Administration of C5-binding protein

Abstract

A method for administering C5 binding protein to a subject is described.The method includes subcutaneously administering a pharmaceutical composition comprising C5 binding protein to a subject in a specific amount, and / or using a specific dosing schedule to reduce the amount of free C5 in the subject and / or inhibit terminal complement activity in the subject.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 274,480, filed November 1, 2021, the contents of which are incorporated by reference in their entirety herein.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated by reference in its entirety. The XML file, created on October 31, 2022, is named ST26-IPC.003.W01-Oct31.xml and is 1983 bytes in size.

[0003] INCORPORATION BY REFERENCE All references cited in this disclosure are incorporated herein by reference in their entirety, solely for the purposes of those jurisdictions that allow incorporation by reference.In addition, any manufacturer's instruction manual or catalog for any product or active agent cited or mentioned herein is also incorporated by reference.Any document incorporated by reference in this text, or any teaching therein, can be used in the practice of the present invention. [Background technology]

[0004] The complement system is a valuable part of the innate immune system that provides an immediate line of defense against microorganisms without prior exposure. The complement cascade is activated by exogenous surface and danger-associated and pathogen-associated molecular patterns and antibodies / immune complexes through three separate routes that converge at the level of complement component C3: the classical pathway, the lectin pathway, and the alternative pathway. Cleavage of C3 into C3a and C3b leads to the formation of convertases, which subsequently cleave complement component C5 into C5a and C5b. The anaphylatoxins C5a and C3a activate inflammation, while C5b forms the membrane attack complex (MAC) by assembling complement components C6, C7, C8, and C9 (C5b-9), which lyses cells by forming holes through the cell wall / membrane. MAC formation is particularly important in defense against encapsulated bacteria, such as Neisseria meningitidis. Furthermore, upon activation, complement fragments (mainly derived from C3 and C4) opsonize surfaces for subsequent recognition by complement receptors on phagocytes and red blood cells, thereby allowing efficient clearance of opsonized microorganisms, immune complexes, and debris (Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3). The complement system is involved in the pathology of several disorders in different disease areas. Diseases with significant complement involvement include autoimmune diseases. Furthermore, mutations in complement proteins or dysfunctional regulation of complement are the cause of several rare (or extremely rare) conditions in which hemolysis is a component of the pathology. Complement component C5 is common in all pathways of complement activation, and interference with C5 inhibits the progression of the terminal complement cascade (downstream of C5) regardless of the stimulus. Inhibition of C5 thereby has the potential to prevent the deleterious properties of terminal complement activation while leaving intact the basic functions of the proximal complement cascade, i.e., opsonization of microorganisms and clearance of immune complexes.

[0005] There have been great efforts to regulate the activation of complement pathway to treat complement-mediated diseases. For example, several antibodies against C5 have been developed for the treatment of various complement-related diseases. However, such antibody-based therapies require high doses and must be delivered by intravenous (IV) infusion (see, for example, Non-Patent Document 4). There are also anti-C5 peptide therapies in clinical development. However, when administered subcutaneously, these peptide therapies require daily administration (see, for example, Non-Patent Document 5; and Non-Patent Document 6). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Chen et al., “The complement system in systemic autoimmune disease”, J.Autoimmun.2010;34(3):J276~J286 [Non-Patent Document 2] Walport, “Complement.First of two parts.” N.Engl.J.Med.2001;344(14):1058 1066 [Non-Patent Document 3] Walport, “Complement.Second of two parts.” N.Engl.J.Med.2001;344(15):1140 1144 [Non-Patent Document 4] Lee et al., “Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study;” Blood.2019 Feb 7;133(6):530~539 [Non-Patent Document 5] Sadik et al., “Evaluation of Nomacopan for Treatment of Bullous Pemphigoid A Phase 2a Nonrandomized Controlled Trial;” JAMA Dermatol.2022;158(6):641~649 [Non-Patent Document 6] Howard et al., "Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients with Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial." JAMA Neurol. 2020;77(5):582~592 Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is a need in the art for new and improved C5 inhibitor therapies that require lower doses, can be delivered by more convenient routes, such as small volume subcutaneous injections, and do not require daily administration. The present invention addresses this need. [Means for solving the problem]

[0008] Some of the main aspects of the present invention are summarized below. Additional aspects are described in the following detailed description, examples, and claims sections of this disclosure. The descriptions in each section of this disclosure are intended to be read in conjunction with the other sections. Furthermore, the various embodiments described in each section of this disclosure can be combined in various ways, regardless of any heading or subheading, and all such combinations are intended to be within the scope of the present invention.

[0009] The present invention involves a C5-binding protein from a class of engineered proteins, commonly referred to as affibodies, derived from the B domain in the immunoglobulin-binding region of Staphylococcus protein A (see Lofblom J, Feldwisch J, Tolmachev V, et al. "Affibody molecules: engineered proteins for therapeutic, diagnostic and biotechnological applications;" FEBS Lett. 2010;584(12):2670-2680). Similar to antibodies, these proteins can be engineered and / or selected to have affinity for a given protein of interest, for example, using phage display-based library screening. The present invention involves such engineered affibody proteins with C5-binding activity. In particular, the present invention provides various methods for administering this C5-binding protein to a human subject. Importantly, as further described in the Examples section of this disclosure, clinical trial data obtained to date indicates that compositions comprising this C5-binding protein, when administered subcutaneously to human subjects, cause a clinically significant reduction in free C5 levels in serum without the occurrence of any serious adverse events. This is particularly important given that preclinical trials in which products containing different C5-binding affibody molecules were administered to patients were terminated as a result of adverse events without any evidence of targeted pharmacological activity or efficacy being reported (see US clinical trial identifier no. NCT02083666; see also Berglund & Stromberg; 2016; "The clinical potential of Affibody-based inhibitors of C5 for therapeutic complement disruption;" Expert Review of Proteomics, 13:3, 241-243).Moreover, clinical trial data obtained to date indicates that the C5 binding protein described herein exhibits desirable pharmacokinetic and pharmacodynamic properties at doses that allow for clinically effective doses to be administered in small subcutaneous injections, much less than those required for anti-C5 antibody therapy.Furthermore, the results presented herein indicate that the serum concentration of the C5 binding protein is relatively stable for at least 3 days after administration, with a serum terminal half-life of more than 300 hours.The combination of these clinical features provides numerous advantages of the C5 binding protein of the present invention over both anti-C5 antibody therapy, which requires intravenous administration, and anti-C5 peptide therapy, which requires daily administration.

[0010] Thus, in some embodiments, the present invention provides a method of administering a C5 binding protein to a subject, the method comprising administering to the subject a pharmaceutical composition comprising a C5 binding protein having the amino acid sequence of SEQ ID NO:1, wherein the pharmaceutical composition is administered subcutaneously to the subject.

[0011] In some embodiments, the methods of the invention involve administering to the subject a single dose of the pharmaceutical composition. In other embodiments, the methods of the invention involve administering to the subject a series of multiple (two or more) doses of the pharmaceutical composition.

[0012] In some of these embodiments in which a series of two or more doses of the pharmaceutical composition is administered to the subject, the doses are administered to the subject at approximately weekly intervals (QW).

[0013] In some of these embodiments in which a series of two or more doses of the pharmaceutical composition is administered to the subject, the method includes administering one or more induction doses of the pharmaceutical composition and one or more maintenance doses of the pharmaceutical composition. In some embodiments, one or more maintenance doses are administered at weekly intervals (QW). In some embodiments, four or more maintenance doses are administered to the subject, each at weekly intervals (QW). In some embodiments, one induction dose of the pharmaceutical composition is administered, in which case the day on which the induction dose is administered is referred to herein as day 1. In some embodiments, two induction doses of the pharmaceutical composition are administered, in which, for example, the first induction dose is administered on day 1 and the second induction dose is administered on day 4. In some embodiments, three induction doses of the pharmaceutical composition are administered, in which, for example, the first induction dose is administered on day 1, the second induction dose is administered on day 3, and the third induction dose is administered on day 5.

[0014] In some embodiments, the dose administered to a subject (whether the dose is a single dose administered, one dose of a series or multiple doses, an induction dose, or a maintenance dose) consists of 2 mg to about 500 mg of C5 binding protein. In some embodiments, the dose administered consists of about 50 mg to about 450 mg of C5 binding protein. In some embodiments, the dose administered consists of about 100 mg to about 450 mg of C5 binding protein. In some embodiments, the dose administered is about 30 mg. In some embodiments, the dose administered is about 40 mg. In some embodiments, the dose administered is about 50 mg. In some embodiments, the dose administered is about 60 mg. In some embodiments, the dose administered is about 70 mg. In some embodiments, the dose administered is about 75 mg. In some embodiments, the dose administered is about 80 mg of C5 binding protein. In some embodiments, the dose of the C5 binding protein administered is about 90 mg. In some embodiments, the dose of the C5 binding protein administered is about 100 mg. In some embodiments, the dose of the C5 binding protein administered is about 125 mg. In some embodiments, the dose of the C5 binding protein administered is about 150 mg. In some embodiments, the dose of the C5 binding protein administered is about 200 mg. In some embodiments, the dose of the C5 binding protein administered is about 250 mg. In some embodiments, the dose of the C5 binding protein administered is about 300 mg.

[0015] In some embodiments, the C5 binding protein is administered to the subject in an amount and / or frequency effective to reduce the amount of free C5 in the subject. In some such embodiments, the C5 binding protein is administered to the subject in an amount and / or frequency effective to reduce the serum free C5 concentration in the subject to about 0.5 micrograms / mL or less. In some embodiments, the C5 binding protein is administered to the subject in an amount and / or frequency effective to reduce the serum free C5 concentration in the subject by about 99% or more compared to the subject's baseline serum free C5 concentration before administration of the C5 binding protein.

[0016] In some embodiments, the C5 binding protein is administered to a subject in an amount and / or frequency effective to inhibit activation of the terminal complement pathway in the subject.

[0017] In some embodiments, the C5 binding protein is greater than or equal to about 0.5 micromolar, or greater than or equal to about 1.0 micromolar, or greater than or equal to about 1.5 micromolar, or greater than or equal to about 2.0 micromolar of C5 binding protein. トラフ The subject is administered an amount and / or frequency effective to achieve this.

[0018] In some embodiments, the C5 binding protein is administered to a subject in the amounts and / or frequencies described in the Examples section of this disclosure.

[0019] In some embodiments, the present invention provides a pharmaceutical composition comprising a C5 binding protein having the amino acid sequence of SEQ ID NO:1. In some embodiments, the pharmaceutical composition comprises a C5 binding protein having the amino acid sequence of SEQ ID NO:1 and at least one additional pharma- ceutically acceptable ingredient. In some embodiments, the pharmaceutical composition comprises one or more additional ingredients selected from the group consisting of histidine, arginine, polysorbate 20, and water. In some embodiments, the pharmaceutical composition comprises each of histidine, arginine, polysorbate 20, and water. In some embodiments, the pharmaceutical composition comprises about 20 mM histidine, about 150 mM arginine, about 0.05% polysorbate 20, and water. In some embodiments, the pharmaceutical composition comprises about 100 mg / ml of C5 binding protein. In some embodiments, the pharmaceutical composition has a pH of about 7.0. In some embodiments, the pharmaceutical composition is stable when stored at about 2°C to about 8°C. In some embodiments, the pharmaceutical composition is stable when stored at about 2°C to about 8°C for up to 18 months or more. In some embodiments, the pharmaceutical composition is stable when stored at about 15° C. to about 25° C. In some embodiments, the pharmaceutical composition is stable when stored at about 15° C. to about 25° C. for up to about 36 hours or longer.

[0020] In some embodiments, the present invention provides an autoinjector comprising the pharmaceutical composition described herein. In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical composition described herein in an amount sufficient for administration of a single dose of C5 binding protein to a subject. In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical composition described herein in an amount sufficient for administration of multiple doses of C5 binding protein to a subject. In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical composition comprising C5 binding protein at a concentration of about 100 mg / mL.

[0021] Further aspects, features, and advantages of the present invention will be better understood by reading the following Detailed Description, Examples, and Claims sections of this disclosure. [Brief description of the drawings]

[0022] [Figure 1] Graph showing ex vivo hemolysis inhibition data for C5 binding protein described herein.C5 binding protein (at 0.0625, 0.125, 0.25, 0.5, 1 and 2 μM) was incubated ex vivo with human serum and the % of hemolysis was determined using standard assay.At a concentration of 0.5 μM (and above) of C5 binding protein, complete hemolysis inhibition was achieved.The percentage of hemolytic activity is shown on the vertical axis, and the concentration of C5 binding protein is shown on the horizontal axis. [Diagram 2] 1 is a graph showing pharmacokinetic (PK) data for healthy participant cohorts 1-4 from the clinical trial described in Examples 2 and 3. The vertical axis shows the concentration of C5 binding protein in serum expressed in micromolar (μM) units, and the horizontal axis shows time post dosing / treatment ("TPT") expressed in hours. [Diagram 3] 1 is a graph showing pharmacokinetic (PK) data for healthy participant Cohort 4 from the clinical trial described in Examples 2 and 3. The vertical axis shows the concentration of C5 binding protein in serum expressed in micromolar (μM) units, and the horizontal axis shows time post dosing / treatment ("TPT") expressed in hours. [Figure 4]4A-B show pharmacodynamic (PD) data for healthy participants in cohorts 2-4 from the clinical trials described in Examples 2 and 3. FIG. 4A and FIG. 4B show graphs in which the measured concentration of free C5 in serum, expressed in ng / mL on the vertical axis, is plotted against the measured concentration of C5-binding protein in serum, expressed in micromolar (μM) units on the horizontal axis. FIG. 4A includes data from 18 subjects. Each plotted data point (represented by an open circle) in FIG. 4A is the averaged (mean) data from 6 subjects, with each data point representing the mean data obtained after administration of a particular dose of administered C5-binding protein (either 10 mg, 30 mg, or 100 mg) as well as at a particular time point after administration (either 0, 2, 4, 12, 24, or 72 hours after administration). In Figure 4B, each plotted data point (represented by an open circle) is the average (mean) data from six subjects obtained after administration of a 100 mg dose of C5 binding protein at a particular time point after administration (either 0, 2, 4, 12, 24, or 72 hours after administration). These data show that serum free C5 concentrations decrease with increasing concentrations of C5 binding protein in serum. [Figure 5-1] 5A-E are graphs of the concentration of C5 binding protein in serum in micromoles (μM) plotted against the timing of multiple doses of 100 mg (FIGS. 5A-D) or 150 mg (FIG. 5E) of C5 binding protein (vertical axis) expressed in units of time. The graphs show modeling data obtained using single dose clinical trial data as input. The modeled dosing schedule is shown in each graph above. The horizontal line plotted in each graph shows the 2 μM concentration of C5 binding protein in serum. In each graph, the upper dotted line represents the 97.5th percentile of the concentration of C5 binding protein, the middle dotted line represents the 50th percentile of the concentration of C5 binding protein, and the lower dotted line represents the 2.5th percentile of the concentration of C5 binding protein. [Figure 5-2] Continued from Figure 5-1. [Figure 5-3]Continued from Figure 5-2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention relates to C5 binding proteins, pharmaceutical compositions comprising C5 binding proteins, and various methods involving administration of C5 binding proteins (or pharmaceutical compositions comprising C5 binding proteins) to a subject, as further described in the Detailed Description of the Invention section of this disclosure below, as well as in the Summary of the Invention, Examples, and Claims sections of this disclosure. The various embodiments described in this Detailed Description of the Invention can be combined in various manners, regardless of any heading or subheading of the invention.

[0024] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmacology, formulation science, immunology, hematology, cell biology, molecular biology, clinical pharmacy, and clinical practice, within the skill of one of ordinary skill in the art.

[0025] All references cited in this disclosure are incorporated herein by reference in their entirety. Additionally, all manufacturer's instructions or catalogs for any product cited or referred to herein are incorporated herein by reference. Any document incorporated by reference into this text, or any teaching therein, may be used in the practice of the present invention. Identification of a reference or other document herein, or incorporation by reference of any of them, is not an admission of the prior art status of any of such references or documents.

[0026] In order that the present invention may be more readily understood, certain terms are defined below. Additional definitions are provided throughout this disclosure. Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0027] definition The phrases and terminology in this disclosure are for purposes of description and not of limitation; thus, the terms and phrases herein should be interpreted by one of ordinary skill in the art in light of the present teachings and guidance.

[0028] As used herein or in the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. The term "a" (or "an"), and the terms "one or more" and "at least one" can be used interchangeably.

[0029] Furthermore, "and / or" is to be understood as a specific disclosure of each of the two specified features or components with or without the other. Thus, when the term "and / or" is used in a phrase such as "A and / or B," it is intended to include "A and B," "A or B," "A" (only), and "B" (only). Similarly, when the term "and / or" is used in a phrase such as "A, B, and / or C," it is intended to encompass A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).

[0030] When an embodiment is described with the phrase "comprising" or "having," other similar embodiments described in the terms "consisting of" and / or "consisting essentially of" are also encompassed.

[0031] Units, prefixes, and symbols are designated in their International System of Units (SI) accepted form.

[0032] Numerical ranges include the numerical values ​​that define the range, and any individual value provided herein can serve as an endpoint for a range that includes other individual values ​​provided herein. For example, a set of values ​​such as 1, 2, 3, 8, 9, and 10 is also a disclosure of the range of values ​​from 1 to 10, 1 to 8, 3 to 9, etc. Similarly, a disclosed range is also a disclosure of each individual value encompassed by the range. For example, a range recited in 5 to 10 is also a disclosure of 5, 6, 7, 8, 9, and 10.

[0033] When a numerical term is preceded by the modifier "about", the term includes the stated numerical value and value ±10% of the stated numerical value. For example, a concentration of about 1 mg / mL encompasses 0.9 mg / mL to 1.1 mg / mL. Furthermore, when a numerical term is preceded by the modifier "about", embodiments having the precise stated numerical value without the "about" modifier are also contemplated and are within the scope of the present invention. Conversely, when an embodiment of the present invention refers to a specific numerical term, other similar embodiments with the "about" modifier are also contemplated and are within the scope of the present invention. Unless otherwise specified, the term "about" preceding a series or list of elements should be understood to mean every element in the series or list. Similarly, unless otherwise specified, the terms "at least" and "up to" preceding a series or list of elements should be understood to mean every element in the series.

[0034] The safety of a drug (as used herein, including biological agents) and the method of administration of the drug are determined based on the evaluation of parameters such as adverse events, vital signs, clinical laboratory values, and electrocardiogram (ECG) findings. The terms "adverse event" and "serious adverse event" are used herein in accordance with their generally accepted meaning in the art and their use by the U.S. Food and Drug Administration. Thus, as used herein, the term "adverse event" ("AE") means any undesirable and unintended sign (e.g., abnormal clinical laboratory findings) or symptoms temporally related to the use of a drug, regardless of whether it is considered to be drug-related. A "mild" adverse event is an AE that is recognized as an easily tolerated symptom that causes slight discomfort but does not interfere with daily activities. A "moderate" adverse event is an AE that is disabling enough to interfere with daily activities. A "severe" adverse event is more medically significant than a mild or moderate adverse event, but does not rise to the level of a "serious" adverse event. "Serious Adverse Event" ("SAE") means a fatal or immediately life-threatening event that requires hospitalization of a patient or an extension of an existing hospitalization; results in permanent disability / incapacity; or is a congenital disorder / birth defect, or another medically significant serious event that may endanger the subject or require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

[0035] The terms "affinity" and "binding affinity" generally refer to the strength of the sum of non-covalent interactions between a single binding site of a molecule and its binding partner (e.g., between an active agent of the present invention and human complement protein C5). The affinity of molecule X for partner Y can generally be expressed as a dissociation constant (KD). Affinity can be measured by common methods known in the art, such as flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or kinetic analysis (e.g., KINEXA®, BIACORE™, or OCTET® analysis). Direct binding assays as well as competitive binding assay formats can be readily adopted. The measured affinity of a particular binding pair interaction may vary when measured under different conditions (e.g., salt concentration, pH, temperature). Thus, measurements of affinity and other binding parameters (e.g., KD or Kd, Kon, Koff) are typically made using standard solutions of the binding partner and standard buffers known in the art.

[0036] "Binding" generally refers to a non-covalent interaction between a single binding site on a molecule and its binding partner (e.g., between an active agent of the invention, which is a C5 binding protein, and the human complement protein C5).

[0037] The terms "C5", "C5 protein", "complement C5", and "complement protein C5" and "complement C5 protein" are used interchangeably herein. C5 protein and its structure and biological function are well known in the art. C5 protein is a component of the complement system and is common to all pathways of complement activation. Blocking C5 (e.g., using C5 inhibitors) inhibits terminal complement activation while leaving intact the basic functions of the proximal complement cascade (e.g., opsonization of microorganisms and clearance of immune complexes, etc.). For example, C5 inhibitors can inhibit the cleavage of C5 into C5a and C5b, thereby inhibiting the generation of the potent proinflammatory anaphylatoxin C5a and inhibiting the assembly of nascent C5b, C6, C7, C8, and C9 molecules into membrane attack complexes.

[0038] An "effective amount" (eg, of an active agent or pharmaceutical composition) is an amount sufficient to achieve a stated purpose or biological or medicinal outcome or response in a subject.

[0039] The terms "induction dose", "induction phase", "maintenance dose" and "maintenance phase" are standard terms in pharmacokinetics and are used herein in accordance with their generally accepted meanings in the art. Typically, an induction dose is a dose given during the initial stage (induction phase) of a course of multiple administrations of treatment, and constitutes either a higher dose of the active agent than is administered during the subsequent maintenance phase, or a more frequent administration of the active agent than is administered during the subsequent maintenance phase. Typically, an induction dose is used to increase the rate at which an effective concentration of the active agent is achieved, e.g., in the present case, to increase the rate at which a concentration of C5 binding protein effective to reduce serum free C5 levels to a clinically significant extent is achieved. Typically, during the maintenance phase, the concentration of the active agent (e.g., in serum) reaches a peak (C max ) concentration and trough (C トラフ ) concentrations remain relatively consistent (i.e., maintained) over time, with some cyclical variation between

[0040] The terms "inhibit", "block", "reduce" and "suppress" are used interchangeably and refer to any statistically significant reduction in the referenced occurrence or activity, including complete prevention of the occurrence or activity. For example, "inhibition" can refer to about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100% reduction in the referenced activity or occurrence. Identifying whether there is a statistically significant reduction in the referenced occurrence or activity, or identifying the extent of any reduction in the referenced occurrence or activity, can be evaluated relative to any suitable comparator or control, for example, relative to the situation before the reduction occurs and / or in the absence of the agent causing the reduction.

[0041] The term "inhibitor" refers to an active agent that inhibits a referenced occurrence or activity. The active agents of the present invention bind to C5 (and thus can be referred to as C5-binding proteins) and inhibit activation of the terminal complement cascade downstream of C5 (and thus can be referred to as complement inhibitors or C5 inhibitors).

[0042] The term "pharmaceutical composition" refers to a preparation that is in such a form that the biological activity of the active agent contained therein can be effective, and does not contain additional components that are unacceptably toxic to the subject to which the composition is administered. Such compositions may be sterile and may contain a pharma-ceutically acceptable carrier, such as water (e.g., water for injection) or saline. Suitable pharmaceutical compositions may contain one or more buffers (e.g., acetate, phosphate, or citrate buffers), surfactants (e.g., polysorbates), stabilizers (e.g., polyols or amino acids), preservatives (e.g., sodium benzoate), and / or other conventional solubilizers or dispersants.

[0043] "Pharmacodynamics" or "PD" refers to the study of the molecular, biochemical, physiological, and other biological effects of an activator in the body of a subject. In the case of C5 inhibitors, pharmacodynamics can be evaluated using metrics related to the effect of the administered agent on, for example, the amount of bound C5 (i.e., C5 bound by the activator), the amount of free C5 (i.e., C5 not bound by the activator), the amount of total C5 (bound C5+free C5), the percentage of total C5 that is free C5, cleavage of C5 by C5 convertase, generation of C5a, generation of C5b, generation of other complement components downstream of C5 in the complement pathway, terminal complement pathway activity, and the like. When specific numerical values ​​of PD parameters are provided herein and unless otherwise specified, the values ​​provided are for serum (typically when measured in serum samples prepared from blood samples obtained from a subject). However, it may be possible to obtain measurements of such PD parameters from plasma, blood, or blood-derived samples obtained from a subject. Thus, when a specific serum PD value is provided, the same or comparable PD value obtained from such plasma, blood, or other blood-derived sample is also within the scope of the description. Some of the embodiments of the present invention involve the PD parameter of serum free C5. Methods for measuring serum free C5 are known in the art. In some embodiments, a specific serum free C5 concentration is specified, such as, for example, a serum free C5 concentration of 0.5 micrograms / mL or less. In some embodiments, instead of referring to a specific concentration of free C5 in serum, the amount of free C5 in serum is referred to in relative terms, typically as a % of the baseline concentration of free C5 present in serum before administration of the C5 binding protein, such as, for example, an amount of free C5 in serum that represents a reduction of 99% or more when compared to the baseline concentration of free C5 in serum before administration of the C5 binding protein. In some embodiments, the amount of free C5 in serum (whether described as a concentration or as a % of baseline concentration) is the amount at a particular time point after administration of the C5 binding protein, such as 12 hours, or 24 hours, or 36 hours, or 48 hours, or 72 hours after administration of the C5 binding protein.In an embodiment in which a series of multiple doses of C5 binding protein is administered to a subject, the amount of free C5 in serum (whether described as a concentration or as a % of baseline concentration) typically refers to the amount achieved during the maintenance phase of the administration protocol. In a preferred embodiment, the specific amount of free C5 in serum (whether described as a concentration or as a % of baseline concentration) is C. max and C. トラフ This refers to a threshold amount (e.g., 0.5 micrograms / mL or less, or a reduction of 99% or more) that is achieved throughout the maintenance phase, despite some variation in the concentration of C5-binding protein in serum between 0.5 and 100 mg / mL.

[0044] "Pharmacokinetics" or "PK" refers to the study of how an administered active agent is processed by a subject's body. PK determinations include how an agent enters the blood circulation (absorption), is dispersed or spread throughout the body's fluids and tissues (distribution), is recognized and transformed by the body (metabolism), and / or is removed from the body (excretion). Pharmacokinetics can be assessed using a variety of well-known metrics, many of which are calculated based on the amount of active agent in the body (or in a biological sample obtained or processed from the body) at various times following administration of the active agent. For example, "AUC" or "area under the curve" (or area under the concentration-time curve) is a pharmacokinetic metric that describes the variation in concentration of an active agent, typically in serum or plasma, as a function of time. AUC is, for example, the area of ​​the active agent from time zero to a specified time t (AUC t or AUC 0-t ), from time zero to infinity (AUC ∞ or AUC 0-∞ ) are calculated for different periods. max " is the peak concentration of the active agent following administration, typically in serum or plasma. トラフ "teeth, The minimum concentration of the active agent after administration, typically in serum or plasma (typically the concentration at the end of a dosing interval, i.e., the concentration after a given dose in the series has been administered and immediately prior to administration of the next dose in the series). Time after administration is the time T at which the active agent is administered. 0 It is measured from "T max " is the administration of an active agent (T 0 After the maximum concentration (C max ) means the time it takes to reach the target value. 1 / 2 " means the half-life of the active agent, i.e., the time required for the concentration of the active agent to reach half of its original value. "CL" is the total body clearance of the drug. "V d " is the amount of drug delivered. Where specific values ​​for PK parameters are provided herein and unless otherwise specified, the values ​​provided are for serum (typically as measured in serum samples prepared from a blood sample obtained from a subject). However, it may also be possible to obtain measurements of such PK parameters from the subject's plasma, blood, or blood-derived samples. Thus, where a specific serum PK value is provided, the same or comparable PK value obtained from such plasma, blood, or other blood-derived sample is also within the scope of the description.

[0045] The terms "polypeptide", "peptide" and "protein" are used interchangeably to refer to polymers of amino acids and their salts. Either the standard three-letter or one-letter amino acid abbreviations used in the art are used herein to represent amino acid residues. Strings of amino acid abbreviations are used to represent peptides by their amino acid sequences. Unless otherwise specified, proteins are shown with the N-terminus on the left and sequences are written from the N-terminus to the C-terminus. The terms "polypeptide", "peptide" and "protein" as used herein include monomeric and multimeric (e.g., dimeric) forms of polymers of amino acids.

[0046] A "subject" or "patient" is an individual, particularly a mammalian individual, for whom prevention or treatment (e.g., using an active agent, pharmaceutical composition, or method described herein) is desired, necessary, or performed. A subject "in need thereof" is a subject who can be reasonably expected to benefit from prevention or treatment using an active agent, pharmaceutical composition, or method described herein, as determined, for example, by a medical professional. In some embodiments of the present invention, the subject is any mammalian subject, such as humans, livestock, farm animals, sports animals, and laboratory animals, such as humans, non-human primates, dogs, cats, pigs, cows, horses, rodents, such as rats and mice, rabbits, etc. In a preferred embodiment, the subject is a human.

[0047] Activator The present invention involves an active agent that is a C5 binding protein. It is a recombinant protein that includes an affibody Z-domain and an albumin binding domain connected by a linker sequence. The C5 binding protein has a theoretical molecular weight of about 11.9 kDa and a theoretical isoelectric point (pI) of 4.42. The amino acid sequence of the C5 binding protein is as follows:

[0048] [Table 1]

[0049] C5 binding protein binds with high affinity to human complement protein C5 and inhibits complement pathway function and terminal complement activation.

[0050] The C5 binding protein can be produced using standard methods known in the art for the production of recombinant proteins. In some embodiments, the C5 binding protein can be produced synthetically, for example, by solid phase synthesis. In some embodiments, the C5 binding protein can be expressed from a recombinant nucleic acid molecule encoding SEQ ID NO:1 in any suitable host cell. In some embodiments, the host cell is a mammalian cell. In some embodiments, the host cell is a plant cell. In some embodiments, the host cell is an insect cell. In some embodiments, the host cell is a yeast cell. In some embodiments, the host cell is a bacterial cell. In some embodiments, the C5 binding protein is produced by expression in an E. coli cell. In some embodiments, the nucleotide sequence encoding SEQ ID NO:1 is codon optimized for expression in a selected host cell type. For example, in some embodiments, the nucleotide sequence encoding SEQ ID NO:1 is codon optimized for bacterial expression. Once expressed, the active agent can be purified using any suitable method known in the art, such as, but not limited to, chromatography-based methods.

[0051] Further details on making the active agents are provided in WO 2015 / 028558 and U.S. Pat. No. 9,994,626, the contents of which are incorporated herein by reference.

[0052] Pharmaceutical Compositions The active agents of the present invention are formulated in pharmaceutical compositions comprising the active agent and one or more additional pharma- ceutically acceptable ingredients.

[0053] In some embodiments, the pharmaceutical composition may include one or more carriers, diluents, excipients, or other additives. For example, in some embodiments, the pharmaceutical composition includes one or more stabilizers, one or more buffers, one or more pH adjusters, one or more surfactants, and / or one or more diluents (e.g., water, saline). In some embodiments, the pharmaceutical composition does not include a preservative.

[0054] In some embodiments, the pharmaceutical composition comprises histidine. In some embodiments, the pharmaceutical composition comprises arginine. In some embodiments, the pharmaceutical composition comprises polysorbate 20. In some embodiments, the pharmaceutical composition comprises histidine, arginine, polysorbate 20, and water (water for injection). In some embodiments, the pharmaceutical composition comprises an active agent, about 20 mM histidine, about 150 mM arginine, and about 0.05% polysorbate 20 (v / v) in water (e.g., water for injection).

[0055] In some embodiments, the pH of the composition is between about 5.0 and about 9.0. In some embodiments, the pH of the composition is between about 6.0 and about 8.0. In some embodiments, the pH of the composition is between about 6.5 and about 7.5. In some embodiments, the pH of the composition is about 7.0.

[0056] In some embodiments, the pharmaceutical composition comprises an active agent, about 20 mM histidine, about 150 mM arginine, and about 0.05% polysorbate 20 (v / v) in water and has a pH of about 7.0.

[0057] In some embodiments, the pharmaceutical composition comprises the active agent in a concentration of about 50 mg / mL to 150 mg / mL. In some embodiments, the pharmaceutical composition comprises the active agent in a concentration of about 60 mg / mL to 140 mg / mL. In some embodiments, the pharmaceutical composition comprises the active agent in a concentration of about 70 mg / mL to 130 mg / mL. In some embodiments, the pharmaceutical composition comprises the active agent in a concentration of about 80 mg / mL to 120 mg / mL. In some embodiments, the pharmaceutical composition comprises the active agent in a concentration of about 90 mg / mL to 110 mg / mL. In some embodiments, the pharmaceutical composition comprises the active agent in a concentration of about 100 mg / mL.

[0058] In some embodiments, the pharmaceutical composition comprises an active agent at a concentration of about 100 mg / mL, about 20 mM histidine, about 150 mM arginine, and about 0.05% polysorbate 20 (v / v) in water and has a pH of about 7.0.

[0059] In some embodiments, the pharmaceutical composition is stable when stored at about 2° C. to about 8° C. In some embodiments, the pharmaceutical composition is stable for about 1 week, or about 2 weeks, or about 1 month, or about 2 months, or about 3 months, or about 6 months, or about 9 months, or about 12 months, or about 18 months, or about 24 months, or about 30 months, or about 36 months, or more, when stored at about 2° C. to about 8° C.

[0060] In some embodiments, the pharmaceutical composition is stable when stored at about 15° C. to about 25° C. In some embodiments, the pharmaceutical composition is stable for about 12 hours, or about 24 hours, or about 36 hours, or about 48 hours, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or for a period of more than 1 week, when stored at about 15° C. to about 25° C.

[0061] Method of administration The present invention provides various methods involving administration of the active agent (C5 binding protein) described herein to a subject.In such methods, the active agent is administered to a subject in a pharmaceutical composition (details of which are also described herein).Therefore, whenever a description is provided herein that refers to an active agent (e.g., in relation to the method of administration, the amount administered, dosage / administration schedule, administration route, etc.), such description should also be understood to refer to the pharmaceutical composition that contains the active agent.

[0062] In some embodiments, the subject to which the active agent is administered is a mammalian subject, hi some embodiments, the subject to which the active agent is administered is a human subject.

[0063] In some embodiments, the methods described herein are performed to achieve a certain biological effect in a subject. In some embodiments, such methods involve administration of a certain amount of an active agent. In some embodiments, such methods involve administration of a certain number of doses of an active agent. In some embodiments, such methods involve administration of an active agent according to a dosing schedule. In some embodiments, such methods involve administration of an active agent using a certain delivery route.

[0064] In some embodiments, the present invention provides a method for achieving a certain biological effect. For example, in some embodiments, the present invention provides a method for inhibiting C5 activity in a subject. In some embodiments, the present invention provides a method for inhibiting cleavage of C5 into C5a and C5b in a subject. In some embodiments, the present invention provides a method for inhibiting activation of the terminal complement pathway in a subject. In some embodiments, the present invention provides a method for decreasing the amount of one or more components of the terminal complement pathway in a subject. In some embodiments, the present invention provides a method for decreasing the amount of a terminal complement pathway component selected from C5a, C5b, C6, C7, C8, and C9 in a subject. In some embodiments, the present invention provides a method for decreasing the amount of C5a in a subject. In some embodiments, the present invention provides a method for decreasing the amount of C5b in a subject.

[0065] In some embodiments, the present invention provides a method for decreasing the amount of free C5 in a subject. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 1.0 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.9 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.8 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.7 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.6 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.5 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.4 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.3 micrograms / mL or less. In some embodiments, the present invention provides a method for decreasing the serum free C5 concentration to about 0.2 micrograms / mL or less. In some embodiments, the invention provides methods for reducing serum free C5 concentrations to about 0.1 micrograms / mL or less. In some embodiments, the invention provides methods for reducing serum free C5 concentrations to about 0.05 micrograms / mL or less. In some embodiments, the invention provides methods for reducing serum free C5 concentrations to about 0.01 micrograms / mL or less. In some embodiments, the invention provides methods for reducing serum free C5 concentrations to about 0.005 micrograms / mL or less. In some embodiments, the invention provides methods for reducing serum free C5 concentrations to about 0.01 micrograms / mL or less.

[0066] In some embodiments, the present invention provides methods involving administration to a subject of a certain amount of an active agent of the present invention. These amounts of active agent are administered to the subject in a pharmaceutical composition.

[0067] In some embodiments, such an amount is administered to the subject only once, i.e., one dose of a certain amount of active agent is administered to the subject. In other embodiments, such an amount is administered to the subject more than once, i.e., a series of multiple (two or more) doses is administered to the subject, as further described below.

[0068] In those embodiments in which a series of multiple doses is administered to a subject, the doses are administered according to a certain dosing schedule, for example, with a certain time interval between each dose in the series.In some embodiments, the amount administered to a subject in each dose in the series is the same (i.e., each dose in the series contains the same amount of active agent).In other embodiments, the amount administered to a subject in each dose in the series is not the same (i.e., each individual dose in the series may contain different amounts of active agent).

[0069] In some embodiments, the amount of active agent administered to a subject is about 2 mg. In some embodiments, the amount administered is about 10 mg. In some embodiments, the amount administered is about 20 mg. In some embodiments, the amount administered is about 30 mg. In some embodiments, the amount administered is about 40 mg. In some embodiments, the amount administered is about 50 mg. In some embodiments, the amount administered is about 60 mg. In some embodiments, the amount administered is about 70 mg. In some embodiments, the amount administered is about 80 mg. In some embodiments, the amount administered is about 90 mg. In some embodiments, the amount administered is about 100 mg. In some embodiments, the amount administered is about 110 mg. In some embodiments, the amount administered is about 120 mg. In some embodiments, the amount administered is about 130 mg. In some embodiments, the amount administered is about 140 mg. In some embodiments, the amount administered is about 150 mg. In some embodiments, the amount administered is about 160 mg. In some embodiments, the amount administered is about 170 mg. In some embodiments, the amount administered is about 180 mg. In some embodiments, the amount administered is about 190 mg. In some embodiments, the amount administered is about 200 mg. In some embodiments, the amount administered is about 210 mg. In some embodiments, the amount administered is about 220 mg. In some embodiments, the amount administered is about 230 mg. In some embodiments, the amount administered is about 240 mg. In some embodiments, the amount administered is about 250 mg. In some embodiments, the amount administered is about 260 mg. In some embodiments, the amount administered is about 270 mg. In some embodiments, the amount administered is about 280 mg. In some embodiments, the amount administered is about 290 mg. In some embodiments, the amount administered is about 300 mg.In some embodiments, the amount administered is about 325 mg. In some embodiments, the amount administered is about 350 mg. In some embodiments, the amount administered is about 375 mg. In some embodiments, the amount administered is about 400 mg. In some embodiments, the amount administered is about 425 mg. In some embodiments, the amount administered is about 450 mg. In some embodiments, the amount administered is about 475 mg. In some embodiments, the amount administered is about 500 mg. In some embodiments, the amount administered is about 600 mg. In some embodiments, the amount administered is about 700 mg. In some embodiments, the amount administered is about 800 mg. In some embodiments, the amount administered is about 900 mg. In some embodiments, the amount administered is about 1000 mg. In some embodiments, the amount administered is up to about 2000 mg. In some embodiments, the amount administered is up to about 3000 mg. In some embodiments, the amount administered is up to the "no observed adverse event level" (NOAEL). These amounts, in any combination, can also serve as endpoints for a range of amounts to be administered, such as, for example, from about 2 mg to about 1000 mg, or from about 100 mg to about 500 mg.

[0070] In some embodiments, the amount administered is from about 2 mg to about 500 mg. In some embodiments, the amount administered is from about 10 mg to about 500 mg. In some embodiments, the amount administered is from about 30 mg to about 500 mg. In some embodiments, the amount administered is from about 50 mg to about 500 mg. In some embodiments, the amount administered is from about 100 mg to about 500 mg. In some embodiments, the amount administered is from about 100 mg to about 400 mg. In some embodiments, the amount administered is from about 100 mg to about 300 mg. In some embodiments, the amount administered is from about 100 mg to about 200 mg. In some embodiments, the amount administered is from about 150 mg to about 500 mg. In some embodiments, the amount administered is from about 150 mg to about 400 mg. In some embodiments, the amount administered is from about 150 mg to about 300 mg. In some embodiments, the amount administered is about 150 mg to about 200 mg. In some embodiments, the amount administered is about 30 mg to about 300 mg. In some embodiments, the amount administered is about 30 mg to about 200 mg. In some embodiments, the amount administered is about 30 mg to about 150 mg. In some embodiments, the amount administered is about 30 mg to about 100 mg. In some embodiments, the amount administered is about 50 mg to about 300 mg. In some embodiments, the amount administered is about 50 mg to about 200 mg. In some embodiments, the amount administered is about 50 mg to about 150 mg. In some embodiments, the amount administered is about 50 mg to about 100 mg. In some embodiments, the amount administered is about 75 mg to about 300 mg. In some embodiments, the amount administered is about 75 mg to about 200 mg. In some embodiments, the amount administered is about 75 mg to about 150 mg. In some embodiments, the amount administered is from about 75 mg to about 100 mg.The amounts above are stated as absolute amounts expressed in milligrams based on the amount administered to an average adult subject of about 70 kg. These absolute amounts expressed in mg are converted to amounts expressed in mg / kg body weight by multiplying the amounts provided above by a factor of about 0.015 (i.e., the 1 mg amount above corresponds to an amount of 0.015 mg / kg body weight).

[0071] For example, in some embodiments, the amount administered may be about 0.03 mg / kg body weight. In some embodiments, the amount administered may be about 0.14 mg / kg body weight. In some embodiments, the amount administered may be about 0.43 mg / kg body weight, and in some embodiments, the amount administered may be about 1.4 mg / kg body weight. In some embodiments, the amount administered may be about 2.2 mg / kg body weight. In some embodiments, the amount administered may be about 2.7 mg / kg body weight. In some embodiments, the amount administered may be about 4.3 mg / kg body weight. In some embodiments, the amount administered may be about 5.4 mg / kg body weight. In some embodiments, the amount administered may be about 6.75 mg / kg body weight. These amounts, in any combination, may also serve as endpoints for a range of amounts administered. For example, an amount of about 0.03 mg / kg to about 6.75 mg / kg, or an amount of about 1.4 mg / kg to about 6.75 mg / kg, or an amount of about 1.4 mg / kg to about 4.3 mg / kg, etc.

[0072] In some embodiments, the above amount of active agent is administered to the subject at one time (as a single dose).However, more typically, the above amount of active agent is administered to the subject more than once, i.e., in a series of multiple doses (two or more).The amount of active agent in each individual dose within such a series of multiple doses can be any of the amounts described above.

[0073] In some embodiments, a series of two or more doses is administered to the subject. In some embodiments, a series of three or more doses is administered to the subject. In some embodiments, a series of four or more doses is administered to the subject. In some embodiments, a series of five or more doses is administered to the subject. In some embodiments, a series of six or more doses is administered to the subject. In some embodiments, a series of seven or more doses is administered to the subject. In some embodiments, a series of eight or more doses is administered to the subject. In some embodiments, a series of nine or more doses is administered to the subject. In some embodiments, a series of ten or more doses is administered to the subject.

[0074] In some embodiments, the individual doses in the series of multiple doses are administered at intervals of about every 2 days (Q2D). In some embodiments, the individual doses in the series of multiple doses are administered at intervals of about every 3 days (Q3D). In some embodiments, the individual doses in the series of multiple doses are administered at intervals of about every 4 days (Q4D). In some embodiments, the individual doses in the series of multiple doses are administered at intervals of about every 5 days (Q5D). In some embodiments, the individual doses in the series of multiple doses are administered at intervals of about every 6 days (Q6D). In some embodiments, the individual doses in the series of multiple doses are administered at intervals of about every 7 days (Q7D / QW). In some embodiments, the individual doses in the series of multiple doses are administered to the subject at intervals of about every 8 days (Q8D). In some embodiments, the individual doses in the series of multiple doses are administered to the subject at intervals of about every 9 days (Q9D). In some embodiments, each dose in the series of multiple doses is administered to the subject at intervals of about every 10 days (Q10D). In some embodiments, each dose in the series of multiple doses is administered to the subject at intervals of about every 11 days (Q11D). In some embodiments, each dose in the series of multiple doses is administered to the subject at intervals of about every 12 days (Q12D). In some embodiments, each dose in the series of multiple doses is administered to the subject at intervals of about every 13 days (Q13D). In some embodiments, each dose in the series of multiple doses is administered to the subject at intervals of about every 14 days (Q14D / Q2W).

[0075] In some of those embodiments in which a series of multiple doses is administered to a subject, the doses are administered in two phases: an initial "induction" phase (sometimes also referred to as a "loading" phase) followed by a "maintenance" phase. The doses administered during the induction phase are referred to as induction doses. Similarly, the doses administered during the maintenance phase are referred to as maintenance doses.

[0076] In some embodiments, the frequency with which each dose is administered to the subject is greater during the induction phase than during the maintenance phase. In another mode, the time interval between administration of each dose is shorter during the induction phase than during the maintenance phase. For example, in one embodiment, each dose is administered to the subject about every 2 days (Q2D) during the induction phase, and then about every week (QW / Q7D) during the maintenance phase. Similarly, in one embodiment, each dose is administered to the subject about every 3 days (Q3D) during the induction phase, and then about every week (QW / Q7D) during the maintenance phase. In other embodiments, each dose is administered to the subject at any of the intervals / frequencies described above during the induction phase and at any of the intervals / frequencies described above during the maintenance phase, when the time interval between doses is shorter during the induction phase than during the maintenance phase.

[0077] In some embodiments, the amount of active agent administered in each dose during induction phase is greater than the amount administered in each dose during maintenance phase.For example, in some embodiments, each dose administered during induction phase comprises about 1.5 times, or about 2 times, or about 3 times, or about 4 times, or about 5 times the amount of active agent administered in each dose during maintenance phase.In some such embodiments, the frequency with which each dose is administered to a subject is the same during induction phase compared to maintenance phase, i.e., the amount administered in each dose is greater during induction phase than during maintenance phase, but the frequency of administration is the same.

[0078] In some embodiments, both the amount administered in each dose and the frequency with which each dose is administered are greater during the induction phase compared to the maintenance phase.

[0079] The following table includes non-limiting examples of methods according to the present invention that include both induction and maintenance phases for administration of an active agent. Many other examples of methods according to the present invention that include both induction and maintenance phases are provided elsewhere herein, such as in the Examples section of the present specification.

[0080] [Table 2]

[0081] In some embodiments, the total duration of the induction phase is about 1 week. In some embodiments, the total duration of the induction phase is about 2 weeks. In some embodiments, the total duration of the induction phase is about 3 weeks.

[0082] The total duration of the maintenance phase may be as long as desired, for example, as long as the subject feels benefit from the administration method, such as indefinitely. In some embodiments, the total duration of the maintenance phase is about 4 weeks. In some embodiments, the total duration of the maintenance phase is about 2 months. In some embodiments, the total duration of the maintenance phase is about 3 months. In some embodiments, the total duration of the maintenance phase is about 6 months. In some embodiments, the total duration of the maintenance phase is about 9 months. In some embodiments, the total duration of the maintenance phase is about 1 year or more.

[0083] In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration to about 0.5 micrograms / mL or less. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration to about 0.1 micrograms / mL or less. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration to about 0.05 micrograms / mL or less. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration to about 0.01 micrograms / mL or less. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration to about 0.005 micrograms / mL or less. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration to about 0.001 micrograms / mL or less.

[0084] In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 90%, or at least 90%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 95%, or at least 95%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 96%, or at least 96%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 97%, or at least 97%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 98%, or at least 98%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 99%, or at least 99%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 99.5%, or at least 99.5%, compared to the baseline serum free C5 concentration before administration of the active agent. In some embodiments, the active agent is administered in an amount and / or frequency effective to reduce serum free C5 concentration by about 99.9%, or at least 99.9%, compared to the baseline serum free C5 concentration before administration of the active agent.

[0085] In some embodiments, the active agent has a C of about 0.1 to about 10.0 micromolar of the active agent. max For example, in some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of about 1.0 to about 5.0 micromolar of the active agent.max In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of about 1.0 micromolar, or about 2.0 micromolar, or about 3.0 micromolar, or about 4.0 micromolar, or about 5.0 micromolar, or about 6.0 micromolar, or about 7.0 micromolar, or about 8.0 micromolar, or about 9.0 micromolar, or about 10.0 micromolar of the active agent. max The therapeutic agent is administered in an amount and / or at a frequency effective to achieve this.

[0086] In some embodiments, the active agent has a C of about 0.1 to about 10 micromolar of the active agent. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of about 0.5 to about 5.0 micromolar of the active agent. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 0.5 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 0.6 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 0.7 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 0.8 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 0.9 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.0 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.1 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.2 micromolar or greater. トラフIn some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.3 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.4 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.5 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.6 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.7 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.8 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.9 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 2.0 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 1.0 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 2.5 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 3.0 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 3.5 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 4.0 micromolar or greater. トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 4.5 micromolar or greater.トラフ In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a C of 5.0 micromolar or greater. トラフ The therapeutic agent is administered in an amount and / or at a frequency effective to achieve this.

[0087] In some embodiments, the active agent has a T of the active agent of about 24 to 72 hours. max For example, in some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a T of the active agent of about 24 hours. max In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a T of the active agent of about 48 hours. max In some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a T of the active agent of about 72 hours. max The therapeutic agent is administered in an amount and / or at a frequency effective to achieve this.

[0088] In some embodiments, the activator has a T of the activator of about 300 to 400 hours. 1 / 2 For example, in some embodiments, the active agent is administered in an amount and / or frequency effective to achieve a T of the active agent of about 350 hours. 1 / 2 The therapeutic agent is administered in an amount and / or at a frequency effective to achieve this.

[0089] In some embodiments, an active agent is administered to a subject in any of the amounts and / or according to any of the dosing schedules described in the Examples section of this disclosure.

[0090] In some embodiments, the active agent of the present invention is administered parenterally to a subject. Parenteral routes of administration include intravenous, intramuscular, intraperitoneal, intrathecal, and subcutaneous administration. In a preferred embodiment, the pharmaceutical composition of the present invention is administered subcutaneously. In some embodiments, the pharmaceutical composition of the present invention is administered as a low volume subcutaneous injection. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 2.5 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 2.25 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 2.0 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 1.75 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 1.5 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 1 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 0.75 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of 0.5 mL or less. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 2.5 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 2.25 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 2.0 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 1.75 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 1.5 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 1 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 0.75 mL. In some embodiments, the pharmaceutical composition of the present invention is administered as a subcutaneous injection having a volume of about 0.5 mL.

[0091] In some embodiments, an active agent of the present invention is administered to a subject by a health care provider. In some embodiments, an active agent of the present invention is administered to a subject by someone other than a health care provider, such as the subject themselves, a family member, a caregiver, etc. In some embodiments, an active agent of the present invention is self-administered. In some embodiments, an active agent of the present invention is administered using an autoinjector device.

[0092] In some embodiments, the active agent of the present invention is provided in an autoinjector. In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical composition according to the present invention. In some of such embodiments, the amount of pharmaceutical composition or active agent in the autoinjector can be any of the amounts described herein, for example, an amount suitable for administration as a single dose (such as one dose in a series of multiple doses) or an amount suitable for administration of two or more doses. In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical composition comprising a C5 binding protein at a concentration of about 100 mg / mL.

[0093] In some embodiments, the invention provides a kit comprising a pharmaceutical composition comprising an active agent of the invention and instructions for its use. In some embodiments, the invention provides a kit comprising a pharmaceutical composition comprising an active agent of the invention in an autoinjector and instructions for its use. In some embodiments, the invention provides a kit comprising a pharmaceutical composition comprising an active agent of the invention, an autoinjector, and instructions for its use.

[0094] In some embodiments, the active agents and pharmaceutical compositions provided herein are administered to a subject without causing a serious adverse event (AE) or without causing a serious adverse event (SAE).

[0095] The embodiments of the present disclosure can be more particularly defined by reference to the following non-limiting examples. It will be apparent to those skilled in the art that numerous modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure. EXAMPLES

[0096] Nonclinical Pharmacology The C5 binding protein of the invention was expressed in Escherichia coli from recombinant nucleic acid encoding SEQ ID NO:1, purified and formulated in phosphate buffered saline (PBS).

[0097] The specificity and affinity of binding of the C5 binding protein (73.46 mg / mL in PBS) to human C5 in vitro was determined by measuring the kinetics of binding to human C5 compared to binding to human C3, C4, and human IgG using surface plasmon resonance. C3 and C4 are the two most closely related proteins to C5, sharing approximately 30% overall protein sequence identity to human C5 (Wetsel et al., 1988, "Molecular Analysis of Human Complement Component C5: Localization of the Structural Gene to Chromosome 9:" Biochemistry; Vol. 27(5): pp. 1474-1482), and IgG is the original ligand of the affibody scaffold from which the C5 binding protein affibody protein was engineered. The C5 binding protein has a K of approximately 0.38 nM (K D ) while no physiologically relevant binding was observed to human C3, C4, or IgG. The results indicate at least a 4000-fold selectivity of the C5-binding protein for human C5 compared to C3, C4, and IgG.

[0098] In order to evaluate the activity of C5 binding protein in blocking complement C5 activation, a hemolysis assay of the classical complement pathway with antibody-sensitized sheep red blood cells was performed. C5 binding protein (0.0625, 0.125, 0.25, 0.5, 1, and 2 μM) was incubated ex vivo with human serum (pooled serum from multiple healthy donors) and the percentage of hemolysis was determined. The hemolytic activity reached >95% inhibition at a concentration of 0.5 μM of C5 binding protein, indicating that this concentration may be sufficient for complement blocking in human serum. The hemolysis inhibition data is shown in Figure 1. EXAMPLES

[0099] Phase 1 Single Ascending Dose and Multiple Ascending Dose Studies to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of C5-Binding Protein in Healthy Participants This is a single-blind, placebo-controlled Phase 1 study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending subcutaneous (SC) doses of a pharmaceutical composition comprising a C5 binding protein of the present invention (sometimes referred to herein as the "investigational drug") in healthy human subjects (herein referred to as study participants).

[0100] [Table 3]

[0101] Comprehensive Design The study is a single-blind, placebo-controlled, ascending-dose, multicenter study to evaluate the safety, tolerability, PK, and PD of single (Part A) and multiple (Part B) doses of C5-binding protein in healthy participants.

[0102] In both parts of the study, participants will enter a 70-day screening period after signing an informed consent form. Eligible participants will be enrolled and enter a treatment period (varies from 1 day to 4 weeks depending on the part of the study). After receiving their last dose, study participants will enter a 10-week follow-up period.

[0103] Part A Up to six ascending dose cohorts will be dosed sequentially in Part A of the study. Eight participants will be treated with a single dose of the investigational drug in each dose cohort (six participants per dose level will receive C5-binding protein and two participants will receive a matching dose of placebo). For each dose cohort, a sentinel group of two participants (one C5-binding protein and one placebo) will receive their assigned treatment, complete scheduled assessments, and undergo safety review up to 24 hours after dosing before continuing enrollment in the dose cohort. No more than four participants will be dosed on Day 1.

[0104] Escalation to the next higher dose level will occur only following completion of review of the clinical safety data by the Safety Review Committee.

[0105] Part B Up to five ascending multiple-dose cohorts will be enrolled sequentially in Part B of the study. The multiple-dose phase will begin after the Safety Review Committee reviews the safety data from the fifth cohort of the single-dose phase and reaches a consensus to proceed with the study.

[0106] In each dose cohort in Part B, 12 participants will be treated with the investigational drug for 4 weeks (10 participants per cohort will receive C5-binding protein and 2 participants per cohort will receive a matching dose of placebo). Escalation to the next higher dose level will occur only after completion of review of the clinical safety data and available PK data by the Safety Review Committee.

[0107] Number of participants Approximately 48 healthy male and female participants (8 participants in each of the 6 dose cohorts) will be included in Part A, and approximately 60 healthy male and female participants (12 participants in each of the 5 dose cohorts) will be included in Part B.

[0108] Eligibility Criteria The inclusion and exclusion criteria for the studies were as follows:

[0109] [Table 4]

[0110] [Table 5]

[0111] research intervention C5 binding protein (purified after expression in E. coli from recombinant nucleic acid encoding SEQ ID NO:1) is provided in a sterile, preservative-free, clear or slightly opalescent liquid formulation containing 100 mg / mL C5 binding protein buffered to a target pH of 7.0 in a formulation containing histidine, arginine, polysorbate 20, and water for injection, and provided in single-dose borosilicate glass vials. Placebo is 0.9% saline (sodium chloride). C5 binding protein is stored at 2-8°C and allowed to come to room temperature for dilution prior to use and administration.

[0112] [Table 6]

[0113] In Part A, up to 48 healthy participants will be enrolled in up to six sequential ascending dose cohorts (8 participants / cohort). Participants will receive a single dose of subcutaneously (SC) C5 binding protein (2, 10, 30, 100, 150, and 300 mg) or placebo.

[0114] In Part B, up to 60 healthy participants will be enrolled in up to five cohorts (12 participants / cohort) to receive C5 binding protein (escalating doses) or placebo in a SC setting, as follows:

[0115] Cohorts 1, 2, and 3: 100 mg, 150 mg, or 300 mg once weekly (QW) (days 1, 8, 15, 22, and 29), respectively.

[0116] Cohort 4: 100 mg or 150 mg on days 1 and 4 (first week) and QW thereafter (days 8, 15, 22, and 29).

[0117] Cohort 5: 100 mg or 150 mg on days 1, 3, and 5 (first week) and QW thereafter (days 8, 15, 22, 29).

[0118] Administered doses of 2, 10, 30, 100, 150 and 300 mg correspond to approximate doses of 0.03, 0.14, 0.43, 1.4, 2.15, 4.3 mg / kg body weight, based on a 70 kg human.

[0119] Details of these study interventions are also presented in the table below.

[0120] [Table 7]

[0121] Dose modification The dosing schedule may be adjusted to expand dosing cohorts, to further evaluate safety, tolerability, PK, and / or PD findings at a given dose level, or to remove or add cohorts to evaluate additional doses up to the maximum feasible dose without exceeding the NOAEL exposure (area under the concentration-time curve [AUC] or maximum plasma concentration [Cmax]) of 48 mg / kg. Study procedures for these additional participants / cohorts will be the same as those described for the other study participants / cohorts.

[0122] For example, Cohort 3 of Part B may be modified to administer 50 mg, or 75 mg, or 80 mg, or 90 mg, or 125 mg, or 150 mg, or 200 mg once weekly (QW) (on days 1, 8, 15, 22, and 29).

[0123] Similarly, Cohort 4 of Part B may be modified to administer 50 mg, or 75 mg, or 80 mg, or 90 mg, or 100 mg, or 125 mg, or 150 mg, or 200 mg on days 1 and 4 (first week) and QW thereafter (days 8, 15, 22, 29).

[0124] Similarly, Cohort 5 of Part B may be modified to administer 50 mg, or 75 mg, or 80 mg, or 90 mg, or 100 mg, or 125 mg, or 150 mg, or 200 mg on days 1, 3, and 5 (first week) and QW thereafter (days 8, 15, 22, 29).

[0125] Safety Review Committee Throughout the duration of the study, the Safety Review Committee will continually evaluate all data and monitor the overall safety of study participants in regular meetings. EXAMPLES

[0126] Clinical trial results The Phase 1 clinical trial described in Example 2 is ongoing. Dosing in Part A of the study has been completed with a protocol change made to remove Cohort 5. Participants in the remaining cohorts of Part A of the study, which included administration of ascending single doses of the investigational drug, have already been dosed, and the first four cohorts have completed the 10-week follow-up period. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were performed on Cohorts 1-4 of Part A (i.e., 2, 10, 30, and 100 mg single doses). In Part A, Cohort 6 (300 mg single dose) analysis of PK and PD data is ongoing. Cohort 5 (150 mg single dose) of Part A was omitted from the study (no subjects were dosed in Cohort 5).

[0127] A safety review committee (SRC) evaluated data from all dosed cohorts. Safety was assessed for each of cohorts 1-4 prior to initiating the subsequent higher dose cohorts. In each case, the safety review committee determined that although some mild or moderate adverse events were observed, safety and tolerability were acceptable for progression to the subsequent higher dose cohorts. No drug-related serious adverse events were reported in any dosed cohort. The PK data obtained to date from Cohorts 1-4 are summarized below in Table 8. Additional PK data are also presented in Figure 2 (Cohorts 1-4) and Figure 3 (Cohort 4).

[0128] [Table 8]

[0129] In Table 8, the data presented are average data obtained from the number of samples (N) indicated and are reported as "R sq " means the statistical measure of correlation R-squared, T 1 / 2 means the half-life of the investigational drug in serum (i.e., the time it takes for the concentration of the investigational drug in serum to decrease by 50%), expressed in hours, and T maxis the maximum concentration (C) of the investigational drug in serum after administration, expressed in hours. max ) and C max means the maximum concentration of the investigational drug in serum, expressed in micromolar (μM), and T last means the time of last measurement of the investigational drug concentration in serum expressed in hours, AUCINF_obs means the area under the concentration-time curve extrapolated to infinity, V means the apparent volume of distribution expressed in liters (L), and CL means the clearance expressed in liters per hour (L / hr).

[0130] Treatment of subjects with the investigational drug reduced the measured serum free C5 in a concentration-dependent manner (see Figures 4A and 4B). Table 9 provides free C5 data for Cohort 4 (100 mg, administered in 1 mL subcutaneous injection), showing baseline (pre-dose) free C5 levels and free C5 concentrations 24 hours after administration in six subjects. The mean free C5 concentration was reduced to 567 ng / ml (i.e., 0.567 micrograms / ml), which represents a mean reduction in free C5 concentrations of 99.4% compared to pre-treatment baseline.

[0131] [Table 9]

[0132] PK data obtained from cohorts 1-4 in Part A were used as input data for multi-dose pharmacokinetic modeling, which was performed using accepted PK modeling methods. The results of these modeling studies for the 100 mg and 150 mg doses administered using various dosing regimens are provided in Figures 5A-E. These results show that in each case, C5 binding protein rapidly reached serum concentrations above 2 μM, and serum concentrations were consistent throughout the trough (C トラフ), the concentration level above 2 μM is maintained. The 2 μM concentration level is shown in the graphs of Figures 5A-E. This is significant because the single dose data described in this Example shows that even at an average serum concentration of C5 binding protein of 1.3 μM, serum free C5 concentrations are reduced by more than 99%, and the hemolysis inhibition data described in Example 1 shows that complete inhibition of hemolysis is achieved at concentrations of C5 binding protein of 0.5 μM or higher. Thus, both the data from the single dose study (which showed sustained C5 binding protein concentrations and good C5 control over time) and the multi-dose modeling data show favorable PK and PD profiles for C5 binding protein, with weekly or even less than weekly dosing resulting in effective free C5 reduction over time.

[0133] In conclusion, the results of this Phase 1 clinical trial obtained to date demonstrate that subcutaneous administration of the C5 binding protein provided herein, at doses that can be administered in a low-volume subcutaneous injection, provides free C5 reductions (as determined by a reduction in free C5 concentrations) similar to those achieved by approved anti-C5 therapies, and has pharmacokinetic properties consistent with providing sustained C5 control over time without the need for frequent (e.g., daily) administration.

[0134] The invention is further described by the following claims.

Claims

1. A pharmaceutical composition comprising a C5-binding protein and at least one additional pharmaceutically acceptable ingredient for use in a method for reducing the amount of free C5 in a human subject or inhibiting activation of the terminal complement pathway in a human subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a C5-binding protein and at least one additional pharmaceutically acceptable ingredient; i. the C5 binding protein comprises SEQ ID NO: 1; ii. A pharmaceutical composition, wherein the pharmaceutical composition is administered subcutaneously to a subject.

2. 2. The pharmaceutical composition of claim 1, wherein the serum free C5 concentration is reduced to about 0.5 micrograms / mL or less.

3. 2. The pharmaceutical composition of claim 1, wherein the serum free C5 concentration is reduced to about 0.1 micrograms / mL or less.

4. 10. The pharmaceutical composition of claim 1, wherein the administering step comprises administering a series of two or more doses of the pharmaceutical composition to the subject at approximately weekly intervals (QW).

5. 5. The pharmaceutical composition of claim 4, wherein each administered dose comprises from about 50 mg to about 450 mg of C5-binding protein.

6. 5. The pharmaceutical composition of claim 4, wherein each administered dose comprises from about 100 mg to about 450 mg of C5-binding protein.

7. 5. The pharmaceutical composition of claim 4, wherein each administered dose comprises from about 100 mg to about 350 mg of C5-binding protein.

8. 10. The pharmaceutical composition of claim 1, wherein the administering step comprises administering to the subject (a) one or more induction doses of the pharmaceutical composition, and (b) one or more maintenance doses of the pharmaceutical composition.

9. 2. The pharmaceutical composition of claim 1, wherein the C5 binding protein is administered to the subject at a dose and / or frequency effective to achieve a serum concentration of the C5 binding protein of about 0.5 to about 5.0 micromolar.

10. The C5 binding protein has a C5 binding protein concentration of about 0.1 to about 10.0 micromolar. max The pharmaceutical composition of claim 1, administered to a subject at a dose and / or frequency effective to achieve the above.

11. 2. The pharmaceutical composition of claim 1, wherein the C5 binding protein is administered to the subject at a dose and / or frequency effective to achieve a C trough of about 0.1 to about 10 micromolar C5 binding protein.

12. A pharmaceutical composition comprising a C5-binding protein comprising SEQ ID NO: 1, histidine, arginine, polysorbate 20, and water.

13. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises about 20 mM histidine, about 150 mM arginine, about 0.05% polysorbate 20, and water.

14. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises about 100 mg / ml of C5-binding protein.

15. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is stable for more than 6 months when stored at about 2°C to about 8°C.

16. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is stable for up to about 1 week when stored at about 15°C to about 25°C.

17. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is stable for more than one week when stored at about 15°C to about 25°C.

18. 13. An automatic injection device comprising the pharmaceutical composition of claim 12.

19. 20. The autoinjector of claim 18, wherein the pharmaceutical composition comprises about 20 mM histidine, about 150 mM arginine, about 0.05% polysorbate 20, and water.

20. 20. The automatic injection device of claim 18, wherein the pharmaceutical composition comprises about 100 mg / ml of C5 binding protein.

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