Liquid guselkumab composition

Abstract

The present invention relates to a liquid composition comprising the antibody guselkumab as well as products related thereto and their uses in medicine, specifically for the treatment of psoriasis, such as plaque psoriasis and / or psoriatic arthritis, and / or inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and / or Crohn's disease.

Description

[0001] Liquid guselkumab composition

[0002] TECHNICAL FIELD

[0003] The present invention relates to the field of antibody compositions, especially compositions comprising interleukin-23 (IL-23) antibodies, such as guselkumab. More specifically, the present invention is directed to liquid or lyophilized compositions comprising the antibody guselkumab, as well as related products and uses for the treatment of psoriasis, such as plaque psoriasis and / or psoriatic arthritis, as well as inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and / or Crohn's disease.

[0004] BACKGROUND

[0005] Therapeutic preparations comprising proteins, especially antibodies, as active ingredients have become more and more important over the past decades. Most of the therapeutic antibodies are administered dissolved in a liquid composition, such as by intravenous infusion or by subcutaneous or intramuscular injection. Stability of the antibody in the composition is a major concern to guarantee safety and efficacy of the applied therapy. Fine-tuning of the composition is used to obtain optimal stability, because already small changes in the nature and / or concentration of the ingredients of the composition may influence the antibody's stability.

[0006] Guselkumab is a monoclonal antibody targeting the cytokine IL-23. It is commonly used for the treatment of psoriasis, an autoimmune disease causing abnormal skin changes. It was found that the IL-23 receptor is strongly linked to psoriasis. By binding to the IL-23 subunit alpha (pl9 subunit) of IL-23, guselkumab prevents binding of IL-23 to the IL-23 receptor. Thereby, IL-23 receptor pathway activation is prevented as well as subsequent release of proinflammatory cytokines. Guselkumab is e.g., placed on the market under the brand name "Tremfya®", which is a liquid composition comprising guselkumab in a buffer comprising 10.9 mM L-histidine / L-histidine HCI, 230.8 mM sucrose, 0.05% PS80 and having a pH of about 5.8. The recommended dose is 100 mg guselkumab, followed by a further dose after 4 weeks and then 100 mg every 8 weeks. For patients with psoriatic arthritis, who have a high risk of joint damage, administration cycles can be set to every 4 weeks.

[0007] Currently, the manufacturer declares a 2-year shelf-life of the product stored at 2-8°C and only 4h of in-use stability (storage at room temperature). However, in practice, accidental increment of temperatures above 8°C apart from preparation of an injection may occur. Further, it is not always possible to keep the duration of storage as short as desired before using the guselkumab composition for treatment. Moreover, during transport, the liquid composition may be exposed to strong agitation stress. All these aspects influence the stability of the guselkumab molecule in the liquid composition.

[0008] Thus there is a long felt need to produce an alternate guselkumab formulation having higher stability that could translate into a longer shelf life and longer in-use stability at room temperature.

[0009] SUMMARY OF THE INVENTION

[0010] It is an object of the present invention to provide an improved liquid composition comprising guselkumab, which increases the stability of the guselkumab molecule during storage and transport, thereby allowing a composition having a longer shelf-life and expiration date.

[0011] The inventors have surprisingly found that a liquid composition comprising:

[0012] (a) guselkumab;

[0013] (b) a buffering agent;

[0014] (c) a surfactant; and

[0015] (d) a sugar compound, wherein the surfactant is a poloxamer and wherein the sugar compound is trehalose, maintains monomer content, prevents particle formation due to agitation stress, reduces changes caused by oxidation and / or stabilizes the pH of the liquid composition.

[0016] The composition described herein differs from known compositions due to the selection of a different quantitative and qualitative composition of excipients in relation to the reference product, which translates into improved stability of the protein, and thus allows for longer storage of the drug, without adversely affecting safety and effectiveness. In detail, the examples surprisingly show that a liquid composition comprising a lower histidine content showed a higher guselkumab conformational stability. Further, formulations having a higher content of poloxamer as a surfactant showed a lower content of sub-visible particles during mechanical stress. Thus surprisingly, poloxamer as a surfactant seems to be preferable to polysorbate 80. Also very surprisingly, the examples show that trehalose as a sugar compound stabilized the liquid composition comprising guselkumab much better than sucrose as a sugar compound. Moreover, the addition of L-proline or L-arginine HCI, resulted in a decrease of aggregation. The addition of L-arginine HCI additionally resulted in a lower acidic peak (AP) content (CEX) when compared to formulations with L-proline or without AA. Finally, the addition of methionine was also shown to improve protein stability.

[0017] To sum up the improved stabilizing effect of the formulation may allow for longer storage of the product at in-use conditions, which would provide greater flexibility in use, increase patient safety and reduce treatment costs, as the product would not have to be discarded in case of accidental, prolonged exposure to the room temperature.

[0018] Accordingly, in a first aspect, the invention relates to a liquid composition comprising:

[0019] (a) guselkumab;

[0020] (b) a buffering agent;

[0021] (c) a surfactant; and

[0022] (d) a sugar compound, wherein the surfactant is a poloxamer, wherein the concentration of the poloxamer is from 0.1% (v / v) to 0.5% (v / v), and wherein the sugar compound is trehalose, wherein the trehalose is present at a concentration of from 200 mM to 300 mM. The buffering agent can be, for example, L-histidine, preferably in a concentration from 5 to 20 mM, from 7 to 15 mM, or from 10 to 12 mM, most preferably about 10.9 mM. The poloxamer can be, for example PX188, preferably wherein the concentration of PX188 is from 0.1% (v / v) to 0.3% (v / v), preferably from 0.15% (v / v) to 0.25% (v / v), most preferably about 0.2% (v / v). The concentration of trehalose can be from 220 mM to 240 mM, preferably from 225 mM to 235 mM, more preferably about 230.8 mM. The liquid composition according to the invention can have a pH of 3 to 9, preferably the liquid composition has a pH of 4 to 8, more preferably the liquid composition has a pH of 5 to 7, most preferably the liquid composition has a pH of about 5.8.

[0023] In one specific embodiment, the liquid composition comprises 50 to 150 mg / ml guselkumab; 10 mM to 12 mM L-histidine / L-histidine HCI; 0.15 to 0.25% (v / v) PX188; and 225 mM to 235 mM trehalose; further having a pH of 5 to 6. In another specific embodiment, the liquid composition comprises about 100 mg / ml guselkumab; about 10.9 mM L-histidine / L-histidine HCI; about 0.2 % (v / v) PX188; and about 230.8 M trehalose; further having a pH of about 5.8.

[0024] In addition, the liquid guselkumab composition of the invention may further comprise at least one excipient, preferably wherein the at least one excipient is at least one amino acid, more preferably wherein the at least one amino acid is L-arginine and / or L-proline. Preferably, the L-arginine is L- arginine HCI and / or the L-proline is L-proline in free form and / or preferably wherein the concentration of L-arginine is 50 mM to 100 mM, preferably 80 mM and / or the concentration of L- proline is 100 mM to 200 mM, preferably about 150 mM.

[0025] Furthermore, the liquid guselkumab composition of the invention may comprise at least one antioxidant, preferably, wherein the at least one antioxidant is methionine, more preferably wherein the at least one antioxidant is L-methionine. Preferably, the concentration of L-methionine is from 0.5 mM to 50 mM, preferably from 1 mM to 20 mM, more preferably from 5 mM to 15 mM and most preferred from 8 mM to 12 mM.

[0026] In a second aspect, the present invention provides a lyophilized composition which can be reconstituted with water to result in a liquid composition according to the first aspect of the invention.

[0027] The present invention further provides in a third aspect a sealed container comprising the liquid composition according to the first aspect of the invention or a lyophilized composition according to the second aspect of the invention.

[0028] In a fourth aspect, the present invention provides an article of manufacture comprising the container according to the third aspect of the invention.

[0029] In a fifth aspect, the present invention relates to the liquid composition according to the first aspect of the invention for use in medicine.

[0030] The present invention in a sixth aspect further provides the liquid composition according to the first aspect of the invention for use in the treatment of psoriasis, such as plaque psoriasis and / or psoriatic arthritis.

[0031] Finally, in a seventh aspect the present invention provides the liquid composition according to the first aspect of the invention for use in the treatment of inflammatory bowel disease (IBD), preferably ulcerative colitis (UC) and / or Crohn's disease. Other objects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the following description, appended claims, and specific examples, which indicate preferred embodiments of the application, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.

[0032] DETAILED DESCRIPTION OF THE INVENTION

[0033] In the following, the present invention is disclosed in detail. The features of the present invention are described in individual paragraphs. This, however, does not mean that a feature described in a paragraph stands isolated from a feature or features described in other paragraphs. Rather, a feature described in a paragraph can be combined with a feature or features described in other paragraphs.

[0034] Further, the term "about", as used herein, is intended to provide flexibility to a specific value or a numerical range endpoint, providing that a given value may be "a little above" or "a little below" the indicated value accounting for variations one might see in the measurements taken among different instruments, samples, and sample preparations. The term "about" usually means within 5%, and preferably within 1% of a given value or range as well as also includes and specifically refers to the exact indicated number or range.

[0035] In order to provide an alternate and improved guselkumab formulation, preliminary studies were performed by replacing and adjusting the individual components of the known formulation buffer of Tremfya ®. In examples 1 to 3 below, the formulation buffer was further significantly improved with respect to the stabilization of guselkumab protein.

[0036] In detail, in example 1, various guselkumab-comprising compositions were created, varying in their content of buffering agent as well as the kind and content of surfactant and sugar compound. Optionally, L-proline or L-arginine were added. These formulations are numbered 1 to 12 in the following Table:

[0037] These compositions were then compared to the known composition (formulation No. 13 in the above Table) with respect to their ability of stabilizing guselkumab protein in standard F / T stress studies, agitation stress studies and short-term stability studies at stress conditions.

[0038] Detailed results of these experiments are shown in Table 6 to 12 in section 4.1 of Example 1.

[0039] First, for all formulations conformational thermal stability was tested directly after formulation preparation at TO via NanoDSF / backreflection (see Figure 1). Formulations comprising 10.9 mM histidine buffer and proline or no AA (F3, F5, F8, Fll, F12, and F13) were characterized by higher Tm when compared to the other formulations (see Figure 1, left diagram), i.e. they show a higher conformational stability. The results of the samples for which Tagg-on could be determined were similar, with a difference of about 3°C between the highest (Fl - 65.91°C) and the lowest result (F9 - 62.85°C) (see Figure 1, right diagram) The effects of agitation stress on the formulations were tested using Micro-Flow Imaging (see Figure 2). It turned out that after agitation stress, the highest total content of sub-visible particles was reported in formulations Fl, F2, and F3, which contained the lowest concentration of PX188 (0.02%), while the lowest level of sub-visible particles was noticed for formulations Fll, F12, and F13. Both compositions, Fll and F12, contain the highest tested concentration of PX188 (0.2%), suggesting that the concentration of 0.2% for PX188 provides the best stabilization of guselkumab during mechanical stress and should be used in further development.

[0040] When investigating short-term stability at stress conditions after 2 months, visual inspection revealed no major changes in the color for compositions containing 230.8 mM trehalose (F1-F6, F8-F11). In contrast thereto, a change in coloration was observed for the sucrose-containing formulations F7, F12, and F13 from slightly brown-yellow (BY4) to slightly brown-yellow to brownyellow (<BY2) or to brown-yellow (BY1) (see Figure 3).

[0041] At the same time, size exclusion chromatography (SEC) revealed for all samples a gradual increase in aggregate content (see Figure 4, top right diagram) and antibody fragments content (see Figure 4, bottom left diagram), which was reflected in a decrease in monomer content (see Figure 4, top left diagram).

[0042] In detail, for trehalose-containing formulations, the greatest decrease in monomer content was observed for formulations F4 and F10, both with higher histidine buffer concentration. In contrast, the smallest decrease was reported for formulation F8, a composition containing L-proline and the highest tested concentration of PX188.

[0043] The sucrose-containing formulations (F7, F12, and F13) presented a greater decrease in monomer content (10.61%-15.53%) after 2 months of storage at stress conditions, when compared to the other formulations, indicating that the addition of trehalose instead of sucrose prevents monomer decrease (see Figure 4, top left diagram).

[0044] Formulations comprising 50 mM histidine buffer (Fl, F4, F9, and F10) were characterized by higher antibody fragments content when compared to other formulations after 2 months of storage under stress conditions, indicating that a lower histidine buffer content is favorable in comparison to a higher histidine buffer content (see Figure 4, bottom left diagram).

[0045] Also in the context of the investigations of short-term stability at stress conditions after 2 months, it was found that it was impossible to determine charge variants profiles for F7, F12, and F13 due to excessive protein degradation. Figure 5 shows the results up to TIM, wherein all compositions were compared, while Figure 6 includes only those compositions for which it was possible to determine the charge variants profile (F1-F6, F8-F11) after 2 months of storage at 40°C±2°C / 75%±5% RH.

[0046] The cation exchange chromatography (CEX) results for samples stored under stress conditions for one month presented a gradual decline in the %MP content in all tested formulations (see Figure 5, top left diagram).

[0047] For trehalose-containing formulations, the greatest decrease in Main peak (MP) protein content was observed for formulations Fl, F4, F9, and F10, all with the higher concentration of histidine buffer (50 mM). In contrast, the smallest decrease was reported for formulations F2, F3, F5, F6, F8, and Fll, all with lower histidine buffer concentration (10.9 mM).

[0048] For the sucrose-containing formulations (F7, F12, and F13), the decrease in MP protein content was the highest after 1 month of storage at 40°C±2°C / 75%±5% RH. The greatest decrease in MP protein content was observed for formulation F13 (originator's composition), while the smallest decrease was reported for formulation F7, a composition containing L-arginine. Moreover, sucrose- containing formulations F7, F12, and F13 were characterized by the highest increase in AP content, when compared to others, which correlated with the subsequent pH changes.

[0049] The same conclusions as after 1 month of storage can be drawn for trehalose-containing compositions also after 2 months of storage at stress conditions. The greatest decrease in MP content was observed for formulations Fl, F4, F9, and F10, all with the higher concentration of histidine buffer (50 mM). The smallest decrease (36.78%-37.84%) was reported for formulations F2, F3, F5, F6, F8, and Fll, all with lower histidine buffer concentration (10.9 mM).

[0050] The results of CE-SDS nr analysis (Figure 7) for samples stored under stress conditions for 2 months showed a gradual decline in the level of purity in all guselkumab antibody compositions tested during storage under stress conditions. After 2 months of storage, the lowest purity results among all tested samples were reported for formulations F12 and F13, which correlated with the highest increase in HM Wl content in these compositions. HMWI were only visible in the sucrose-containing formulations F7, F12 and F13. The increase in antibody fragments content was similar (5.3%-7.4%) for all the formulations after 2 months of storage, apart from originator formulation F13, for which an unexpected increase of 8.9% is set out in the result section.

[0051] In a next step, the pH of all formulations Fl to F13 was examined after two months storage at stress conditions (see Figure 8). It was observed that during 2 months of storage of the trehalose- containing formulations F1-F6 and F8-F11 under stress conditions, the pH remained stable, the changes were within ±0.11 compared to TO. In contrast, the sucrose-containing compositions (F7, F12, F13) showed a decrease in pH in the range of 0.20-0.27, when compared to the starting values. ELISA investigations revealed a decrease in potency (relative binding affinity to rhulL-23) for all formulations (see Figure 9). The greatest decrease (56%-79%) was observed for the sucrose- containing formulations F7, F12, and F13, when compared to the TO. The remaining formulations were characterized by a similar decrease in potency (26%-42%).

[0052] In summary, it was surprisingly observed in Example 1 that compositions comprising 10.9 mM histidine mostly show better results in comparison to compositions comprising 50 mM histidine. The liquid compositions comprising a lower histidine content showed a higher guselkumab conformational stability. Further, formulations having a higher content of poloxamer as a surfactant showed a lower content of sub-visible particles during mechanical stress. Thus surprisingly, poloxamer as a surfactant seems to be preferable to polysorbate 80. Also very surprisingly, the examples showed that trehalose as a sugar compound stabilized the liquid composition comprising guselkumab much better than sucrose as a sugar compound. Moreover, the addition of L-proline or L-arginine HCI, resulted in a decrease of aggregation. The addition of L- arginine HCI additionally resulted in a lower acidic peak (AP) content (CEX) when compared to formulations with L-proline or without AA. Finally, the addition of methionine was also shown to improve protein stability.

[0053] The improved stabilizing effect of the formulation may allow for longer storage of the product at in-use conditions, which would provide greater flexibility in use, increase patient safety and reduce treatment costs, as the product would not have to be discarded in case of accidental, prolonged exposure to the room temperature.

[0054] Based on these results, the compositions having the numbers 2, 3, 5, 6, 8, 11, and 13 (F2, F3, F5, F6, F8, Fll, and F13, respectively) were further analyzed using Size Exclusion Chromatography (SEC), Enzyme-Linked Immunosorbent Assay (ELISA), Capillary Electrophoresis Sodium Dodecyl Sulfate technique (CE-SDS) and Cation Exchange Chromatography (CEX) in Example 2.

[0055] The results of SEC (see Figure 10) showed gradual increase in the HMWI and antibody fragments content for all samples, which was reflected in a decrease in monomer content. In detail, formulation 13 (originator) presented higher HMWI levels compared to the guselkumab formulations F2, F3, F5, F6, F8, and Fll.

[0056] The results of ELISA (see Figure 11) showed a sizeable decrease in the potency value for all samples. Especially, formulation 13 (originator) presented a higher decrease in relative binding affinity to rhulL-23 compared to the guselkumab formulations F2, F3, F5, F6, F8, and Fll. The results of CE-SDS in non-reduced conditions (see Figure 12) showed a general gradual increase in antibody fragments, which resulted in a decrease in purity content. Formulation 13 (originator) presented lower purity level compared to the guselkumab formulations F2, F3, F5, F6, F8, and Fll at the 8-week time point.

[0057] The results of CEX (see Figure 13) generally showed gradual increase in acidic peaks, which was reflected in a decrease in main peak content. Formulation 13 (originator) presented lower main peak and higher acidic peaks content compared to the guselkumab formulations F2, F3, F5, F6, F8, and Fll.

[0058] Considering all the data, new formulations F14 and F15 were designed and tested in Example 3. The concentration of the amino acids L-proline and L-arginine was increased to maximize the stabilizing properties. In composition F17, L-methionine was added instead of L-proline or L- arginine. Composition F16 depicts a reference sample without any amino acids.

[0059] The compositions F14, F15, F16 and F17 as well as Tremfya as a reference were further analyzed using Size Exclusion Chromatography (SEC), Capillary Electrophoresis Sodium Dodecyl Sulfate technique (CE-SDS) and Cation Exchange Chromatography (CEX).

[0060] The results of SEC showed gradual increase in the HMWI and antibody fragments content, which was reflected in a decrease in monomer content. Tremfya presented higher degradation rates compared to the guselkumab antibody compositions of the invention. The results of SEC at 40°C are shown in Figure 14.

[0061] At 25°C and 40°C, the results of CE-SDS in non-reduced conditions showed a gradual increase in antibody fragments, which resulted in a decrease in purity content. Tremfya presented higher degradation rates compared to guselkumab compositions of the invention. The results of CE-SDS at 40°C are shown in Figure 15. The results of CEX showed a gradual increase in acidic peaks. Tremfya presented a higher degradation rate compared to guselkumab compositions of the invention. The results of CEX at 40°C are shown in Figure 16.

[0062] In summary, marked differences between studied guselkumab DP formulations stored at accelerated (25°C±2°C / 60%±5%) and stress (40°C±2°C / 75%±5% RH) conditions were observed in QAs corresponding to SEC, CEX and CE-SDS nr analyses.

[0063] Guselkumab DP is characterized by comparable viscosity (approx. 4 cP) and osmolality (approx. 330 mOsmol / kg) to the reference product, and has a relatively low number of sub-visible particles. Unlike guselkumab DP, the reference product showed an increase in sub-visible particles under long-term (5°C±3°C), accelerated (25°C±2°C / 600 / o±50 / o RH), and stress (40°C±2°C / 750 / o±50 / o RH) conditions.

[0064] Under stress conditions, each of the compositions F14, F15, F16, and F17 in comparison to Tremfya shows a much higher stability after three months of storage. This is represented by more guselkumab monomers remaining and less HMWI content (see Figure 14), by increased purity content (see Figure 15) as well as a decreased acidic species content (see Figure 16).

[0065] No marked changes or differences were observed for guselkumab DS samples when stored at -60°C±3°C and -20°C±5°C conditions for up to 12 months.

[0066] Consequently, in a first aspect, the present invention provides a liquid composition comprising:

[0067] (a) guselkumab;

[0068] (b) a buffering agent;

[0069] (c) a surfactant; and

[0070] (d) a sugar compound, wherein the surfactant is a poloxamer, wherein the concentration of the poloxamer is from 0.1% (v / v) to 0.5% (v / v), and wherein the sugar compound is trehalose, wherein the trehalose is present at a concentration of from 200 mM to 300 mM.

[0071] The liquid composition according to the first aspect comprises the antibody guselkumab. Guselkumab is a fully human monoclonal immunoglobulin G1 lambda (IgGIX) antibody (mAb), which targets the cytokine IL-23. The related composition Tremfya® was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the treatment of moderate-to-severe plaque psoriasis in adults. In July 2020, the FDA also approved Tremfya to treat adults with active psoriatic arthritis. The term "antibody" as used in the context of the present invention in particular refers to a protein comprising at least two heavy chains and two light chains connected by disulfide bonds. Each heavy chain usually is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). Each light chain is usually comprised of a light chain variable region (VL) and a light chain constant region (CL). The heavy chain constant region generally comprises three heavy chainconstant domains (CHI, CH2 and CH3) wherein the first constant domain CHI is adjacent to the variable region and is connected by a hinge region to the second constant domain CH2, which is followed by CH3. The light chain-constant region usually consists only of one constant domain. The variable regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR), wherein each variable region generally comprises three CDRs and four FRs. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.

[0072] Guselkumab in particular comprises a heavy chain sequence of SEQ ID No. 1 and a light chain sequence of SEQ ID No. 2:

[0073] EVQLVQSGAE VKKPGESLKI SCKGSGYSFS NYWIGWVRQM PGKGLEWMGI IDPSNSYTRY

[0074] SPSFQGQVTI SADKSISTAY LQWSSLKASD TAMYYCARWY YKPFDVWGQG TLVTVSSAST

[0075] KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY

[0076] SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APE LLGGPSV

[0077] F LFPPKPKDT LMISRTPEVT CVWDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY

[0078] RWSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDE LTK

[0079] NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFF LYSKL TVDKSRWQQG

[0080] NVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ ID No. 1)

[0081] QSVLTQPPSV SGAPGQRVTI SCTGSSSNIG SGYDVHWYQQ LPGTAPKLLI YGNSKRPSGV

[0082] PDRFSGSKSG TSASLAITGL QSEDEADYYC ASWTDGLSLV VFGGGTKLTV LGQPKAAPSV

[0083] TLFPPSSEE L QANKATLVCL ISDFYPGAVT VAWKADSSPV KAGVETTTPS KQSNNKYAAS

[0084] SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS (SE Q ID No. 2).

[0085] Guselkumab may be recombinantly produced in various host cells and suitable cells for recombinant antibody production are known to the person skilled in the art, such as Chinese Hamster Ovary (CHO) cells. Preferably, guselkumab is recombinantly produced in a mammalian cell. Suitable mammalian cells are known by the person skilled in the art and comprise rodent as well as human cell lines. More preferably, guselkumab is recombinantly produced in a hamster cell, most preferably guselkumab is recombinantly produced in a CHO cell. The concentration of guselkumab in the liquid composition may be from 50 to 150 mg / ml, preferably from 75 to 125 mg / ml, more preferably from 90 to 110 mg / ml, most preferably be about 100 mg / ml.

[0086] The liquid composition according to the first aspect further comprises a buffering agent.

[0087] Suitable buffering agents for liquid compositions comprising antibodies, especially for pharmaceutical application, are well-known to the person skilled in the art.

[0088] For example, the buffering agent in the liquid composition according to the first aspect may comprise histidine.

[0089] Histidine may be present in the liquid composition in form of the free base or as acid addition salt. In particular, histidine is present in the liquid composition as a mixture of free base and acid addition salt. Preferably, histidine is used as buffering agent and the ratio of free base and acid addition salt is chosen so as to adjust the liquid composition to the desired pH value. In certain embodiments, the acid addition salt of histidine may in particular be histidine HCI. In particular, the L-enantiomer of histidine is used, i.e. L-histidine. In certain embodiments, histidine is present in the liquid composition as a mixture of L-histidine and L-histidine HCI.

[0090] The concentration of histidine in the liquid composition may be from 1 to 100 mM, preferably from 5 to 20 mM, more preferably of from 7 to 15 mM, especially more preferably from 10 to 12 mM, most preferably be about 10.9 mM.

[0091] In a preferred embodiment of the first aspect of the invention, the buffering agent comprises histidine, preferably the buffering agent comprises L-histidine / L-histidine HCI. In a further preferred embodiment of the first aspect of the invention, the concentration of histidine is from 5 to 20 mM, preferably of from 7 to 15 mM, more preferably of from 10 to 12 mM, most preferably about 10.9 mM.

[0092] Moreover, the liquid composition according to the first aspect comprises a surfactant, wherein the surfactant is a poloxamer, wherein the concentration of the poloxamer is from 0.1% (v / v) to 0.5% (v / v).

[0093] Suitable poloxamers are well-known to the person skilled in the art, such as poloxamers 188 and 407, preferably poloxamer 188. Poloxamer 188, also known as Pluronic F68, is a nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. In particular, poloxamer 188 has an oxyethylene content of about 80% and an average molecular weight of about 8400 Da. The concentration of the poloxamer in the liquid composition may be from 0.1 to 0.5% (v / v), preferably from 0.1% (v / v) to 0.3% (v / v), more preferably from 0.15% (v / v) to 0.25% (v / v) and most preferably be about 0.2% (v / v).

[0094] In a preferred embodiment of the first aspect of the invention, the poloxamer is PX188, preferably wherein the concentration of PX188 in the liquid composition is from 0.1% (v / v) to 0.3% (v / v), more preferably from 0.15% (v / v) to 0.25% (v / v) and most preferably about 0.2% (v / v).

[0095] The liquid composition according to the first aspect further comprises a sugar compound, wherein the sugar compound is trehalose, wherein the trehalose is present at a concentration of from 200 mM to 300 mM.

[0096] Trehalose is a disaccharide formed by a 1,1-glycosidic bond between two a-glucose units. Trehalose may be present in the liquid composition or used for its preparation in form of pure trehalose or as trehalose dihydrate, i.e. in complex with two water molecules. The weight amount of trehalose in the liquid composition, as indicated herein, always refers to the trehalose molecule as such, i.e. without including the mass of the dihydrate in the calculation of the weight amount.

[0097] The concentration of trehalose in the liquid composition may be from 200 to 300 mM, preferably from 220 mM to 240 mM, more preferably from 225 mM to 235 mM, and most preferably be about 230.8 mM.

[0098] In a preferred embodiment of the first aspect of the invention, the concentration of trehalose is from 220 mM to 240 mM, preferably from 225 mM to 235 mM, more preferably about 230.8 mM.

[0099] In another embodiment, the liquid composition does not comprise any sugar except for trehalose. Moreover, the liquid composition may also not comprise any sugar alcohol.

[0100] The liquid composition in particular may have a neutral to light acidic pH. In a preferred embodiment of the first aspect of the invention, the liquid composition has a pH of 3 to 9, preferably the liquid composition has a pH of 4 to 8, more preferably the liquid composition has a pH of 5 to 7, most preferably the liquid composition has a pH of about 5.8. Methods for determining the pH of a liquid composition are well known to the person skilled in the art.

[0101] In preferred embodiment of the first aspect of the invention, the liquid composition according to the first aspect of the invention comprises

[0102] (a) 50 to 150 mg / ml guselkumab; (b) 10 mM to 12 mM L-histidine / L-histidine HCI;

[0103] (c) 0.15 to 0.25% (v / v) PX188; and

[0104] (d) 225 mM to 235 M trehalose; further having a pH of 5 to 6.

[0105] In a further preferred embodiment of the first aspect of the invention, the liquid composition according to the first aspect of the invention comprises

[0106] (a) about 100 mg / ml guselkumab;

[0107] (b) about 10.9 mM L-histidine / L-histidine HCI;

[0108] (c) about 0.2 % (v / v) PX188; and

[0109] (d) about 230.8 mM trehalose; further having a pH of about 5.8.

[0110] The liquid composition according to the first aspect of the invention may further comprise at least one excipient. The term "excipient" describes any substance enhancing the manufacturability, stability, and / or delivery of the liquid composition. Suitable excipients for liquid compositions comprising an antibody, especially for pharmaceutical application, are well-known to the person skilled in the art.

[0111] For example, the excipient may be one or more amino acids, preferably basic amino acids, neutral amino acids and / or acidic amino acids. For example, the liquid composition may comprise histidine, lysine, arginine, serine, alanine, glutamine, proline, aspartate, and / or glutamate.

[0112] Preferably, the liquid composition comprises arginine and / or proline, more preferably, the liquid composition comprises L-arginine and / or L-proline.

[0113] Arginine may be present in the liquid composition or used for its preparation in form of the free base or as acid addition salt. For example, arginine may be present or used as arginine HCI. In particular, the L-enantiomer of arginine is used, i.e. L-arginine. The concentration of arginine in the liquid composition may be from 10 mM to 200 mM, preferably from 25 mM to 150 mM, more preferably from 50 mM to 100 mM, and most preferably be about 80 mM.

[0114] Proline may be present in the liquid composition or used for its preparation in free form. In particular, the L-enantiomer of proline is used, i.e. L-proline. The concentration of L-proline in the liquid composition may be from 50 mM to 200 mM, preferably from 100 mM to 175 mM, more preferably from 125 mM to 160 mM, and most preferably be about 150 mM.

[0115] In preferred embodiment of the first aspect of the invention, the liquid composition according to the first aspect of the invention further comprises at least one excipient, preferably wherein the at least one excipient is at least one amino acid, more preferably wherein the at least one amino acid is L-arginine and / or L-proline.

[0116] In a further preferred embodiment of the first aspect of the invention, the L-arginine is L-arginine HCI and / or the L-proline is L-proline in free form and / or preferably wherein the concentration of L-arginine is from 50 mM to 100 mM, preferably about 80 mM and / or the concentration of L- proline is from 100 mM to 200 mM, preferably about 150 mM.

[0117] The liquid composition according to the first aspect may further comprise at least one antioxidant. For example, the liquid composition according to the first aspect may comprise methionine, preferably L-methionine. Thereby, L-methionine may be present in a concentration from 0.5 mM to 50 mM, preferably from 1 mM to 20 mM, more preferably from 5 mM to 15 mM, and most preferred from 8 mM to 12 mM.

[0118] In a preferred embodiment of the first aspect, the liquid composition further comprises at least one antioxidant, preferably, wherein the at least one antioxidant is methionine, more preferably wherein the at least one antioxidant is L-methionine.

[0119] Moreover, it is more preferred that the liquid composition comprises an antioxidant, preferably methionine, than it is preferred that the liquid composition comprises arginine and / or proline.

[0120] In a more preferred embodiment of the first aspect, the liquid composition further comprises L- methionine, wherein the concentration of L-methionine is from 0.5 mM to 50 mM, preferably from 1 mM to 20 mM, more preferably from 5 mM to 15 mM, and most preferred from 8 mM to 12 mM.

[0121] In a particular preferred embodiment of the first aspect, the liquid composition according to the first aspect of the invention consists of

[0122] (a) about 100 mg / ml guselkumab;

[0123] (b) about 10.9 mM L-histidine / L-histidine HCI;

[0124] (c) about 0.2 % (v / v) PX188; and

[0125] (d) about 230.8 mM trehalose;

[0126] (e) about 10 mM methionine;

[0127] (f) water; further having a pH of about 5.8, wherein "about" refers to a variation by + / - 5% of the indicated value. The liquid composition may be an aqueous composition. The liquid composition may consist of guselkumab, a buffering agent, trehalose, a poloxamer and water, optionally including arginine, proline and / or suitable counterions. The liquid composition may consist of guselkumab, histidine, trehalose, a poloxamer and water, optionally including arginine, proline and / or suitable counterions. The liquid composition may consist of guselkumab, histidine, trehalose, PX188 and water, optionally including arginine, proline, methionine and / or suitable counterions.

[0128] In an also preferred embodiment of the first aspect of the invention, the liquid composition according to the first aspect of the invention is a liquid pharmaceutical composition.

[0129] The term "pharmaceutical composition" particularly refers to a composition suitable for administering to a human or animal. Hence, the components of a pharmaceutical composition usually are pharmaceutically acceptable.

[0130] The liquid composition may also comprise further compounds known to the person skilled in the art to be suitable or commonly used for antibody comprising liquid compositions. Also in this context, suitable concentrations are well-known to the person skilled in the art.

[0131] In total, the liquid composition may comprise above-mentioned ingredients in concentrations that the composition osmolality does not exceed 1000 mOsmol / kg, preferably 800 mOsmol / kg, more preferably 700 mOsmol / kg, and most preferably 600 mOsmol / kg.

[0132] The liquid composition can be prepared by providing a purified guselkumab composition and exchanging the buffer using well-known methods. The buffer exchanging may for example be the last step of a purification process of guselkumab. Guselkumab in the final buffer may be concentrated to a desired concentration or a more concentrated form of the antibody is diluted to achieve the desired concentration. Concentration of the formulation can be carried out by any suitable method. For example, the concentration process can include ultrafiltration.

[0133] The liquid composition can alternatively be prepared by providing a purified guselkumab composition comprising some, but not all of the components described herein, and adding the missing components to the composition. In particular, the purified guselkumab composition may be a stock solution having a higher concentration than the final liquid composition and the missing components may be present in one or more further stock solution. Upon mixing these stock solutions, the liquid composition having the desired concentrations of the components is obtained.

[0134] In a second aspect, the present invention provides a lyophilized composition which can be reconstituted with water to result in a liquid composition according to the first aspect of the invention. With respect to the lyophilized composition according to the second aspect of the present invention, it is referred to the terms, examples, and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0135] The terms "lyophilization," or "lyophilized" describe a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment. Such technologies are well-known by the person skilled in the art and therefore, are not described in detail herein.

[0136] The term "reconstituted formulation", as generally used herein, describes a formulation which has generally been prepared by dissolving a dry powder, lyophilized, spray-dried or solvent- precipitated antibody and optionally further components in a solvent, such that the antibody and the optional further components are dissolved or dispersed in solution for administration. The solvent in particular is water.

[0137] The concentration of guselkumab in the lyophilized composition may be from 30% (w / w) to 40% (w / w). Preferably, the concentration of guselkumab in the lyophilized composition is from 32% (w / w) to 36% (w / w), more preferably the concentration of guselkumab in the lyophilized composition is from 33% (w / w) to 35% (w / w), most preferably the concentration of guselkumab in the lyophilized composition is about 34% (w / w).

[0138] The concentration of histidine in the lyophilized composition may be from 4% (w / w) to 8% (w / w). Preferably, the concentration of histidine in the lyophilized composition is from 5% (w / w) to 7% (w / w), more preferably the concentration of histidine in the lyophilized composition is about 5.8% (w / w).

[0139] The concentration of the poloxamer in the lyophilized composition may be from 0.1% (w / w) to 2% (w / w). In embodiments wherein the surfactant is poloxamer 188, the concentration of the surfactant in the lyophilized composition is preferably from 0.5 (w / w) to 1.5% (w / w), more preferably from 0.9 (w / w) to 1.3% (w / w), most preferably about 1.1% (w / w).

[0140] The concentration of trehalose in the lyophilized composition may be from 35% (w / w) to 55% (w / w). Preferably, the concentration of trehalose in the lyophilized composition is from 40% (w / w) to 50% (w / w), more preferably from 43% (w / w) to 47% (w / w), and most preferably about 45% (w / w). The concentration of arginine in the lyophilized composition may be from 5% (w / w) to 15% (w / w). Preferably, the concentration of arginine in the lyophilized pharmaceutical composition is from 7% (w / w) to 12% (w / w), more preferably about 9% (w / w).

[0141] The concentration of proline in the lyophilized composition may be from 10% (w / w) to 25% (w / w). Preferably, the concentration of proline in the lyophilized pharmaceutical composition is from 15% (w / w) to 20% (w / w), more preferably about 18% (w / w).

[0142] The liquid composition according to the first aspect can also be prepared by reconstitution of a suitable lyophilized composition, especially a lyophilized composition according to the second aspect. Reconstitution in particular may be performed by adding water to the lyophilized composition.

[0143] In a third aspect, the present invention provides a sealed container comprising the liquid composition according to the first aspect of the invention or a lyophilized composition according to the second aspect of the invention.

[0144] With respect to the sealed container according to the third aspect of the present invention, it is referred to the terms, examples, and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0145] The sealed container may contain the liquid composition according to the first aspect or the lyophilized composition according to the second aspect. The sealed container may further be a vial, preferably a glass vial or a metal vial.

[0146] In a fourth aspect, the present invention provides an article of manufacture comprising the container according to the third aspect of the invention.

[0147] With respect to the article of manufacture according to the fourth aspect of the present invention, it is referred to the terms, examples, and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0148] If the article of manufacture comprises a container according to the third aspect, which further comprises a lyophilized composition according to the second aspect, the article of manufacture may comprise one or more tools for reconstituting the lyophilized composition according to the second aspect of the present invention, such as a container with distilled water. The article of manufacture may also comprise one or more tools for administering the liquid composition according to the first aspect of the invention to a subject, such as a syringe or a pen. Preferably, the syringe or the pen is pre-filled with the liquid composition according to the first aspect of the invention.

[0149] If the sealed container in the article of manufacture comprises a lyophilized composition according to the second aspect, the syringe may also be empty so that it may be filled with sterile water for reconstitution of the lyophilized composition.

[0150] Moreover, the article of manufacture may comprise instructions for use such as a patient information leaflet.

[0151] In a fifth aspect, the present invention provides the liquid composition according to the first aspect of the invention for use in medicine.

[0152] With respect to the liquid composition according to the first aspect of the invention for use in medicine according to the fifth aspect of the present invention, it is referred to the terms, examples, and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0153] For example, the use in medicine comprises the use in the treatment of a disease in a subject. Thereby, the term "treatment" describes any activity intended to control a disease, lessen or eliminating associated symptoms or to cure the disease. The term "disease" describes any abnormal condition deviating from the normal structural or functional state of an organism, and which is not immediately caused by a physical injury.

[0154] The term "subject" generally describes a human being, a non-human primate or another animal, in particular a mammal such as a cow, horse, pig, sheep, goat, dog, cat, camel, or a rodent such as a mouse or a rat. Preferably, the subject is a human being.

[0155] Moreover, the use in medicine may not only comprise the treatment of a disease in a subject, but also its prevention.

[0156] In the context of the present invention, treatment generally comprises administering the liquid composition of the first aspect of the invention to the subject in the need thereof.

[0157] The liquid composition is advantageously suitable for parenteral administration. The liquid composition may also be administered by parenteral administration. Parenteral administration comprises e.g., subcutaneous, intramuscular, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal and intravitreal administration.

[0158] Preferably, the liquid composition is an injectable composition. Preferably, the liquid composition is suitable for subcutaneous, intravenous, or intramuscular administration. More preferably, the liquid composition is suitable for subcutaneous injection.

[0159] In a sixth aspect, the present invention provides the liquid composition according to the first aspect of the invention for use in the treatment of psoriasis, such as plaque psoriasis and / or psoriatic arthritis.

[0160] With respect to the liquid composition according to the first aspect of the invention for use in the treatment of psoriasis and / or psoriatic arthritis according to the sixth aspect of the present invention, it is referred to the terms, examples and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0161] The term "psoriasis" thereby describes any psoriatic disease as e.g., summarized under ICD-11 code EA90. For example, psoriasis may comprise any type of psoriatic disease, such as Plaque psoriasis (EA90.0), Guttate psoriasis (EA90.1), Unstable psoriasis (EA90.2), Erythrodermic psoriasis (EA90.3), Pustular psoriasis (EA90.4), Psoriasis of specified site or distribution (EA90.5), Other specified forms of psoriasis (EA90.Y), Psoriasis of unspecified type (EA90.Z) and / or psoriatic arthritis.

[0162] The term "psoriatic arthritis" describes any psoriatic disease as summarized under ICD-11 code FA21 and / or F24.2. For example, psoriatic arthritis may comprise Psoriatic spondyloarthritis (FA21.0), Other specified psoriatic arthritis (FA21.Y), Psoriatic arthritis, unspecified (FA21.Z) and / or Juvenile psoriatic arthritis (FA24.2). Psoriatic arthritis may cause e.g., scaly skin patches with joint inflammation.

[0163] The liquid composition according to the first aspect may thereby be applied as a treatment of first choice, but also when previous treatments, such as treatments of the skin or treatments using alternative antibodies, are not suitable, did not show the desired or any effect, and / or had too many side effects.

[0164] The liquid composition may be injected under the skin in an area that is clear of psoriasis. The recommended dose is 100 mg, followed e.g. by a further dose after 4 weeks and then 100 mg every 8 weeks. For patients with psoriatic arthritis who have a high risk of joint damage, the doctor may decide that it can be injected every 4 weeks. The doctor may stop treatment if the condition does not improve after 16 or 24 weeks. After training, patients may inject the guselkumab composition of the invention themselves if the doctor considers it appropriate.

[0165] The liquid composition according to the first aspect may be used alone for treating psoriasis and / or psoriatic arthritis or in combination with other medicine, such as methotrexate, cyclosporine, and / or retinoid capsules. For example, in the case of psoriatic arthritis, the liquid composition according to the first aspect treatment may be accompanied with methotrexate treatment.

[0166] Further, the liquid composition according to the first aspect may be administered in combination with topical medications, such as creams and ointments that are directly applied to the skin e.g., corticosteroids, vitamin D compounds, anthralin, topical retinoids, calcineurin inhibitors, salicylic acid, and / or coal tar.

[0167] Moreover, treatment with the liquid composition according to the first aspect may be accompanied with phototherapy, also known as ultraviolet radiation treatment. Phototherapy usually uses several forms of light, including sunlight, ultraviolet B (UVB), and photochemotherapy (PUVA), which uses deeper-piercing ultraviolet A rays.

[0168] Finally, in a seventh aspect, the present invention provides the liquid composition according to the first aspect of the invention for use in the treatment of inflammatory bowel disease (IBD), preferably ulcerative colitis (UC) and / or Crohn's disease.

[0169] With respect to the liquid composition according to the first aspect of the invention for use in the treatment of inflammatory bowel disease (IBD), preferably ulcerative colitis (UC) and / or Crohn's disease, according to the seventh aspect of the invention, it is referred to the terms, examples, and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0170] The term "inflammatory bowel disease (IBD)" describes a group comprising two inflammatory conditions of the colon and small intestine, namely ulcerative colitis (UC) and / or Crohn's disease. The liquid composition according to the first aspect may be used alone for treating IBD, such as UC and / or Crohn's Disease, or in combination with other medicine well-known to the person skilled in the art for the treatment of IBD, such as UC and / or Crohn's Disease.

[0171] Finally, the present invention provides a method of treatment of a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of the liquid composition according to the first aspect of the present invention. Preferably, such treatment comprises the treatment of psoriasis, psoriatic arthritis and / or inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and / or Crohn's disease. With respect to such method of treatment, it is referred to the terms, examples, and specific embodiments used in the context of the other aspects of the present invention, which are also applicable to this aspect.

[0172] As used herein and also in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Similarly, the words "comprise", "contain", and "encompass" are to be interpreted inclusively rather than exclusively; that is to say, in the sense of "including, but not limited to". Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The terms "plurality", "multiple", or "multitude" refer to two or more, i.e. 2 or >2, with integer multiples, wherein the terms "single" or "sole" refer to one, i.e. =1. Furthermore, the term "at least one" is to be understood as one or more, i.e. 1 or >1, also with integer multiples. Accordingly, words using the singular or plural number also include the plural and singular number, respectively. Additionally, the words "herein", "above", "previously", and "below" and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portion(s) of the application. The description of specific embodiments of the present invention is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While the specific embodiments of, and examples for, the present disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure as presented by the appended claims, as those skilled in the relevant art will recognize. Specific elements of any foregoing and later described embodiments can be combined or substituted for elements in other embodiments. Also, in drawings, same reference numerals denote same elements to avoid repetition, and parts readily implemented by one of ordinary skill in the art may be omitted. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure as defined by the appended claims. The following examples are intended to illustrate specific embodiments of the present invention. As such, the specific implementations as discussed hereinafter are not to be construed as limitations on the scope of the present invention. It will be apparent to the person skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the present invention as defined by the appended claims, and it is thus to be understood that such equivalent embodiments are to be included herein. Further aspects and advantages of the present invention will become apparent from the following description of particular embodiments illustrated in the figures.

[0173] BRIEF DESCRIPTION OF THE FIGURES Figure 1. Nano Differential Scanning Fluorimetry (nanoDSF) results (left) and back reflection results (right) at TO for samples Fl to F13. The diagrams show on their x-axis the respective samples (Fl- F13) from left (Fl) to right (F13), meaning the melting temperature for the nanoDSF results (left) and Aggregation Temperature - Onset for the backreflection results (right). Both diagrams depict on their y-axis the temperature in [°C], The legend on the right side provides the datapoint code for the respective samples from Fl (top) to F13 (bottom).

[0174] Figure 2. Micro-Flow Imaging (MFI) (Agitation) results for samples Fl to F13 considering the total content of sub-visible particles ("All MFI (Agitation)", left) and considering all particles x>2 pm ("x>2 MFI (Agitation)", right). The y-axis of the left diagram represents the number of all particles per ml [# / m LAII] and the y-axis of the right diagram shows the number of particles >2 pm per ml [# / mL x>2], The diagrams show on their x-axis the time in [Days], The legend on the right side provides the datapoint code for the respective samples from Fl (top) to F13 (bottom).

[0175] Figure 3. Samples Fl to F13 after 2 months of storage under stress conditions.

[0176] Figure 4. SEC results showing short-term stability at stress conditions. The top left diagram shows the purity during storage at 40°C, the top right diagram the high molecular weight impurities (HMWI) content and the bottom left diagram the content of antibody fragments. The y-axis of the top left diagram represents the percentage of purity [%], the y-axis of the top right diagram shows the percentage of HMWI [%] and the y-axis on the bottom left the percentage of antibody fragments [%]. The diagrams all show on their x-axis the storage duration in weeks [Weeks], The legend on the bottom right provides the datapoint code for the respective samples from Fl (top) to F13 (bottom). IRS represents the Internal Reference Standard.

[0177] Figure 5. Cation Exchange Chromatography (CEX) results after 1 month of short-term stability at stress conditions. The top left diagram shows the main peak (MP) percentage, the top right diagram shows the corresponding acidic peak (AP) percentage and the bottom left diagram shows the corresponding basic peak (BP) percentage. The y-axis of the top left diagram represents the MP percentage [%], the y-axis of the top right diagram shows the AP percentage [%] and the y-axis on the bottom left the BP percentage [%]. The diagrams all show on their x-axis the storage duration in weeks [Weeks], The legend on the bottom right provides the datapoint code for the respective samples from Fl (top) to F13 (bottom). IRS represents the Internal Reference Standard.

[0178] Figure 6. Cation Exchange Chromatography (CEX) results after 2 months of short-term stability at stress conditions. The top left diagram shows the main peak (MP) percentage, the top right diagram shows the corresponding acidic peak (AP) percentage and the bottom left diagram shows the corresponding basic peak (BP) percentage. The y-axis of the top left diagram represents the MP percentage [%], the y-axis of the top right diagram shows the AP percentage [%] and the y-axis on the bottom left the BP percentage [%]. The diagrams all show on their x-axis the storage duration in weeks [Weeks], The legend on the bottom right provides the datapoint code for the respective samples from Fl to F6 and F8 to Fll from top to bottom. IRS represents the Internal Reference Standard.

[0179] Figure 7. Capillary Electrophoresis-Sodium Dodecyl Sulfate In Non-Reduced Conditions (CE-SDS nr) results - short-term stability at stress conditions. The top left diagram shows the purity during storage at 40°C, the top right diagram the high molecular weight impurities (HMWI) content and the bottom left diagram the content of antibody fragments. The y-axis of the top left diagram represents the percentage of purity [%], the y-axis of the top right diagram shows the percentage of HMWI [%] and the y-axis on the bottom left the percentage of antibody fragments [%]. The diagrams all show on their x-axis the storage duration in weeks [Weeks], The legend on the bottom right provides the datapoint code for the respective samples from Fl (top) to F13 (bottom). IRS represents the Internal Reference Standard.

[0180] Figure 8. pH results - short-term stability at stress conditions. The y-axis of the diagram represents the pH values. The x-axis depicts the storage duration in weeks [Weeks], The legend on the right provides the datapoint code for the respective samples from Fl (top) to F13 (bottom).

[0181] Figure 9. Potency Enzyme-Linked Immunosorbent Assay (ELISA) results - short-term stability at stress conditions. The y-axis of the diagram represents the potency percentage [%]. The x-axis depicts the storage duration in weeks [Weeks], The legend on the right provides the datapoint code for the respective samples from Fl (top) to F13 (bottom).

[0182] Figure 10. SEC (%Monomer) results - short-term stability at stress conditions (top) and SEC (%HMWI) results - short-term stability at stress conditions (bottom). The y-axes represent the monomer content (top) and HMWI content (bottom) in percent [%], respectively, while the x-axis shows the time in weeks. The legend on the right provides the datapoint code for the respective samples.

[0183] Figure 11. Potency results - short term stability at stress conditions. The y-axis represent the potency content in percent [%], while the x-axis shows the time in weeks. The legend on the right provides the datapoint code for the respective samples.

[0184] Figure 12. CE-SDS nr (%Purity) results - short term stability at stress conditions (top) and CE-SDS nr (%Antibody fragments) results - short term stability at stress conditions (bottom). The y-axes represent the purity (top) and antibody fragments content (bottom) in percent [%], respectively, while the x-axis shows the time in weeks. The legend on the right provides the datapoint code for the respective samples. Figure 13. CEX (%MP) results - short term stability at stress conditions (top) and CEX (%AP) results - short term stability at stress conditions (bottom). The y-axes represent the MP (top) and AP (bottom) content in percent [%], respectively, while the x-axis shows the time in weeks. The legend on the right provides the datapoint code for the respective samples.

[0185] Figure 14. SEC (%Monomer) results - stability study at stress conditions (top) and SEC (%HMWI) results -stability study at stress conditions (bottom). The y-axes represent the monomer content (top) and HMWI content (bottom) in percent [%], respectively, while the x-axis shows the time in months. The legend on the right provides the datapoint code for the respective samples.

[0186] Figure 15. CE-SDS nr (%Purity) results -stability study at stress conditions (top) and CE-SDS nr (%Antibody fragments) results -stability study at stress conditions (bottom). The y-axes represent the purity (top) and antibody fragments content (bottom) in percent [%], respectively, while the x-axis shows the time in months. The legend on the right provides the datapoint code for the respective samples.

[0187] Figure 16. CEX (%AP) results -stability study at stress conditions. The y-axis represents the AP content in percent [%], while the x-axis shows the time in months. The legend on the right provides the datapoint code for the respective samples.

[0188] 1. EXAMPLE 1

[0189] 1.1. Purpose

[0190] The purpose of this study was to evaluate the impact of proposed changes of the original formulation buffer of Tremfya® (see Table 1) on the guselkumab protein stability.

[0191] Table 1. Tremfya® formulation

[0192] Modifications (see Table 2) that may increase the stability of the molecule were defined and tested within 13 different compositions during the following sub-studies described below:

[0193] F / T stress study agitation stress study short-term stability study at stress conditions

[0194] Table 2. Proposed preliminary modifications

[0195] . DEFINITIONS AND ABBREVIATIONS

[0196] Table 3. Abbreviations and definitions (continuation on the next page) Table 3. Abbreviations and definitions (continuation)

[0197] 3. STUDY DESCRIPTIONS

[0198] Based on the modifications (see Table 2) that were identified as having the potential to increase the stability of the molecule, a set of 13 formulations was designed. For these formulations, the combinations of 3 factors were selected in a way that is expected to differentiate between the individual impacts. The factors were concentration of PX188 (0.02 %, 0.06 %, 0.2%), histidine buffer molarity (10.9 mM, 50 mM), presence of viscosity reducing agent / stabilizer (none, L- proline, L-arginine HCI). All 10 formulations contained trehalose.

[0199] To compare the effect of trehalose with sucrose, additional 2 formulations containing sucrose were included in the final design.

[0200] A 13thformulation with a composition identical to the original drug product Tremfya® was added as a reference. The list of formulations included in the study is shown in Table 4.

[0201] Table 4 Compositions of the formulations included in the study. 3.1. Agitation stress

[0202] The agitation stress test was performed using a variable-angle rotator. Samples in glass vials were subjected to hard vibrations (1°, 5 s) with minimal reciprocal rotation (1°, 10 s) - to prevent / diminish contact of the formulation with the stopper. For the details refer to Table 5. The samples were subjected to agitation for 48 hours at RT protected from light (wrapped in aluminum foil).

[0203] Table 5. Agitation stress test - Grant bio PTR-45 instrument parameters lThe samples were subjected to agitation for 48 h .2 F / T cycles

[0204] A total of five F / T cycles were performed in the 1 ml cryovials. For each F / T cycle, the vials were stored for minimum 4h at -60±10°C. to ensure complete freezing and cooling to the freezer setpoint (-60°C) and then thawed for 4h at RT, protected from light. Samples were analyzed after five cycles of F / T. .3 Short-term stability at stress conditions

[0205] The samples were incubated at stress conditions (40°C±2°C / 75%±5% RH) for 2 months. The vials were stored in an upright position to exclude the possible influence of the contact with the stopper on the protein stability in the tested formulations (the interaction with PP was not in the scope of the study). The quality of the investigated compositions was monitored over time. . RESULTS .1. Data management

[0206] Numerical results are given in Tables 6-12.

[0207] Table 6. Summary o the results for samples from TO (continuation on the next page)

[0208] Table 6. Summary of the results for samples from TO (continuation)

[0209] Table 7. Summary of the results for samples after agitation stress (continuation on the next page)

[0210] Table 7. Summary of t results for samples after agitation stress (continuation)

[0211] Table 8. Summary of the results for samples after 5 cycles of F / T (continuation on the next page)

[0212] Table 8. Summary of the results for samples after 5 cycles of F / T (continuation)

[0213] Table 9. Summary of the results for samples from short-term stability; T1W (continuation on the next page)

[0214] Table 9. Summary of the results for samples from short-term stability; T1W (continuation)

[0215] Table 10. Summary of the results for samples from short-term stability; T2W (continuation on the next page)

[0216] Table 10. Summary of the results for samples from short-term stability; T2W (continuation)

[0217] Table 11. Summary of the results for samples from short-term stability; TIM (continuation on the next page)

[0218] Table 11. Summary of t le results for samples from short-term stability; TIM (continuation)

[0219] Table 12. Summary of the results for samples from short-term stability; T2M (continuation on the next page)

[0220] Table 12. Summary of the results for samples from short-term stability; T2M (continuation)

[0221] .2. Summary of results

[0222] This section summarizes the results obtained from example 1. Graphs are presented only for data for which marked changes between time-points were observed (changes over time). The complete results are presented in tabular form above (Tables 6-12). .2.1 Testing after formulation preparation (TO) .2.1.1 nanoDSF / backreflection

[0223] For all the formulations conformational thermal stability was tested at TO. Formulations F3, F5, F8, Fll, F12, and F13 (formulations containing 10.9 mM histidine buffer and proline or no AA) were characterized by higher Tm when compared to the other formulations (see Figure 1, left diagram). In addition, Tagg-on was not determined for these compositions (F3, F5, F8, Fll, F12 and F13). The results of the samples for which Tagg-on could be determined were similar, with a difference of about 3°C between the highest (Fl - 65.91°C) and the lowest result (F9 - 62.85°C) (see Figure 1, right diagram).

[0224] Note: The manufacturer of the equipment used during analysis (Prometheus Panta) declares accuracy only for the Tm parameter (±0.2°C) and the accuracy of the Tagg-on parameter is clearly lower (the standard deviation for one sample reaches 1.03°C), therefore, it is difficult to draw any conclusions based on Tagg-on results.

[0225] 4.2.2 Agitation stress

[0226] 4.2.2.1 VI

[0227] No major changes were observed after agitation stress in color, turbidity and visible particles when compared to TO for all tested samples.

[0228] 4.2.2.2 MFI

[0229] After the agitation stress, the highest total content of sub-visible particles (All particles >6000 / ml) was reported in formulations Fl, F2, and F3, which contained the lowest concentration of PX188 (0.02%). Nevertheless, among the three, the Fl (the buffer containing L-proline) had the lowest content of sub-visible particles (see Figure 2).

[0230] The lowest level of sub-visible particles (All particles <1000 / ml) after agitation stress was noticed for formulations Fll, F12, and F13 (originator's formulation buffer). Both compositions, Fll and F12, contain the highest tested concentration of PX188 (0.2%).

[0231] 4.2.2.3 SEC

[0232] The results of the SEC analysis did not show marked changes in the content of monomer and total aggregates (the maximum difference was 0.10% when compared to TO) for all tested guselkumab antibody compositions subjected to the agitation stress. 4.2.2.4 CEX

[0233] The results of the CEX analysis did not show marked changes in the charge variants profile for all tested guselkumab antibody compositions subjected to the agitation stress.

[0234] 4.2.2.5 CE-SDS nr

[0235] The results of the CE-SDS nr analysis in non-reduced conditions did not show marked changes in the purity for all tested guselkumab antibody compositions subjected to the agitation stress.

[0236] 4.2.3 F / T experiments

[0237] 4.2.3.1 VI

[0238] No major changes were observed after 5 F / T cycles in color and turbidity when compared to TO for all tested samples.

[0239] No visible particles were found in any of the samples after 5 F / T cycles.

[0240] 4.2.3.2 MFI

[0241] No major changes were observed after 5 F / T cycles.

[0242] 4.2.3.3 SEC

[0243] The results of SEC analysis did not show marked changes in the content of monomer and total aggregates (the maximum difference 0.12% when compared to TO) for all tested guselkumab antibody compositions subjected to the 5 F / T cycles.

[0244] 4.2.3.4 CEX

[0245] The results of the CEX analysis did not show marked changes in the charge variants profile for all tested guselkumab antibody compositions subjected to the 5 F / T cycles.

[0246] 4.2.3.5 CE-SDS nr

[0247] The results of the CE-SDS nr analysis in non-reduced conditions did not show marked changes in the purity for guselkumab antibody samples subjected to the 5 F / T cycles.

[0248] 4.2.3.6 pH

[0249] After 5 F / T cycles, an increase in pH results between 0.01-0.09 was observed for all tested samples. However, considering the measurement variability that can result from differences in sample temperature and measurement accuracy itself, these differences are considered negligible. 4.2.4 Short-term stability at stress conditions

[0250] 4.2.4.1 VI

[0251] In Figure 3 samples after 2 months of storage in stressed conditions were presented.

[0252] No major changes were reported in the color for compositions containing 230.8 mM trehalose (F1-F6, F8-F11). The results for these samples were within ±0.5 standard of the results from TO. The change in coloration was observed for formulations F7, F12, and F13 from slightly brownyellow (BY4) to slightly brown-yellow to brown-yellow (<BY2) or to brown-yellow (BY1). According to the literature, the color changes may be caused by degradants from tryptophan oxidation (refer to section 9, point 3). Therefore, it can be assumed that formulations F7, F12, and F13 were characterized by higher oxidation when compared to other formulations after 2 months of storage under stress conditions.

[0253] No major changes were observed after 2 months of storage at stress conditions in turbidity when compared to TO for all tested samples. The turbidity was assessed at the level of II standard (slightly opalescent) at time-point T2M, while at TO the results were in the range from II (slightly opalescent) to <111 (slightly opalescent to opalescent). Differences of ±0.5 standard between the results should be considered irrelevant, as this level of variability is expected during turbidity assessment by VI.

[0254] No visible particles were observed in any of the samples during 2 months of storage at stress conditions.

[0255] 4.2.4.2 MFI

[0256] After 2 months of storage at stressed conditions, most of the formulations were characterized by similar particle concentration, and the observed differences are at the level of expected method variability.

[0257] 4.2.4.3 SEC

[0258] The SEC results for samples stored under stress conditions presented a gradual increase in the aggregate content (see Figure 4, top right diagram) and antibody fragments content (see Figure 4, bottom left diagram), which was reflected in a decrease in monomer content (see Figure 4, top left diagram).

[0259] For trehalose-containing formulations, similar changes were noted after 2 months of storage under stress conditions, the decrease in monomer content was in the range of 6.20%-7.20%. Among these compositions, the greatest decrease in monomer content (7.16%-7.20%) was observed for formulations F4 and F10, both with higher histidine buffer concentration. In contrast, the smallest decrease (6.2%) was reported for formulation F8, a composition containing L-proline and the highest tested concentration of PX188.

[0260] Formulations F7, F12, and F13 (sucrose-containing formulations) presented a greater decrease in monomer content (10.61%-15.53%) after 2 months of storage at 40°C±2°C / 75%±5% RH, when compared to the other formulations. The greatest decrease in monomer content (15.53%) was observed for formulation F13 (originator's composition), while the smallest decrease (10.61%) was reported for formulation F7, a composition containing L-arginine.

[0261] The increase in antibody fragments content was similar for formulations containing 10.9 mM histidine buffer. Formulations Fl, F4, F9, and F10 (50 mM histidine buffer) were characterized by higher antibody fragments content when compared to other formulations after 2 months of storage under stress conditions.

[0262] 4.2.4.4 CEX

[0263] After two months of storage under stress conditions, it was impossible to determine charge variants profiles for F7, F12, and F13 due to excessive protein degradation. Therefore, the results are presented in two Figures (Figures 5 and 6). Figure 5 shows the results up to TIM, to compare all the compositions, while Figure 6 includes only those compositions for which it was possible to determine the charge variants profile (F1-F6, F8-F11) after 2 months of storage at 40°C±2°C / 75%±5% RH.

[0264] The CEX results for samples stored under stress conditions for one month presented a gradual decline in the %MP content in all tested formulations (see Figure 5, top left diagram).

[0265] As with the results of the SEC analysis, two populations of results stood out: one for trehalose- containing compositions (F1-F6, F8-F11) and another for sucrose-containing compositions (F7, F12, F13).

[0266] For trehalose-containing formulations, similar changes were noted after 1 month of storage under stress conditions, the decrease in MP content was in the range of 25.25%-28.58%. Among these compositions, the greatest decrease in MP content (28.21%-28.58%) was observed for formulations Fl, F4, F9, and F10, all with the higher concentration of histidine buffer (50 mM). In contrast, the smallest decrease (25.25%-26.46%) was reported for formulations F2, F3, F5, F6, F8, and Fll, all with lower histidine buffer concentration (10.9 mM).

[0267] For formulations F7, F12, and F13 (sucrose-containing formulations), the decrease in MP content was the highest (32.42%-36.6%) after 1 month of storage at 40°C±2°C / 75%±5% RH. The greatest decrease in MP content (36.6%) was observed for formulation F13 (originator's composition), while the smallest decrease (32.42%) was reported for formulation F7, a composition containing L-arginine. Moreover, formulations F7, F12, and F13 were characterized by the highest increase in AP content (25.52%-34.68%), when compared to others (9.79%-13.84%), which correlated with the subsequent pH changes.

[0268] The same conclusions as after 1 month of storage can be drawn for trehalose-containing compositions also after 2 months of storage at stress conditions. The greatest decrease in MP content (39.06%-39.72%) was observed for formulations Fl, F4, F9, and F10, all with the higher concentration of histidine buffer (50 mM). The smallest decrease (36.78%-37.84%) was reported for formulations F2, F3, F5, F6, F8, and Fll, all with lower histidine buffer concentration (10.9 mM).

[0269] 4.2.4.5 CE-SDS nr

[0270] The results of CE-SDS nr (Figure 7) analysis showed the gradual decline in the level of purity in all guselkumab antibody compositions tested during storage under stress conditions. After 2 months of storage, the lowest purity results among all tested samples were reported for formulations F12 and F13, which correlated with the highest increase in HMWI content in these compositions. HMWI were only visible in formulations F7, F12, and F13 (sucrose-containing formulations). The increase in antibody fragments content was similar (5.3%-7.4%) for all the formulations after 2 months of storage, apart from formulation F13, for which an increase of 8.9% was reported.

[0271] 4.2.4.6 pH

[0272] During 2 months of storage of formulations F1-F6 and F8-F11 under stress conditions (trehalose- containing formulations), pH remained stable, the changes were within ±0.11 compared to TO. In contrast, sucrose-containing compositions (F7, F12, F13) showed a decrease in pH in the range of 0.20-0.27, when compared to the starting values (see Figure 8).

[0273] 4.2.4.7 Protein concentration

[0274] The protein concentration remained stable for all tested compositions during the entire storage period under stress conditions (40°C±2°C / 75%±5% RH). All results were within ± 10% of the concentration at TO.

[0275] 4.2.4.8 ELISA

[0276] A decrease in potency (relative binding affinity to rhulL-23) was observed for all the formulations. The greatest decrease (56%-79%) was observed for formulations F7, F12, and F13 (sucrose-containing formulations), when compared to the TO. The remaining formulations were characterized by a similar decrease in potency (26%-42%) (see Figure 9). DISCUSSION AND CONCLUSIONS

[0277] IQ

[0278] • Based on the nanoDSF / backreflection data at TO, it can be concluded that formulations F3, F5, F8, Fll, F12, F13 (formulations containing 10.9 mM histidine buffer with L-proline or no AA) were characterized by higher conformational stability.

[0279] F / T stress

[0280] • There were no clear changes in any of the monitored quality attributes for all tested formulations after 5 F / T cycles, in most cases at the level of IRS results variability.

[0281] Agitation stress

[0282] • The only attribute that allowed to distinguish formulations after agitation stress was the content of sub-visible particles. Formulations (F1-F3) containing the lowest concentration of PX188 (0.02%) had the highest content of sub-visible particles after agitation stress. Nevertheless, among the three, the Fl (the buffer containing L-proline) had the lowest content of sub-visible particles. The lowest level of sub-visible particles after agitation stress was noticed for formulations Fll, F12, and F13 (the originator's formulation buffer). Both compositions, Fll and F12, contained the highest tested concentration of PX188 (0.2%).

[0283] Therefore, the results suggest that the concentration of 0.2% for PX188 provides the best stabilization of the protein during mechanical stress and should be used in further development. Short-term stability at stress conditions (visual assessment of trends)

[0284] • After two months of storage at stress conditions, the results of VI, SEC, CEX, CE-SDS nr, pH, ELISA presented clearly worse results for sucrose-containing formulations (F7, F12, and F13). Therefore, trehalose was used in further composition designing.

[0285] • The results of SEC analysis show that the greatest decrease in monomer content was observed for formulations F4 and F10, both with higher histidine buffer concentration. In contrast, the smallest decrease was reported for formulation F8, a composition containing L- proline and the highest tested concentration of PX188.

[0286] • For all formulations containing higher concentration of histidine buffer, the greater decrease in MP content (CEX) was observed after 2 months of storage at stress conditions, when compared to the formulations containing lower histidine buffer concentration.

[0287] • Compositions containing L-arginine HCI were found to exhibit lower increases in aggregate content and fewer changes in the charge variants profile, compared to those without this additive. This was evident in sucrose-containing formulations, as shown by the results of SEC and CEX analysis.

[0288] Considering all the data, new formulations F14, F15 (refer to Table 13) were designed and tested in Example 3 below. The concentration of AA was increased to maximize the stabilizing properties and not to exceed the formulation osmolality of 600 mOsmol / kg.

[0289] These formulations are expected to ensure the best stabilization of the guselkumab antibody protein and will allow to determine the influence of AA type (F14 and F15) on protein stability in further studies.

[0290] EXAMPLE 2

[0291] From the following formulations that were already tested above, those with the numbers 2, 3, 5, 6, 8, 11, and 13 (marked in Table 14 by asterisk *) were chosen for further studies. This selection was based on the findings that it was generally observed in previous experiments that 10.9 mM histidine gives mostly better results than 50 mm histidine and trehalose gives mostly better results than sucrose. For comparison, the originator formulation (F13) was used.

[0292] Table 14: Tested formulations variants

[0293] The compositions having the numbers 2, 3, 5, 6, 8, 11 and 13 (F2, F3, F5, F6, F8, Fll and F13, respectively) were further analyzed using Size Exclusion Chromatography (SEC), Enzyme-Linked Immunosorbent Assay (ELISA), Capillary Electrophoresis Sodium Dodecyl Sulfate technique (CE- SDS) and Cation Exchange Chromatography (CEX) as described below in detail.

[0294] Table 15: Size exclusion chromatography of formulations F2, F3, F5, F6, F8, Fll, and F13

[0295] Table 16: Relative binding affinity to rhulL-23 of formulations F2, F3, F5, F6, F8, Fll, and F13

[0296] (originator) (see also Figure 11).

[0297]

[0298] Table 17: Capillary electrophoresis-sodium dodecyl sulfate in non-reduced conditions of formulations F2, F3, F5, F6, F8, Fll, and F13 (originator) (see also Figure 12).

[0299] Table 18: Cation exchange chromatography of formulations F2, F3, F5, F6, F8, Fll, and F13

[0300] (originator) (see also Figure 13).

[0301] EXAMPLE 3 - Stability study

[0302] 1. Purpose and scope

[0303] Further development of possible formulation in order to

[0304] • determine a guselkumab antibody formulation composition of the present invention, which will ensure the best protein stability during storage for 12 months under long-term conditions (5°C±3°C; -60°C±3°C; -20°C±5°C), 6 months under accelerated conditions (25°C±2°C / 600 / o±50 / o RH) and 3 months under stress condition (40°C±2°C / 75%±5% RH);

[0305] • To preliminarily estimate two different storage temperatures (-60°C±3°C; -20°C±5°C) for guselkumab antibody;

[0306] • To provide preliminary stability data for guselkumab antibody;

[0307] • To compare the results obtained for guselkumab antibody with those of the reference product Tremfya® DP.

[0308] 2. Abbreviations and Definitions

[0309] Table 19. Abbreviations and definitions (continuation on the next page) Strategy of the study / experiment Study / experiment description

[0310] The guselkumab presented at the target concentration of 100 mg / ml was used for this study. Tested formulations were aliquoted to two types of PFSs (stability study at long-term, accelerated and stress conditions; 1.1 mL per syringe; guselkumab antibody DP) and to cryogenic tubes (stability study in a frozen state; 1 mL per tube; guselkumab antibody DS).

[0311] The PFSs were stored in a horizontal position which provides the highest air / liquid and stopper / liquid interface area ('worst case').

[0312] The long-term storage conditions for guselkumab antibody DP were aligned with the conditions specified for DP of originator product -Tremfya® (expiry date 31 July 2024). On the other hand, the active substance used in the manufacturing process of the finished product Tremfya® DP is stored frozen (reference: EMA / 692068 / 2017), therefore frozen storage was also proposed for guselkumab DS.

[0313] The quality of the investigated compositions (Table 20) was monitored as follows:

[0314] • Over 12 months at long-term storage conditions, 5°C±3°C (guselkumab antibody DP / Tremfya® DP - intended storage conditions);

[0315] • Over 6 months at accelerated storage conditions, 25°C±2°C / 60%±5% RH (guselkumab antibody DP / Tremfya® DP);

[0316] • Over 3 months at stress storage conditions, 40°C±2°C / 75%±5% RH (guselkumab antibody DP / Tremfya® DP);

[0317] • Over 12 months in a frozen state, -60°C±3°C (guselkumab antibody DS - proposed storage conditions);

[0318] • Over 12 months in a frozen state, -20°C±5°C (guselkumab antibody DS - proposed storage conditions).

[0319] The formulations, which were tested during the study, are listed in Table 20. The selection of studied compositions (F14 and F15) was based on previously performed experiments of examples 1 and 2 above.

[0320] Formulations F16 and F17 were chosen as an additional composition and were not tested in examples 1 and 2 above.

[0321] Formulation F17 was designed by substituting the amino acid in the F14 / F15 formulation with L-methionine, a thiol-containing amino acid. One of the study's objectives is to evaluate the effect of L-methionine on protein stability during storage over time.

[0322] Formulation F16 without added amino acids will be used as a reference during this stability study to assess the effect of amino acids on protein stability under the intended storage conditions, as well as under accelerated and stressed storage conditions. Testing .1 Conditions and sampling plan The conditions for the stability studies with test intervals are listed in Tables 21-23.

[0323] Table 21. Storage conditions and test intervals for guselkumab antibody DP xT0 was tested once for a I study conditions. Table 22. Storage conditions and test intervals for Tremfya® DP lTO will be tested once for all study conditions.

[0324] Table 23. Storage conditions and test intervals for guselkumab antibody DS 4.2 Methods and results

[0325] 4.2.1 DP The compositions F14, F15, F16, and F17 were further analyzed using Size Exclusion Chromatography (SEC), Capillary Electrophoresis Sodium Dodecyl Sulfate technique (CE-SDS) and Cation Exchange Chromatography (CEX) as described below in detail.

[0326] Table 23: Tested formulations variants

[0327] Table 24: Size exclusion chromatography of formulations F14, F15, F16, F17 and Tremfya Table 25: Capillary electrophoresis-sodium dodecyl sulfate in non-reduced conditions of formulations F14, F15, F16, F17, and Tremfya

[0328] Table 26: Cation exchange chromatography of formulations F14, F15, F16, F17, and Tremfya

[0329] Summary

[0330] Marked differences between studied guselkumab DP formulations stored at accelerated (25°C±2°C / 60%±5%) and stress (40°C±2°C / 75%±5% RH) conditions were observed in QAs corresponding to SEC, CEX and CE-SDS nr analyses.

[0331] Guselkumab DP is characterized by comparable viscosity (approx. 4 cP) and osmolality (approx. 330 mOsmol / kg) to the reference product, and has a relatively low number of sub-visible particles. Unlike guselkumab DP, the reference product showed an increase in sub-visible particles under long-term (5°C±3°C), accelerated (25°C±2°C / 600 / o±50 / o RH), and stress (40°C±2°C / 750 / o±50 / o RH) conditions.

[0332] Under stress conditions, each of the compositions F14, F15, F16 and F17 in comparison to

[0333] Tremfya shows a much higher stability after three months of storage. This is represented by more guselkumab monomers remaining and less HMWI content (see Figure 14), by increased purity content (see Figure 15) as well as decreased acidic species content (see Figure 16).

[0334] 4.2.2 DS

[0335] The compositions F14, F15, F16, and F17 were further analyzed using Size Exclusion Chromatography (SEC), Capillary Electrophoresis Sodium Dodecyl Sulfate technique (CE-SDS) and Cation Exchange Chromatography (CEX) as described below in detail. Table 27: Tested formulations variants

[0336] Table 28: Size exclusion chromatography of formulations F14, F15, F16, and F17 cryotubes

[0337] Table 29: Capillary electrophoresis-sodium dodecyl sulfate in non-reduced conditions of formulation s F14, F15, F16, and F17 cryotubes

[0338] Table 30: Cation exchange chromatography of formulations F14, F15, F16, and F17 cryotubes

[0339] Summary

[0340] No marked changes or differences were observed for guselkumab DS samples when stored at -60°C±3°C and -20°C±5°C conditions for up to 12 months.

Claims

Claims1. A liquid composition comprising:(a) guselkumab;(b) a buffering agent;(c) a surfactant; and(d) a sugar compound, wherein the surfactant is a poloxamer, wherein the concentration of the poloxamer is from 0.1% (v / v) to 0.5% (v / v), and wherein the sugar compound is trehalose, wherein the trehalose is present at a concentration of from 200 mM to 300 mM.

2. The liquid composition according claim 1, wherein the buffering agent comprises histidine, preferably wherein the buffering agent comprises L-histidine / L-histidine HCI.

3. The liquid composition according to claim 2, wherein the concentration of histidine is from 5 to 20 mM, preferably of from 7 to 15 mM, more preferably of from 10 to 12 mM, most preferably about 10.9 mM.

4. The liquid composition according to any one of claims 1 to 3, wherein the poloxamer is PX188, preferably wherein the concentration of PX188 is from 0.1% (v / v) to 0.3% (v / v), preferably from 0.15% (v / v) to 0.25% (v / v), most preferably about 0.2% (v / v).

5. The liquid composition according to any one of claims 1 to 4, wherein the concentration of trehalose is from 220 mM to 240 mM, preferably from 225 mM to 235 mM, more preferably about 230.8 mM.

6. The liquid composition according to any one of claims 1 to 5, wherein the liquid composition has a pH of 3 to 9, preferably the liquid composition has a pH of 4 to 8, more preferably the liquid composition has a pH of 5 to 7, most preferably the liquid composition has a pH of about 5.8.

7. The liquid composition according to any one of claims 1 to 6, comprising(a) 50 to 150 mg / ml guselkumab;(b) 10 mM to 12 mM L-histidine / L-histidine HCI;(c) 0.15 to 0.25% (v / v) PX188; and(d) 225 mM to 235 mM trehalose; further having a pH of 5 to 6.

8. The liquid composition according to any one of claims 1 to 7 , comprising(a) about 100 mg / ml guselkumab;(b) about 10.9 mM L-histidine / L-histidine HCI;(c) about 0.2 % (v / v) PX188; and(d) about 230.8 mM trehalose; further having a pH of about 5.8.

9. The liquid composition according to any one of claims 1 to 8, wherein the liquid composition further comprises at least one excipient, preferably wherein the at least one excipient is at least one amino acid, more preferably wherein the at least one amino acid is L-arginine and / or L-proline.

10. The liquid composition according to claim 9, wherein the L-arginine is L-arginine HCI and / or the L-proline is L-proline in free form and / or preferably wherein the concentration of L- arginine is 50 mM to 100 mM, preferably 80 mM and / or the concentration of L-proline is 125 mM to 160 mM, preferably about 150 mM.

11. The liquid composition according to any one of claims 1 to 10, wherein the liquid composition further comprises at least one antioxidant, preferably, wherein the at least one antioxidant is methionine, more preferably wherein the at least one antioxidant is L- methionine.

12. The liquid composition according to claim 11, wherein the concentration of L-methionine is from 0.5 mM to 50 mM, preferably from 1 mM to 20 mM, more preferably from 5 mM to 15 mM, and most preferred from 8 mM to 12 mM.

13. The liquid composition according to any one of claims 1 to 12, consisting of(a) about 100 mg / ml guselkumab;(b) about 10.9 mM L-histidine / L-histidine HCI;(c) about 0.2 % (v / v) PX188; and(d) about 230.8 mM trehalose; further having a pH of about 5.8;(e) about 10 mM methionine;(f) water; further having a pH of about 5.8, wherein "about" refers to a variation by + / - 5% of the indicated value.

14. The liquid composition according to any one of claims 1 to 13, wherein the liquid composition is a pharmaceutical composition.

15. A lyophilized composition which can be reconstituted with water to result in a liquid composition according to any one of claims 1 to 14.

16. A sealed container comprising the liquid composition according to any one of claims 1 to 14, or a lyophilized composition according to claim 15.

17. An article of manufacture comprising the container according to claim 16.

18. The liquid composition according to any one of claims 1 to 14 for use in medicine.

19. The liquid composition according to any one of claims 1 to 14 for use in the treatment of psoriasis, such as plaque psoriasis and / or psoriatic arthritis.

20. The liquid composition according to any one of claims 1 to 14 for use in the treatment of inflammatory bowel disease (IBD), preferably ulcerative colitis (UC) and / or Crohn's disease.

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