Therapeutic antibody formulations

Abstract

Stable aqueous pharmaceutical formulations for therapeutic antibodies and methods of using such stable aqueous pharmaceutical formulations.

Description

[0001] This application is a divisional application of a patent application for an invention named "Therapeutic Antibody Preparation" with an application date of February 11, 2020, an application number of 202080015310.4. Technical Field

[0002] The present invention is in the field of medicine. More specifically, the present invention relates to an aqueous pharmaceutical preparation comprising a therapeutic antibody suitable for subcutaneous ("SQ"), intramuscular ("IM") and / or intraperitoneal ("IP") administration. Background Art

[0003] It is both common and advantageous to administer therapeutic antibodies via SQ, IP and / or IM administration. Such administration routes allow for the delivery of therapeutic antibodies over a short period of time and allow for self-administration of the therapeutic antibodies by the patient without the need to visit a medical practitioner. However, formulating therapeutic antibodies into aqueous pharmaceutical preparations suitable for SQ, IM and / or IP administration is both challenging and unpredictable. In addition, it has been reported that there is unwanted injection-related pain using such administration routes, even after removal of the syringe needle, and this can compromise patient compliance with the therapy.

[0004] The challenges and unpredictability associated with formulating therapeutic antibodies into aqueous pharmaceutical preparations suitable for SQ, IM and / or IP administration are due in part to the fact that the pharmaceutical preparation must have many properties to be therapeutically viable. The aqueous pharmaceutical preparation must provide stability to the therapeutic antibody in solution while maintaining the functional properties essential for the therapeutic efficacy of the therapeutic antibody, such as target affinity, selectivity and potency. In addition, the aqueous pharmaceutical preparation must also be safe for administration to a patient and well tolerated by the patient, as well as suitable for manufacture and storage.

[0005] Formulating high concentrations of therapeutic antibodies is even more complex. For example, for aqueous formulations of highly concentrated therapeutic antibodies, increased rates of antibody degradation, cleavage, shearing, high molecular weight aggregation, dimerization, trimerization, precipitation, pH shift, turbidity, solution color change, charge change, isomerization, oxidation and / or deamination (all of which affect the concentration, function and potency of the therapeutic antibody) have been reported. Another known challenge when formulating high concentrations of therapeutic antibodies is an increase in viscosity, which can negatively impact SQ, IM and / or IP administration of the aqueous pharmaceutical preparation. In addition, injection-related pain has been reported for formulations with increased viscosity.

[0006] In addition, some therapeutic antibodies, such as ixekizumab, have a charge distribution that results in high levels of intermolecular interactions (e.g., as can be shown by dynamic light scattering), phase separation, gelation, and precipitation, making it very challenging to balance the solubility of the molecule in aqueous solution, especially at high concentrations. The charge distribution of such antibodies can also manifest in the isoelectric point, precluding formulation at neutral pH. For example, some therapeutic antibodies have a polarity or dipole moment such that they are stable only in aqueous formulations within a narrow non-neutral pH window. However, injection-related pain has been reported for acidic (e.g., ≤pH 6.5) pharmaceutical formulations of therapeutic antibodies. Thus, such therapeutic antibodies, such as ixekizumab, which has an isoelectric point of 8.1 (requiring an acidic pH formulation), present additional, unpredictable challenges in formulating in a manner that balances the functional properties required for the stability and potency of the therapeutic antibody as well as the tolerance of the patient.

[0007] Ixekizumab is a highly specific anti-IL17A antagonistic antibody, as described, for example, in U.S. Patent No. 7,838,638. Under the trade name Commercially available ixekizumab is administered subcutaneously to patients as a highly concentrated (about 80 mg / mL) pharmaceutical formulation having an acidic pH (about 5.7). The commercial pharmaceutical formulation of ixekizumab as described in U.S. Patent No. 9,376,491 also includes a high concentration 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-related pain, and patients have reported injection-related pain after injection of the commercial pharmaceutical formulation of ixekizumab.

[0008] Injection-related pain of aqueous pharmaceutical formulations containing therapeutic antibodies is a complex, multifactorial problem. For example, each individual component and / or its concentration, ratio, and characteristics of the aqueous pharmaceutical formulation can affect injection-related pain associated with the therapeutic agent. Similarly, the individual components (and / or their concentration, ratio, and properties) can affect the stability, functional characteristics, manufacturability, and / or tolerance of the therapeutic antibody formulated in the aqueous pharmaceutical formulation. Thus, although a particular formulation adjustment may provide a beneficial effect on a given aspect of the formulation, the same adjustment may also negatively impact other aspects of the formulation. An almost infinite number of different formulation components (e.g., buffers and excipients) and their concentrations and ratios have been reported, further increasing the complexity. However, there is still little correlation for predicting the effect of a particular formulation on the various properties and characteristics of a given therapeutic antibody.

[0009] Accordingly, there is a need for aqueous pharmaceutical formulations of therapeutic antibodies that are suitable for SQ, IM, and / or IP administration and are well tolerated by patients, exhibiting a therapeutically favorable level of injection-related pain. More specifically, there is a need for such aqueous pharmaceutical formulations for highly concentrated therapeutic antibodies that have an isoelectric point incompatible with neutral pH in solution and that require an aqueous formulation at acidic pH. Even more specifically, there is a need for an aqueous pharmaceutical formulation of ixekizumab that is suitable for SQ, IM, and / or IP administration and is well tolerated by patients, exhibiting an improved level of injection-related pain compared to the commercial pharmaceutical formulation of ixekizumab (as described in U.S. Patent No. 9,376,491). Such an aqueous pharmaceutical formulation must also provide stability to the therapeutic antibody and maintain the properties of the therapeutic antibody that are essential for therapeutic efficacy. Such an aqueous pharmaceutical formulation must also be suitable for manufacturing, preferably having an extended shelf life. Summary of the Invention

[0010] The aqueous pharmaceutical formulations provided herein meet the above needs in a surprising and unexpected manner. More specifically, the aqueous pharmaceutical formulations provided herein are unbuffered aqueous pharmaceutical formulations suitable for SQ, IM, and / or IP administration of high concentrations of ixekizumab while also maintaining the functional characteristics of ixekizumab that are essential for therapeutic efficacy. In addition, the aqueous pharmaceutical formulations provided herein are well tolerated by patients, exhibit an improved level of injection-related pain compared to the commercial pharmaceutical formulation of ixekizumab, and provide a therapeutically favorable level of injection-related pain.

[0011] Accordingly, the present disclosure provides a buffered aqueous pharmaceutical formulation for administering a high concentration of a therapeutic antibody to a patient SQ, IM, or IP at a therapeutically favorable injection-related pain level, the aqueous pharmaceutical formulation comprising a therapeutic antibody at a concentration greater than 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, or 120 mg / mL; sucrose at a concentration of 234 mM + / - 10%; and a surfactant at a concentration between 0.005% w / v + / - 10% and 0.05% w / v + / - 10%, wherein the pharmaceutical formulation is an aqueous solution having a pH between 5.2 and 6.5. According to a specific embodiment, the surfactant is polysorbate 20 or polysorbate 80. In a further specific embodiment, the surfactant is polysorbate 80. According to some embodiments, the buffered aqueous pharmaceutical formulation is substantially free of ionic strength excipients. In some embodiments, the pharmaceutical formulation is substantially free of L-amino acid excipients. In a further embodiment, the antibody has an isoelectric point incompatible with neutral pH in solution. In some such embodiments, the antibody has an isoelectric point of ≥7.5, and in an even further embodiment, the antibody has an isoelectric point of ≥8.0. In a further specific embodiment of the aqueous pharmaceutical formulation provided herein, the therapeutic antibody is an anti-IL-17A antibody comprising an LCVR having the amino acid sequence of SEQ ID NO. 7 and an HCVR having the amino acid sequence of SEQ ID NO. 8. In an even further specific embodiment, the anti-IL17A 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. According to an embodiment of the present disclosure, there is provided the aqueous pharmaceutical formulation of the present disclosure, wherein the aqueous pharmaceutical formulation exhibits a reduced risk of injection-related pain and / or a therapeutically favorable injection-related pain level upon administration to a patient SQ, IP, and / or IM.

[0012] According to specific embodiments of the present disclosure, a buffer-free aqueous pharmaceutical formulation for an anti-IL7A antibody is provided. In an embodiment, the anti-IL7A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the light chain variable region (LCVR) comprises complementary determining regions (CDRs) LCDR1, LCDR2, and LCDR3, and the heavy chain variable region (HCVR) comprises CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO.1, LCDR2 has the amino acid sequence of SEQ ID NO.2, LCDR3 has the amino acid sequence of SEQ ID NO.3, HCDR1 has the amino acid sequence of SEQ ID NO.4, HCDR2 has the amino acid sequence of SEQ ID NO.5, and HCDR3 has the amino acid sequence of SEQ ID NO.6. According to such embodiments, the aqueous pharmaceutical formulation is an aqueous solution having a pH between 5.2 and 6.5 and comprises an anti-IL17A antibody at a concentration greater 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 a surfactant at a concentration of 0.005 + / - 10% to 0.05 + / - 10% w / v. According to some embodiments, the buffer-free aqueous pharmaceutical formulation is substantially free of ionic strength excipients. In some embodiments, the pharmaceutical formulation is substantially free of L-amino acid excipients. In some embodiments, the surfactant is one of polysorbate 20 or 80. In a more specific embodiment, the surfactant is polysorbate 80. In an even more specific embodiment, the concentration of the polysorbate 80 is 0.03% w / v + / - 10%. According to such embodiments, the buffer-free aqueous pharmaceutical formulation is suitable for SQ, IP, and / or IM administration to a patient and exhibits an improved injection-related pain level and / or provides a therapeutically favorable injection-related pain level compared to the commercial pharmaceutical formulation of ixekizumab.

[0013] In a specific embodiment, the aqueous pharmaceutical formulation provided herein comprises an antibody at a concentration of about 80 mg / mL (e.g., + / - 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 formulation is substantially free of ionic strength excipients, substantially free of L-amino acid excipients, and has a pH of about 5.7 (e.g., + / - 10%), and the antibody is an anti-IL17A antibody that comprises an LCVR having the amino acid sequence of SEQ ID NO. 7 and an HCVR having the amino acid sequence of SEQ ID NO. 8. In further such embodiments, the anti-IL17A 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 such embodiments, the aqueous pharmaceutical formulation is suitable for SQ, IP, and / or IM administration to a patient and exhibits an improved injection-related pain level and / or provides a therapeutically favorable injection-related pain level compared to the commercial pharmaceutical formulation of ixekizumab.

[0014] In a further embodiment, a system for subcutaneous delivery of an aqueous pharmaceutical formulation to a patient in need of treatment is provided. Such a system includes a device having a chamber, a drive mechanism operably coupled to the chamber, and a needle, the chamber being capable of storing a liquid, the needle having an aperture in fluid communication with an outlet of the chamber to receive the liquid from the chamber, and the drive mechanism being operable to force the liquid from the chamber into the aperture of the needle. Such a system further includes the pharmaceutical formulation of the present disclosure disposed within the chamber and an inner wall of the chamber having a silicone oil coating in an amount less than about 0.4 mg. According to some more specific embodiments, the inner wall of the chamber has a silicone oil coating in an amount of about 0.2 mg or less than about 0.2 mg. According to some embodiments of the system, the patient is in need of treatment for RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM.

[0015] In a further embodiment, the present disclosure provides a method for reducing injection-related pain experienced by a patient at or shortly after SQ, IM, and / or IP injection of an aqueous pharmaceutical formulation comprising a therapeutic antibody and / or providing a therapeutically favorable level of injection-related pain experienced by the patient at or shortly after SQ, IM, and / or IP injection of an aqueous pharmaceutical formulation comprising a therapeutic antibody, the method comprising administering to the patient the aqueous pharmaceutical formulation of the present disclosure. According to an embodiment, the present disclosure provides a method for delivering a therapeutic antibody to a patient at a therapeutically favorable level of injection-related pain, wherein the method comprises administering to the patient the pharmaceutical formulation of the present disclosure, wherein the method provides a therapeutically favorable level of injection-related pain. According to a further embodiment, the present disclosure provides an improved method for delivering a therapeutic antibody to a patient, wherein the improvement comprises reducing injection-related pain and / or providing a therapeutically favorable level of injection-related pain by SQ, IM, or IP administration of an aqueous pharmaceutical formulation, the method comprising administering to the patient the aqueous pharmaceutical formulation of the present disclosure. According to an embodiment, reducing injection-related pain comprises reducing from a commercially available formulation and / or providing a therapeutically favorable level of injection-related pain. According to an embodiment, a therapeutically favorable level of injection-related pain may comprise a VAS score of less than 30 mm or a VAS score of less than 20 mm.

[0016] According to an embodiment, the present disclosure provides an improved method for administering an anti-IL17A antibody to a patient in need thereof, wherein the improvement comprises a reduction in the level of injection-related pain after SQ, IM, or IP injection of an aqueous pharmaceutical formulation, the method comprising administering to the patient the aqueous pharmaceutical formulation of the present disclosure, wherein the administering step provides an improved level of injection-related pain and / or provides a therapeutically favorable level of injection-related pain. According to some embodiments, the aqueous pharmaceutical formulation consists essentially of the aqueous pharmaceutical formulation of the present disclosure. According to an embodiment, the reduction in the level of injection-related pain comprises providing an improved level of injection-related pain (e.g., a reduction in VAS score compared to a commercial formulation of ixekizumab, i.e., the citrate and NaCl formulation exemplified by the control formulation in Table 2). According to some embodiments, the method provides a therapeutically favorable level of injection-related pain, comprising a VAS score of less than 30 mm or less than 20 mm. According to an embodiment, the anti-IL17A antibody is ixekizumab, and according to some such embodiments, the improved level of injection-related pain comprises a reduction in VAS score compared to a commercial formulation of ixekizumab (the citrate and NaCl formulation exemplified by the control formulation in Table 2). According to some embodiments, the aqueous pharmaceutical formulation is administered by SQ injection.

[0017] According to a further embodiment of the present disclosure, there is provided an improved method of treating at least one of PsO, PsA, and AxSpa, wherein the improvement comprises a reduction in injection-related pain following SQ administration of an aqueous pharmaceutical formulation comprising an anti-IL17A antibody, the method comprising administering the aqueous pharmaceutical formulation of the present disclosure, wherein the administering step provides an improved injection-related pain level and / or provides a therapeutically favorable injection-related pain level. According to some embodiments, a therapeutically favorable injection-related pain level is provided, including a VAS score of less than 30 mm or less than 20 mm. In some more specific embodiments, the anti-IL17A antibody is ixekizumab, and according to some such embodiments, the improved injection-related pain level comprises a reduction in the VAS score compared to a commercial formulation of ixekizumab (the citrate and NaCl formulation exemplified by the control formulation in Table 2).

[0018] The present disclosure also provides the aqueous pharmaceutical formulation of the present disclosure for use in therapy. In a specific embodiment, the present disclosure provides the aqueous pharmaceutical formulation of the present disclosure for treating rheumatoid arthritis (RA), psoriasis (Ps), genital psoriasis (GenPs), pruritus, ankylosing spondylitis (AS), psoriatic arthritis (PA), palmoplantar pustulosis (PPP), hidradenitis suppurativa (HS), or multiple myeloma (MM). According to a further embodiment of the present disclosure, there is provided the use of the aqueous pharmaceutical formulation of the present disclosure for the preparation of a medicament for treating RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM. According to such embodiments, the use of such an aqueous pharmaceutical formulation is suitable for SQ, IP, and / or IM administration to a patient and exhibits an improved injection-related pain level and / or provides a therapeutically favorable injection-related pain level compared to a commercial pharmaceutical formulation of ixekizumab.

[0019] According to specific embodiments, the present disclosure provides methods for treating RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM, which comprise administering to a patient in need thereof an effective amount of an aqueous pharmaceutical formulation of the present disclosure, wherein the aqueous pharmaceutical formulation comprises an anti-IL17A antibody. In a more specific embodiment, such a treatment method comprises subcutaneously administering an initial dose of the aqueous pharmaceutical formulation to the patient on day 0, and subsequently subcutaneously administering the aqueous pharmaceutical formulation to the patient at four-week intervals thereafter, wherein the aqueous pharmaceutical formulation administered to the patient at four-week intervals after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. In another specific embodiment, such a treatment method comprises subcutaneously administering an initial dose of the aqueous pharmaceutical formulation to the patient on day 0, and subsequently subcutaneously administering the aqueous pharmaceutical formulation to the patient at two-week intervals thereafter, wherein the aqueous pharmaceutical formulation administered to the patient at two-week intervals after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. In yet another specific embodiment, such a treatment method comprises subcutaneously administering an initial dose of the aqueous pharmaceutical formulation to the patient on day 0, and subsequently subcutaneously administering the aqueous pharmaceutical formulation to the patient on days 14, 28, 42, 56, 70 and 84 respectively, and then subcutaneously administering the aqueous pharmaceutical formulation to the patient at four-week intervals thereafter, wherein the aqueous pharmaceutical formulation administered to the patient on days 14, 28, 42, 56, 70 and 84 respectively and at four-week intervals thereafter comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. According to some treatment methods provided by the present disclosure, the initial dose of the aqueous pharmaceutical formulation comprises about 160 mg of anti-IL17A antibody. In some such embodiments, the initial dose of about 160 mg of the aqueous pharmaceutical formulation comprises two doses of the aqueous pharmaceutical formulation, each dose comprising about 80 mg of anti-IL17A antibody. According to such methods, the aqueous pharmaceutical formulation exhibits an improved injection-related pain level and / or provides a therapeutically favorable injection-related pain level compared to a commercial pharmaceutical formulation of ixekizumab.

[0020] According to specific embodiments, provided herein are aqueous pharmaceutical formulations comprising an anti-IL17A antibody for treating RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM, wherein the pharmaceutical formulation is administered subcutaneously at an initial dose on day 0, followed by one dose at intervals of every four weeks thereafter, wherein the pharmaceutical formulation administered at intervals of every four weeks after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. In another specific embodiment, provided is a pharmaceutical formulation comprising an anti-IL17A antibody as disclosed herein for treating RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM, wherein the pharmaceutical formulation is administered subcutaneously at an initial dose on day 0, followed by one dose at intervals of every two weeks thereafter, wherein the pharmaceutical formulation administered at intervals of every two weeks after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. In yet another specific embodiment, provided is a pharmaceutical formulation comprising an anti-IL17A antibody as disclosed herein for treating RA, Ps, GenPs, pruritus, AS, PA, PPP, HS, or MM, wherein the pharmaceutical formulation is administered subcutaneously at an initial dose on day 0, followed by one dose on each of days 14, 28, 42, 56, 70, and 84 thereafter, wherein the pharmaceutical formulation administered on each of days 14, 28, 42, 56, 70, and 84 after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. According to some embodiments, the aqueous pharmaceutical formulation of the initial dose comprises about 160 mg of the anti-IL17A antibody. In some such embodiments, the aqueous pharmaceutical formulation of about 160 mg of the initial dose comprises two doses of the aqueous pharmaceutical formulation, each dose comprising about 80 mg of the anti-IL17A antibody. According to such embodiments, the aqueous pharmaceutical formulations provided herein exhibit an improved level of injection-related pain and / or provide a therapeutically favorable level of injection-related pain compared to the commercial pharmaceutical formulation of ixekizumab.

[0021] As used interchangeably herein, the phrase "aqueous pharmaceutical formulation" or "pharmaceutical formulation" refers to an aqueous solution having at least one therapeutic antibody capable of exerting a biological effect in humans, at least one inactive ingredient (e.g., excipient, surfactant, etc.) (which, when combined with the therapeutic antibody, is suitable for therapeutic administration to humans). The pharmaceutical formulations provided by the present disclosure are unbuffered (i.e., do not contain reagents such as citrate buffers, histidine buffers, acetate buffers, etc. or combinations thereof having acid-base conjugate components for resisting pH changes), aqueous stable formulations, wherein the degree of degradation, modification, aggregation, loss of biological activity, etc. of the therapeutic antibody therein is acceptably controlled and does not increase unacceptably over time.

[0022] As used herein, the term "antibody" refers to an immunoglobulin G (IgG) molecule comprising two heavy chains ("HC") and two light chains ("LC") interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region ("HCVR") and a heavy chain constant region ("CH"). Each light chain is composed of a light chain variable region ("LCVR") and a light chain constant region ("CL"). Each HCVR and LCVR is further subdivided into hypervariable regions, called complementarity determining regions ("CDR"), which are dispersed in more conserved regions, called framework regions ("FR"). Each HCVR and LCVR is composed of three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of each HC and LC contain binding domains that interact with an antigen. The constant region of the antibody 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 of the classical complement system (Clq).

[0023] According to a specific embodiment of the aqueous pharmaceutical formulation provided herein, the antibody is an anti-IL17A antibody. Interleukin 17A or IL17A as used herein refers to a cytokine of the IL17 cytokine family (also known as cytotoxic T-lymphocyte-associated antigen 8 ("CTLA8")). The IL17A cytokine exists as a homodimeric complex (e.g., IL17A / A) or as a heterodimeric complex (e.g., IL17A / F) complexed with another member of the IL17 cytokine family, such as IL17F. The IL17A cytokine is thought to be produced primarily by effector T helper (Th17) cells and has been shown to induce the secretion of pro-inflammatory cytokines, such as IL-6, IL-8, IL-1, and TNF. The homodimeric complex form of IL17A, IL17A / A, has been shown to play a role in diseases, such as psoriasis and psoriatic arthritis, both of which are immune-related diseases associated with T cell dysregulation.

[0024] As used herein, such anti-IL17A antibodies are antibodies that specifically bind and antagonize human IL17A through specificity for the A subunit (e.g., one or both of the A subunits of IL17A / F or the A subunit of IL17A / A). According to specific embodiments of the anti-IL17A antibody, LCDR1 comprises the amino acid sequence of SEQ ID NO.1, LCDR2 comprises the amino acid sequence of SEQ ID NO.2, LCDR3 comprises the amino acid sequence of SEQ ID NO.3, HCDR1 comprises the amino acid sequence of SEQ ID NO.4, HCDR2 comprises the amino acid sequence of SEQ ID NO.5, and HCDR3 comprises the amino acid sequence of SEQ ID NO.6. According to some such 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 of such anti-IL17 antibodies, LC comprises the amino acid sequence of SEQ ID NO.9 and HC comprises the amino acid sequence of SEQ ID NO.10. An exemplary embodiment of the anti-IL17A antibody is ixekizumab, as described, for example, in U.S. Patent No. 7,838,638. An additional example of an anti-IL17A antibody is secukinumab (sold under the trade name ), as described, for example, in U.S. Patent No. 7,807,155.

[0025] As used herein, the terms "about" or "approximate", when used in reference to a specifically recited numerical value or range of values, mean that the value can vary from the recited value by no more than 10% (e.g., + / - 10%). For example, as used herein, the expression "about 100" includes all values between 90 and 110 (e.g., 91, 92, 93, 94, etc.).

[0026] As used herein, the terms "substantially free of" or "substantially without" mean that the presence of a given substance (e.g., an ionic strength excipient) is below the limit of detection of an assay used to detect the presence of such substance.

[0027] As used herein, the term "ionic strength excipient" refers to an excipient that comprises an ionic compound (e.g., an electrolyte such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, arginine hydrochloride, etc.), which is different from the antibody and surfactant that make up an aqueous pharmaceutical formulation. As is known in the art, ionic strength excipients can be used to adjust the osmotic pressure of a pharmaceutical formulation. However (and as provided in the examples herein), the adjustment of pH with HCl or NaOH, if necessary, after dissolution and mixing of the aqueous pharmaceutical formulation is not within the meaning of the term ionic strength excipient as used herein (since the addition of HCl or NaOH used to adjust pH does not act as an ionic strength excipient in the formulation).

[0028] As mentioned herein, the term L-amino acid excipient refers to an L-amino acid added as part of a buffer (e.g., L-histidine in a histidine buffer; L-arginine in an arginine buffer, etc.) or as an excipient component of an aqueous pharmaceutical formulation (but not as a component of a therapeutic antibody).

[0029] As used interchangeably herein, "Visual Analogue Scale" or "VAS" refers to an assessment tool used to evaluate injection-related pain experienced by a patient. The VAS consists of a 100 mm continuous scale on which the patient identifies their pain level after an injection. The extreme VAS scores are "no pain at all" (e.g., 0) and "the worst pain imaginable" (e.g., 100). According to the VAS tool, the severity of pain can be classified as mild pain (≤30 mm); moderate pain (>30 mm - ≤70 mm) and severe pain (>70 mm). When referred to herein, "injection-related pain" refers to the acute pain experienced by a patient at the time of or shortly after injection of an aqueous pharmaceutical formulation. A desirable property of a stable pharmaceutical formulation is to be well tolerated by the patient, e.g., providing a therapeutically favorable injection-related pain level (e.g., a VAS score of <30 mm and / or <20 mm). As is known, the components of a pharmaceutical formulation and their concentrations and / or ratios may affect the injection-related pain experienced by a patient.

[0030] As used interchangeably herein, "treatment" and / or "treating" and / or "treat" mean all processes in which there may be complete elimination, alleviation or delay, reduction in severity or frequency (e.g., sudden onset or attack), interruption or cessation of progression of a disease and / or its symptoms, but without the need to completely eliminate all symptoms of the disease. Treatment includes administering the aqueous pharmaceutical formulations of the present disclosure for treating a disease in a human, the disease being one that would benefit from at least one of the processes listed above, including: (a) inhibiting further progression of the symptoms and effects of the disease, i.e., arresting its development; (b) alleviating the disease, i.e., causing elimination or regression of the disease, the disease symptoms or its complications; and (c) preventing or reducing the frequency of disease onset or attack. According to specific embodiments, the pharmaceutical formulations provided herein can be used to treat at least one of RA, Ps, GenPs, AS, PA, PPP, HS or MM.

[0031] As used interchangeably herein, the terms "patient", "subject" and "individual" refer to a human. Unless otherwise specified, the subject is further characterized as having a disease or being at risk of developing or experiencing symptoms of a disease that would benefit from administration of the pharmaceutical formulations disclosed herein.

[0032] As used interchangeably herein, an "effective amount" or "therapeutically effective amount" of a pharmaceutical formulation of the present disclosure refers to the amount necessary to achieve a desired therapeutic effect (in terms of dose, frequency of administration, and duration of a particular mode of administration). The effective amount of a pharmaceutical formulation of the present disclosure can vary depending on factors such as the disease state, age, sex, and weight of the subject, as well as the ability of the pharmaceutical formulation of the present disclosure to elicit a desired response in the subject. The effective amount is also the amount at which the therapeutic beneficial effects exceed any toxic or detrimental effects of the pharmaceutical formulation of the present disclosure.

[0033] The present disclosure also relates to a dosing regimen for treating a disease with a pharmaceutical formulation of the present disclosure. As mentioned herein and as is well known in the art, the term "dose" refers to the amount of a pharmaceutical formulation administered to a subject. As is well known in the art and as interchangeably mentioned herein, a "dose regimen" or "dosage regimen" includes a treatment schedule of a set (i.e., series or sequence) of doses to be administered to a patient over a period of time.

[0034] By way of example, a dosing regimen of the present disclosure can include an initial dose of an aqueous pharmaceutical formulation of the present disclosure (e.g., comprising an anti-IL17A antibody) administered to a patient on the first day of treatment (e.g., day 0). The initial dose can be referred to herein as a "loading dose". Additionally, a dosing regimen of the present disclosure can include an initial treatment period, sometimes referred to herein as an "induction period", which follows the loading dose. During the induction period, for example, a dose (or doses) comprising a therapeutic antibody (e.g., an anti-IL17A antibody) at a particular concentration can be administered to the patient at a given frequency of administration (e.g., daily, every 2 weeks, every 4 weeks, etc.) for a given duration (e.g., 4, 12, or 16 weeks). Additionally, a dosing regimen of the present disclosure can include a period following the induction period, sometimes referred to herein as a "maintenance period", in which a dose comprising a therapeutic antibody at a particular concentration is administered to the patient at a given frequency of administration (e.g., every 2 or 4 weeks, etc.).

[0035] The aqueous pharmaceutical formulations of the present disclosure can be administered to a patient via parenteral administration. As understood in the medical field, parenteral administration refers to injecting a dose into the body through a sterile syringe or some other drug delivery system, including an autoinjector or an infusion pump. Exemplary drug delivery systems for use with the aqueous pharmaceutical formulations of the present disclosure are described in the following references, the disclosures of which are hereby expressly incorporated by reference in their entirety: U.S. Patent Publication No. 2014 / 0054883 to Lanigan et al., filed Mar. 7, 2013 and titled "Infusion Pump Assembly"; U.S. Patent No. 7,291,132 to DeRuntz et al., filed Feb. 3, 2006 and titled "Medication Dispensing Apparatus with Triple Screw Threads for Mechanical Advantage"; U.S. Patent No. 7,517,334 to Jacobs et al., filed Sep. 18, 2006 and titled "Medication Dispensing Apparatus with Spring-Driven Locking Feature Enabled by Administration of Final Dose"; and U.S. Patent No. 8,734,394 to Adams et al., filed Aug. 24, 2012 and titled "Automatic Injection Device with Delay Mechanism Including Dual Functioning Biasing Member". Parenteral routes include IM, SQ, and IP administration routes. Detailed Description

[0036] Examples

[0037] Exemplary aqueous pharmaceutical formulations

[0038] Table 1: Exemplary aqueous pharmaceutical formulations

[0039] Concentration Anti-IL17A antibody * 80 mg / mL PS-80 0.03% w / v (0.3 mg / mL) Sucrose 234 mM (8% w / v) pH 5.7

[0040] *The anti-IL17A antibody comprises the HCVR of SEQ ID NO: 8 and the LCVR of SEQ ID NO: 7.

[0041] The manufacturing process of the anti-IL17A antibody pharmaceutical preparation presented in Table 1 can be accomplished by weighing an appropriate amount of water (e.g., at a temperature of 20 + / - 5 °C) into an empty container of appropriate size tared weight. Add an appropriate amount of sucrose and mix. Weigh out polysorbate 80 precisely in a glass container and add an appropriate amount of water at a temperature of 20 + / - 5 °C to the glass container to give the desired concentration and mix the solution. Add the entire contents of the polysorbate 80 solution to the other excipients. Rinse the polysorbate 80 solution container with water to ensure transfer of all contents. After adding the polysorbate 80 solution, mix the solution. After dissolution and mixing are complete, check that the pH of the solution is within 5.7 + / - 0.3; if necessary, adjust with HCl or NaOH solution. Pass the excipient composition through a filter (polyvinylidene fluoride [PVDF]) to reduce the bioburden.

[0042] Mix the anti-IL17A antibody previously expressed, purified, and concentrated in cells with an appropriate amount of the formulation excipient solution. Re-check that the pH of the solution is within 5.7 + / - 0.3. Pass the pharmaceutical preparation through a PVDF filter to reduce the bioburden and then it can be stored at 5 °C.

[0043] Physico-chemical properties

[0044] Both physical and chemical stability are essential for a pharmaceutical preparation of a therapeutic antibody to allow storage and transportation (e.g., for 1 year, 18 months, or 2 years) and to maintain safety and efficacy. Exemplary evaluations for measuring the physical stability of a pharmaceutical preparation include solubility (phase-separation, gelation) assessment, molecular interactions (e.g., as measured by DLS), characterization of visual clarity (i.e., opalescence) by turbidity assessment, and viscosity measurement. In addition, various analytical methods can be used to evaluate chemical stability, including size exclusion chromatography (SEC), cation exchange chromatography (CEX) HPLC, reducing and non-reducing capillary electrophoresis (CE-SDS R / NR), and particle analysis. As demonstrated herein, the exemplified anti-IL17A antibody pharmaceutical preparation of Table 1 exhibits chemical and physical stability and solubility for the highly concentrated therapeutic antibody ixekizumab, which has an isoelectric point of ≥7.5 and is incompatible with a formulation at neutral pH in solution.

[0045] Solubility assessment:

[0046] Sufficiently high solubility is essential for an aqueous pharmaceutical preparation. The aqueous pharmaceutical preparation must maintain a high concentration of the antibody in the monomeric state without high molecular weight (HMW) aggregation. Analyze the solubility of the anti-IL17A antibody with an isoelectric point ≥8.0 (in solution) at high concentration under different conditions.

[0047] Samples of each of the aqueous formulations provided in Table 2 are incubated at each of 5, 0, and -5 degrees Celsius (e.g., samples of each formulation can be incubated in parallel at 5, 0, and -5 °C) for one week. The phase separation, gelation, turbidity, and viscosity of the samples after incubation are evaluated.

[0048] Table 2: Formulations

[0049]

[0050] *The anti-IL17A antibody comprises two HCVRs having the amino acid sequence of SEQ ID NO: 8 and two LCVRs having the amino acid sequence of SEQ ID NO: 7.

[0051] **In addition to the tested aqueous pharmaceutical formulations listed in Table 2, an aqueous pharmaceutical formulation containing 10 mM acetate buffer, 150 mM NaCl, and 80 mg / mL anti-IL17A antibody, pH 5.0, is evaluated after incubation, in which an unacceptable level of antibody shear is observed by non-reducing CD-SDS.

[0052] ***Furthermore, as described in U.S. Patent No. 9,376,491, an unacceptable cloud point is observed for anti-IL17A antibodies at concentrations below 20 mM citrate buffer and 150 mM NaCl.

[0053] Phase separation :

[0054] As detailed in U.S. Patent No. 9,376,491, the exemplified anti-IL17A antibody (comprising two LCVRs having the amino acid sequence of SEQ ID NO: 7 and two HCVRs having the amino acid sequence of SEQ ID NO: 8) has a tendency to phase separate in solutions below 0 degrees Celsius (°C). However, the drug product is stored at 5 °C and requires stability under periodic refrigerated temperature fluctuations below 0 °C. As provided in U.S. Patent No. 9,376,491, increasing the citrate buffer and NaCl concentrations sufficiently reduces the temperature at which phase separation occurs. However, it has been reported that injection-related pain is associated with formulations containing increased citrate buffer and NaCl concentrations, and patients have reported injection-related pain after injecting the commercial pharmaceutical formulation of ixekizumab.

[0055] After incubation at -5 °C for one week, the phase separation of the formulations provided in Table 2 is evaluated by visually monitoring for signs of phase separation (e.g., formation of a dense protein-rich layer at the bottom of the vial). The results are provided in Table 3.

[0056] Gelation :

[0057] Events such as thermodynamic solid-phase changes (e.g., gelation) can occur at lower temperatures (5 °C or lower), negatively impacting stability. As detailed in U.S. Patent No. 9,376,491, gelation was observed with high concentrations of the exemplified anti-IL17A antibodies at temperatures of 5 °C and below. U.S. Patent No. 9,376,491 also showed that increasing the citrate buffer and NaCl concentrations was sufficient to avoid gelation at lower temperatures. However, as shown, injection-related pain has been reported to be associated with formulations containing increased citrate buffer and NaCl concentrations, and patients have reported injection-related pain after injecting commercial drug formulations of ixekizumab.

[0058] The gelation evaluations of the formulations provided in Table 2 are presented in Table 3. Briefly, after incubation as described above, each vial was agitated (e.g., inverted and then returned to vertical), and then visually inspected for solidification or lack of liquid flow.

[0059] Turbidity :

[0060] Turbidity (i.e., loss of transparency due to the suspension of particulate matter) is an inherent challenge for aqueous drug formulations of therapeutic antibodies. At high antibody concentrations and lower temperatures, the challenge is exacerbated, which can lead to failure in the visual inspection of the formulation.

[0061] Briefly, after incubation as described above, turbidity was evaluated visually (e.g., a light-based method using purified water as a comparator) and by a turbidimeter (HACH turbidimeter, generating quantitative measurements (NTU), according to the manufacturer's instructions) (measurements were made at ambient temperature). Lower NTUs are desired; more specifically, an NTU value of less than 50 is desired, with a failure cut-off value of 80 NTU. The results are provided in Table 3.

[0062] Viscosity :

[0063] An aqueous drug formulation acceptable for manufacturing, administration to patients, and patient tolerance must have an appropriate viscosity. Subcutaneous delivery requires a less viscous (at least <20 cP) aqueous solution. Increasing the concentration of the therapeutic antibody presents a challenge of increasing viscosity. Drug formulations with NaCl are known to have a reduced viscosity, but as shown, an increase in the NaCl concentration in the drug formulation is associated with injection-related pain.

[0064] After incubation at 20 °C, the viscosities of Formulation 1 of Table 2 and the control formulation were evaluated by a viscometer (Anton Paar AMVn viscometer, generating centipoise (cP) measurements, according to the manufacturer's instructions). Lower cPs are desired, especially e.g., <20 cP. The results are provided in Table 3.

[0065] Table 3: Solubility evaluation of the formulations in Table 2

[0066] <![CDATA Sample ID > <![CDATA Phase separation evaluation > <![CDATA Gelation evaluation > <![CDATA Turbidity (NTUs)]]> <![CDATA Viscosity (cPs)]]> Control No No 63 3 1 No No 10 5 2 Yes ND ND ND 3 Yes ND ND ND 4 Yes ND ND ND 5 No No 85 ND 6 No Yes ND ND 7 No Yes ND ND 8 No No 95 ND 9 Yes ND ND ND 10 Yes ND ND ND 11 Yes ND ND ND 12 Yes ND ND ND

[0067] As shown in Table 3, unacceptable phase separation or gelling was observed for all formulations lacking at least 150 mM NaCl (and NaCl unbuffered formulations) (), except for Formulation 1 which did not exhibit phase separation. The phase separation results for Formulation 1 were comparable to those of the control formulation (high citrate, high NaCl formulation). In addition, unacceptable gelling was observed for formulations containing histidine buffer and NaCl (pH 6.5). Formulation 1 did not exhibit gelling and was comparable to the control formulation (high citrate, high NaCl formulation). In addition, unacceptable turbidity was observed for Formulation 5 (citrate (5 mM), NaCl (175 mM)) and Formulation 8 (histidine (9 mM) and NaCl (150 mM)). Formulation 1 exhibited an acceptable turbidity level and provided an unexpectedly improved turbidity level compared to the control formulation (high citrate, high NaCl formulation). Further, as shown, both Formulation 1 and the control formulation exhibited acceptable and comparable viscosities.

[0068] Chemical stability:

[0069] Chemical stability is essential for the development of aqueous pharmaceutical formulations that allow both storage (i.e., sufficient shelf life) and maintain safety and potency. In an accelerated degradation study, the chemical stability of the control and Formulation 1 (provided in Table 2) was evaluated and compared after incubation for a 4-week period at 25 °C or 40 °C. The change in % HMW aggregates was compared to the % HMW aggregates at time 0.

[0070] In one evaluation, the change in high molecular weight (HMW) aggregates in the formulations was evaluated using size exclusion chromatography (SEC) according to standard procedures. The results are provided in Table 4.

[0071] Table 4: Overview of the change in % HMW aggregates measured by SEC

[0072]

[0073] As shown, in the accelerated degradation study, both the control formulation and Formulation 1 in Table 2 exhibited acceptable and comparable chemical stability.

[0074] Additional accelerated chemical stability of the control and Formulation 1 in Table 2 was studied using cation exchange (CEX) HPLC. Briefly, the samples were incubated at 25 °C for 4 weeks. After incubation, the increase in the total % acidic variants (% AV) of the samples was analyzed using CEX HPLC. The increase in the total % acidic variants (% AV) provides an indicator of the degradation of the therapeutic antibody in the aqueous formulation. The results are provided in Table 5.

[0075] Table 5: Increase in % AV over 4 weeks at 25 °C

[0076] Formulation # (from Table 2) Increase in % AV Control 2.0 1 2.3

[0077] As shown, in further accelerated degradation studies, both the control of Table 2 and Formulation 1 demonstrated acceptable and comparable levels of chemical stability.

[0078] Multivariate evaluation of Formulation 1 in Table 2

[0079] As demonstrated herein, Formulation 1 of Table 2 provided unexpectedly stability comparable (or improved) to the control formulation of Table 2. Multivariate evaluation of the physical and chemical stability of Formulation 1 of Table 2 was conducted as follows.

[0080] Briefly, four variables of Formulation 1 of Table 2 (antibody concentration; pH; sucrose concentration; and PS-80 concentration) were modified to evaluate the physical and chemical stability responses of each variable and / or the interactions between variables. Formulation 1 of Table 2 was set as the central point formulation for such experiments. Variant formulations are provided in Table 6.

[0081] Table 6: Variant formulations

[0082] <![CDATA Sample ID > <![CDATA Sucrose > <![CDATA PS-80 **]]> <![CDATA Anti-IL17A * Antibody > <![CDATA pH > Center point (Formulation 1 in 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

[0083] *The anti-IL17A antibody comprises two HCVRs having the amino acid sequence of SEQ ID NO: 8 and two LCVRs having the amino acid sequence of SEQ ID NO: 7.

[0084] **The polysorbate tolerance within the ranges listed in Table 6 was confirmed by accelerated freeze-thaw studies.

[0085] Phase separation, gelation, and turbidity of each variant formulation were evaluated according to the above procedure. This multivariate evaluation provided the identification of tolerance limits for the variables evaluated. No phase separation or gelation was observed, and acceptable turbidity values were observed.

[0086] Long-term stability evaluation

[0087] Long-term stability of the aqueous pharmaceutical formulation is required to demonstrate storage ability and sufficient shelf life (e.g., 1 year, 2 years, or longer). The long-term stability of the central point formulation of Table 6 (which corresponds to the formulation provided in Table 1 and Formulation 1 of Table 2) was evaluated after incubating the samples as follows: at 5°C for 1, 3, and 6 months; at 25°C for 1 and 3 months; and at 35°C for 1 and 3 months (sample evaluation before incubation was also conducted).

[0088] After incubation, the monomer percentage and high molecular weight (HMW) aggregate percentage of the samples were analyzed using size exclusion chromatography (SEC) according to standard procedures. The results are provided in Table 7.

[0089] Table 7: Long-term stability evaluation of the center point formulation

[0090] Incubation temperature (°C) Incubation period (months) Monomer (%) HMW aggregates (%) Control (before incubation) NA 98.61 1.27 5 1 98.83 1.10 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

[0091] As provided, the central formulation of Table 6 demonstrates the long-term stability of the therapeutic antibody, even under extended time stress conditions at elevated temperatures.

[0092] In vivo tolerance study

[0093] Based on the following study, the injection-related pain of an aqueous pharmaceutical formulation of ixekizumab at a high concentration (80 mg / mL) administered subcutaneously was evaluated, in which subjects received an SQ injection of one of Formulation A or B (as provided in Table 8), and subsequently received an SQ injection of the other of Formulation A or B after a period of time (e.g., 1, 5, 7, 10, 14 days, etc.). The injection-related pain of the subjects was then evaluated based on the VAS scale scores at specified time points after each injection (e.g., within 1 minute (i.e., immediately after injection), within 10 minutes, within 1 hour, within 4 hours, within 1 day).

[0094] Table 8: Ixekizumab pharmaceutical formulations

[0095]

[0096] Accordingly, a single-dose, subject-blinded, randomized, crossover study was conducted in which subjects were randomly assigned to one of two treatment groups. Each treatment group received a subcutaneous injection of a pharmaceutical formulation containing 80 mg / ml ixekizumab according to the following injection schedule, as listed in Table 8.

[0097] Treatment Group 1 received a single dose of Formulation B, followed by a single dose of Formulation A after 7 days. Treatment Group 2 received a single dose of Formulation A by SQ injection, followed by a single dose of Formulation B by SQ injection after 14 days. When the subject was in a sitting or reclined position, the injection was administered by a medical staff member in the subject's abdomen. Subsequent injections could be alternated between abdominal quadrants. The injection-related pain was evaluated based on the VAS scale scores immediately after each injection (e.g., within 1 minute) and 10 minutes after injection. The results are provided in Tables 9 and 10 below.

[0098] Table 9: Comparability data for injection-related pain

[0099]

[0100] As shown in Table 9, at both immediately after injection and 10 minutes after injection, Formulation A provided a significant reduction in VAS scores compared to Formulation B (a commercially available formulation).

[0101] Table 10. Patient tolerance analysis

[0102]

[0103] As shown in Table 10, compared to Formulation B (a commercially available formulation), Formulation A provides a significant improvement in that patients do not immediately experience injection-related pain after injection and a significant benefit in reducing the number of patients who immediately experience moderate to severe injection-related pain after injection.

[0104] In vivo pharmacokinetic analysis

[0105] Pharmacokinetic analysis of the aqueous pharmaceutical formulation of ixekizumab can be performed according to the following study, in which subjects receive an SQ injection of either Formulation A or B (as provided in Table 8). Then, pharmacokinetic analysis of the subjects is evaluated at different time points (e.g., before SQ injection and then after SQ injection, such as 1 - 24 hours, 1 - 90 days after injection).

[0106] Accordingly, a single-dose, subject-blinded, randomized, parallel-design study is conducted, in which, on Day 1, subjects are randomized into one of two treatment groups. Before receiving treatment (e.g., on Day 1, before dosing), pre-dose samples are obtained from patients in both treatment groups for evaluation of pharmacokinetic characteristics. On Day 1, Treatment Group 1 receives a single SQ injection of Formulation A, and Treatment Group 2 receives a single subcutaneous injection of Formulation B (as described in Table 8). Medical personnel can administer the injection in the abdomen of the subjects. After dosing, samples are obtained on Study Days 3, 5 (±1 day), 8 (±1 day),

[0107] 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 (the observed maximum drug concentration), AUC[0-∞] (the area under the concentration-time curve from time zero to infinity), AUC[0-t 最后 (the area under the concentration-time curve from time zero on Study Day 1 to the time of the last measurable concentration) and Tmax (the time at which the maximum drug concentration is observed). The results are provided in Table 11.

[0108] Table 11: In vivo pharmacokinetic analysis

[0109]

[0110] As shown in Table 11, Formulation A demonstrates comparable P to Formulation B (a commercially available formulation)K Parameters. In addition, no serious adverse events were reported for any of the formulations, and the overall safety was consistent and comparable to that of Formulation B.

[0111] Target neutralization evaluation

[0112] Samples of Formulation A were incubated at 5 °C for 1, 6, and 12 months; at 25 °C for 1 month; and at 35 °C for 1 month, and the efficacy of Formulation A was evaluated by a cell-based bioassay compared to Formulation B (of Table 8). Briefly, the murine osteoblast cell line MC3T3-E1, which endogenously expresses the IL-17A receptor and stably expresses the firefly luciferase gene, was cultured such that when IL-17A was present, transcription of luciferase was induced at a level proportional to the activity of IL-17A. Samples of previously incubated Formulation A and B were introduced into the culture wells of the cell-based bioassay, respectively, and after measuring luciferase expression, an inhibition dose curve was generated. The data were analyzed using four-parameter logistic curve fitting. By calculating the ratio of the EC 50 of Formulation A compared to the EC 50 of Formulation B (e.g., the reference standard), the relative efficacy was determined. The results are provided in Table 12.

[0113] Table 12: Relative efficacy evaluation of Formulation A (relative to Formulation B in %)

[0114]

[0115] As shown in Table 12, after long-term storage and under stress conditions, Formulation A demonstrated a comparable level of target neutralization to Formulation B (the commercially available formulation).

[0116]

Claims

1. An aqueous pharmaceutical formulation comprising: (i) an anti-IL-17A antibody at a concentration of 80 mg / mL ± 10%; (ii) sucrose at a concentration of 234 mM ± 10%; and (iv) a surfactant at a concentration between 0.005% w / v ± 10% and 0.05% w / v ± 10%, Among them, wherein the pharmaceutical formulation is an aqueous solution having a pH between 5.2 and 6.5, and the anti-IL17A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, and the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, wherein: LCDR1 comprises the amino acid sequence of SEQ ID NO.1, LCDR2 comprises the amino acid sequence of SEQ ID NO.2, LCDR3 comprises the amino acid sequence of SEQ ID NO.3, HCDR1 comprises the amino acid sequence of SEQ ID NO.4, HCDR2 comprises the amino acid sequence of SEQ ID NO.5, and HCDR3 comprises the amino acid sequence of SEQ ID NO.

6.

2. The aqueous pharmaceutical formulation of claim 1, wherein the surfactant is polysorbate 20 or polysorbate 80.

3. The aqueous pharmaceutical formulation of claim 2, wherein the surfactant is polysorbate 80.

4. The aqueous pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is substantially free of ionic tonicity excipients.

5. The aqueous pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is substantially free of L-amino acid excipients.

6. The aqueous pharmaceutical formulation of claim 1, wherein the LCVR comprises the amino acid sequence of SEQ ID NO:7, and the HCVR comprises the amino acid sequence of SEQ ID NO:

8.

7. The aqueous pharmaceutical formulation of claim 6, wherein the anti-IL17A antibody comprises a light chain (LC) and a heavy chain (HC), wherein the LC comprises the amino acid sequence of SEQ ID NO.9, and the HC comprises the amino acid sequence of SEQ ID NO.

10.

8. The aqueous pharmaceutical formulation of claim 1, wherein the anti-IL17A antibody is ixekizumab.

9. Use of the aqueous pharmaceutical formulation of claim 1 for the manufacture of a medicament for use in a method of treating rheumatoid arthritis, psoriasis, genital psoriasis, pruritus, ankylosing spondylitis, psoriatic arthritis, palmoplantar pustulosis, hidradenitis suppurativa, or multiple myeloma, which comprises administering to a patient in need thereof an effective amount of the aqueous pharmaceutical formulation of claim 1.

10. The use of claim 9, wherein the method comprises: subcutaneously administering to the patient an initial dose of the pharmaceutical formulation on day 0, followed by subcutaneously administering to the patient the pharmaceutical formulation at four-week intervals thereafter, wherein the pharmaceutical formulation administered to the patient at four-week intervals after the initial dose comprises an anti-IL-17A antibody at a concentration of about 80 mg / mL.

11. Use according to claim 9, wherein the method comprises: administering an initial dose of the pharmaceutical formulation subcutaneously to the patient on day 0, and subsequently administering the pharmaceutical formulation subcutaneously to the patient at two-week intervals thereafter, wherein the pharmaceutical formulation administered to the patient at two-week intervals after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL.

12. Use according to claim 9, wherein the method comprises: administering an initial dose of the pharmaceutical formulation subcutaneously to the patient on day 0, and subsequently administering the pharmaceutical formulation subcutaneously to the patient on days 14, 28, 42, 56, 70 and 84 respectively, and subsequently administering the pharmaceutical formulation subcutaneously to the patient at four-week intervals thereafter, wherein the pharmaceutical formulation administered to the patient on days 14, 28, 42, 56, 70 and 84 respectively and at four-week intervals thereafter comprises an anti-IL17A antibody at a concentration of about 80 mg / mL.

13. Use according to claim 10, wherein the initial dose of the pharmaceutical formulation comprises about 160 mg of the anti-IL17A antibody.

14. Use according to claim 13, wherein the initial dose of about 160 mg of the pharmaceutical formulation comprises two doses of the pharmaceutical formulation, each dose comprising about 80 mg of the anti-IL17A antibody.

15. Use of the aqueous pharmaceutical formulation according to claim 1 for the manufacture of a medicament for performing a method of reducing injection-related pain experienced by a patient at or shortly after subcutaneous, intraperitoneal and / or intramuscular administration of an aqueous pharmaceutical formulation comprising an anti-IL17A antibody, the method comprising administering to the patient the aqueous pharmaceutical formulation according to claim 1, wherein the administering step provides a therapeutically advantageous level of injection-related pain.

16. Use according to claim 15, wherein the therapeutically advantageous level of injection-related pain comprises a VAS score of less than 30 mm or less than 20 mm.

17. Use according to claim 15, wherein the anti-IL17A antibody is ixekizumab.

18. The aqueous pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is unbuffered.

19. The aqueous pharmaceutical formulation according to claim 18, wherein the pharmaceutical formulation is substantially free of L-amino acid excipients.

20. The aqueous pharmaceutical formulation according to claim 19, wherein the surfactant is polysorbate 80 and the anti-IL17A antibody is ixekizumab.

21. Use according to claim 9, wherein the aqueous pharmaceutical formulation is unbuffered, substantially free of L-amino acid excipients, and the surfactant is polysorbate 80.

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