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Article ; Online: Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149.

Vanhove, Marc / Noppen, Bernard / Wagner, Jean-Marc / Van Bergen, Tine / Barbeaux, Philippe / Stitt, Alan W

Journal of pharmacokinetics and pharmacodynamics

2021 Volume 48, Issue 6, Page(s) 825–836

Abstract: Intravitreal (IVT) injection of pharmacological agents is an established and widely used procedure for the treatment of many posterior segment of the eye diseases. IVT injections permit drugs to reach high concentrations in the retina whilst limiting ... ...

Abstract	Intravitreal (IVT) injection of pharmacological agents is an established and widely used procedure for the treatment of many posterior segment of the eye diseases. IVT injections permit drugs to reach high concentrations in the retina whilst limiting systemic exposure. Beyond the risk of secondary complications such as intraocular infection, the potential of systemic adverse events cannot be neglected. Therefore, a detailed understanding of the rules governing systemic exposure following IVT drug administration remains a prerequisite for the evaluation and development of new pharmacological agents intended for eye delivery. We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies. The mathematical expression was derived from a pharmacokinetic model that assumes the existence of a compartment between the vitreous humor compartment itself and the systemic compartment. We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye has broader relevance to the human eye and can be used to analyze systemic exposure of a variety of drugs delivered in the eye.
MeSH term(s)	Animals ; Diabetic Retinopathy/drug therapy ; Macular Edema/drug therapy ; Macular Edema/metabolism ; Pharmaceutical Preparations/metabolism ; Rabbits ; Retina/metabolism ; Vitreous Body/metabolism
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-021-09773-w
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Article: Assessment of Ocriplasmin Effects on the Vitreoretinal Compartment in Porcine and Human Model Systems.

Jonckx, Bart / Porcu, Michael / Candi, Aurelie / Etienne, Isabelle / Barbeaux, Philippe / Feyen, Jean H M

Journal of ophthalmology

2017 Volume 2017, Page(s) 2060765

Abstract: Ocriplasmin (Jetrea®) is a recombinant protease used to treat vitreomacular traction. To gain insight into vitreoretinal observations reported after ocriplasmin treatment, we have developed ... ...

Abstract	Ocriplasmin (Jetrea®) is a recombinant protease used to treat vitreomacular traction. To gain insight into vitreoretinal observations reported after ocriplasmin treatment, we have developed an
Language	English
Publishing date	2017-10-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2546525-9
ISSN	2090-0058 ; 2090-004X
ISSN (online)	2090-0058
ISSN	2090-004X
DOI	10.1155/2017/2060765
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Article ; Online: The potent small molecule integrin antagonist THR-687 is a promising next-generation therapy for retinal vascular disorders.

Hu, Tjing-Tjing / Vanhove, Marc / Porcu, Michaël / Van Hove, Inge / Van Bergen, Tine / Jonckx, Bart / Barbeaux, Philippe / Vermassen, Elke / Feyen, Jean H M

Experimental eye research

2018 Volume 180, Page(s) 43–52

Abstract: Integrins are associated with various eye diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) and implicated in main pathologic disease hallmarks like neovascularization, inflammation, fibrosis and vascular leakage. ... ...

Abstract	Integrins are associated with various eye diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) and implicated in main pathologic disease hallmarks like neovascularization, inflammation, fibrosis and vascular leakage. Targeting integrins has the potential to attenuate these vision-threatening processes, independent of anti-vascular endothelial growth factor (VEGF) responsiveness. The current investigation characterized THR-687 as a novel pan RGD (arginylglycylaspartic acid) integrin receptor antagonist able to compete for binding with the natural ligand with nanomolar potency (e.g. α
MeSH term(s)	Animals ; Capillary Permeability/drug effects ; Cell Movement/drug effects ; Choroidal Neovascularization/drug therapy ; Diabetic Retinopathy/drug therapy ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Fluorescein Angiography ; Human Umbilical Vein Endothelial Cells ; Humans ; Injections, Intraperitoneal ; Intravitreal Injections ; Macaca fascicularis ; Male ; Mice ; Mice, Inbred C57BL ; Organic Chemicals/pharmacology ; Organic Chemicals/therapeutic use ; Rabbits ; Receptors, Immunologic/antagonists & inhibitors ; Receptors, Peptide/antagonists & inhibitors ; Retinal Vessels/drug effects ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/pharmacology ; Wet Macular Degeneration/drug therapy
Chemical Substances	Organic Chemicals ; Receptors, Immunologic ; Receptors, Peptide ; Vascular Endothelial Growth Factor A ; arginyl-glycyl-aspartic acid directed cell adhesion receptor ; integrin receptor antagonist THR-687
Language	English
Publishing date	2018-11-22
Publishing country	England
Document type	Journal Article
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2018.11.022
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Article ; Online: Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema.

Teufel, Daniel P / Bennett, Gavin / Harrison, Helen / van Rietschoten, Katerine / Pavan, Silvia / Stace, Catherine / Le Floch, François / Van Bergen, Tine / Vermassen, Elke / Barbeaux, Philippe / Hu, Tjing-Tjing / Feyen, Jean H M / Vanhove, Marc

Journal of medicinal chemistry

2018 Volume 61, Issue 7, Page(s) 2823–2836

Abstract: Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma ... ...

Abstract	Plasma kallikrein, a member of the kallikrein-kinin system, catalyzes the release of the bioactive peptide bradykinin, which induces inflammation, vasodilation, vessel permeability, and pain. Preclinical evidence implicates the activity of plasma kallikrein in diabetic retinopathy, which is a leading cause of visual loss in patients suffering from diabetes mellitus. Employing a technology based on phage-display combined with chemical cyclization, we have identified highly selective bicyclic peptide inhibitors with nano- and picomolar potencies toward plasma kallikrein. Stability in biological matrices was either intrinsic to the peptide or engineered via the introduction of non-natural amino acids and nonpeptidic bonds. The peptides prevented bradykinin release in vitro, and in vivo efficacy was demonstrated in both a rat paw edema model and in rodent models of diabetes-induced retinal permeability. With a highly extended half-life of ∼40 h in rabbit eyes following intravitreal administration, the bicyclic peptides are promising novel agents for the treatment of diabetic retinopathy and diabetic macular edema.
MeSH term(s)	Animals ; Bradykinin/metabolism ; Bridged Bicyclo Compounds/chemical synthesis ; Bridged Bicyclo Compounds/pharmacology ; Diabetes Complications/drug therapy ; Diabetic Retinopathy/drug therapy ; Edema/drug therapy ; Eye/metabolism ; Foot/pathology ; Half-Life ; Intravitreal Injections ; Macular Edema/drug therapy ; Macular Edema/etiology ; Male ; Mice ; Mice, Inbred C57BL ; Permeability ; Plasma Kallikrein/antagonists & inhibitors ; Protease Inhibitors/administration & dosage ; Protease Inhibitors/chemical synthesis ; Protease Inhibitors/pharmacology ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Substrate Specificity ; Vitreous Body/chemistry ; Vitreous Body/metabolism
Chemical Substances	Bridged Bicyclo Compounds ; Protease Inhibitors ; Plasma Kallikrein (EC 3.4.21.34) ; Bradykinin (S8TIM42R2W)
Language	English
Publishing date	2018-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.7b01625
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Article: The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons.

Fontayne, Alexandre / Meiring, Muriel / Lamprecht, Seb / Roodt, Jan / Demarsin, Eddy / Barbeaux, Philippe / Deckmyn, Hans

Thrombosis and haemostasis

2008 Volume 100, Issue 4, Page(s) 670–677

Abstract: The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibalpha and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding ...

Abstract	The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibalpha and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding or thrombocytopenia. Recently, we developed a fully recombinant and humanized version of 6B4-Fab-fragment, h6B4-Fab, which maintains its inhibitory capacities in vitro and ex vivo after injection in baboons. We here investigated the antithrombotic properties, the effect on bleeding time and blood loss and initial pharmacokinetics of h6B4-Fab in baboons. The antithrombotic effect of h6B4-Fab on acute platelet-mediated thrombosis was studied in baboons where thrombus formation is induced at an injured and stenosed site of the femoral artery, allowing for cyclic flow reductions (CFRs) which are measured on an extracorporeal femoral arteriovenous shunt. Injection of 0.5 mg/kg h6B4-Fab significantly reduced the CFRs by 80%, whereas two extra injections, resulting in cumulative doses of 1.5 and 2.5 mg/kg, completely inhibited the CFRs. Platelet receptor occupancy, plasma concentrations and effects ex vivo were consistent with what was previously observed. Finally, minimal effects on bleeding time and blood loss, no spontaneous bleeding and no thrombocytopenia were observed. We therefore conclude that h6B4-Fab maintains the antithrombotic capacities of the murine 6B4-Fab, without causing side effects and therefore can be used for further development.
MeSH term(s)	Acute Disease ; Animals ; Anti-Bacterial Agents/pharmacology ; Bleeding Time ; Blood Platelets/immunology ; Constriction, Pathologic ; Disease Models, Animal ; Femoral Artery/injuries ; Femoral Artery/pathology ; Hemorrhage/chemically induced ; Hemorrhage/immunology ; Humans ; Immunoglobulin Fab Fragments/adverse effects ; Immunoglobulin Fab Fragments/immunology ; Mice ; Papio ; Platelet Adhesiveness/drug effects ; Platelet Adhesiveness/immunology ; Platelet Count ; Platelet Glycoprotein GPIb-IX Complex/adverse effects ; Platelet Glycoprotein GPIb-IX Complex/immunology ; Regional Blood Flow ; Ristocetin/pharmacology ; Stress, Mechanical ; Thrombocytopenia/chemically induced ; Thrombocytopenia/immunology ; Thrombosis/drug therapy ; Thrombosis/immunology ; Thrombosis/physiopathology
Chemical Substances	Anti-Bacterial Agents ; Immunoglobulin Fab Fragments ; Platelet Glycoprotein GPIb-IX Complex ; Ristocetin (1404-55-3)
Language	English
Publishing date	2008-10
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	518294-3
ISSN	0340-6245
ISSN	0340-6245
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Uh III Zs.192: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article: The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons

Fontayne, Alexandre / Meiring, Muriel / Lamprecht, Seb / Roodt, Jan / Demarsin, Eddy / Barbeaux, Philippe / Deckmyn, Hans

Thrombosis and Haemostasis

2008 Volume 99, Issue 04, Page(s) 670–677

Abstract: The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibα and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding or ... ...

Abstract	The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibα and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding or thrombocytopenia. Recently, we developed a fully recombinant and humanized version of 6B4-Fab-fragment, h6B4-Fab, which maintains its inhibitory capacities in vitro and ex vivo after injection in baboons. We here investigated the antithrombotic properties, the effect on bleeding time and blood loss and initial pharmacokinetics of h6B4-Fab in baboons. The antithrombotic effect of h6B4-Fab on acute platelet-mediated thrombosis was studied in baboons where thrombus formation is induced at an injured and stenosed site of the femoral artery, allowing for cyclic flow reductions (CFRs) which are measured on an extracorporeal femoral arteriovenous shunt. Injection of 0.5 mg/kg h6B4-Fab significantly reduced the CFRs by 80%, whereas two extra injections, resulting in cumulative doses of 1.5 and 2.5 mg/kg, completely inhibited the CFRs. Platelet receptor occupancy, plasma concentrations and effects ex vivo were consistent with what was previously observed. Finally, minimal effects on bleeding time and blood loss, no spontaneous bleeding and no thrombocytopenia were observed. We therefore conclude that h6B4-Fab maintains the antithrombotic capacities of the murine 6B4-Fab, without causing side effects and therefore can be used for further development.
Keywords	Antithrombotic ; glycoprotein Ib ; humanized antibody ; platelet adhesion ; thrombosis
Language	English
Publishing date	2008-01-01
Publisher	Schattauer GmbH
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1160/TH08-02-0073
Database	Thieme publisher's database

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Article: Humanization by variable domain resurfacing and grafting on a human IgG4, using a new approach for determination of non-human like surface accessible framework residues based on homology modelling of variable domains.

Staelens, Stephanie / Desmet, Johan / Ngo, Thu Hoa / Vauterin, Stephan / Pareyn, Inge / Barbeaux, Philippe / Van Rompaey, Isabel / Stassen, Jean-Marie / Deckmyn, Hans / Vanhoorelbeke, Karen

Molecular immunology

2006 Volume 43, Issue 8, Page(s) 1243–1257

Abstract: Many antithrombotic agents have only a small therapeutic window, frequently leading to bleeding problems. However, interfering with platelet adhesion through the collagen-VWF-GPIbalpha axis is expected to cause less bleeding problems. Our group developed ...

Abstract	Many antithrombotic agents have only a small therapeutic window, frequently leading to bleeding problems. However, interfering with platelet adhesion through the collagen-VWF-GPIbalpha axis is expected to cause less bleeding problems. Our group developed a monoclonal antibody, 82D6A3, directed against the von Willebrand factor (VWF) A3-domain, which inhibits the VWF-interaction to fibrillar collagen. 82D6A3 has antithrombotic effects in vivo without bleeding time prolongation. To further investigate the promising features of 82D6A3, we have humanized it by variable domain resurfacing and grafting on the constant regions of a human IgG4. First, the sequence of the variable domains was determined and the murine scFv was constructed. The expressed scFv had a comparable activity as the IgG of 82D6A3, and its DNA was thus used in subsequent humanization procedures. For this, a new approach was introduced to identify non-human like framework surface residues, since the general distribution of accessible residues described for human and murine heavy and light chain variable domains showed several discrepancies with the homology modelled Fv of 82D6A3. Identification of non-human like framework residues and evaluation of their surface accessibility within the context of the homology modelled Fv of 82D6A3, revealed 10 residues that need to be humanized without influencing the conformation of the CDR loops. Indeed, the humanized scFv of 82D6A3, obtained by mutating all 10 residues to their human counterpart, was still binding with high affinity to VWF and retained the inhibitory properties of the murine scFv. Next, in order to increase its half life and to decrease its immunogenicity, the humanized variable domains were grafted on the constant regions of a human IgG4, resulting in h82D6A3 with an in vitro activity comparable to that of the murine IgG.
MeSH term(s)	Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/metabolism ; Base Sequence ; Binding Sites, Antibody ; CHO Cells ; Collagen/metabolism ; Cricetinae ; Cricetulus ; Humans ; Immunoglobulin G/chemistry ; Immunoglobulin G/genetics ; Immunoglobulin G/metabolism ; Immunoglobulin Variable Region/chemistry ; Immunoglobulin Variable Region/genetics ; Immunoglobulin Variable Region/metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism ; Sequence Homology, Amino Acid ; von Willebrand Factor/metabolism
Chemical Substances	Antibodies, Monoclonal ; Immunoglobulin G ; Immunoglobulin Variable Region ; Recombinant Fusion Proteins ; von Willebrand Factor ; Collagen (9007-34-5)
Language	English
Publishing date	2006-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2005.07.018
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Article ; Online: Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149.

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Article: Assessment of Ocriplasmin Effects on the Vitreoretinal Compartment in Porcine and Human Model Systems.

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Article ; Online: The potent small molecule integrin antagonist THR-687 is a promising next-generation therapy for retinal vascular disorders.

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Article ; Online: Stable and Long-Lasting, Novel Bicyclic Peptide Plasma Kallikrein Inhibitors for the Treatment of Diabetic Macular Edema.

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Article: The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons.

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Article: The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons

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Article: Humanization by variable domain resurfacing and grafting on a human IgG4, using a new approach for determination of non-human like surface accessible framework residues based on homology modelling of variable domains.

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