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WO2012162215A1 - Promotion de la cicatrisation de fracture à l'aide d'inhibiteurs du complément - Google Patents

Promotion de la cicatrisation de fracture à l'aide d'inhibiteurs du complément Download PDF

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Publication number
WO2012162215A1
WO2012162215A1 PCT/US2012/038769 US2012038769W WO2012162215A1 WO 2012162215 A1 WO2012162215 A1 WO 2012162215A1 US 2012038769 W US2012038769 W US 2012038769W WO 2012162215 A1 WO2012162215 A1 WO 2012162215A1
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Prior art keywords
inhibitor
complement
fracture
c5ar
trauma
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John D. Lambris
Anita Ignatius
Markus Huber-Lang
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UNIVERSITY MEDICAL CENTER ULM
University of Pennsylvania Penn
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UNIVERSITY MEDICAL CENTER ULM
University of Pennsylvania Penn
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease

Definitions

  • This invention relates to the field of trauma and healing.
  • Methods for stimulating fracture healing, particularly in the presence of other systemic trauma, are provided.
  • the methods involve administration of a complement inhibitor to inhibit C5a receptor signaling to promote fracture healing.
  • a severe trauma such as a blunt chest trauma is considered a potent initiator of a systemic inflammatory response, being characterized by a strong systemic activation of the complement and coagulation cascades, and the release of pro-inflammatory cytokines and prostanoids. 1"3 It has been reported that fracture healing is delayed and more non-unions occur in severely injured patients. 4 ' 5 In confirming the clinical evidence, it was recently demonstrated experimentally in rats that a blunt chest trauma, which induced a post-traumatic systemic inflammation, considerably impaired fracture healing. 6
  • complement system One trigger of post-traumatic systemic inflammation is the complement system. 1 ' 7 ' 8
  • the complement cascade consisting of over 30 proteins, is an important component of innate immunity and can be activated by four pathways, the classical, the lectin, the alternative and the extrinsic pathways. In all cases, the activation pathways lead to the production of the anaphylatoxin C5a. 9 ' 10 In trauma victims, systemic C5a was reported to be increased within minutes after trauma, and was strongly correlated with injury severity.
  • C5a induces, for example, the migration of phagocytes, degranulation of mast cells, systemic cytokine release, respiratory burst induction and the regulation of apoptosis in inflammatory cells, thus acting at the very first line of defense in the post-traumatic systemic inflammatory response.
  • the excessive activation of complement can also cause harmful effects, for example immunoparalysis and organ dysfunction.
  • 12 ' 13 Due to its strong pro-inflammatory character, C5a is regarded as being a hazardous molecule if the complement cascade is over- activated. 1 ' 13 ' 14
  • Complement activation appears to be involved in fracture healing, yet complement activation from systemic trauma has been observed to delay fracture healing. Advances in the art are needed to provide a practical link between the complement system and its modulation for the purpose of promoting the bone healing process.
  • One aspect of the invention features a method for promoting healing of a fracture in an individual who has suffered a fracture and another trauma.
  • the method comprises first identifying an individual who has suffered a fracture and another trauma, and then administering to the individual a therapeutically effective amount of a complement inhibitor to the individual, wherein the complement inhibitor reduces or prevents systemic C5a receptor signaling (including C5L2 signaling) resulting from the trauma, thereby promoting healing of the bone fracture.
  • the individual is a human. In other embodiments, the individual is a non-human animal.
  • the complement inhibitor can be any complement inhibitor that inhibits complement activation in a manner resulting in a decrease in production or activity of C5a.
  • the complement inhibitor can be selected from one or more of a C5a inhibitor, a C5aR inhibitor, a C3 inhibitor, a C3aR inhibitor, a factor D inhibitor, a factor B inhibitor, a C4 inhibitor, a Clq inhibitor, or any combination thereof.
  • the complement inhibitor is a C5a inhibitor or a C5aR inhibitor.
  • Nonlimiting examples of C5a inhibitors or C5aR inhibitors include acetyl-Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg] (PMX-53), PMX-53 analogs, neutrazumab, TNX-558, eculizumab, pexelizumab or ARC1905, or any combination thereof.
  • the complement inhibitor is a C3 inhibitor.
  • the C3 inhibitor is Compstatin (SEQ ID NO: l), a Compstatin analog, a Compstatin peptidomimetic, a Compstatin derivative, or any combinations thereof.
  • Specific examples of Compstatin analogs include peptides comprising SEQ ID NO.:2, SEQ ID NO:3 or SEQ ID NO:4.
  • the complement inhibitor is a C4 inhibitor.
  • the complement inhibitor can be administered systemically, by different selected routes. Combinations of complement inhibitors can be utilized. In one embodiment, the complement inhibitor is administered together or concurrently with, or sequentially before or after, at least one other treatment for the fracture.
  • the pharmaceutical composition comprises one or more complement inhibitors and at least one other agent for treating the fracture, in a pharmaceutically acceptable medium.
  • the complement inhibitor comprises one or more of a C5a inhibitor, a C5aR inhibitor, a C3 inhibitor, a C3aR inhibitor, a factor D inhibitor, a factor B inhibitor, a C4 inhibitor, a Clq inhibitor, or any combination thereof.
  • the complement inhibitor is a C5a inhibitor or a C5aR inhibitor.
  • C5a inhibitors or C5aR inhibitors include acetyl-Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg] (PMX-53), PMX-53 analogs, neutrazumab, TNX-558, eculizumab, pexelizumab or
  • the complement inhibitor is a C3 inhibitor.
  • the C3 inhibitor is Compstatin (SEQ ID NO: l), a Compstatin analog, a Compstatin peptidomimetic, a Compstatin derivative, or any combinations thereof.
  • Specific examples of Compstatin analogs include peptides comprising SEQ ID NO.:2, SEQ ID NO:3 or SEQ ID NO:4.
  • the complement inhibitor is a C4 inhibitor.
  • the pharmaceutical composition typically is formulated for systemic administration, using a variety of routes of administration.
  • FIG. 1 Relative amounts of osseous tissue (TOT), cartilage tissue (Cg) and fibrous tissue (FT) within the callus of rats without (Ctrl) or with treatment with a C5aR-antagonist.
  • TOT osseous tissue
  • Cg cartilage tissue
  • FT fibrous tissue
  • FIG. 1 Absolute amounts of osseous tissue (TOT), cartilage tissue (Cg) and fibrous tissue (FT) within the callus of rats without (Ctrl) or with treatment with a C5aR- antagonist.
  • TOT osseous tissue
  • Cg cartilage tissue
  • FT fibrous tissue
  • FIG. 1 Micro-computed tomography ( ⁇ ) analysis in normal versus C3- or C5- deficient strains of mice after 21 days of healing from fracture.
  • Top panel callus volume (mm 3 ); bottom panel: moment of inertia of ostomy gap (mm 4 ).
  • 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., Ausubel et al, 2011, Current Protocols in Molecular Biology, John Wiley & Sons, NY), which are provided throughout this document.
  • Dosages expressed herein are in units per kilogram of body weight (e.g., ⁇ g/kg or mg/kg) unless expressed otherwise.
  • Ranges are used herein in shorthand, to avoid having to list and describe each and every value within the range. Any appropriate value within the range is intended to be included in the present invention, as is the lower terminus and upper terminus, independent of each other.
  • antibody refers to an immunoglobulin molecule that is able to bind specifically to a particular 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. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).
  • a “complement inhibitor” is a molecule that prevents or reduces activation and/or propagation of the complement cascade that results in the formation of C3a or signaling through the C3a receptor, or 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.
  • a "C3 inhibitor” is a molecule or substance that prevents or reduces the cleavage of C3 into C3a and C3b.
  • a “C5a inhibitor” is a molecule or substance that prevents or reduces the activity of C5a.
  • a “C5aR inhibitor” is a molecule or substance that prevents or reduces the binding of C5a to the C5a receptor.
  • a “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.
  • a “factor B inhibitor” is a molecule or substance that prevents or reduces the activity of factor B.
  • a “C4 inhibitor” is a molecule or substance that prevents or reduces the cleavage of C4 into C4b and C4a.
  • a “Clq inhibitor” is a molecule or substance that prevents or reduces Clq binding to antibody-antigen complexes, virions, infected cells, or other molecules to which Clq binds to initiate complement activation. Any of the complement inhibitors described herein may comprise antibodies or antibody fragments, as would be understood by the person of skill in the art.
  • a "fracture” is a break or discontinuation in bone or cartilage. Fractures are classified according to their character and location as, for example, a transverse fracture of the tibia. Clinically most fractures may be classified by the AO-classification system.
  • a “subject”, “individual” or “patient” refers to an animal of any species.
  • the animal is a mammal.
  • the mammal is a human.
  • the mammal is a non-human animal.
  • Systemic complement activation or “systemic C5a formation” refers to an activation of the complement system in the circulating blood measured by an increase of complement components in the blood and decrease in complement hemolytic activity.
  • local complement activation occurring at the site of injury (fracture) does not lead to a systemic activation of the complement cascade in the circulating blood, as reflected by unchanged complement activation products and unaltered complement hemolytic activity in the peripheral blood.
  • Trauma or “traumatic injury” as used herein refers to a severe physical injury, including for example open wounds, dismemberment, blunt injury, crush injury and major burns.
  • Treating refers to any indicia of success in the treatment or amelioration of the disease or condition, or promotion of the healing process. 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, or it can include speeding, promoting or otherwise improving the healing process following injury to cells, tissues or organs.
  • 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).
  • “Promoting,” such as promoting the healing process, refers to improving or accelerating the rate at which healing of a wounded cell, tissue or organ occurs.
  • 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.
  • promotion does not establish a requirement that the healing of an entire population of injured cells, tissues or organs will be accelerated or improved.
  • a “prophylactic” treatment is a treatment administered to a subject (or sample) that does not exhibit signs of a disease or condition, or in advance of signs of the condition that are expected to manifest, such as symptoms of inflammation or stress after a trauma.
  • 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.
  • One aspect of the invention provides a method for promoting healing of fractures accompanied by one or more other traumatic injuries that result in systemic complement activation.
  • the method comprises identifying or determining that an individual has suffered a fracture and another trauma, and administering a complement inhibitor to the individual.
  • a typical candidate for the method of the invention is an individual who has experienced a fracture in the course of a more complex traumatic injury. For instance, someone injured in a moving vehicle collision may suffer one or more fractures, as well as a blunt trauma to the head or chest, or a crushing trauma to the pelvis. In such instances, the trauma experienced by the individual is expected to stimulate a complement activation response, resulting in systemic formation and activity of C5a; therefore, the individual is a suitable candidate for practice of the method.
  • any inhibitor of 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. A number of C5aR inhibitors are known in the art. Acetyl-Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg]
  • Neutrazumab (G2 Therapies) binds to extracellular loops of C5aR and thereby inhibits the binding of C5a to C5aR.
  • TNX-558 (Tanox) is an antibody that neutralized C5a by binding to C5a.
  • C5a activity may also be inhibited by reducing or preventing the formation of C5a.
  • formation of C5a may be inhibited directly by inhibiting the cleavage of C5 by C5-convertase.
  • Eculizumab Alexion Pharmaceuticals, Cheshire, CT
  • Pexelizumab a scFv fragment of Eculizumab
  • ARC 1905 an anti-C5 aptamer, binds to and inhibits cleavage of C5, inhibiting the generation of C5b and C5a.
  • C3 inhibitor is Compstatin or a Compstatin analog, derivative, aptamer or peptidomimetic.
  • Compstatin is a small molecular weight cyclic peptide having the sequence Ile-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. 6,319,897, U.S. Patent No. 7,888,323, WO/1999/013899, WO/2004/026328 and WO/2010/127336.
  • An exemplary Compstatin analog comprises a peptide having a sequence: Xaal - Cys
  • Xaal is He, Val, Leu, Ac -He, Ac -Val, 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, He, Val, Gly, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal -OH of any of the L-Thr, D-Thr, He, Val, Gly 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-naphthylalanine, 1 -naphthylalanine, 2-indanylglycine carboxylic acid, dihydrotryptophan or
  • Compstatin analog comprises a peptide having a sequence: Xaal
  • Xaal is He, Val, Leu, Ac -He, Ac -Val, 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, Val, Gly, 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, He, Val, Gly 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 - methyltryptophan or 1 -formyltryptophan.
  • the analog of Trp of Xaa3 is a halogenated tryptophan such as 5-fluoro-l-tryptophan or 6-fluoro-l-tryptophan.
  • Compstatin analog of this type is Ac-I[CVW(Me)QDWGAHRCT]I- NH 2 (SEQ ID NO:4), which can be synthesized as described by Katragadda M, et ah, 2006, J Med Chem. 49: 4616-4622.
  • Another set of exemplary Compstatin analogs features Compstatin or any of the foregoing analogs, in which Gly at position 8 is modified to constrain the backbone conformation at that location.
  • the backbone is constrained by replacing the Gly at position 8 (Gly8) with Not-methyl Gly.
  • 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
  • formation of C5a is reduced or prevented through the use of an inhibitor of complement activation prior to 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 TA106 (Taligen Therapeutics), (3) C4 inhibitors (e.g., anti-C4 antibodies) and (4) Clq inhibitors (e.g., anti-Clq antibodies).
  • factor D inhibitors such as diisopropyl fluorophosphates and TNX-234 (Tanox)
  • factor B inhibitors such as the anti-B antibody TA106 (Taligen Therapeutics)
  • C4 inhibitors e.g., anti-C4 antibodies
  • Clq inhibitors e.g., anti-Clq antibodies.
  • inhibitors of signaling via the C3a receptor are also contemplat
  • 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, Clq, 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, 180,370), Wright et al., (1992, Critical Rev. in Immunol.
  • Anti-C3 and anti-C5 antibodies are also commercially available.
  • the complement inhibitor can be administered immediately upon identifying the individual as a target candidate, i.e., the individual having experienced a fracture and another trauma that is expected to stimulate systemic complement activation.
  • complement inhibitors can be administered as a prophylactic measure, if the nature and extent of an individual's injuries are not fully determined. Since traumatic injury typically occurs outside the setting of a health care facility, the complement inhibitor may be administered "in the field", for instance, at or near the location where the injury occurred or during transport of the patient to a health care facility such as a hospital, clinic, or physician's office.
  • the complement inhibitor can be administered any time from immediately following the injury, to within minutes, or an hour, or several hours, or within 24 hours following occurrence of the injury, and typically until a point at which the systemic complement activation would be expected to subside to a point that it no longer interferes with the local balance of inflammation and healing at the fracture point.
  • a single dose or multiple doses of complement inhibitor can be administered, as would be understood by the skilled practitioner.
  • a sufficient dose (or multiple doses) of complement inhibitor can be administered to reduce complement activation in the individual to within e.g., 1, 2, or 5 times the average level in individuals who have not suffered trauma.
  • complement inhibitors can be administered singly or in combination with one another. They may also be administered as part of a treatment regimen to promote healing of a fracture. For example, complement inhibitors can be administered within the first hours after fracture has occurred or before, during or after operative (e.g., external fixator, K-wires, screws, intramedullary nail, plate osteosynthesis) or conventional fracture treatment (cast, splint, brace) once or several times within several days up to one week.
  • operative e.g., external fixator, K-wires, screws, intramedullary nail, plate osteosynthesis
  • conventional fracture treatment cast, splint, brace
  • 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 developed 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 that 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 may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day.
  • the invention envisions administration of a dose that results in a concentration of a complement inhibitor between 1 ⁇ and 10 ⁇ in an individual identified as an appropriate candidate for treatment, i.e., having one or more fractures and a concomitant trauma causing a systemic inflammatory response.
  • the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of patient and type of disease state being treated, the age of the patient and the route of administration.
  • the dosage of the compound will vary from about 1 mg to about 10 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.
  • fixed dose formulations containing sufficient complement inhibitor to significantly inhibit complement activation in individuals of different size or maturity e.g., a child or adult human, following a single administration (which may take the form of an IV bolus or infusion or, in the case of orally bioavailable agents, oral
  • such formulations may be designed to reduce systemic complement activation by between 50% and 99%, e.g., by at least 50%, 60%, 70%, 80% or 90%, relative to levels present prior to administration or relative to levels that would have been expected in the individual under the circumstances, in the absence of the complement inhibitor.
  • a single complement inhibitor may be administered, or two or more different complement inhibitors may be administered, in the practice of the method of the invention.
  • the method comprises administration of only a complement inhibitor.
  • other biologically active agents are administered in addition to the complement inhibitor in the method of the invention.
  • Non- limiting examples of other biologically active agents useful in the invention include other modulators; e.g., bisphosphonates (such as aledronate), and cathepsin-K inhibitors, modulators of the coagulation cascade (such as factor XIII, Xa), or growth factors (e.g., bone morphogenetic proteins such as BMP-2 and -7, and growth differentiation factor (GDF) -5).
  • compositions that are useful in the methods of the invention may be administered systemically in oral solid formulations, parenteral, ophthalmic, suppository, aerosol, topical/transdermal 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
  • compositions 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
  • the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable or infusible 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.
  • Other useful parentally-administrable formulations include those comprising the active ingredient in microcrystalline form, in a liposomal preparation, in microbubbles for ultrasound-released delivery or as a component of a biodegradable polymer systems.
  • 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 including replacement pulmonary surfactants; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents;
  • 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; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
  • Other "additional ingredients” that may be included in the pharmaceutical 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.
  • the pharmaceutical composition may be a liquid formulation provided in a vial, a prefilled syringe, and the like.
  • Such fixed dose formulations can be assembled into an article of manufacture containing a fixed dose of complement inhibitor in a convenient form for rapid administration to an individual.
  • the formulation may be prepared for adding directly to an IV fluid solution.
  • kits comprise at least the complement inhibitor and instructions for its use in treating fractures accompanied by one or more other traumatic injuries.
  • kits may also comprise the complement inhibitor and another treatment agent, along with instructions for their use.
  • the kits may also comprise one or more of the diluents, excipients, carriers and other ingredients referred to above.
  • kits containing at least one fixed dose formulation comprising a complement inhibitor are also provided. Also provided are kits containing multiple fixed dose formulations of a complement inhibitor, with at least two of the fixed dose formulations containing different amounts of the complement inhibitor. The different amounts can be selected to achieve a desired amount of complement inhibition depending on the size and/or maturity of the patient being treated; e.g., infants, children, and adults.
  • the animal experiment was performed according to international regulations for the care and use of laboratory animals, and approved by the local ethical committee
  • An analgesic (20 mg/kg, Tramal ® , Gruenenthal GmbH, Aachen, Germany) was administered subcutaneously during the operation and was diluted in the drinking water (25 mg/1) for the first 3 days following surgery. Each animal was individually housed, given unrestricted access to food and monitored daily for infection and mobility.
  • a quasistatic load was applied in a three-point bending mode with a materials testing machine (1454, Zwick GmbH, Ulm, Germany) using a 500 N load cell (System-Technik GmbH, Germany) and the flexural rigidity (EI) was calculated from the slope of the force deflection curve.
  • the absolute values of the operated femora were related to the contralateral values of the un-operated femora to eliminate individual differences.
  • the femora were scanned using a ⁇ scanning device (skyscan 1172, Kontich, Belgium), operating at a peak voltage of 50 kV and 200 ⁇ at a resolution of 15 ⁇ .
  • the former osteotomy gap was segmented and the total tissue volume and the bone volume fraction (BV/TV) were calculated by global thresholding to distinguish between mineralized and non-mineralized tissue.
  • the maximum moment of inertia was calculated based on the tissue area on the transversal slices in the fracture gap.
  • the apparent modulus of elasticity was calculated as the flexural rigidity divided by the maximum moment of inertia. 24
  • Results are presented as mean and standard deviation.
  • the software PASW Statistics 18.0 SPSS Inc., Chicago, USA was used. Differences between groups were calculated using a Mann- Whitney U test. The level of significance was p ⁇ 0.05.
  • Table 2 Number of bridged cortices of the calli evaluated by ⁇ -computed tomography in two planes of rats without (Control) or with treatment with a C5aR-antagonist.
  • mice 157 male mice, aged 8-12 weeks, were divided into 4 experimental groups.
  • mice received analgetics in the drinking water from 2 days preoperatively to 3 days postoperatively (12.55 mg/500 ml tramalhydrochloride, Tramal ® , Gruenenthal, Aachen, Germany).
  • atropine sulfate 50 ⁇ g/kg, Atropin ® , Braun, Melsungen, Germany
  • mice were anesthetized with 2 % isoflurane (Forene ® , Abbott, Wiesbaden, Germany).
  • Antibiotic prophylaxis with Clindamycin was performed for 3 days postoperatively (45 mg/kg, Sobelin 600 ® , Pfizer Pharma, Düsseldorf, Germany).
  • the surgical procedure was conducted after skin incision and blunt, careful preparation to the right femur. After stabilization of the femur with 4 pins the osteotomy was carried out using a gigli saw wire (0,45mm) between pin 2 and 3 (RI Systems, AO
  • the flexural rigidity of the healed femora was evaluated using a non-destructive three point bending test.
  • the contralateral femora served as controls.
  • the proximal femora were embedded in aluminium cylinder using SelfCem (Heraeus Kulzer, Hanau, Germany). Then the embedded femora were inserted into a material testing machine (Mod. Z010, Zwick GmbH & Co., Ulm, Germany). The bending load (F) was applied on top of the callus and was recorded continuously versus sample deflection (d). At a maximum speed of 2 mm/min the maximum load was 1,5N. The first two tests conditioned each sample and the last test was used for the measurement.
  • Histological slices were harvested from longitudinal cuts through the center of the bone.
  • the 70 ⁇ -thick sections from undecalcified bones were surface-stained (5 ⁇ ) with Paragon (toluidine blue and fuchsin; both Waldeck GmbH & Co KG, Munster, Germany).
  • the histological slices were examined under a light microscope (Leica DMI6000B) at a fivefold magnification. The amount of bone, cartilage and fibrous tissue was assessed by
  • Micro computed tomography Besides postoperative native radiological analysis a CT-analysis of the fractured femora was conducted. For bone characterization ⁇ - ⁇ from the lumbar column as well as from the intact femora was performed.
  • ⁇ scanning device (Skyscan 1172, Kontich, Belgium) was used with a resolution of 15 ⁇ (voltage 50kV and 200mA).
  • ROI regions of interest
  • the callus was segmented and the undesirable parts of the callus were discarded.
  • the total tissue volume and the bone volume fraction (BV/TV) was calculated.
  • the maximum moment of inertia was calculated based on the tissue area on the transversal slices in the fracture gap.
  • the apparent modulus of elasticity was calculated as the flexural rigidity divided by the maximum moment of inertia.
  • bone mineral density as well as structural parameters such as cortical thickness and trabecular number were calculated automatically.
  • the differentiation potential of mouse derived osteoblast- like cells was measured.
  • To isolate osteoblast like cells the long bones were minced and digested with 300 U/ml collagenase type IV (Sigma, Germany) in alpha medium (F025, Biochrom, Germany) for 2h.
  • the bone chips were washed with PBS twice and once with alpha medium.
  • the chips were plated in six- well plates and cultivated with alpha medium +15%FBS.
  • Osteoblasts were seeded with 10.000 cells/cm 2 into 24-well culture plates and cultivated in differentiation medium consisting of osteoblast medium supplemented with 10 nM disodium ⁇ - glycerophosphate and 0.2 mM ascorbate -2 -phosphate. After 3 weeks matrix mineralization was analyzed by von Kossa staining. Alkaline phosphatase activity was proven by a commercially available staining kit (Sigma, Germany). Semi-quantitative PCR was used to analyze osteogenic differentiation on gene expression level. RNA was isolated on day 0 and day 21 using the RNeasy Mini Kit (Qiagen, Germany).
  • Omniscript RT Kit Qiagen, Germany
  • HotStarTaq DNA polymerase Qiagen, Germany
  • osteoclast medium F0925, Biochrom, Germany
  • alpha medium F0925, Biochrom, Germany
  • FBS fetal bovine serum
  • PAA 4 mM L-glutamine
  • penicillin 0.1 mg/ml streptomycin
  • Biochrom, Germany 0.25 mg/ml amphotericin B (Fungizone®, Gibco, Germany) (osteoclast medium).
  • Bone marrow cells were seeded with 350.000 cells/cm 2 in culture flasks in osteoclast medium supplemented with 10 ng/ml rh M-CSF (Chemicon, Germany) for stimulation and cultivated at 37 °C, 5 % C02 and saturated humidity for three days.
  • Stimulated non-adherent cells were seeded with 5 x 10 5 cells/cm 2 in osteoclast medium supplemented with 25 ng/ml rh M-CSF and 50 ng/ml murine RANKL (R&D Systems, USA) in 96-well Plates and plates with a synthetic calcium phosphate coating respectively.
  • TRAP staining was performed using a commercially available kit (Acid Phosphatase Leukocyte (TRAP) Kit, Sigma, Germany) to assess osteoclast formation.
  • TRAP -positive cells with at least three nuclei were counted as osteoclasts.
  • Resorption activity of osteoclasts was assessed by resorption assay (BD BioCoatTM OsteologicTM Bone Cell Culture System plates, Becton Dickinson GmbH, Germany). After 7 days cells were removed with 6% sodium hypochloride. Von Kossa staining was used to visualize the remaining calcium phosphate coating. White and grey areas represent the surface resorbed by osteoclasts, hence lacking calcium. Resorption area was quantified by using the image processing software MetaMorph AF, version 1.4.0 (Leica, Germany). Results:
  • Fracture healing experiments were performed with C3-/- and C5-/- mice.
  • the femurs were osteotomized and stabilized by an external fixator. After a healing period of 21 days, the healed and contralateral femors were explanted and analyzed biomechanically (Fig. 4), by micro-computed tomography ( ⁇ ) (Fig. 5) and by histological methods (not shown).
  • Micro-computed tomography analysis revealed that the total callus volume (including bone, cartilage and soft tissue) in the fracture gap was significantly decreased in C5-/- mice.
  • the maximum moment of inertia (I max ) was determined based on the tissue area on the transversal slices in the fracture gap. This geometrical parameter is an important determinant of bending stiffness. It was also significantly decreased in C5-/- mice.

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Abstract

L'invention concerne des procédés de promotion de la cicatrisation d'une fracture en présence d'autres lésions traumatiques. Les procédés entraînent l'administration d'un inhibiteur du complément pour inhiber la signalisation systémique par le récepteur de C5a, résultant du traumatisme. L'invention concerne également des compositions pharmaceutiques comportant un inhibiteur du complément et au moins un autre agent pour le traitement de la fracture.
PCT/US2012/038769 2011-05-20 2012-05-21 Promotion de la cicatrisation de fracture à l'aide d'inhibiteurs du complément Ceased WO2012162215A1 (fr)

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US9937222B2 (en) 2015-01-28 2018-04-10 Ra Pharmaceuticals, Inc. Modulators of complement activity
WO2018106859A1 (fr) 2016-12-07 2018-06-14 Ra Pharmaceuticals, Inc. Modulateurs de l'activité du complément
US10106579B2 (en) 2014-06-12 2018-10-23 Ra Pharmaceuticals, Inc. Modulation of complement activity
WO2019112984A1 (fr) 2017-12-04 2019-06-13 Ra Pharmaceuticals, Inc. Modulateurs de l'activité du complément
WO2020185541A2 (fr) 2019-03-08 2020-09-17 Ra Pharmaceuticals, Inc. Modulateurs d'activité du complément
WO2020205501A1 (fr) 2019-03-29 2020-10-08 Ra Pharmaceuticals, Inc. Modulateurs du complément et procédés associés
WO2020219822A1 (fr) 2019-04-24 2020-10-29 Ra Pharmaceuticals, Inc. Compositions et méthodes de modulation de l'activité du complément

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