Anti-FEL D1 antibody preparation

Abstract

The present disclosure provides pharmaceutical formulations comprising one or more antibodies or antigen-binding fragments thereof that bind to the cat allergen Fel d1. In addition to the anti-Fel d1 antibodies, the formulations may include a buffer, a heat stabilizer, a viscosity-reducing agent, and a surfactant. In one aspect, a co-formulation comprising two anti-Fel d1 antibodies with acceptable stability and optimal viscosity is provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 487,791, filed March 1, 2023, the contents of which are incorporated herein by reference.

[0002] Sequence Listing An official copy of the Sequence Listing will be submitted electronically via the Patent Center contemporaneously with the present specification. The contents of the electronic Sequence Listing (10852WO01_Sequence_Listing_ST26.xml, size: 32,768 bytes, and created on February 29, 2024) are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION The present disclosure relates to therapeutic antibody formulations. More specifically, the present disclosure relates to the field of pharmaceutical formulations comprising one or more human antibodies that specifically bind to the cat allergen Fel d1. [Background technology]

[0004] background Cat allergens are one of the most important indoor allergens and a common cause of IgE-mediated allergic diseases worldwide. The most dominant cat allergen is Felis domesticus allergen 1 (Fel d1), and it is estimated that approximately 90% to 95% of cat-allergic individuals are sensitized to Fel d1 (van Ree et al., J. Allergy Clin. Immunol. 1999, 104:1223-1230). Fel d1 is produced by cat skin and salivary and lacrimal glands (Kleine-Tebbe et al., Int Arch Allergy Immunol. 1993, 100:256-62). Dried saliva and dander are dispersed from cat hair into the surrounding environment as small airborne particles that readily adhere to surfaces such as walls, carpets, and furniture. Although the highest amounts of Fel d1 allergen are found in homes with cats, the allergen can also be carried into cat-free areas such as cars, schools, and homes, where it can persist for months to years (see, e.g., Neisler et al., Aerobiologia 2016, 32:571-580 (Non-Patent Document 3)). Fel d1 is therefore an attractive therapeutic target for the treatment of patients with cat allergies. Antibodies against Fel-d1 are described, for example, in U.S. Patent Nos. 9,079,948 (Patent Document 1), 10,047,153 (Patent Document 2), and 11,174,305 (Patent Document 3).

[0005] Therapeutic macromolecules, such as antibodies, must be formulated in a manner that not only makes the molecule suitable for administration to patients but also maintains its stability during storage. For example, therapeutic antibodies in liquid solution are prone to degradation, aggregation, and / or undesirable chemical modification unless the solution is properly formulated. The stability of antibodies in liquid formulations depends not only on the types of excipients used in the formulation but also on the amounts and ratios of the excipients relative to each other. Furthermore, other considerations besides stability must be taken into account when preparing liquid antibody formulations. Examples of such additional considerations include the solution viscosity and antibody concentration that can be accommodated by a given formulation, as well as the visual quality or appeal of the formulation. Co-formulation of two or more therapeutic antibodies in the same formulation is even more challenging, as each antibody may have very different requirements for suitable pH, excipients, and / or ionic strength. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 9,079,948 [Patent Document 2] U.S. Patent No. 10,047,153 [Patent Document 3] U.S. Patent No. 11,174,305 [Non-patent literature]

[0007] [Non-Patent Document 1] van Ree et al.,J.Allergy Clin.Immunol.1999,104:1223-1230 [Non-patent document 2] Kleine-Tebbe et al.,Int Arch Allergy Immunol 1993,100:256-62 [Non-patent document 3] Neisler et al.,Aerobiologia 2016,32:571-580 Summary of the Invention

[0008] overview In one aspect, a stable liquid pharmaceutical formulation is provided comprising at least one antibody that specifically binds to Fel d1. In some embodiments, the formulation comprises: (a)(i) an antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14; and (ii) an antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. at least one antibody that specifically binds to Fel d1 selected from the group consisting of: (b) a buffer containing histidine; (c) a heat stabilizer; (d) surfactants and and has a pH of 6.0±0.3.

[0009] In some embodiments, the stable liquid pharmaceutical formulation comprises (i) a first antibody that specifically binds to Fel d1, the first antibody comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 4, an HCDR2 having the amino acid sequence of SEQ ID NO: 6, an HCDR3 having the amino acid sequence of SEQ ID NO: 8, an LCDR1 having the amino acid sequence of SEQ ID NO: 12, an LCDR2 having the amino acid sequence AAS, and an LCDR3 having the amino acid sequence of SEQ ID NO: 14, and (ii) a second antibody that specifically binds to Fel d1, the second antibody comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 18, an HCDR2 having the amino acid sequence of SEQ ID NO: 20, an HCDR3 having the amino acid sequence of SEQ ID NO: 22, an LCDR1 having the amino acid sequence of SEQ ID NO: 26, an LCDR2 having the amino acid sequence KAS, and an LCDR3 having the amino acid sequence of SEQ ID NO: 28.

[0010] In some embodiments, the first antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:10.

[0011] In some embodiments, the second antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO:16 and an LCVR comprising the amino acid sequence of SEQ ID NO:24.

[0012] In some embodiments, the total antibody concentration is up to 200 mg / mL (e.g., up to 50 mg / mL, up to 100 mg / mL, or up to 150 mg / mL). In some embodiments, the total antibody concentration is between 5 mg / mL and 200 mg / mL. In some embodiments, the total antibody concentration is between 50 mg / mL and 200 mg / mL. In some embodiments, the total antibody concentration is 150 mg / mL ± 15 mg / mL. In some embodiments, the formulation comprises two antibodies, wherein the first antibody and the second antibody are present in the formulation at a molar ratio of 1:1 or about 1:1. In some embodiments, the first antibody is present at a concentration of 75 mg / mL ± 7.5 mg / mL and the second antibody is present at a concentration of 75 mg / mL ± 7.5 mg / mL.

[0013] In some embodiments, the buffer contains histidine at a concentration of 5 mM to 25 mM.

[0014] In some embodiments, histidine is present at a concentration of 10 mM±2 mM.

[0015] In some embodiments, the thermal stabilizer comprises sucrose, trehalose, proline, or sorbitol.

[0016] In some embodiments, the thermal stabilizer comprises sucrose at a concentration of 2.5% w / v to 7.5% w / v, hi some embodiments, the sucrose is present at a concentration of 5% w / v ± 1% w / v.

[0017] In some embodiments, the stable liquid pharmaceutical formulation further comprises a viscosity-lowering agent.

[0018] In some embodiments, the viscosity-lowering agent comprises arginine. In some embodiments, arginine is present at a concentration of 60 mM to 130 mM. In some embodiments, arginine is present at a concentration of at least 70 mM. In some embodiments, arginine is present at a concentration of 70 mM ± 14 mM.

[0019] In some embodiments, the surfactant comprises polysorbate 20 or polysorbate 80. In some embodiments, polysorbate 20 or polysorbate 80 is present at a concentration of 0.05% w / v to 0.25% w / v, e.g., 0.05% w / v to 0.2% w / v, or 0.075% w / v to 0.2% w / v. In some embodiments, the surfactant comprises polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v.

[0020] In some embodiments, the stable liquid pharmaceutical formulation comprises: histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Arginine at a concentration of 70 mM ± 14 mM; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v wherein the total antibody concentration is 150 mg / mL ± 15 mg / mL and the formulation has a pH of 6.0 ± 0.3.

[0021] In some embodiments, the stable liquid pharmaceutical formulation has a viscosity of ≦30 cP at 20° C. In some embodiments, the stable liquid pharmaceutical formulation has a viscosity of ≦25 cP at 20° C. In some embodiments, the stable liquid pharmaceutical formulation has a viscosity of ≦20 cP at 20° C. In some embodiments, the stable liquid pharmaceutical formulation has a viscosity of ≦15 cP at 20° C.

[0022] In some embodiments, the stable liquid pharmaceutical formulation comprises: an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the antibody concentration is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Arginine at a concentration of 70 mM ± 14 mM; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v and has a pH of 6.0±0.3.

[0023] In some embodiments, the stable liquid pharmaceutical formulation comprises: an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the antibody concentration is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Polysorbate 20 or polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v and has a pH of 6.0±0.3.

[0024] In some embodiments, the stable liquid pharmaceutical formulation further comprises a viscosity-lowering agent, hi some embodiments, the viscosity-lowering agent is arginine at a concentration of 70 mM ± 14 mM.

[0025] In some embodiments, the stable liquid pharmaceutical formulation comprises: a first antibody that specifically binds to Fel d1, the first antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the concentration of the first antibody is 75 mg / mL ± 10 mg / mL; a second antibody that specifically binds to Fel d1, the second antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the concentration of the second antibody is 75 mg / mL ± 10 mg / mL; histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Arginine at a concentration of 70 mM ± 14 mM; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v and has a pH of 6.0±0.3.

[0026] In some embodiments, the stable liquid pharmaceutical formulation is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector delivery device. In some embodiments, the stable liquid pharmaceutical formulation is contained in a large volume device or a bolus injector.

[0027] In another aspect, a container containing a stable liquid pharmaceutical formulation described herein is provided.

[0028] In yet another aspect, kits are provided. In some embodiments, the kit comprises: (i) a container containing a stable liquid pharmaceutical formulation described herein; (ii) Labeling for use of pharmaceutical preparations; In some embodiments, the labeling describes subcutaneous or intravenous administration of the pharmaceutical formulation.

[0029] In some embodiments, the kit comprises: (a) an antibody that specifically binds to Fel d1, comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14; (b) a buffer containing histidine; (c) a heat stabilizer; (d) surfactants and wherein the formulation has a pH of 6.0±0.3.

[0030] In some embodiments, the kit comprises an antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO:2 and an LCVR comprising the amino acid sequence of SEQ ID NO:10.

[0031] In some embodiments, the kit comprises: an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the antibody concentration is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v wherein the formulation has a pH of 6.0±0.3.

[0032] In some embodiments, the kit comprises: (a) an antibody that specifically binds to Fel d1, comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; (b) a buffer containing histidine; (c) a heat stabilizer; (d) surfactants and wherein the formulation has a pH of 6.0±0.3.

[0033] In some embodiments, the kit comprises an antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO:16 and an LCVR comprising the amino acid sequence of SEQ ID NO:24.

[0034] In some embodiments, the kit comprises: an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the antibody concentration is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Polysorbate 20 or polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v wherein the formulation has a pH of 6.0±0.3.

[0035] In some embodiments, the kit comprises the stable liquid pharmaceutical formulation described above and further comprises a viscosity-lowering agent, hi some embodiments, the viscosity-lowering agent is arginine at a concentration of 70 mM ± 14 mM.

[0036] In some embodiments, the kit comprises: a first antibody that specifically binds to Fel d1, the first antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the concentration of the first antibody is 75 mg / mL ± 10 mg / mL; a second antibody that specifically binds to Fel d1, the second antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the concentration of the second antibody is 75 mg / mL ± 10 mg / mL; histidine at a concentration of 10 mM ± 2 mM; sucrose at a concentration of 5% w / v ± 1% w / v; Arginine at a concentration of 70 mM ± 14 mM; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v wherein the formulation has a pH of 6.0±0.3.

[0037] Other embodiments will be apparent from consideration of the detailed description that follows. [Brief explanation of the drawings]

[0038] [Figure 1A] Percentage increase in HMW species for formulations of 150 mg / mL REGN1908 (■) or REGN1909 (◆) in 10 mM histidine buffer at different pH after 28 days of incubation at 45°C. [Figure 1B] Percentage increase in HMW species for formulations of 150 mg / mL REGN1908 (■) or REGN1909 (◆) in 10 mM histidine buffer at different pH after 2 months of incubation at 25°C. [Figure 2] Viscosity (cP at 20°C) of 150 mg / mL REGN1908 (■) or REGN1909 (●) formulations in 10 mM histidine buffer at different pH. [Figure 3] Viscosity (cP at 20°C) of formulations containing 10 mM histidine, pH 6.0, and different concentrations of REGN1908 (■) or REGN1909 (●). [Figure 4] Effect of excipients on viscosity (cP at 20°C) for formulations containing REGN1908 or REGN1909 at a target concentration of 150 mg / mL and either 10 mM histidine pH 6.0, 10 mM histidine pH 6.0 + 70 mM arginine, 100 mM histidine pH 6.0, 10 mM histidine pH 6.0 + 3% proline, or 10 mM histidine pH 6.0 + 70 mM NaCl. [Figure 5] Effect of the cryoprotectant sucrose on viscosity (cP at 20° C.) for formulations containing REGN1908 (◆) or REGN1909 (■) at a target concentration of 150 mg / mL, 10 mM histidine, pH 6.0. [Figure 6]Effect of viscosity-reducing agents and cryoprotectants on viscosity (cP at 20°C) for formulations containing REGN1908, 10 mM, pH 6.2 at a target concentration of 150 mg / mL in the absence of viscosity-reducing agents and cryoprotectants, or in the presence of 70 mM arginine + 5% sucrose. [Figure 7A] Average viscosity (mPa-s / cP) of formulations containing REGN1908 at a target concentration of 150 mg / mL, 10 mM histidine, 5% sucrose, pH 6.1, with different amounts of the viscosity-lowering agent arginine. [Figure 7B] Average viscosity (mPa-s / cP) of formulations containing REGN1909 at a target concentration of 150 mg / mL, 10 mM histidine, 5% sucrose, pH 6.1, with different amounts of the viscosity-lowering agent arginine. [Figure 7C] Average viscosity (mPa-s / cP) of formulations containing a target concentration of 150 mg / mL total antibody (REGN1908 + REGN1909), 10 mM histidine, 5% sucrose, pH 6.1, with different amounts of the viscosity-lowering agent arginine. [Figure 8A] REGN1908-REGN1909 co-formulations containing no polysorbate 20 (PS20) or 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, or 0.2% (w / v) PS20 were evaluated in a stirring assay for aggregation inhibition, measured by the percent change in HMW at 0 hours (●), 24 hours (▲), or 48 hours (▼). Inset graph = expanded / exploded view of the data, allowing visualization of the minimum amount of PS20 surfactant required to result in little or no change in the percent HMW species (aggregates). LSL = lower specification limit. [Figure 8B]REGN1908-REGN1909 co-formulations containing no polysorbate 80 (PS80) or 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, or 0.2% (w / v) PS80 were evaluated in a stirring assay for aggregation inhibition, measured by the percent change in HMW at 0 hours (●), 24 hours (▲), or 48 hours (▼). Inset graph = expanded / exploded view of the data, allowing visualization of the minimum amount of PS80 surfactant required to result in little or no change in the percent HMW species (aggregates). LSL = lower specification limit. [Figure 9] Subvisible particle formation was assessed using microfluidic imaging (>10 μM and >25 μM) at 0 or 48 hours for REGN1908-REGN1909 co-formulations without polysorbate 20 (PS20) or polysorbate 80 (PS80), or with 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, or 0.2% (w / v) PS20 or PS80. [Figure 10A] Accelerated stability testing for co-formulations containing REGN1908-REGN1909 (150 mg / mL total antibody), 10 mM histidine, 70 mM arginine, 0.15% (w / v) polysorbate 20, pH 6.0, and either 2.5% sorbitol (●), 3% proline (▲), 5% sucrose (▼), 5% trehalose (■), or no cryoprotectant (◆). [Figure 10B] Freeze / thaw stability studies on co-formulations containing REGN1908-REGN1909 (150 mg / mL total antibody), 10 mM histidine, 70 mM arginine, 0.15% (w / v) polysorbate 20, pH 6.0, and either 2.5% sorbitol (●), 3% proline (▲), 5% sucrose (▼), 5% trehalose (■), or no cryoprotectant (◆). [Figure 10C]Accelerated stability testing for co-formulations containing REGN1908-REGN1909 (150 mg / mL total antibody), 10 mM histidine, 70 mM arginine, 0.15% (w / v) polysorbate 80, pH 6.0, and either 2.5% sorbitol (●), 3% proline (▲), 5% sucrose (▼), 5% trehalose (■), or no cryoprotectant (◆). [Figure 10D] Freeze / thaw stability studies on co-formulations containing REGN1908-REGN1909 (150 mg / mL total antibody), 10 mM histidine, 70 mM arginine, 0.15% (w / v) polysorbate 80, pH 6.0, and either 2.5% sorbitol (●), 3% proline (▲), 5% sucrose (▼), 5% trehalose (■), or no cryoprotectant (◆). [Figure 11] Thermal profiler demonstrates predicted formulation response at 40 °C depending on a range of formulation components. Columns illustrate formulation components: REGN1908-REGN1909 concentration (135 mg / mL - 165 mg / mL), pH (5.5 - 6.5), histidine (6 mM - 14 mM), polysorbate 80 (0.075% - 0.2% w / v), arginine (42 mM - 98 mM), and sucrose (3% - 7% w / v). Rows illustrate predicted responses of formulation attributes: change in total protein recovery (%), change in total HMW fraction (%), change in total acidic species fraction (%), change in total basic species fraction (%), change in particle formation (10 micron bins), and change in particle formation (25 micron bins). [Figure 12] The Agitation Profiler demonstrates the predicted formulation response under agitation stress as a function of a range of formulation components. Columns illustrate the formulation components: REGN1908-REGN1909 concentration (135 mg / mL to 165 mg / mL), pH (5.5 to 6.5), histidine (6 mM to 14 mM), polysorbate 80 (0.075% to 0.2% w / v), arginine (42 mM to 98 mM), and sucrose (3% to 7% w / v). Rows illustrate the predicted response of formulation attributes: change in total protein recovery (%), change in total HMW fraction (%), change in particle formation (10 micron bins), and change in particle formation (25 micron bins). [Figure 13] The freeze-thaw profiler demonstrates the predicted formulation response under freeze-thaw stress as a function of a range of formulation components. Columns illustrate the formulation components: REGN1908-REGN1909 concentration (135 mg / mL - 165 mg / mL), pH (5.5 - 6.5), histidine (6 mM - 14 mM), polysorbate 80 (0.075% - 0.2% w / v), arginine (42 mM - 98 mM), and sucrose (3% - 7% w / v). Rows illustrate the predicted response of formulation attributes: change in total protein recovery (%), change in total HMW fraction (%), change in particle formation (10 micron bins), and change in particle formation (25 micron bins). [Figure 14] The T=0 Profiler demonstrates predicted viscosity and osmolality responses as a function of a range of formulation components. Columns illustrate formulation components: REGN1908-REGN1909 concentration (135 mg / mL to 165 mg / mL), pH (5.5 to 6.5), histidine (6 mM to 14 mM), polysorbate 80 (0.075% to 0.2% w / v), arginine (42 mM to 98 mM), and sucrose (3% to 7% w / v). Rows illustrate predicted responses of formulation attributes: viscosity at t=0, and osmolality concentration at t=0. DETAILED DESCRIPTION OF THE INVENTION

[0039] Detailed Description definition Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0041] As used herein, the term "about," when used in reference to a specific recited numerical value, means that the value may vary by no more than 1% from the recited value. For example, as used herein, the phrase "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0042] As used herein, the phrase "pharmaceutical formulation" refers to a combination of at least one active ingredient (e.g., an antibody, a small molecule, a compound, etc., capable of exerting a biological effect in a human or non-human animal) and at least one inactive ingredient that, when combined with the active ingredient and / or one or more additional inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. As used herein, the term "formulation" refers to a "pharmaceutical formulation" unless otherwise indicated. The present disclosure provides pharmaceutical formulations comprising at least one therapeutic polypeptide. According to certain embodiments of the present disclosure, the therapeutic polypeptide is an antibody or antigen-binding fragment thereof that specifically binds to Fel d1. In some embodiments, the present disclosure includes pharmaceutical formulations comprising: (i) one or more human antibodies that specifically bind to Fel d1; (ii) one or more buffers; (iii) a thermostabilizer; (iv) a viscosity-lowering agent; and, optionally, (v) a surfactant. In some embodiments, the present disclosure includes a pharmaceutical formulation comprising (i) one or more human antibodies that specifically bind to Fel d1, (ii) one or more buffers, (iii) a thermostabilizer, (iv) a surfactant, and optionally (v) a viscosity-lowering agent. In one particular embodiment, the pharmaceutical formulation comprises (i) two human antibodies, each specifically binding to Fel d1, (ii) one or more buffers, (iii) a thermostabilizer, (iv) a viscosity-lowering agent, and (v) a surfactant. Additional components may be included in the formulations of the present disclosure if such components do not significantly interfere with the viscosity and stability of the formulation. Certain exemplary components and formulations included in the present disclosure are described in detail below.

[0043] The term "excipient" as used herein means any non-therapeutic agent added to a formulation to provide a desired consistency, viscosity, or stabilizing effect.

[0044] In certain embodiments, the pharmaceutical formulation of the present disclosure may be a fluid formulation. As used herein, the term "fluid formulation" refers to a mixture of at least two components that exists primarily in a fluid state at about 2°C to about 45°C. Fluid formulations include, among others, liquid formulations. Fluid formulations may be low, medium, or high viscosity, depending on the specific components.

[0045] The term "antibody" as used herein refers to an antigen-binding molecule or molecular complex comprising a set of complementarity-determining regions (CDRs) that specifically bind to or interact with a particular antigen (e.g., Fel d1). The term "antibody" as used herein includes immunoglobulin molecules, and multimers thereof (e.g., IgM), which comprise four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. In a typical antibody, each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or V H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (herein referred to as LCVR or V L The light chain constant region comprises one domain (C L 1) V H Area and V L The regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). H and V Lis composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an antibody (or antigen-binding portion thereof) can be identical to human germline sequences or can be naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0046] Unless specifically indicated otherwise, the term "antibody," as used herein, also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, "antigen-binding domain" of an antibody, and equivalents include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions (e.g., isolated complementarity-determining regions (CDRs) such as CDR3 peptides) of an antibody, or a constrained FR3-CDR3-FR4 peptide. Domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the expression "antigen-binding fragment" as used herein.

[0047] The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may nevertheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), e.g., in the CDRs, particularly CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0048] The term "recombinant antibody," as used herein, is intended to encompass all antibodies that are prepared, expressed, created, or isolated by recombinant means. This term includes, but is not limited to, antibodies expressed using a recombinant expression vector transfected into a host cell (e.g., Chinese hamster ovary (CHO) cell) or cellular expression system, antibodies isolated from a recombinant combinatorial human antibody library, and non-human animals (e.g., mice, such as mice transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295). In some embodiments, the recombinant antibody is a recombinant human antibody. In some embodiments, the recombinant human antibody has variable and constant domains derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used), thus modifying the V and V sequences of the recombinant antibody. H and V L The amino acid sequence of the region is human germline V H Sequence and V L These are sequences that are derived from and related to sequences, but that may not naturally occur within the human antibody germline repertoire in vivo.

[0049] An "isolated antibody" means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0050] The term "specifically binds" or equivalent means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding is defined as binding to an antigen with a specific binding affinity of at least about 1 x 10 -6 M or less, e.g., 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 can be characterized by an equilibrium dissociation constant of M (e.g., a smaller K D indicates tighter binding). Methods for determining whether an antibody specifically binds to an antigen are known in the art and include, for example, equilibrium dialysis, surface plasmon resonance (e.g., BIACORE™), biolayer interferometry assays (e.g., Octet® HTX biosensor), solution affinity ELISA, and the like. In some embodiments, specific binding is measured in a surface plasmon resonance assay, e.g., at 25°C or 37°C. An antibody or antigen-binding fragment that specifically binds to an antigen from one species may or may not have cross-reactivity to other antigens, such as orthologous antigens from another species.

[0051] Anti-Fel d1 antibodies and antigen-binding fragments thereof The pharmaceutical formulations of the present disclosure may comprise a human antibody or antigen-binding fragment thereof that specifically binds to the cat allergen Fel d1. In some embodiments, the pharmaceutical formulations of the present disclosure comprise one or more (e.g., two, three, or more) antibodies that specifically bind to Fel d1. Antibodies to Fel d1 are described, for example, in U.S. Patent Nos. 9,079,948, 10,047,153, and 11,174,305, and WO2013 / 166236, each of which is incorporated herein by reference.

[0052] In some embodiments, the pharmaceutical formulation comprises one or more antibodies or antigen-binding fragments thereof that specifically bind to Fel d1, wherein the antibodies are (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4 and 18; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 20; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8 and 22; (d) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12 and 26; (e) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence selected from the group consisting of AAS and KAS; (f) a light chain complementarity-determining region 3 (LCDR3) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14 and 28; Includes.

[0053] In some embodiments, an anti-Fel d1 antibody comprises a heavy chain variable region (HCVR) comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 and 16. In some embodiments, an anti-Fel d1 antibody comprises a HCVR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 and 16.

[0054] In some embodiments, an anti-Fel d1 antibody comprises a light chain variable region (LCVR) comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 and 24. In some embodiments, an anti-Fel d1 antibody comprises a LCVR comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 and 24.

[0055] In some embodiments, the pharmaceutical formulation of the present disclosure comprises: (a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14, or (b) HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, LCDR2 comprising the amino acid sequence KAS, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 28 The present invention also includes an anti-Fel d1 antibody or an antigen-binding fragment thereof, comprising:

[0056] In some embodiments, the pharmaceutical formulation of the present disclosure comprises at least two anti-Fel d1 antibodies or antigen-binding fragments thereof. In some embodiments, the pharmaceutical formulation comprises: (i) a first antibody that specifically binds to Fel d1, the first antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14, and (ii) a second antibody that specifically binds to Fel d1, the second antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0057] In some embodiments, the anti-Fel d1 antibody comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0058] In some embodiments, an anti-Fel d1 antibody comprises an HCVR comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 2, and / or an LCVR comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 10. In some embodiments, an anti-Fel d1 antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and / or an LCVR comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, an anti-Fel d1 antibody comprises an HCVR consisting of the amino acid sequence of SEQ ID NO: 2 and / or an LCVR consisting of the amino acid sequence of SEQ ID NO: 10.

[0059] In some embodiments, an anti-Fel d1 antibody comprises a heavy chain comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 29, and a light chain comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 30. In some embodiments, an anti-Fel d1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and / or a light chain comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, an anti-Fel d1 antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 29 and / or a light chain consisting of the amino acid sequence of SEQ ID NO: 30.

[0060] In some embodiments, the anti-Fel d1 antibody comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0061] In some embodiments, an anti-Fel d1 antibody comprises an HCVR comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 16, and / or an LCVR comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 24. In some embodiments, an anti-Fel d1 antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and / or an LCVR comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, an anti-Fel d1 antibody comprises an HCVR consisting of the amino acid sequence of SEQ ID NO: 16 and / or an LCVR consisting of the amino acid sequence of SEQ ID NO: 24.

[0062] In some embodiments, an anti-Fel d1 antibody comprises a heavy chain comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 31, and a light chain comprising an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 32. In some embodiments, an anti-Fel d1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and / or a light chain comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, an anti-Fel d1 antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 31 and / or a light chain consisting of the amino acid sequence of SEQ ID NO: 32.

[0063] In some embodiments, the anti-Fel d1 antibody comprises an Fc region selected from the group consisting of human IgG1, IgG2, IgG3, and IgG4 isotypes, hi some embodiments, the anti-Fel d1 antibody comprises a human IgG4 isotype.

[0064] In some embodiments, anti-Fel d1 antibodies or antigen-binding fragments thereof comprise one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and / or light chain variable domains compared to the corresponding germline sequences from which the individual antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Antibodies of the present disclosure may comprise antigen-binding fragments derived from any of the exemplary amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions are mutated to the corresponding residue in the germline sequence from which the antibody was derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce numerous antibodies and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll of the framework and / or CDR residues within a domain are mutated back to the residues found in the original germline sequence from which the antibody was originally derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). Furthermore, an antibody or antigen-binding fragment can contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are either maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies or antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties, reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed by the present disclosure.

[0065] The present disclosure also includes antibodies or antigen-binding fragments comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the present disclosure includes antibodies or antigen-binding fragments comprising HCVR, LCVR, and / or CDR amino acid sequences with, for example, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 conservative amino acid substitution relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein. A "conservative amino acid substitution" is one in which an amino acid residue is replaced with another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of a protein. Examples of groups of amino acids having side chains with similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine, (2) aliphatic-hydroxyl side chains: serine and threonine, (3) amide-containing side chains: asparagine and glutamine, (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan, (5) basic side chains: lysine, arginine, and histidine, (6) acidic side chains: aspartic acid and glutamic acid, and (7) sulfur-containing side chains: cysteine ​​and methionine. Preferred conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-1445. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0066] The present disclosure also includes antibodies or antigen-binding fragments comprising HCVR, LCVR, and / or CDR amino acid sequences that are substantially identical to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein. In some embodiments, the antigen-binding molecule comprises an HCVR, LCVR, and / or CDR amino acid sequence that has at least 85% sequence identity, e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, to a sequence disclosed in Table 1. In some embodiments, the antigen-binding molecule comprises an HCVR, LCVR, and / or CDR amino acid sequence having at least 85% sequence identity, e.g., at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity, to a sequence disclosed in Table 1, and the amino acid sequence differences relative to the sequence disclosed in Table 1 are conservative or moderately conservative substitutions.

[0067] In some embodiments, the antibody or antigen-binding fragment thereof is chimeric, humanized, or fully human. In some embodiments, the antibody or antigen-binding fragment thereof is humanized. In some embodiments, the antibody or antigen-binding fragment thereof is fully human.

[0068] The amount of antibody or antigen-binding fragment thereof contained in a pharmaceutical formulation of the present disclosure (or, in the case of two or more antibodies, the amount of each antibody or the total amount of antibodies) can vary depending on the specific desired properties of the formulation and the particular situation and purpose for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation can contain about 1 mg / mL to about 500 mg / mL of total antibody, about 5 mg / mL to about 250 mg / mL of total antibody, about 5 mg / mL to about 200 mg / mL of total antibody, about 15 mg / mL to about 250 mg / mL of total antibody, about 25 mg / mL to about 200 mg / mL of total antibody, about 50 mg / mL to about 200 mg / mL of total antibody, about 100 mg / mL to about 200 mg / mL of total antibody, about 125 mg / mL to about 175 mg / mL of total antibody, or about 150 mg / mL to about 200 mg / mL of total antibody. For example, formulations of the present disclosure may contain at least about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, about 130 mg / mL The total antibody or antigen-binding fragment thereof that specifically binds to Fel d1 may comprise about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, about 200 mg / mL, about 205 mg / mL, about 210 mg / mL, about 215 mg / mL, about 220 mg / mL, about 225 mg / mL, about 230 mg / mL, about 235 mg / mL, about 240 mg / mL, about 245 mg / mL, or about 250 mg / mL of the total antibody or antigen-binding fragment thereof that specifically binds to Fel d1.In certain embodiments, the pharmaceutical formulation contains about 50±5 mg / mL of total antibody, about 75±7.5 mg / mL of total antibody, about 100±10 mg / mL of total antibody, about 120±12 mg / mL of total antibody, about 140±14 mg / mL of total antibody, about 150±15 mg / mL of total antibody, about 170±17 mg / mL of total antibody, or about 190±19 mg / mL of total antibody. In certain embodiments, the pharmaceutical formulation may contain up to 100 mg / mL, up to 150 mg / mL, up to 200 mg / mL, up to 250 mg / mL, up to 300 mg / mL, up to 400 mg / mL, or up to 500 mg / mL of total antibody.

[0069] For formulations containing two or more anti-Fel d1 antibodies, in some embodiments, each antibody is present in an amount of about 1 mg / mL to about 250 mg / mL, e.g., about 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 150 mg / mL, about 20 mg / mL to about 100 mg / mL, about 50 mg / mL to about 150 mg / mL, or about 50 mg / mL to about 100 mg / mL. In some embodiments, each antibody is at about 1 mg / mL, about 2 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL , about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, or about 200 mg / mL. In certain embodiments, the pharmaceutical formulation contains about 25±3 mg / mL of each antibody, about 50±5 mg / mL of each antibody, about 75±7.5 mg / mL of each antibody, or about 100±10 mg / mL of each antibody. In some embodiments, each antibody is present in the formulation in the same amount. In some embodiments, the antibodies are present in the formulation in different amounts. In some embodiments, the antibodies (e.g., REGN1908 and REGN1909) are present in a 1:1 molecular ratio or about a 1:1 molecular ratio. In some embodiments, the antibodies (e.g., REGN1908 and REGN1909) are present in a molecular ratio of about 1.5:1 or about 1:1.5. In some embodiments, the antibodies (e.g., REGN1908 and REGN1909) are present in a molecular ratio of about 2:1 or about 1:2.

[0070] biological equivalent The present disclosure encompasses formulations comprising antibodies having amino acid sequences that differ from those of the described antibodies but retain the ability to bind to Fel d1. Such variant molecules contain one or more additions, deletions, or substitutions of amino acids compared to the parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Similarly, nucleic acid sequences encoding the antibodies of the present disclosure encompass sequences that contain one or more additions, deletions, or substitutions compared to the disclosed sequences, but encode antibodies or antibody fragments that are essentially biologically equivalent to the antibodies disclosed herein.

[0071] The present disclosure includes formulations comprising antibodies that are bioequivalent to any of the exemplary antibodies described herein. Two antibodies are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical substitutes that exhibit no significant differences in the rate and extent of absorption when administered in either single or multiple doses at the same molar dose under similar experimental conditions. Some antibodies are considered equivalents or pharmaceutical substitutes if the extent of absorption is comparable but the rate of absorption is not, but the antibodies can be considered bioequivalent because the difference in absorption rate is intentional, reflected in the labeling, and is not considered medically significant for the particular pharmaceutical product being tested, for example.

[0072] In one embodiment, two antibodies are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

[0073] In one embodiment, two antibodies are bioequivalent if a patient can be switched between a first antibody (e.g., a reference product) and a second antibody (e.g., a biological product) one or more times without an expected increased risk of adverse effects, including clinically significant changes in immunogenicity or decreased efficacy, compared to continuous therapy without such switching.

[0074] In one embodiment, two antibodies are bioequivalent if they both operate by a common mechanism of action for the conditions of use, to the extent that such mechanism is known.

[0075] Bioequivalence may be demonstrated by in vivo and in vitro methods. Non-limiting examples of bioequivalence measurements include, for example, (a) in vivo tests in humans or other mammals in which the concentration of an antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time, (b) in vitro tests that correlate with and reasonably predict human in vivo bioavailability data, (c) in vivo tests in humans or other mammals in which the relevant acute pharmacological effect of the antibody (or its target) is measured as a function of time, and (d) well-controlled clinical trials that demonstrate the safety, efficacy, or bioavailability or bioequivalence of an antibody.

[0076] Formulation excipients and pH The pharmaceutical formulations of the present disclosure include one or more excipients. As used herein, the term "excipient" refers to any non-therapeutic agent added to a formulation to provide a desired consistency, viscosity, or stabilizing effect.

[0077] The pharmaceutical formulations of the present disclosure may also contain a buffer or buffering system that serves to maintain a stable pH and aid in stabilizing the anti-Fel d1 antibody. In some embodiments, the buffer or buffering system includes at least one buffer having a buffer range that fully or partially overlaps the pH 5.5 to 6.3 range (e.g., a histidine buffer or a phosphate buffer). In various embodiments, the pH of the formulation is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, or 6.3. In some embodiments, the formulation has a pH of 5.8±0.3, e.g., a pH of 5.8±0.2, or a pH of 5.8±0.1. In some embodiments, the formulation has a pH of 5.9±0.3, e.g., a pH of 5.9±0.2, or a pH of 5.9±0.1. In some embodiments, the formulation has a pH of 6.0±0.3, e.g., a pH of 6.0±0.2, or a pH of 6.0±0.1.

[0078] In certain embodiments, the buffer contains histidine. In the context of this disclosure, a "histidine buffer" or a "histidine-containing buffer" is a buffer containing the amino acid histidine. Examples of histidine buffering agents include histidine chloride, histidine acetate, histidine phosphate, and histidine sulfate. In one embodiment, the histidine buffer is prepared by dissolving L-histidine and L-histidine hydrochloride (e.g., as the monohydrate) in a specified amount and ratio. In one embodiment, the histidine buffer is prepared by titrating L-histidine (free base, solid) with dilute hydrochloric acid. The term "histidine" is used interchangeably with "histidine buffer" throughout this disclosure. In certain embodiments, the buffer (e.g., histidine) is present at a concentration of about 1 mM to about 100 mM, e.g., about 1 mM to about 70 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, about 5 mM to about 25 mM, or about 5 mM to about 20 mM. In some embodiments, the buffer comprises a histidine buffer at a concentration of 5 mM to 15 mM. In some embodiments, the buffer comprises a histidine buffer at a concentration of 10 mM ± 2 mM.

[0079] The pharmaceutical formulations of the present disclosure may include one or more thermostabilizers. In some embodiments, the term "stabilized" refers to maintaining greater than about 91% of the antibody in a native conformation when a solution containing the antibody and thermostabilizer is incubated at an elevated temperature of about 37°C, about 40°C, or about 45°C for at least about 28 days (e.g., one month). In some embodiments, "stabilized" refers to less than about 6% (e.g., less than 5%, less than 4%, less than 3%, or less than 2.5%) of the antibody being aggregated when a solution containing the antibody and thermostabilizer is incubated at an elevated temperature of about 37°C, about 40°C, or about 45°C for at least about 28 days (e.g., one month). As used herein, "native" refers to the primary or predominant form of the antibody by size exclusion, which is generally an intact monomeric form of the antibody. The term "native" also refers to non-aggregated and non-degraded forms of the antibody.

[0080] In some embodiments, the thermal stabilizer is a polyol such as sorbitol. In some embodiments, the thermal stabilizer is an amino acid such as proline. In some aspects, the thermal stabilizer is a sugar such as sucrose or trehalose. The amount of stabilizer contained within the formulation can vary depending on the particular context and intended purpose in which the formulation is used. In certain embodiments, the thermal stabilizer may be present in the formulation in an amount of about 0.1% to about 20%, about 0.5% to about 20%, about 1% to about 20%, about 1% to about 10%, about 2% to about 15%, about 3% to about 8%, or about 4% to about 6%. For example, pharmaceutical formulations of the present disclosure may contain about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 15%, or about 20% heat stabilizer (e.g., sucrose). In some embodiments, the formulation contains about 10% heat stabilizer (e.g., sucrose). In some embodiments, the formulation contains about 1% to about 10% heat stabilizer (e.g., sucrose), for example, about 3%, about 5%, about 7.5%, or about 10%. In some embodiments, the formulation contains about 5% heat stabilizer (e.g., sucrose). In some embodiments, the formulation contains about 5%±1% heat stabilizer (e.g., sucrose). In some embodiments, the formulation contains about 5%±0.5% heat stabilizer (e.g., sucrose). Each of the above percentages corresponds to a weight / volume (w / v) percent.

[0081] The pharmaceutical formulations of the present disclosure may include one or more viscosity-lowering agents. In some embodiments, the viscosity-adjusting agent is an amino acid or a salt. Exemplary amino acids that can be used as viscosity-adjusting agents include, but are not limited to, alanine, proline, arginine, histidine, glycine, and lysine. Exemplary salts (e.g., inorganic salts) that can be used as viscosity-adjusting agents include sodium chloride, calcium chloride, magnesium chloride, and calcium acetate. In some embodiments, the viscosity-adjusting agent is an amino acid in its salt form (e.g., arginine hydrochloride, histidine hydrochloride, or histidine acetate).

[0082] In certain embodiments, the viscosity modifier is present in an amount of at least 50 mM, e.g., at least 60 mM, at least 65 mM, at least 70 mM, or at least 75 mM. In some embodiments, the viscosity modifier is present in an amount of about 50 mM to about 200 mM, e.g., about 50 mM to about 175 mM, about 60 mM to about 150 mM, or about 60 mM to about 130 mM. In some embodiments, the viscosity modifier (e.g., arginine or arginine hydrochloride, or sodium chloride) is present in an amount of at least 60 mM, e.g., at least 65 mM, at least 70 mM, or about 70 mM to about 120 mM. In certain embodiments, the viscosity modifier is present in an amount of about 0.5% w / v to about 5% w / v, e.g., about 1% w / v to about 5% w / v. In one embodiment, the viscosity modifier (eg, proline) is present in an amount of about 1% w / v to about 5% w / v (eg, about 1.5% or about 3%).

[0083] The pharmaceutical formulations of the present disclosure may also include one or more surfactants, for example, of a type and in an amount that stabilizes the anti-Fel d1 antibody under conditions of rough handling or agitation. As used herein, the term "surfactant" refers to a substance that reduces absorption of the hydrophobic antibody patch to other hydrophobic surfaces and / or reduces the tendency for aggregation at the air-water interface, where hydrophobic antibody regions tend to undergo unfolding events. Surfactants can be ionic or nonionic. Specific nonionic surfactants that can be included in the formulations of the present disclosure include, for example, polysorbates such as polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, and polysorbate 85; poloxamers such as poloxamer 181, poloxamer 188, and poloxamer 407; or polyethylene glycols (PEGs) such as PEG 3350. Polysorbate 20 is also known as TWEEN 20, sorbitan monolaurate, or polyoxyethylene sorbitan monolaurate. Poloxamer 188 is also known as KOLLIPHOR® P 188 (BASF) or PLURONIC™ F-68 (Gibco).

[0084] The amount of surfactant contained within the pharmaceutical formulations of the present disclosure can vary depending on the specific properties desired of the formulation, as well as the particular environment and purpose for which the formulation is intended to be used. In certain embodiments, the formulation can contain 0.01% to 0.5% surfactant, e.g., about 0.05% to about 0.5%, about 0.05% to about 0.25%, about 0.075% to about 0.25%, or about 0.075% to about 0.2%. For example, formulations of the present disclosure may contain about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about The formulation may contain 0.20%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.46%, about 0.47%, about 0.48%, about 0.49%, or about 0.50% surfactant. In some embodiments, the surfactant is a polysorbate, e.g., polysorbate 20 or polysorbate 80. In some embodiments, the formulation contains about 0.1% to about 0.2% polysorbate 20 or polysorbate 80. In some embodiments, the formulation contains about 0.1% or about 0.15% polysorbate 20 or polysorbate 80. Each of the above percentages corresponds to a weight / volume (w / v) percent.

[0085] Exemplary Formulations In some embodiments, the stable liquid pharmaceutical formulation comprises at least one antibody that specifically binds to Fel d1 and a buffer that maintains a stable pH of about 6.0 (eg, pH 6.0±0.3).

[0086] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1 and about 5 mM to about 20 mM of a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3). In some embodiments, the buffer is histidine.

[0087] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1, about 5 mM to about 20 mM of a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3), and about 1% to about 10% of a cryoprotectant. In some embodiments, the buffer is histidine. In some embodiments, the cryoprotectant is sucrose, proline, trehalose, or sorbitol.

[0088] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1; about 5 mM to about 20 mM buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3); and about 0.01% to about 0.5% surfactant. In some embodiments, the buffer is histidine. In some embodiments, the surfactant is a polysorbate, such as polysorbate 20 or polysorbate 80.

[0089] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1, about 5 mM to about 20 mM of a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3), and about 50 mM to about 200 mM of a viscosity-lowering agent. In some embodiments, the buffer is histidine. In some embodiments, the viscosity-lowering agent is arginine, histidine, or sodium chloride.

[0090] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1; about 5 mM to about 20 mM of a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3); about 1% to about 10% of a cryoprotectant; and about 50 mM to about 200 mM of a viscosity-reducing agent. In some embodiments, the buffer is histidine. In some embodiments, the cryoprotectant is sucrose, proline, trehalose, or sorbitol. In some embodiments, the viscosity-reducing agent is arginine, histidine, or sodium chloride.

[0091] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1; about 5 mM to about 20 mM of a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3); about 0.01% to about 0.5% of a surfactant; and about 50 mM to about 200 mM of a viscosity-lowering agent. In some embodiments, the buffer is histidine. In some embodiments, the surfactant is a polysorbate, such as polysorbate 20 or polysorbate 80. In some embodiments, the viscosity-lowering agent is arginine, histidine, or sodium chloride.

[0092] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 to 250 mg / mL (e.g., 20 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 150 mg / mL, or 200 mg / mL) of at least one antibody that specifically binds to Fel d1; about 5 mM to about 20 mM of a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3); about 1% to about 10% of a cryoprotectant; about 0.01% to about 0.5% of a surfactant; and about 50 mM to about 200 mM of a viscosity-reducing agent. In some embodiments, the buffer is histidine. In some embodiments, the cryoprotectant is sucrose, proline, trehalose, or sorbitol. In some embodiments, the surfactant is a polysorbate, such as polysorbate 20 or polysorbate 80. In some embodiments, the viscosity-lowering agent is arginine, histidine, or sodium chloride.

[0093] In some embodiments, the stable liquid pharmaceutical formulation comprises 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, or 200 mg / mL of at least one antibody that specifically binds to Fel d1 and a 10 mM histidine buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3, or a pH of 5.8 or 5.9). In some embodiments, the formulation further comprises 5% (w / v) sucrose. In some embodiments, the formulation further comprises 0.1% (w / v) polysorbate 80.

[0094] In some embodiments, the stable liquid pharmaceutical formulation comprises REGN1908 at a concentration of about 150 mg / mL ± 15 mg / mL and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0 ± 0.3, or pH 5.8 or pH 6.2). In some embodiments, the buffer is 10 mM histidine.

[0095] In some embodiments, the stable liquid pharmaceutical formulation comprises REGN1909 at a concentration of about 150 mg / mL ± 15 mg / mL and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0 ± 0.6, or pH 5.4, 5.6, 5.8, 6.0, 6.2, or 6.5). In some embodiments, the buffer is 10 mM histidine.

[0096] In some embodiments, the stable liquid pharmaceutical formulation comprises REGN1908 and / or REGN1909 and a viscosity-lowering agent. In some embodiments, the viscosity-lowering agent is arginine-HCl, proline, or sodium chloride. In some embodiments, the formulation comprises 70 mM arginine-HCl. In some embodiments, the formulation comprises 3% proline. In some embodiments, the formulation comprises 70 mM sodium chloride.

[0097] In some embodiments, the stable liquid pharmaceutical formulation comprises 150 mg / mL ± 15 mg / mL of REGN1908 or REGN1909 and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0 ± 0.3, or pH 5.8 or pH 6.2). In some embodiments, the buffer is 10 mM histidine. In some embodiments, the formulation further comprises one of: (i) 10 mM histidine (i.e., no viscosity-lowering agent), (ii) 10 mM histidine + 70 mM arginine-HCl, (iii) 100 mM histidine, (iv) 10 mM histidine + 3% proline, or (v) 10 mM histidine + 70 mM sodium chloride. In some embodiments, the formulation comprises 150 mg / mL REGN1908 and 70 mM arginine, 100 mM histidine, or 70 mM sodium chloride. In some embodiments, the formulation comprises 150 mg / mL REGN1908 and 70 mM arginine. In some embodiments, the formulation comprises 150 mg / mL REGN1909 and a viscosity-lowering agent effective to maintain a viscosity of less than 10 cP in the formulation.

[0098] In some embodiments, the stable liquid pharmaceutical formulation comprises 150 mg / mL of REGN1908 or REGN1909 and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3, or pH 5.8 or pH 6.2). In some embodiments, the buffer is 10 mM histidine. In some embodiments, the formulation further comprises a cryoprotectant. In some aspects, the cryoprotectant is 5% w / v or 10% w / v sucrose. In some aspects, the formulation comprises 70 mM arginine-HCl in the presence of sucrose, e.g., 5% w / v sucrose.

[0099] In some embodiments, the stable liquid pharmaceutical formulation comprises 175 mg / mL of REGN1908 or REGN1909 and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3, or pH 5.8 or pH 6.2). In some embodiments, the formulation further comprises 10 mM histidine. In some embodiments, the formulation further comprises 70 mM arginine. In some embodiments, the formulation further comprises 5% sucrose.

[0100] In some embodiments, anti-Fel d1 antibodies (e.g., REGN1908 and REGN1909) are individually formulated in an aqueous buffer formulation containing (a) 5 mM to 20 mM histidine buffer, (b) 60 mM to 130 mM arginine, and (c) 50 to 200 mg of anti-Fel d1 antibody at pH 6.0±0.3. In some embodiments, the formulation further comprises 2.5% to 7.5% w / v sucrose and / or 0.01% to 0.5% w / v polysorbate.

[0101] In some embodiments, anti-Fel d1 antibodies (e.g., REGN1908 and REGN1909) are individually formulated in an aqueous buffer formulation containing (a) 5 mM to 20 mM histidine buffer, (b) 2.5% to 7.5% w / v sucrose, (c) 60 mM to 130 mM arginine, and (d) 50 to 200 mg of anti-Fel d1 antibody at pH 6.0±0.3. In some embodiments, the formulation further comprises 0.01% to 0.5% w / v polysorbate.

[0102] In some embodiments, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, and (d) 190 mg / mL ± 10 mg / mL REGN1908 at pH 6.0 ± 0.3.

[0103] In some embodiments, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, (d) 0.15% ± 0.075% w / v polysorbate 80, and (e) 150 mg / mL ± 15 mg / mL REGN1908 at pH 6.0 ± 0.3.

[0104] In some embodiments, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, and (d) 190 mg / mL ± 10 mg / mL REGN1909 at pH 6.0 ± 0.3.

[0105] In some embodiments, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, (d) 0.15% ± 0.075% w / v polysorbate 80, and (e) 150 mg / mL ± 15 mg / mL REGN1909 at pH 6.0 ± 0.3.

[0106] In some aspects, the stable liquid pharmaceutical formulation comprises two anti-Fel d1 antibodies (75 mg / mL REGN1908 and 75 mg / mL REGN1909) at a target total antibody concentration of 150 mg / mL and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3). In some embodiments, the buffer is 10 mM histidine. In some embodiments, the formulation has a pH of 6.1. In some embodiments, the formulation comprises 10 mM histidine and 5% sucrose. In some embodiments, the formulation does not comprise arginine, or further comprises 20 mM, 50 mM, 70 mM, 100 mM, or 130 mM arginine.

[0107] In some embodiments, the stable liquid pharmaceutical formulation comprises two anti-Fel d1 antibodies (75 mg / mL REGN1908 and 75 mg / mL REGN1909) at a target total antibody concentration of 150 mg / mL and a buffer that maintains a stable pH of about 6.0 (e.g., pH 6.0±0.3). In some embodiments, the formulation further comprises 10 mM histidine and 70 mM arginine hydrochloride. In some embodiments, the formulation further comprises no polysorbate or polysorbate 20 or polysorbate 80 in an amount of 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, or 0.2% (all percentages w / v). In some embodiments, the formulation comprises ≧0.05% w / v polysorbate 20, and / or the formulation comprises ≧0.025% w / v or ≧0.075% w / v polysorbate 80.

[0108] In some embodiments, the stable liquid pharmaceutical formulation comprises 150 mg / mL REGN1908-REGN1909 (75 mg / mL of each antibody), 10 mM histidine, 70 mM arginine hydrochloride, and 0.15% (w / v) polysorbate at pH 6.0. In some embodiments, no cryoprotectant is added. In some embodiments, 5% sucrose, 3% proline, 5% trehalose, or 2.5% sorbitol is added (all percentages w / v).

[0109] In some embodiments, the stable liquid pharmaceutical formulation comprises two anti-Fel d1 antibodies in an aqueous buffer formulation at pH 6.0±0.3 and comprising: (a) 5 mM to 20 mM histidine buffer; (b) 2.5% to 7.5% w / v sucrose; (c) 60 mM to 130 mM arginine; (d) 0.01% to 0.5% w / v polysorbate; and (e) 50 to 200 mg of total anti-Fel d1 antibodies.

[0110] In some embodiments, the stable liquid formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, (d) 0.15% ± 0.075% w / v polysorbate 80, and (e) 150 mg / mL ± 15 mg / mL REGN1908-REGN1909 (75 mg / mL REGN1908 + 75 mg / mL REGN1909) at pH 6.0 ± 0.3.

[0111] Characterization of pharmaceutical formulations In some embodiments, the anti-Fel D1 antibody formulation exhibits the following attributes: Formulations that are stable after being subjected to stresses, such as temperature cycling, extreme temperatures, agitation during transport, etc. a formulation having a concentration of anti-Fel D1 antibody / antibodies high enough to support delivery of a single dose of antibody / antibodies to a patient (e.g., a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg); A formulation with a low enough viscosity to be administered by intravenous or subcutaneous injection, even at high antibody concentrations (e.g., antibody concentrations of 100-200 mg / mL or 150-175 mg / mL). A formulation with a physiological osmolality or close to it that supports administration by intravenous or subcutaneous injection, even at high antibody concentrations (e.g., antibody concentrations of 100-200 mg / mL or 150-175 mg / mL). · Stable formulation, compatible with Type 1 clear glass vials and standard serum stoppers as packaging One or more of the following may be present:

[0112] The pharmaceutical formulations of the present disclosure typically exhibit a high level of stability. As used herein in connection with a pharmaceutical formulation, the term "stable" means that the antibody in the pharmaceutical formulation retains an acceptable degree of chemical structure or biological function after storage under specified conditions. A formulation may be stable even if the antibody contained within the formulation does not retain 100% of its chemical structure or biological function after storage for a specified period of time. Under certain circumstances, a formulation may be considered "stable" if about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% of the antibody's structure or function is maintained after storage for a specified period of time.

[0113] In some embodiments, "stability" refers to physical stability. Physical stability of a formulation refers to properties such as color, appearance, pH, turbidity, and protein concentration. The presence of visible particles in a solution can be detected by visual inspection, while particles submerged by the naked eye can be measured using a microscope, high-intensity optical contrast (HIAC), or microflow imaging (MFI). A solution passes visual inspection if it is clear to slightly opalescent, essentially free of visible particles, and colorless to pale yellow. Additionally, turbidity, as measured by OD at 405 nm, can also be used to detect particles in a solution. An increase in OD at 405 nm may indicate the presence of particulates, increased opalescence, or a discoloration of the test article. In some embodiments, antibody protein concentration can be measured by RP-UPLC assay and reported as percent protein recovery compared to the starting material. In RP-UPLC assays, the antibody elutes from the RP column as a single peak. Protein concentration is determined from the antibody total peak area by comparison to a calibration curve generated using antibody standards. Percent recovery is calculated based on the measured protein concentration relative to the starting protein concentration. In some embodiments, antibody protein concentration is measured by SoloVPE (Repligen Corp., Bridgewater, NJ).

[0114] In some embodiments, "stability" refers to chemical stability. Chemical stability refers to the formation of covalently modified forms (e.g., covalent aggregates, cleavage products, or charge variant forms) and non-covalently modified forms (e.g., non-covalent aggregates) of the protein. High- and low-molecular-weight degradation products can be separated from native antibodies by methods such as size-exclusion ultra-performance liquid chromatography (SE-UPLC) and microchip electrophoresis (MCE-SDS). The percentage of degraded antibody in the SE-UPLC and MCE-SDS methods is calculated from the ratio of the area of ​​all non-native peaks to the total area of ​​all antibody peaks. Charge variant forms of antibodies are separated using CEX-UPLC and iCIEF. In the CEX-UPLC method, peaks with retention times earlier than the main peak are labeled as "acidic" peaks, and peaks with retention times later than the main peak are labeled as "basic" peaks. In the iCIEF method, peaks focused at a lower pI than the main peak are labeled "acidic" peaks, and peaks focused at a higher pI than the main peak are labeled "basic" peaks.

[0115] In some embodiments, stability is measured under stress conditions. For example, the formulation may be subjected to agitation stress (e.g., vortexing at 1000 rpm for 5 or 10 minutes or using an orbital shaker at 250 rpm for 24 or 48 hours), accelerated stability testing (e.g., subjecting the formulation to elevated temperature, humidity, and / or pH conditions), or thermal stress (e.g., subjecting the formulation to multiple freeze-thaw cycles).

[0116] In some embodiments, stability can be measured by determining the percentage of native antibody remaining in the formulation after storage at a specified temperature for a specified time. The percentage of native antibody can be determined, inter alia, by size exclusion chromatography (e.g., SE-UPLC), where native means non-aggregated and non-degraded. "Acceptable stability," as that phrase is used herein, means that at least 90% native antibody can be detected in the formulation after storage at a given temperature for a specified amount of time. In certain embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% native antibody can be detected in the formulation after storage at a specified temperature for a specified time. The specified time period after which stability is measured can be at least 14 days, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or more. The specified temperature at which the pharmaceutical formulation can be stored when assessing stability can be any temperature between about -80°C and about 60°C, such as storage at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C to 8°C, about 5°C, about 25°C, about 35°C, about 37°C, about 40°C, or about 45°C. For example, a pharmaceutical formulation can be considered stable if greater than about 95%, 96%, 97%, or 98% of the native antibody is detected by SE-UPLC after 28 days of storage at 40°C / 75% humidity (RH). A pharmaceutical formulation may be considered stable if greater than about 95%, 96%, 97%, or 98% of the native antibody is detected by SE-UPLC after 12 months of storage at 5° C. A pharmaceutical formulation may also be considered stable if greater than about 95%, 96%, 97%, or 98% of the native antibody is detected by SE-UPLC after 3 months of storage at 25° C.A pharmaceutical formulation may also be considered stable if greater than about 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 96% of native antibodies are detected by SE-UPLC after 28 days of storage at 45° C. A pharmaceutical formulation may also be considered stable if greater than about 96%, 97%, or 98% of native antibodies are detected by SE-UPLC after 12 months of storage at −20° C. A pharmaceutical formulation may also be considered stable if greater than about 96%, 97%, or 98% of native antibodies are detected by SE-UPLC after 12 months of storage at −30° C. A pharmaceutical formulation may also be considered stable if greater than about 96%, 97%, or 98% of native antibodies are detected by SE-UPLC after 12 months of storage at −80° C.

[0117] In some embodiments, stability is measured by determining the percentage of antibody that forms aggregates in the formulation after storage at a specified temperature for a specified time, with stability being inversely proportional to the percent aggregates formed. The percentage of aggregated antibody can be determined, inter alia, by size exclusion chromatography (e.g., SE-UPLC). "Acceptable stability," as that term is used herein, means that after storage at a given temperature for a specified time, at most 5% of the antibody is detected in aggregated form (also referred to as high molecular weight ("HMW") form) in the formulation. In certain embodiments, acceptable stability means that after storage at a given temperature for a specified time, at most about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody may be detected in aggregate form in the formulation. The specified amount of time after which stability is measured can be at least 2 weeks, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or more. The temperature at which the pharmaceutical formulation can be stored when assessing stability can be any temperature between about -80°C and about 45°C, e.g., storage at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C to 8°C, about 5°C, about 25°C, about 35°C, about 37°C, about 40°C, or about 45°C. For example, a pharmaceutical formulation can be considered stable if, after 12 months of storage at 5°C, less than about 2%, 1%, 0.5%, or 0.1% of the antibody is detected in aggregated form.

[0118] In some embodiments, stability is measured by determining the percentage of antibody ("acidic form") that migrates into a more acidic fraction than into the main antibody fraction ("major charge form") during ion exchange, with stability being inversely proportional to the fraction of antibody in the acidic form. Without wishing to be bound by theory, deamidation of an antibody may render the antibody more negatively charged and therefore more acidic compared to a non-deamidated antibody (see, e.g., Robinson, PNAS, April 16, 2002, 99:5283-5288). The percentage of "acidic" antibody may be determined, inter alia, by ion exchange chromatography (e.g., cation exchange high-performance liquid chromatography [CEX-UPLC]). "Acceptable stability," as that term is used herein, means that after storage at a specified temperature for a specified time, at most 45% of the antibody is detected in the more acidic form in the formulation. In certain embodiments, an acceptable degree of stability means that at most about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in the acidic form in the formulation after storage at a given temperature for a specified period of time. In one embodiment, an acceptable degree of stability means that less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in the acidic form in the formulation after storage at a given temperature for a specified period of time. The specified time period after which stability is measured can be at least 2 weeks, at least 28 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or more. The temperature at which the pharmaceutical formulation can be stored when assessing stability can be any temperature between about -80°C and about 45°C, for example, about -80°C, about -30°C, about -20°C, about 0°C, about 4°C to 8°C, about 5°C, about 25°C, or about 45°C.For example, a pharmaceutical formulation can be considered stable if less than about 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in the more acidic form after 3 months of storage at -80°C, -30°C, or -20°C. A pharmaceutical formulation may be considered stable if less than about 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in a more acidic form after storage at 5°C for 12 months. A pharmaceutical formulation may be considered stable if less than about 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody is in the more acidic form after 3 months of storage at 25°C. A pharmaceutical formulation may be considered stable if less than about 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of the antibody can be detected in the more acidic form after 28 days of storage at 45°C.

[0119] Other methods may be used to assess the stability of formulations of the present disclosure, such as, for example, differential scanning calorimetry (DSC) to determine thermal stability, controlled stirring to determine mechanical stability, and absorbance at about 350 nm or about 405 nm to determine solution turbidity. For example, formulations of the present disclosure may be tested for the OD of the formulation after storage at about 5° C. to about 25° C. for 6 months or more. 405 The change in OD of the formulation at time zero 405 to less than about 0.05 (e.g., 0.04, 0.03, 0.02, 0.01 or less).

[0120] Measurements of antibody binding affinity to a target or antibody biological activity may be used to assess stability or potency. For example, a formulation of the present disclosure may be considered stable if, after storage for a specified period of time (e.g., 1-36 months) at, e.g., 5°C, 25°C, 45°C, etc., the anti-Fel d1 antibody contained within the formulation binds to the Fel d1 antigen with an affinity that is at least 90%, 95%, or greater than the binding affinity of the antibody prior to storage. In some embodiments, the potency of the antibody in the formulation is assessed by ELISA or bioassay in comparison to a reference standard (e.g., the antibody or antibody-containing formulation prior to storage), with the acceptance criteria for a test article being 50-150% potency relative to the reference standard. Binding affinity may be determined, for example, by ELISA or surface plasmon resonance. Biological activity (i.e., the ability of the antibody to inhibit the activity of Fel D1) can be determined by standard in vitro or in vivo assays (such as the passive cutaneous anaphylaxis assay disclosed in WO2013 / 166236 or the basophil activation test disclosed in WO2018 / 118713).

[0121] Additional methods for assessing antibody stability in formulations are demonstrated in the examples presented below.

[0122] The liquid pharmaceutical formulations of the present disclosure may exhibit low to moderate viscosity in certain embodiments. As used herein, "viscosity" can be "kinematic viscosity" or "absolute viscosity." "Kinematic viscosity" is a measure of the resistive flow of a fluid under the influence of weight. When two fluids of equal volume are placed in the same capillary viscometer and allowed to flow by gravity, the more viscous fluid will take longer to flow through the capillary than the less viscous fluid. For example, if one fluid takes 200 seconds to complete its flow and another takes 400 seconds, the second fluid has twice the viscosity of the first fluid on the kinematic viscosity scale. "Absolute viscosity," sometimes referred to as dynamic viscosity or simple viscosity, is the product of kinematic viscosity and fluid density (absolute viscosity = kinematic viscosity × density). The dimensions of kinematic viscosity are L 2 / T, where L is length and T is time. Kinematic viscosity is generally expressed in centistokes (cSt). The SI unit of kinematic viscosity is mm 2 / s, which is 1 cSt. Absolute viscosity is expressed in units of centipoise (cP). The SI unit of absolute viscosity is millipascal-second (mPa-s), with 1 cP = 1 mPa-s.

[0123] As used herein, in the context of the fluid formulations of the present disclosure, a low level of viscosity refers to an absolute viscosity of less than about 20 cPoise (cP). For example, a fluid formulation disclosed herein would be considered to have a "low viscosity" if the formulation exhibits an absolute viscosity of about 20 cP, about 19 cP, about 18 cP, about 17 cP, about 16 cP, about 15 cP, about 14 cP, about 13 cP, about 12 cP, about 11 cP, about 10 cP, about 9 cP, about 8 cP, or less, when measured using standard viscosity measurement techniques. As used herein, in the context of the fluid formulations of the present disclosure, a moderate level of viscosity refers to an absolute viscosity of about 35 cP to about 20 cP. For example, a fluid formulation disclosed herein is considered to have a "moderate viscosity" if the formulation exhibits an absolute viscosity of about 34 cP, about 33 cP, about 32 cP, about 31 cP, about 30 cP, about 29 cP, about 28 cP, about 27 cP, about 26 cP, about 25 cP, about 24 cP, about 23 cP, about 22 cP, about 21 cP, or about 20 cP when measured using standard viscosity measurement techniques. In some embodiments, the formulations provided herein have a viscosity of ≦30 cP, e.g., ≦25 cP. In some embodiments, the formulations provided herein have a viscosity of ≦20 cP, e.g., ≦15 cP.

[0124] Container and administration method The pharmaceutical formulations of the present disclosure may be contained in any container suitable for storing pharmaceuticals and other therapeutic compositions. For example, the pharmaceutical formulations may be contained in a sealed and sterilized plastic or glass container having a predetermined volume, such as a vial, an ampoule, a syringe, a cartridge, a bottle, or an IV bag. Different types of vials, such as clear and opaque (e.g., tan) glass or plastic vials, can be used to contain the formulations of the present disclosure. Similarly, any type of syringe can be used to contain and / or administer the pharmaceutical formulations of the present disclosure. In some embodiments, the pharmaceutical formulation is contained in a pre-filled syringe. In some embodiments, the pharmaceutical formulation is contained in a pre-filled fixed-needle syringe. In some embodiments, the pharmaceutical formulation is housed in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector.

[0125] The pharmaceutical formulations of the present disclosure may be contained in "normal tungsten" syringes or "low tungsten" syringes. As will be recognized by those skilled in the art, the process of making glass syringes generally involves the use of a hot tungsten rod, which functions to puncture the glass, thereby creating a hole through which liquid can be drawn and expelled from the syringe. This process deposits trace amounts of tungsten on the interior surface of the syringe. Subsequent cleaning and other processing steps can be used to reduce the amount of tungsten in the syringe. As used herein, the term "normal tungsten" means that the syringe contains greater than 500 parts per billion (ppb) of tungsten. The term "low tungsten" means that the syringe contains less than 500 ppb of tungsten. For example, according to the present disclosure, a low tungsten syringe can contain about 490, 480, 470, 460, 450, 440, 430, 420, 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 ppb or less of tungsten.

[0126] Rubber plungers used in syringes and rubber stoppers used to close the openings of vials can be coated to prevent contamination of the pharmaceutical contents of the syringe or vial and / or to preserve their stability. Thus, according to certain embodiments, the pharmaceutical formulations of the present disclosure can be contained in a syringe with a coated plunger or in a vial sealed with a coated rubber stopper. For example, the plunger or stopper can be coated with a fluorocarbon film. Examples of coated stoppers or plungers suitable for use in vials and syringes containing the pharmaceutical formulations of the present disclosure are mentioned in, for example, U.S. Patent Nos. 4,997,423, 5,908,686, 6,286,699, 6,645,635, and 7,226,554, the contents of which are incorporated herein by reference in their entireties. Certain exemplary coated rubber stoppers and plungers that can be used in the context of the present disclosure are commercially available under the trade name "FluroTec®" available from West Pharmaceutical Services, Inc. (Lionville, PA). According to certain embodiments of the present disclosure, the pharmaceutical formulation may be contained within a low-tungsten syringe including a fluorocarbon-coated plunger. In some embodiments, the container is a syringe, such as an Ompi EZ-Fill™ syringe or a BD Neopak™ syringe. In some cases, the syringe is a 1 mL long glass syringe with a 1 mL West piston, a 27G thin-walled needle, and an FM30 or BD260 needle shield. In some cases, the syringe is a 2.25 mL glass syringe (e.g., Nuova Ompi).In various embodiments, the syringe is a 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, 2.0 mL, 2.1 mL, 2.2 mL, 2.3 mL, 2.4 mL, 2.5 mL, 2.6 mL, 2.7 mL, 2.8 mL, 2.9 mL, 3.0 mL, 3.5 mL, 4.0 mL, 4.5 mL, 5.0 mL, 5.5 mL, 6.0 mL, 6.5 mL, 7.0 mL, 7.5 mL, 8.0 mL, 8.5 mL, 9.0 mL, 9.5 mL, or 10 mL syringe (e.g., a glass syringe).

[0127] The pharmaceutical formulations can be administered to a patient by parenteral routes, such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.), or by transdermal, mucosal, nasal, pulmonary, and / or oral administration. Many reusable pen and / or autoinjector delivery devices can be used to deliver the pharmaceutical formulations of the present disclosure subcutaneously. Examples include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN™, to name just a few. STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen and / or autoinjector delivery devices that have application in the subcutaneous delivery of pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ Pen (Abbott Labs, Abbott Park, IL), to name just a few.In some cases, the pharmaceutical formulation is contained in a syringe specially adapted for use with an autoinjector. Subcutaneous injections may be administered using a 20-30 gauge needle, or a 25-30 gauge needle. In some cases, subcutaneous injections may be administered using a 25 gauge needle. In some cases, subcutaneous injections may be administered using a 27 gauge needle. In some cases, subcutaneous injections may be administered using a 29 gauge needle.

[0128] Another type of delivery device can include a safety system. Such devices can be relatively inexpensive and can be operated manually or automatically to extend a safety sleeve over the needle once the injection is complete. Examples of safety systems can include the ERIS device by West Pharmaceutical or the UltraSafe device by Becton Dickinson. Additionally, the use of a large volume device ("LVD") or bolus injector to deliver the pharmaceutical formulations of the present disclosure is also contemplated herein. In some cases, the LVD or bolus injector can be configured to inject the medication into the patient. For example, the LVD or bolus injector can be configured to deliver a "large" volume of medication (typically about 2 mL to about 10 mL).

[0129] The pharmaceutical formulations of the present disclosure may also be contained in unit dosage forms. As used herein, the term "unit dosage form" refers to physically discrete units suitable as single dosages for the patient to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier, diluent, or excipient. In various embodiments, the unit dosage form is contained within a container as discussed herein. The actual dosage level of the active ingredient (e.g., anti-Fel d1 antibody) in the formulations of the present disclosure may be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for the particular patient, composition, and mode of administration without adversely affecting the patient. The selected dosage level will depend on various pharmacokinetic factors, including the activity of the particular composition of the present disclosure employed, the route of administration, the time of administration, the excretion rate of the particular compound employed, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts. The term "diluent" as used herein refers to a solution suitable for modifying or achieving the exemplary or suitable concentrations described herein.

[0130] In various embodiments, a unit dosage form contains an amount of active ingredient (e.g., one or more anti-Fel d1 antibodies) intended for a single use. In various embodiments, the amount of active ingredient in a unit dosage form is about 0.1 mg to about 5000 mg, about 25 mg to about 1000 mg, about 50 mg to about 500 mg, or about 100 mg to about 750 mg, or a range or interval therein. For example, a range of values ​​using any combination of the values ​​recited above as upper and / or lower limits (or values ​​included within the ranges recited above) is intended to be included. In certain embodiments, formulations are often supplied as liquids in unit dosage form. In some embodiments, the unit dosage form contains about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg of the active ingredient. In some embodiments, a unit dosage form contains two anti-Fel d1 antibodies and contains about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of each antibody. In some embodiments, a unit dosage form according to the present disclosure is suitable for subcutaneous or intravenous administration to a patient.

[0131] The present disclosure also includes methods of preparing unit dosage forms. In an exemplary embodiment, the method for preparing a pharmaceutical unit dosage form includes combining the formulations of any of the foregoing embodiments in a suitable container (e.g., a container discussed herein).

[0132] kit Further provided are kits comprising one or more components, including, but not limited to, a stable liquid pharmaceutical formulation comprising at least one antibody that specifically binds to Fel d1, alone or in association with one or more additional components, including, but not limited to, an additional therapeutic agent, as discussed herein. The stable liquid pharmaceutical formulation and / or the additional therapeutic agent can be formulated as a single composition or separately in two or more compositions, e.g., together with a pharmaceutically acceptable carrier in a pharmaceutical composition.

[0133] Exemplarily, the kit may include a stable liquid pharmaceutical formulation comprising an antibody that specifically binds to Fel d1, the antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0134] In some embodiments, the kit may comprise a stable liquid pharmaceutical formulation comprising an antibody that specifically binds to Fel d1, wherein the antibody comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0135] In some embodiments, the kit comprises: a first antibody that specifically binds to Fel d1, the first antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the concentration of the first antibody is up to about 100 mg / mL (e.g., 50 mg / mL ± 5 mg / mL or 75 mg / mL ± 10 mg / mL); a second antibody that specifically binds to Fel d1, the second antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the concentration of the second antibody is up to about 100 mg / mL (e.g., 50 mg / mL ± 5 mg / mL or 75 mg / mL ± 10 mg / mL); The present invention can include a stable liquid pharmaceutical formulation comprising:

[0136] In one embodiment, the kit comprises a stable liquid pharmaceutical formulation in one container (e.g., a sterile glass or plastic vial). In one embodiment, the kit further comprises an additional therapeutic agent in another container (e.g., a sterile glass or plastic vial).

[0137] In another embodiment, the kit comprises in a single common container a combination of a stable liquid pharmaceutical formulation and, optionally, one or more additional therapeutic agents formulated together in a pharmaceutical composition.

[0138] When the kit includes a stable liquid pharmaceutical formulation for parenteral or subcutaneous administration to a subject, the kit can include a device (e.g., an injection device) for performing such administration. For example, the kit can include one or more hypodermic needles or other injection devices, as discussed above, containing the stable liquid pharmaceutical formulation.

[0139] The kit can include a package insert containing information regarding the stable liquid pharmaceutical formulation and dosage form within the kit. Generally, such information assists patients and physicians in effectively and safely using the enclosed pharmaceutical composition and dosage form. For example, the following information may be provided within the package insert: pharmacokinetics, pharmacodynamics, clinical studies, efficacy parameters, indications and usage, contraindications, warnings, precautions, side effects, overdose, proper dosage and administration, delivery method, suitable storage conditions, references, manufacturer / distributor information, and patent information. In some embodiments, the kit includes instructions for using the formulation in the treatment of a disease, disorder, or condition associated with Fel d1 expression or activity, e.g., as disclosed herein.

[0140] Therapeutic Use The pharmaceutical formulations of the present disclosure are useful, inter alia, for the treatment, prevention, and / or amelioration of any disease, disorder, or condition associated with Fel d1 expression or activity.

[0141] Therapeutic methods of the present disclosure include administering to a subject any formulation comprising one or more anti-Fel d1 antibodies disclosed herein. The subject to which the pharmaceutical formulation is administered can be, for example, any human or non-human animal in need of such treatment, prevention, and / or amelioration. The present disclosure includes the use of any of the pharmaceutical formulations disclosed herein in the manufacture of a medicament for the treatment, prevention, and / or amelioration of any disease or disorder associated with Fel d1 expression or activity.

[0142] In some embodiments, pharmaceutical formulations of the present disclosure are used to treat, prevent, or ameliorate one or more symptoms associated with exposure to the cat allergen Fel d1. In some embodiments, pharmaceutical formulations of the present disclosure are used to treat cat allergy patients, such as patients suffering from allergies to cat dander or patients who exhibit sensitivity to the Fel d1 allergen. In some embodiments, pharmaceutical formulations of the present disclosure are used to prevent an increased response to Fel d1 or associated symptoms associated with allergy upon secondary exposure, or to reduce the severity and / or duration of an allergic reaction associated with primary exposure to a cat carrying the Fel d1 allergen or the recurrence of symptoms upon secondary exposure. In some embodiments, pharmaceutical formulations of the present disclosure are used to treat or prevent cat allergen-induced asthma.

[0143] In some embodiments, the patient treated with the pharmaceutical formulations disclosed herein is sensitized to Fel d1 antigen or cat dander. In some embodiments, the patient is a cat allergy patient. In some embodiments, the patient is a cat allergy patient with conjunctivitis and rhinitis. In some embodiments, the patient is a cat allergy patient with rhinitis, with or without conjunctivitis symptoms. In some embodiments, the patient is a cat allergy patient with rhinitis, with or without conjunctivitis symptoms, and with or without asthma. In some embodiments, the patient is a cat allergy patient with asthma (e.g., mild asthma). In some embodiments, the patient is ≥ 12 years old. In some embodiments, the patient is ≥ 18 years old.

[0144] In some embodiments, treatment with the pharmaceutical formulations disclosed herein results in a reduction in the severity and / or duration of at least one symptom or complication associated with an allergic reaction to a Fel d1 allergen. In some embodiments, the symptom or complication associated with an allergic reaction is sneezing, rhinorrhea, nasal itching, or nasal congestion. In some embodiments, treatment results in a reduction in allergic rhinitis, allergic conjunctivitis, rhinoconjunctivitis, allergic asthma, asthma exacerbation, or anaphylactic response following exposure of a patient to an allergen.

[0145] In some embodiments, treatment with the pharmaceutical formulations disclosed herein includes: (a) reduction in daily total nasal symptom score (TNSS); (b) reduction in daily ocular symptom score (TOSS); (c) reduction in the total daily symptom score (TSS), calculated as the sum of the TNSS and TOSS; (d) reduction in daily medication score (DMS); (e) a reduction in the daily Combined Symptom and Medication Score (CSMS), calculated as the daily TSS+DMS; and / or (f) Reduction in the mean wheal diameter in cat skin prick tests (SPTs) This results in one or more of the following:

[0146] In some embodiments, the pharmaceutical formulations of the present disclosure are used in combination with a second therapeutic agent. For example, in some embodiments, the pharmaceutical formulations are used in combination with one or more other therapeutic moieties or modalities known in the art to treat, prevent, or reduce the severity of allergies, such as, but not limited to, treatment with antihistamines, corticosteroids, epinephrine, anti-IgE antibodies (e.g., omalizumab), or allergen-specific immunotherapy (e.g., SCIT or SLIT).

[0147] A summary of the sequences referred to herein and their corresponding SEQ ID NOs is provided in Table 1 below.

[0148] (Table 1) Unofficial sequence listing TIFF2026508525000001.tif208151TIFF2026508525000002.tif222151TIFF2026508525000003.tif27151 [Example]

[0149] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the disclosed methods and compositions, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0150] Example 1: Antibodies against Fel d1 Antibodies specific for Fel d1 were generated as described in U.S. Patent No. 9,079,948, incorporated herein by reference. Exemplary fully human anti-Fel d1 antibodies (i.e., antibodies possessing human variable and constant domains) that have been generated include H4H1232N (REGN1908) and H4H2636P (REGN1909). The nucleic acid and amino acid sequences of the CDRs, heavy chain variable regions, and light chain variable regions of these antibodies are set forth in Table 1. Tables 2-3 below set forth the amino acid sequence identifiers (Table 2) and nucleic acid sequence identifiers (Table 3) of these antibodies.

[0151] Table 2: Amino acid sequence identifiers TIFF2026508525000004.tif20151

[0152] Table 3: Nucleic acid sequence identifiers TIFF2026508525000005.tif20151

[0153] Example 2: Identification of suitable buffers, pH, and excipients for individual anti-Fel d1 antibodies Initial formulation development work included screening buffer and pH conditions that exhibited a good balance of physical and chemical stability for each of the anti-Fel d1 antibodies REGN1908 and REGN1909. Anti-Fel D1 antibodies (REGN1908 or REGN1909) at a concentration of 5 mg / mL were incubated in phosphate buffer at pH 6.0, 6.5, 7.0, 7.5, or 8.0, in histidine buffer at pH 5.5, 6.0, or 6.5, or in acetate buffer at pH 4.5, 5.0, or 5.5. The formulations were subjected to a stirring assay to evaluate the formation of aggregates and charge variant species. 10 mM histidine was found to confer the best stability to both REGN1908 and REGN1909. In the stirring assay, the REGN1908 formulation ≥pH 6.0 and the REGN1909 formulation >pH 6.0 and <pH 5.5 failed the stirring study. REGN1908 was determined to be most stable with respect to aggregate formation in the pH range 5.5 - 6.0 and with respect to charge variants at pH 5.0 - 6.0. REGN1909 was determined to be most stable with respect to aggregate formation in the pH range 6.0 - 6.5 and with respect to charge variants at pH 5.5. Thus, pH 5.8 was determined to provide a good balance of physical and chemical stability for both molecules.

[0154] Formulations containing REGN1908 or REGN1909 at a concentration of 20 mg / mL in 10 mM histidine buffer at pH 6.0 were evaluated for thermal stability in the absence or presence of a cryoprotectant. Both antibodies were determined to be stable in formulations containing 5% (w / v) sucrose as a cryoprotectant, but an increase in the percentage of high molecular weight species was observed in control formulations lacking the sucrose cryoprotectant.

[0155] Formulations containing REGN1908 or REGN1909 were also screened for the effects of surfactants on agitation and thermal stability. Agitation stress was applied to all formulations by vortexing at 1000 rpm for 120 minutes. Thermal stability was evaluated by incubating all formulations at accelerated conditions of 45°C for 28 days. Polysorbate 20 (0.1% w / v), polysorbate 80 (0.1% w / v), PEG3350 (0.5% w / v), and PEG3350 (1.5% w / v) were all tested in formulations containing REGN1908 or REGN1909 at a concentration of 20 mg / mL, 5% (w / v) sucrose, and 10 mM histidine buffer at pH 6.0. All of the tested surfactants provided agitation protection. In the thermal stability assay, REGN1908 was found to have lower thermal stability in polysorbate 20 compared to polysorbate 80 (thermal stability ranking: 0.1% PS80 > 0.5% PEG > 1.5% PEG > 0.1% PS20). REGN1909 was thermally stable in all tested surfactants.

[0156] Based on these initial formulation development efforts, it was determined that a formulation containing 10 mM histidine, 5% (w / v) sucrose, and 0.1% (w / v) polysorbate 80 at pH 5.8 was suitable for formulating REGN1908 or REGN1909.

[0157] Example 3: Formulation of anti-Fel d1 antibodies at high concentrations Subsequent formulation development efforts include formulating the anti-Fel d1 antibody individually at higher concentrations, desirably to minimize the amount of drug delivered to the patient. However, it is known in the art that as antibody concentration increases, the viscosity of the formulation also increases. Higher viscosity can lead to challenges in manufacturing and patient administration.

[0158] REGN1908 at a concentration of 150 mg / mL was formulated with 10 mM histidine at different pH values ​​ranging from 5.4 to 6.5. The formulations were evaluated by SE-UPLC for aggregate formation under two different conditions: after 28 days of incubation at 45°C and after 2 months of incubation at 25°C. As shown in Figure 1A, after 28 days of incubation at 45°C, undesirable levels of HMW aggregates were observed in the pH 5.4 formulation. After 28 days of incubation at 45°C, the lowest levels of HMW species were observed for the formulation at pH 6.0 (Figure 1A), whereas after 2 months of incubation at 25°C, the lowest levels of HMW species were observed for the formulations at pH 5.8, 6.0, and 6.2 (Figure 1B).

[0159] REGN1908 formulations were also evaluated for viscosity at 20° C. As shown in Figure 2, REGN1908 formulated at 150 mg / mL at pH 5.4 had the lowest viscosity, while formulations at pH 6.2 or 6.5 had viscosities >20 cP.

[0160] As shown in Table 4 below, formulating 150 mg / mL REGN1908 at pH 6.0 provides the best balance of acceptable viscosity and low HMW aggregate formation. The formulation at pH 6.0 was then tested to determine the effect of further increasing REGN1908 concentration on viscosity. As shown in Figure 3, it was found that 150 mg / mL REGN1908 exhibited a low viscosity of 19.7 cP, while higher concentrations resulted in formulations with viscosities >20 cP.

[0161] Table 4. Viscosity and aggregation of high-concentration REGN1908 formulations TIFF2026508525000006.tif31128+ Favorable, 0 Neutral, - Unfavorable, NA Not Applicable

[0162] REGN1909 at a concentration of 150 mg / mL was formulated with 10 mM histidine at different pH values ​​ranging from 5.4 to 6.8. The formulations were evaluated by SE-UPLC for aggregate formation under two different conditions: after 28 days of incubation at 45°C and after 2 months of incubation at 25°C. As shown in Figure 1A, after 28 days of incubation at 45°C, undesirable levels of HMW aggregates were observed in the pH 5.4 formulation. After 28 days of incubation at 45°C, the lowest levels of HMW species were observed for formulations at pH 6.2 and 6.5 (Figure 1A). After 2 months of incubation at 25°C, the lowest levels of HMW species were observed for formulations at pH 5.4, 5.6, 5.8, and 6.0 (Figure 1B).

[0163] REGN1909 formulations at different pH were evaluated for viscosity at 20° C. As shown in Figure 2, REGN1908 formulated at 150 mg / mL pH 5.4 had the lowest viscosity, but all tested formulations exhibited viscosities < 20 cP.

[0164] As shown in Table 5 below, formulating 150 mg / mL REGN1909 at pH 5.6-6.0 provides the best balance of acceptable viscosity and low HMW aggregate formation. The formulation at pH 6.0 was then tested to determine the effect of further increasing REGN1909 concentration on viscosity. As shown in Figure 3, it was found that 150 mg / mL REGN1909 exhibited a viscosity of 11.8 cP. Higher concentrations, up to approximately 180 mg / mL, still exhibited acceptable viscosity.

[0165] Table 5. Viscosity and aggregation of high-concentration REGN1909 formulations TIFF2026508525000007.tif35128+ favorable, 0 neutral, - unfavorable

[0166] The effect of four different viscosity-lowering agents on high-concentration formulations of REGN1908 or REGN1909 was also tested. 150 mg / mL of REGN1908 or REGN1909 was formulated at pH 6.0 with the following excipients: (i) 10 mM histidine (i.e., no viscosity-lowering agent), (ii) 10 mM histidine + 70 mM arginine-HCl, (iii) 100 mM histidine, (iv) 10 mM histidine + 3% proline, or (v) 10 mM histidine + 70 mM sodium chloride. The formulations were evaluated for viscosity at 20°C. As shown in Figure 4 and Table 6 below, 70 mM arginine was most effective at reducing the viscosity of REGN1908 (the more viscous of the two antibodies). For REGN1908, a viscosity of <10 cP was obtained using 70 mM arginine, 100 mM histidine, or 70 mM sodium chloride as the viscosity-lowering agent. For REGN1909, each of the viscosity-lowering agents tested resulted in a formulation with a viscosity of <10 cP.

[0167] Table 6: Effect of viscosity reducers TIFF2026508525000008.tif28134

[0168] The effect of cryoprotectants on viscosity was tested for REGN1908 and REGN1909. REGN1908 or REGN1909 was formulated at a target concentration of 150 mg / mL with 10 mM histidine at pH 6.0. As shown in Figure 5, the viscosity of REGN1909 was essentially unaffected by the addition of 5% w / v or 10% w / v cryoprotectant sucrose. However, the viscosity of REGN1908 was approximately 20 cP in the presence of 5% sucrose and increased to 30 cP in the presence of 10% sucrose. Further studies were performed with REGN1908 to determine the effect on viscosity of including 70 mM arginine-HCl in the presence of sucrose. As shown in Figure 6, 70 mM arginine-HCl was able to reduce the viscosity of REGN1908 formulations at a concentration of approximately 140 mg / mL containing 5% sucrose w / v; it was determined that the formulation containing 70 mM arginine-HCl and 5% sucrose had a viscosity of approximately 8 cP at 20°C, compared to a viscosity of approximately 24 cP in the absence of arginine and sucrose (Figure 6), or a viscosity of approximately 20 cP in the presence of 5% sucrose (Figure 5).

[0169] Table 7 below shows seven formulations each for REGN1908 and REGN1909 that were evaluated for stability at a target protein concentration of 175 mg / mL; this higher antibody concentration was selected given the potential need for high antibody doses in clinical trials. As shown in Table 7 below, in the absence of a viscosity-lowering agent and sucrose, the REGN1908 formulation had a viscosity of 34.8 cP. Formulating REGN1908 with 10 mM histidine and 70 mM arginine, without sucrose, or with 5% sucrose, yielded formulations with minimal viscosity (13.7 cP and 18.0 cP, respectively). Formulating REGN1908 with 80 mM histidine without sucrose yielded a formulation with a viscosity of 15.8 cP; adding 5% or 10% sucrose increased the viscosity to 20.5 cP or 23.3 cP, respectively. For the REGN1909 formulations, all of the formulations tested had a viscosity of <20 cP.

[0170] Table 7. Viscosity of 175 mg / mL REGN1908 or REGN1909 Formulations TIFF2026508525000009.tif44146*The measured concentration of REGN1909 in this sample was 183 mg / mL. For the other sample, the concentration was approximately 175 mg / mL.

[0171] Example 4: Exemplary single antibody formulations In certain embodiments, anti-Fel d1 antibodies (e.g., REGN1908 and REGN1909) are individually formulated in an aqueous buffer formulation containing (a) 5 mM to 20 mM histidine buffer, (b) 60 mM to 130 mM arginine, and (c) 50 to 200 mg of anti-Fel d1 antibody at pH 6.0±0.3. In some embodiments, the formulation further comprises 2.5% to 7.5% w / v sucrose and / or 0.01% to 0.5% w / v polysorbate.

[0172] In certain embodiments, anti-Fel d1 antibodies (e.g., REGN1908 and REGN1909) are individually formulated in an aqueous buffer formulation containing (a) 5 mM to 20 mM histidine buffer, (b) 2.5% to 7.5% w / v sucrose, (c) 60 mM to 130 mM arginine, and (d) 50 to 200 mg of anti-Fel d1 antibody at pH 6.0±0.3. In some embodiments, the formulation further comprises 0.01% to 0.5% w / v polysorbate.

[0173] In one exemplary embodiment, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, and (d) 190 mg / mL ± 10 mg / mL REGN1908 at pH 6.0 ± 0.3.

[0174] In one exemplary embodiment, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, (d) 0.15% ± 0.075% w / v polysorbate 80, and (e) 150 mg / mL ± 15 mg / mL REGN1908 at pH 6.0 ± 0.3.

[0175] In one exemplary embodiment, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, and (d) 190 mg / mL ± 10 mg / mL REGN1909 at pH 6.0 ± 0.3.

[0176] In one exemplary embodiment, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, (d) 0.15% ± 0.075% w / v polysorbate 80, and (e) 150 mg / mL ± 15 mg / mL REGN1909 at pH 6.0 ± 0.3.

[0177] Example 5: Stability testing of REGN1908 formulations REGN1908 was formulated at approximately 150 mg / mL or approximately 190 mg / mL for various long-term stability studies. "REGN1908 Formulation #1" contained 191.2 mg / mL REGN1908, 10 mM histidine, 70 mM arginine-HCl, and 5% (w / v) sucrose at pH 6.0. "REGN1908 Formulation #2" contained 155.7 mg / mL REGN1908, 10 mM histidine, 70 mM arginine-HCl, 5% (w / v) sucrose, and 0.15% (w / v) highly purified polysorbate 80 at pH 6.0. Stability studies of REGN1908 Formulations #1 and #2 were conducted in 5 mL polycarbonate vials.

[0178] REGN1908 Formulation #1 For the stability study of REGN1908 Formulation #1, long-term storage conditions were -80°C or -30°C for 0, 1, 3, 6, 9, 12, 18, and 24 months. Accelerated conditions were -20°C for 0, 1, 3, and 6 months, 5°C for 0, 0.5, 1, 3, and 6 months, or 25°C / 60% RH for 0, 0.5, 1, 3, and 6 months. Thermal stress conditions were 40°C / 75% RH for 0, 0.25, 0.5, 1, and 3 months. Stability under physical stress, including agitation and freeze / thaw, was also evaluated. For the agitation assay, samples were vortexed at 1000 RPM for 0, 5, and 10 minutes. For the freeze / thaw assay, samples were frozen at -30°C and thawed at room temperature for 0, 2, and 4 cycles.

[0179] Twelve months of storage stability data are available for REGN1908 Formulation #1. No apparent changes in the physical or chemical stability of REGN1908 Formulation #1 were detected when stored at -80°C and -30°C for up to 24 months (Tables 8 and 9). All attributes tested met quality targets under the storage conditions. These results indicate that REGN1908 Formulation #1 is stable for at least 24 months when frozen at either -30°C or -80°C storage conditions.

[0180] Stability testing studies showed that REGN1908 Formulation #1 was physically and chemically stable when incubated at -20°C for up to 6 months, at 5°C for up to 6 months, and at 25°C / 60% RH for up to 0.5 months (Table 10), with no significant changes observed in the monitored stability attributes. At 25°C / 60% RH, a 1.1% increase in HMW species was observed by SE-UPLC, an 8.8% increase in Region 1 (acidic variants) by iCIEF, and no significant changes in Region 3 (basic variants) were observed over 6 months of storage.

[0181] After 3 months of incubation at 40°C / 75% RH, a 14.7% increase in HMW species was observed by SE-UPLC. In region 1 (acidic charge variants), a 35.8% increase was observed by iCIEF (Table 10). A concomitant 31.8% decrease in region 2 (main peak) was observed by iCIEF, with no significant change to region 3 (basic charge variants).

[0182] REGN1908 Formulation #1 was chemically stable when vortexed for either 5 or 10 minutes (Table 11). However, after 5 and 10 minutes of the extreme stress conditions of vortexing, the formulation experienced a 0.3% and 0.5% increase in HMW species, respectively. REGN1908 Formulation #1 was physically and chemically stable when subjected to four freeze-thaw cycles (Table 11). No apparent changes in physical or chemical stability were detected in any of the monitored attributes.

[0183] Table 8. Stability of REGN1908 Formulation #1 at -80°C TIFF2026508525000010.tif77146NP=Not implemented

[0184] Table 9. Stability of REGN1908 Formulation #1 at -30°C TIFF2026508525000011.tif77146NP=Not implemented

[0185] Table 10. Stability of REGN1908 Formulation #1 incubated at -20°C, 5°C, 25°C / 60% RH, and 40°C / 75% RH TIFF2026508525000012.tif217106NP=Not implemented

[0186] Table 11. Stability of REGN1908 Formulation #1 - Effect of Agitation and Freeze / Thaw TIFF2026508525000013.tif158128NP=Not implemented

[0187] REGN1908 Formulation #2 For the stability study of REGN1908 Formulation #2, long-term storage conditions were -80°C or -30°C for 0, 1, 3, 6, 9, 12, 18, and 24 months. Accelerated conditions were -20°C for 0, 1, 3, and 6 months, 5°C for 0, 0.5, 1, 3, and 6 months, or 25°C / 60% RH for 0, 0.5, 1, 3, and 6 months. Thermal stress conditions were 40°C / 75% RH for 0, 0.25, 0.5, 1, and 3 months. Stability under physical stress, including agitation and freeze / thaw, was also evaluated. For the agitation assay, samples were vortexed at 1000 RPM for 0, 30, and 60 minutes. For the freeze / thaw assay, samples were frozen at -30°C and thawed at room temperature for 0, 2, and 4 cycles.

[0188] Storage stability data for 24 months is available for REGN1908 Formulation #2. No apparent changes in the physical or chemical stability of REGN1908 Formulation #2 were detected when stored at -80°C and -30°C for up to 24 months (Tables 12 and 13). All attributes tested met quality targets under storage conditions. These results indicate that REGN1908 Formulation #2 is stable for at least 24 months when frozen at storage conditions.

[0189] Stability testing studies showed that REGN1908 Formulation #2 was physically and chemically stable when incubated at -20°C for up to 6 months, at 5°C for up to 6 months, and at 25°C / 60% RH for up to 0.5 months (Table 14), with no significant changes observed in the monitored stability attributes. At 25°C / 60% RH, a 0.8% increase in HMW species was observed by SE-UPLC, a 7.6% increase in Region 1 (acidic variants) by iCIEF, and no significant changes in Region 3 (basic variants) were observed over 6 months of storage.

[0190] After 3 months of incubation at 40°C / 75% RH, a 13.1% increase in HMW species was observed by SE-UPLC. In region 1 (acidic charge variants), a 34.8% increase was observed by iCIEF (Table 14). A concomitant 31.1% decrease in region 2 (main peak) was observed by iCIEF, with no significant change to region 3 (basic charge variants).

[0191] REGN1908 Formulation #2 was physically and chemically stable when vortexed for either 60 or 120 minutes (Table 15). No obvious changes in physical or chemical stability were detected in any of the monitored attributes. REGN1908 Formulation #2 was physically and chemically stable when subjected to up to four freeze-thaw cycles (Table 15). No obvious changes in physical or chemical stability were detected in any of the monitored attributes.

[0192] Table 12. Stability of REGN1908 Formulation #2 at -80°C TIFF2026508525000014.tif82161

[0193] Table 13. Stability of REGN1908 Formulation #2 at -30°C TIFF2026508525000015.tif82161

[0194] Table 14. Stability of REGN1908 Formulation #2 incubated at -20°C, 5°C, 25°C / 60% RH, and 40°C / 75% RH TIFF2026508525000016.tif214106NP=Not implemented

[0195] Table 15. Stability of REGN1908 Formulation #2 - Effect of Agitation and Freeze / Thaw TIFF2026508525000017.tif149128NP=Not implemented

[0196] Example 6: Stability testing of REGN1909 formulations REGN1909 was formulated at approximately 150 mg / mL or approximately 190 mg / mL for various long-term stability studies. "REGN1909 Formulation #1" contained 189.4 mg / mL REGN1909, 10 mM histidine, 70 mM arginine-HCl, and 5% (w / v) sucrose at pH 6.0. "REGN1909 Formulation #2" contained 152.6 mg / mL REGN1909, 10 mM histidine, 70 mM arginine-HCl, 5% (w / v) sucrose, and 0.15% (w / v) highly purified polysorbate 80 at pH 6.0. Stability studies of REGN1909 Formulations #1 and #2 were conducted in 5 mL polycarbonate vials.

[0197] REGN1909 Formulation #1 For the stability study of REGN1909 Formulation #1, long-term storage conditions were -80°C or -30°C for 0, 1, 3, 6, 9, 12, 18, and 24 months. Accelerated conditions were -20°C for 0, 1, 3, and 6 months, 5°C for 0, 0.5, 1, 3, and 6 months, or 25°C / 60% RH for 0, 0.5, 1, 3, and 6 months. Thermal stress conditions were 40°C / 75% RH for 0, 0.25, 0.5, 1, and 3 months. Stability under physical stress, including agitation and freeze / thaw, was also evaluated. For the agitation assay, samples were vortexed at 1000 RPM for 0, 5, and 10 minutes. For the freeze / thaw assay, samples were frozen at -30°C and thawed at room temperature for 0, 2, and 4 cycles.

[0198] Storage stability data for 24 months is available for REGN1909 Formulation #1. No apparent changes in the physical or chemical stability of REGN1909 Formulation #1 were detected when stored at -80°C and -30°C for up to 24 months (Tables 16 and 17). All attributes tested met quality targets under storage conditions. These results indicate that REGN1909 Formulation #1 is stable for at least 24 months when frozen at either -30°C or -80°C storage conditions.

[0199] Stability testing studies showed that REGN1909 Formulation #1 was physically and chemically stable when incubated at -20°C for up to 6 months, at 5°C for up to 6 months, and at 25°C / 60% RH for up to 0.5 months (Table 18), with no significant changes observed in the monitored stability attributes. At 25°C / 60% RH, a 1.8% increase in HMW species was observed by SE-UPLC, an 8.8% increase in Region 1 (acidic variants) by iCIEF, and no significant changes in Region 3 (basic variants) were observed over 6 months of storage.

[0200] After 3 months of incubation at 40°C / 75% RH, a 6.4% increase in HMW species was observed by SE-UPLC. In region 1 (acidic charge variants), a 28.4% increase was observed by iCIEF (Table 18). A concomitant 28.8% decrease in region 2 (main peak) was observed by iCIEF, with no significant change to region 3 (basic charge variants).

[0201] REGN1909 Formulation #1 was physically and chemically stable when vortexed for 5 minutes (Table 19). However, after the extreme stress of vortexing for 10 minutes, REGN1909 Formulation #1 was chemically stable but not physically stable due to a 0.3% increase in HMW species. REGN1909 Formulation #1 was physically and chemically stable when subjected to four freeze-thaw cycles (Table 19). No obvious changes in physical or chemical stability were detected in any of the monitored attributes.

[0202] Table 16. Stability of REGN1909 Formulation #1 at -80°C TIFF2026508525000018.tif82161

[0203] Table 17. Stability of REGN1909 Formulation #1 at -30°C TIFF2026508525000019.tif82161

[0204] Table 18. Stability of REGN1909 Formulation #1 incubated at -20°C, 5°C, 25°C / 60% RH, and 40°C / 75% RH TIFF2026508525000020.tif19699NP=Not implemented

[0205] Table 19. Stability of REGN1909 Formulation #1 - Effect of Agitation and Freeze / Thaw TIFF2026508525000021.tif149128NP=Not implemented

[0206] REGN1909 Formulation #2 For the stability study of REGN1909 Formulation #2, long-term storage conditions were -80°C or -30°C for 0, 1, 3, 6, 9, 12, 18, and 24 months. Accelerated conditions were -20°C for 0, 1, 3, and 6 months, 5°C for 0, 0.5, 1, 3, and 6 months, or 25°C / 60% RH for 0, 0.5, 1, 3, and 6 months. Thermal stress conditions were 40°C / 75% RH for 0, 0.25, 0.5, 1, and 3 months. Stability under physical stress, including agitation and freeze / thaw, was also evaluated. For the agitation assay, samples were vortexed at 1000 RPM for 0, 30, and 60 minutes. For the freeze / thaw assay, samples were frozen at -30°C and thawed at room temperature for 0, 2, and 4 cycles.

[0207] Storage stability data for 24 months is available for REGN1909 Formulation #2. No obvious changes in the physical or chemical stability of REGN1909 Formulation #2 were detected when stored at 80°C and -30°C for up to 24 months (Tables 20 and 21). These results indicate that REGN1909 Formulation #2 is stable for at least 24 months when stored frozen at either -30°C or -80°C.

[0208] Stability testing studies showed that REGN1909 Formulation #2 was physically and chemically stable when incubated at -20°C for up to 6 months, at 5°C for up to 6 months, and at 25°C / 60% RH for up to 0.5 months (Table 22), with no significant changes observed in the monitored stability attributes. At 25°C / 60% RH, a 1.5% increase in HMW species was observed by SE-UPLC, an 11.0% increase in Region 1 (acidic variants) by iCIEF, and no significant changes in Region 3 (basic variants) were observed over 6 months of storage.

[0209] After 3 months of incubation at 40°C / 75% RH, a 5.4% increase in HMW species was observed by SE-UPLC. In region 1 (acidic charge variants), a 31.3% increase was observed by iCIEF (Table 22). A concomitant decrease of 29.6% in region 2 (main peak) was observed by iCIEF, with no significant change to region 3 (basic charge variants).

[0210] REGN1909 Formulation #2 was physically and chemically stable when vortexed for either 60 or 120 minutes (Table 23). After 120 minutes of vortexing, more subvisible particles than normal were observed. However, no increase in the HMW percentage was observed. More extensive agitation of Formulation #2 was performed using an orbital shaker for 24 and 48 hours. After 48 hours on the orbital shaker, a 0.1% increase in HMW species was observed, along with small subvisible particles in the 10 μm and 25 μm bin ranges (255 and 21 particles / mL, respectively). No significant changes in physical or chemical stability were detected in any of the other monitored attributes. REGN1909 Formulation #2 was physically and chemically stable when subjected to up to four freeze-thaw cycles (Table 23). No significant changes in physical or chemical stability were detected in any of the monitored attributes.

[0211] Table 20. Stability of REGN1909 Formulation #2 at -80°C TIFF2026508525000022.tif82161

[0212] Table 21. Stability of REGN1909 Formulation #2 at -30°C TIFF2026508525000023.tif82161

[0213] Table 22. Stability of REGN1909 Formulation #2 incubated at -20°C, 5°C, 25°C / 60% RH, and 40°C / 75% RH TIFF2026508525000024.tif210106NP=Not implemented

[0214] Table 23. Stability of REGN1909 Formulation #2 - Effect of Agitation and Freeze / Thaw TIFF2026508525000025.tif149128NP=Not implemented

[0215] Example 7: Co-formulation of anti-Fel d1 antibodies In situations where multiple antibodies are administered to a patient simultaneously, it may be beneficial to co-formulate the antibodies together in a single formulation (e.g., for ease of patient administration and improved patient compliance). Development work has begun on the co-formulation of a fixed-dose combination of REGN1908 and REGN1909. A histidine buffer at pH 6.0 was selected to co-formulate REGN1908 and REGN1909; as shown in Tables 4 and 5 above, pH 6.0 was the optimal pH for achieving both acceptable viscosity and low or low / moderate aggregation stability for both REGN1908 and REGN1909.

[0216] As disclosed in Example 3 above, REGN1908 was found to have a higher viscosity than REGN1909 in otherwise identical formulations. Formulations containing both REGN1908 and REGN1909 were tested to determine whether co-formulation of REGN1908 and REGN1909 increased formulation viscosity. Formulations containing a target total antibody concentration of 150 mg / mL (approximately 75 mg / mL REGN1908 and approximately 75 mg / mL REGN1909) were formulated at pH 6.1 with 10 mM histidine and 5% sucrose, and either no arginine or 20, 50, 70, 100, or 130 mM arginine. Co-formulations with at least 50 mM arginine had similar viscosities to the corresponding separately formulated REGN1908 or REGN1909 (Figures 7A-7C). A significant difference in viscosity was observed between the formulations without arginine and those with 20 mM arginine (FIGS. 7A-7C).

[0217] REGN1908 and REGN1909 were co-formulated in the absence or presence of polysorbate surfactants to assess their effect on stability. Starting with a base formulation containing REGN1908-REGN1909 (approximately 75 mg / mL of each antibody) at a target total antibody concentration of 150 mg / mL, 10 mM histidine, and 70 mM arginine hydrochloride at pH 6.0, no polysorbate was added, or polysorbate 20 or polysorbate 80 was added in amounts of 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, or 0.2% (all percentages are w / v). The formulations were subjected to agitation stress induced by orbital shaking at 250 rpm for 24 or 48 hours. As shown in Figure 8, formulations containing ≥0.05% w / v polysorbate 20 were protected from aggregate formation (Figure 8A), while formulations containing ≥0.075% w / v polysorbate 80 were protected from aggregate formation (Figure 8B). In addition, for the 48-hour samples, the presence of subvisible particles at >10 microns and >25 microns was determined using microfluidic imaging (MFI). As shown in Figure 9, both polysorbate 20 and polysorbate 80 were effective at ≥0.025% w / v, but polysorbate 80 resulted in lower particle counts in both the 10- and 25-micron bins compared to polysorbate 20.

[0218] Co-formulations containing polysorbate 20 or polysorbate 80 and further comprising a cryoprotectant were generated and tested for stability under accelerated stability storage conditions (40°C at 75% relative humidity) and repeated freeze-thaw conditions. Starting with a base formulation containing REGN1908-REGN1909 (approximately 75 mg / mL of each antibody) at a target total antibody concentration of 150 mg / mL at pH 6.0, 10 mM histidine, 70 mM arginine hydrochloride, and 0.15% (w / v) polysorbate, no cryoprotectant was added, or 5% sucrose, 3% proline, 5% trehalose, or 2.5% sorbitol was added (all percentages w / v).

[0219] Figures 10A-10B show the stability data for the co-formulations containing polysorbate 20, and Figures 10C-10D show the stability data for the co-formulations containing polysorbate 80. Figures 10A and 10C show that the aggregate formation rate (slope) of the cryoprotectant was higher in the presence of polysorbate 20 than polysorbate 80, suggesting a better stability profile for the polysorbate 80 formulation. As shown in Figures 10B and 10D, the presence of the cryoprotectant protected HMW formation after eight freeze / thaw cycles for both the polysorbate 20- and polysorbate 80-containing formulations.

[0220] Example 8: Co-formulation Characterization (DoE) A design of experiments (DoE) analysis was performed on the components of an exemplary formulation scaled over a range wider than typical manufacturing specifications. Table 24 below shows the factors and ranges investigated. REGN1908 and REGN1909 were co-formulated in an approximately 1:1 ratio.

[0221] Table 24: Factors investigated by DoE TIFF2026508525000026.tif49145

[0222] Figure 11 shows the predicted formulation response at 40°C as a function of the range of formulation components. The positive or negative slope across the component range (x-axis) indicates the formulation's attribute response (y-axis) to that change, and the vertical dotted lines indicate the selected target value for each formulation component. Most of the thermal profiler trends are flat, indicating that the protein and formulation are thermally stable across the functional range of the components. Most of the response (y-axis) is largely unaffected except for a change as a function of pH, indicating that protein stability is affected by the pH of the formulation.

[0223] Figure 12 shows the predicted formulation response under agitation as a function of the range of formulation components. The trend for most of the agitation profiler is fairly flat across the range, indicating that the protein and formulation are thermally stable across the functional range of the components. However, a significant decrease in particle formation is predicted with increasing sucrose concentration.

[0224] Figure 13 shows the predicted formulation response under repeated freeze-thaw cycles as a function of the range of formulation components. The trends for most of the freeze-thaw profilers are fairly flat across the range, indicating that the protein and formulation are stable to freeze-thaw stress across the functional range of the components. A significant increase in particle formation is predicted with increasing pH, although particle counts are very low at the target pH of 6.0.

[0225] Figure 14 shows the predicted osmolality and viscosity responses as a function of the range of formulation components. The trends for most of the t=0 profilers are flat across the range, indicating that the protein formulation will not experience significant changes in viscosity and osmolality across the functional range of the components. For viscosity, a significant increase in viscosity is predicted with increasing protein concentration, and a significant decrease in viscosity is predicted with increasing viscosity-lowering agent (arginine). For osmolality, a significant increase in osmolality is predicted with increasing arginine and sucrose concentrations, but these predicted changes do not fall outside the manufacturing range and do not exceed physiological tolerance.

[0226] Example 9: Stability Study of REGN1908-REGN1909 Co-formulations In certain embodiments, two anti-Fel d1 antibodies are co-formulated in an aqueous buffer formulation at pH 6.0±0.3, comprising: (a) 5 mM to 20 mM histidine buffer; (b) 2.5% to 7.5% w / v sucrose; (c) 60 mM to 130 mM arginine; (d) 0.01% to 0.5% w / v polysorbate; and (e) 50 to 200 mg of total anti-Fel d1 antibody.

[0227] In one exemplary embodiment, the anti-Fel d1 antibody formulation comprises (a) 10 mM ± 2 mM histidine, (b) 5% ± 1% w / v sucrose, (c) 70 mM ± 14 mM arginine, (d) 0.15% ± 0.075% w / v polysorbate 80, and (e) 150 mg / mL ± 15 mg / mL REGN1908-REGN1909 (75 mg / mL REGN1908 + 75 mg / mL REGN1909) at pH 6.0 ± 0.3.

[0228] REGN1908 and REGN1909 were co-formulated for various long-term stability studies at a concentration of approximately 150 mg / mL total antibody (approximately a 1:1 ratio of REGN1908:REGN1909, containing approximately 75 mg / mL REGN1908 and approximately 75 mg / mL REGN1909) in 10 mM histidine, 70 mM arginine-HCl, 5% (w / v) sucrose, and 0.15% (w / v) highly purified polysorbate 80 at pH 6.0. Stability studies on the REGN1908-1909 co-formulation were conducted in glass vials and pre-filled syringes (PFS).

[0229] As shown below in Tables 25 and 26, stability testing studies demonstrated that the REGN1908-1909 co-formulation, when stored in glass vials or PFS, was physically and chemically stable when incubated at 5° C. for up to 24 months, with no significant changes observed in monitored stability attributes. Vial and PFS stability were comparable.

[0230] After 3 months of incubation at 40°C / 75% RH, a 10.9% increase in HMW species was observed by SE-UPLC for the REGN1908-1909 co-formulation stored in glass vials, and a 9.8% increase in HMW species was observed for the co-formulation stored in PFS. See Tables 27 and 28.

[0231] The REGN1908-1909 co-formulation was physically and chemically stable under agitation stress (see Tables 29 and 30) and when subjected to four freeze-thaw cycles (Table 29). No apparent changes in physical or chemical stability were detected in any of the monitored attributes.

[0232] Table 25. Stability of REGN 1908-1909 Co-formulated Vial Drug Product at 5°C TIFF2026508525000027.tif114158

[0233] Table 26. Stability of REGN1908-1909 co-formulated PFS drug at 5°C TIFF2026508525000028.tif138161

[0234] Table 27. Stability of REGN 1908-1909 Co-formulated Vial Drug Product at 25°C / 60% RH and 40°C / 75% RH TIFF2026508525000029.tif86150

[0235] Table 28. Stability of REGN1908-1909 co-formulated PFS drug at 25°C / 60%RH and 40°C / 75%RH TIFF2026508525000030.tif86150

[0236] Table 29. REGN 1908-1909 Co-formulated Vial Drug Product Agitation and Freeze / Thaw Stability TIFF2026508525000031.tif86150

[0237] Table 30. REGN1908-1909 Co-formulation PFS Drug Product Stability TIFF2026508525000032.tif78128

[0238] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. The disclosures of all patent and non-patent literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. 1. A stable liquid pharmaceutical formulation comprising: (a)(i) an antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14; and (ii) an antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:

28. at least one antibody that specifically binds to Fel d1 selected from the group consisting of: (b) a buffer containing histidine; (c) a heat stabilizer; and (d) a surfactant; and having a pH of 6.0±0.

3.

2. 2. The stable liquid pharmaceutical formulation of claim 1, comprising: (i) a first antibody that specifically binds to Fel d1, the first antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14; and (ii) a second antibody that specifically binds to Fel d1, the second antibody comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:

28.

3. 3. The stable liquid pharmaceutical formulation of claim 2, wherein the first antibody comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

10.

4. 3. The stable liquid pharmaceutical formulation of claim 2, wherein the second antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO:

24.

5. The stable liquid pharmaceutical formulation according to any one of claims 1 to 4, wherein the total antibody concentration is from 5 mg / mL to 200 mg / mL.

6. 6. The stable liquid pharmaceutical formulation of claim 5, wherein the total antibody concentration is 150 mg / mL ± 15 mg / mL.

7. 7. The stable liquid pharmaceutical formulation of any one of claims 2 to 6, wherein the first antibody and the second antibody are present in the formulation in a molecular ratio of about 1:

1.

8. 8. The stable liquid pharmaceutical formulation of any one of claims 2 to 7, wherein the first antibody is present at a concentration of 75 mg / mL ± 7.5 mg / mL and the second antibody is present at a concentration of 75 mg / mL ± 7.5 mg / mL.

9. 9. The stable liquid pharmaceutical formulation according to any one of claims 1 to 8, wherein the buffer comprises histidine at a concentration of 5 mM to 25 mM.

10. 10. The stable liquid pharmaceutical formulation of claim 9, wherein the histidine is present at a concentration of 10 mM ± 2 mM.

11. 11. The stable liquid pharmaceutical formulation according to any one of claims 1 to 10, wherein the heat stabilizer comprises sucrose, trehalose, proline, or sorbitol.

12. 12. The stable liquid pharmaceutical formulation of claim 11, wherein the heat stabilizer comprises sucrose at a concentration of 2.5% to 7.5% w / v.

13. 13. The stable liquid pharmaceutical formulation of claim 12, wherein the sucrose is present at a concentration of 5% w / v ± 1% w / v.

14. 14. The stable liquid pharmaceutical formulation according to any one of claims 1 to 13, further comprising a viscosity-lowering agent.

15. 15. The stable liquid pharmaceutical formulation of claim 14, wherein the viscosity-lowering agent comprises arginine.

16. 16. The stable liquid pharmaceutical formulation of claim 15, wherein the arginine is present at a concentration of 60 mM to 130 mM.

17. 16. The stable liquid pharmaceutical formulation of claim 15, wherein the arginine is present at a concentration of at least 70 mM.

18. 16. The stable liquid pharmaceutical formulation of claim 15, wherein the arginine is present at a concentration of 70 mM ± 14 mM.

19. 19. The stable liquid pharmaceutical formulation according to any one of claims 1 to 18, wherein the surfactant comprises polysorbate 20 or polysorbate 80.

20. 20. The stable liquid pharmaceutical formulation of claim 19, wherein the polysorbate 20 or polysorbate 80 is present in a concentration of 0.05% w / v to 0.2% w / v.

21. 20. The stable liquid pharmaceutical formulation of claim 19, wherein the surfactant comprises polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v.

22. histidine at a concentration of 10 mM ± 2 mM, sucrose at a concentration of 5% w / v ± 1% w / v, Arginine at a concentration of 70 mM ± 14 mM, Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v Including, 22. The stable liquid pharmaceutical formulation of any one of claims 1 to 21, wherein the total antibody concentration in the formulation is 150 mg / mL ± 15 mg / mL and the formulation has a pH of 6.0 ± 0.

3.

23. 23. The stable liquid pharmaceutical formulation of any one of claims 1 to 22, having a viscosity of ≦25 cP at 20°C.

24. 24. The stable liquid pharmaceutical formulation of claim 23, having a viscosity of ≦15 cP at 20° C.

25. an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the concentration of the antibody is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; Sucrose at a concentration of 5% w / v ± 1% w / v; Arginine at a concentration of 70 mM ± 14 mM; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v; and having a pH of 6.0±0.

3.

26. an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the concentration of the antibody is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; Sucrose at a concentration of 5% w / v ± 1% w / v; Polysorbate 20 or Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v and having a pH of 6.0±0.

3.

27. 27. The stable liquid pharmaceutical formulation of claim 26, further comprising a viscosity-lowering agent.

28. 28. The stable liquid pharmaceutical formulation of claim 27, wherein the viscosity-lowering agent is arginine at a concentration of 70 mM ± 14 mM.

29. a first antibody that specifically binds to Fel d1, the first antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the concentration of the first antibody is 75 mg / mL ± 10 mg / mL; a second antibody that specifically binds to Fel d1, the second antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the concentration of the second antibody is 75 mg / mL ± 10 mg / mL; histidine at a concentration of 10 mM ± 2 mM; Sucrose at a concentration of 5% w / v ± 1% w / v; Arginine at a concentration of 70 mM ± 14 mM; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v; and having a pH of 6.0±0.

3.

30. 1. A stable liquid pharmaceutical formulation comprising: (a) an antibody that specifically binds to Fel d1, comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 14; (b) a buffer containing histidine; (c) a heat stabilizer; and (d) a surfactant; and having a pH of 6.0±0.

3.

31. 31. The stable liquid pharmaceutical formulation of claim 30, wherein the antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO:

10.

32. an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 2 and an LCVR comprising the amino acid sequence of SEQ ID NO: 10, wherein the concentration of the antibody is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; Sucrose at a concentration of 5% w / v ± 1% w / v; Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v; and having a pH of 6.0±0.

3.

33. 1. A stable liquid pharmaceutical formulation comprising: (a) an antibody that specifically binds to Fel d1, comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 20, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 22, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 26, an LCDR2 comprising the amino acid sequence KAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; (b) a buffer containing histidine; (c) a heat stabilizer; and (d) a surfactant; and having a pH of 6.0±0.

3.

34. 34. The stable liquid pharmaceutical formulation of claim 33, wherein the antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO:

24.

35. an anti-Fel D1 antibody comprising an HCVR comprising the amino acid sequence of SEQ ID NO: 16 and an LCVR comprising the amino acid sequence of SEQ ID NO: 24, wherein the concentration of the antibody is 50 mg / mL to 190 mg / mL; histidine at a concentration of 10 mM ± 2 mM; Sucrose at a concentration of 5% w / v ± 1% w / v; Polysorbate 20 or Polysorbate 80 at a concentration of 0.15% w / v ± 0.075% w / v and having a pH of 6.0±0.

3.

36. 36. The stable liquid pharmaceutical formulation of claim 35, further comprising a viscosity-lowering agent.

37. 37. The stable liquid pharmaceutical formulation of claim 36, wherein the viscosity-lowering agent is arginine at a concentration of 70 mM ± 14 mM.

38. 38. The stable liquid pharmaceutical formulation of any one of claims 1 to 37, housed in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector delivery device.

39. 38. The stable liquid pharmaceutical formulation of any one of claims 1 to 37, contained in a large volume device or bolus injector.

40. A container containing the stable liquid pharmaceutical formulation according to any one of claims 1 to 37.

41. (i) a container containing the stable liquid pharmaceutical formulation of any one of claims 1 to 37; (ii) labeling for use of said pharmaceutical preparation; and A kit comprising:

42. 42. The kit of claim 41, wherein the labeling describes subcutaneous or intravenous administration of the pharmaceutical formulation.

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