WO2010039690A1 - Method of inhibiting biomaterial-induced procoagulant activity using complement inhibitors - Google Patents
Method of inhibiting biomaterial-induced procoagulant activity using complement inhibitors Download PDFInfo
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- WO2010039690A1 WO2010039690A1 PCT/US2009/058745 US2009058745W WO2010039690A1 WO 2010039690 A1 WO2010039690 A1 WO 2010039690A1 US 2009058745 W US2009058745 W US 2009058745W WO 2010039690 A1 WO2010039690 A1 WO 2010039690A1
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions
- This invention relates to the field of extracorporeal treatment of blood, such as hemodialysis.
- Methods for reducing or eliminating biomaterial-induced procoagulant activity in blood subjected to extracorporeal treatment that exposes the blood to the biomaterial are provided.
- the methods involve treatment of the blood, or the extracorporeal biomaterial, or both, with a complement inhibitor to inhibit C5a/C5aR-mediated tissue factor formation in the blood.
- thrombootic cardiovascular complications represent the leading cause of death among patients with end-stage renal disease (ESRD) and account for more than half of death in such patients.
- ESRD end-stage renal disease
- the well-documented high mortality rate in ESRD is especially prominent in patients on dialysis. Since the cardiovascular death rate in dialysis patients is unaccepted high (almost 40-fold higher than in the general population), great scientific interest has gathered on this topic and intense efforts aim in attenuating this phenomenon.
- vascular-access thrombotic events in hemodialysis patients constitute a major morbidity cause.
- spectacular achievements have been accomplished in reducing cardiovascular death and thrombotic events in the general population through better control of traditional risk factors, no such trend has been detected for patients with ESRD and results are far from optimal.
- Inflammation and thrombosis are linked in certain clinical models. Biomaterials are known inflammatory agonists and induce leukocytes and complement activation [15-19]. Neutrophils and complement are key mediators of innate immunity and play a pivotal role in the inflammatory response to various stimuli [20]. Thus, chronic hemodialysis in ESRD patients is considered as a major contributor for atherosclerosis through chronic inflammatory activation [21 f 22]. In addition, TF extrinsic pathway plays the main in vivo role for coagulation triggering [23]. However, the mechanisms of TF regulation in coagulant process in such patients remain elusive. Different inflammatory agonists are responsible for TF induction in monocytes and activated endothelial cells. Recently it has been reported that neutrophils are able to produce functional TF through C5a/C5aR, thus suggesting that this novel pathway may be implicated in different clinical models [24].
- One aspect of the invention provides a method for reducing or eliminating biomaterial- induced procoagulant activity in blood subjected to extracorporeal treatment that exposes the blood to the biomaterial.
- the method comprises treating the blood, or the biomaterial, or both, with a complement inhibitor in an amount effective to reduce or prevent C5a/C5aR-mediated tissue factor (TF) formation, thereby reducing or eliminating the biomaterial-induced procoagulant activity in the blood.
- TF tissue factor
- Any inhibitor of the complement cascade leading to the formation or activity of C5a or the C5a receptor (C5aR) can be used in the method.
- the complement inhibitor comprises one or more of a C 5a inhibitor, a C5aR inhibitor, a C3 inhibitor, a factor D inhibitor, a factor B inhibitor, a C4 inhibitor, a CIq inhibitor, or any combination thereof.
- suitable C5a inhibitors or C5aR inhibitors include but are not limited to acetyl-Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg] (PMX-53), PMX-53 analogs, neutrazumab, TNX-558, eculizumab, pexelizumab or AR.C1905, or any combination thereof.
- Suitable C3 inhibitors include but are not limited to is compstatin, a compstatin analog, a compstatin peptidomimetic, a compstatin derivative, or any combinations thereof,
- the extracorporeal treatment of blood comprises hemodialysis, and the biomaterial comprises hemodialysis filter fibers.
- This embodiment is suitable for treatment of individuals suffering from renal disease, particularly end stage renal disease (ESDR).
- ESDR end stage renal disease
- the blood can be contacted with the complement inhibitor prior to and/or during the extracorporeal treatment.
- the biomaterial can contacted with the complement inhibitor prior to its use in the extracorporeal treatment. Such prior contacting can be performed immediately prior to use, or at some period of time prior to use, within the stability and activity parameters of the selected complement inhibitor(s).
- the complement inhibitor treatment is used together or concurrently with, or sequentially before or after, at least one other anti-coagulant or antiinflammatory treatment of the blood or of the individual.
- kits, or article of manufacture comprising a complement inhibitor and a biomaterial for use in an extracorporeal treatment device, and, optionally, instructions for using the complement inhibitor in a method such as the one described above.
- the biomaterial comprises a hemodialysis filtration material.
- Another aspect of the invention features an extracorporeal treatment device that includes a complement inhibitor-treated biomaterial, or a biomaterial adapted for or amenable to treatment with a complement inhibitor.
- the device is a hemodialysis unit.
- Figure 1 TF - dependent procoagulant properties of ESRD serum.
- A The supernatants from PMNs incubated with predialysis serum (bar 3) showed higher procoagulant activity than unstimulated neutrophils (UN: bar 1) as well as cells incubated with sera of healthy subjects (HI: bar 2).
- Figure 2 TF expression in ESRD peripheral leukocytes at both mRNA and protein levels.
- TF appears to be elevated even at predialysis status (bar 2) compared to healthy control (HI: bar 1).
- PMN isotype control is shown as shaded gray, and the remaining peaks from left to right are: PMN HI, PMN ESRD 120 min, PMN ESRD predialysis and PMN ESRD 30 min.
- C Western blot analysis (representative data from 4 experiments) detected a pattern of TF expression similar to that of the flow cytometry data (lysates from neutrophils incubated with serum at predialysis status (ii), taken at 30 (iii) and 120 min (iv) of hemodialysis). Lysates from blood cells incubated with PBS were used as a negative control (i).
- FIG. 3 Complement activation in hemodialysis ESRD plasma.
- TCC levels in plasma collected from ESRD patients at different lime points of hemodialysis were measured using ELISA. TCC increased during the hemodialysis procedure; bar 2, 3, 4. These data were in concordance with the procoagulant activity differences observed in ESRD patients sera over the same time course.
- FIG. 5 Hemodialysis filter fibers induce in vitro TF dependent procoagulant properties in both ESRD and healthy serum through complement activation.
- A 300ul of plasma was incubated with 15 mg fibers in glass vials for different time intervals in the presence of different concentration of 4(1MeW) compstatin or inactive linear compstatin. C3b generation was detected by ELISA. CVF-activated plasma was used as a standard for 100% complement activation. The percentage of complement activation is depicted in the diagram.
- B Serum from healthy donors was preincubated with hollow fibers from polysulfone hemodialysis filters at different time periods (10, 30, 60 & 120 min).
- FIG. 6 Protein analysis confirms complement's role in TF expression by healthy PMNs in vitro. Cultured PMNs with activated or blocked healthy serum were analysed for TF antigen presence. A: MFI fold expression revealed an increase of intracellular TF protein expression (bar 2), while Compstatin promoted the inhibition of the effect (bar 3). B: Western blot analysis results come in par with those of flow cytometry (neutrophils incubated with: untreated serum (V), treated with filter fibers (IV) and serum blocked with Compstatin (III); extracts from PMNs incubated with PBS (I) and APS serum (II) were used as negative and positive controls, respectively (representative data from four independent experiments).
- FIG. 7 Complement activation during hemodialysis simulation is reduced or prevented by a compstatin analog. Analysis of complement activation in plasma samples collected at several time points during simulation of hemodialysis procedure in blood treated with 40 uM of compstatin analog [4MeW] or an inactive analog.
- C Detection of coagulation cascade activation by flow cytometry after intracellular staining of blood neutrophils for tissue factor (TF).
- TF tissue factor
- Standard techniques are used for nucleic acid and peptide synthesis.
- the techniques and procedures are generally performed according to conventional methods in the art and various general references (e.g.,, Sambrook and Russell, 2001, Molecular Cloning, A Laboratory Approach, Cold Spring Harbor Press, Cold Spring Harbor, NY, and Ausubel et al., 2002, Current Protocols in Molecular Biology, John Wiley & Sons, NY), which are provided throughout this document.
- an element means one element or more than one element.
- antibody refers to an immunoglobulin molecule which is able to specifically bind to a specific epitope on an antigen.
- Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins.
- the antibodies useful in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, intracellular antibodies (“intrabodies”), Fv, Fab and F(ab) 2 , as well as single chain antibodies (scFv), camelid antibodies and humanized antibodies (Harlow et al., 1999, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. ScL USA 85:5879-5883; Bird et al, 1988, Science 242:423-426).
- complement inhibitor is a molecule that prevents or reduces activation and/or propagation of the complement cascade that results in the formation of C5a or signaling through the C5a receptor.
- a complement inhibitor can operate on one or more of the complement pathways, i.e., classical, alternative or lectin pathway.
- C3 inhibitor is a molecule or substance that prevents or reduces the cleavage of C3 into C3a and C3b.
- C5a inhibitor is a molecule or substance that prevents or reduces the activity of C5a.
- C5aR inhibitor is a molecule or substance that prevents or reduces the binding of C5a to the C5a receptor.
- C3aR inhibitor is a molecule or substance that prevents or reduces binding of C3a to the C3a receptor.
- a "factor D inhibitor” is a molecule or substance that prevents or reduces the activity of Factor D.
- factor B inhibitor is a molecule or substance that prevents or reduces the activity of factor B.
- C4 inhibitor is a molecule or substance that prevents or reduces the cleavage of C4 into C4b and C4a.
- CIq inhibitor is a molecule or substance that prevents or reduces CIq binding to antibody-antigen complexes, virions, infected cells, or other molecules to which CIq binds to initiate complement activation.
- inhibitors described herein may comprise antibodies or antibody fragments, as would be understood by the person of skill in the art.
- Treating refers to any indicia of success in the treatment or amelioration of the disease or condition. Treating can include, for example, reducing or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. “Treating” can also refer to reducing or eliminating a condition of a part of the body, such as a cell, tissue or bodily fluid, e.g., blood. "Preventing” refers to the partial or complete prevention of the disease or condition in an individual or in a population, or in a part of the body, such as a cell, tissue or bodily fluid (e.g., blood). The term “prevention” does not establish a requirement for complete prevention of a disease or condition in the entirety of the treated population of individuals or cells, tissues or fluids of individuals.
- treat or prevent is sometimes used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and contemplates a range of results directed to that end, including but not restricted to prevention of the condition entirely.
- a “prophylactic” treatment is a treatment administered to a subject (or sample) who does not exhibit signs of a disease or condition, or exhibits only early signs of the disease or condition, for the purpose of decreasing the risk of developing pathology associated with the disease or condition.
- This term may be used interchangeably with the term “preventing,” again with the understanding that such prophylactic treatment or “prevention” does not establish a requirement for complete prevention of a disease in the entirety of the treated population of individuals or tissues, cells or bodily fluids.
- a “therapeutically effective amount” or simply an “effective amount” is the amount of a composition sufficient to provide a beneficial effect to the individual to whom the composition is administered, or who is otherwise treated using a method involving the composition.
- extracorporeal treatment refers generally to treatment or manipulation of cells, tissues or bodily fluids that have been removed from an individual and are thereafter returned to the same individual or to another individual.
- extracorporeal treatments include, but are not limited to, extracorporeal shunting of blood during surgical procedures, for example, hemodialysis, and cell or tissue transplantation, to name a few.
- biomaterials refers to components of equipment, devices or articles that come into contact with, and particularly that perform a function in connection with, the cells, tissues or biological fluids being subjected to the extracorporeal treatment.
- a biomaterial is the filter material in a hemodialysis unit.
- Cardiovascular and/or vascular-access thrombotic events are very prominent in ESRD patients, especially those on dialysis. Although several mechanisms have been proposed, no substantial progress in reducing morbidity and mortality has been accomplished. Biomaterials used in hemodialysis are known complement activators, and previous studies reported a link between complement - neutrophil crosstalk and thrombosis through Tissue Factor (TF) pathway in patients with antiphospho lipid syndrome [24].
- TF Tissue Factor
- TF-dependent procoagulant activity of supernatants was observed, which was inhibited by specific anti-TF mAb.
- ex vivo ability of ESRD serum to induce TF was associated with TF expression in RNA and protein levels from patient leukocytes.
- This TF induction from patient serum was shown to be complement dependent, in particular C5a mediated, as it was demonstrated in ELISA analysis and complement blockade studies using the complement inhibitor compstatin and a selective C5a-Receptor antagonist.
- hemodialysis-ESRD patients have identified hemodialysis-ESRD patients as a clinical disorder where the C5aR/blood leukocytes crosstalk is strongly implicated with subsequent TF pathway triggering. This pathway functions as an additional inducer of thrombotic events, and thus indicates novel therapeutic targets and interventions, as described below.
- extracorporeal treatment of blood during hemodialysis reduces or prevents complement activation, as evidenced by several factors, including TF production in neutrophils.
- one aspect of the present invention features a method for reducing or eliminating biomaterial-induced procoagulant activity in blood subjected to extracorporeal treatment that exposes the blood to the biomaterial.
- the method comprises treating the blood, or the biomaterial, or both, with a complement inhibitor in an amount effective to reduce or prevent C5a/C5aR-mediated tissue factor (TF) formation, thereby reducing or eliminating the biomaterial-induced procoagulant activity in the blood.
- TF C5a/C5aR-mediated tissue factor
- the method is particularly applicable to hemodialysis the treatment of hemodialysis filter fibers, for the treatment of individuals suffering from renal disease, particularly end stage renal disease (ESDR).
- ESDR end stage renal disease
- a complement inhibitor is a molecule that prevents or reduces activation and/or propagation of the complement cascade that results in the formation of C5a or signaling through the C5a receptor, also referred to herein as "C5a activity".
- a complement inhibitor can operate on one or more of the complement pathways, i.e., classical, alternative or lectin pathway.
- C5a formation or activity may be used in the method of the invention. Inhibition of C5a formation or activity may be accomplished in a variety of ways. For instance, C5a activity may be inhibited directly by preventing or significantly reducing the binding of C5a to its receptor, C5aR.
- C5aR inhibitors are known in the art. Acetyl-Phe ⁇ [Orn-Pro- D-cyclohexylalanine-Trp-ArgJ (AcF [OPdCha WR]; PMX-53; Peptech) is a small cyclic hexapeptide that is a C5aR antagonist and is exemplified herein.
- C5a activity may also be inhibited by reducing or preventing the formation of C5a.
- inhibition of any step in the complement cascade which contributes to the downstream formation of C5a is expected to be effective in practicing the invention.
- Formation of C5a may be inhibited directly by inhibiting the cleavage of C5 by C5-convertase.
- Eculizumab Alexion Pharmaceuticals, Cheshire, CT
- Pexelizumab an scFv fragment of Eculizumab, has the same activity.
- ARC 1905 an anti ⁇ C5 aptamer, binds to and inhibits cleavage of C5, inhibiting the generation of C5b and C5a.
- formation of C5a is reduced or prevented through the use of a C3 inhibitor.
- the C3 inhibitor is compstatin or a compstatin analog, derivative, aptamer or peptidomimetic.
- Compstatin is a small molecular weight disulfide bonded cyclic peptide having the sequence lie- Cys-Val-Val-Gln-Asp-Trp ⁇ Gly-His-His-Arg-Cys ⁇ Thr (SEQ ID NO. 1). Examples of compstatin analogs, derivatives and peptidomimetics are described in the art. See, for instance, U.S. Pat. No.
- An exemplary compstatin analog comprises a peptide having a sequence: Xaal - Cys - VaI - Xaa2 - GIn - Asp - Trp - GIy - Xaa3 - His - Arg - Cys - Xaa4 (SEQ ID NO. 2); wherein:
- Xaal is He, VaI, Leu, Ac-He, Ac-VaI, Ac-Leu or a dipeptide comprising Gly-Ile;
- Xaa2 is Trp or a peptidic or non-peptidic analog of Trp
- Xaa3 is His, Ala, Phe or Trp;
- Xaa4 is L-Thr, D-Thr, lie, VaI, GIy, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal -OH of any of the L-Thr, D-Thr, He, VaI, GIy or Asn optionally is replaced by -NH 2 ; and the two Cys residues are joined by a disulfide bond.
- Xaal may be acetylated, for instance, Ac-He.
- Xaa2 may be a Trp analog comprising a substituted or unsubstituted aromatic ring component.
- Non-limiting examples include 2-napthylalanine, 1 -naphthylalanine, 2- indanylglycine carboxylic acid, dihydrotryptophan or benzoylphenylalanine.
- Another exemplary compstatin analog comprises a peptide having a sequence: Xaal - Cys - VaI - Xaa2 - GIn - Asp - Xaa3 - GIy - Xaa4 - His - Arg - Cys - Xaa5 (SEQ ID NO, 3); wherein:
- Xaal is He, VaI 5 Leu, Ac-He, Ac-VaI, Ac-Leu or a dipeptide comprising Gly-Ile;
- Xaa2 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp, with the proviso that, if Xaa3 is Trp, Xaa2 is the analog of Trp;
- Xaa3 is Trp or an analog of Trp comprising a chemical modification to its indole ring wherein the chemical modification increases the hydrogen bond potential of the indole ring;
- Xaa4 is His, Ala, Phe or Trp
- Xaa5 is L-Thr, D-Thr, He, VaI, GIy, a dipeptide comprising Thr-Asn or Thr-Ala, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal -OH of any of the L-Thr, D-Thr, lie, VaI, GIy or Asn optionally is replaced by -NH 2 ; and the two Cys residues are joined by a disulfide bond.
- the analog of Trp of Xaa2 may be a halogenated trpytophan, such as 5-fluoro-l- tryptophan or 6-fluoro-l-tryptophan.
- the Trp analog at Xaa2 may comprise a lower alkoxy or lower alkyl substituent at the 5 position, e.g., 5-methoxytryptophan or 5-methyltryptophan.
- the Trp analog at Xaa 2 comprises a lower alkyl or a lower alkenoyl substituent at the 1 position, with exemplary embodiments comprising 1 -methyl tryptophan or 1- formyltryptophan.
- the analog of Trp of Xaa3 is a halogenated tryptophan such as 5-fluoro-l-tryptophan or 6-fluoro-l-tryptophan.
- C3 inhibitors include vaccinia virus complement control protein (VCP) and antibodies that specifically bind C3 and prevent its cleavage.
- VCP vaccinia virus complement control protein
- Anti-C3 antibodies useful in the present invention can be made by the skilled artisan using methods known in the art. See, for instance, Harlow, et al. (1988, In: Antibodies, A Laboratory Manual, Cold Spring Harbor, NY), Tuszynski et al (1988, Blood, 72:109-1 15), U.S. patent publication 2003/0224490, Queen et al. (U.S. Patent No. 6, 180,370), Wright et al, (1992, Critical Rev.
- C3 antibodies are also commercially available.
- Other C3 inhibitors include C3-binding and complement inhibitory secreted S. aureus extracellular fibrinogen- binding protein Efb (Lee et al, 2004, J Biol Chem. 279: 50710-50716) and the Efb homologous protein, Ehp (Hammel et al, 2007, J Biol Chem. 282: 30051-30061).
- formation of C3a or C5a is reduced or prevented through the use of an inhibitor of complement activation prior C3 cleavage, e.g., in the classical or lectin pathways of complement activation.
- inhibitors include, but are not limited to: (1) factor D inhibitors such as diisopropyl fluorophosphates and TNX-234 (Tanox), (2) factor B inhibitors such as the anti-B antibody TA 106 (Taligen Therapeutics), (3) C4 inhibitors (e.g., anti-C4 antibodies) and (4) CIq inhibitors (e.g., anti-Clq antibodies).
- Antibodies useful in the present invention such as antibodies that specifically bind to either C4, C3 or C5 and prevent cleavage, or antibodies that specifically bind to factor D, factor B, CIq, or the C3a or C5a receptor, can be made by the skilled artisan using methods known in the art. See, for instance, Harlow, et al. (1988, In: Antibodies, A Laboratory Manual, Cold Spring Harbor, NY), Tuszynski et al. (1988, Blood, 72:109-115), U.S. patent publication 2003/0224490, Queen et al. (U.S. Patent No. 6, 180,37O) 5 Wright et al., (1992, Critical Rev. in Immunol.
- Anti-C3 and anti-C5 antibodies are also commercially available.
- compositions comprising a complement inhibitor to practice the methods of the invention.
- a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
- the active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
- compositions described herein may be prepared by any method known or hereafter develop in the art of pharmacology.
- preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-or multi-does unit.
- the term "pharmaceutically-acceptable carrier” means a chemical composition with which a complement inhibitor may be combined and which, following the combination, can be used to administer the complement inhibitor to a mammal.
- physiologically acceptable ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
- compositions useful for practicing the invention are used to treat or contact either the blood or the biomaterial, or both, prior to, during and/or after the extracorporeal treatment.
- concentration of active ingredient for such use may range broadly. While the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of patient, the type or severity of the condition, the age of the patient and the route of administration.
- the dosage of the compound will vary from about 1 mg to about 1O g per kilogram of body weight of the patient. More preferably, the dosage will vary from about 10 mg to about 1 g per kilogram of body weight of the patient. Higher concentrations of active ingredient may be beneficial for application to the biomaterial, as dilution will occur as the blood contacts the biomaterial.
- a single complement inhibitor may be administered or applied, or two or more different complement inhibitors may be administered or applied in the practice of the method of the invention.
- the method comprises administration of only a complement inhibitor or a combination of complement inhibitors.
- other biologically active agents are administered in addition to the complement inhibitor(s) in the method of the invention.
- Non-limiting examples of other biologically active agents useful in the invention include anticoagulants antithrombotics and anti-inflammatory agents, as would be known and appreciated by the skilled artisan.
- the complement inhibitor is used to treat blood just prior to, or during the extracorporeal treatment, or it is used to treat the biomaterial used in the extracorporeal treatment.
- An alternative or supplementary treatment can involve administering a complement inhibitor to an individual, alone or combined with other anti-coagulants or antiinflammatory agents before or after the extracorporeal treatment.
- compositions that are useful in the aforementioned embodiment may be administered systemically in oral solid formulations, parenteral, intravenous, ophthalmic, suppository, aerosol, topical or other similar formulations.
- Such pharmaceutical compositions may contain pharmaceutically-acceptable carriers and other ingredients known to enhance and facilitate drug administration.
- Other formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer a complement inhibitor according to the methods of the invention.
- parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
- Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
- parenteral administration is contemplated to include, but is not limited to, intravenous, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
- Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
- the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
- a suitable vehicle e.g. sterile pyrogen-free water
- compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
- This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
- Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example.
- Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
- compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
- additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; binding agents; lubricating agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibacterial agents; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
- compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, which is incorporated herein by reference.
- This example describes an investigation into whether hemodialysis biomaterials lead blood leukocytes to express functional TF through complement activation.
- C5a-C5aR/neutrophils cross-talk plays a role in TF pathway activity in hemodialysis - ESRD patients, thereby clarifying a potent mechanism implicated in their thrombotic manifestations.
- ESRD serum and plasma preparation Serum samples were drawn from the afferent line immediately before hemodialysis and at specific time points during hemodialysis. All samples were collected in polypropylene tubes without anticoagulant or clot activator. Furthermore, EDTA-treated tubes were used for plasma isolation since they do not interfere with complement activation. Both serum and plasma were isolated after centrifugation at 1.400 g for 15 min at room temperature.
- Complement and anaphylatoxin inhibition studies I) Compstatin., a 13-residue cyclic peptide (Ac-I [CVWQDWGAHRTC]TNH 2 ) that inhibits the cleavage of native C3 by the C3 convertase, was used as a specific inhibitor of complement activation at the C3 level. In certain studies, a compstatin analog (1 -methyl tryptophan as the 4th residue) was used. A linear inactive analogue of compstatin (IAVWQDWGAHRTAT-NH 2 ) was used as a control [26].
- SB- 290152 a selective nonpeptide antagonist of the complement anaphylatoxin receptor C3aR, was used in this study to dissect the involvement of C3aR signalling in the generation of neutrophil derived TF [27].
- a small cyclic hexapeptide (AcF- [OP dCha WR]) that acts as a selective C5aR antagonist [28, 29] was used. Sera were pre- incubated for 30 min with Compstatin or its linear analogue (15 ⁇ M final concentration), before incubation with leukocytes.
- Modified prothrombin time (mPT) assay to examine TF mediated coagulation activity in cell supernatants, complement inhibition and anaphylatoxin receptor studies. Since it has been shown previously that TF dependent procoagulant activity in leukocyte culture supernatants is altered after C5a/C5aR stimulation or blockade [30], the mPT method was used in order to estimate primarily the kinetics of TF induction. The presence of TF in supernatants is probably due to the presence of the soluble, spliced TF isoform [31] or TF microparticles.
- coagulation activity properties (TF/FVIIa binding activity) of the cell supernatants were determined using a modified prothrombin time (mPT) assay. Briefly, after performing the "classic" PT test (100 ⁇ l platelet poor plasma [PPP] plus 200 ⁇ l thromboplastin ISI 1.7 (Instrumentation Laboratory, Milan, Italy), the modified PT analysis was carried out. Namely, 125 ⁇ l of cell supernatant and 75 ⁇ l thromboplastin were added to 100 ⁇ l of PPP to measure the changes of PT. As control of mPT, 125 ⁇ l of PBS was used instead of cell supernatant and the in vitro clotting time usually ranged from 31 to 34 sec.
- mPT modified prothrombin time
- thromboplastic activity was due to TF alone, supernatants were incubated for 30 min with a specific neutralizing anti-TF monoclonal antibody (mAb, No 4509, American Diagnostica, Greenwich, Ct., USA), 10 ⁇ g/ml, at room temperature. PT was then measured by the mPT method. Non-specific controls involved incubation with the same subclass and concentration of mouse anti-human antibodies, as well as with different secondary antibodies.
- mAb neutralizing anti-TF monoclonal antibody
- RNA extraction, RT & relative quantitative real-time PCR analysis Total RNA was isolated from double-gradient purified peripheral blood PMNs and PBMCs using the TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to manufacturer's instructions. cDNA was synthesized from l ⁇ g of isolated RNA using Superscript III reverse transcriptase (Invitrogen, Carlsbad, CA, USA).
- 'TF' full-length TF
- asTF alternative spliced TF
- membranes were electroblotted onto methanol treated PVDF membranes (BioRad, CA) and blocked in 5% non-fat dry milk in TBS containing 0.1% Tween 20 (TBS-T) for Ih at RT.
- Membranes were incubated with anti-TF polyclonal antibody (4501, American Diagnostica Inc, Stamford, CT) for 3h or with G3PDH polyclonal antibody (2275, R&D Systems Inc.), in order to confirm equal loading, 2h at RT in dilutions of 1/1000 and 1/5000, respectively.
- HRP Horseradish peroxidase
- HAF 109 whole anti-goat
- HAF008, R&D Systems Inc anti-rabbit antibodies
- ECL enhanced chemiluminescence
- peripheral blood PMNs and mononuclear cells from healthy volunteers (N 4) were separately incubated with 50 ⁇ l of serum (1/5 of final volume) from 6 ESRD patients collected during several time points of hemodialysis (immediately before hemodialysis and after lrnin, 15 min, 30min, 60min, 120min, and 240min).
- the mean "classic" PT was 12.76 1 0.17 sec at baseline, while the mean baseline modified PT (mPT) was 33.34 1 O ⁇ o sec.
- Complement is activated during hemodialysis course in ESRD patients.
- hemodialysis biomaterials induce complement activation and considering the previously observed complement - leukocyte crosstalk with subsequent TF expression [24, 30], a time point analysis of complement activation during the hemodialysis procedure was conducted.
- TCC levels at predialysis status were slightly elevated (Figure 3 - bar 2) compared to healthy controls ( Figure 3- bar 1), but at less than statistical significance.
- Plasma samples taken within the first hour of hemodialysis denoted elevated levels of TCC ( Figure 3 - bars 3, 4), while the values of the complex were decreased at samples that were isolated after the first hour of hemodialysis procedure ( Figure 3 - bars 5, 6).
- the pattern of complement activation during the course of hemodialysis showed resembled the variations of procoagizlant activity caused by the ESRD sera as shown in Figure 1, probably underlining a link between complement and the coagulation cascade in ESRD patients' blood leukocytes.
- TF dependent procoagulant activity in ESRD patients is C5a mediated and dialyzer fibers trigger the extrinsic coagulation system through C5a signaling.
- the above findings collectively indicated a homologous "bell shaped" time dependent pattern in both TF expression and complement activation during the hemodialysis course.
- thrombootic complications in hemodialysis ESRD patients represent a common and significant clinical problem. Biomaterial-induced effects on inflammation and coagulation have recently attracted wide scientific interest [18, 19]. However, clear causal mechanisms resulting in thrombotic events have not been described in these patients. Hemodialysis procedure is considered a strong inducer of inflammatory mechanisms [43]. Among various inflammatory mediators and cells involved during hemodialysis therapy, complement activation [44] and neutrophil stimulation [45-47] largely contribute in clinical manifestations of this disorder. However, a direct link between them and ESRD thrombogenicity has never been indicated. Studies in both humans and animal models indicated that TF expression by leukocytes plays an important role in thrombosis associated with a variety of diseases [48].
- the findings presented herein suggest a mechanism involving the complement activation on patient serum with subsequent induction of neutrophils and CD14 M cells through C5a/C5aR which once stimulated express functional TF.
- the observations indicating the ability of ESRD serum to induce via C5a, TF expression by healthy PBMCs and PMNs were not only restricted in in vitro experiments but were also supported by in vivo analyses indicating that ESRD patient leukocytes, during hemodialysis course, expressed TF in a similar time pattern as was observed in the in vitro experiments.
- the TF procoagulant properties of ESRD serum reach a peak at 15 to 30 min after hemodialysis and gradually decrease thereafter.
- the chronic inflammation in hemodialysis ESRD patients results in a basal prothrombotic state, as shown by the reduced mPT (caused by predialysis patient serum compared to serum of healthy controls) and TF mRNA and protein expression studies on leukocytes.
- the observed complete attenuation of coagulation activity by the specific monoclonal anti-TF antibody suggests that the predialysis prothrombotic tendency of ESRD patients is also TF-dependent.
- the use of Compstatin and C5aR antagonist indicates that complement activation induced by pulsed chronic contact to biomaterials might, at least in part, be an effector of the prothrombotic state of such patients.
- TF expression through biomaterial C5a/C5aR activation ranks the ESRD clinical model in a wider group of acquired thrombotic disorders induced by this cross-talk, such as APS [24], sepsis [63-65] and ARDS [30], thus indicating that the close interaction of complement and thrombosis might be a more universal phenomenon.
- Current therapeutic strategies have reduced the incidence of thrombotic events; however, the results achieved are far from optimal.
- the findings set forth herein, indicating biomaterial-induced procoagulant activity mediated by a chain of subsequent "domino" events, including complement activation, C5a production, neutrophils and other cells e.g.
- CD14 monocytes CD14 monocytes
- C5aR stimulation and finally TF generation provide important evidence on a novel thrombotic process that is largely unaffected by treatment strategies applied to patients with ESRD. This observation points to potential therapeutic targets of significance.
- biomaterials devoid of inducing complement activation, complement inhibition by compstatin or similar analogues, C5aR blockade by specific inhibitors and the application of selective TF inhibitors or use of TFPI are expected to be beneficial in patients with ESRD and result in reduction of thrombotic complications in such patients.
- Example! This example sets forth experimental evidence showing that hemo dialysis-induced complement activation and subsequent TF upregulation in peripheral blood leukocytes can be efficiently reduced by inhibiting complement activation.
- a protocol was devised to mimic hemodialysis procedure. Whole blood obtained from healthy donors was circulated in a hemodialysis machine, which is normally used to perform this procedure in adult patients.
- HPH Junior polysulfone dialyzers (Minntech Corporation) were used. Standard bloodline components served as tubing system (Arterial & venous blood lines, Set a/v for Fresenius 2008/4008, HMC Premedical S. p. A., Italy).
- the compstatin analog (sometimes referred to as "compstatin 4[1MeW]") was I [CV (! - Me) WQD WG AHRC] L-NH 2 (SEQ ID NO:4).
- the inactive control peptide was I[C (N"Me) G ⁇ "Me) WQD WGAHRC]I-NH 2 (SEQ ID NO:5).
- the dialysate compartment was filled with saline solution (0.9% NaCl) and clamped.
- the circuits were pre-rinsed with saline solution for approximately 30 minutes.
- the saline solution was then removed and the circuits were filled with blood. Blood volume was adjusted to 35 ml in each circuit and flow rate at 200ml/min, 37° C.
- complement activation was measured in plasma using a monoclonal antibody C3-9 (2 ug/ml), which recognizes a neoantigen that is exposed in C3(H 2 ⁇ ), C3b and C3c but not in native C3.
- Neutrophil activation was assessed using flow cytometry after surface staining of CDl Ib (PE Mouse Anti-human CDl lb/Mac-1, Cat. No 555388, BD Pharmigen).
- Tissue factor (TF) protein expression was used as a marker of coagulation pathway activation. TF expression was examined in purified neutrophils after intracellular indirect staining (MAb ag. human tissue factor, Cat. No 4509, American Diagnostica and FITC goat Anti-mouse IgG/IgM.
- Cellular and coagulation cascade activation were analyzed in blood neutrophils after surface staining for CDl Ib and intracellular staining for TF 5 using flow cytometry. Cellular and coagulation cascade activation were upregulated during the hemodialysis simulation (Fig. 7B, Fig. 7C. Treatment with compstatin analog 4[1MeW] attenuated both types of complement activation (Fig. 7B, Fig. 7C).
- Kario K Matsuo T 1 Yamada T et al. Increased tissue factor pathway inhibitor levels in uremic patients on regular hemodialysis. Thromb Haemost 1994; 71: 275-9.
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US8703136B2 (en) | 2006-10-10 | 2014-04-22 | Regenesance B.V. | Complement inhibition for improved nerve regeneration |
EP2886142A1 (en) * | 2013-12-17 | 2015-06-24 | University of Limerick | An apparatus for the extracorporeal treatment of blood |
US9907789B2 (en) | 2011-10-21 | 2018-03-06 | Takeda Pharmaceutical Company Limited | Sustained-release preparation |
WO2021037942A1 (en) * | 2019-08-27 | 2021-03-04 | Zp Spv 3 K/S | Compstatin analogues and their medical uses |
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CA2738930C (en) * | 2008-09-30 | 2021-08-17 | The Trustees Of The University Of Pennsylvania | Method of inhibiting biomaterial-induced procoagulant activity using complement inhibitors |
US10633434B2 (en) | 2016-06-14 | 2020-04-28 | Regeneron Pharmaceuticals, Inc. | Anti-C5 antibodies |
KR20200098528A (en) | 2017-12-13 | 2020-08-20 | 리제너론 파아마슈티컬스, 인크. | Anti-C5 antibody combinations and uses thereof |
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US9907789B2 (en) | 2011-10-21 | 2018-03-06 | Takeda Pharmaceutical Company Limited | Sustained-release preparation |
EP2886142A1 (en) * | 2013-12-17 | 2015-06-24 | University of Limerick | An apparatus for the extracorporeal treatment of blood |
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