PPP clot and PRP clot, although plasma clot from pregnant woman was lysed slowly. These results strongly suggest that endogenous t-PA in plasma is still functionally active after blood collection and CL is mainly prevented by α2-PI in vitro.

Identification and characterisation of monoclonal antibodies that impair the activation of human thrombin activatable fibrinolysis inhibitor through different mechanisms

2011 ◽  
Vol 106 (07) ◽  
pp. 90-101 ◽  
Author(s):  
Niraj Mishra ◽  
Ellen Vercauteren ◽  
Jan Develter ◽  
Riet Bammens ◽  
Paul J. Declerck ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Lysis Time ◽  
Human Thrombin ◽  
Fibrinolysis Inhibitor ◽  
Dose Dependent ◽  
Clot Lysis Time

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) forms a molecular link between coagulation and fibrinolysis and is a putative target to develop profibrinolytic drugs. Out of a panel of monoclonal antibodies (MA) raised against TAFI-ACIIYQ, we selected MA-TCK11A9, MA-TCK22G2 and MA-TCK27A4, which revealed high affinity towards human TAFITI- wt. MA-TCK11A9 was able to inhibit mainly plasmin-mediated TAFI activation, MA-TCK22G2 inhibited plasmin- and thrombin-mediated TAFI activation and MA-TCK27A4 inhibited TAFI activation by plasmin, thrombin and thrombin/thrombomodulin (T/TM) in a dose-dependent manner. These MA did not interfere with TAFIa activity. Using an eightfold molar excess of MA over TAFI, all three MA were able to reduce clot lysis time significantly, i.e. in the presence of exogenous TM, MATCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 47 ± 9.1%, 80 ± 8.6% and 92 ± 14%, respectively, compared to PTCI. This effect was even more pronounced in the absence of TM i.e. MATCK11A9, MA-TCK22G2 and MA-TCK27A4 reduced clot lysis time by 90 ± 14%, 140 ± 12% and 147 ± 29%, respectively, compared to PTCI. Mutagenesis analysis revealed that residues at position 268, 272 and 276 are involved in the binding of MA-TCK11A9, residues 147 and 148 in the binding of MA-TCK22G2 and residue 113 in the binding of MATCK27A4. The present study identified three MA, with distinct epitopes, that impair the activation of human TAFI and demonstrated that MATCK11A9 which mainly impairs plasmin-mediated TAFI activation can also reduce significantly clot lysis time in vitro.

In Vitro Activity of a Novel Fully Human Anti-CD40 Antibody CHIR-12.12 in Chronic Lymphocytic Leukemia: Blockade of CD40 Activation and Induction of ADCC.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2504-2504 ◽  
Author(s):  
Xia Tong ◽  
Georgios V. Georgakis ◽  
Long Li ◽  
O’Brien Susan ◽  
Younes Anas ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Line ◽  
Blood Donors ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Dose Dependent

Abstract B-cell chronic lymphocytic leukemia (CLL) is characterized by in vivo accumulation of long-lived CD5+ B cells. However when cultured in vitro CLL cells die quickly by apoptosis. Protection from apoptosis in vivo is believed to result from supply of survival signals provided by cells in the microenvironment. We and others have previously reported that CLL cells express CD40 receptor, and that CD40 stimulation of CLL cells may rescue CLL cells from spontaneous and drug-induced apoptosis in vitro. These observations suggested that blocking CD40-CD40L pathway might deprive CLL cells from survival signals and induce apoptosis. To test this hypothesis, we have generated a fully human anti-CD40 blocking monoclonal antibody in XenoMousemice (Abgenix, Inc.). The antibody CHIR-12.12 was first evaluated for its effect on normal human lymphocytes. Lymphocytes from all 10 healthy blood donors did not proliferate in response to CHIR-12.12 at any concentration tested (0.0001 mg/ml to 10 mg/ml range). In contrast, activating CD40 on normal B-lymphocytes by CD40L induced their proliferation in vitro. Importantly, CHIR-12.12 inhibited CD40L- induced proliferation in a dose dependent manner with an average IC50 of 51 ± 26 pM (n=10 blood donors). The antagonistic activity of CHIR-12.12 was then tested in primary CLL samples from 9 patients. CHIR-12.12 alone did not induce CLL cell proliferation. In contrast, primary CLL cells incubated with CD40L, either resisted spontaneous cell death or proliferated. This effect was reversed by co-incubation with CHIR-12.12 antibody, restoring CLL cell death (n=9). CHIR-12.12 was then examined for its ability to lyse CLL cell line EHEB by antibody dependent cell mediated cytotoxicity (ADCC). Freshly isolated human NK cells from normal volunteer blood donors were used as effector cells. CHIR-12.12 showed lysis activity in a dose dependent manner and produced maximum lysis levels at 0.1 mg/ml. When compared with rituximab, CHIR-12.12 mediated greater maximum specific lysis (27.2 % Vs 16.2 %, p= 0.007). The greater ADCC by CHIR-12.12 was not due to higher density of CD40 molecules on CLL cell line compared to CD20 molecules. The CLL target cells expressed 509053 ±13560 CD20 molecules compared to 48416 ± 584 CD40 molecules. Collectively, these preclinical data suggest that CHIR-12.12 monoclonal antibody may have a therapeutic role in patients with CLL.

scholarly journals Hybrid Au@alendronate nanoparticles as dual chemo-photothermal agent for combined cancer treatment

2018 ◽  
Vol 9 ◽  
pp. 2947-2952 ◽  
Author(s):  
Anouchka Plan Sangnier ◽  
Romain Aufaure ◽  
Laurence Motte ◽  
Claire Wilhelm ◽  
Erwann Guenin ◽  
...  
Keyword(s):  
Photothermal Therapy ◽  
Therapeutic Agent ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Tumor Cell Death ◽  
Antitumor Effects ◽  
One Pot ◽  
The Core ◽  
Dose Dependent

A gold therapeutic nanoplatform with the same molecule used as reductant, coating and therapeutic agent has been developed in a one-pot, one-phase process using alendronate, a drug from the bisphosphonate family known for its antitumor effects. In addition, the core made of gold nanoparticles (NPs) brings thermal functionalities under irradiation within the first biological window (650–900 nm). The Au@alendronate nanoplatform thus provided a combined antitumor activity through drug delivery and photothermal therapy. Au@alendronate NPs inhibited in vitro the proliferation of prostate cancer cells (PC3) in a dose-dependent manner, with an IC50 value of 100 µM. Under NIR irradiation a temperature increase was observed leading to a reduction of the IC50 value to 1 µM, with total tumor cell death at 100 µM.

scholarly journals Schisandrol A Suppresses Catabolic Factor Expression by Blocking NF-κB Signaling in Osteoarthritis

2021 ◽  
Vol 14 (3) ◽  
pp. 241
Author(s):  
Seong Jae Han ◽  
Jimoon Jun ◽  
Seong-il Eyun ◽  
Choong-Gu Lee ◽  
Jimin Jeon ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Cartilage Destruction ◽  
Dependent Manner ◽  
Oral Gavage ◽  
Osteoarthritic Cartilage ◽  
Surgical Model ◽  
Dose Dependent ◽  
Cox2 Expression

Schisandrol A possesses pharmacological properties and is used to treat various diseases; however, its effects on osteoarthritis (OA) progression remain unclear. Here, we investigated Schisandrol A as a potential therapeutic agent for OA. In vitro, Schisandrol A effects were confirmed based on the levels of expression of catabolic factors (MMPs, ADAMTS5, and Cox2) induced by IL-1β or Schisandrol A treatment in chondrocytes. In vivo, experimental OA in mice was induced using a destabilized medial meniscus (DMM) surgical model or oral gavage of Schisandrol A in a dose-dependent manner, and demonstrated using histological analysis. In vitro and in vivo analyses demonstrated that Schisandrol A inhibition attenuated osteoarthritic cartilage destruction via the regulation of Mmp3, Mmp13, Adamts5, and Cox2 expression. In the NF-κB signaling pathway, Schisandrol A suppressed the degradation of IκB and the phosphorylation of p65 induced by IL-1β. Overall, and Schisandrol A reduced the expression of catabolic factors by blocking NF-κB signaling and prevented cartilage destruction. Therefore, Schisandrol A attenuated OA progression, and can be used to develop novel OA drug therapies.

scholarly journals Pharmacological insights into Merremia vitifolia (Burm.f.) Hallier f. leaf for its antioxidant, thrombolytic, anti-arthritic and anti-nociceptive potential

2020 ◽  
Author(s):  
Sahida Akter ◽  
Israt Jahan ◽  
Riniara Khatun ◽  
Mohammad Forhad Khan ◽  
Laiba Arshad ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Protein Denaturation ◽  
Antioxidant Activities ◽  
Reducing Power ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Aqueous Fraction ◽  
Writhing Test ◽  
Dose Dependent

Merremia vitifolia (Burm.f.) Hallier f., an ethnomedicinally important plant, used in the tribal areas to treat various ailments including fever, headache, eye inflammation, rheumatism, dysentery, jaundice and urinary diseases. The present study explored the biological efficacy of the aqueous fraction of M. vitifolia leaves (AFMV) through in vitro and in vivo experimental models. The thrombolytic and anti-arthritic effects of AFMV were evaluated by using the clot lysis technique and inhibition of protein denaturation technique, respectively. The anti-nociceptive activity of AFMV was investigated in Swiss Albino mice by acetic acid-induced writhing test and formalin-induced paw licking test. The antioxidant activities of AFMV, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and total reducing power, were also tested. The qualitative phytochemical assays exhibited AFMV contains secondary metabolites such as alkaloid, carbohydrate, flavonoid, tannin, triterpenoids and phenols. In addition, AFMV showed strong antioxidant effects with the highest scavenging activity (IC50 146.61 µg/mL) and reducing power was increased with a dose-dependent manner. AFMV also revealed notable clot lysis effect and substantial anti-arthritic activity at higher doses (500 µg/mL) as  compared to the control. The results demonstrated a promising reduction of the number of writhing and duration of paw licking in acetic acid-induced writhing test and formalin-induced paw licking test in a dose-dependent manner, respectively. In conclusion, AFMV provides the scientific basis of its folkloric usage,  suggesting it as the vital source of dietary supplement.

Abstract 354: Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Robert A Campbell ◽  
Adriana Vieira-de-Abreu ◽  
Jesse W Rowley ◽  
Zechariah G Franks ◽  
Matthew T Rondina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Inflammatory Responses ◽  
Vascular Diseases ◽  
Clot Formation ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Plasma Clot ◽  
Monocyte Chemoattractant Protein 1

Objective: Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine if clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. Approach and Results: We performed Next Generation RNA sequencing on monocytes extracted from whole blood clots. Thousands of mRNAs were differentially expressed by monocytes from clotted versus unclotted whole blood, including upregulation of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1). Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in LPS-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent, but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (i.e., 1-2 hours) reduced the synthesis of IL-8 and MCP-1, while delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. Conclusions: These findings demonstrate that clots are potent inducers of monocyte gene expression, and that timely fibrinolysis attenuates inflammatory responses. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically-proven efficacy of fibrinolytic drug treatment within hours of stroke onset.

Pharmacodynamic properties of the anti-IGF-IR monoclonal antibody CP-751,871 in cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3587-3587 ◽  
Author(s):  
M. N. Pollak ◽  
M. Q. Lacy ◽  
A. Lipton ◽  
L. Demers ◽  
K. Leitzel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Dependent Manner ◽  
Igf I ◽  
Dose Dependent ◽  
Igfbp 3

3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.

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