Pharmaceutical products and stable liquid compositions of il-17 antibodies

Abstract

The present disclosure relates to pharmaceutical products and stable liquid compositions of IL-17 antibodies and antigen-binding fragments thereof, such as AIN457 (secukinumab), and processes for manufacturing these pharmaceutical products and compositions. The present disclosure also relates to the use of these pharmaceutical products and liquid compositions (e.g., as part of a kit with instructions for use) for the treatment of various IL-17-mediated diseases (e.g., autoimmune diseases, such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis).

Description

[0001] Related applications

[0002] The present application is a divisional application of Chinese invention patent application No. 201580076632.9, whose invention name is “Drug product and stable liquid composition of IL-17 antibody” and whose application date is December 21, 2015.

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 095210, filed December 22, 2014, which is incorporated herein by reference in its entirety. Technical Field

[0004] The present disclosure relates to drug products comprising stable liquid pharmaceutical compositions of IL-17 antibodies and antigen-binding fragments thereof, such as AIN457 (secukinumab), and processes for making these drug products and liquid pharmaceutical compositions. Background Art

[0005] IL-17A is a central lymphokine of the newly defined inflammatory T cell subset, Th17 cells, which are crucial in several autoimmune and inflammatory processes. Neutralization of IL-17A is expected to treat the underlying pathophysiology of immune-mediated diseases, thereby providing symptom relief. Secukinumab (AIN457), a high-affinity, fully human monoclonal anti-human antibody that inhibits IL-17A activity, has emerged as a potential treatment for patients with various autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, diabetes, asthma, chronic plaque psoriasis, and multiple sclerosis. Several Phase II and Phase III studies have shown that secukinumab is superior to placebo in achieving PASI 75 in the treatment of chronic plaque psoriasis (e.g., in study CAIN457A2220, both secukinumab 3 × 150 mg and 3 × 75 mg were superior to placebo in achieving PASI 75 at Week 12 (81.5% and 57.1%, respectively, versus 9.1%). Secukinumab is currently being studied in a global Phase III study for the treatment of chronic plaque psoriasis, where it has also been shown to be superior to placebo and has recently been shown to be superior to etanercept.

[0006] International Patent Application PCT / EP2011 / 069476 provides a sucrose-based secukinumab lyophilized composition that is reconstituted with 1 mL of water just prior to use. However, PCT / EP2011 / 069476 does not disclose a secukinumab ready-to-use drug product or liquid pharmaceutical composition having long-term stability. In fact, the marginal stability of proteins in liquid compositions often precludes long-term storage at room temperature or refrigerated conditions. In addition, various physical and chemical reactions can occur in solution (aggregation [covalent and non-covalent], deamidation, oxidation, shear, isomerization, denaturation), leading to increased levels of degradation products and / or loss of biological activity. Commercial ready-to-use liquid antibody compositions should provide sufficient physical and chemical stability of the antibody during shipping and handling to ensure that the requirements for dose and product safety are met when the molecule is administered to a patient. Specifically, an acceptable liquid antibody composition must enhance stability and minimize protein degradation, particularly protein aggregation, to avoid serious immunogenic reactions. Moreover, the composition must also have an acceptable osmolarity and pH for subcutaneous application, and have low viscosity as a prerequisite for manufacturing (compounding, filtration, filling) and injectability. Balancing so many requirements is difficult, making the production of a commercially viable aqueous biopharmaceutical composition a technical challenge.

[0007] Despite the technical challenges outlined above, we have now successfully developed novel and beneficial ready-to-use drug products and liquid pharmaceutical compositions of the IL-17 antibodies and antigen-binding fragments described herein (e.g., secukinumab). SUMMARY

[0008] The present disclosure provides drug products comprising a container (e.g., pen, syringe, vial, auto-injector) and a liquid composition disposed within the container, the headspace of the container comprising less than about 12% oxygen (e.g., less than about 10% oxygen, less than about 8% oxygen, less than about 6% oxygen, etc.). The liquid composition is not reconstituted from a lyophilisate, but is a ready-to-use liquid composition and generally comprises at least one disclosed IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab), a buffer, a surfactant, methionine, and a stabilizer, and subcombinations thereof. We have found that the combined use of specific stabilizers and low oxygen content in the headspace of the container significantly contributes to the long-term stability of the liquid drug product and prevents oxidation of the IL-17 antibody (e.g., secukinumab) contained in the composition. These liquid compositions have excellent properties, e.g.,

[0009] Aggregates are formed < 3.5% (for 2.5 mM methionine), < 3.0% (for 5 mM) and < 2.2% (for compositions containing 20 mM methionine) by SEC after 13 months storage at 25 °C; and

[0010] After 13 months of storage at 25 °C, the degradation products (sum of variants before main peak) were measured by RP-HPLC to be < 39.4% (for 2.5 mM), < 37.8% (for 5.0 mM), and < 34.5% (for the composition containing 20 mM methionine).

[0011] The present disclosure thus provides a pharmaceutical product comprising a container having a headspace and a liquid pharmaceutical composition having a pH of about 5.2 to about 6.2 disposed within the container, wherein the oxygen content in the headspace is less than about 12%, the composition comprising about 20 mg / ml to about 175 mg / ml secukinumab and about 2.5 to about 20 mM L-methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilisate.

[0012] The present disclosure also provides a pharmaceutical product comprising a container having a headspace and a liquid pharmaceutical composition disposed within the container, wherein the oxygen content in the headspace is less than about 6%, the composition comprising about 25 mg / mL to about 150 mg / mL of an IL-17 antibody described herein (e.g., secukinumab), about 10 mM to about 30 mM histidine at pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilisate.

[0013] The present disclosure also provides a method of reducing oxidation of secukinumab, the method comprising: preparing a liquid composition having a pH of about 5.2 to about 6.2 and comprising about 25 mg / ml to about 150 mg / ml of an IL-17 antibody described herein (e.g., secukinumab) and about 2.5 mM to about 20 mM methionine; disposing the liquid composition in a container having a headspace; and adjusting the oxygen content in the headspace to be less than or equal to about 12%.

[0014] The present disclosure also provides a stable liquid pharmaceutical composition comprising about 25 mg / mL to about 150 mg / mL of an IL-17 antibody described herein (e.g., secukinumab), about 10 mM to about 30 mM buffer (e.g., histidine) at pH 5.8, about 200 mM to about 225 mM stabilizer (e.g., trehalose), about 0.02% surfactant (e.g., polysorbate 80), and about 2.5 mM to about 20 mM methionine.

[0015] The present disclosure also relates to the use of these pharmaceutical products and stable liquid compositions for the treatment of various IL-17 mediated diseases (e.g., autoimmune diseases, such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), as well as kits comprising these pharmaceutical products and stable liquid compositions.

[0016] Other compositions, products, methods, protocols, uses, and kits are provided in the following description and appended claims. Other features, advantages, and aspects of the present disclosure will become apparent to those of ordinary skill in the art upon reading the following description and appended claims. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 A-D show the influence of different antioxidant stabilizers on the stability of 150 mg / ml infliximab liquid in syringes: parameter estimation of 1 pm sub-visible particles (particles / ml) after 8 weeks storage at 5°C by light block method (A), substance before main peak (%) after 8 weeks storage at 25°C by RP-HPLC (B), DP-SEC (%) after 8 weeks storage at 40°C (C), AP-SEC (%) after 8 weeks storage at 40°C (D).

[0018] Figure 2 A-D show the influence of different antioxidant stabilizers on the stability of 150 mg / ml infliximab liquid in syringes: parameter estimation of 1 pm sub-visible particles (particles / ml) after 8 weeks storage at 5°C by light block method (A), substance before main peak (%) after 8 weeks storage at 25°C by RP-HPLC (B), DP-SEC (%) after 8 weeks storage at 40°C (C), AP-SEC (%) after 8 weeks storage at 40°C (D).

[0019] Figure 3 A-D show the influence of different antioxidant stabilizers on the stability of 150 mg / ml infliximab liquid in syringes: parameter estimation of 1 pm sub-visible particles (particles / ml) after 8 weeks storage at 5°C by light block method (A), substance before main peak (%) after 8 weeks storage at 25°C by RP-HPLC (B), DP-SEC (%) after 8 weeks storage at 40°C (C), AP-SEC (%) after 8 weeks storage at 40°C (D).

[0020] Figure 4 A and B show the influence of L-methionine concentration on the stability of 150 mg / ml infliximab liquid in syringes in the presence of 5 mM and 0 mM L-methionine AP-SEC (%) (A) and substance before main peak (%) by RP-HPLC (B) upon storage at 5°C.

[0021] Figure 5 A and B show the influence of L-methionine concentration on the stability of 150 mg / ml infliximab liquid in syringes in the presence of 5 mM and 0 mM L-methionine AP-SEC (%) (A) and substance before main peak (%) by RP-HPLC (B) upon storage at 5°C.

[0022] Figure 6A and B show the influence of L-methionine concentration on the stability of 25 mg / ml secukinumab liquid in vials (10% headspace oxygen content) after 3 months storage at 40°C: AP-SEC (%) (A) and sum of impurities (non-reduced) (%) measured by CE-SDS (B).

[0023] Figure 7 A and B show the influence of L-methionine concentration on the stability of 25 mg / ml secukinumab liquid in vials (10% headspace oxygen content) after 3 months storage at 40°C: AP-SEC (%) (A) and sum of impurities (non-reduced) (%) measured by CE-SDS (B).

[0024] Figure 8 A-D show the influence of headspace oxygen content and fill volume on the AP-SEC (%) of 150 mg / ml secukinumab liquid in syringes after storage at 25°C (A, B) and 5°C (C, D). Fill volume for A and C is 0.5 mL. Fill volume for B and D is 1.0 mL.

[0025] Figure 9 A and B show the influence of L-methionine concentration on the stability of 25 mg / ml secukinumab liquid in vials (10% headspace oxygen content) after 3 months storage at 40°C: AP-SEC (%) (A) and sum of impurities (non-reduced) (%) measured by CE-SDS (B).

[0026] Figure 10 A and B show the influence of L-methionine concentration on the stability of 25 mg / ml secukinumab liquid in vials (10% headspace oxygen content) after 3 months storage at 40°C: AP-SEC (%) (A) and sum of impurities (non-reduced) (%) measured by CE-SDS (B).

[0027] Figure 11 A and B show the influence of L-methionine concentration on the stability of 25 mg / ml secukinumab liquid in vials (10% headspace oxygen content) after 3 months storage at 40°C: AP-SEC (%) (A) and sum of impurities (non-reduced) (%) measured by CE-SDS (B).

[0028] Figure 12 A and B show the influence of L-methionine concentration on the stability of 25 mg / ml secukinumab liquid in vials (10% headspace oxygen content) after 3 months storage at 40°C: AP-SEC (%) (A) and sum of impurities (non-reduced) (%) measured by CE-SDS (B).

[0029] Figure 13 A-D show the influence of pH on the stability of 150 mg / ml secukinumab liquid in syringes after storage at 5°C: turbidity (NTU) (A), purity (%) measured by SEC (B), acidic variants (%) measured by CEX (C), AP-SEC (%) (D).

[0030] Figure 14Effect of stabilizers on the stability of 150 mg / ml infliximab liquid in syringe after 8 weeks storage at 25°C: estimation of the parameters of AP-SEC.

[0031] Figure 15 Effect of surfactants on the stability of 150 mg / ml infliximab liquid in syringe after shaking: estimation of the parameters of >1 μm insoluble microparticles (particles / ml) measured by light block method.

[0032] Figure 16 A-D Effect of buffer type on the stability of 150 mg / ml infliximab liquid in syringe: estimation of the parameters of AP-SEC after freeze-thaw stress (A), AP-SEC after shaking stress (B), material before main peak measured by RP-HPLC after 8 weeks storage at 25°C (C), DP-SEC after shaking stress (D). DETAILED DESCRIPTION

[0033] The term "comprising" encompasses the meaning of "including" as well as "consisting of" e.g. a composition "comprising" X can consist exclusively of X or can include something additional, e.g. X + Y.

[0034] The term "about" in relation to a numerical value x means ± 10%, unless otherwise indicated by the context.

[0035] "Monthly" means about every 4 weeks (e.g. every 4 weeks), which is about every 28 days (e.g. every 28 days).

[0036] The term "antibody" as used herein refers to whole antibodies and any antigen binding fragments or single chains thereof. A naturally occurring "antibody" is a glycoprotein comprising at least two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as V H H) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as V L L) and a light chain constant region. The light chain constant region comprises one domain, CL. The V H H) and V L regions can be further subdivided: interspersed between regions of more conserved sequence called framework regions (FR) are regions of hypervariability, termed hypervariable regions or complementarity determining regions (CDRs). Each V H H) and V Lcomprise three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable region of the heavy and light chains contains a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. In some embodiments of the disclosed methods, protocols, kits, processes, uses, and compositions, an IL-17 antibody or an antibody to an IL-17 receptor is employed, preferably an antibody to IL-17, such as secukinumab.

[0037] An "isolated antibody," as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds IL-17 is substantially free of antibodies that specifically bind antigens other than IL-17). The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. The term "human antibody," as used herein, is intended to include antibodies having variable regions in which the framework and CDR regions are of human origin. "Human antibodies" need not necessarily be produced by human, human tissue or human cells. The human antibodies disclosed herein can contain amino acid residues not encoded by human sequences (e.g., mutations introduced by way of random or site-directed mutagenesis in vitro, by addition of N-nucleotides at junctions during recombination of antibody genes in vivo, or by somatic mutation in vivo). In some embodiments of the disclosed methods, protocols, kits, processes, uses, and compositions, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody.

[0038] The term "antigen-binding fragment" of an antibody, as used herein, refers to fragments of an antibody that retain the ability to specifically bind to an antigen, such as IL-17. It has been shown that the antigen binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the V L , V H , CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the V H and CH1 domains; a Fv fragment consisting of the V L and V H domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989 Nature 341 :544-546), which consists of a V HDomain composition; and isolated CDRs. Exemplary antigen-binding sites include the CDRs of secukinumab, as shown in SEQ ID NOs: 1-6 and 11-13 (Table 1), preferably the heavy chain CDR3. Moreover, although the two domains V L and V H Encoded by separate genes, they can be recombinantly linked via synthetic linkers, allowing them to be produced as a single protein chain, with V L and V H The domains are paired to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., 1988 Science 242:423-426; Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883). These single-chain antibodies are also encompassed by the term "antibody". Single-chain antibodies and antigen-binding fragments can be obtained using conventional techniques known to those skilled in the art. In some embodiments of the disclosed methods, protocols, kits, processes, uses, and compositions, single-chain antibodies or antigen-binding fragments directed against IL-17 (e.g., secukinumab) or IL-17 receptor antibodies are used.

[0039] The term "drug product" refers to a container (e.g., a pen, syringe, bag, pump, etc.) in which a pharmaceutical composition is placed. A "container" refers to any means of holding a liquid pharmaceutical composition, such as a pen, syringe, vial, autoinjector, patch, etc. Each container has a "head space," which is an area within the container that does not contain a liquid pharmaceutical composition. This head space contains a gas, such as a mixture of oxygen and other gases commonly found in air. The oxygen content in the head space can be adjusted, for example, by introducing an inert gas (e.g., nitrogen, argon, etc.) into the head space to replace oxygen. This can be achieved actively (e.g., by purging), or passively (by, for example, placing the container in a system and removing oxygen (e.g., by vacuum, etc.). Purging (e.g., using an inert gas, preferably nitrogen) can occur before the composition is filled into the container, during the filling process, or before and during the placement of the stopper. As used herein, the term "oxygen content in the head space" refers to the percentage of oxygen found in the head space of a given container.

[0040] A "stable" composition is one in which the protein therein substantially maintains its stability (e.g., physical, chemical, and / or biological activity) upon storage. A variety of analytical techniques for determining protein stability are known in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee, Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be tested at a selected temperature for a selected time period. A "stable" liquid antibody composition is one that shows no appreciable change upon storage at refrigerated temperatures (2-8°C) for at least 6 months, 12 months, preferably 2 years, more preferably 3 years, or at room temperature (23-27°C) for at least 3 months, preferably 6 months, more preferably 1 year, or at stress conditions (-40°C) for at least 1 month, preferably 3 months, more preferably 6 months. Various criteria for stability can be used, such as no more than 10%, preferably 5% degradation of the antibody monomer (e.g., as determined by SEC purity, RP-HPLC purity, CEX purity, CE-SDS purity (non-reducing), etc.). Alternatively, stability can be shown if the solution remains clear to slightly opalescent upon visual analysis or by use of a hazemeter. Alternatively, stability can be shown if the change in concentration, pH, and osmolality of the composition is no more than ±10% after a given time period, e.g., at least 3 months, preferably 6 months, more preferably 1 year. Alternatively, stability can be shown if the potency (e.g., as measured by biological activity among others, such as inhibition or CEX) is within 70-130% (e.g., at least 70%, at least 75%, at least 76%, at least 80%, at least 90%, at least 91%, at least 95%), preferably 80-120% of a control, after a given time period, e.g., at least 3 months, preferably 6 months, more preferably 1 year. Alternatively, stability can be shown if the observed clipping of the antibody is no more than 10%, preferably 5% (e.g., as determined by DP-SEC, etc.) after a given time period, e.g., at least 3 months, preferably 6 months, more preferably 1 year. Alternatively, stability can be shown if the formation of aggregates is less than 10%, preferably less than 5% (e.g., as determined by AP-SEC, etc.) after a given time period, e.g., at least 3 months, preferably 6 months, more preferably 1 year. Alternatively, stability can be shown if the formation of aggregates is ≤ about 3.5%, ≤ about 3.0%, or ≤ about 2.2% as measured by SEC after 13 months of storage at 25°C. Alternatively, stability can be shown if the formation of degradation products (as measured by RP-HPLC (material before main peak)) is ≤ about 39.4%, ≤ about 37.8%, or ≤ about 34.5% after 13 months of storage at 25°C.

[0041] An antibody retains its physical stability in a pharmaceutical composition if there is no significant increase in aggregation, precipitation, and / or denaturation of the antibody as measured by visual inspection of color and / or clarity (turbidity), or by ultraviolet light scattering, size exclusion chromatography (SEC), and dynamic light scattering (DLS). In addition, the protein conformation should not have changed significantly, for example, as assessed by fluorescence spectroscopy (determining protein tertiary structure) or by FTIR spectroscopy (determining protein secondary structure).

[0042] An antibody retains its chemical stability in a pharmaceutical composition if the antibody shows no significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often alter the chemical structure of a protein include hydrolysis or clipping (assessed by methods such as size exclusion chromatography [SEC] and SDS-PAGE), oxidation (assessed by methods such as peptide mapping in conjunction with mass spectrometry or MALDI / TOF / MS), deamidation (assessed by methods such as cation exchange chromatography (CEX), capillary isoelectric focusing, peptide mapping, isoaspartate determination), and isomerization (assessed by determining isoaspartate content, peptide mapping, etc.).

[0043] An antibody retains its biological activity in a pharmaceutical composition if the biological activity of the protein / antibody at a given time is within a predetermined range of the biological activity exhibited when the pharmaceutical composition was prepared. The biological activity of an antibody can be determined, for example, by antigen binding ELISA assay, potency assay (e.g., assessing the ability of an IL-17 antibody (e.g., secukinumab) to bind IL-17 and inhibit IL-6 release from chondrocytes), or cysteamine-CEX derivatization.

[0044] "RP-HPLC purity" is used herein to mean the percentage of the main peak in RP-HPLC and can be used to assess the stability of secukinumab. RP-HPLC separates secukinumab and variants thereof based on hydrophobicity. The material before the main peak of RP-HPLC is the sum of the percentage of peaks eluted before the main peak and can include fragmented, isomerized, and oxidized material of the antibody.

[0045] "CEX purity" is used herein to mean the percentage of the main peak in CEX and can be used to assess the stability of secukinumab antibody. CEX is used to assess the charge heterogeneity of secukinumab by determining the percentage of acidic and basic variants.

[0046] "SEC purity" is used herein to refer to the percentage of monomer in SEC and can be used to assess the stability of secukinumab. SEC is used to separate monomeric secukinumab from aggregates and fragments based on size under non-denaturing conditions. The sum of the peaks eluting before the main peak is reported as the percentage of aggregate products (AP-SEC) and the sum of the peaks eluting after the main peak is reported as the percentage of degradation products (DP-SEC).

[0047] "CE-SDS purity" is used herein to refer to the percentage of intact antibody in CE-SDS and can be used to assess the stability of secukinumab. CE-SDS is used to separate by-products and degradation products from intact secukinumab based on molecular size under non-reducing conditions. The sum of the peaks separated from the main peak is reported as the percentage of impurities.

[0048] "Liquid pharmaceutical composition" is used herein to refer to an aqueous composition that is not reconstituted from a lyophilisate and comprises at least one IL-17 antibody or antigen binding fragment thereof (e.g. secukinumab) and at least one other excipient (e.g. a buffer). The liquid pharmaceutical composition can comprise other excipients (stabilizers, surfactants) and other active ingredients. Such a formulation is also referred to as a "ready-to-use" formulation.

[0049] The term "lyophilisate" is used herein to refer to a substantially water-free, dry (e.g. freeze-dried) pharmaceutical composition. Antibody lyophilization techniques are well known in the art, see for example Rey and May (2004) Freeze-Drying / Lyophilization of Pharmaceutical & Biological Products ISBN 0824748689. Reconstitution of a lyophilisate results in an aqueous composition, which is typically used immediately (e.g. within 1-10 days) as lyophilisates often have a limited shelf life after reconstitution.

[0050] The term "high concentration" refers to a composition comprising more than 50 mg / ml of an antibody or antigen binding fragment thereof. In preferred embodiments, the high concentration liquid composition comprises > about 50 mg / ml, > about 75 mg / ml, > about 100 mg / ml, > about 125 mg / ml, > about 150 mg / ml, > about 175 mg / ml, > about 200 mg / ml or > about 225 mg / ml.

[0051] The term "IL-17" refers to IL-17A, formerly known as CTLA8, and includes wild-type IL-17A, polymorphic variants of IL-17A, and functional equivalents of IL-17A from different species (e.g., human, mouse, and monkey). Functional equivalents of IL-17A according to the present disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with wild-type IL-17A (e.g., human IL-17A) and substantially retain the ability to induce IL-6 production in human dermal fibroblasts.

[0052] The term "K D ” is intended to indicate the dissociation rate of a particular antibody-antigen interaction. As used herein, the term “K D " is intended to represent the dissociation constant, which is derived from K d Relative to K a The ratio of K d / K a ) and expressed as molar concentration (M). D The value can be determined using methods that have long been used in the art. D One way to do this is by using surface plasmon resonance, or using biosensor systems such as In some embodiments, the K of the IL-17 antibody or antigen-binding fragment thereof that binds to human IL-17 is D About 100-250pM (through measured).

[0053] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody "arm" interacts with the antigen at many sites through weak non-covalent forces; the more interactions, the stronger the affinity. Standard assays for evaluating the binding affinity of antibodies for IL-17 of various species are known in the art, including, for example, ELISA, Western blotting, and RIA. Binding kinetics (e.g., binding affinity) can also be assessed by standard assays known in the art, such as by analyze.

[0054] The terms "subject" and "patient" as used herein include any human or non-human animal. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

[0055] An antibody that "inhibits" one or more of these IL-17 functional properties (e.g., biochemical, immunochemical, cellular, physiological, or other biological activities, etc.) as determined by methods known in the art and as described herein, is understood to correlate with a statistically significant decrease in the particular activity relative to the absence of the antibody (or presence of a control antibody of unrelated specificity). An antibody that inhibits IL-17 activity causes a statistically significant decrease in the measured parameter, e.g., a decrease of at least about 10%, at least 50%, 80%, or 90%, in some embodiments of the disclosed methods, uses, processes, kits, and compositions, the IL-17 antibody used can inhibit more than 95%, 98%, or 99% of the functional activity of IL-17.

[0056] As used herein, "inhibits IL-6" refers to the ability of an IL-17 antibody (e.g., secukinumab) to decrease IL-6 production from chondrocytes. The biological activity of an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) can be determined based on its ability to inhibit IL-17-induced release of IL-6 by an immortalized human chondrocyte cell line, such as C-20 / A4. Briefly, on day one of the assay, C-20 / A4 cells are seeded into a 96-well plate, allowed to adhere, and then incubated overnight in the presence of a fixed submaximal concentration of IL-17 (e.g., about 20-200 ng / mL, e.g., about 80 ng / mL, in culture medium) and various concentrations of antibody (e.g., about 0.01 μg / mL to about 4 μg / mL, e.g., about 0.5 μg / mL to about 2 μg / mL, in the assay plate). TNF alpha (e.g., about 0.01 ng / mL to about 1 ng / mL, e.g., about 0.5 ng / mL, in culture medium) is also included to increase the dynamic range of the assay, as it promotes IL-17-induced IL-6 production. On day two, the IL-6 concentration in the cell supernatant is quantified by ELISA. The amount of IL-6 in the cell supernatant is inversely proportional to the activity of the IL-17 antibody present in the sample. The biological activity of the antibody test sample is quantified by comparing its ability to inhibit IL-17-dependent IL-6 release to the ability of antibody reference standards. Samples and standards are normalized based on protein content. Relative potency is calculated using the parallel line assay according to the European Pharmacopoeia. The final result is expressed as the relative potency (percent) of the sample compared to the reference standard.

[0057] Unless otherwise indicated, the term "derivative" is used to define amino acid sequence variants and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.) of IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab) according to the present disclosure, e.g., of a particular sequence (e.g., variable domain). "Functional derivatives" include molecules that have the qualitative biological activity characteristic of the disclosed IL-17 antibodies or antigen-binding fragments thereof. Functional derivatives include fragments and peptide analogs of IL-17 antibodies or antigen-binding fragments thereof as disclosed herein. Fragments comprise regions located within the sequence of a polypeptide according to the present disclosure, e.g., of a particular sequence. Functional derivatives of IL-17 antibodies or antigen-binding fragments thereof disclosed herein (e.g., functional derivatives of secukinumab) preferably comprise a V H and / or a V L sequence having at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity, and substantially retain the ability to bind human IL-17 or, e.g., inhibit IL-17-induced human dermal fibroblast IL-6 production. H and / or a V L domain (e.g., of a V H and / or a V L sequence of Table 1), and substantially retain the ability to bind human IL-17 or, e.g., inhibit IL-17-induced human dermal fibroblast IL-6 production.

[0058] "Substantially identical" means that the relevant amino acid or nucleotide sequence (e.g., a V H or a V L domain) is identical to a specified reference sequence or has non-substantial differences (e.g., by conservative amino acid substitutions). Non-substantial differences include minor amino acid changes, e.g., 1 or 2 substitutions in a 5 amino acid sequence of a specified region (e.g., a V H or a V L domain). In the case of antibodies, the second antibody has the same specificity and has at least 50% of the same affinity. Sequences that are substantially identical (e.g., at least about 85% sequence identity) to the sequences disclosed herein are also part of the present application. In some embodiments, the sequence identity of a derivative IL-17 antibody (e.g., a secukinumab derivative, e.g., a secukinumab biosimilar antibody) can be about 90% or greater than 90%, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater, relative to the disclosed sequence.

[0059] "Identity" with respect to a native polypeptide and functional derivatives thereof is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the corresponding native polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity, and not considering any conservative substitutions as part of the identity. Neither N- nor C-terminal extensions nor insertions are to be construed as reducing identity. Methods and computer programs for alignment are well known. The percent identity can be determined by standard alignment algorithms, such as the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol., 215:403-410); the algorithm of Needleman et al. ((1970) J. Mol. Biol., 48:444-453); or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., 4:11-17). A set of parameters can be the Blosum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0060] "Amino acid" refers to all naturally occurring L-a-amino acids, for example, and includes D-amino acids. "Amino acid sequence variant" refers to a molecule having some differences in its amino acid sequence as compared to a sequence according to the present disclosure. Amino acid sequence variants of the polypeptides according to the present disclosure, e.g., of the specified sequences, retain the ability to bind human IL-17, or, e.g., to inhibit IL-17-induced production of IL-6 by human dermal fibroblasts. Amino acid sequence variants include substitutional, insertional and deletional variants in which at least one amino acid residue in the polypeptides according to the present disclosure is removed and a different amino acid is inserted at the same position, one or more amino acids are inserted next to each other amino acid in the polypeptides according to the present disclosure at a particular position, or one or more amino acids are removed from the polypeptides according to the present disclosure.

[0061] The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.

[0062] The term "administering" in connection with a compound, e.g., an IL-17 binding molecule or another agent, means delivering the compound to a patient by any route.

[0063] As used herein, "therapeutically effective amount" means an amount of an IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab, effective to treat, prevent, prevent the onset of, cure, delay, lessen the severity of, ameliorate at least one symptom of, or prolong the survival of a patient beyond that expected in the absence of such treatment. When used in reference to an individual active ingredient (e.g., an IL-17 antibody, e.g., secukinumab) applied alone, the term refers only to that ingredient. When used in reference to a combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered together, sequentially, or simultaneously.

[0064] The term "treatment" refers to both prophylactic or preventative treatment as well as curative or disease-modifying treatment, including treatment of patients at risk of developing an infection disease, or suspected to have developed an infection disease, as well as patients who have developed or been diagnosed with a disease or medical condition, and also to the inhibition of clinical relapse. Treatment can be administered to a patient already suffering from a medical condition or who can eventually develop a medical condition, in order to prevent, cure, delay the onset of, lessen the severity of, ameliorate, or prolong the survival of the patient beyond that expected in the absence of such treatment.

[0065] "Administration means" is used to mean any available appliance for the systemic administration of a drug to a patient, including, but not limited to, pre-filled syringes, vials and syringes, injection pens, auto-injectors, intravenous drip bags, pumps, patch pumps, and the like. The patient can self-administer the drug using these appliances (i.e., administer the drug alone) or a physician can administer the drug using these appliances. Typically, doses given in "mg / kg" are administered via intravenous routes, and doses given in "mg" are administered via intramuscular or subcutaneous injection. In some embodiments of the disclosed methods, kits, regimens, and uses, the IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab, is delivered to the patient via an intravenous route. In some embodiments of the disclosed methods, kits, regimens, and uses, the IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab, is delivered to the patient via a subcutaneous route.

[0066] IL-17 antibodies and antigen binding fragments thereof

[0067] The disclosed pharmaceutical products, compositions, liquid compositions, regimens, processes, uses, methods, and kits comprise or utilize an IL-17 antibody or antigen binding fragment thereof.

[0068] In one embodiment, the IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab, comprises at least one immunoglobulin heavy chain variable domain (V H), which comprises hypervariable regions CDR1, CDR2 and CDR3, wherein the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3. In one embodiment, the IL-17 antibody or its antigen-binding fragment, such as secukinumab, comprises at least one immunoglobulin light chain variable domain (V L ), which comprises hypervariable regions CDR1', CDR2' and CDR3', wherein the CDR1' has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6. In one embodiment, the IL-17 antibody or its antigen-binding fragment, such as secukinumab, comprises at least one immunoglobulin heavy chain variable domain (V H ), which comprises hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein the CDR1-x has the amino acid sequence of SEQ ID NO:11, the CDR2-x has the amino acid sequence of SEQ ID NO:12, and the CDR3-x has the amino acid sequence of SEQ ID NO:13.

[0069] In one embodiment, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, comprises at least one immunoglobulin V H domain and at least one immunoglobulin V L domain, wherein: a) the immunoglobulin V H The immunoglobulin VL domain comprises (e.g., in order): i) hypervariable regions CDR1, CDR2 and CDR3, wherein the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3; or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein the CDR1-x has the amino acid sequence of SEQ ID NO: 11, the CDR2-x has the amino acid sequence of SEQ ID NO: 12, and the CDR3-x has the amino acid sequence of SEQ ID NO: 13; and b) the immunoglobulin VL domain comprises (e.g., in order) hypervariable regions CDR1', CDR2' and CDR3', wherein the CDR1' has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6.

[0070] In one embodiment, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, comprises: a) an immunoglobulin heavy chain variable domain (V H), comprising the amino acid sequence set forth in SEQ ID NO: 8; b) an immunoglobulin light chain variable domain (V L ), comprising the amino acid sequence set forth in SEQ ID NO: 10; c) an immunoglobulin V H domain and an immunoglobulin V L domain, which V H comprises the amino acid sequence set forth in SEQ ID NO: 8, which V L comprises the amino acid sequence set forth in SEQ ID NO: 10; d) an immunoglobulin V H domain comprising hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; e) an immunoglobulin V L domain comprising hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; f) an immunoglobulin V H domain comprising hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13; g) an immunoglobulin V H domain and an immunoglobulin V L domain, which V H comprises hypervariable regions set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, which V L comprises hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; or h) an immunoglobulin V H domain and an immunoglobulin V L domain, which V H comprises hypervariable regions set forth in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, which V L comprises hypervariable regions set forth in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6.

[0071] For ease of reference, the amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody are provided in Table 1 below based on the Kabat definition and as determined by X-ray analysis and using the method of Chothia and colleagues.

[0072]

[0073] Table 1: Amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody.

[0074] In preferred embodiments, the constant region also preferably comprises a suitable human constant region, for example as described in "Sequences of Proteins of Immunological Interest", Kabat E.A. et al., U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. The DNA encoding the V L region of secukinumab is shown in SEQ ID NO: 9. The DNA encoding the V H region of secukinumab is shown in SEQ ID NO: 7.

[0075] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody comprises the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody comprises the three CDRs of SEQ ID NO: 10 and the three CDRs of SEQ ID NO: 8. Those CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 can be found in Table 1 according to the definitions of Chothia and Kabat.

[0076] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the heavy chain of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the light chain of SEQ ID NO: 14 and the heavy chain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the three CDRs of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, comprises the three CDRs of SEQ ID NO: 14 and the three CDRs of SEQ ID NO: 15. Those CDRs of SEQ ID NO: 15 and SEQ ID NO: 17 can be found in Table 1 according to the definitions of Chothia and Kabat.

[0077] The hypervariable region can be associated with any kind of framework region, although human origin is preferred. Suitable framework regions are described in Kabat E. A. et al. (supra). A preferred heavy chain framework is a human heavy chain framework, such as the heavy chain framework of the secukinumab antibody. This in turn consists of, for example, FR1 (amino acids 1 to 30 of SEQ ID NO: 8), FR2 (amino acids 36 to 49 of SEQ ID NO: 8), FR3 (amino acids 67 to 98 of SEQ ID NO: 8) and FR4 (amino acids 117 to 127 of SEQ ID NO: 8) regions. Another preferred heavy chain framework, taking into account the secukinumab hypervariable regions determined by X-ray analysis, in turn consists of FR1-x (amino acids 1 to 25 of SEQ ID NO: 8), FR2-x (amino acids 36 to 49 of SEQ ID NO: 8), FR3-x (amino acids 61 to 95 of SEQ ID NO: 8) and FR4 (amino acids 119 to 127 of SEQ ID NO: 8) regions. In a similar manner, the light chain framework in turn consists of FR1’ (amino acids 1 to 23 of SEQ ID NO: 10), FR2’ (amino acids 36 to 50 of SEQ ID NO: 10), FR3’ (amino acids 58 to 89 of SEQ ID NO: 10) and FR4’ (amino acids 99 to 109 of SEQ ID NO: 10) regions.

[0078] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, is selected from a human IL-17 antibody comprising at least: a) an immunoglobulin heavy chain or fragment thereof comprising a variable domain comprising in turn hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence of SEQ ID NO: 1, said CDR2 having the amino acid sequence of SEQ ID NO: 2, said CDR3 having the amino acid sequence of SEQ ID NO: 3, and a constant portion of a human heavy chain or fragment thereof, and b) an immunoglobulin light chain or fragment thereof comprising a variable domain comprising in turn hypervariable regions CDR1’, CDR2’ and CDR3’, said CDR1’ having the amino acid sequence of SEQ ID NO: 4, said CDR2’ having the amino acid sequence of SEQ ID NO: 5, said CDR3’ having the amino acid sequence of SEQ ID NO: 6, and a constant portion of a human light chain or fragment thereof.

[0079] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, is selected from a single chain binding molecule comprising an antigen binding site comprising: a) a first domain comprising, in order, hypervariable regions CDR1, CDR2, and CDR3, said CDR1 having the amino acid sequence of SEQ ID NO: 1, said CDR2 having the amino acid sequence of SEQ ID NO: 2, said CDR3 having the amino acid sequence of SEQ ID NO: 3; and b) a second domain comprising, in order, hypervariable regions CDR1', CDR2', and CDR3', said CDR1' having the amino acid sequence of SEQ ID NO: 4, said CDR2' having the amino acid sequence of SEQ ID NO: 5, said CDR3' having the amino acid sequence of SEQ ID NO: 6; and c) a peptide linker connecting the N-terminal end of the first domain and the C-terminal end of the second domain or connecting the C-terminal end of the first domain and the N-terminal end of the second domain.

[0080] Alternatively, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, used in the disclosed methods can comprise a derivative of the molecule as shown by the sequences herein (e.g., a pegylated form of secukinumab). Alternatively, the V H or V L domain of the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, used in the disclosed methods can have substantially the same V H or V L domain as those shown herein (e.g., those shown in SEQ ID NO: 8 and 10). The human IL-17 antibody disclosed herein can comprise a heavy chain substantially identical to that shown as SEQ ID NO: 15 and / or a light chain substantially identical to that shown as SEQ ID NO: 14. The human IL-17 antibody disclosed herein can comprise a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. H or V L domain. The human IL-17 antibody disclosed herein can comprise a heavy chain substantially identical to that shown as SEQ ID NO: 15 and / or a light chain substantially identical to that shown as SEQ ID NO: 14. The human IL-17 antibody disclosed herein can comprise a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14.

[0081] The human IL-17 antibodies disclosed herein can comprise: a) a heavy chain comprising a variable domain having substantially the same amino acid sequence as set forth in SEQ ID NO: 8 and a constant portion of a human heavy chain; and b) a light chain comprising a variable domain having substantially the same amino acid sequence as set forth in SEQ ID NO: 10 and a constant portion of a human light chain. Alternatively, the IL-17 antibodies or antigen binding fragments thereof, e.g., secukinumab, used in the disclosed methods can be amino acid sequence variants of the reference molecules set forth herein. In all these derivatives and variants, the IL-17 antibodies or antigen binding fragments thereof, e.g., secukinumab, are capable of inhibiting the activity of about 1 nM (= 30 ng / ml) human IL-17 by 50% at a concentration of the molecule of about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less, the inhibitory activity being determined by human-IL-17 induced IL-6 production in human dermal fibroblasts.

[0082] Inhibition of IL-17 binding to its receptor can be conveniently tested in various assays including, for example, those described in WO 2006 / 013107. The term "to the same extent" means that in one of the assays mentioned herein, the reference and derivative molecules exhibit substantially the same IL-17 inhibitory activity on a statistical basis (see WO 2006 / 013107 Example 1). For example, for inhibition of IL-6 production induced by human IL-17 in human dermal fibroblasts, the IL-17 antibodies or antigen binding fragments thereof disclosed herein typically have an IC 50 of less than about 10 nM, more preferably about 9, 8, 7, 6, 5, 4, 3, 2, or about 1 nM, when tested as described in WO 2006 / 013107 Example 1. Alternatively, the assay used can be one in which IL-17 binding is competitively inhibited by the soluble IL-17 receptor (e.g., human IL-17R / Fc construct of WO 2006 / 013107 Example 1) and the IL-17 antibodies or antigen binding fragments thereof of the present disclosure. 50 The IL-17 antibodies or antigen binding fragments thereof, e.g., secukinumab, of the present disclosure are typically capable of inhibiting the activity of about 1 nM (= 30 ng / ml) human IL-17 by 50% at a concentration of the molecule of about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less, the inhibitory activity being determined by human-IL-17 induced IL-6 production in human dermal fibroblasts.

[0083] The present disclosure also includes IL-17 antibodies or antigen binding fragments thereof, e.g., secukinumab, in which one or more amino acid residues (typically only a few, e.g., 1-10) of the V H or V L domain are altered, e.g., by mutation, e.g., site-directed mutagenesis of the corresponding DNA sequence, relative to the V H or V L domain set forth in SEQ ID NO: 8 and SEQ ID NO: 10. The present disclosure includes DNA sequences encoding these altered IL-17 antibodies.

[0084] The present disclosure also includes IL-17 antibodies or antigen-binding fragments thereof having binding specificity for human IL-17, such as secukinumab, in particular IL-17 antibodies that can inhibit the binding of IL-17 to its receptor and IL-17 antibodies that can inhibit the activity of 1 nM (= 30 ng / ml) human IL-17 by 50% at the following molecular concentrations: about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less (the inhibitory activity is measured by IL-6 production induced by human-IL-17 in human skin fibroblasts).

[0085] In some embodiments, an IL-17 antibody, such as secukinumab, binds to a mature human IL-17 epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129. In some embodiments, an IL-17 antibody, such as secukinumab, binds to a mature human IL-17 epitope comprising Tyr43, Tyr44, Arg46, Ala79, Asp80. In some embodiments, an IL-17 antibody, such as secukinumab, binds to an epitope of an IL-17 homodimer having two mature human IL-17 chains comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain. The residue numbering scheme used to define these epitopes is based on the residue that is the first amino acid of the mature protein (i.e., IL-17A lacking the 23 amino acid N-terminal signal peptide and beginning with glycine). The sequence of immature IL-17A is shown in Swiss-Prot record Q16552. In some embodiments, the IL-17 antibody has a K of about 100-200 pM. D , for example by In some embodiments, the IL-17 antibody has an IC for neutralizing about 0.67 nM human IL-17A bioactivity in vitro. 50 In some embodiments, the absolute bioavailability of the IL-17 antibody administered subcutaneously (sc) is in the range of about 60% to about 80%, for example, about 76%. In some embodiments, the IL-17 antibody, such as secukinumab, has an elimination half-life of about 4 weeks (e.g., about 23 to about 35 days, about 23 to about 30 days, for example, about 30 days). In some embodiments, the IL-17 antibody, such as secukinumab, has a T half-life of about 7-8 days. max.

[0086] Particularly preferred IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab, for use in the methods, applications, kits, etc. of the present disclosure are human antibodies, particularly secukinumab as described in Examples 1 and 2 of WO 2006 / 013107 (US Pat. No. 7,807,155, which is incorporated herein by reference in its entirety). Secukinumab is a recombinant, high-affinity, fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody of the IgG1 / kappa isotype that is currently in clinical trials for the treatment of immune-mediated inflammatory disorders. Secukinumab (see, for example, WO 2006 / 013107 and WO 2007 / 117749) has a very high affinity for IL-17, i.e., K D About 100-200 pM (e.g., by , and neutralized the bioactivity of human IL-17A with an IC of approximately 0.67 nM in vitro. 50 The binding affinity of secukinumab is approximately 0.4 nM. Thus, secukinumab inhibits antigen at a molar ratio of approximately 1:1. This high binding affinity makes the secukinumab antibody particularly suitable for therapeutic applications. Furthermore, secukinumab has been determined to have a very long half-life of approximately 4 weeks, which allows for extended periods between administrations, a valuable property in treating chronic, lifelong conditions such as psoriasis.

[0087] Drug products containing IL-17 antibodies or antigen-binding fragments

[0088] The present disclosure broadly provides a pharmaceutical product comprising a container and a liquid composition disposed within the container, wherein the headspace of the container comprises less than about 12% oxygen, the liquid composition comprising the above-described IL-17 antibody or antigen-binding fragment thereof, such as secukinumab.

[0089] container

[0090] The pharmaceutical products of the present disclosure utilize primary packaging, i.e., containers, to store, transport, and maintain the disclosed liquid compositions. Pharmaceutically acceptable containers for use as part of the disclosed pharmaceutical products include syringes (e.g., available from Beckton Dickinson, Nuova Ompi, etc.), stoppered vials, cartridges, autoinjectors, diaphragm pumps, and injection pens.

[0091] Headspace oxygen

[0092] We have found that the stability of an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) in a liquid composition of the present disclosure can be enhanced by including a particular stabilizer (e.g., methionine) and simultaneously replacing oxygen in the headspace of the drug product with an inert gas (e.g., argon, helium, nitrogen), preferably N2. Specifically, we have found that drug products in which the container is oxygen purged, i.e., the oxygen in the headspace is less than about 12%, have increased stability, e.g., as measured by SEC and RP-HPLC, relative to non-purged products.

[0093] The use of purging (e.g., nitrogen purging) to alter the oxygen content in the headspace can be achieved during the fill phase and / or the overfill phase (or both). Purging (e.g., nitrogen purging) can be achieved by actively introducing the inert gas (e.g., using a needle) or during the overfill phase.

[0094] In some embodiments, the oxygen content in the headspace is less than about 12% (e.g., less than about 10%, less than about 8%, less than about 6%, etc.). In some embodiments, the oxygen content in the headspace is less than about 6%. The oxygen content in the headspace can be monitored by laser absorption spectroscopy or fluorescence quenching or gas chromatography. It should be understood that the oxygen content in the headspace of a given container can increase over time, e.g., due to outgassing. Accordingly, the use of "oxygen content in the headspace" herein refers to the initial oxygen content in the headspace of the container immediately after the product is closed (e.g., overfilled).

[0095] Liquid composition

[0096] The liquid composition of the present disclosure comprises at least one IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) as described above, and at least one other excipient, e.g., a buffer, a surfactant, and a stabilizer, etc. In some embodiments, the liquid composition comprises at least two other excipients, e.g., a buffer and a stabilizer. In some embodiments, the liquid composition comprises a buffer, at least one stabilizer, and a surfactant.

[0097] In general, pharmaceutical compositions are formulated with excipients that are compatible with the intended route of administration (e.g., oral compositions generally include inert diluents or an edible carrier). Examples of routes of administration include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., by mouth or inhalation), transdermal (topical), transmucosal, and rectal. The liquid antibody compositions of the present disclosure are suitable for parenteral administration, e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous injection; and are particularly suitable for subcutaneous injection.

[0098] In some embodiments, the liquid compositions of the present disclosure maintain at least about 86% RP-HPLC purity after 6 months storage at 2-8°C, at least about 76% RP-HPLC purity (preferably at least about 76%) after 6 months storage at 25°C / 60% RH, and / or at least about 60% RP-HPLC purity after 6 months storage at 30°C / 75% RH. In some embodiments, the liquid compositions of the present disclosure maintain at least about 84% RP-HPLC purity after 24 months storage at 2-8°C.

[0099] In some embodiments, the liquid compositions of the present disclosure maintain at least about 77% CEX purity after 6 months storage at 2-8°C, at least about 62% CEX purity after 6 months storage at 25°C / 60% RH, and / or at least about 50% CEX purity after 6 months storage at 30°C / 75% RH. In some embodiments, the liquid compositions of the present disclosure maintain at least about 73% CEX purity after 24 months storage at 2-8°C.

[0100] In some embodiments, the liquid compositions of the present disclosure maintain at least about 98% SEC purity after 6 months storage at 2-8°C, at least about 96% SEC purity after 6 months storage at 25°C / 60% RH, and / or at least about 94% SEC purity after 6 months storage at 30°C / 75% RH. In some embodiments, the liquid compositions of the present disclosure maintain at least about 97% SEC purity after 24 months storage at 2-8°C.

[0101] In some embodiments, the liquid compositions of the present disclosure maintain at least about 97% CE-SDS purity (non-reduced conditions) after 6 months storage at 2-8°C, at least about 95% CE-SDS purity (non-reduced conditions) after 6 months storage at 25°C / 60% RH, and / or at least about 94% (preferably at least about 92%) CE-SDS purity (non-reduced conditions) after 6 months storage at 30°C / 75% RH. In some embodiments, the liquid compositions of the present disclosure maintain at least about 97% CE-SDS purity (non-reduced conditions) after 24 months storage at 2-8°C.

[0102] In some embodiments, the liquid compositions disclosed herein maintain less than about 0.57% CE-SDS impurity (reduced conditions) after 6 months storage at 2-8°C, less than about 1.1% CE-SDS impurity (reduced conditions) after 6 months storage at 25°C / 60% RH, and / or less than about 1.9% CE-SDS impurity (reduced conditions) after 6 months storage at 30°C / 75% RH. In some embodiments, the liquid compositions of the present disclosure maintain less than about 0.91% CE-SDS impurity (non-reduced conditions) after 24 months storage at 2-8°C.

[0103] In some embodiments, the liquid compositions of the present disclosure maintain at least about 88% relative bioactivity for inhibition of C-20 / A4 chondrocyte IL-6 release after 24 months of storage at 2-8°C, at least about 94% relative bioactivity for inhibition of chondrocyte IL-6 release after 6 months of storage at 25°C / 60% RH, and / or at least about 85% relative bioactivity for inhibition of chondrocyte IL-6 release after 6 months of storage at 30°C / 75% RH.

[0104] Antibody concentration

[0105] The IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) used in the liquid compositions of the present disclosure is as described above. One preferred composition comprises secukinumab. We have found that antibody concentration does not significantly affect composition stability at least in the range of about 25 mg / ml to about 150 mg / ml. Thus, in some embodiments, the antibody in the liquid composition is present at a concentration of at least 25 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml). In some embodiments, the antibody concentration in the liquid composition is at least about 25 mg / mL, at least about 50 mg / ml, at least about 75 mg / ml, at least about 100 mg / mL, or at least about 150 mg / ml, a high concentration. In some embodiments, the antibody concentration in the liquid composition is about 25 mg / mL to about 150 mg / mL, a high concentration. In one embodiment, the secukinumab concentration in the liquid composition is about 25 mg / ml. In one embodiment, the secukinumab concentration in the liquid composition is about 150 mg / ml.

[0106] Buffer and pH

[0107] Suitable buffer agents for use in the liquid compositions of the present disclosure include, but are not limited to, gluconate buffer, histidine buffer, citrate buffer, phosphate [e.g., sodium or potassium] buffer, succinate [e.g., sodium] buffer, acetate buffer, Tris buffer, glycine, arginine, and combinations thereof. We have found that succinate or acetate buffer does not have a beneficial effect on the stability of secukinumab liquid compositions. Citrate buffer was evaluated as being beneficial in the composition with respect to degradation products as measured by SEC, CEX-acidic, and aggregate products as measured by RP-HPLC. Overall, histidine buffer showed advantages with respect to aggregate and degradation products as measured by SEC, CEX-acidic, and RP-B. Thus, histidine buffer is the preferred buffer for the disclosed stable secukinumab liquid compositions.

[0108] Histidine buffers (e.g., at a concentration of about 5 mM to about 50 mM, e.g., about 20 mM to about 50 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM) are particularly useful. In one embodiment, the stable liquid composition comprises about 20 mM to about 50 mM histidine buffer. The pH of the liquid composition can range from 4.0-8.0, with a pH in the range of about 5.5 to about 7.4 being typical, e.g., about 5.2 to about 6.2, about 5.2 to about 5.8, e.g., about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.2, about 6.4, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4. We have found a trend of increasing stability (SEC-AP, DLS, SEC-DP, ALP-DP, CEX basic, RP-HPLC) as the pH is raised from 5.2 to 5.8. Overall testing indicates that the ideal composition pH for the liquid compositions of the present disclosure is 5.8. Thus in one embodiment, the pH of the stable liquid antibody composition is about 5.8.

[0109] Surfactants

[0110] Surfactants suitable for use in the liquid compositions of the present disclosure include, but are not limited to, nonionic surfactants, ionic surfactants, zwitterionic surfactants, and combinations thereof. Typical surfactants for use in the present application include, but are not limited to, sorbitan fatty acid esters (e.g., sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), sorbitan trioleate, glycerol fatty acid esters (e.g., glycerol monocaprylate, glycerol monomyristate, glycerol monostearate), polyglycerol fatty acid esters (e.g., decaglycerol monostearate, decaglycerol distearate, decaglycerol monolinoleate), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate), polyoxyethylene sorbitol fatty acid esters (e.g., polyoxyethylene sorbitol tetra stearate, polyoxyethylene sorbitol tetraoleate), polyoxyethylene glycerol fatty acid esters (e.g., polyoxyethylene glyceryl monostearate), polyethylene glycol fatty acid esters (e.g., polyethylene glycol distearate), polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether), polyoxyethylene polyoxypropylene alkyl ethers (e.g., polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylene alkyl phenyl ethers (e.g., polyoxyethylene nonyl phenyl ether), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil), polyoxyethylene beeswax derivatives (e.g., polyoxyethylene sorbitol beeswax), polyoxyethylene lanolin derivatives (e.g., polyoxyethylene lanolin), and polyoxyethylene fatty acid amides (e.g., polyoxyethylene stearic acid amide); C10-C18 alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate), polyoxyethylene C10-C18 alkyl ether sulfates with an average addition of 2 to 4 moles of ethylene oxide units (e.g., polyoxyethylene sodium lauryl sulfate), and C1-C18 alkyl sulfosuccinates (e.g., sodium lauryl sulfosuccinate); and natural surfactants such as lecithin, glycerophospholipids, sphingomyelin (e.g., sphingomyelin), and sucrose esters of C12-C18 fatty acids. The compositions can include one or more of these surfactants. A preferred surfactant is a poloxamer (e.g., poloxamer 188) or a polyoxyethylene sorbitan fatty acid ester, such as polysorbate 20, 40, 60, or 80. Polysorbate 80 (Tween 80) (e.g., at a concentration of about 0.01% to about 0.1% (w / v), such as about 0.01% to about 0.04% (w / v), such as about 0.01%, about 0.02%, about 0.04%, about 0.06%, about 0.08%, about 0.1%) is particularly suitable. In one embodiment, the stable liquid composition comprises about 0.02% (w / v) polysorbate 80.In one embodiment, the stable liquid composition comprises about 0.02% (w / v) polysorbate 20.

[0111] We found that turbidity increased significantly and visible particulate increased in the liquid composition in the absence of surfactant. However, compared to polysorbate 20 and 80, no advantage was detected for poloxamer 188 other than increased ALP-DP and RP. Polysorbate 20 and 80 showed comparable efficacy in preventing increases in turbidity, insoluble particulate, and visible particulate. Thus, polysorbate 20 and 80 are preferred surfactants for the stable liquid compositions of the present disclosure.

[0112] Stabilizers

[0113] Stabilizers help prevent protein oxidation and aggregation in pharmaceutical compositions, particularly liquid pharmaceutical compositions, that have a short shelf life due to the propensity of the protein in aqueous solution to oxidize and / or aggregate. Various analytical methods can be used to assess the stability of a given composition, for example, RP-HPLC can be used to assess the content of oxidation products (before the main peak) in the liquid compositions of the present disclosure, and SEC can be used to assess the level of aggregation in the liquid compositions of the present disclosure.

[0114] Stabilizers suitable for use in the liquid compositions of the present disclosure include ionic and non-ionic stabilizers (and combinations thereof), such as sugars, glycine, sodium chloride, arginine, EDTA, sodium ascorbate, cysteine, sodium bisulfite, sodium citrate, methionine, and benzyl alcohol. In some embodiments, the liquid pharmaceutical composition comprises at least one stabilizer from Group 1 (e.g., sugars [e.g., trehalose, mannitol], amino acids [e.g., glycine, arginine], and sodium chloride). In some embodiments, the liquid pharmaceutical composition comprises at least one stabilizer from Group 2 (EDTA, sodium ascorbate, cysteine, sodium bisulfite, sodium citrate, methionine, and benzyl alcohol). The Group 2 stabilizers tend to have antioxidant properties and can reduce oxidation of residues in the IL-17 antibody. In preferred embodiments, the liquid pharmaceutical composition comprises two stabilizers, one from Group 1 and one from Group 2.

[0115] For Group 1 stabilizers, non-ionic stabilizers are preferred. Suitable non-ionic stabilizers include monosaccharides, disaccharides, and trisaccharides, such as trehalose, raffinose, maltose, sorbitol, or mannitol. The sugar can be a sugar alcohol or an amino sugar. The concentration of the Group 1 stabilizer can be about 175 mM to about 350 mM, such as about 200 mM to about 300 mM, such as about 250 mM to about 270 mM, such as about 180 to about 300 mM, about 200 mM to about 225 mM, about 175 mM, about 180 mM, about 185 mM, about 190 mM, about 195 mM, about 200 mM, about 225 mM, about 250 mM, about 270 mM, 275 mM, about 300 mM. Mannitol at a concentration of about 200 mM to about 300 mM, such as about 250 mM to about 270 mM, trehalose at a concentration of about 180 mM to about 300 mM, such as about 200 mM to about 225 mM, sodium chloride at a concentration of about 130 mM to about 150 mM, arginine at a concentration of about 160 mM, and glycine at a concentration of about 270 mM are particularly useful.

[0116] We found that using glycine as a stabilizer (Group 1) had a slight advantage in SEC-AP and DLS, but observed an increase in almost all degradation products. NaCl as a stabilizer (Group 1) resulted in an increase in degradation and aggregation products as measured by SEC and CEX basic variants. Almost all analyses verified that trehalose and mannitol functioned as about equally beneficial stabilizers, but mannitol showed a slightly worse effect (SEC-AP, DLS) and was less water soluble than trehalose. Thus, trehalose is the preferred Group 1 stabilizer due to its positive effect on degradation products. In one embodiment, the liquid composition comprises about 200 mM to about 225 mM trehalose. In one embodiment, the liquid composition comprises about 200 mM trehalose. In one embodiment, the liquid composition comprises about 225 mM trehalose.

[0117] We found that the Group 2 stabilizers had a significant impact on the stability of the secukinumab liquid compositions. Experiments showed that the compositions without the Group 2 stabilizers were not as good (SEC-AP, DLS, turbidity, RP-B) as the compositions containing the Group 2 stabilizers. Tetrasodium EDTA and cysteine showed an increase in aggregates and degradation products in each of the analytical methods. When cysteine was added as the Group 2 stabilizer, the compositions were hazy after freeze-thaw stress and precipitated after 4 weeks of storage at 40 °C. However, we found that methionine was beneficial in all of the compositions when the analytical results were considered. Therefore, methionine, which also has antioxidant properties, is preferred for the Group 2 stabilizer. The concentration of the Group 2 stabilizer (e.g., methionine) can be at least about 2.5 mM, such as about 2.5 to about 20 mM, such as at least about 2.5 mM, at least about 5 mM, at least about 10 mM, or at least about 20 mM (e.g., about 2.5 mM, about 5 mM, about 10 mM, or about 20 mM). In preferred embodiments, the liquid pharmaceutical composition comprises at least one stabilizer from Group 1 and methionine. In some embodiments, the liquid compositions of the present disclosure comprise about 5 mM methionine.

[0118] Other excipients

[0119] The liquid antibody compositions of the present disclosure can comprise other excipients, such as other buffering agents, salts (e.g., sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride), other stabilizers, tonicity adjusting agents (e.g., salts and amino acids [e.g., proline, alanine, L-arginine, asparagine, L-aspartic acid, glycine, serine, lysine, and histidine]), glycerin, albumin, alcohols, preservatives, other surfactants, antioxidants, and the like. See Gennaro (2000) Remington: The Science and Practice of Pharmacy. 20th edition, ISBN: 0683306472 for a detailed discussion of these other pharmaceutical ingredients.

[0120] Other active agents

[0121] In addition to an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, the pharmaceutical products and stable liquid compositions of the present disclosure can also comprise one or more other active agents (e.g., psoriasis agents, psoriatic arthritis agents, ankylosing spondylitis agents, rheumatoid arthritis agents). These other factors and / or agents can be included in the pharmaceutical composition to produce a synergistic effect with the IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, or to minimize side effects caused by the IL-17 antibody or antigen-binding fragment thereof, such as secukinumab.

[0122] Examples of psoriasis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, include cyclosporine, methotrexate, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6-mercaptopurine, fumarates (e.g., dimethyl fumarate and fumarate esters), azathioprine, corticosteroids, leflunomide, tacrolimus, T-cell blockers (e.g., (alefacept) and (efalizumab), tumor necrosis factor-alpha (TNF-a) blockers (e.g., (etanercept), (adalimumab), (infliximab), and (golimumab)), and interleukin 12 / 23 blockers (e.g., (ustekinumab), tofacitinib, and briakinumab.

[0123] Other psoriasis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, for the treatment of psoriasis include Apremilast, mometasone, voclosporin, ketoconazole, Neuroskin Forte, recombinant human interleukin-10, voclosporin, MK-3222, tofacitinib, VX-765, MED-1545, fluazacort decanoate, paracetamol, Bimoxy Sugar Cream, doxycycline, vancomycin, AbGn168, vitamin D3, RO5310074, fludarabine calcipotriol and hydrocortisone (LEO 80190), Fovista (monovalent MF59-adjuvanted vaccine, tgAAC94 gene therapy vector, capsaicin, Protopic, ABT-874 (anti-IL-12), IDEC-114, MEDI-522, LE29102, BMS 587101, CD 2027, CRx-191, 8-methoxypsoralen or 5-methoxypsoralen, Bicillin L-A, LY2525623, INCB018424, LY2439821, CEP-701, CC-10004, Certolizumab pegol (CZP), GW786034 (Pazopanib), doxycycline class curcumin class C3 complex, NYC 0462, RG3421, hOKT3 gamma 1 (Ala-Ala), BT061, Tremfya, Chondroitin sulfate, CNTO1275, monoclonal antibodies to IL-12p40 and IL-23p40 subunits, BMS-582949, MK0873, MEDI-507, M518101, ABT-874, AMG 827, AN2728, AMG714, AMG 139, PTH (1-34), U0267 Foam, CNTO 1275, QRX-101, CNTO1959, LEO 22811, Imiquimod, CTLA4lg, Dunaliella bardawil, Pioglitazone, Pimecrolimus, Ranibizumab, Zidovudine CDP870 (Certolizumab pegol), Onercept (gamma-hTBP-1), ACT-128800, 4,4-dimethyl-benzis-2H-selenazin, CRx-191, CRx-197, Doxercalciferol, LAS 41004, WBI-1001, Tacrolimus, RAD001, Rapamycin, Rosiglitazone, Pioglitazone, ABT-874, Aminopterin, AN2728, CD2027, ACT-128800, Mometasone furoate, CT327, Clobetasol + LCD, BTT1023, E6201, Topical vitamin B12, IP10.C8, BFH772, LEO 22811, fluphenazine, MM-093, Clobex, SCH 527123, CF101, SRT2104, BIRT2584, CC10004, tetrathiomolybdate, CP-690, 550, U0267, ASP015K, VB-201, Atacicept A (also known as U0279), RWJ-445380, clobetasol propionate, botulinum toxin type A, Afamelose, Erlotinib, BCT194, Roflumilast, CNTO 1275, Uvaretin, ILV-094, CTA018 cream, COL-121, MEDI-507, AEB071.

[0124] Other psoriasis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, include IL-6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-17 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonists, VGEF antagonists, CXCL antagonists, MMP antagonists, defensin antagonists, IL-1 beta antagonists, and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.). Preferred psoriasis agents that can be co-formulated with secukinumab are DMARDs (e.g., MTX and cyclosporin), IL-12 / -23 antagonists (e.g., ustekinumab), CTLA-4 antagonists (e.g., CTLA4-Ig), and TNF-alpha antagonists.

[0125] Broadly, the rheumatoid arthritis agents, psoriatic arthritis agents, and ankylosing spondylitis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, can specifically be immunosuppressants, DMARDs, pain control drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, bone anabolic agents, bone anti-resorptive agents, and combinations thereof. Representative agents include cyclosporin, retinol, corticosteroids, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprofen, choline magnesium salicylate, fenoprofen, salsalate, diflunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966, rofecoxib, acetaminophen, celecoxib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, indoxole, lomoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprofen, firocoxib, methotrexate (MTX), antimalarials (e.g., hydroxychloroquine and chloroquine), sulfasalazine, leflunomide, azathioprine, cyclosporin, auranofin, myocrisin, cyclophosphamide, D-penicillamine, minocycline, auranofin, tacrolimus, aurothioglycerol, chlorambucil, TNFα antagonists (e.g., TNFα antagonists or TNFα receptor antagonists), e.g., adalimumab etanercept infliximab TA-650), certolizumab CDP870), golimumab CNTO148), anakinra rituximab abatacept tocilizumab (RoActemra ), integrin antagonists (natalizumab), IL-1 antagonists (ACZ885 (Ilaris)), anakinra ), CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g., atacicept, belimumab), p38 inhibitors, CD20 antagonists (ocrelizumab, ofatumumab ), interferon gamma antagonists (efalizumab), prednisolone, prednisone, dexamethasone, cortisone, cortisone acetate, hydrocortisone, methylprednisolone, betamethasone, fluprednisolone, beclomethasone, flurandrenolide, deoxycorticosterone, aldosterone, SB-681323, Rob 803, AZD5672, AD452, SMP 114, HZT-501, CP-195, 543, doxycycline, vancomycin, CRx-102, AMG108, pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin + Viusid, TwHF, PF-04171327, AZD5672, methoxsalen, ARRY-438162, vitamin D-ergocalciferol, milnacipran, paclitaxel, GW406381, rosiglitazone, SC12267 (4SC-101), LY2439821, BTT-1023, ERB-041, ERB-041, KB003, CF101, ADL5859, MP-435, ILV-094, GSK706769, GW856553, ASK8007, MOR103, HE3286, CP-690, 550 (tofacitinib), REGN88 (SAR153191), TRU-015, BMS-582949, SBI-087, LY2127399, E-551 S-551, H-551, GSK3152314A, RWJ-445380, tacrolimus RAD001, sirolimus, rapamycin, foretinib, fentanyl, XOMA 052, CNTO 136, JNJ 38518168, imatinib, ATN-103, ISIS 104838, folate, folate salt, TNF alpha kinoid, MM-093, type II collagen, VX-509, AMG 827 70, masitinib (AB1010), LY2127399, cyclosporine, SB-681323, MK0663, NNC 0151-0000-0000, ATN-103, CCX 354-C, CAM3001, LX3305, cilengitide, MDX-1342, TMI-005, MK0873, CDP870, trodusquid, CF101, mycophenolic acid (and esters thereof), VX-702, GLPG0259, SB-681323, BG9924, ART621, LX3305, T-614, foretinib disodium (R935788), CCI-779, ARRY-371797, CDP6038, AMG719, BMS-582949, GW856553, rosiglitazone, CH-4051, CE-224, 535, GSK1827771, GW274150, BG9924, PLX3397, TAK-783, INCB028050, LY2127399, LY3009104, R788, curcumin (Longvida TM), rosuvastatin, PRO283698, AMG 714, MTRX1011A, maraviroc, MEDI-522, MK0663, STA 5326 mesylate, CE-224, 535, AMG108, BG00012 (BG-12; Biogen), ramipril, VX-702, CRx-102, LY2189102, SBI-087, SB-681323, CDP870, milnacipran, PD 0360324, PH-797804, AK106-001616, PG-760564, PLA-695, MK0812, ALD518, coprostone, somatotropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, bone anabolic and antiresorptive agents (e.g., PTH, bisphosphonates (e.g., zoledronic acid), JAK1 and JAK2 inhibitors, pan-JAK inhibitors Preparations such as tetracyclic pyridone 6 (P6), 325, PF-956980, sclerostin protein antagonists (e.g., in WO09047356, WO2000 / 32773, WO2006102070, US20080227138, US20100028335, US20030229041, WO2005003158, WO2009039175WO2009079471, WO03106657, WO2 006119062, WO08115732, WO2005 / 014650, WO2005 / 003158, WO2006 / 119107, WO2008 / 061013, WO2008 / 133722, WO2008 / 115732, US7592429, US7879322, US7744874, the contents of which are incorporated herein by reference in their entirety [preferably for use in the disclosed methods, pharmaceutical compositions, test Kits and anti-chitosan antibodies and antigen-binding portions thereof are described in WO09047356 (equivalent to US7879322), WO06119107 (equivalent to US7872106 and US7592429) and WO08115732 (equivalent to US7744874)]), denosumab, IL-6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonists, integrin antagonists ( (Enbrel®), etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), and natalizumab (Antegren® or Tysabri®). Preferred rheumatoid arthritis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, are DMARDs (e.g., methotrexate) and TNFα antagonists. Preferred ankylosing spondylitis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, are NSAIDs, DMARDs (e.g., sulfasalazine), and TNFα antagonists. Preferred psoriatic arthritis agents that can be co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab, are DMARDS (e.g., cyclosporine), CTLA-4 blockers (e.g., CLTA4-Ig), alefacept, and TNFα antagonists.

[0126] Those skilled in the art will appreciate the appropriate dosages of the above agents when co-formulated with the IL-17 antibodies of the present disclosure, e.g., secukinumab.

[0127] Disclosed herein are stable liquid pharmaceutical compositions comprising about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen binding fragment thereof of the present disclosure (e.g., secukinumab), about 10 mM to about 30 mM buffer (e.g., histidine) at pH 5.2 to about 6.0, about 200 mM to about 225 mM stabilizer (e.g., trehalose), about 0.02% surfactant (e.g., polysorbate 80), and about 2.5 mM to about 20 mM methionine.

[0128] In some embodiments, the methionine concentration in a liquid pharmaceutical composition of a pharmaceutical of the present disclosure is about 2.5 mM, about 5 mM, about 10 mM, or about 20 mM, preferably about 5 mM. In some embodiments, the pH of the liquid pharmaceutical composition is about 5.8. In some embodiments, the secukinumab concentration of a composition of the present disclosure is about 25 mg / ml or about 150 mg / ml. In some embodiments, the liquid pharmaceutical composition comprises a buffer selected from the group consisting of histidine buffer, citrate buffer, acetate buffer, and succinate buffer. In some embodiments, the liquid pharmaceutical composition employs a histidine buffer at a concentration of about 20 mM. In some embodiments, the liquid pharmaceutical composition comprises a surfactant selected from the group consisting of polysorbate and poloxamer. In some embodiments, the liquid pharmaceutical composition further comprises a surfactant selected from the group consisting of polysorbate 80, polysorbate 20, and poloxamer 188. In some embodiments, the liquid pharmaceutical composition comprises polysorbate 80 at a concentration of about 0.01% (w / v) to about 0.04% (w / v), preferably about 0.02% (w / v). In some embodiments, the liquid pharmaceutical composition comprises polysorbate 20 at a concentration of about 0.02% (w / v). In some embodiments, the liquid pharmaceutical composition comprises a stabilizer selected from the group consisting of mannitol, sodium chloride, trehalose, arginine HC1, and glycine. In some embodiments, the liquid pharmaceutical composition comprises trehalose at a concentration of about 180 mM to about 300 mM, preferably about 200 mM or about 225 mM.

[0129] The present disclosure provides a pharmaceutical product comprising: a container having a headspace, wherein the oxygen content in the headspace is less than about 12%, and a liquid pharmaceutical composition having a pH of about 5.2 to about 6.2 disposed within the container, the composition comprising: about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen binding fragment thereof of the present disclosure (e.g., secukinumab); and about 2.5 to about 20 mM L-methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilisate.

[0130] In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure has a methionine concentration of about 2.5 mM, about 5 mM, about 10 mM, or about 20 mM, preferably about 5 mM. In some embodiments, the oxygen content in the headspace of the pharmaceutical product of the present disclosure is less than about 10%, for example, less than about 8%, preferably less than about 6%. In some embodiments, the pH of the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure is about 5.8. In some embodiments, the secukinumab concentration of the pharmaceutical product of the present disclosure is about 25 mg / ml or about 150 mg / ml. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises a buffer selected from the group consisting of histidine buffer, citrate buffer, acetate buffer, and succinate buffer. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure employs a buffer at a concentration of about 10 mM to about 30 mM. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure employs a histidine buffer at a concentration of about 20 mM. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises a surfactant selected from the group consisting of polysorbate and poloxamer. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises a surfactant selected from the group consisting of polysorbate 80, polysorbate 20, and poloxamer 188. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises polysorbate 80 at a concentration of about 0.01% (w / v) to about 0.04% (w / v), preferably about 0.02% (w / v). In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises polysorbate 20 at a concentration of about 0.02% (w / v). In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises a stabilizer selected from the group consisting of mannitol, sodium chloride, trehalose, arginine HC1, and glycine. In some embodiments, the liquid pharmaceutical composition of the pharmaceutical product of the present disclosure further comprises trehalose at a concentration of about 180 mM to about 300 mM, preferably about 200 mM to about 225 mM. In some embodiments, the container of the pharmaceutical product of the present disclosure is a cartridge, a syringe, a pen, or a vial.

[0131] The present disclosure provides a pharmaceutical product comprising: a container having a headspace, wherein the oxygen content in the headspace is less than about 6%; and a liquid pharmaceutical composition disposed within the container, the composition comprising about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen binding fragment thereof of the present disclosure (e.g., secukinumab), about 10 mM to about 30 mM histidine at pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilized material.

[0132] In some embodiments, the drug product comprises about 25 mg / ml secukinumab and about 225 mM trehalose. In some embodiments, the drug product comprises about 150 mg / ml secukinumab and about 200 mM trehalose. In some embodiments, the container of the drug product of the present disclosure is a cartridge, a syringe, a pen, or a vial.

[0133] In some embodiments, the drug product has a sufficient amount of IL-17 antagonist to enable delivery of at least about 75 mg to about 300 mg of IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) per unit dose. In some embodiments, the drug product has a sufficient amount of IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) to enable delivery of at least about 10 mg / kg per unit dose. In some embodiments, the drug product is formulated to enable intravenous delivery of a dose of about 10 mg / kg of IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) per unit dose. In some embodiments, the drug product is formulated to enable subcutaneous delivery of a dose of about 75 mg to about 300 mg of IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) per unit dose.

[0134] Processes for manufacturing liquid compositions and drug products

[0135] Processes for manufacturing the drug products and liquid compositions of the present disclosure are also described herein. These processes help reduce oxidation of the IL-17 antibodies of the present disclosure. Briefly, a liquid composition is prepared by combining the desired excipients (e.g., Group 1 stabilizer (e.g., trehalose), Group 2 stabilizer (methionine), surfactant (e.g., PS80), buffer (e.g., histidine)) with the IL-17 antibody or antigenic stage fragment thereof (e.g., secukinumab) to the desired concentration (e.g., about 25 to about 150 mg / ml secukinumab, about 20 mM histidine pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine) and pH (e.g., about pH 5.8). This liquid composition is then placed in a selected container (e.g., vial, syringe, cartridge [e.g., for use with a self-injector]). The oxygen content in the headspace is adjusted to the desired level (e.g., less than about 12%, less than 10%, less than about 8%, less than about 6%, etc.), which can be done prior to filling the container with the liquid composition, during filling of the container with the liquid composition, or during crimping / sealing of the container.

[0136] The present disclosure provides a process for reducing oxidation of secukinumab, comprising: preparing a liquid composition having a pH of about 5.2 to about 6.2 and comprising about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen-binding fragment thereof of the present disclosure (e.g., secukinumab) and about 2.5 mM to about 20 mM methionine; placing the liquid composition in a container having a headspace; and adjusting the oxygen content in the headspace to less than or equal to about 12%.

[0137] In some embodiments of the disclosed process, the adjusting step c) is performed by purging the headspace with an inert gas. In some embodiments of the disclosed process, the inert gas is nitrogen or argon. In some embodiments of the disclosed process, the methionine concentration in the liquid composition is about 2.5 mM, about 5 mM, about 10 mM or about 20 mM, preferably about 5 mM. In some embodiments of the disclosed process, the oxygen content in the headspace is adjusted to less than about 10%, such as less than about 8%, preferably less than about 6%. In some embodiments of the disclosed process, the pH of the liquid composition is about 5.8. In some embodiments of the disclosed process, the concentration of secukinumab in the liquid composition is about 25 mg / ml or about 150 mg / ml. In some embodiments of the disclosed process, the container is a cartridge, a syringe, a pen or a vial.

[0138] Methods of using the pharmaceutical products and liquid compositions

[0139] The pharmaceutical products and liquid compositions disclosed herein are intended for use in treating patients suffering from, for example, autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, etc.). Of course, the appropriate dosage will vary depending on, for example, the specific IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, to be used, the host, the mode of administration, and the nature and severity of the condition to be treated, and will depend on the nature of the patient's prior treatment. Ultimately, the attending healthcare provider will determine the amount of IL-17 antibody to administer to each individual patient they treat. In some embodiments, the attending healthcare provider may administer a low dose of the IL-17 antibody and observe the patient's response. In other embodiments, the patient is initially administered a higher dose of the IL-17 antibody, which is then gradually titrated downward until signs of relapse appear. Larger doses of the IL-17 antibody may be administered until the patient achieves optimal therapeutic benefit, generally without further dose increases.

[0140] Dosing time is usually measured from the day of the first dose of the active compound (e.g., secukinumab) (called "baseline"). However, different health care providers use different nomenclature, as follows

[0141] As shown in Table 2.

[0142] Week 0 / 1 1 / 2 2 / 3 3 / 4 4 / 5 5 / 6 6 / 7 7 / 8 8 / 9 etc. Day 1 0 / 1 7 / 8 14 / 15 21 / 22 28 / 29 35 / 36 42 / 43 49 / 50 56 / 57 etc.

[0143] Table 2 - Conventional dosing schedule nomenclature rules. Bolded items represent the nomenclature rules used herein.

[0144] It will be apparent that zero weeks can be referred to by some healthcare providers as week 1, and zero days can be referred to by some healthcare providers as day 1. Thus, different physicians can specify, for example, a dose during week 3 / at day 21, during week 3 / at day 22, during week 4 / at day 21, during week 4 / at day 22, all to represent the same dosing schedule. For consistency, the first week of dosing will be referred to herein as week 0, and the first day of dosing will be referred to as day 1. However, one skilled in the art will understand that the use of this nomenclature is simply for the sake of consistency, and should not be construed as limiting, i.e., a weekly dose is a dose of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, in a week, regardless of whether the physician refers to a particular week as "week 1" or "week 2". As a nomenclature example employing the rules specified herein, five doses of secukinumab administered weekly can be provided during week 0 (e.g., on about day 1), during week 1 (e.g., on about day 8), during week 2 (e.g., on about day 15), during week 3 (e.g., on about day 22), and during week 4 (e.g., on about day 29). It will be understood that the doses need not be provided at the exact time points, e.g., the dose on about day 29 can be provided, e.g., between days 24 and 34, e.g., on day 30, so long as it is provided within the appropriate week.

[0145] In some embodiments, the methods and uses of the disclosure employ an initial (sometimes referred to as "induction") regimen that lasts for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the initial regimen uses doses during weeks 0, 1, 2, and 3. In other embodiments, the initial regimen uses doses during weeks 0, 1, 2, 3, 4, 8, and 12. In some embodiments, the initial regimen comprises administration of several (e.g., 1, 2, 3, 4, 5, 6, 7, preferably 4 or 5) doses of about 150 mg - 300 mg, e.g., about four or five doses of 150 mg or 300 mg (preferably five doses of about 150 mg - about 300 mg) of an IL-17 antibody, e.g., secukinumab. In other embodiments, the initial doses are delivered weekly, biweekly, every other week, or monthly [every 4 weeks], preferably weekly. In some embodiments, 150 mg or 300 mg of an IL-17 antibody, e.g., secukinumab, is administered by subcutaneous injection at the initial dose during weeks 0, 1, 2, and 3.

[0146] For the maintenance regimen, a dose can be provided every month (also referred to as "monthly" dosing) (i.e., every 4 weeks, i.e., about every 28 days), every two months (i.e., every 8 weeks, i.e., about every 56 days), or every three months (i.e., every 12 weeks, i.e., about every 84 days). In some embodiments, the maintenance regimen begins after week 12. In some embodiments, the maintenance regimen begins after week 3. The first dose of the maintenance regimen is typically administered on a certain date from the final dose of the induction regimen. Thus, for example, if the final dose of the induction regimen is given during week 12, the first dose as part of a monthly [every 4 weeks] maintenance regimen would be delivered during week 16, the first dose as part of a bi-monthly maintenance regimen would be delivered during week 20, the first dose as part of a tri-monthly maintenance regimen would be delivered during week 24, etc. In some embodiments, the maintenance regimen comprises administering a dose of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, weekly, biweekly, monthly [every 4 weeks], every other month, quarterly, semiannually, or annually. In some embodiments, the maintenance regimen employs monthly dosing (every 4 weeks). In some embodiments, the first dose of the maintenance regimen is delivered during week 4 or during week 16. In some embodiments, the maintenance regimen comprises administering a dose of about 150 mg - 300 mg (e.g., about 150 mg or about 300 mg) of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab.

[0147] During the loading regimen, the induction regimen, and / or the maintenance regimen, delivery of the IL-17 antibody, e.g., secukinumab, can be via a subcutaneous route, e.g., delivery of a dose of about 75 mg - about 300 mg (e.g., about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg), via an intravenous route, e.g., delivery of a dose of about 1 mg / kg - about 50 mg / kg (e.g., about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, etc.), or any other route of administration (e.g., intramuscular, i.m.). In preferred embodiments, the dose of the IL-17 antibody is delivered subcutaneously.

[0148] In preferred embodiments, a dose of about 150 mg - about 300 mg (e.g., about 150 mg or about 300 mg) of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, is administered to the patient by subcutaneous injection at an initial dose at weeks 0, 1, 2, and 3, and then at a monthly maintenance dose beginning at week 4. In this regimen, dosing occurs at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, etc. The 300 mg dose can be provided as two 150 mg subcutaneous injections.

[0149] The present disclosure provides methods of treating an autoimmune disease (e.g., psoriasis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis) comprising administering to a patient in need thereof by subcutaneous injection an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, at an initial dose of about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg) at weeks 0, 1, 2, and 3, and then a monthly maintenance dose starting at week 4, wherein the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, is provided as part of a pharmaceutical composition comprising the following components: about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen-binding fragment thereof of the present disclosure (e.g., secukinumab), a buffer having a pH of about 5.2 to about 6.2, and about 2.5 to about 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilisate.

[0150] The present disclosure provides uses of an IL-17 antibody (e.g., secukinumab) for the manufacture of a medicament for treating an autoimmune disease (e.g., psoriasis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis) in a patient, wherein the medicament is formulated to include a container and a liquid pharmaceutical composition disposed within the container, each container having an oxygen content of less than about 12% (e.g., less than about 10%, less than about 8%, less than about 7%, less than about 6%, etc.) headspace, the composition comprising: about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen-binding fragment thereof of the present disclosure (e.g., secukinumab); a buffer having a pH of about 5.2 to about 6.2; and about 2.5 to 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilisate.

[0151] Kits comprising a pharmaceutical product and a liquid composition

[0152] The present disclosure also encompasses kits for treating various autoimmune diseases (e.g., psoriasis). These kits generally include at least one pharmaceutical product or liquid composition of the present disclosure and instructions for use. The instructions disclose suitable techniques for providing the stable liquid composition to a patient as part of a dosing regimen. These kits can also include other agents (as described above) for treating an autoimmune disease, e.g., psoriasis, for delivery in conjunction with (i.e., simultaneously or sequentially [before or after]) the liquid composition contained therein.

[0153] The present disclosure provides a kit for treating a patient suffering from an autoimmune disease (e.g., psoriasis), comprising: a) a container having a headspace, wherein the oxygen content in the headspace is less than about 12% (e.g., less than about 10%, less than about 8%, less than about 7%, less than about 6%, etc.), b) a liquid pharmaceutical composition disposed within the container, the composition comprising: i) about 20 mg / ml to about 175 mg / ml (e.g., about 25 mg / ml to about 150 mg / ml) of an IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab); ii) a buffer having a pH of about 5.2 to about 6.2; and iii) about 2.5 to 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilizate; and c) instructions for administering the liquid pharmaceutical composition to a patient. In some embodiments, the container is a pen, a prefilled syringe, an autoinjector, or a vial.

[0154] Overview

[0155] In some embodiments of the present disclosure, the IL-17 antibody or antigen-binding fragment thereof is selected from: a) an IL-17 antibody that binds to an IL-17 epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, and His129; b) an IL-17 antibody that binds to an IL-17 epitope comprising Tyr43, Tyr44, Arg46, Ala79, and Asp80; c) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, wherein the epitope comprises Leu74, Tyr85, His86, Met87, Asn88 on one chain; , Val124, Thr125, Pro126, Ile127, Val128, His129 and on the other chain Tyr43, Tyr44, Arg46, Ala79, Asp80; d) an IL-17 antibody that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 binding molecule has (e.g., by K of about 100-200 pM (measured) D , and wherein the IL-17 binding molecule has an in vivo half-life of about 23 to about 30 days; and e) an IL-17 antibody comprising an antibody selected from the group consisting of: i) an immunoglobulin heavy chain variable domain (V H), comprising the amino acid sequence shown in SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (V L ), comprising the amino acid sequence shown in SEQ ID NO: 10; iii) an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 8 H domain and an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 10 L iv) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 in sequence H domain; v) immunoglobulin V comprising, in sequence, the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain; vi) immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 in sequence H vii) an immunoglobulin V domain comprising, in sequence, the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain and an immunoglobulin V domain comprising, in sequence, the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain; and viii) an immunoglobulin V comprising, in sequence, the hypervariable regions shown in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H domain and an immunoglobulin V domain comprising, in sequence, the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain; ix) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 15 (with or without the C-terminal lysine); x) an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 14; xi) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 15 (with or without the C-terminal lysine) and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments of the disclosed methods, the IL-17 antibody or antigen-binding fragment thereof is a humanized antibody, preferably secukinumab.

[0156] The details of one or more embodiments of the disclosure are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described below. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, 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 disclosure belongs. All patents and publications cited in this specification are incorporated by reference. In order to fully appreciate the preferred embodiments of the present disclosure, the following examples are presented. These examples are in no way to be construed as limiting the scope of the disclosed subject matter, which is defined solely by the claims appended hereto.

[0157] Examples

[0158] It is to be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications and changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

[0159] These examples describe the development of stable liquid compositions of secukinumab. The data show that the pH of the composition and the selection of the Group 2 stabilizer have a large effect on the stability of the liquid composition. The data also show the effect of the oxygen content of the headspace on the stability of the liquid composition. The effect of antibody concentration, the selection of surfactant, the selection of Group 1 stabilizer, and the selection of the buffer system on stability is less. Thus, when considering the variables that have a large effect on stability, the disclosed drug product includes a container (e.g., PFS or vial) having a headspace, wherein the oxygen content of the headspace is less than about 12%, and a liquid pharmaceutical composition disposed within the container, the composition having a pH of about 5.2 to about 6.2 and comprising secukinumab at a concentration of about 20 mg / mL to 175 mg / mL and about 2.5 to about 20 mM L-methionine. When considering both the variables that have a large effect on stability and the variables that have a small effect on stability, the disclosed drug product includes a container (e.g., PFS or vial) having a headspace, wherein the oxygen content of the headspace is less than about 12%, and a liquid pharmaceutical composition disposed within the container, the composition having a pH of about 5.2 to about 6.2 and comprising secukinumab, a buffer, a surfactant, a stabilizer, and about 2.5 to about 20 mM L-methionine.

[0160] A preferred liquid composition comprises about 25 mg / mL to about 165 mg / mL secukinumab, about 185 mM to about 225 mM trehalose, about 0.01 % to about 0.03 % polysorbate 80, about 2.5 mM to about 20 mM L-methionine, and about 10-30 mM histidine buffer at about pH 5.8 (e.g., about 20 mM histidine buffer).

[0161] A preferred liquid composition I comprises about 150 mg / mL secukinumab, about 200 mM trehalose, about 0.02 % polysorbate 80, about 5 mM L-methionine, and about 20 mM histidine buffer at about pH 5.8. A preferred pharmaceutical product I comprises the above liquid composition I disposed in a pre-filled syringe (PFS).

[0162] Another preferred liquid composition II comprises about 25 mg / mL secukinumab, about 225 mM trehalose, about 0.02 % polysorbate 80, about 5 mM L-methionine, and about 20 mM histidine buffer at about pH 5.8. A preferred pharmaceutical product II comprises the above liquid composition II disposed in a vial.

[0163]

[0164] Table 3: Abbreviations used in the Examples

[0165]

[0166] Table 4: Assays used in the Examples

[0167] 1.1 Section I - Detailed analysis of variables that have a large impact on secukinumab liquid stability (headspace oxygen, pH, and L-methionine)

[0168] 1.1.1 Example 1 : L-methionine

[0169] A large set of analytical techniques was used to characterize the effect of several antioxidant stabilizers on secukinumab stability.

[0170] In early studies, a range of antioxidant stabilizers were evaluated, including tetrasodium EDTA, sodium ascorbate, cysteine, sodium bisulfite, and sodium citrate. While none of these stabilizers sufficiently stabilized the molecule, a small stabilizing effect was observed with tetrasodium EDTA and sodium citrate on aggregate product as measured by SEC compared to the composition without antioxidant stabilizer (data not shown).

[0171] In further studies, the stabilizers cysteine, EDTA tetrasodium and L-methionine at a concentration of 10 mM were evaluated using the DoE approach at a secukinumab concentration of 150 mg / mL compared to no stabilizer. The compositions were filled into PFS and subjected to a 2 month stability study at long term (5°C), accelerated (25°C) and stress (40°C) conditions and evaluated for physical stability (AP-SEC, DLS, turbidity, visible particles and sub-visible particles by light obscuration), chemical stability (CEX purity, RP-HPLC purity, color) and biological activity indicators (Cys-CEX activity, free SH groups). In addition, the compositions filled in 2 mL vials were subjected to freeze-thaw (5 cycles from -20°C to room temperature) and shaking stress (150 rpm for one week).

[0172] L-methionine was found to be the best 2ndgroup stabilizer for secukinumab. This could be demonstrated by the higher purity levels measured by CEX purity and RP-HPLC purity, lower turbidity levels and visible particle counts. L-methionine showed significantly better stability compared to the composition without stabilizer. After 8 weeks of stability testing at 25°C and 40°C accelerated conditions, the composition with L-methionine had lower levels of AP-SEC, more consistent DLS data, lower turbidity and lower amounts of pre-peak material by RP-HPLC. EDTA was disadvantageous due to increases in AP-SEC, DLS, basic variants measured by CEX and pre-peak material by RP-HPLC. Cysteine caused an increase in almost all aggregates and degradation products as shown by various analytical methods.

[0173] Figure 1 Selected property attributes after storage under different conditions are listed. Only L-methionine was observed to have a consistent stabilizing effect on secukinumab. In particular, the pre-peak material by RP-HPLC Figure 1 B) and AP-SEC Figure 1 D) were observed. Further effects were observed in turbidity and hydrodynamic radius by DLC. Different L-methionine concentrations were evaluated for their effect on secukinumab property attributes in follow-up studies.

[0174] Figure 2Shown is the change in material preceding the main peak measured by RP-HPLC during storage at 25°C at a secukinumab concentration of 25 mg / mL, a trehalose concentration of 225 mM, a polysorbate 80 concentration of 0.02%, and a pH 5.8 histidine buffer, with and without L-methionine. The compositions were filled into 2 mL vials and stored under stress conditions for up to 3 months. The black dashed line represents the linear fit of the values ​​obtained for the composition containing 0 mM L-methionine, and the gray dashed line represents the linear fit of the values ​​obtained for the composition containing 10 mM L-methionine. Clearly, reduced degradation kinetics were observed with the inclusion of L-methionine.

[0175] Concentration-dependent effects were also observed for compositions containing 150 mg / mL secukinumab. Compositions with trehalose concentrations between 200 mM and 300 mM, polysorbate 80 concentrations between 0.01% and 0.04%, and L-methionine concentrations between 0 mM and 10 mM were studied. The compositions were filled into 1 mL PFS and stored for up to three months under long-term, accelerated, and stress conditions. The physical (AP-SEC, DLS, insoluble and visible particles by light obscuration, turbidity) and chemical (CEX purity, RP-HPLC purity, color) stability and biological activity of secukinumab were monitored.

[0176] Figure 3 Shown is material preceding the main peak measured by RP-HPLC after 6 months of storage at 25°C. While trehalose and polysorbate 80 had negligible effects on degradation, a significant reduction in degradation was observed in the presence of L-methionine. This effect was more pronounced compared to the stability of secukinumab with and without L-methionine, and a concentration dependence was also observed within the 2.5-10 mM L-methionine range.

[0177] The same L-methionine stabilizing effect was observed in a composition containing 150 mg / mL secukinumab, 200 mM trehalose, 0.02% polysorbate 80 in pH 5.8 histidine buffer filled into 1 mL PFS after long-term storage (up to 30 months). Figure 4 AP-SEC (A) and material preceding the main peak as measured by RP-HPLC (B) are shown during storage at 5°C for up to 30 months. The black dashed line represents a linear fit to the values ​​obtained for a composition containing 5 mL of L-methionine, and the gray dashed line represents a linear fit to the values ​​obtained for a composition containing 0 mM L-methionine. Clearly, reduced degradation kinetics were observed in the presence of L-methionine.

[0178] The concentration dependence was further verified in a study evaluating the effect of L-methionine concentration (0-20 mM) on the stability of secukinumab (150 mg / mL, trehalose 200 mM, polysorbate 80 0.02%, pH 5.8 histidine buffer). The different compositions were filled into PFS and stored under long-term and accelerated conditions for 13 months and 30 months (5°C only). Secukinumab stability was evaluated by a selected set of analytical techniques (RP-HPLC purity, SEC purity, turbidity) that had been observed to be indicative of stability in previous screening. No clear trend conclusions could be drawn from the turbidity measurements. However, the material before the main peak measured by AP-SEC and by RP-HPLC clearly showed a dependence on the L-methionine concentration. The effect was smaller under real-time storage conditions, but a clear difference was observed at 25°C ( Figure 5 ).

[0179] After 13 months of storage at 25°C, the level of aggregates in the composition without L-methionine, as measured by SEC, increased from an initial level of <1% at t0 to 4.5%. By adding L-methionine to the composition, the increase in aggregate formation was reduced to 3.5% for 2.5 mM L-methionine, 3.0% for 5 mM L-methionine, and 2.2% for 20 mM L-methionine. At 5°C, the difference between the composition without L-methionine and the composition containing 20 mM L-methionine was only 0.3%. For the sample containing 0 mM L-methionine, the amount of material preceding the main peak, as measured by RP-HPLC, increased from 9.1% to 42.7% during 13 months of storage at 25°C. This increase in material preceding the main RP-HPLC peak decreased to 39.4% for the sample containing 2.5 mM L-methionine, 37.8% for 5.0 mM L-methionine, and 34.5% for 20 mM L-methionine. Overall, in the presence of L-methionine, a decrease in the levels of material preceding the main peak by AP-SEC and RP-HPLC was observed during storage in PFS at both 5°C and 25°C. The differences observed after storage at 25°C were more pronounced, but were also detectable after storage at 5°C.

[0180] Compared to compositions without L-methionine, the degradation rate was significantly reduced at 2.5 mM L-methionine. This was also confirmed in a further study comparing the stability of secukinumab in the presence of 0, 2.5, and 5.0 mM L-methionine. After 24 months of storage under expected storage conditions, no differences were observed between the compositions containing 2.5 mM and 5.0 mM L-methionine in terms of RP-HPLC purity, SEC purity, and turbidity.

[0181] Addition of L-methionine to the liquid antibody composition in the vial also reduced AP-SEC and CE-SDS impurities (non-reducing) (Figure 6 ). Interestingly, a reduced L-methionine concentration dependency was observed for the liquid antibody composition with 25 mg / mL secukinumab in the vial ( Figure 6 ), indicating that lower concentrations of L-methionine are sufficient to maintain antibody integrity and stability in compositions with lower antibody concentrations.

[0182] From the combined data from the above experiments, the ideal methionine concentration for liquid compositions of secukinumab is at least 2.5 mM (preferably about 5 mM) and superior to other 2ndgroup stabilizers.

[0183] 1.1.2 Example 2: Headspace oxygen content

[0184] 1.1.2.1 Primary packaging - PFS:

[0185] The effect of headspace oxygen content on secukinumab stability was evaluated in a 150 mg / mL secukinumab concentration and in a composition with 200 mM trehalose, 5 mM L-methionine, 0.02% polysorbate 80 at pH 5.8 histidine buffer. The compositions were filled into 1 mL PFS from each PFS supplier. The measured headspace oxygen content was between 13% and 15% (0.5 mL fill volume) or between 3-4% (0.5 mL fill volume) / 7-8% (1.0 mL fill volume), respectively. The samples were stored under long-term, accelerated and stress conditions for up to six months. Selected compositions were stored under long-term conditions for up to 24 months. Secukinumab stability was monitored by SEC purity, RP-HPLC purity, CEX purity, CE-SDS purity (non-reduced), turbidity, color, free SH groups, bioactivity, insoluble microparticles and visible particles by light obstruction.

[0186] The effect of headspace oxygen content was observed by RP-HPLC main peak fronting and AP-SEC under long-term, accelerated and stress conditions. Figure 7 AP-SEC is shown over a period of 9 months storage at 25°C. It is evident that PFS with headspace oxygen content between 13-15% show an increase in aggregation under 25°C conditions. But under storage conditions at 2-8°C there is almost no absolute difference in aggregation levels related to headspace oxygen content (6 months data) (data not shown).

[0187] The influence of different headspace oxygen content levels ranging from 6% to 21% (i.e. no purge) on the properties attributes of secukinumab (turbidity, SEC purity, RP-HPLC purity, CE-SDS purity (non-reduced), free SH groups, bioactivity, insoluble particulates by light block, visible particles, color) was further evaluated during 12 months storage at 5°C, during 6 months storage under accelerated conditions (25°C) and during 3 months storage under stress conditions (40°C). The study was performed in a composition of 150 mg / mL secukinumab and a pH 5.8 histidine buffer containing 200 mM trehalose, 5 mL L-methionine, 0.02% polysorbate 80. Samples were filled into PFS and purged with a certified oxygen mixture to obtain the target headspace oxygen content.

[0188] No changes in turbidity were observed over the storage time; no significant influence of headspace oxygen content on insoluble particulates by light block, color and free SH groups was observed and the differences between the different headspace oxygen content samples were within the dispersion of the method. No relevant changes in methionine concentration occurred during storage at 5°C or 25°C and no matter the headspace oxygen content, a 4.9 mM (initial value 4.9-5.0 mM) was observed after 12 months at 5°C.

[0189] In contrast to the previous finding showing a relatively large influence of headspace oxygen content on SEC aggregate production, only minor changes were observed during the long storage period of up to 12 months at the expected storage condition (5°C), even in the non-purged reference sample. No relevant differences in purity and SEC aggregates were observed between the samples with different headspace oxygen content for the different stability points tested (up to 12 months storage at 2-8°C and up to 6 months storage at 25°C Figure 8 ). In contrast, we did notice an increase in RP-HPLC main purity with increasing headspace oxygen content. This phenomenon was observed at 5°C (after 12 months storage) (data not shown) and at 25°C (after 6 months storage) Figure 9 ). No new peaks appeared.

[0190] 1.1.2.2 Primary packaging - vials:

[0191] Compositions were filled into 2 mL vials and stored under refrigerated conditions for 12 months and under accelerated and stressed conditions for up to 3 months. Tables 5-7 summarize the change in pre-peak material by RP-HPLC and SEC-AP for secukinumab concentrations of 25 mg / mL, trehalose concentrations of 225 mM, polysorbate 80 concentrations of 0.02% in pH 5.8 histidine buffer stored at 5°C, 25°C, and 40°C in the presence and absence of 5 mM L-methionine.

[0192]

[0193] Table 5: RP-HPLC and SEC results for 25 mg / ml secukinumab liquid after 6 and 12 months storage at 5°C in vials. Compositions contain 25 mg / ml secukinumab, 225 mM trehalose, 5 mM L-methionine, 0.02% PS80.

[0194]

[0195] Table 6: RP-HPLC and SEC results for 25 mg / ml secukinumab liquid after 3 months storage at 25°C and 40°C in vials. Compositions contain 25 mg / ml secukinumab, 225 mM trehalose, 5 mM L-methionine, 0.02% PS80.

[0196]

[0197] Table 7: RP-HPLC and SEC results for 25 mg / ml secukinumab liquid after 6 and 12 months storage at 5°C in vials. Compositions contain 25 mg / ml secukinumab, 225 mM trehalose, 0 mM L-methionine, 0.02% PS80.

[0198]

[0199]

[0200] Table 8: RP-HPLC and SEC results for 25 mg / ml secukinumab liquid after 3 months storage at 25°C and 40°C in vials. Compositions contain 25 mg / ml secukinumab, 225 mM trehalose, 0 mM L-methionine, 0.02% PS80.

[0201] The effect of oxygen content in the headspace on the liquid stability of 25 mg / ml secukinumab in the vial was seen by RP-HPLC on the material before the main peak: after 12 months at 5°C (4.5% for 5% headspace oxygen content vs. 7.1% for 20% headspace oxygen content, see Table 5), after 3 months at 25°C (17.9% for 5% headspace oxygen content vs. 20.6% for 20% headspace oxygen content, see Table 6), and after 3 months at 40°C (40.6% for 5% headspace oxygen content vs. 46.2% for 20% headspace oxygen content, see Table 6). The same trend was also seen by AP-SEC after 3 months at 40°C (1.8% for 5% headspace oxygen content vs. 2.5% for 20% headspace oxygen content, see Table 6). Furthermore, the concentration of L-methionine had a further impact when combined with lower headspace oxygen content. For example, comparing the RP-HPLC material before the main peak for the composition with 5% oxygen content in the headspace and stored for 12 months at 5°C, the composition without L-methionine was 6.1% (Table 7), while the composition with 5 mM L-methionine was 4.5% (Table 5). The same difference was seen for the material before the main peak of the RP-HPLC: after 3 months at 25°C (5-20% oxygen: 20.9-25.5% without L-methionine (Table 8) vs. 17.9-25.5% with 5 mM L-methionine (Table 6)) and after 3 months at 40°C (5-20% oxygen: 44.6-50.9% without L-methionine (Table 8) vs. 40.6-46.2% with 5 mM L-methionine (Table 6)).

[0202] Based on the above experiments, nitrogen sparging to reduce the headspace oxygen content to less than about 12% was considered beneficial to enhance PFS and liquid composition stability in the vial (evaluated by material before the main peak of the RP-HPLC).

[0203] 1.1.3 Example 3: Interaction between L-methionine concentration and headspace oxygen content

[0204] The interaction between L-methionine concentration and headspace oxygen content was further investigated. Compositions containing L-methionine in the range of 2.5-7.5 mM and headspace oxygen content between 3 and 9% were prepared. The compositions were filled into PFS and stored for 6 months under long-term and accelerated conditions. Relevant secukinumab property attributes (SEC purity, RP-HPLC purity, CEX purity, free SH groups, bioactivity, insoluble microparticles and visible particles by light obstruction, turbidity and color of the solution) were monitored after 3 and 6 months of storage. Figure 10The AP-SEC purity after 6 months storage at 25°C was shown as a function of L-methionine and headspace oxygen content. No interactions were observed in the range tested when analyzing with AP-SEC purity.

[0205] In another study, the impact of headspace oxygen content reduction and L-methionine concentration was evaluated at a 150 mg / mL secukinumab concentration. The compositions contained 270 mM mannitol, 0.04% polysorbate 80, and different L-methionine concentrations ranging from 0.15% to 2%. The compositions were filled into 2 mL glass vials, purged with nitrogen or not, and stored for up to 6 months in long-term, accelerated, and stress conditions.

[0206] Figure 11 The RP-HPLC pre-peak material of compositions containing 0.15% (10 mM), 1% (67 mM), or 2% (134 mM) L-methionine and having a nitrogen or air headspace was shown after storage for up to 36 months. As observed before, the RP-HPLC pre-peak material of compositions containing higher amounts of L-methionine was at lower levels. Also in the case of compositions having a headspace purged with nitrogen, lower levels of RP-HPLC pre-peak material were shown.

[0207] From the combined data from different experiments using vials and PFS as primary packaging, it is desirable for liquid compositions of secukinumab that the headspace oxygen content is less than about 12% and the L-methionine concentration is at least about 2.5 mM.

[0208] 1.1.4 Example 4: pH

[0209] The impact of pH on secukinumab stability was evaluated starting with a concentration of 10 mg / ml in 100 mM citric acid / sodium phosphate buffer with 90 mM sodium chloride at a pH ranging between 4.0 and 7.5. The samples were stored for 3 weeks at 5°C and 40°C. Secukinumab stability after five cycles of freeze-thaw from ≤ -60°C to room temperature was monitored in parallel.

[0210] The optimal pH for secukinumab varies depending on the degradation pathway being analyzed. Aggregation and proteolysis, as determined by SEC purity, SDS-PAGE purity (reducing properties), and LLS average molecular weight, are minimal at pH 5.7 to 6.2, while the optimal pH for CEX purity is 5.3. Active secukinumab contains one free cysteine ​​residue on each light chain, so 2 mol thiol groups / mol secukinumab are expected. Since a decrease in the level of free SH groups is associated with a loss of secukinumab bioactivity, a method based on Ellman's reagent was used to quantify the free SH groups. A slightly reduced value of 1.94 mol / mol was only observed at pH 4.3. The freeze-thaw tolerance of secukinumab, monitored by SEC purity and LLS average molecular weight, was maximal at pH 5.3 to 5.7. pH 5.8 was selected for further formulation of secukinumab.

[0211] The effect of pH on the stability of secukinumab was further investigated using a DoE approach in the PFS. The effect of pH in the range of 5.2-5.8 was evaluated at a secukinumab concentration of 150 mg / mL. The composition was subjected to a 2-month stability study under long-term (5°C), accelerated (25°C) and stress (40°C) conditions and evaluated for physical stability (AP-SEC, DLS, turbidity, visible particles and insoluble particles measured by light obscuration), chemical stability (CEX purity, RP-HPLC purity, color) and bioactivity indicators (Cys-CEX activity, free SH groups). In addition, freeze-thaw (5 cycles from -20°C to room temperature) and shaking stress (150 rpm for one week) were applied to the composition filled in a 2 mL vial. It was found that pH values ​​within the study range significantly affected the stability of secukinumab (AP-SEC, DP-SEC, DLS, CEX alkaline variants, RP-HPLC purity). The results from previous studies that pH 5.8 is the ideal value (the material before the main peak of AP-SEC, DP-SEC and RP-HPLC) were confirmed ( Figure 12 ).

[0212] The effect of pH was further evaluated in compositions containing 150 mg / mL secukinumab, 200 mM trehalose, L-methionine in the range of 2.5-7.5 mM, and headspace oxygen levels between 3 and 9%. The pH of the histidine buffer was varied between 5.4 and 6.2. The compositions were filled into PFS and stored for 6 months under long-term and accelerated conditions. Relevant secukinumab properties (SEC purity, RP-HPLC purity, CEX purity, free SH groups, biological activity, insoluble particulate matter measured by light obscuration, visible particles, turbidity and color of the solution) were monitored after 3 and 6 months of storage. Figure 13Effect of pH on the properties attributes of secukinumab after storage at 5°C. Increase in turbidity, AP-SEC and CEX acidic variants and decrease in SEC purity at higher pH values were observed, further confirming what was observed in the initial screening.

[0213] From the combined data from various experiments, the ideal pH range for secukinumab liquid compositions is from about 5.2 to about 6.2.

[0214] 1.2 Section 2 - Detailed analysis of excipients (stabilizers, surfactants and buffers) having a minor impact on the liquid stability of secukinumab

[0215] 1.2.1 Example 5 - Selection of stabilizers having little impact on stability

[0216] The initial composition development for the liquid dosage form was dedicated to evaluate the impact of different stabilizers on the solubility and insoluble aggregate formation (AP-SEC, SDS-PAGE purity, light scattering techniques), chemical stability (RP-HPLC purity, CEX purity, color) and biological activity (Cys-CEX activity, free SH groups, bioactivity) of secukinumab during storage under long-term, accelerated and stress conditions.

[0217] The stabilizers were divided into three different groups: Group I included non-ionic (mannitol, trehalose dihydrate) and ionic (sodium chloride and arginine hydrochloride) stabilizers. All Group I stabilizers provided a benefit compared to no stabilizer. However, the non-ionic stabilizers (trehalose and mannitol) were better stabilizers for the molecule as observed by lower aggregate levels and higher Cys-CEX activity.

[0218] Based on the conclusions from the initial composition development study, further studies were performed using the DoE approach in PFS. The effect of Group I stabilizers (glycine, mannitol, trehalose dihydrate, sodium chloride) was evaluated. The compositions were filled into pre-filled syringes and subjected to a 2 month stability study under long-term, accelerated and stress conditions and evaluated for physical stability (AP-SEC, DLS, turbidity, visible particles and insoluble microparticles by light obscuration), chemical stability (CEX purity, RP-HPLC purity, color) and biological activity indicators (Cys-CEX activity, free SH groups). In addition, the compositions filled into 2 mL vials were subjected to freeze-thaw (-20°C to room temperature for 5 cycles) and shaking stress (150 rpm for one week). With respect to Group I stabilizers, the observations from the previous screening were confirmed: 1) all Group I stabilizers provided a benefit compared to no stabilizer; and 2) non-ionic stabilizers were found to be better stabilizers for the secukinumab protein (mannitol and trehalose dihydrate) than ionic stabilizers (sodium chloride and arginine hydrochloride). Figure 14). This was particularly pronounced in SEC purity, RP-HPLC purity and DLS polydispersity. Comparing different non-ionic stabilizers, no relevant effects were observed.

[0219] Secondly we identified the ideal concentration of the group I stabilizer (trehalose dihydrate 200-300 mM). The samples were filled into PFS and stored for up to three months under long-term, accelerated and stress conditions. The physical (AP-SEC, DLS, sub-visible particles by light obscuration, visible particles, turbidity) and chemical (CEX purity, RP-HPLC purity, color) stability as well as the bioactivity of secukinumab were monitored. No relevant changes in the property attributes of secukinumab were observed with varying trehalose concentrations Figure 3 ).

[0220] 1.2.2 Example 6: Selection of surfactants with little impact on stability

[0221] The initial composition development of the 150 mg / ml liquid composition was dedicated to evaluate the impact of different excipients (e.g. stabilizers and surfactants) on the solubility of secukinumab and the formation of soluble and insoluble aggregates (AP-SEC, SDS-PAGE purity, light scattering techniques), chemical stability (RP-HPLC purity, CEX purity, color) and bioactivity (Cys-CEX activity, free SH groups, bioactivity) during storage under long-term storage conditions as well as accelerated and stress conditions. The excipients were divided into three different groups: Group III included the surfactants polysorbate 20 and 80. No differences between polysorbate 20 and 80 at a concentration of 0.04% were observed during the static storage compared to no surfactant.

[0222] Based on the conclusions of the initial composition development study, further studies were performed in PFS using the DoE approach. The impact of surfactants (polysorbate 20, polysorbate 80, poloxamer 188, no surfactant) was evaluated. The compositions were filled into PFS and subjected to a 2 month stability study under long-term, accelerated and stress conditions, evaluating the physical stability (AP-SEC, DLS, turbidity, visible particles and sub-visible particles by light obscuration), chemical stability (CEX purity, RP-HPLC purity, color) and bioactivity indicators (Cys-CEX activity, free SH groups). In addition, the compositions filled in 2 mL vials were subjected to freeze-thaw (-20 °C to room temperature for 5 cycles) and shaking stress (150 rpm for one week). The presence of surfactants was observed to be beneficial by lower turbidity levels and by the count of visible particles and sub-visible particles by light obscuration. However, the surfactant class had only a weak impact Figure 15 ).

[0223] We next determined the ideal concentration of Group III surfactant (polysorbate 800.01-0.04 (w / v)%). Samples were filled into PFS and stored under long-term, accelerated, and stressed conditions for up to three months. The physical (AP-SEC, DLS, insoluble particulate matter by light obscuration, visible particles, turbidity) and chemical (CEX purity, RP-HPLC purity, color) stability and bioactivity of secukinumab were monitored. Figure 3 ) and after one week of shaking at 150 rpm, no significant effect of polysorbate 80 concentration on the performance properties of secukinumab was observed. At higher surfactant concentrations, DLS polydispersity and insoluble particulate matter measured by light obscuration slightly increased; therefore, a polysorbate 80 concentration of 0.02% was established to maintain a safety margin at the lowest evaluated concentration.

[0224] 1.2.3 Example 5: Selection of a buffer with little effect on stability

[0225] The effect of buffer type (citrate, histidine, succinate, acetate) was evaluated using a DoE approach in PFS. The composition was filled into PFS and subjected to a 2-month stability study under long-term, accelerated, and stress conditions to evaluate physical stability (AP-SEC, DLS, turbidity, visible particles and insoluble particles measured by light obscuration), chemical stability (CEX purity, RP-HPLC purity, color), and bioactivity indicators (Cys-CEX activity, free SH groups). In addition, freeze-thaw (5 cycles from -20°C to room temperature) and shaking stress (150 rpm for one week) were applied to the composition filled in a 2 mL vial. No relevant effect of buffer type was observed. Figure 16 Displays the properties of the selected property.

[0226] 1.2.4 Example 6: Antibody concentration within the tested range has little effect on stability

[0227] The effect of secukinumab concentration on the properties of the liquid composition was evaluated in the range of 124.5-175.5 mg / mL. The composition also contained 200 mM trehalose, 5 mM L-methionine and 0.02% polysorbate in a pH 5.8 histidine buffer. The composition was filled into PFS and stored for 6 months under long-term and accelerated conditions. Relevant secukinumab properties (SEC purity, RP-HPLC purity; CEX purity, free SH groups, biological activity, insoluble particulate matter measured by light obscuration, visible particles, turbidity and color of the solution) were monitored after 3 and 6 months of storage. No relevant effect of secukinumab concentration on the properties of the liquid composition was observed in the range of 25 mg / ml to 150 mg / ml (data not shown).

[0228] 1.3 Part 3 - Properties of preferred final marketed compositions

[0229] Preferred secukinumab drug products include a liquid composition provided in a PFS comprising 150 mg / ml secukinumab, 200 mM trehalose, 0.02% polysorbate 80, and 5 mM L-methionine in 20 mM histidine buffer, pH 5.8. The oxygen content of the headspace in the PFS is less than 12% at initial fill and completion. These drug products have superior shelf life and overall stability.

[0230] Stability testing was performed on various batches of secukinumab drug product in PFS (150 mg / ml secukinumab, 200 mM trehalose dihydrate, 20 mM L-histidine / L-histidine hydrochloride monohydrate, 5 mM L-methionine, 0.02% polysorbate 80 (% w / v), pH 5.8). The test results after storage for up to 24 months under long-term storage conditions (2-8°C), after storage for up to 6 months under accelerated storage conditions (25°C), and after storage for up to 6 months under temperature stress conditions (30°C) are shown in Tables 9-11 below. Based on the stability data presented, real-time data for 150 mg / 1 ml liquid secukinumab in PFS for up to 24 months, and stability data generated during development for up to 36 months (bulk syringes), for 150 mg / 1 ml liquid secukinumab in PFS, a shelf life of 24 months is recommended when stored at 5°C ± 3°C under long-term conditions, protected from light, and protected from freezing.

[0231] Table 9 SEC, CEX, and RP-HPLC purity. * This higher value is related to a small peak that appears just before the main peak. Since this new peak is integrated independently from the main peak, the sum of variants before the main peak becomes higher.

[0232]

[0233] Table 10 CE-SDS purity (non-reduced) and SDS-PAGE impurities (reduced).

[0234]

[0235] Table 11 Potency and amount. * Samples were tested >30 days after the day of withdrawal, this deviation had no impact on the potency test results.

[0236]

[0237] The present application also relates to the following technical solutions.

[0238] Item 1. A pharmaceutical product comprising:

[0239] a. a container having a headspace, wherein the oxygen content in the headspace is less than about 12%, and

[0240] b. a liquid pharmaceutical composition having a pH of about 5.2 to about 6.2 disposed within the container, the composition comprising:

[0241] i. about 20 mg / ml to about 175 mg / ml secukinumab; and

[0242] ii. about 2.5 to about 20 mM L-methionine,

[0243] wherein the liquid pharmaceutical composition is not reconstituted from a lyophilized.

[0244] Item 2. The pharmaceutical product of item 1, wherein the concentration of methionine is about 2.5 mM, about 5 mM, about 10 mM, or about 20 mM.

[0245] Item 3. The pharmaceutical product of item 2, wherein the concentration of methionine is about 5 mM.

[0246] Item 4. The pharmaceutical product of any of the preceding items, wherein the oxygen content in the headspace is less than about 10%.

[0247] Item 5. The pharmaceutical product of any of the preceding items, wherein the oxygen content in the headspace is less than about 8%.

[0248] Item 6. The pharmaceutical product of any of the preceding items, wherein the oxygen content in the headspace is less than about 6%.

[0249] Item 7. The pharmaceutical product of any of the preceding items, wherein the pH of the liquid pharmaceutical composition is about 5.8.

[0250] Item 8. The pharmaceutical product of any of the preceding items, wherein the concentration of secukinumab is about 25 mg / ml or about 150 mg / ml.

[0251] Item 9. The pharmaceutical product of any of the preceding items, wherein the liquid pharmaceutical composition further comprises a buffer selected from the group consisting of a histidine buffer, a citrate buffer, an acetate buffer, and a succinate buffer.

[0252] Item 10. The pharmaceutical product of item 9, wherein the concentration of the buffer is about 10 mM to about 30 mM.

[0253] Item 11. The pharmaceutical product as described in Item 10, characterized in that the buffer is a histidine buffer with a concentration of about 20 mM.

[0254] Item 12. The pharmaceutical product according to any of the preceding items, characterized in that the liquid pharmaceutical composition further comprises a surfactant selected from polysorbates and poloxamers.

[0255] Item 13. The pharmaceutical product according to any of the preceding items, characterized in that the surfactant is polysorbate 80, polysorbate 20 or poloxamer 188.

[0256] Item 14. The pharmaceutical product of Item 13, wherein the surfactant is polysorbate 80 at a concentration of about 0.01% (w / v) to about 0.04% (w / v).

[0257] Item 15. The pharmaceutical product of Item 14, wherein the concentration of polysorbate 80 is about 0.02% (w / v).

[0258] Item 16. The pharmaceutical product of Item 13, wherein the surfactant is polysorbate 20 at a concentration of about 0.02% (w / v).

[0259] Item 17. The pharmaceutical product according to any of the preceding items, characterized in that the liquid pharmaceutical composition further comprises a stabilizer selected from mannitol, sodium chloride, trehalose, arginine HCl and glycine.

[0260] Item 18. The pharmaceutical product of Item 17, wherein the stabilizer is trehalose at a concentration of about 180 mM to about 300 mM.

[0261] Item 19. The pharmaceutical product of Item 18, wherein the concentration of trehalose is about 200 mM or about 225 mM.

[0262] Item 20. The pharmaceutical product according to any of the preceding items, characterized in that the container is a cartridge, a syringe, a pen or a vial.

[0263] Item 21. A pharmaceutical product comprising

[0264] a. a container having a head space, wherein the oxygen content in the head space is less than about 6%; and

[0265] b. a liquid pharmaceutical composition disposed within the container, the composition comprising about 25 mg / mL to about 150 mg / mL secukinumab, about 10 mM to about 30 mM histidine at pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilized material.

[0266] Item 22. The pharmaceutical product of item 21, comprising about 25 mg / ml secukinumab and about 225 mM trehalose.

[0267] Item 23. The pharmaceutical product of item 21, comprising about 150 mg / ml secukinumab and about 200 mM trehalose.

[0268] Item 24. The pharmaceutical product of any of the preceding items, wherein the liquid composition:

[0269] a. retains at least about 86% RP-HPLC purity after 6 months storage at 2-8°C, at least about 76% RP-HPLC purity after 6 months storage at 25°C / 60% RH, and / or at least about 60% RP-HPLC purity after 6 months storage at 30°C / 75% RH;

[0270] b. retains at least about 77% CEX purity after 6 months storage at 2-8°C, at least about 62% CEX purity after 6 months storage at 25°C / 60% RH, and / or at least about 50% CEX purity after 6 months storage at 30°C / 75% RH;

[0271] c. the liquid composition retains at least about 98% SEC purity after 6 months storage at 2-8°C, at least about 96% SEC purity after 6 months storage at 25°C / 60% RH, and / or at least about 94% SEC purity after 6 months storage at 30°C / 75% RH;

[0272] d. retains at least about 97% CE-SDS purity (non-reducing conditions) after 6 months storage at 2-8°C, at least about 95% CE-SDS purity (non-reducing conditions) after 6 months storage at 25°C / 60% RH, and / or at least about 94% (preferably at least about 92%) CE-SDS purity (non-reducing conditions) after 6 months storage at 30°C / 75% RH;

[0273] e. retains less than about 0.57% CE-SDS impurities (reducing conditions) after 6 months storage at 2-8°C, less than about 1.1% CE-SDS impurities (reducing conditions) after 6 months storage at 25°C / 60% RH, and / or less than about 1.9% CE-SDS impurities (reducing conditions) after storage at 30°C / 75% RH; and / or

[0274] f. retains at least about 88% relative bioactivity for inhibiting release of IL-6 from C-20 / A4 chondrocytes after 24 months storage at 2-8°C, at least about 94% relative bioactivity for inhibiting release of IL-6 from chondrocytes after 6 months storage at 25°C / 60% RH, and / or at least about 85% relative bioactivity for inhibiting release of IL-6 from chondrocytes after 6 months storage at 30°C / 75% RH.

[0275] Item 25. The pharmaceutical product of any of the preceding items, wherein the liquid composition:

[0276] a. retains at least about 84% RP-HPLC purity after 24 months storage at 2-8°C;

[0277] b. retains at least about 73% CEX purity after 24 months storage at 2-8°C;

[0278] c. retains at least about 97% SEC purity after 24 months storage at 2-8°C;

[0279] d. retains at least about 97% CE-SDS purity (non-reducing conditions) after 24 months storage at 2-8°C; and / or

[0280] e. retains less than about 0.91% CE-SDS impurities (non-reducing conditions) after 24 months storage at 2-8°C.

[0281] Item 26. A method of reducing oxidation of secukinumab, comprising:

[0282] a. preparing a liquid composition having a pH of about 5.2 to about 6.2 and comprising:

[0283] i. about 25 mg / ml to about 150 mg / ml secukinumab; and

[0284] ii. about 2.5 mM to about 20 mM methionine;

[0285] b. placing the liquid composition in a container having a headspace; and

[0286] c. adjusting the oxygen content in the headspace to less than or equal to about 12%.

[0287] Item 27. The method of item 26, wherein the adjusting step c) is performed by purging the headspace with an inert gas.

[0288] Item 28. The method of item 27, wherein the inert gas is nitrogen or argon.

[0289] Item 29. The method of item 26, wherein the methionine is at a concentration of about 2.5 mM, about 5 mM, about 10 mM, or about 20 mM.

[0290] Item 30. The method of item 29, wherein the methionine is at a concentration of about 5 mM.

[0291] Item 31. The method of item 26, wherein the oxygen content in the headspace is adjusted to less than about 10%.

[0292] Item 32. The method of item 26, wherein the oxygen content in the headspace is adjusted to less than about 8%.

[0293] Item 33. The method of item 26, wherein the oxygen content in the headspace is adjusted to less than about 6%.

[0294] Item 34. The method of item 26, wherein the pH of the liquid composition is about 5.8.

[0295] Item 35. The method of item 26, wherein the secukinumab concentration is about 25 mg / ml or about 150 mg / ml.

[0296] Item 36. A liquid pharmaceutical composition comprising about 25 mg / mL to about 150 mg / mL secukinumab, about 10 mM to about 30 mM histidine, pH 5.8, about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine, wherein the liquid pharmaceutical composition is not reconstituted from a lyophilized material.

Claims

1. A stable, ready-to-use liquid pharmaceutical composition having a pH of 5.2 to 6.2, comprising: i. 50 mg / ml to 175 mg / ml of secukinumab; and ii. 2.5 mM to about 20 mM methionine; iii. a non-ionic stabilizer, a surfactant selected from the group consisting of polysorbates and poloxamers, and a buffer selected from the group consisting of histidine buffer, citrate buffer, succinate buffer, acetate buffer, or a combination thereof.

2. The pharmaceutical composition according to claim 1, wherein the concentration of methionine is 2.5 mM, 5 mM, 10 mM or 20 mM.

3. The pharmaceutical composition according to claim 1, wherein The pH of the liquid pharmaceutical composition is 5.

8.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The concentration of secukinumab is 150 mg / ml.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein The composition includes an ionic stabilizer.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein The buffer is a histidine buffer.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein The concentration of the buffer is 10 mM to 30 mM.

8. The pharmaceutical composition according to claim 6, wherein The buffer is a histidine buffer with a concentration of 10 mM to 20 mM.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein The non-ionic stabilizer is selected from mannitol and trehalose.

10. The pharmaceutical composition according to claim 5, wherein The ionic stabilizer is selected from sodium chloride, arginine and glycine.

11. The pharmaceutical composition according to claim 9, wherein The non-ionic stabilizer is trehalose.

12. The pharmaceutical composition according to any one of claims 1 to 3, wherein The concentration of the non-ionic stabilizer is 180 mM to 300 mM.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein The concentration of the non-ionic stabilizer is 200 mM to 225 mM.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein The surfactant is selected from polysorbate 80, polysorbate 20 or poloxamer 188.

15. The pharmaceutical composition according to any one of claims 1 to 3, wherein The surfactant is polysorbate 80.

16. The pharmaceutical composition according to any one of claims 1 to 3, wherein The concentration of the surfactant is 0.01% (w / v) to 0.04% (w / v).

17. The pharmaceutical composition according to any one of claims 1 to 3, wherein The buffer is a histidine buffer, the nonionic stabilizer is trehalose, and the surfactant is polysorbate 80.

18. The pharmaceutical composition according to any one of claims 1 to 3, wherein The liquid pharmaceutical composition does not contain arginine.

19. Use of a stable, ready-to-use liquid pharmaceutical composition in the preparation of a medicament for treating an IL-17-mediated disease, wherein: The composition comprises 50 mg / mL to 175 mg / mL secukinumab, 10 mM to 30 mM histidine at pH 5.2-6.2, 200 mM to 225 mM trehalose, 0.01% to 0.04% polysorbate, and 2.5 mM to 20 mM methionine.

20. Use of a stable, ready-to-use liquid pharmaceutical composition in the preparation of a medicament for treating an IL-17-mediated disease, wherein: The composition contained 150 mg / ml secukinumab, 20 mM histidine at pH 5.8, 200 mM trehalose, 0.02% polysorbate 80, and 5 mM L-methionine.

21. A pharmaceutical product comprising: (1) a container, and (2) a pharmaceutical composition according to any one of claims 1 to 18 placed in the container; The container has a head space containing a mixture of oxygen and other gases commonly found in air, and the oxygen content in the head space is adjusted by introducing an inert gas into the head space. (a) actively by purging with an inert gas before filling the container with the composition, during filling, or before and during placement of the stopper; or (b) This is accomplished passively by placing the container in a system and removing oxygen.

22. The pharmaceutical product according to claim 21, wherein The container is a pen, syringe, vial or autoinjector.

23. The pharmaceutical product according to claim 21 or 22, wherein The pharmaceutical composition is a composition as defined in any one of claims 1 to 18.

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