Therapeutic antibody preparations

Abstract

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

Description

[0001] The present invention is in the field of medicine. More specifically, the present invention relates to aqueous pharmaceutical formulations comprising therapeutic antibodies suitable for subcutaneous ("SQ"), intramuscular ("IM") and / or intraperitoneal ("IP") administration.

[0002] Administration of therapeutic antibodies via SQ, IP and / or IM administration is both common and advantageous. Such routes of administration allow for delivery of therapeutic antibodies in a short period of time and allow patients to self-administer therapeutic antibodies without visiting a medical practitioner. However, formulating therapeutic antibodies into aqueous pharmaceutical formulations suitable for SQ, IM and / or IP administration is both challenging and unpredictable. In addition, undesirable injection-related pain has been reported using such routes of administration, even after the syringe needle is removed, and can compromise patient compliance with therapy.

[0003] The challenges and unpredictability associated with formulating therapeutic antibodies into aqueous pharmaceutical formulations suitable for SQ, IM and / or IP administration are due in part to the many properties that the pharmaceutical formulation must possess to be therapeutically viable. The aqueous pharmaceutical formulation must provide stability for the therapeutic antibody in solution while maintaining the functional properties of the therapeutic antibody that are essential for therapeutic efficacy, such as target affinity, selectivity and efficacy. In addition, the aqueous pharmaceutical formulation must also be safe for administration to patients and well tolerated by patients, as well as suitable for manufacture and storage.

[0004] The therapeutic antibodies of high concentration are even more complicated to prepare.For example, for the aqueous preparations of highly concentrated therapeutic antibodies, it has been reported that the antibody degradation, cutting, shearing, high molecular weight aggregation, dimerization, trimerization, precipitation pH shift, turbidity, solution color change, charge change, isomerization, oxidation and / or deamination (wherein all affect therapeutic antibody concentration, function and effectiveness) of increasing ratios.Another known challenge when preparing the therapeutic antibodies of high concentration is that viscosity increases, which can negatively affect the SQ, IM and / or IP use of aqueous pharmaceutical preparations.In addition, injection-related pain has been reported for preparations with increased viscosity.

[0005] 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 (particularly at high concentrations). The charge distribution of such antibodies can also be present in the isoelectric point, preventing formulations at neutral pH. For example, some therapeutic antibodies have polarity or dipole moments that make them 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) drug formulations of therapeutic antibodies. Therefore, such therapeutic antibodies, such as ixekizumab with an isoelectric point of 8.1 (requiring an acidic pH formulation), are formulated in a manner that balances the stability of the therapeutic antibody with the functional properties required for efficacy and the tolerance of the patient, bringing additional, unpredictable challenges.

[0006] Ixekizumab is a highly specific anti-IL17A antagonist antibody, as described, for example, in U.S. Pat. No. 7,838,638. It is marketed under the trade name TALTZ ® Commercially sold ixekizumab is administered subcutaneously to patients in a highly concentrated (about 80 mg / mL) pharmaceutical formulation with an acidic pH (about 5.7). Commercial pharmaceutical formulations of ixekizumab as described in U.S. Patent No. 9,376,491 also include high concentrations of citrate buffer (about 20 mM) and NaCl (about 200 mM). However, pharmaceutical formulations with 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 commercial pharmaceutical formulations of ixekizumab.

[0007] The injection-related pain of aqueous pharmaceutical formulations comprising therapeutic antibodies is a complex multifactorial problem. For example, each individual component and / or its concentration, ratio and feature of aqueous pharmaceutical formulations can affect the injection-related pain associated with the therapeutic agent. Similarly, individual components (and / or their concentration, ratio and characteristics) can affect the stability, functional characteristics, manufacturability and / or tolerance of the therapeutic antibodies prepared in aqueous pharmaceutical formulations. Therefore, although specific formulation adjustments may provide a beneficial effect on a given aspect of a formulation, the same adjustments may also negatively affect other aspects of the formulation. Almost an unlimited number of different formulation components (e.g., buffers and excipients) and their concentrations and ratios have been reported, even further increasing complexity. However, there is still almost no correlation for predicting the impact of a specific formulation on the various characteristics and features of a given therapeutic antibody.

[0008] Therefore, there is a need for an aqueous pharmaceutical formulation of a therapeutic antibody that is suitable for SQ, IM and / or IP administration and is well tolerated by the patient, showing a therapeutically favorable level of injection-related pain. More specifically, such an aqueous pharmaceutical formulation is needed for highly concentrated therapeutic antibodies, which have an isoelectric point incompatible with the neutral pH in the solution, which requires an aqueous formulation of acidic pH. Even more specifically, an aqueous pharmaceutical formulation of ixekizumab suitable for SQ, IM and / or IP administration and well tolerated by the patient is needed, which shows an improved injection-related pain level compared to the commercial pharmaceutical formulation of ixekizumab (as described in U.S. Patent No. 9,376,491). This aqueous pharmaceutical formulation must also provide stability for the therapeutic antibody and maintain the characteristics of the therapeutic antibody that are essential for therapeutic efficacy. Such aqueous pharmaceutical formulations must also be suitable for manufacturing, preferably with an extended shelf life.

[0009] 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 essential for therapeutic efficacy. In addition, the aqueous pharmaceutical formulations provided herein are well tolerated by patients, exhibit improved injection-related pain levels compared to commercial pharmaceutical formulations of ixekizumab, and provide therapeutically favorable injection-related pain levels.

[0010] Thus, the present disclosure provides an unbuffered aqueous pharmaceutical formulation for administering a high concentration of a therapeutic antibody to a patient SQ, IM or IP with a therapeutically beneficial 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 at a pH between 5.2 and 6.5. According to specific embodiments, the surfactant is polysorbate 20 or polysorbate 80. In further specific embodiments, the surfactant is polysorbate 80. According to some embodiments, the unbuffered aqueous pharmaceutical formulation is substantially free of ionic tonicity excipients. In some embodiments, the pharmaceutical formulation is substantially free of L-amino acid excipients. In further embodiments, the antibody has an isoelectric point that is incompatible with a neutral pH in solution. In some such embodiments, the antibody has an isoelectric point of ≥7.5, and in even further embodiments, the antibody has an isoelectric point of ≥8.0. In further specific embodiments of the aqueous pharmaceutical formulations provided herein, the therapeutic antibody is an anti-IL-17A antibody comprising a LCVR having an amino acid sequence of SEQ ID NO.7 and a HCVR having an amino acid sequence of SEQ ID NO.8. In even further specific embodiments, the anti-IL17A antibody comprises a light chain (LC) having an amino acid sequence of SEQ ID NO.9 and a heavy chain (HC) having an amino acid sequence of SEQ ID NO.10. According to an embodiment of the present disclosure, an aqueous pharmaceutical formulation of the present disclosure is provided, wherein the aqueous pharmaceutical formulation exhibits a reduced risk of injection-related pain and / or a therapeutically favorable injection-related pain level after administration to a patient SQ, IP and / or IM.

[0011] According to a specific embodiment of the present disclosure, an unbuffered 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), wherein the light chain variable region (LCVR) comprises complementarity determining regions (CDRs) LCDR1, LCDR2 and LCDR3, and the heavy chain variable region (HCVR) comprises CDRs HCDR1, HCDR2 and HCDR3, wherein LCDR1 has an amino acid sequence of SEQ ID NO.1, LCDR2 has an amino acid sequence of SEQ ID NO.2, LCDR3 has an amino acid sequence of SEQ ID NO.3, HCDR1 has an amino acid sequence of SEQ ID NO.4, HCDR2 has an amino acid sequence of SEQ ID NO.5, and HCDR3 has an amino acid sequence of SEQ ID NO.6. According to such embodiments, the aqueous pharmaceutical formulation is an aqueous solution with 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 234mM + / - 10%; and a surfactant at a concentration of 0.005 + / - 10% to 0.05 + / - 10% %w / v. According to some embodiments, the unbuffered aqueous pharmaceutical formulation is substantially free of ionic tonicity 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 more specific embodiments, the surfactant is polysorbate 80. In an even more specific embodiment, the concentration of polysorbate 80 is 0.03% w / v + / - 10%. According to such embodiments, the unbuffered aqueous pharmaceutical formulation is suitable for administration to a patient SQ, IP and / or IM and exhibits improved injection-related pain levels and / or provides a therapeutically favorable injection-related pain level compared to a commercial pharmaceutical formulation of ixekizumab.

[0012] In specific embodiments, the aqueous pharmaceutical formulations provided herein comprise 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 tonicity 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 comprising a LCVR having an amino acid sequence of SEQ ID NO. 7 and a HCVR having an amino acid sequence of SEQ ID NO. 8. In further such embodiments, the anti-IL17A antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO. 10 and a light chain having an 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 improved injection-related pain levels and / or provides therapeutically favorable injection-related pain levels compared to commercial pharmaceutical formulations of ixekizumab.

[0013] In a further embodiment, a system for subcutaneously delivering an aqueous drug formulation to a patient in need of treatment is provided. This 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 a hole in fluid communication with the outlet of the chamber to receive the liquid from the chamber, and the drive mechanism being operable to force the liquid to be transferred from the chamber to the hole of the needle. This system also includes a drug formulation of the present disclosure disposed in the chamber, and an inner wall of the chamber having a silicone oil coating in an amount of 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 needs treatment of RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM.

[0014] 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 beneficial injection-related pain level experienced by a patient at or shortly after SQ, IM and / or IP injection of an aqueous pharmaceutical formulation comprising a therapeutic antibody, the method comprising administering an aqueous pharmaceutical formulation of the present disclosure to the patient. According to an embodiment, the present disclosure provides a method for delivering a therapeutic antibody to a patient at a therapeutically beneficial injection-related pain level, wherein the method comprises administering a pharmaceutical formulation of the present disclosure to the patient, wherein the method provides a therapeutically beneficial injection-related pain level. 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 beneficial injection-related pain level by administering an aqueous pharmaceutical formulation by SQ, IM or IP, the method comprising administering an aqueous pharmaceutical formulation of the present disclosure to the patient. According to an embodiment, reducing injection-related pain comprises reducing and / or providing a therapeutically beneficial injection-related pain level from a commercially available formulation. According to embodiments, a therapeutically favorable injection-related pain level may include a VAS score of less than 30 mm or a VAS score of less than 20 mm.

[0015] 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 includes a reduction in injection-related pain levels after administration of an SQ, IM or IP injection of an aqueous pharmaceutical formulation, the method comprising administering an aqueous pharmaceutical formulation of the present disclosure to the patient, wherein the administration step provides an improved injection-related pain level and / or provides a therapeutically favorable injection-related pain level. According to some embodiments, the aqueous pharmaceutical formulation consists essentially of an aqueous pharmaceutical formulation of the present disclosure. According to an embodiment, the reduction in injection-related pain levels includes providing an improved injection-related pain level (e.g., a reduced VAS score compared to a commercial formulation of ixekizumab, i.e., a citrate and NaCl formulation exemplified by the control formulation of Table 2). According to some embodiments, the method provides a therapeutically favorable injection-related pain level, including a VAS score of less than 30 mm or less than 20 mm. According to embodiments, the anti-IL17A antibody is ixekizumab, and according to some such embodiments, the improved injection-related pain level comprises a reduction in VAS score compared to a commercial formulation of ixekizumab (the citrate and NaCl formulations exemplified by the control formulations of Table 2). According to some embodiments, the aqueous pharmaceutical formulation is administered by SQ injection.

[0016] According to further embodiments of the present disclosure, an improved method for treating at least one of PsO, PsA, and AxSpa is provided, 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 an 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 formulations exemplified by the control formulations of Table 2).

[0017] The present disclosure also provides an aqueous pharmaceutical formulation of the present disclosure, which is used in therapy. In a specific embodiment, the present disclosure provides an aqueous pharmaceutical formulation of the present disclosure, which is used to treat rheumatoid arthritis (RA), psoriasis (Ps), genital psoriasis (GenPs), pruritus, ankylosing spondylitis (AS), psoriatic arthritis (PA), palmoplantar pustulosis (PPP), suppurative hidradenitis (HS) or multiple myeloma (MM). According to a further embodiment of the present disclosure, there is provided the use of an aqueous pharmaceutical formulation of the present disclosure for preparing a drug, the drug being used to treat RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM. According to such embodiments, the use of such aqueous pharmaceutical formulations is suitable for administration to patients SQ, IP and / or IM, and exhibits improved injection-related pain levels compared to commercial pharmaceutical formulations of ixekizumab and / or provides injection-related pain levels that are therapeutically advantageous.

[0018] According to a specific embodiment, the present disclosure provides a method for treating RA, Ps, GenPs, pruritus, AS, PA, PPP, HS or MM, comprising administering an effective amount of an aqueous pharmaceutical formulation of the present disclosure to a patient in need thereof, wherein the aqueous pharmaceutical formulation comprises an anti-IL17A antibody. In a more specific embodiment, this method of treatment comprises administering an initial dose of the aqueous pharmaceutical formulation subcutaneously to the patient on day 0, and then administering the aqueous pharmaceutical formulation subcutaneously to the patient at intervals of four weeks thereafter, wherein the aqueous pharmaceutical formulation administered to the patient at intervals of four weeks after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. In another specific embodiment, this method of treatment comprises administering an initial dose of the aqueous pharmaceutical formulation subcutaneously to the patient on day 0, and then administering the aqueous pharmaceutical formulation subcutaneously to the patient at intervals of two weeks thereafter, wherein the aqueous pharmaceutical formulation administered to the patient at intervals of two weeks after the initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. In yet another specific embodiment, this method of treatment comprises administering an initial dose of the aqueous pharmaceutical formulation subcutaneously to the patient on day 0, then administering the aqueous pharmaceutical formulation subcutaneously to the patient on each of days 14, 28, 42, 56, 70 and 84, and then administering the aqueous pharmaceutical formulation subcutaneously to the patient at intervals of every four weeks thereafter, wherein the aqueous pharmaceutical formulation administered to the patient on each of days 14, 28, 42, 56, 70 and 84 and every 4-week interval thereafter comprises an anti-IL17A antibody at a concentration of about 80 mg / mL. According to some methods of treatment provided by the present disclosure, the initial dose of the aqueous pharmaceutical formulation comprises about 160 mg of the anti-IL17A antibody. In some such embodiments, the initial dose of the aqueous pharmaceutical formulation of about 160 mg comprises two doses of the aqueous pharmaceutical formulation, each dose comprising about 80 mg of the anti-IL17A antibody. According to such methods, the aqueous pharmaceutical formulation exhibits improved injection-related pain levels and / or provides a therapeutically advantageous injection-related pain level compared to a commercial pharmaceutical formulation of ixekizumab.

[0019] According to a specific embodiment, provided herein is an aqueous pharmaceutical formulation comprising an anti-IL17A antibody for the treatment of 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 herein is a pharmaceutical formulation comprising an anti-IL17A antibody for the treatment of 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, a pharmaceutical formulation comprising an anti-IL17A antibody disclosed herein is provided for the treatment of 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 each on days 14, 28, 42, 56, 70 and 84, wherein the pharmaceutical formulation administered each on 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 the initial dose of about 160 mg comprises two doses of aqueous pharmaceutical formulation, each comprising about 80 mg of the anti-IL17A antibody. According to such embodiments, the aqueous pharmaceutical formulation provided herein exhibits improved injection-related pain levels and / or provides a therapeutically advantageous injection-related pain level compared to the commercial pharmaceutical formulation of ixekizumab.

[0020] As used interchangeably herein, the expression "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 agents such as citrate buffers, histidine buffers, acetate buffers, etc., or combinations thereof, which have acid-base conjugate components for resisting pH changes), aqueous stable formulations, wherein the extent of degradation, modification, aggregation, loss of biological activity, etc. of the therapeutic antibody therein is acceptably controlled and does not unacceptably increase over time.

[0021] 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 interspersed with more conserved regions, called framework regions ("FR"). Each HCVR and LCVR is composed of three CDRs and four FRs, which are arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable region of each HC and LC contains a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.

[0022] 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 referred to 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 IL17 cytokine family member, such as IL17F. The IL17A cytokine is believed to be produced primarily by effector T helper (Th17) cells and has been shown to induce the secretion of proinflammatory cytokines such as IL-6, IL-8, IL-1, and TNF. IL17A / A, a homodimeric complex form of IL17A, has been shown to play a role in diseases such as psoriasis and psoriatic arthritis (both immune-related diseases are associated with T cell dysregulation).

[0023] When referred to herein, such anti-IL17A antibodies are antibodies that specifically bind and antagonize human IL17A through specificity for the A subunit (e.g., the A subunit of IL17A / F or one or both of the A subunit of IL17A / A). According to specific embodiments of the anti-IL17A antibodies, 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 an anti-IL17A antibody is ixekizumab, as described, for example, in U.S. Pat. No. 7,838,638. An additional example of an anti-IL17A antibody is secukinumab (available under the trade name COSENTYX ® , sold herein), as described, for example, in U.S. Pat. No. 7,807,155.

[0024] As used herein, the term "about" or "approximately", when used with respect to a particular recited value or range of values, means that the value may vary from the recited value by no more than 10% (e.g., + / - 10%). For example, as used herein, the expression "about 100" includes 90 and 110 and all values ​​therebetween (e.g., 91, 92, 93, 94, etc.).

[0025] As referred to herein, the term "substantially free" or "substantially free" means that the presence of a given substance (eg, ionic tonicity excipient) is below the detection limit of the assay used to detect the presence of such substance.

[0026] The term "ionic tonicity excipient" as referred to herein refers to an excipient comprising 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 antibodies and surfactants that make up the aqueous pharmaceutical formulation. As is known in the art, ionic tonicity excipients can be used to adjust the osmotic pressure of the pharmaceutical formulation. However (and as provided in the Examples provided herein), adjusting the 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 tonicity excipient as used herein (because the addition of HCl or NaOH for adjusting the pH does not act as an ionic tonicity excipient in the formulation).

[0027] As referred to 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 a component of a therapeutic antibody).

[0028] As interchangeably mentioned herein, "visual analog scale" or "VAS" refers to an assessment tool for evaluating the injection-related pain experienced by patients. VAS consists of a 100 mm continuous scale, and patients identify their pain level after injection according to the scale. The VAS score extremes 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 mentioned herein, "injection-related pain" refers to the acute pain that a patient experiences when or shortly after injecting an aqueous pharmaceutical formulation. The desired properties of a stable pharmaceutical formulation are to be well tolerated by the patient, for example, to provide a therapeutically favorable injection-related pain level (e.g., <30 mm and / or <20 mm VAS score). As known, the components of the pharmaceutical formulation and their concentrations and / or ratios may affect the injection-related pain experienced by the patient.

[0029] As used interchangeably herein, "treatment" and / or "treating" and / or "treat" means all processes in which there may be complete elimination, mitigation or delay of a disease and / or its symptoms, reduction in severity or frequency (e.g., flare-ups or attacks), interruption or cessation of its progression, but complete elimination of all disease symptoms is not required. Treatment includes administration of the aqueous pharmaceutical formulations of the present disclosure for treating a disease in a human that would benefit from at least one of the processes listed above, including: (a) inhibiting further progression of disease symptoms and effects, i.e., arresting their development; (b) alleviating the disease, i.e., causing elimination or regression of the disease, disease symptoms, or complications thereof; and (c) preventing or reducing the frequency of disease attacks or flare-ups. 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.

[0030] As used interchangeably herein, the terms "patient," "subject," and "individual" refer to a human. Unless otherwise specified, the subject is further characterized as having, being at risk of developing, or experiencing symptoms of a disease that would benefit from the administration of a pharmaceutical formulation disclosed herein.

[0031] As used interchangeably herein, an "effective amount" or "therapeutically effective amount" of a pharmaceutical formulation of the present disclosure refers to the amount necessary (in terms of dosage, frequency of administration, and time period for a particular mode of administration) to achieve the desired therapeutic effect. The effective amount of a pharmaceutical formulation of the present disclosure may vary depending on factors such as the disease state, age, sex, and weight of the subject, and the ability of the pharmaceutical formulation of the present disclosure to elicit a desired response in the subject. An effective amount is also an amount in which the therapeutic beneficial effects outweigh any toxic or deleterious effects of the pharmaceutical formulation of the present disclosure.

[0032] The present disclosure also relates to dosage regimens for treating diseases with the pharmaceutical preparations of the present disclosure. As mentioned herein and as well known in the art, the term "dose" refers to the amount of the pharmaceutical preparation administered to a subject. As well known in the art and as interchangeably referred to herein, "dose regimen" or "dosage regimen" includes a treatment schedule for a group (i.e., a series or sequence) of dosages to be administered to a patient over a certain period of time.

[0033] By way of example, the dosage regimen of the present disclosure may 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 may be referred to herein as a "loading dose". In addition, the dosage regimen of the present disclosure may include an initial treatment period, sometimes referred to herein as an "induction period", which is after the loading dose. During the induction period, for example, a dose (or multiple doses) of a therapeutic antibody (e.g., an anti-IL17A antibody) containing a specific concentration may be administered to the patient at a given frequency of administration (e.g., every day, every 2 weeks, every 4 weeks, etc.) for a given duration (e.g., 4, 12, or 16 weeks). In addition, the dosage regimen of the present disclosure may include a period after the induction period, sometimes referred to herein as a "maintenance period", in which a dose of a therapeutic antibody containing a specific concentration is administered to the patient at a given frequency of administration (e.g., every 2 or 4 weeks, etc.).

[0034] The aqueous pharmaceutical formulations of the present disclosure can be administered to a patient via parenteral administration. Parenteral administration as understood in the medical art refers to injecting a dose into the body via a sterile syringe or some other drug delivery system, including an auto-injector or an infusion pump. Exemplary drug delivery systems for use with the aqueous drug formulations of the present disclosure are described in the following references, the disclosures of which are expressly incorporated herein by reference in their entireties: U.S. Patent Publication No. 2014 / 0054883 to Lanigan et al., filed on March 7, 2013, and entitled “Infusion Pump Assembly”; U.S. Patent No. 7,291,132 to DeRuntz et al., filed on February 3, 2006, and entitled “Medication Dispensing Apparatus with Triple Screw Threads for Mechanical Advantage”; U.S. Patent No. 7,517,334 to Jacobs et al., filed on September 18, 2006, and entitled “Medication Dispensing Apparatuswith Spring-Driven Locking Feature Enabled by Administration of Final Dose”; and U.S. Patent No. 8,734,394 to Adams et al., filed on August 24, 2012, and entitled “Automatic Injection Device with Delay Mechanism Including Dual Functioning Biasing Member". Parenteral routes include IM, SQ and IP administration routes. Example

[0035] Exemplary Aqueous Pharmaceutical Formulations

[0036] Table 1: Exemplary aqueous pharmaceutical formulations

[0037] 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

[0038] *Anti-IL17A antibody comprises the HCVR of SEQ ID NO: 8 and the LCVR of SEQ ID NO: 7.

[0039] The manufacturing process of the anti-IL17A antibody drug formulation presented in Table 1 can be completed by weighing an appropriate amount of water (e.g., at a temperature of 20+ / -5°C) into an empty container of appropriate size and tared. Add an appropriate amount of sucrose and mix. Polysorbate 80 is accurately weighed out in a glass container, and an appropriate amount of water at a temperature of 20+ / -5°C is added to the glass container to give the desired concentration, and the solution is mixed. The entire contents of the polysorbate 80 solution are added to the other excipients. The polysorbate 80 solution container is rinsed with water to ensure that the entire contents are transferred. After adding the polysorbate 80 solution, the solution is mixed. After dissolution and mixing have been completed, check that the pH of the solution is within 5.7+ / -0.3; if necessary, adjust with HCl or NaOH solution. The excipient composition is passed through a filter (polyvinylidene fluoride [PVDF]) to reduce bioburden.

[0040] The anti-IL17A antibody previously expressed in cells, purified and concentrated is mixed with the appropriate amount of formulation excipient solution. The pH of the solution is rechecked to be within 5.7 + / - 0.3. The drug formulation is passed through a PVDF filter for bioburden reduction and can then be stored at 5°C.

[0041] Physical-chemical properties

[0042] Both physical and chemical stability are essential for pharmaceutical formulations of therapeutic antibodies to allow storage and transportation (e.g., 1 year, 18 months, or 2 years) and maintain safety and effectiveness. Exemplary assessments for measuring the physical stability of pharmaceutical formulations include solubility (phase-separation, gelation) evaluation, molecular interactions (e.g., as measured by DLS), visual clarity (i.e., opalescence) characterization by turbidity evaluation, and viscosity measurement. In addition, chemical stability can be evaluated using various analytical methods, including size exclusion chromatography (SEC), cation exchange chromatography (CEX) HPLC, reduced and non-reduced capillary electrophoresis (CE-SDS R / NR), and particle analysis. As demonstrated herein, the exemplified anti-IL17A antibody pharmaceutical formulations of Table 1 show chemical and physical stability and solubility for the highly concentrated therapeutic antibody ixekizumab, which has an isoelectric point of ≥7.5, which is incompatible with formulations in the neutral pH of the solution.

[0043] Solubility evaluation:

[0044] Sufficiently high solubility is essential for aqueous pharmaceutical formulations. The aqueous pharmaceutical formulation must maintain high concentrations of antibodies in a monomeric state without high molecular weight (HMW) aggregation. The solubility of anti-IL17A antibodies with an isoelectric point ≥ 8.0 (in solution) at high concentrations was analyzed under different conditions.

[0045] Samples of each aqueous formulation provided in Table 2 were incubated at each of 5, 0, and -5 degrees Celsius (e.g., samples of each formulation can be incubated at 5, 0, and -5°C in parallel) for one week. The samples were evaluated for phase separation, gelation, turbidity, and viscosity after incubation.

[0046] Table 2: Preparation

[0047]

[0048] *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.

[0049] **In addition to the tested aqueous drug formulations listed in Table 2, an aqueous drug formulation comprising 10 mM acetate buffer, 150 mM NaCl, and 80 mg / mL anti-IL17A antibody, pH 5.0 was evaluated after incubation where unacceptable levels of antibody shearing were observed by non-reducing CD-SDS.

[0050] *** In addition, as described in US Patent No. 9,376,491, unacceptable turbidity points were observed for anti-IL17A antibodies at concentrations below 20 mM citrate buffer and 150 mM NaCl.

[0051] Phase separation :

[0052] As detailed in U.S. Pat. No. 9,376,491, the exemplary 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 solution 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. Pat. No. 9,376,491, increasing the citrate buffer and NaCl concentrations substantially reduces the temperature at which phase separation occurs. However, injection-related pain has been reported to be associated with formulations comprising increased citrate buffer and NaCl concentrations, and patients have reported injection-related pain after injection of commercial pharmaceutical formulations of ixekizumab.

[0053] The formulations provided in Table 2 were evaluated for phase separation by visually monitoring for signs of phase separation (eg, formation of a dense protein-rich layer at the bottom of the vial) after one week of incubation at -5°C.

[0054] Gelation :

[0055] At lower temperatures (5°C or lower), events such as thermodynamic solid phase changes (e.g., gelation) may occur, negatively affecting stability. As detailed in U.S. Pat. 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. Pat. No. 9,376,491 also shows that increasing the concentration of citrate buffer and NaCl is 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 injection of commercial pharmaceutical formulations of ixekizumab.

[0056] The gelling evaluations of the formulations provided in Table 2 are provided in Table 3. Briefly, after incubation as described above, each vial was agitated (eg, inverted and then returned to vertical) and then visually inspected for lack of coagulation or liquid flow.

[0057] Turbidity :

[0058] Turbidity (i.e., loss of clarity due to suspension of particulate matter) is an inherent challenge for aqueous pharmaceutical formulations of therapeutic antibodies. The challenge is exacerbated at high antibody concentrations and lower temperatures, which can cause formulations to fail visual inspection.

[0059] Briefly, after incubation as described above, turbidity was assessed visually (e.g., a light-based method using purified water as a comparator) and by a nephelometer (HACH turbidimeter, according to the manufacturer's instructions) that produces a quantitative measurement (NTU) (measurements performed at ambient temperature). Lower NTUs were desired; more specifically, NTU values ​​of less than 50 were desired, with a failure cutoff of 80 NTU. The results are provided in Table 3.

[0060] Viscosity :

[0061] For manufacturing, administration to patients and being tolerated by patients, acceptable aqueous pharmaceutical formulations must have appropriate viscosity. Subcutaneous delivery requires less viscous (at least <20 cP) aqueous solutions. The increase in therapeutic antibody concentration presents the challenge of increased viscosity. It is known that pharmaceutical formulations with NaCl have reduced viscosity, but as shown, the increase in NaCl concentration in the pharmaceutical formulation is associated with injection-related pain.

[0062] After incubation at 20°C, the viscosity of Formulation 1 and the control formulation of Table 2 was evaluated by a viscometer (Anton Paar AMVn viscometer, according to the manufacturer's instructions) that produces centipoise (cP) measurements. Lower cPs are desirable, especially for example <20 cP. The results are provided in Table 3.

[0063] Table 3: Solubility evaluation of the formulations in Table 2

[0064] <![CDATA[ Sample ID ]]> <![CDATA[ Phase separation evaluation ]]> <![CDATA[ Gelation evaluation ]]> <![CDATA[ Turbidity (NTUs)]]> <![CDATA[ Viscosity (cPs)]]> Comparison 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

[0065] As shown in Table 3, except for the preparation 1 that does not show phase separation, for all preparations lacking at least 150 mM NaCl (and NaCl bufferless preparations) (), unacceptable phase separation or gelation is observed. The phase separation result of preparation 1 is comparable to the control preparation (high citrate, high NaCl preparation). In addition, for the preparation comprising histidine buffer and NaCl (pH 6.5), unacceptable gelation is observed. Preparation 1 does not show gelation, and is comparable to the control preparation (high citrate, high NaCl preparation). In addition, unacceptable turbidity is observed for preparation 5 (citrate (5mM), NaCl (175mM)) and preparation 8 (histidine (9mM) and NaCl (150mM)). Preparation 1 shows acceptable turbidity levels, and compared with the control preparation (high citrate, high NaCl preparation), unexpectedly improved turbidity levels are provided. Further, as shown, both preparation 1 and the control preparation show acceptable and comparable viscosity.

[0066] Chemical stability:

[0067] Chemical stability is essential for developing aqueous pharmaceutical formulations that allow storage (i.e., adequate shelf life) while maintaining safety and efficacy. In an accelerated degradation study, the chemical stability of the comparative control and Formulation 1 (provided in Table 2) was evaluated after incubation for a period of 4 weeks at 25°C or 40°C. The change in % HMW aggregates was compared against % HMW aggregates at time 0.

[0068] In one evaluation, size exclusion chromatography (SEC) was used to evaluate changes in high molecular weight (HMW) aggregates in the formulations according to standard procedures. The results are provided in Table 4.

[0069] Table 4: Summary of changes in % HMW aggregates measured by SEC

[0070] Formulation # (from Table 2) Change in %HMW aggregates at 25°C Changes in %HMW aggregates at 40°C Comparison 0.25 0.05 1 0.49 0.43

[0071] As shown, both the control formulation and Formulation 1 of Table 2 exhibited acceptable and comparable chemical stability in the accelerated degradation study.

[0072] The additional accelerated chemical stability of the control and formulation 1 of Table 2 was studied using cation exchange (CEX) HPLC. In brief, the samples were incubated at 25°C for 4 weeks. After incubation, the samples were analyzed for an increase in the total % acidic variants (% AV) 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.

[0073] Table 5: Increase in % AV over 4 weeks at 25°C

[0074] Formulation # (from Table 2) % AV increase Comparison 2.0 1 2.3

[0075] As shown, in further accelerated degradation studies, both the control and Formulation 1 of Table 2 demonstrated acceptable and comparable levels of chemical stability.

[0076] Table 2 Multivariate evaluation of Formulation 1

[0077] As demonstrated herein, Formulation 1 of Table 2 provides unexpected stability comparable to (or improved upon) the control formulation of Table 2. A multivariate evaluation of the physical and chemical stability of Formulation 1 of Table 2 was performed as follows.

[0078] Briefly, the four variables (antibody concentration; pH; sucrose concentration; and PS-80 concentration) of Formulation 1 of Table 2 were modified to evaluate the physical and chemical stability responses of each variable and / or the interactions between the variables. Formulation 1 of Table 2 was set as the central point formulation for such experiments. The variant formulations are provided in Table 6.

[0079] Table 6: Variant Formulations

[0080] <![CDATA[ Sample ID ]]> <![CDATA[ sucrose ]]> <![CDATA[ PS-80 **]]> <![CDATA[ Anti-IL17A * Antibody ]]> <![CDATA[ pH ]]> Center point (Formulation 1 of 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

[0081] *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.

[0082] **Polysorbate tolerance ranges listed in Table 6 were confirmed by accelerated freeze-thaw studies.

[0083] Each variant formulation was evaluated for phase separation, gelation, and turbidity according to the above procedure. This multivariate evaluation provides identification of tolerance limits for the variables evaluated. No phase separation or gelation was observed, and acceptable turbidity values ​​were observed.

[0084] Long-term stability evaluation

[0085] Long-term stability of aqueous pharmaceutical formulations is required to demonstrate storage capability and adequate shelf life (e.g., 1 year, 2 years, or longer). The long-term stability of the center point formulations of Table 6 (which correspond to the formulations provided in Table 1 and Formulation 1 of Table 2) was evaluated after incubating 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 evaluations were also performed).

[0086] After incubation, the samples were analyzed for monomer percentage and high molecular weight (HMW) aggregate percentage using size exclusion chromatography (SEC) according to standard procedures. The results are provided in Table 7.

[0087] Table 7: Long-term stability evaluation of center-point formulations

[0088] 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

[0089] As provided, the center point formulations of Table 6 demonstrate long-term stability of the therapeutic antibodies, even under stress conditions at elevated temperatures for extended periods of time.

[0090] In vivo tolerance studies

[0091] Evaluation of injection-related pain from subcutaneous injections of high concentration (80 mg / mL) aqueous pharmaceutical formulations of ixekizumab was performed according to the following study in which subjects received an SQ injection of one of formulations A or B (as provided in Table 8) followed by an SQ injection of the other of formulations A or B after a period of time (e.g., 1, 5, 7, 10, 14 days, etc.). The subjects were then evaluated for injection-related pain based on the VAS scale score at designated 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).

[0092] Table 8: Ixekizumab Drug Formulations

[0093]

[0094] Therefore, 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 drug formulation containing 80 mg / ml ixekizumab according to the following injection schedule, as listed in Table 8.

[0095] Treatment group 1 received a single dose of formulation B, followed by a single dose of formulation A 7 days later. Treatment group 2 received a single dose of formulation A by SQ injection, followed by a single dose of formulation B by SQ injection 14 days later. The injection was performed by medical staff in the abdomen of the subject while the subject was in a sitting or reclining position. Subsequent injections can alternate between abdominal quadrants. Evaluation of injection-related pain based on VAS scale scores was performed immediately after each injection (e.g., within 1 minute) and 10 minutes after injection. The results are provided in Tables 9 and 10 below.

[0096] Table 9: Comparative data on injection-related pain

[0097] .

[0098] As shown in Table 9, Formulation A provided a significant reduction in VAS scores compared to Formulation B (the commercially available Taltz® formulation) both immediately after injection and at 10 minutes after injection.

[0099] Table 10. Analysis of patient tolerance

[0100] .

[0101] As shown in Table 10, Formulation A provided significant improvement in patients not experiencing injection-related pain immediately following injection as well as a significant benefit in reducing patients experiencing moderate to severe injection-related pain immediately following injection compared to Formulation B (the commercially available Taltz® formulation).

[0102] In vivo pharmacokinetic analysis

[0103] The pharmacokinetic analysis of the aqueous pharmaceutical formulation of ixekizumab can be performed according to the following study, in which the subjects receive an SQ injection of one of the formulations A or B (as provided in Table 8). The pharmacokinetic analysis of the subjects is then evaluated at different time points (e.g., before the SQ injection and then after the SQ injection, such as 1-24 hours, 1-90 days after injection).

[0104] Therefore, a single dose, subject-blind, randomized, parallel design study was conducted, wherein, on the 1st day, subjects were randomized to one of the two treatment groups. Before receiving treatment (e.g., on the 1st day, before administration), pre-dose samples were obtained from patients in the two treatment groups for pharmacokinetic properties evaluation. On the 1st day, treatment group 1 received a single SQ injection of preparation A, and treatment group 2 received a single subcutaneous injection of preparation B (as described in Table 8). Medical personnel can implement injections in the abdomen of subjects. After administration, samples were obtained at the 3rd, 5th (± 1 day), 8th (± 1 day), 11th (± 1 day), 15th (± 2 days), 22th (± 2 days), 29th (± 2 days), 43rd (± 2 days), 57th (± 3 days), 71st (± 3 days) and 85th (± 3 days) of the study to evaluate pharmacokinetic parameters, including Cmax (maximum observed drug concentration), AUC[0-∞] (area under the concentration to time curve from zero time to infinity), AUC[0-t 最后 The results are provided in Table 11.

[0105] Table 11: In vivo pharmacokinetic analysis

[0106]

[0107] As shown in Table 11, Formulation A exhibited a P value comparable to Formulation B (the commercially available Taltz® formulation). KIn addition, no serious adverse events were reported for either formulation, and the overall safety profile was consistent and comparable to that of formulation B.

[0108] Target Neutralization Evaluation

[0109] After incubation of samples of formulation A at 5°C for 1, 6 and 12 months; at 25°C for 1 month; and at 35°C for 1 month, the efficacy of formulation A was evaluated by cell-based bioassay compared with formulation B (Table 8). In brief, the mouse osteoblast cell line MC3T3-E1, which endogenously expresses the IL-17A receptor and stably expresses the firefly luciferase gene, was cultured so that when IL-17A is present, the transcription of luciferase is induced at a level proportional to the activity of IL-17A. Samples of formulations A and B previously incubated were introduced into the culture wells of the cell-based bioassay, respectively, and after measuring luciferase expression, an inhibitory dose curve was generated. The data were analyzed using a four-parameter logistic curve fit. The EC of formulation A was calculated by 50 Compared to the EC of formulation B (e.g., reference standard) 50 The relative efficacy was determined by the ratio of . The results are provided in Table 12.

[0110] Table 12: Relative efficacy evaluation of formulation A (% relative to formulation B)

[0111]

[0112] As shown in Table 12, Formulation A demonstrated comparable target neutralization levels to Formulation B (the commercially available Taltz® formulation) after long-term storage and under stress conditions.

[0113] sequence

[0114] SEQ ID NO: 1 (LCDR1 of an exemplary anti-IL17A antibody)

[0115]

[0116] SEQ ID NO: 2 (LCDR2 of an exemplary anti-IL17A antibody)

[0117]

[0118] SEQ ID NO: 3 (LCDR3 of an exemplary anti-IL17A antibody)

[0119]

[0120] SEQ ID NO: 4 (HCDR1 of an exemplary anti-IL17A antibody)

[0121]

[0122] SEQ ID NO: 5 (HCDR2 of an exemplary anti-IL17A antibody)

[0123]

[0124] SEQ ID NO: 6 (HCDR3 of an exemplary anti-IL17A antibody)

[0125]

[0126] SEQ ID NO: 7 (LCVR of an exemplary anti-IL17A antibody)

[0127]

[0128] SEQ ID NO: 8 (HCVR of an exemplary anti-IL17A antibody)

[0129]

[0130] SEQ ID NO: 9 (light chain of an exemplary anti-IL17A antibody)

[0131]

[0132] SEQ ID NO: 10 (heavy chain of an exemplary anti-IL17A antibody)

[0133] Sequence Listing <110> ELI LILLY AND COMPANY <120> Therapeutic antibody preparations <130> X22251 <150> 62 / 807,006 <151> 2019-02-27 <150> 62 / 880,846 <151> 2019-08-05 <150> 62 / 947,198 <151> 2019-12-18 <150> PCT / US2020 / 017594 <151> 2020-02-11 <160> 10 <170> PatentIn version 3.5 <210> 1 <211> 16 <212> PRT <213> Artificial sequence <220> <223> LCDR1 <400> 1 Arg Ser Ser Arg Ser Leu Val His Ser Arg Gly Asn Thr Tyr Leu His 1 5 10 15 <210> 2 <211> 7 <212> PRT <213> Artificial sequence <220> <223> LCDR2 <400> 2 Lys Val Ser Asn Arg Phe Ile 1 5 <210> 3 <211> 9 <212> PRT <213> Artificial sequence <220> <223> LCDR3 <400> 3 Ser Gln Ser Thr His Leu Pro Phe Thr 1 5 <210> 4 <211> 10 <212> PRT <213> Artificial sequence <220> <223> HCDR1 <400> 4 Gly Tyr Ser Phe Thr Asp Tyr His Ile His 1 5 10 <210> 5 <211> 17 <212> PRT <213> Artificial sequence <220> <223> HCDR2 <400> 5 Val Ile Asn Pro Met Tyr Gly Thr Thr Asp Tyr Asn Gln Arg Phe Lys 1 5 10 15 Gly <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 6 Tyr Asp Tyr Phe Thr Gly Thr Gly Val Tyr 1 5 10 <210> 7 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> LCVR <400> 7 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Val His Ser 20 25 30 Arg Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ile Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser 85 90 95 Thr His Leu Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 8 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> HCVR <400> 8 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr 20 25 30 His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Asn Pro Met Tyr Gly Thr Thr Asp Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Asp Tyr Phe Thr Gly Thr Gly Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 9 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Light Chain <400> 9 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Arg Ser Leu Val His Ser 20 25 30 Arg Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ile Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser 85 90 95 Thr His Leu Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 10 <211> 445 <212> PRT <213> artificial sequence <220> <223> Heavy chain <400> 10 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr 20 25 30 His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Asn Pro Met Tyr Gly Thr Thr Asp Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Asp Tyr Phe Thr Gly Thr Gly Val Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445

Claims

1. An unbuffered aqueous pharmaceutical formulation comprising: (i) anti-IL-17A antibody at a concentration of 80 mg / mL + / - 10%; (ii) sucrose at a concentration of 234 mM + / - 10%; and (iii) a surfactant at a concentration between 0.005% w / v + / - 10% and 0.05% w / v + / - 10%, wherein the surfactant is polysorbate 20 or polysorbate 80, in, The pharmaceutical formulation is an aqueous solution with a pH between 5.2 and 6.5, the pharmaceutical formulation is substantially free of ionic tonicity excipients and the anti-IL17A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), 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.

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

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

4. The unbuffered aqueous pharmaceutical formulation of claim 1, 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.

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

6. Use of the unbuffered aqueous pharmaceutical formulation of claim 1 for the preparation of a medicament for carrying out a method of treating rheumatoid arthritis, psoriasis, genital psoriasis, pruritus, ankylosing spondylitis, psoriatic arthritis, palmoplantar pustulosis, hidradenitis suppurativa, or multiple myeloma, comprising administering an effective amount of the unbuffered aqueous pharmaceutical formulation of claim 1 to a patient in need thereof.

7. The method of claim 6, 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 four-week intervals thereafter, wherein the pharmaceutical formulation administered to said patient at four-week intervals after said initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL.

8. The method of claim 6, 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 said patient at two-week intervals after said initial dose comprises an anti-IL17A antibody at a concentration of about 80 mg / mL.

9. The method of claim 6, wherein the method comprises: administering an initial dose of the pharmaceutical formulation subcutaneously to the patient on day 0, subsequently administering the pharmaceutical formulation subcutaneously to the patient on each of days 14, 28, 42, 56, 70, and 84, and subsequently administering the pharmaceutical formulation subcutaneously to the patient at four-week intervals thereafter, wherein the pharmaceutical formulation administered to the patient on each of days 14, 28, 42, 56, 70 and 84 and every 4-week interval thereafter comprises an anti-IL17A antibody at a concentration of about 80 mg / mL.

10. The use of claim 9, wherein the initial dose of the pharmaceutical formulation comprises about 160 mg of the anti-IL17A antibody.

11. The use of claim 10, wherein the initial dose of about 160 mg of the pharmaceutical preparation comprises two doses of the pharmaceutical preparation, each dose comprising about 80 mg of the anti-IL17A antibody.

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

13. The use of claim 12, wherein the therapeutically favorable injection-related pain level comprises a VAS score of less than 30 mm or less than 20 mm.

14. The use of claim 12, wherein the anti-IL17A antibody is ixekizumab.

15. The use of claim 6, wherein the unbuffered aqueous pharmaceutical formulation is substantially free of L-amino acid excipients and the surfactant is polysorbate 80.

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