EA045866B1 - COMPOSITION OF THERAPEUTIC ANTIBODY - Google Patents

Description

The present invention relates to the field of medicine. More specifically, the present invention relates to aqueous pharmaceutical compositions containing therapeutic antibodies that are suitable for subcutaneous (SC), intramuscular (IM) and/or intraperitoneal (IP) administration.

Administration of therapeutic antibodies by PC, PI and/or IM routes is widespread and preferred. These routes of administration provide delivery of the therapeutic antibody in a short period of time and allow patients to self-administer the therapeutic antibody without visiting a healthcare professional. However, the incorporation of therapeutic antibodies into aqueous pharmaceutical formulations suitable for PC, IM and/or PI administration is difficult and cannot be adequately controlled. In addition, with these routes of administration, there is unwanted pain associated with the injection, even after removal of the syringe needle, which may interfere with patient compliance with therapy.

The difficulty and inability to properly control the incorporation of therapeutic antibodies into aqueous pharmaceutical formulations suitable for PC, IM and/or PI administration is due, in part, to the fact that the pharmaceutical formulation must have many different properties to be therapeutically useful. Aqueous pharmaceutical formulations must provide stability of the therapeutic antibody in solution while maintaining the functional characteristics of the therapeutic antibody necessary to achieve therapeutic efficacy, such as affinity, selectivity and activity for the target. In addition, the aqueous pharmaceutical composition must also be safe and well tolerated when administered to patients, and must be suitable for production and storage.

Producing formulations with high concentrations of therapeutic antibodies is even more challenging. For example, in aqueous formulations with high concentrations of therapeutic antibodies, increased rates of antibody degradation, cleavage, fragmentation, formation of high molecular weight aggregates, dimerization, trimerization, precipitation with pH changes, turbidity, solution color changes, charge changes, isomerization, oxidation and/or observed. or deamination (all of which affect the concentration, functionality and efficacy of the therapeutic antibody). Another known problem when preparing formulations with high concentrations of therapeutic antibodies is the increase in viscosity, which can adversely affect the PC, IM and/or IP administration of an aqueous pharmaceutical formulation. In addition, there are reports of pain associated with injection of compounds having increased viscosity.

Additionally, in some therapeutic antibodies, such as ixekizumab, charge distribution results in high levels of intermolecular interactions (e.g., as can be demonstrated by dynamic light scattering), phase separation, gelation, and precipitation, making it extremely difficult to balance the molecule's solubility in aqueous solution, in particular at high concentrations. The charge distribution of these antibodies may also result in them having an isoelectric point that does not permit formulation at neutral pH. For example, some therapeutic antibodies have a polarity, or dipole moment, such that they are stable in aqueous formulations within a narrow non-neutral pH range. However, there are reports of pain associated with injection of acidic (eg, <pH 6.5) pharmaceutical formulations of therapeutic antibodies. Thus, these therapeutic antibodies, such as ixekizumab, which have an isoelectric point of 8.1 (and require formulation at an acidic pH), pose additional uncontrollable challenges in formulating a balance between the stability of the therapeutic antibody and the functional properties required for achieving effectiveness as well as patient tolerability.

Ixekizumab is a highly specific IL-17A antagonist antibody as described, for example, in US Pat. No. 7,838,638. Commercially marketed under the brand name TALTZ®, ixekizumab is administered subcutaneously to patients as a highly concentrated (approximately 80 mg/mL) pharmaceutical formulation having an acidic pH ( approximately 5.7). A commercial pharmaceutical formulation of ixekizumab, such as described in US Pat. No. 9,376,491, also includes high concentrations of citrate buffer (about 20 mM) and NaCl (about 200 mM). However, pharmaceutical formulations having an acidic pH and high concentrations of NaCl and/or citrate buffer have been associated with injection site pain, and patients have reported injection-related pain following administration of the commercial pharmaceutical formulation of ixekizumab.

Pain associated with injection of aqueous pharmaceutical formulations containing therapeutic antibodies is a complex, multifaceted problem. For example, each individual component of an aqueous pharmaceutical formulation and/or its concentration, relative content and characteristics may influence the pain associated with injection of a therapeutic agent. Likewise, individual components (and/or their concentrations, relative amounts and characteristics) can affect the stability, functional characteristics, processing characteristics and/or tolerability of a therapeutic antibody included in an aqueous pharmaceutical composition. Thus, while a particular composition change may have a beneficial effect on a given aspect of the composition, the same

- 1 045866 change may adversely affect other aspects of the composition. To further complicate matters, a virtually unlimited number of different formulation components (e.g., buffers and excipients), as well as their concentrations and ratios, have been described. However, relationships to predict the effect of a specific composition on various properties and characteristics of a given therapeutic antibody have not been established.

Accordingly, there is a need for an aqueous pharmaceutical formulation of therapeutic antibodies suitable for PC, IM and/or PI administration that is well tolerated by patients and has a therapeutically favorable level of pain associated with injection. More specifically, there is a need for said aqueous pharmaceutical composition with a high concentration of therapeutic antibodies having an isoelectric point that does not allow a neutral pH of the solution, which requires an aqueous composition with an acidic pH. More specifically, there is a need for an aqueous pharmaceutical formulation of ixekizumab suitable for PC, IM and/or PI administration, which is well tolerated by patients, characterized by a reduced level of pain associated with injection compared to a commercial pharmaceutical formulation of ixekizumab (such as described in the patent US No. 9376491). Said aqueous pharmaceutical composition must also provide stability to the therapeutic antibody and maintain the properties of the therapeutic antibody necessary to achieve therapeutic efficacy. Said aqueous pharmaceutical compositions must also be suitable for production and preferably have a long shelf life.

The aqueous pharmaceutical compositions provided herein satisfy the above needs in a surprising and unexpected manner. More specifically, the aqueous pharmaceutical formulations provided herein are non-buffered aqueous pharmaceutical formulations suitable for PC, IM and/or PI administration of high concentrations of ixekizumab that also retain the functional characteristics of ixekizumab necessary to achieve therapeutic efficacy. In addition, the aqueous pharmaceutical formulations provided herein are well tolerated by patients, have a reduced level of injection pain compared to the commercial pharmaceutical formulation of ixekizumab, and provide a therapeutically advantageous level of injection pain.

Accordingly, the present invention provides a non-buffered aqueous pharmaceutical composition for PC, IM or PI administration of a high concentration of a therapeutic antibody to a patient, characterized by a therapeutically preferable level of pain associated with the injection, containing a therapeutic antibody at a concentration of greater than 50, 60, 70, 80, 90 , 100, 110 or 120 mg/ml; sucrose at a concentration of 234 mM ± 10% and a surfactant at a concentration of 0.005% (w/v) ± 10% to 0.05% (w/v) ± 10%, where the pharmaceutical composition is aqueous solution with pH from 5.2 to 6.5. In certain embodiments, the surfactant is polysorbate 20 or polysorbate 80. In further specific embodiments, the surfactant is polysorbate 80. In some embodiments, the bufferless aqueous pharmaceutical composition is substantially free of an ionic tonicity excipient . In some embodiments, the pharmaceutical composition is substantially free of L-amino acid excipients. In additional embodiments, the antibody has an isoelectric point that does not allow a neutral solution pH. In some of these embodiments, the antibody has an isoelectric point >7.5, and in other additional embodiments, the antibody has an isoelectric point >8.0. In additional specific embodiments of the aqueous pharmaceutical formulations provided herein, the therapeutic antibody is an anti-IL-17A antibody comprising LCVR having the amino acid sequence of SEQ ID NO: 7 and HCVR having the amino acid sequence of SEQ ID NO: 8. In additional In specific embodiments, the anti-IL-17A antibody comprises a light chain (LC) having the amino acid sequence of SEQ ID NO: 9 and a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 10. In embodiments of the present invention, an aqueous pharmaceutical composition according to the present invention, wherein the aqueous pharmaceutical composition after PC, PI and/or IM administration to a patient has a reduced risk and/or provides a therapeutically advantageous level of pain associated with the injection.

According to specific embodiments of the present invention, a buffer-free aqueous pharmaceutical composition of an anti-IL-7A antibody is provided. In some embodiments, an anti-IL-7A antibody comprises a light chain variable region (LCVR) comprising the complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3, and a heavy chain variable region (HCVR) comprising the CDRs HCDR1, HCDR2 and HCDR3, where LCDR1 has the amino acid sequence SEQ ID NO: 1, LCDR2 has the amino acid sequence SEQ ID NO: 2, LCDR3 has the amino acid sequence SEQ ID NO: 3, HCDR1 has the amino acid sequence SEQ ID NO: 4, HCDR2 has the amino acid sequence SEQ ID NO: 5 and HCDR3 has the amino acid sequence SEQ ID NO: 6. In said embodiments, aqueous

- 2 045866 pharmaceutical composition is an aqueous solution with a pH from 5.2 to 6.5 and contains an antibody to IL-17A in a concentration of more than 60 mg/ml ± 10%, 70 mg/ml ± 10%, 80 mg/ml ± 10%, 88 mg/ml ± 10%, 100 mg/ml ± 10%, 120 mg/ml ± 10% or 160 mg/ml ± 10%; sucrose at a concentration of 234 mM ± 10% and surfactant at a concentration of 0.005 ± 10% to 0.05 ± 10% (w/v). In some embodiments, the unbuffered aqueous pharmaceutical composition is substantially free of the ionic tonicity excipient. In some embodiments, the pharmaceutical composition is substantially free of L-amino acid excipients. In some embodiments, the surfactant is one of polysorbate 20 or 80. In more specific embodiments, the surfactant is polysorbate 80. In even more specific embodiments, polysorbate 80 is present at a concentration of 0.03% (wt/wt). vol.) ± 10%. In these embodiments, the buffer-free aqueous pharmaceutical formulation is suitable for PC, PI, and/or IM administration to a patient and has a reduced level of injection pain compared to a commercial pharmaceutical formulation of ixekizumab and/or provides a therapeutically advantageous level of injection pain. .

In specific embodiments, the aqueous pharmaceutical compositions provided herein contain the antibody at a concentration of about 80 mg/ml (eg, ±10%); sucrose at a concentration of about 234 mM (e.g., ±10%), and polysorbate 80 at a concentration of about 0.03% (w/v) (e.g., ±10%), and the pharmaceutical composition is substantially free of ionic excipient that regulates tonic, substantially free of L-amino acid excipients and having a pH of about 5.7 (e.g., ±10%), and the antibody is an anti-IL-17A antibody containing LCVR having the amino acid sequence of SEQ ID NO: 7, and HCVR having the amino acid sequence of SEQ ID NO: 8. In further embodiments, the anti-IL-17A antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO: 9. According to In said embodiments, the aqueous pharmaceutical formulation is suitable for PC, PI and/or IM administration to a patient and is characterized by a reduced level of injection-associated pain compared to a commercial pharmaceutical formulation of ixekizumab and/or provides a therapeutically advantageous level of injection-associated pain.

Additional embodiments provide a system for subcutaneously delivering an aqueous pharmaceutical composition to a patient in need of treatment. The system includes a device comprising a chamber, an actuator operably connected to the chamber, and a needle, the chamber being configured to store liquid, the needle having an opening in fluid communication with the chamber outlet for receiving liquid from the chamber, and the actuator being used. for forced transfer of liquid from the chamber to the needle hole. The system also includes a pharmaceutical composition of the present invention placed within a chamber and an inner wall of the chamber having a coating of silicone oil in an amount of less than about 0.4 mg. In some more specific embodiments, the inner wall of the chamber is coated with silicone oil in an amount of about 0.2 mg or in an amount of less than about 0.2 mg. In some embodiments of the system, the patient requires treatment for RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM.

In additional embodiments, the present invention provides a method of reducing injection-related pain and/or providing a therapeutically preferable level of injection-related pain felt by a patient during or immediately after PC, IM, and/or PI injection of an aqueous pharmaceutical composition containing a therapeutic agent. an antibody comprising administering to a patient an aqueous pharmaceutical composition according to the present invention. In some embodiments, the present invention provides a method of delivering a therapeutic antibody to a patient at a therapeutically advantageous level of injection pain, wherein the method comprises administering to the patient a pharmaceutical composition of the present invention, wherein the method provides a therapeutically advantageous level of injection pain. In further embodiments, the present invention provides an improved method of delivering a therapeutic antibody to a patient, wherein the improvement includes reducing and/or providing a therapeutically preferable level of injection-related pain during SC, IM and/or PI administration of an aqueous pharmaceutical composition, the method comprising administering to the patient an aqueous pharmaceutical composition according to the present invention. In some embodiments, reducing injection-related pain includes reducing and/or providing a therapeutically advantageous level of injection-related pain compared to commercially available formulations. In some embodiments, the therapeutically preferred level of injection-related pain may include a VAS (visual analogue scale) score of less than 30 mm or a VAS score of less than 20 mm.

According to some embodiments, the present invention provides an improvement

- 3 045866 a method of administering an anti-IL-17A antibody to a patient in need thereof, wherein the improvement includes reducing the level of pain associated with the injection following administration of a PC, IM or PI injection of an aqueous pharmaceutical composition, the method comprising administering to the patient an aqueous pharmaceutical composition according to the present the invention, wherein said administration step provides a reduced level of injection-related pain and/or provides a therapeutically advantageous level of injection-related pain. In some embodiments, the aqueous pharmaceutical composition consists essentially of the aqueous pharmaceutical composition of the present invention. In some embodiments, reducing the level of injection-related pain includes providing a reduced level of injection-related pain (e.g., a decrease in VAS score compared to a commercial formulation of ixekizumab, i.e., a formulation containing citrate and NaCl, provided as a control composition in Table 2). In some embodiments, the method provides a therapeutically preferable level of injection-related pain, including a VAS score of less than 30 mm or less than 20 mm. In some embodiments, the anti-IL-17A antibody is ixekizumab, and in some of these embodiments, the reduced level of injection-related pain includes a reduction in VAS score compared to a commercial formulation of ixekizumab (a formulation containing citrate and NaCl, given as control composition in Table 2). In some embodiments, the aqueous pharmaceutical composition is administered by PC injection.

According to additional embodiments of the present invention, there is provided an improved method for treating at least one of PsO, PsA, and AxSpa, wherein the improvement includes reducing injection pain following PC administration of an aqueous pharmaceutical composition containing an anti-IL-17A antibody, the method comprising administering an aqueous a pharmaceutical composition according to the present invention, wherein said administration step provides a reduced level of injection-related pain and/or provides a therapeutically advantageous level of injection-related pain. In some embodiments, a therapeutically preferable level of injection-related pain is provided, including a VAS score of less than 30 mm or less than 20 mm. In some more specific embodiments, the anti-IL-17A antibody is ixekizumab, and in some of these embodiments, the reduced level of injection-related pain includes a reduction in VAS score compared to a commercial formulation of ixekizumab (the citrate-NaCl formulation described in as a control composition in Table 2).

The present invention also provides an aqueous pharmaceutical composition according to the present invention for use in therapy. In specific embodiments, the present invention provides an aqueous pharmaceutical composition of the present invention for use in the treatment of rheumatoid arthritis (RA), psoriasis (Ps), genital psoriasis (GenPs), pruritus, ankylosing spondylitis (AS), psoriatic arthritis (RA), palmoplantar pustulosis (PPP), hidradenitis suppurativa (HS) or multiple myeloma (MM). According to additional embodiments of the present invention, the use of an aqueous pharmaceutical composition according to the present invention is provided for the preparation of a medicament for the treatment of RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM. In said embodiments, the use of said aqueous pharmaceutical formulations is suitable for PC, PI and/or IM administration to a patient and is characterized by a reduced level of injection-related pain compared to a commercial pharmaceutical formulation of ixekizumab and/or provides a therapeutically advantageous level of injection-related pain.

According to specific embodiments, the present invention provides a method of treating RA, Ps, GenPs, skin itching, AS, PA, PPP, HS or MM, comprising administering to a patient in need thereof an effective amount of an aqueous pharmaceutical composition according to the present invention, wherein the aqueous pharmaceutical composition contains an antibody to IL-17A. In a more specific embodiment, the method of treatment comprises subcutaneously administering an initial dose of an aqueous pharmaceutical formulation to a patient on Day 0, subsequently subcutaneously administering an aqueous pharmaceutical formulation to the patient at four-week intervals, wherein the aqueous pharmaceutical formulation administered to the patient at four-week intervals after the initial dose contains an anti-IL antibody -17A at a concentration of approximately 80 mg/ml. In another specific embodiment, the method of treatment comprises subcutaneously administering an initial dose of an aqueous pharmaceutical formulation to a patient on Day 0, then subcutaneously administering an aqueous pharmaceutical formulation to the patient at two-week intervals, wherein the aqueous pharmaceutical formulation administered to the patient at two-week intervals after the initial dose contains an anti-IL antibody -17A at a concentration of approximately 80 mg/ml. In yet another specific embodiment, the method of treatment comprises subcutaneously administering an initial dose of an aqueous pharmaceutical formulation to a patient on day 0, subsequently subcutaneously administering an aqueous pharmaceutical formulation to the patient on each of days 14, 28, 42, 56, 70, and 84, and then subcutaneously administering an aqueous pharmaceutical formulation to the patient. formulation to the patient at four-week intervals, wherein the aqueous pharmaceutical formulation administered to the patient on each of days 14, 28, 42, 56, 70 and 84 and at four-week intervals thereafter contains an anti-IL-17A antibody at a concentration of approximately 80 mg/ml. According to some

- 4 045866 treatment dogs according to the present invention, the initial dose of the aqueous pharmaceutical composition contains approximately 160 mg of anti-IL-17A antibody. In some of these embodiments, the initial approximately 160 mg dose of the aqueous pharmaceutical formulation comprises two doses of the aqueous pharmaceutical formulation, each containing approximately 80 mg of anti-IL-17A antibody. According to these methods, the aqueous pharmaceutical formulation has a reduced level of injection pain compared to a commercial pharmaceutical formulation of ixekizumab and/or provides a therapeutically advantageous level of injection pain.

In specific embodiments, provided herein is an aqueous pharmaceutical composition comprising an anti-IL-17A antibody for use in the treatment of RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM, where the pharmaceutical composition must be administered subcutaneously at initial dose on day 0, then at four-week intervals, wherein the pharmaceutical formulation, which is administered at four-week intervals after the initial dose, contains an antibody to IL-17A at a concentration of approximately 80 mg/ml. In another specific embodiment, pharmaceutical compositions described herein are provided containing an anti-IL-17A antibody for use in the treatment of RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM, where the pharmaceutical composition must be administered subcutaneously at an initial dose on day 0, then at two-week intervals, wherein the pharmaceutical composition, which is administered at two-week intervals after the initial dose, contains an antibody to IL-17A at a concentration of approximately 80 mg/ml. In yet another specific embodiment, pharmaceutical compositions described herein are provided containing an anti-IL-17A antibody for use in the treatment of RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM, where the pharmaceutical composition needs to be administered subcutaneously at an initial dose on day 0, then on each of days 14, 28, 42, 56, 70 and 84, with the pharmaceutical composition administered on each of days 14, 28, 42, 56, 70 and 84 after the initial dose, contains an antibody to IL-17A at a concentration of approximately 80 mg/ml. In some embodiments, an initial dose of the aqueous pharmaceutical composition contains approximately 160 mg of anti-IL-17A antibody. In some of these embodiments, the initial approximately 160 mg dose of the aqueous pharmaceutical formulation comprises two doses of the aqueous pharmaceutical formulation, each containing approximately 80 mg of anti-IL-17A antibody. In these embodiments, the aqueous pharmaceutical formulations provided herein have a reduced level of injection pain compared to a commercial pharmaceutical formulation of ixekizumab and/or provide a therapeutically advantageous level of injection pain.

As used interchangeably herein, the expressions aqueous pharmaceutical composition or pharmaceutical composition mean an aqueous solution containing at least one therapeutic antibody capable of providing a biological effect in humans, at least one inactive ingredient (e.g., excipient, surfactant, etc.) which, when combined with a therapeutic antibody, is suitable for therapeutic administration to humans. The pharmaceutical compositions provided by the present invention are non-buffered (i.e., free of agents such as citrate buffer, histidine buffer, acetate buffer, etc., or combinations thereof, which contain conjugated acid-base pairs to counteracting changes in pH) aqueous stable formulations in which the degree of destruction, modification, aggregation, reduction of biological activity, etc., of the contained therapeutic antibodies is properly controlled and does not increase over time to unacceptable levels.

As used herein, the term antibody refers to an immunoglobulin G (IgG) molecule containing two heavy chains (HC) and two light chains (LC) linked to each other by disulfide bonds. Each heavy chain consists of a heavy chain variable region (HCVR) and a heavy chain constant region (CH). Each light chain consists of a light chain variable region (LCVR) and a light chain constant region (CL). Each of the HCVR and LCVR can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each HCVR and LCVR consists of three CDRs and four FRs, located from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of each HC and LC contain a binding domain that interacts with the antigen. Antibody constant regions can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (C1q) of the classical complement system.

In specific embodiments of the aqueous pharmaceutical compositions provided herein, the antibodies are anti-IL-17A antibodies. Interleukin 17A, or IL-7A, as used herein refers to a cytokine of the IL-17 family of cytokines (also called cytotoxic T-lymphocyte-associated antigen 8 (CTLA8)). IL-17A cytokines exist as homodimeric complexes (eg, IL-17A/A) or heterodimeric complexes with another member of the IL-17 cytokine family, such as IL-17F (eg, IL-17A/F). IL-17A cytokines are believed to be produced primarily by effector T helper (Th17) cells and have been shown to induce the secretion of proinflammatory cytokines such as IL-6, IL-8, IL-1 and TNF. Was shown,

- 5 045866 that a form of the homodimeric IL-17A complex, IL-17A/A, is involved in diseases such as psoriasis and psoriatic arthritis, both of which are immune diseases associated with dysregulated T cells.

When referred to herein, anti-IL-17A antibodies are antibodies that specifically bind and act as antagonists of human IL-17A due to specificity for the A subunit (e.g., the A subunit of IL-17A/F or one or both of the A subunits in IL-17A/A). In specific embodiments of anti-IL-17 antibodies, ALCDR1 contains the amino acid sequence of SEQ ID NO: 1, LCDR2 contains the amino acid sequence of SEQ ID NO: 2, LCDR3 contains the amino acid sequence of SEQ ID NO: 3, HCDR1 contains the amino acid sequence of SEQ ID NO: 4, HCDR2 contains the amino acid sequence of SEQ ID NO: 5, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 6. In some of these embodiments, LCVR comprises the amino acid sequence of SEQ ID NO: 7 and HCVR comprises the amino acid sequence of SEQ ID NO: 8. In even more specific embodiments implementations of these antibodies to IL-17 LC contains the amino acid sequence of SEQ ID NO: 9 and HC contains the amino acid sequence of SEQ ID NO: 10. An exemplary embodiment of the antibody to IL-17A is ixekizumab, such as described, for example, in US patent No. 7838638. An additional example of an anti-IL-17A antibody is secukinumab (marketed under the brand name COZENTIX®), such as described, for example, in US Pat. No. 7,807,155.

The terms "approximately" or "approximately" may be used herein, which, when describing a particular specified numerical value or range of values, means that the value may deviate from the specified value by no more than 10% (eg, ±10%). For example, as used herein, the expression about 100 includes 90 and 110 and all values in between (eg, 91, 92, 93, 94, etc.).

As used herein, the terms substantially does not contain or substantially does not include mean that the amount of a given substance (eg, an ionic tonicity excipient) is below the limit of detection in the assay used to detect the presence of the specified substance.

The term ionic tonicity excipient as used herein means an excipient that contains an ionic compound (eg, an electrolyte such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, arginine hydrochloride, etc.) other than an antibody and surfactant included in an aqueous pharmaceutical composition. An ionic tonicity excipient, as known in the art, can be used to control the osmotic pressure of a pharmaceutical formulation. However (as suggested in the examples provided herein), adjusting the pH using HCl or NaOH, as needed, after dissolving and mixing the aqueous pharmaceutical composition is not included within the meaning of the term ionic tonicity excipient as used herein (since HCl or NaOH added to adjust pH does not act as an ionic excipient in the formulation to regulate tonicity).

As used herein, the term L-amino acid excipients refers to L-amino acids that are added either as part of a buffer (e.g., L-histidine in histidine buffer; L-arginine in arginine buffer, etc.) or as an excipient. component in an aqueous pharmaceutical composition (but does not apply to therapeutic antibody components).

As used herein interchangeably, the terms visual analogue scale or VAS refer to a means of assessing injection-related pain experienced by a patient. The VAS consists of a 100 mm continuous scale on which the patient notes the level of pain after the injection. The extremes of the VAS score are no pain at all (eg, 0) and the worst pain imaginable (eg, 100). According to the severity of pain, according to the VAS, it can be classified as mild pain (<30 mm); moderate pain (>30-<70 mm) and severe pain (>70 mm). As used herein, injection pain refers to the acute pain felt by a patient during or immediately after injection of an aqueous pharmaceutical composition. A desirable property of a stable pharmaceutical formulation is good patient tolerance, eg, providing a therapeutically preferable level of injection-related pain (eg, VAS <30 mm and/or <20 mm). It is known that the components of a pharmaceutical formulation and their concentrations and/or relative amounts can influence the injection pain experienced by a patient.

When used interchangeably herein, the terms treatment, and/or treatment, and/or treat are intended to refer to all processes in which complete elimination, slowing or delay, reduction in severity or frequency (eg, exacerbations or attacks), interruption or blocking the progression of the disease and/or its symptoms, but not

- 6 045866 require complete elimination of all symptoms of the disease. The treatment involves administering an aqueous pharmaceutical composition according to the present invention to treat a disease in a person who may benefit from at least one of the above processes, including (a) inhibiting further progression of symptoms and effects of the disease, i.e. blocking its development; (b) alleviation of the disease, i.e. providing elimination or regression of disease, disease symptoms or complications; and (c) preventing or reducing the frequency of attacks or exacerbations of the disease. In specific embodiments, the pharmaceutical compositions provided herein can be used to treat at least one of RA, Ps, GenPs, AS, PA, PPP, HS, or MM.

As used interchangeably herein, the terms patient, subject, and individual refer to a person. Unless otherwise specified, the subject is further characterized as suffering from, at risk of developing, or experiencing symptoms of a disease in which administration of the pharmaceutical composition described herein may provide a beneficial effect.

As used interchangeably herein, the terms effective amount or therapeutically effective amount of a pharmaceutical composition of the present invention refer to the amount (at selected dosages, frequency of administration, and duration of a particular route of administration) required to achieve the desired therapeutic result. The effective amount of the pharmaceutical composition of the present invention may vary depending on factors such as the disease state, age, sex and body weight of the subject and the ability of the pharmaceutical composition of the present invention to produce the desired response in the subject. An effective amount is also an amount for which any toxic or harmful effects of the pharmaceutical composition of the present invention are outweighed by the therapeutically beneficial effects.

The present invention also relates to modes of administration for treating a disease with a pharmaceutical composition according to the present invention. As used herein and is commonly known in the art, the term dose refers to the amount of the pharmaceutical composition that is administered to a subject. The terms administration regimen or dosage regimen, as commonly known in the art and used interchangeably herein, include a treatment regimen for administering a collection (ie, group or sequence) of doses to be administered to a patient over a period of time.

For example, an administration regimen according to the present invention may include an initial dose of an aqueous pharmaceutical composition (eg, containing an anti-IL-17A antibody) according to the present invention, which is administered to the patient on the first day of treatment (eg, day 0). The initial dose may be described herein as a loading dose. In addition, the administration regimen of the present invention may include an initial treatment period, sometimes referred to herein as an induction period, which follows administration of the loading dose. During the induction period, for example, a dose (or doses) containing a specific concentration of therapeutic antibody (eg, anti-IL-17A antibody) may be administered to the patient at a given frequency of administration (eg, once daily, once every 2 weeks, once every 4 weeks, etc.) within a given period of time (eg 4, 12 or 16 weeks). In addition, the administration regimens of the present invention may include a period following an induction period, sometimes referred to herein as a maintenance period, during which the patient is administered a dose containing a specific concentration of therapeutic antibody at a given frequency of administration (e.g., every 2 or 4 weeks and etc.).

The aqueous pharmaceutical compositions of the present invention can be administered to a patient by parenteral route. Parenteral administration, as interpreted in the medical field, refers to the injection of a dose into the body using a sterile syringe or some other drug delivery system, including an auto-injector or infusion pump. Examples of drug delivery systems for use with aqueous pharmaceutical formulations of the present invention are described in the following documents, the contents of which are expressly incorporated herein by reference in their entirety: US Patent Application Published No. 2014/0054883 by Lanigan et al. et al.), filed March 7, 2013, title: Infusion Pump Assembly; US Patent No. 7291132, authors DeRuntz et al., application date February 3, 2006, title Medication Dispensing Apparatus with Triple Screw Threads for Mechanical Advantage ; US Patent No. 7517334, authors Jacobs et al., application date September 18, 2006, title Medication Dispensing Apparatus with Spring-Driven Locking Feature Enabled by Administration of Final Dose); and US Patent No. 8734394, Adams et al., application date: August 24, 2012, title: Automatic injection device with a delay mechanism, including a dual function clamping element (Automatic

- 7 045866

Injection Device with Delay Mechanism Including Dual Functioning Biasing Member). Parenteral routes include IM, PC and PI routes of administration.

Examples

Example of an aqueous pharmaceutical composition.

Table 1

Example of an aqueous pharmaceutical composition

Concentration

antibody to IL17A* 80 mg/ml PS-80 0.03% (w/v) (0.3 mg/ml) Sucrose 234 mM (8% (w/v)) pH 5.7

*Anti-IL-17A antibody contains HCVR with SEQ ID NO: 8 and LCVR with SEQ ID NO: 7.

The method for obtaining the pharmaceutical composition of the antibody to IL-17A, presented in table. 1, can be carried out by weighing an appropriate amount of water (for example, at a temperature

20±5°C) in a weighed empty container of appropriate size. The appropriate amount of sucrose was added and mixed. Weigh the exact amount of polysorbate 80 into a glass container, add the appropriate amount of water at 20 ± 5°C to the glass container to obtain the desired concentration, and mix the solution. The entire contents of the polysorbate 80 solution were added to the other excipients. Rinse the polysorbate 80 solution container with water to ensure all contents are transferred. After the addition of the polysorbate 80 solution was completed, the solution was stirred. After completion of dissolution and mixing, the pH of the solution was checked, which should be 5.7 ± 0.3; adjusted with HCl or NaOH solution if necessary. Pass the excipient composition through a filter (polyvinylidene fluoride [PVDF]) to reduce bioburden.

The anti-IL-17A antibody, pre-expressed in cells, purified and concentrated, was mixed with the appropriate amount of solution of excipients for the formulation. The pH of the solution was re-checked, which should have been 5.7 ± 0.3. The pharmaceutical formulation was passed through a PVDF filter to reduce bioburden, after which it could be stored at 5°C.

Physicochemical characteristics.

Both physical and chemical stability are required for the pharmaceutical formulation of a therapeutic antibody to allow storage and transport (e.g., 1 year, 18 months, or 2 years) and maintain safety and efficacy. Examples of assessment methods for measuring the physical stability of a pharmaceutical formulation include determination of solubility (phase separation, gel formation), molecular interactions (eg, as measured by DLS), determination of visual clarity characteristics (ie, opalescence) by estimating turbidity, and measuring viscosity. In addition, chemical stability can be determined by a variety of analytical methods, including gel permeation chromatography (GPC), cation exchange (CEC) HPLC, capillary electrophoresis under reducing and non-reducing conditions (CE-SDS R/NR) and sieve analysis. As demonstrated herein, for the proposed pharmaceutical composition of the anti-IL-17A antibody shown in table. 1 shows the chemical and physical stability, as well as the solubility of the therapeutic antibody present in high concentration, ixekizumab, having an isoelectric point >7.5, which does not allow formulation at a neutral pH solution.

Determination of solubility.

For an aqueous pharmaceutical composition, sufficiently high solubility is required. In an aqueous pharmaceutical formulation, the antibody present in high concentration should be maintained in a monomeric state in the absence of formation of high molecular weight (HMW) aggregates. The solubility of an antibody to IL-17A having an isoelectric point >8.0 (in solution) at high concentrations under different conditions was analyzed.

Samples of each aqueous composition given in table were incubated. 2, at each of 5, 0 and -5°C (for example, samples of each composition can be incubated in parallel at 5, 0 and -5°C) for one week. After incubation, phase separation, gel formation, turbidity, and viscosity were assessed for each sample.

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table 2

Compositions

Sample No. Buffer Excipients other than buffer Anti-IL17A antibody concentration* ^{* * * * * * * ***} 1111 Control (commercial formulation such as described in US Patent No. 9376491) 20 mM citrate 200 mM NaCl 0.03% PS-80 80 mg/ml 5.7 1 (composition is given in table 1) No 234 mM sucrose 0.03% PS-80 80 mg/ml 5.7 2 10 mM citrate 274 mM mannitol 80 mg/ml 5.7 3 10 mM citrate 274 mM mannitol 0.03% PS-80 80 mg/ml 5.7 4 10 mM citrate 234 mM sucrose 0.03% PS-80 80 mg/ml 5.7 5 5 mM citrate 175 MMNaCl 80 mg/ml 5.7 0.03% PS-80 6 2.69 mM Lhistidine 6.28 mM Lhistidine hydrochloride monohydrate 150 MMNaCl 80 mg/ml 6.5 7 2.69 mM Lhistidine 6.28 mM Lhistidine hydrochloride monohydrate 150 MMNaCl 0.03% PS-80 80 mg/ml 6.5 8 2.69 mM Lhistidine 6.28 mM Lhistidine hydrochloride monohydrate 150 MMNaCl 0.03% PS-80 80 mg/ml 5.7 9 No 130 MMNaCl 80 mg/ml 5.7 10 No 100 MMNaCl 80 mg/ml 5.7 eleven No 65 mM NaCl 50 mg/ml 5.7 12 10 mM citrate No 80 mg/ml 5.7

*The anti-IL-17A antibody contains two HCVRs having the amino acid sequence SEQ ID NO: 8 and two LCVRs having the amino acid sequence SEQ ID NO: 7.

**In addition to the studied aqueous pharmaceutical compositions given in table. 2, evaluated an aqueous pharmaceutical formulation containing mM acetate buffer, 150 mM NaCl and 80 mg/ml anti-IL-17A antibody, pH 5.0, after incubation, for which unacceptable levels of antibody fragmentation were observed when using CD-SDS in non-reducing conditions.

***Additionally, as reported in US Pat. No. 9,376,491, unacceptable cloud point was observed for the anti-IL-17A antibody when agents were used at concentrations of less than 20 mM for citrate buffer and 150 mM for NaCl.

Phase separation.

As described in detail in US Pat. No. 9,376,491, the proposed anti-IL-17A antibody (comprising two LCVRs having the amino acid sequence SEQ ID NO: 7, and two HCVRs having the amino acid sequence SEQ ID NO: 8) is prone to phase separation in solution at temperature below 0°C. However, the drug product is stored at 5°C, which requires periodic reduction of the refrigerator temperature below 0°C. As proposed in US Pat. No. 9,376,491, increasing the concentration of citrate buffer and NaCl sufficiently lowers the temperature at which phase separation occurs. However, there are reports of injection-related pain with formulations containing elevated concentrations of citrate buffer and NaCl, and patients have reported injection-related pain following administration of the commercial pharmaceutical formulation of ixekizumab.

Phase separation was assessed in the compositions given in table. 2, after incubation at -5°C for one week by visually observing signs of phase separation (eg, formation of a dense protein-rich layer at the bottom of the tube). The results are presented in table. 3.

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Gel formation.

Phenomena such as thermodynamic change of the solid phase (eg, gel formation) can occur at lower temperatures (5°C or lower), adversely affecting stability. As described in detail in US Pat. No. 9,376,491, the proposed anti-IL-17A antibody exhibits gel formation at temperatures of 5° C. and below at high concentrations. US Pat. No. 9,376,491 also shows that appropriately increasing the concentration of citrate buffer and NaCl avoids gelation at lower temperatures. However, as noted above, there are reports of injection-related pain with formulations containing elevated concentrations of citrate buffer and NaCl, and patients have reported injection-related pain following administration of the commercial pharmaceutical formulation of ixekizumab.

The results of assessing the formation of gel in the compositions given in table. 2 are presented in table. 3. Briefly, after incubation, each tube was mixed as described above (eg, inverted and then returned to its original upright position) and visually inspected for thickening or lack of flow.

Turbidity.

Turbidity (ie, loss of clarity due to the formation of a suspension of particulate matter) is an inherent problem in aqueous pharmaceutical formulations of therapeutic antibodies. The problem is exacerbated at high antibody concentrations and low temperatures, which may result in the formulation failing visual inspection.

Briefly, after incubation as described above, turbidity was assessed (measured at ambient temperature), both visually (e.g., in the light using purified water for comparison) and using a nephelometer (HACH Turbidimeter, according to the manufacturer's instructions) to obtain quantitative results (in NTU). Lower NTU values are desirable; in particular, NTU values of less than 50 are desirable, with the test passing limit being 80 NTU. The results are presented in table. 3.

Viscosity.

An aqueous pharmaceutical composition that is acceptable for preparation, administration to patients and tolerated must have an appropriate viscosity. Subcutaneous delivery requires a less viscous (at least <20 cP) aqueous solution. Elevated concentrations of therapeutic antibody create the problem of increased viscosity. Pharmaceutical formulations containing NaCl are known to have reduced viscosity, but as noted, increasing the concentration of NaCl in the pharmaceutical formulation causes pain associated with injection.

The viscosity of composition 1 and the control composition given in table was assessed. 2, after incubation at 20°C on a viscometer (Anton Paar AMVn Viscometer, according to manufacturer's instructions) to obtain results in centipoise (cP). Lower values in cP are desirable, particularly, for example, <20 cP. The results are presented in table. 3.

Table 3

Assessment of the solubility of the compositions given in table. 2

Sample No. Evaluation of phase separation Gel Formation Assessment Turbidity (NTU) Viscosity (cP) Control No No 63 3 1 No No 10 5 2 Yes BUT But BUT 3 Yes BUT But But 4 Yes BUT But But 5 No No 85 But 6 No Yes BUT But 7 No Yes But But 8 No No 95 But 9 Yes BUT BUT But 10 Yes BUT But But eleven Yes BUT But But 12 Yes BUT But But

As shown in table. 3, unacceptable phase separation or gel formation was observed for all formulations that lacked at least 150 mM NaCl (as well as all NaCl formulations not containing a buffer), with the exception of formulation 1, in which no phase separation was observed. The phase separation results for formulation 1 are comparable to the control formulation (high citrate, high NaCl formulation). In addition, unacceptable gel formation was observed for formulations containing histidine buffer and NaCl at pH 6.5. No gelation was observed in formulation 1 and was comparable to the control formulation (high citrate, high NaCl formulation). In addition, unacceptable turbidity was observed for both formulation 5 (citrate (5 mM), NaCl (175 mM)) and formulation 8 (histidine (9 mM) and NaCl (150 mM)). Formulation 1 showed an acceptable level of turbidity which, surprisingly, was significantly better than the control formulation (high citrate, high NaCl formulation). As shown

- 10 045866 additionally, both formulation 1 and the control formulation had acceptable and comparable viscosity.

Chemical stability.

Chemical stability is important when developing an aqueous pharmaceutical formulation to allow storage (i.e., adequate shelf life) while maintaining safety and effectiveness. Chemical stability was assessed to compare control and formulation 1 (shown in Table 2) after incubation for four weeks at 25 or 40°C in accelerated degradation studies. The change in the level of HMW aggregates in % was compared with the level of HMW aggregates at % time point 0.

In one evaluation method, changes in the level of high molecular weight (HMW) aggregates in the formulations were determined by gel permeation chromatography (GPC) according to standard methods. The results are presented in table. 4.

Table 4

Brief description of the change in the level of HMW aggregates in % when measured by GPC

Composition No. (according to table 2) Change in HMW level of units in % 25°С Change in HMW level of units in % 40°C Control 0.25 0.05 1 0.49 0.43

It is shown that both the control composition and composition 1 according to table. 2 demonstrate acceptable and comparable chemical stability in accelerated degradation studies.

In addition, the chemical stability under accelerated aging conditions was studied for control and composition 1 according to Table. 2 by cation exchange (CEX) HPLC. Briefly, samples were incubated at 25°C for four weeks. After incubation, samples were analyzed to determine the % increase in acid species (%AV) by HPLC-SEC. The increase in % acid species (%AV) is an indicator of the degradation of the therapeutic antibody in the aqueous formulation. The results are presented in table. 5.

Table 5

Increase in % AV for 4 at 25 °C

Composition No. (according to table 2) Increase %AV Control 2.0 1 2.3

It was shown that both control and composition 1 according to table. 2 demonstrate acceptable and comparable levels of chemical stability in additional accelerated degradation studies.

Multiparameter assessment of composition 1 according to table. 2.

As demonstrated herein, composition 1 according to table. 2 provides unexpected stability, comparable to (or improved compared to) the control composition according to table. 2. A multi-parameter assessment of the physical and chemical stability of composition 1 was carried out according to table. 2, as follows.

Briefly, four variables (antibody concentration; pH; sucrose concentration; and PS-80 concentration) in composition 1 were modified according to Table 1. 2 to evaluate changes in physical and chemical stability in response to changes in each variable and/or cumulative changes in different variables. Composition 1 according to table. 2 was chosen as the main composition for this experiment. Composition options are presented in table. 6.

Table 6

Formulation options

Sample No. Sucrose PS-80** Antibody to IL17A* 1111 Main cast (composition 1 according to table 2) 234 mM 0.03% 80 mg/ml 5.7 13 205 mM 0.05% 72 mg/ml 5.2 14 205 mM 0.005% 72 mg/ml 6.2 15 205 mM 0.005% 88 mg/ml 5.2 16 205 mM 0.05% 88 mg/ml 6.2 17 263 mM 0.005% 72 mg/ml 5.2 18 263 mM 0.05% 72 mg/ml 6.2 19 263 mM 0.05% 88 mg/ml 5.2 20 263 mM 0.005% 88 mg/ml 6.2

*The anti-IL-17A antibody contains two HCVRs having the amino acid sequence SEQ ID NO: 8 and two LCVRs having the amino acid sequence SEQ ID NO: 7.

**Compliance of the amounts of polysorbate with the ranges given in table. 6 was confirmed in accelerated freezing-thawing studies.

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Phase separation, gel formation and turbidity were assessed for each formulation according to the methods described above. The specified multiparameter assessment allows you to determine the tolerance limits for the evaluated variables. No phase separation or gel formation was observed and acceptable turbidity was observed.

Assessing long-term stability.

Determination of the long-term stability of an aqueous pharmaceutical formulation is required to demonstrate storage feasibility and adequate shelf life (e.g., 1 year, 2 years, or longer). The long-term stability of the base composition was assessed according to Table 6 (which corresponds to the composition given in Table 1 and composition 1 according to Table 2) after incubating the samples at 5°C for 1, 3 and 6 months; 25°C for 1 and 3 months and 35°C for 1 and 3 months (pre-incubation sample was also assessed).

After incubation, samples were analyzed to determine the percentage monomer level and the percentage high molecular weight (HMW) aggregate level by gel permeation chromatography (GPC) according to standard methods. The results are presented in table. 7.

Table 7

Assessing the long-term stability of the core team

Incubation temperature (°C) Incubation duration Monomer (%) HMW units (%) (months) Control (before incubation) ND 98.61 1.27 5 1 98.83 1D0 5 3 98.57 1.39 5 6 98.61 1.27 5 12 98.67 1.28 25 1 98.59 1.32 25 3 98.01 1.85 35 1 97.93 1.70 35 3 95.54 3.30

According to the given data for the main composition according to table. 6 demonstrated the long-term stability of the therapeutic antibody even under the stressful conditions of exposure for a long time at high temperature.

In vivo tolerability study.

Injection pain was assessed during subcutaneous injection of a high concentration aqueous pharmaceutical formulation of ixekizumab (80 mg/mL) in a study in which subjects were given a PC injection of one of formulations A or B (as listed in Table 8) and then PC injection of another of the compositions A or B after some time (for example, after 1, 5, 7, 10, 14 days, etc.). Subjects are then assessed for injection-related pain using a VAS rating scale at specified time points (eg, 1 minute (i.e., immediately after injection), 10 minutes, 1 hour, 4 hours, 1 day) after each injection.

Table 8

Pharmaceutical composition of ixekizumab

Composition A (corresponds to the main composition according to table 6) Composition B (commercial composition Taltz®) ixekizumab 80 mg/ml ixekizumab 80 mg/ml pH 5.7 pH 5.7 PS-80 0.3 mM PS-80 0.03% (w/v) sucrose 80 mg/ml NaCl 200 mM III/IIII/IIIIII1IIII1IIII1IIIIIIIIIIII/IIII/II citrate buffer 20 mM

Accordingly, a randomized, single-dose, crossover, blinded study was conducted in which subjects were randomly assigned to one of two treatment groups. Each treatment group received subcutaneous injections of pharmaceutical formulations containing 80 mg/ml ixekizumab, such as those presented in Table 8, according to the following injection schedules.

Treatment group 1 received one dose of formulation B, followed by one dose of formulation A seven days later. Treatment group 2 received one dose, by PC injection, of Formulation A, followed by one dose, by PC injection, of Formulation B 14 days later. Medical personnel administered injections into the abdomen of the subject while they were in a sitting or reclining position. Subsequent injections can be alternated between different quadrants of the abdomen. Injection-related pain was assessed based on a rating scale

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VAS immediately after each injection (for example, within 1 min) and 10 min after the injection. The results are presented in the table below. 9 and 10.

Table 9

Data for comparison of injection-related pain

Compound YOUR index time after injection (within 1 min) YOUR index time after injection (10 min) A (N=63) 3.52 0.68 B(N=61) 25.21 5.15

As shown in table. 9, formulation A provided a significant reduction in VAS score compared to formulation B (commercially available Taltz® formulation) both immediately after injection and 10 minutes after injection.

Table 10

Patient tolerance analysis

YOUR index Composition A time after injection (within 1 min) Composition B time after injection (within 1 min) No pain (VAS=0) 26 (out of 63 patients): 41.3% 5 (out of 61 patients): 8.2% Mild pain (YOUR<30) 36 (out of 63 patients): 57.1% 36 (out of 61 patients): 59.0% Moderate to severe pain (VAS>30) 1 (of 63 patients): 1.6% 20 (out of 61 patients): 32.8%

As shown in table. 10, Formulation A provided a significant increase in the number of patients experiencing no injection-related pain immediately after injection, as well as a significant benefit in reducing the number of patients experiencing moderate to severe injection-related pain immediately after injection compared with composition B (commercially available composition Taltz®).

In vivo pharmacokinetic analysis.

Analysis of the pharmacokinetics of the aqueous pharmaceutical formulation of ixekizumab can be performed according to a study in which subjects are administered a PC injection of one of formulations A or B (as listed in Table 8). PK analysis is then performed in subjects at different time points (eg, before PC injection, and then after PC injection, eg, 1-24 hours, 1-90 days after injection).

Accordingly, a randomized, single-dose, parallel-group, blinded study was conducted in which subjects were randomly assigned to one of two treatment groups on day 1. Before receiving treatment (eg, 1 day before dosing), predose samples were collected from both treatment groups to evaluate pharmacokinetic properties. On day 1, treatment group 1 received one SC injection of formulation A, and treatment group 2 received one subcutaneous injection of formulation B (as described in Table 8). Medical personnel may administer injections into subjects' abdomen. After dosing, samples were collected on study days 3, 5 (±1 day), 8 (±1 day), 11 (±1 day), 15 (±2 days), 22 (±2 days), 29 (±2 days ), 43 (±2 days), 57 (±3 days), 71 (±3 days) and 85 (±3 days) to evaluate pharmacokinetic parameters, including Cmax (maximum observed drug concentration), AUC[0-ot] (area under the concentration-time curve from time zero to infinity), AUC^-t^J (area under the concentration-time curve from time zero on day 1 of the study to the time of the last measurable concentration), and Tmax (time , at which the maximum concentration of the drug was observed). The results are presented in table. eleven.

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Table 11

In vivo pharmacokinetic analysis

Compound Parameter Pk Meaning (geometric mean using the least squares method) Ratio (Composition A / Composition B) Composition A (N=33) AUC[0-co] (µg*day/ml) 159 1.05 Composition B (N=32) 152 Composition A (N=33) AUC[0-tnocn] (µg*day/ml) 153 1.04 Composition B (N=32) 146 Composition A (N=33) Stach (mcg/ml) 6.29 1.00 Composition B (N=33) 6.31 Composition A (N=33) Ttah (days) 4.09 (median difference) 0 Composition B (N=33) 3.95

As shown in table. 11, formulation A showed comparable PK parameters to formulation B (commercially available Taltz® formulation). In addition, no serious adverse events were reported for any of the formulations, and the overall safety of formulation A is consistent with and comparable to that of formulation B.

Target neutralization assessment.

After incubation of samples of composition A at 5°C for 1, 6 and 12 months; 25°C for 1 month and 35°C for 1 month assessed the activity of formulation A compared to formulation B (according to Table 8) in a cell bioassay. Briefly, a murine osteoblast cell line MC3T3-E1 was grown that endogenously expressed the IL-17A receptor and stably expressed the firefly luciferase gene and in which, in the presence of IL-17A, luciferase transcription was induced at a level proportional to IL-17A activity. In a cell bioassay, preincubated samples of Formulations A and B were injected into culture wells, respectively, and dose-inhibition curves were generated after measuring luciferase expression. The data were analyzed by plotting a curve using a four-parameter logistic equation. Relative activity was determined by calculating the ratio of the EC50 for formulation A to the EC50 for formulation B (eg, the reference standard). The results are presented in table. 12.

Table 12

Estimation of the relative activity of composition A (in% relative to composition B)

Incubation Duration (Months) Incubation temperature (°C) 5°С 25°C 35°C 1 101% 98% 101% 6 103% BUT But 12 98% BUT But

As shown in table. 12, formulation A demonstrated a level of target neutralization comparable to formulation B (commercially available Taltz® formulation) after long-term storage under stressful conditions.

Sequences of SEQ ID NO: 1 (LCDR1 of the proposed anti-IL-17A antibody):

RS SRSL VHSRGNT YLH

SEQ ID NO: 2 (LCDR2 of the proposed anti-IL-17A antibody):

KVSNRFI

SEQ ID NO: 3 (LCDR3 of the proposed anti-IL-17A antibody):

SQSTHLPFT

SEQ ID NO: 4 (HCDR1 Proposed Anti-IL-17A Antibody):

GYSFTDYHIH

SEQ ID NO: 5 (HCDR2 of the proposed anti-IL-17A antibody):

VINPMYGTTDYNQRFKG

SEQ ID NO: 6 (HCDR3 Proposed Anti-IL-17A Antibody):

YDYFTGTGVY

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SEQ ID NO: 7 (LCVR of the proposed anti-IL-17A antibody):

DIVMTQTPLSLSVTPGQPASISCRSSRSLVHSRGNTYLHWYLQKPGQSPQLLIY KVSNRFIGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHLPFTFGQGTK LEIK

SEQ ID NO: 8 (HCVR of the proposed anti-IL-17A antibody):

QVQLVQSGAEVKKPGSSVKVSCKASGYSFTDYHIHWVRQAPGQGLEWMGVIN PMYGTTDYNQRFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARYDYFTGT GVYWGQGTL VT VS S

SEQ ID NO: 9 (proposed anti-IL-17A antibody light chain):

DIVMTQTPLSLSVTPGQPASISCRSSRSLVHSRGNTYLHWYLQKPGQSPQLLIY KVSNRF IGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHLPFTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQES VTEQDSKD STYSL S STLTLSKAD YEKHK VYACEVTHQGL S SP VTKS FNRGEC

SEQ ID NO: 10 (proposed anti-IL-17A antibody heavy chain):

QVQLVQSGAEVKKPGSSVKVSCKASGYSFTDYHIHWVRQAPGQGLEWMGVI NPMYGTTDYNQRFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARYDYFT GTGVYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV T VSWNSGALTSGVHTFP AVLQS SGL YSLS S VVTVPS S SLGTKT YTCNVDHKPS NTKV DKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDW LN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT CLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNV FSCSVMHEALHNHYTQKSLSLSLG

Claims (9)

1. A non-buffered aqueous pharmaceutical composition containing: (i) anti-IL-17A antibody at a concentration of 80 mg/ml ± 10%; (ii) sucrose at a concentration of 234 mM ± 10%; (iii) a surfactant in a concentration of from 0.005% (w/v) ± 10% to 0.05% (w/v) ± 10%, where the pharmaceutical composition is an aqueous solution with a pH of 5, 2 to 6.5 and the anti-IL-17A antibody contains a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein LCVR contains the complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3 and HCVR contains the CDRs HCDR1, HCDR2 and HCDR3, while: LCDR1 contains the amino acid sequence SEQ ID NO: 1, LCDR2 contains the amino acid sequence SEQ ID NO: 2, LCDR3 contains the amino acid sequence SEQ ID NO: 3, HCDR1 contains the amino acid sequence SEQ ID NO: 4, HCDR2 contains the amino acid sequence SEQ ID NO: 5 and HCDR3 contains the amino acid sequence SEQ ID NO: 6. 2. The pharmaceutical composition according to claim 1, characterized in that said surfactant is polysorbate 20 or polysorbate 80. 3. The pharmaceutical composition according to claim 2, characterized in that said surfactant is polysorbate 80. 4. The pharmaceutical composition according to claim 1, characterized in that said pharmaceutical composition does not contain an ionic excipient that regulates tonicity. 5. Pharmaceutical composition according to claim 1, characterized in that said pharmaceutical composition does not contain excipients based on L-amino acids. 6. The pharmaceutical composition according to claim 1, characterized in that said LCVR contains the amino acid sequence SEQ ID NO: 7 and HCVR contains the amino acid sequence SEQ ID NO: 8. 7. The pharmaceutical composition according to claim 6, characterized in that said anti-IL-17A antibody contains a light chain (LC) and a heavy chain (HC), where LC contains the amino acid sequence of SEQ ID NO: 9 and HC contains the amino acid sequence of SEQ ID NO: : 10. 8. The pharmaceutical composition according to claim 1, characterized in that said antibody to IL-17A is ixekizumab. 9. Pharmaceutical composition according to claim 1, characterized in that said surfactant - 15 045866 the composition is polysorbate 80, said pharmaceutical composition does not contain an ionic excipient that regulates tonicity and does not contain L-amino acid excipients, and characterized in that said LCVR contains the amino acid sequence SEQ ID NO: 7 and HCVR contains amino acid sequence SEQ ID NO: 8.