A PHARMACEUTICAL COMPOSITION AND A METHOD FOR PREPARING IT

Abstract

This refers to pharmaceutical compositions comprising an antibody or a fragment thereof that binds to IL-17A and IL-17F and a combination of glycine, acetate buffer at pH 4.6 to 5.5 and polysorbate 80.

Description

The present invention pertains to the field of pharmaceutical formulations. More specifically, it relates to a pharmaceutical composition comprising an antibody, glycine, acetate buffer, and polysorbate 80. The number of biological products gaining approval since the early days of recombinant DNA technologies has increased, and while the field has remained dynamic in terms of types of biological products, specific indications, and mechanistic bases of pharmacological activity, in recent years, the approval of antibody-based therapies has far surpassed the approval of other biological products. For antibody therapy to be administered in a patient-friendly manner, the method and timing of administration are critical. These aspects are especially important in chronic diseases where patients depend on the medication to lead a life as close as possible to that of healthy individuals. Drugs that require lengthy administration times, possibly involving hospitalization, are generally not considered patient-friendly. Subcutaneous administration in the comfort of a patient's home is highly desirable. However, multiple problems arise when antibodies must be formulated in high concentrations in liquid formulations, such as IF-2019-00825794- APN-ANP#INPI Page 1 of 115 such as those administered subcutaneously and directly by a patient. Although antibodies are relatively stable molecules, they can suffer from chemical and physical instability when stored for extended periods. Typical chemical instability can lead to deamidation, hydrolysis, oxidation, beta-elimination, disulfide exchange, or reduction. Physical instability can lead to denaturation, aggregation, or precipitation. Both chemical and physical instability are much more pronounced when antibodies are stored in high-concentration liquid solution. However, highly concentrated, water-based liquid antibody formulations are particularly complex; water acts as a reagent or facilitates the transfer of reagents, leading to chemical degradation and protein instability. There is no simple, universal protocol for formulating antibodies at high concentrations, and while stabilizers can help reduce instability and aggregation, their presence at high concentrations can affect other physicochemical properties of the final pharmaceutical formulation, such as viscosity and osmolarity. Preventing or minimizing aggregation, precipitation, or degradation remains a particular challenge. Aggregation, with 2 IF-2019-00825794- APN-ANP#INPI Page 2 of 115 The formation of soluble matter and / or insoluble precipitate is a particular problem. This can cause several issues, such as the formation of aggregates, which can lead to immunological reactions after administration and / or difficulties in performing adequate administration of the pharmaceutical formulation, for example, by causing a blockage of the administration device. Problems can also arise during the preparation of the antibody at high concentration and the processing capacity of the formulation, since the way the formulation behaves* through the various manufacturing stages, including filtration, the appearance of turbidity and long-term stability, is a very important aspect of pharmaceutical formulation manufacturing and another obstacle to overcome. Studies conducted at low antibody concentrations often do not translate well when the antibody is formulated at high concentrations. Depending on the nature of the antibody and the necessary excipients, large-scale production can be unexpectedly affected. Undoubtedly, a successful pharmaceutical formulation is achieved by identifying the best combination of all these factors. Given the above, the need remains in the IF-2019-00825794- APN-ANP#INPI Page 3 of 115 technique of providing other improved pharmaceutical compositions of therapeutic antibodies. SUMMARY OF THE INVENTION The present invention addresses the previously identified need by providing pharmaceutical compositions comprising an antibody, or an antigen-binding fragment thereof, with suitable physicochemical properties. The following specific realizations are described as listed below; Embodiment 1: A pharmaceutical composition comprising: a. from approximately 80 mg / ml to approximately 200 mg / ml of an antibody, or an antigen-binding fragment thereof, having a heavy chain variable region comprising SEQ ID NO:1 and a light chain variable region comprising SEQ ID NO:2; b. acetate; c. glycine; d. polysorbate 80 and; that has a pH of approximately 4.6 to approximately 5.5 or of approximately 4.6 to approximately 5.3. IF-2019-00825794- APN-ANP#INPI Page 4 of 115 Embodiment 2: The pharmaceutical composition according to embodiment 1, comprising from approximately 120 mg / ml to approximately 185 mg / ml of the antibody, or antigen-binding fragment thereof, preferably approximately 160 mg / ml. Embodiment 3: The pharmaceutical composition according to embodiment 1 or embodiment 2, wherein the composition comprises from approximately 0.01% to approximately 0.07% (w / v) of polysorbate 80. Embodiment 4: The pharmaceutical composition according to any of the preceding embodiments, wherein the composition comprises from approximately 140 mM to approximately 350 mM of glycine. Embodiment 5: The pharmaceutical composition according to any of the preceding embodiments, wherein the composition comprises from approximately 20 mM to approximately 100 mM of acetate, and preferably from approximately 40 mM to approximately 90 mM of acetate or from approximately 50 mM to approximately 90 mM of acetate. Embodiment 6: The pharmaceutical composition according to any of the preceding embodiments, wherein the antibody or antigen-binding fragment thereof specifically binds human IL-17A and human IL-17F. IF-2019-00825794- APN-ANP#INPI Page 5 of 115 Embodiment 7: The pharmaceutical composition according to any of the preceding embodiments, wherein the composition comprises: a. from approximately 120 mg / ml to approximately 185 mg / ml of antibody, or antigen-binding fragment thereof; b. from approximately 20 mM to approximately 100 mM of acetate, preferably from approximately 40 mM to approximately 90 mM of acetate or from approximately 50 mM to approximately 90 mM of acetate; c. from about 140 mM to about 350 mM glycine; d. from approximately 0.01% to approximately 0.07% (w / v) of polysorbate 80, wherein the composition has a pH of approximately 4.6 to approximately 5.5 or from approximately 4.6 to approximately 5.3. Implementation 8: A method for preparing the pharmaceutical composition, wherein the method comprises the steps of: a. Prepare a low-concentration formulation by combining approximately 40 mg / ml to approximately 50 mg / ml of an antibody, or an antigen-binding fragment thereof, having a IF-2019-00825794- APN-ANP#INPI Page 6 of 115 variable heavy chain region comprising SEQ ID N0:ly a variable light chain region comprising SEQ ID NO:2 with a buffer solution comprising glycine and acetate at pH from approximately 4.6 to approximately 5.5 or from approximately 4.6 to approximately 5.3; b. prepare a high concentration formulation by concentrating the antibody or antigen-binding fragment thereof from the low concentration formulation obtained in a) to a concentration of approximately 120 mg / ml to approximately 185 mg / ml; c. add polysorbate 80 to the high concentration formulation obtained in b); d. Optionally, before step c) adjust the concentration of the antibody or antigen-binding fragment thereof with the buffer solution comprising glycine and acetate from approximately 4.6 to approximately 5.5 or from approximately 4.6 to approximately 5.3. Embodiment 9: The method according to Embodiment 8, wherein the buffer solution comprises from approximately 20 mM to approximately 100 mM of acetate, preferably from approximately 40 mM to approximately 90 mM of acetate or from approximately 50 mM to approximately 90 mM of acetate and from approximately 140 7 IF-2019-00825794- APN-ANP#INPI Page 7 of 115 mM to approximately 350 mM of glycine and where polysorbate 80 is added in step c) to give a final concentration of approximately 0.01 to approximately 0.07% (w / v). Embodiment 10: A pharmaceutical composition obtained by embodiment 8 or embodiment 9. Embodiment 11: The pharmaceutical composition according to embodiment 10 wherein the pH of the composition is from approximately 4.6 to approximately 5.5 or from approximately 4.6 to approximately 5.3 Embodiment 12: A container comprising the pharmaceutical composition according to any of embodiments 1 to 7, 10 or 11. Embodiment 13: The pharmaceutical composition according to any of* embodiments 1 to 7, 10 or 11 for use in therapy. Embodiment 14: The pharmaceutical composition according to any of embodiments 1 to 7, 10 or 11 for use in the treatment or prophylaxis of a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F. Embodiment 15: Use of a pharmaceutical composition according to any of embodiments 1 to 7, 10 or 11 in the manufacture of a medicament for the treatment or prophylaxis of a disorder 8 IF-2019-00825794- APN-ANP#INPI Page 8 of 115 pathological mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F. Embodiment 16: A method for treating or preventing a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F in a mammalian subject comprising administering the pharmaceutical composition according to any of embodiments 1 to 7, 10 or 11. Embodiment 17: The pharmaceutical composition for use according to embodiment 14, the use according to embodiment 15, or the method according to embodiment 16, wherein the pathological disorder is selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis of systemic onset (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, scleroderma, systemic sclerosis, pulmonary sclerosis, pulmonary fibrosis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, axial spondyloarthritis, and other spondyloarthropathies. Embodiment 18: The pharmaceutical composition for use according to embodiment 14, use according to embodiment 15 or method 9 IF-2019-00825794- APN-ANP#INPI Page 9 of 115 in accordance with embodiment 16, where the pathological disorder is selected from the group consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis. DETAILED DESCRIPTION OF THE INVENTION The invention is based on the combination of polysorbate 80 and a buffer solution comprising an acetate buffer (as a buffering agent) and glycine (as a zwitterion) at a pH of approximately 4.6 to approximately 5.5 to prepare a pharmaceutical composition suitable for human use of an antibody, or an antigen-binding fragment thereof, having a heavy-chain variable region comprising SEQ ID NO:l and a light-chain variable region comprising SEQ ID NO:2, at a concentration of 80 mg / ml to 200 mg / ml, without affecting the processability of the pharmaceutical composition and the long-term stability of the antibody. The inventors have found that the pharmaceutical compositions according to the invention are stable over time, particularly when stored at 2–25 °C, as shown, for example, at 2–8 °C and 25 °C. The term stable formulation refers to a formulation in which the protein of interest (in this case 10) IF-2019-00825794- APN-ANP#INPI Page 10 of 115. An antibody (or an antigen-binding fragment thereof) essentially retains its physical, chemical, and / or biological properties during storage. To measure the stability of the protein in a formulation, several analytical methods are well within the knowledge of experts (see some examples in the Examples section). Stability is generally assessed at a selected temperature (e.g., -70°C, 2–8°C, 25°C, 35°C, or higher) for a selected period of time (e.g., 3 months, 6 months, 12 months, or longer). Since an antibody, once formulated, is normally stored in a refrigerator (typically 2–8°C) or at room temperature (typically 15–25°C) before administration to a patient, it is important that such a formulated antibody be stable for a period of time at least at 2–25°C, as shown, for example, at 2–8°C and 25°C.Several values ​​can be used to draw conclusions about stability over a given time period (compared to initial data), such as (and not limited to): 1) no more than 10% alteration of the monomeric form of the antibody, 2) no more than 5% increase in high molecular weight species (HMW or HMWS; also referred to herein as aggregates), 3) no more than 10% increase in low molecular weight species (LMW or LMWS), or 4) no more than + / - 0.3 pH units variation. IF-2019-00825794- APN-ANP#INPI Page 11 of 115 In all embodiments of the invention, the pharmaceutical composition may also be referred to as a stable pharmaceutical composition without any differentiation. In one embodiment of the invention, the pharmaceutical composition according to the invention preferably comprises of or about 80 mg / ml to about 200 mg / ml, preferably of or about 120 mg / ml to about 185 mg / ml or of or about 120 mg / ml to about 180 mg / ml of the antibody, or antigen-binding fragment thereof, such as about 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 or 180 mg / ml, including preferably about 160 mg / ml of the antibody, or antigen-binding fragment thereof. In another embodiment, the pharmaceutical composition according to the invention comprises from or approximately 0.01% to approximately 0.07% (w / v) of polysorbate 80, such as approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06 or 0.07% (w / v polysorbate 80). In another embodiment, the pharmaceutical composition according to the invention comprises approximately 140 mM or approximately 350 mM of glycine. Preferably, the pharmaceutical composition according to the invention comprises approximately 12 IF-2019-00825794- APN-ANP#INPI Page 12 of 115 160 mM to approximately 300 mM of glycine, such as approximately 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mM of glycine. Glycine, in the context of the present invention as a whole, is not a buffering agent. Indeed, at pH from approximately 4.6 to approximately 5.5, glycine is a zwitterion. As a zwitterion, it has the ability to interact with hydrophobic and hydrophilic portions of the antibody or antigen-binding fragment thereof, thereby possibly reducing self-interaction between the antibody or antigen-binding fragment, thus providing a stabilizing effect. In yet another embodiment, the pharmaceutical composition according to the invention as a whole comprises from approximately 20 mM to approximately 100 mM of acetate, and preferably from approximately 40 mM to approximately 90 mM of acetate, such as approximately 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 mM of acetate. Alternatively, the pharmaceutical composition according to the invention as a whole comprises from approximately 50 mM to approximately 90 mM of acetate, such as approximately 50, 55, 60, 65, 70, 75, 80, 85, or 90 mM of acetate. In one embodiment, the pharmaceutical composition comprises approximately 55 mM of acetate. Acetate, in the context of the present invention as a whole, is the buffering agent. IF-2019-00825794- APN-ANP#INPI Page 13 of 115 Any type of acetate can be used, such as calcium acetate, magnesium acetate, sodium acetate, or zinc acetate. Sodium acetate is preferred. Preferably, the pharmaceutical composition according to the invention does not comprise any non-polyol sugars (such as monosaccharides, disaccharides or polysaccharides). The antibody or antigen-binding fragment thereof comprising the pharmaceutical composition according to the invention specifically binds to human IL-17A and IL-17F. The expression "specifically binds to human IL-17A and IL-17F" means that the antibody will bind to human IL-17A and IL-17F with sufficient affinity and specificity to achieve a biologically significant effect. The selected antibody will typically have a binding affinity for human IL-17A and IL-17F; for example, the antibody may bind to human IL-17A and IL-17F with a Kd value between 100 nM and 1 pM. Antibody affinities can be determined, for example, by a surface plasmon resonance base assay, such as the BIAcore assay; an enzyme-linked immunosorbent assay (ELISA); and competitive assays (e.g., RIA). Within the meaning of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to IL-17A and IL-17F IF-2019-00825794- APN-ANP#INPI Page 14 of 115 Human IL-17F can also bind to another molecule, for example, IL-17A and IL-17F cyno, or, by way of non-limiting example, when the antibody or its antigen-binding fragment is incorporated into an abi or multispecific antibody. In particular, this antibody or its antigen-binding fragment does not bind to any human IL-17 isoform other than IL-17A, IL-17F, and the IL-17A / IL-17F heterodimer. IL-17A (originally called CTLA-8) is a pro-inflammatory cytokine and the first IL-17 of the IL-17 family to be discovered. Subsequently, five additional members of the family (IL-17B to F) were identified. IL-17A and F share approximately 55% amino acid sequence homology, are expressed as homodimers and heterodimers, are signaled through the IL-17R, IL-17RC, or IL-17RA / RC receptors, and have been associated with several autoimmune diseases. The antibody or antigen-binding fragment of this antibody that specifically binds to human IL-17A and IL-17F preferentially also neutralizes human IL-17A and IL-17F. The term neutralizes, as used herein, refers to an antibody that inhibits or substantially reduces the biological effect of the molecule to which it specifically binds. Therefore, the expression "the antibody neutralizes human IL-17A and IL-17F" refers to a 15 IF-2019-00825794- APN-ANP#INPI Page 15 of 115 antibody that binds specifically to human IL-17A and IL-17F and inhibits or substantially reduces its biological effect, such as by blocking the binding of IL-17A and IL-17F to its receptor. The term antibody or antibodies, as used herein, refers to monoclonal or polyclonal antibodies and is not limited to recombinant antibodies generated by recombinant technologies as known in the art. The antibody, or antigen-binding fragment thereof, having a variable heavy chain comprising SEQ ID N0: and a variable light chain comprising SEQ ID NO: 2, as shown in Table 1, is described in more detail in document WO2012095662, the contents of which are incorporated herein by reference. The terms antibody or antibodies also refer to humanized antibodies. Humanized antibodies are antibodies that contain a sequence derived from non-human antibodies. For the most part, humanized antibodies are human antibodies (recipient antibody) in which residues from a hypervariable region of the receptor are replaced by residues from a hypervariable region or complementarity-determining region (CDR) of a non-human species (donor antibody) such as mouse, rat, rabbit, chicken, or non-human primate IF-2019-00825794- APN-ANP#INPI Page 16 of 115. Humanized antibodies have the desired specificity, affinity, and activity. In most cases, the human antibody (receptor) residues outside the CDR (combinant receptor region), i.e., in the structural region (FR), are further replaced with the corresponding non-human residues. Additionally, humanized antibodies may include residues not found in either the receptor or donor antibody. These modifications are made to further refine antibody performance. Humanization reduces the immunogenicity of non-human antibodies in humans, thus facilitating the application of antibodies for the treatment of human diseases. Humanized antibodies and various technologies for generating them are well-established in the field. The terms antibody or antibodies can also refer to human antibodies, which can be generated as an alternative to humanization.For example, it is possible to produce transgenic animals (e.g., mice) that, after immunization, are capable of producing a full repertoire of human antibodies in the absence of endogenous murine antibody production. For example, homozygous deletion of the antibody heavy chain (JH) binding region gene in chimeric and germline mimic mice has been shown to result in complete inhibition of antibody production. IF-2019-00825794- APN-ANP#INPI Page 17 of 115. Transfer of the human germline immunoglobulin gene array into such germline mutant mice will result in the production of human antibodies specific to a particular antigen after immunization of the transgenic animal carrying the human germline immunoglobulin genes with that antigen. The technologies for producing such transgenic animals and the technologies for isolating and producing human antibodies from such transgenic animals are known in the art. Alternatively, in the transgenic animal, e.g., a mouse, only the immunoglobulin genes encoding the variable regions of the mouse antibody are replaced with the corresponding sequences from the human variable immunoglobulin gene. The mouse germline immunoglobulin genes encoding the constant regions of the antibody remain unchanged.In this way, the effector functions of antibodies in the immune system of the transgenic mouse, and consequently the development of B cells, remain essentially unchanged, which can lead to an enhanced antibody response after in vivo antigenic exposure. Once the genes encoding a particular antibody of interest have been isolated from such transgenic animals, the genes encoding the constant regions can be replaced with the genes from the IF-2019-00825794- APN-ANP#INPI Page 18 of 115 human constant region to obtain a fully human antibody. The term antibody or antibodies, as used herein, also refers to an aglycosylated antibody. The term antigen-binding fragment or its grammatical variations as used herein refers to an antibody fragment. Examples of antibody fragments according to the invention include Fab, Fab', F(ab')2, and Fv, scFv fragments, single-chain antibodies, bispecific, trispecific, tetraspecific, or multispecific antibodies formed from antibody fragments or antibodies, including but not limited to Fab-Fv or Fab-FvFv constructs. Antibody fragments as defined above are known in the art. Preferably, the pharmaceutical composition according to the invention comprises (Table 1): 1) an antibody comprising a heavy chain having the sequence defined in SEQ ID NO: 1 and a light chain having the sequence defined in SEQ ID NO: 2 2) an antibody comprising a heavy chain having the sequence defined in SEQ ID NO: 3 and a light chain having the sequence defined in SEQ ID NO: 4; or IF-2019-00825794- APN-ANP#INPI Page 19 of 115 3) an antibody comprising a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity to the variable region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% identity or similarity, preferably 90% identity or similarity to the variable region of the sequence defined in SEQ ID NO: 4. Table 1 Region and identifier SEQ ID Amino acid sequences Heavy chain variable region SEQ ID NO:1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYNMAWVRQAPGKGL EWVATITYEGRNTYYRDSVKGRFTISRDNAKNSLYLQMNSLRAED TAVYYCASPPQYYEGSIYRLWFAHWGQGTLVTVSS Light chain variable region SEQ ID NO:2 AIQLTQSPSSLSASVGDRVTITCRADESVRTLMHWYQQKPGKAPK LLIYLVSNSEIGVPDRFSGSGSGTDFRLTISSLQPEDFATYYCQQ TWSDPWTFGQGTKVEIK Heavy chain SEQ ID NO:3 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYNMAWVRQAPGKGL EWATITYEGRNTYYRDSVKGRFTISRDNAKNSLYLQMNSLRAED TAVYYCASPPQYYEGSIYRLWFAHWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA IF-2019-00825794- APN-ANP#INPI Page 20 of 115 VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV WDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG(K)* ★ The final F may be absent Light chain SEQ ID NO:4 AIQLTQSPSSLSASVGDRVTITCRADESVRTLMHWYQQKPGKAPK LLIYLVSNSEIGVPDRFSGSGSGTDFRLTISSLQPEDFATYYCQQ TWSDPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Antibody molecules can normally be produced by culturing a host cell containing a vector encoding antibody sequence 5 under conditions suitable to produce protein expression from the DNA encoding the antibody molecule of the present invention, and isolating the antibody molecule. For the production of products comprising both heavy and light chains, the cell line can be transfected with two vectors, a first vector encoding a light chain polypeptide and a second vector that 21 IF-2019-00825794- APN-ANP#INPI Page 21 of 115 encodes a heavy chain polypeptide. Alternatively, a single vector can be used, the vector that includes sequences encoding light chain and heavy chain polypeptides. An antibody or an antigen-binding fragment that can be manufactured on an industrial scale can be produced by culturing eukaryotic host cells transfected with one or more expression vectors encoding the recombinant antibody fragment. Preferably, the eukaryotic host cells are mammalian cells, most preferably Chinese hamster ovary (CHO) cells. Mammalian cells can be cultured in any medium that will support their growth and recombinant protein expression. Preferably, the medium should be chemically defined and free of animal-derived products such as animal serum and peptone. Various cell culture media are available to those skilled in the art, comprising different combinations of vitamins, amino acids, hormones, growth factors, ions, buffers, nucleosides, glucose, or an equivalent energy source, present in concentrations appropriate to allow cell growth and protein production. Additional cell culture medium components may be included within the culture medium. IF-2019-00825794- APN-ANP#INPI Page 22 of 115 cell culture at appropriate concentrations at different times during a cell culture cycle that can be known by experts in the technique. Mammalian cell culture can take place in any suitable vessel, such as a shaker flask or a bioreactor, which may or may not operate in batch mode depending on the required production scale. These bioreactors can be stirred-tank or air-lift reactors. Several large-scale bioreactors are available with capacities ranging from over 1,000 L to 50,000 L, preferably between 5,000 L and 20,000 L, or up to 10,000 L. Alternatively, smaller-scale bioreactors, such as those between 2 L and 100 L, can also be used to manufacture an antibody or antibody fragment. An antibody or antigen-binding fragment of an antibody is normally found in the supernatant of a mammalian host cell culture, typically a CHO cell culture. For CHO culture processes in which the protein of interest, such as an antibody or antigen-binding fragment of an antibody, is secreted into the supernatant, this supernatant is collected using methods known to the technique, usually by centrifugation. IF-2019-00825794- APN-ANP#INPI Page 23 of 115 Therefore, the method for producing the antibody or antigen-binding fragment thereof comprises a step of centrifugation and recovery of the supernatant after cell culture and before protein purification. In one further embodiment, this centrifugation is continuous. For the avoidance of doubt, the supernatant refers to the liquid above the sedimented cells resulting from centrifugation of the cell culture. Alternatively, the host cells are prokaryotic cells, preferably Gram-negative bacteria. More preferably, the host cells are E. coli cells. Prokaryotic host cells for protein expression are well known in the art (Terpe, K. Appl Microbiol Biotechnol 72, 211-222 (2006)). The host cells are recombinant cells that have been genetically modified to produce the protein of interest, such as an antigen-binding fragment of an antibody. Recombinant E. coli host cells can be derived from any suitable E. coli strain, including MC4100, TGI, TG2, DHB4, DH5a, DH1, BL21, K12, XL1Blue, and JM109. An example is the E. coli strain W3110 (ATCC 27,325), a host strain commonly used for recombinant protein fermentations. Antibody fragments can also be produced by culturing strains of 24 IF-2019-00825794- APN-ANP#INPI Page 24 of 115 Modified E. coli, for example, metabolic mutant or protease-deficient strains of E. coli. E. coli host cell cultures (fermentations) can be grown in any medium that will support the growth of E. coli and the expression of the recombinant protein. The medium can be any chemically defined medium such as, for example, described in Durany O, et al. (2004). Studies on the expression of recombinant fuculose-l-phosphate aldolase in Escherichia coli. Process Biochem 39, 1677-1684. The cultivation of E. coli host cells can take place in any suitable container, such as a shaking flask or a dehydrator, depending on the required production scale. Various large-scale dehydrators are available with capacities ranging from over 1,000 liters up to approximately 100,000 liters. Dehydrators with capacities of 1,000 to 50,000 liters are preferred, with 1,000 to 25,000, 20,000, 15,000, 12,000, or 10,000 liters being more common. Smaller-scale dehydrators with capacities between 0.5 and 1,000 liters can also be used. Other methods for obtaining the antigen-binding fragment of a human antibody in vitro are based on display technologies such as phage display or ribosome display, where recombinant DNA libraries are used that are generated at 25 IF-2019-00825794- APN-ANP#INPI Page 25 of 115 Human antibodies can be generated, at least in part artificially or from donor immunoglobulin variable (V) domain gene repertoires. Phage and ribosome display technologies for generating human antibodies are well known in the field. Human antibodies can also be generated from isolated human B cells that are immunized ex vivo with an antigen of interest and subsequently fused to generate hybridomas, which can then be screened for the optimal human antibody. Those skilled in the technique will understand that antibodies can undergo a variety of post-translational modifications. The type and extent of these modifications often depend on the host cell line used to express the antibody, as well as the culture conditions. Such modifications can include variations in glycosylation, methionine oxidation, diketopiperazine formation, aspartate isomerization, and asparagine deamidation. A common modification is the loss of a basic carboxy-terminal residue (such as lysine or arginine) due to the action of carboxypeptidases (as described in Harris, RJ. Journal of Chromatography 705: 129-134, 1995). Consequently, the C-terminal lysine of the antibody heavy chain may be absent. IF-2019-00825794- APN-ANP#INPI Page 26 of 115 The pharmaceutical composition according to the invention as a whole has a pH of approximately 4.6 to approximately 5.5, such as 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. Alternatively, it has a pH of approximately 4.6 to approximately 5.3, such as 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or 5.3. In all embodiments of the present invention, unless otherwise stated, the pH value was measured at 23-25 ​​°C and is within ±0.1 or ±0.2 of a pH unit. The present invention provides a method for preparing a pharmaceutical composition comprising an antibody, or an antigen-binding fragment thereof, having a heavy-chain variable region comprising SEQ ID NO:1 and a light-chain variable region comprising SEQ ID NO:2. The method comprises the steps of preparing a) a low-concentration formulation by combining approximately 40 mg / ml to approximately 50 mg / ml of the antibody, or antigen-binding fragment thereof, with a buffer solution comprising glycine and acetate at pH approximately 4.6 to approximately 5.5; and then b) preparing a high-concentration formulation by concentrating the antibody or antigen-binding fragment thereof in the low-concentration formulation obtained in a) to a concentration of approximately 160 mg / ml to 180 mg / ml; and finally c) adding polysorbate 80. IF-2019-00825794- APN-ANP#INPI Page 27 of 115 to the high concentration formulation obtained in b). Optionally, before step c) the concentration of the antibody or antigen-binding fragment thereof can be adjusted with the buffer solution comprising glycine and acetate. Additional excipients for use within pharmaceutical compositions according to the invention include, but are not limited to, viscosity enhancers, bulking agents, solubilizing agents, or combinations thereof. The present invention also provides a container comprising the pharmaceutical composition according to the invention. In particular, the container may be, without limitation, a vial, ampoule, tube, bottle, or syringe (such as a pre-filled syringe) comprising the pharmaceutical composition. The container may be part of a kit of parts comprising one or more containers comprising the pharmaceutical compositions according to the invention and delivery devices such as a syringe, a pre-filled syringe, an auto-injector, a needle-free device, an implant or a patch, or other devices for parenteral administration and instructions for use. In one embodiment of the present invention, IF-2019-00825794- APN-ANP#INPI Page 28 of 115 A container comprises the pharmaceutical composition comprising: a. from approximately 80 mg / ml to approximately 200 mg / ml, or alternatively from approximately 120 mg / ml to approximately 185 mg / ml of antibody, or antigen-binding fragment thereof, having: i. a variable heavy chain region comprising SEQ ID NO: and a variable light chain region comprising SEQ ID NO:2; or ii. a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:4; or iii. a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity to the constant region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% identity or similarity, preferably 90% identity or similarity to the constant region of the sequence defined in SEQ ID NO: 4. b. acetate; c. glycine; d. polysorbate 80, IF-2019-00825794- APN-ANP#INPI Page 29 of 115 where the composition has a pH of approximately 4.6 to approximately 5.5. In a preferred embodiment of the present invention, a container comprises the pharmaceutical composition comprising: a, approximately 160 mg / ml of antibody, or antigen-binding fragment thereof having: i. a variable heavy chain region comprising SEQ ID NO:1 and a variable light chain region comprising SEQ ID NO:2; or ii. a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:4; or iii. a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO:3 and a light chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO:4. b. sodium acetate; c. glycine; IF-2019-00825794- APN-ANP#INPI Page 30 of 115 d. polysorbate 80, wherein the composition has a pH of approximately 4.6 to approximately 5.5. Furthermore, preferably, the present invention provides a container comprising a pharmaceutical composition obtained by the method according to the present invention, said method comprising the steps of: a. preparing a low concentration formulation by combining approximately 40 mg / ml to approximately 50 mg / ml of an antibody, or an antigen-binding fragment thereof, having a variable heavy chain region comprising SEQ ID NO:1 and a variable light chain region comprising SEQ ID NO:2 with a buffer solution comprising glycine and acetate at pH of approximately 4.6 to approximately 5.5; b. prepare a high concentration formulation by concentrating the antibody or antigen-binding fragment thereof from the low concentration formulation obtained in a) to a concentration of approximately 160 mg / ml to 180 mg / ml; IF-2019-00825794- APN-ANP#INPI Page 31 of 115 c. add polysorbate 80 to the high concentration formulation obtained in b), preferably at approximately 0.01 to 0.07% (w / v); d. Optionally, before step c) adjust the concentration of the antibody or antigen-binding fragment of the antibody with the buffer solution comprising glycine and acetate. The pharmaceutical composition obtained by the method of the present invention and contained in the container has a pH of approximately 4.6 to 5.5. Preferably, the buffer solution comprises from approximately 20 mM to approximately 100 mM of acetate, preferably from approximately 40 mM to approximately 90 mM of acetate and from approximately 140 mM to approximately 350 mM of glycine. Pharmaceutical compositions or liquid pharmaceutical formulations according to the invention are for use in therapy. In one embodiment, the pharmaceutical composition for use in therapy comprises 80 mg / ml to 200 mg / ml, preferably about 120 to about 185 mg / ml of an antibody or antigen-binding fragment thereof, acetate, glycine, polysorbate 80, at a pH of about 4.6 to about 5.5; IF-2019-00825794- APN-ANP#INPI Page 32 of 115 where the antibody or antigen-binding fragment thereof (which may apply) comprises: 1) a variable heavy chain region comprising SEQ ID NO: 1 and a variable light chain region comprising SEQ ID NO: 2; or 2) a heavy chain comprising SEQ ID NO: 3 and a light chain comprising SEQ ID NO: 4; or 3) a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 4; with preference of approximately 20 mM to approximately 100 mM of acetate, approximately 140 mM to approximately 350 mM of glycine and approximately 0.01% to approximately 0.07% (w / v) of polysorbate 80 at a pH of approximately 4.6 to approximately 5.5. In another embodiment, the pharmaceutical composition for use in therapy is obtained by the method according to the present invention, such method comprising the steps of: IF-2019-00825794- APN-ANP#INPI Page 33 of 115 a. preparing a low concentration formulation by combining approximately 40 mg / ml to approximately 50 mg / ml of an antibody, or an antigen-binding fragment thereof, having a heavy chain variable region comprising SEQ ID N0:l and a light chain variable region comprising SEQ ID N0:2 with a buffer solution comprising glycine and acetate at pH of approximately 4.6 to approximately 5.5; b. prepare a high concentration formulation by concentrating the antibody or antigen-binding fragment thereof from the low concentration formulation obtained in a) to a concentration of approximately 160 mg / ml to 180 mg / ml; c. add polysorbate 80 to the high concentration formulation obtained in b), preferably at approximately 0.01 to 0.07(w / v)%; d. Optionally, before step c) adjust the concentration of the antibody or antigen-binding fragment thereof with the buffer solution comprising glycine and acetate. The pharmaceutical composition according to the invention is also for use in the treatment or prophylaxis of a 34 IF-2019-00825794- APN-ANP#INPI Page 34 of 115 pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F. In one embodiment, the pharmaceutical composition for use in the treatment or prophylaxis of a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F, comprises 80 mg / ml to 200 mg / ml, preferably approximately 120 to approximately 185 mg / ml of an antibody or antigen-binding fragment thereof, acetate, glycine, polysorbate 80, at a pH of approximately 4.6 to approximately 5.5; wherein the antibody or antigen-binding fragment thereof (which may apply) comprises: 1) a variable heavy chain region comprising SEQ ID NO: 1 and a variable light chain region comprising SEQ ID NO: 2; or 2) a heavy chain comprising SEQ ID NO: 3 and a light chain comprising SEQ ID NO: 4; or 3) a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% identity or similarity, preferably 90% IF-2019-00825794- APN-ANP#INPI Page 35 of 115 identity or similarity with the constant region of the sequence defined in SEQ ID NO: 4; with preference of approximately 20 mM to approximately 100 mM of acetate, approximately 140 mM to approximately 350 mM of glycine and approximately 0.01% to approximately 0.07% (w / v) of polysorbate 80 at a pH of approximately 4.6 to approximately 5.5. In a preferred embodiment, the pharmaceutical composition for use in the treatment or prophylaxis of a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F, is obtained by the method according to the present invention, said method comprising the steps of: a. preparing a low concentration formulation by combining approximately 40 mg / ml to approximately 50 mg / ml of an antibody, or an antigen-binding fragment thereof, having a heavy chain variable region comprising SEQ ID NO:1 and a light chain variable region comprising SEQ ID NO:2 with a buffer solution comprising glycine and acetate at pH of approximately 4.6 to approximately 5.5; b. Prepare a high-concentration formulation by concentrating the antibody or IF-2019-00825794- APN-ANP#INPI Page 36 of 115 antigen-binding fragment of this from the low concentration formulation obtained in a) at a concentration of approximately 160 mg / ml to 180 mg / ml; c. add polysorbate 80 to the high concentration formulation obtained in b), preferably from approximately 0.01 to approximately 0.07 (w / v)%; d. Optionally, before step c) adjust the concentration of the antibody or antigen-binding fragment of the antibody with the buffer solution comprising glycine and acetate. The present invention also provides for the use of the pharmaceutical composition in the manufacture of a medicament for the treatment or prophylaxis of a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F, wherein the pharmaceutical composition comprises from approximately 80 mg / ml to approximately 200 mg / ml, preferably from approximately 120 to approximately 180 mg / ml of an antibody or antigen-binding fragment thereof, acetate, glycine, polysorbate 80, at a pH of approximately 4.6 to approximately 5.5; where the antibody or antigen-binding fragment thereof (which may be applied) comprises: IF-2019-00825794- APN-ANP#INPI Page 37 of 115 1) a variable heavy chain region comprising SEQ ID NO: 1 and a variable light chain region comprising SEQ ID NO: 2; or 2) a heavy chain comprising SEQ ID NO: 3 and 5 and a light chain comprising SEQ ID NO: 4; either 3) a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 4; with preference of approximately 20 mM to approximately 100 mM sodium acetate, approximately 140 mM to approximately 350 mM glycine and approximately 0.01 to approximately 0.07(w / v) % polysorbate 80 at a pH of approximately 4.6 to approximately 5.5. In a preferred embodiment, the pharmaceutical composition is used in the manufacture of a medicament for the treatment or prophylaxis of a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F, wherein the composition IF-2019-00825794- APN-ANP#INPI Page 38 of 115. The pharmaceutical product is obtained by the method according to the present invention, said method comprising the steps of: a. preparing a low concentration formulation by combining approximately 40 mg / ml to approximately 50 mg / ml of an antibody, or an antigen-binding fragment thereof, having a heavy chain variable region comprising SEQ ID NO:1 and a light chain variable region comprising SEQ ID NO:2 with a buffer solution comprising glycine and acetate at pH of approximately 4.6 to approximately 5.5; b· prepare a high concentration formulation by concentrating the antibody or antigen-binding fragment thereof from the low concentration formulation obtained in a) to a concentration of approximately 160 mg / ml to 180 mg / ml; c. add polysorbate 80 to the high concentration formulation obtained in b), preferably at approximately 0.01 to approximately 0.07 (w / v)%; d. Optionally, before step c) adjust the concentration of the antibody or binding fragment IF-2019-00825794- APN-ANP#INPI Page 39 of 115 to the antigen of this with the buffer solution comprising glycine and acetate. The present invention also contemplates a method of treating or preventing a pathological disorder mediated by IL-17A and / or IL-17F, or associated with increased levels of IL-17A and / or IL-17F in a mammalian subject, comprising administering the pharmaceutical composition comprising approximately 80 mg / ml to approximately 200 mg / ml, preferably approximately 120 to approximately 185 mg / ml of an antibody or antigen-binding fragment thereof, acetate, glycine, polysorbate 80, at a pH of approximately 4.6 to approximately 5.5; where the antibody or antigen-binding fragment thereof (which may be applied) comprises: 1) a variable heavy chain region comprising SEQ ID NO: 1 and a variable light chain region comprising SEQ ID NO: 2; or 2) a heavy chain comprising SEQ ID NO: 3 and a light chain comprising SEQ ID NO: 4; or 3) a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% of 40 IF-2019-00825794- APN-ANP#INPI Page 40 of 115 identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 4; with preference of approximately 20 mM to approximately 5,100 mM of acetate, approximately 150 mM to approximately 250 mM of glycine and approximately 0.01 to approximately 0.07 (w / v)% polysorbate 80 at a pH of approximately 4.6 to approximately 5.5. Preferably, the pathological disorder is selected from the group consisting of infections (viral, bacterial, fungal, and parasitic), infection-associated endotoxic shock, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic-onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman disease, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease pilonidal, peritonitis, 41 IF-2019-00825794- APN-ANP#INPI Page 41 of 115 psoriasis, atopic dermatitis, vasculitis, surgical adhesions, stroke, autoimmune diabetes, type I diabetes, Lyme arthritis, arthritis due to meningoencephalitis, immune-mediated inflammatory disorders of the central and peripheral nervous system, such as multiple sclerosis and Guillain-Barr syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrosis disorders including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, scleroderma or systemic sclerosis, cancer (both solid tumors such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies and in particular acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer),heart disease (which includes ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis and hypochlorhydria.) Most preferentially, the pathological disorder is selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis of systemic onset (JIA), systemic lupus erythematosus (SLE), asthma, obstructive disease of 42 IF-2019-00825794- APN-ANP#INPI Page 42 of 115 chronic respiratory disease (COAD), chronic obstructive pulmonary disease (COPD), atopic dermatitis, scleroderma, systemic sclerosis, pulmonary fibrosis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, axial spondyloarthritis and other spondyloarthropathies; and even more preferentially the pathological disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis and axial spondyloarthritis. Even more preferentially, the pathological disorder is selected from the group consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis. In a preferred embodiment of the present invention, the pharmaceutical composition is for use in the treatment or prophylaxis of rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis and comprises approximately 160 mg / ml of an antibody or antigen-binding fragment thereof, acetate, glycine, polysorbate 80, at a pH of approximately 4.6 to approximately 5.5; IF-2019-00825794- APN-ANP#INPI Page 43 of 115 where the antibody or antigen-binding fragment thereof (which may apply) comprises: 1) a variable heavy chain region comprising SEQ ID NO: 1 and a variable light chain region comprising SEQ ID NO: 2; or 2) a heavy chain comprising SEQ ID NO: 3 and a light chain comprising SEQ ID NO: 4; either 3) a heavy chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 3 and a light chain having at least 80% identity or similarity, preferably 90% identity or similarity with the constant region of the sequence defined in SEQ ID NO: 4. In another preferred embodiment, the pharmaceutical composition is for use in the treatment or prophylaxis of rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis, wherein the pharmaceutical composition is obtained by the method according to the present invention, such method comprising the steps of: a. Prepare a low concentration formulation •25 by combining approximately 40 IF-2019-00825794- APN-ANP#INPI Page 44 of 115 mg / ml to approximately 50 mg / ml of an antibody, or an antigen-binding fragment thereof, having a heavy chain variable region comprising SEQ ID N0:ly and a light chain variable region comprising SEQ ID NO:2 with a buffer solution comprising glycine and acetate at pH from approximately 4.6 to approximately 5.5; b. prepare a high concentration formulation by concentrating the antibody or antigen-binding fragment thereof from the low concentration formulation obtained in a) to a concentration of approximately 160 mg / ml to 180 mg / ml; c. add polysorbate 80 to the high concentration formulation obtained in b), preferably from approximately 0.01 to approximately 0.07 (w / v)%; d. Optionally, before step c) adjust the concentration of the antibody or antigen-binding fragment of the antibody with the buffer solution comprising glycine and acetate. The pharmaceutical composition according to the invention can be administered in a therapeutically effective amount. The expression "therapeutically effective amount" refers to the fact that the pharmaceutical composition according to the invention can be administered in a therapeutically effective amount. 45 IF-2019-00825794- APN-ANP#INPI Page 45 of 115, as used herein, refers to the amount of a therapeutic agent (i.e., an antibody) needed to treat, ameliorate, or prevent a specific disease, disorder, or condition, or to exhibit a detectable therapeutic, pharmacological, or preventive effect. For any antibody or antigen-binding fragments thereof, the therapeutically effective amount can initially be estimated in cell culture assays or animal models, typically rodents, rabbits, dogs, pigs, or primates. The animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes of administration in humans. The precise therapeutically effective amount for a human subject will depend on the severity of the disease, the subject's general health, age, weight, and gender, diet, timing and frequency of administration, drug combinations, sensitivity to the reaction, and tolerance / response to treatment. This amount can be determined through routine experimentation and is within the clinician's judgment. In general, a therapeutically effective antibody dose will be from 0.01 mg / kg to 500 mg / kg, for example, from 0.1 mg / kg to 200 mg / kg or from 1 mg / kg to 100 mg / kg. IF-2019-00825794- APN-ANP#INPI Page 46 of 115 For the treatment of the aforementioned diseases and / or disorders, the appropriate dose will vary according to, for example, the specific antibody being used, the patient, the route of administration, and the nature and severity of the condition being treated. In one particular embodiment, the pharmaceutical composition according to the invention is administered intravenously or subcutaneously. When administered by intravenous injection, it may be given as a bolus injection or as a continuous infusion. The pharmaceutical composition according to any embodiment of the invention may also be administered by intramuscular injection. The pharmaceutical composition may be injected using a syringe, an injection device such as an autoinjector, a needle-free device, an implant, or a patch. The liquid pharmaceutical formulation of the invention is appropriately administered to the patient at one time or during a series of treatments and can be administered to the patient at any time after diagnosis; it can be administered as the sole treatment or together with other drugs or therapies useful for treating the conditions as described herein above. The antibody or antigen-binding fragment of the antibody may be the only active ingredient in the formulation 47 IF-2019-00825794- APN-ANP#INPI Page 47 of 115 liquid pharmaceutical. Alternatively, the antibody or antigen-binding fragment thereof may be administered in combination, for example, simultaneously, sequentially, or separately, with one or more therapeutically active ingredients. The active ingredient as used herein refers to an ingredient having a pharmacological effect, such as a therapeutic effect, at a relevant dose. In some embodiments, the antibody or antigen-binding fragment thereof in the pharmaceutical composition may be accompanied by other active ingredients, including other antibodies or non-antibody ingredients, administered by the same or a different route of administration, to treat other inflammatory or autoimmune diseases.In one embodiment, the subject is administered, simultaneously or sequentially (before and / or after), other antibody ingredients, such as anti-TNF antibodies, or non-antibody ingredients such as small molecule drug molecules. The invention will now be described in more detail by means of examples with reference to embodiments illustrated in the accompanying drawings. EXAMPLES Abbreviations IF-2019-00825794- APN-ANP#INPI Page 48 of 115 Anti-IL-17A / F Ab: Anti-IL-17A and IL-17F antibody having sequences as defined in SEQ ID NOs: 3 and 4 of Table 1; AFT: Accelerated freeze / thaw; BPP: Biological Pilot Plant; CCPS: Cell Culture Process Sciences; CEX-HPLC: Cation exchange chromatography / High-performance liquid chromatography; cIEF: Capillary isoelectric focusing; DSL: Dynamic light scattering; DFS: Differential scanning fluorimetry; DPS: Downstream Process Sciences; DTT: Dithiothreitol; FZT: Freeze / thaw; HMW: Heavy molecular weight; HPLC: High-performance liquid chromatography; HSC: High-performance self-interaction chromatography; IAA: Iodoacetamide; ICE: Capillary imaging electrophoresis; LMW: Low molecular weight; MW: Molecular weight; NP: Not available; PCR: polymerase chain reaction; PEG: Polyethylene glycol; PES: Polyether sulfone; PS20: polysorbate 20; PS80: polysorbate 80; PTFE: polytetrafluoroethylene; PVDF: polyvinylidene fluoride; RH: relative humidity;% RSD: % relative standard deviation; SDS-PAGE: Sodium dodecyl sulfate-amide gel electrophoresis; s: Seconds; SEC: Size exclusion chromatography; SEC-HPLC: Size exclusion chromatography-high-performance liquid chromatography; SIC: Self-interaction chromatography; Trp: Tryptophan; WFI: Water for injection; w / v: weight / volume; IF-2019-00825794- APN-ANP#INPI Page 49 of 115 Example 1: Selection of additives Initial screening studies were conducted by investigating the effect of different additives on the anti-IL-17A and IL-17F antibodies at 1 mg / ml by determining the B22 value (second viral coefficient) using SIC and selecting the 5 best formulations with the highest probability of success (HSC™ Technology). Positive B22 values ​​indicate which additive can most effectively mitigate protein-protein interactions that can lead to aggregation and other types of degradation in a formulation containing the anti-IL-17A / F antibody. Different additives were selected. The superior additives that produced the highest B22 values ​​without compromising the conformational stability of the antibody were identified. From an incomplete factorial design of the possible combinations of the 9 best additives and 3 buffer systems, a total of 36 formulations were generated, and the resulting B22 values ​​were measured using HSC™ Technology (Soluble Therapeutics™). From the analysis of these 36 formulations, 5 formulations were predicted and validated (Table 2) using SIC (data not shown). In Table 2, M represents the measured B22 value and C represents the calculated B22 value. IF-2019-00825794- APN-ANP#INPI Page 50 of 115 Table 2 MC 1 citrate 0.04 M pH 5.5 3 mM KH2PO4 PEG 3350 l.5%(w / v) 3.8 3.6 2 citrate 0.04 MpH 5.5 K2HPO4 50 mM PS20 35 uM Sacchars at 75 mM 3.5 3.4 3 acetate 0.04 M pH 5.7 NaOAc 15 mM Benzyl alcohol 0.1% (w / v) saccharide at 100 mM 2.9 2.7 4 citrate 0.04 M pH 5.5 K2HPO4 25 mM PS20 17.5 uM saccharose at 100 mM 2.8 2.5 5 acetate 0.04 M pH 5.7 K2HPO4 25 mM Sucrose 125 mM 2.8 2.4 Example 2: Effect of high antibody concentration on best-performing formulations The results of the study conducted in Example 1, performed with the anti-IL-17A / F Ab at 1 mg / ml, were subsequently verified at a concentration of approximately 160 mg / ml of anti-IL-17A / F Ab and were found to be non-representative. The formulations that were included in the test were (Table 3): IF-2019-00825794- APN-ANP#INPI Page 51 of 115 Table 3 1 Sodium citrate 40 mM pH 5.6 KH2PO4 3 mM PEG 3350 1.5% (w / v) 2 Sodium citrate 40 mM pH 5.6 KH2PO4 50 mM Sucrose 75 mM PS20 0.00044% (w / v) 3 Sodium acetate 40 mM pH 5.7 NaOAc 15 mM Sucrose 100mM Benzyl alcohol 0.1% (w / v) 4 Sodium citrate 40mM pH 5.5 KH2PO4 25mM Sucrose 100mM PS20 0.00022% (W / v) 5 Sodium acetate __40mM pH 5.7 KH2PO4 25mM Sucrose 125mM 6 Sodium citrate 40mM pH 5.5 KH2PO4 50 mM Histidine 6 mM The anti-IL-17A / F antibody at 88.7 mg / ml in 20 mN histidine, 250 mH sorbitol, pH 6.0 was concentrated using 50 x 5 vivaflow 50 cassettes with a 30 kDa PES membrane MWCO. Antibody loss was observed, and to account for this predicted loss, the antibody was concentrated to 175 mg / ml before buffer swapping into the relevant formulation buffers using PD10 columns containing 10 Sephadex G-25 medium. After buffer exchange, formulations 52 IF-2019-00825794- APN-ANP#INPI Page 52 of 115 finals were adjusted to 160 mg / ml using the relevant formulation buffers (Table 3 - formulations 1 to 6); the amounts are negligible and do not affect the concentration of the buffer components). After this adjustment, PS20 5 was added to formulations 2 and 4 to achieve a final content of 0.00044 and 0.00022% (w / v) respectively and benzyl alcohol was added to formulation 3 to achieve a final content of 0.1% (w / v). Under a laminar flow hood, formulations 1, 10, and 6 were transferred to 2 mL deep 96-well plates, then subaliquoted into twenty sterile 96-well half-area plates (80 pL per well). One mL of each formulation was also transferred to sterile 2 mL Schott Type I glass vials sealed with Flurotec-coated Westar rubber stoppers and Tru-Edge flip-off seals for initial testing. The plates were stored as follows (Table 4; a: 2 ml Schott vials - remaining in the 96-well plate; b: for formulation 1 only; c: for all 20 formulations 2-6; d: for formulation 2-6 this measurement was taken at 5 weeks): IF-2019-00825794- APN-ANP#INPI Page 53 of 115 Table 4 Conditions Time points in week Start 1 2 weeks 4 weeks 6 weeks 8 weeks 12 weeks: Rep • 5 °C ✓ zc ✓ ✓ ✓ 25 °C / 60%RH ✓ ✓ 35 °C / 75%RH ✓c ✓ FZT ✓b ✓c AFT 1 ✓° The freeze-thaw stress test was performed by freezing and thawing the formulation five times using a Cryomed controlled-rate freezer with freezing and thawing rates set at 0.5 °C / min for the low-rate freeze-thaw (FZT) experiment and 2 °C / min for the accelerated-rate freeze-thaw (AFT) experiment. In each case, the freezer probe was inserted into the well of an additional plate. IF-2019-00825794- APN-ANP#INPI Page 54 of 115 containing a glycerol / water solution of similar viscosity to that of the samples. FZT analysis was performed after 4 weeks at 5 °C for formulation 1, while it was performed after 8 weeks at 5 °C for formulations 2 to 6. AFT analysis was performed after 1 week at 5 °C for formulation 1 and after 5 weeks at 5 °C for formulations 2 to 6. Visual assessment The plates were scanned using an Epson scanner Expression v750 Pro model J221A in color (1200 dpi, 24 bits, no image processing) and grayscale (1200 dpi, 16 bits, no image processing). An automated visual inspection scan was performed using the Molecular Devices M5 plate reader, which performs a 1-point well scan measuring absorbance at 600 nm. By visual inspection, for all time points and conditions, formulation 1 consistently appeared more turbid than all other formulations. For A600, under all 20 conditions, formulations 1 and 2 appeared to show an increase in absorbance at 600 nm (Table 8); however, the increase was smaller. After FZT and AFT stress, formulation 1 showed an increase in absorbance at 600 nm (Table 5), with the least pronounced increase occurring after the AFT stress. IF-2019-00825794- APN-ANP#INPI Page 5 of 115 Table 5 Conditions Time period in weeks Formulations 1 2 3 4 5 6 5°C Tinidal 0.10 0.09 o.os 0.12 0.10 0.13 T04 0.12 020 0.09 0.12 0.08 0.10 T08 0.16 020 0.13 0.11 0.08 0.10 τη NP1 021 ο.φ 0.08 0.08 0 09 25°C / 60» / *RH Tinidal 0.10 0.09 0.08 0.12 0.10 0.13 T04 027 0.15 0.09 0.09 0.10 0.07 TOS 0.10 024 0.18 0.15 0.15 0.09 T12 NP* 024 0.12 0.11 0.15 0.09 35°C / 75*iRH Tinidal 0.10 0.09 0.08 0.12 0.10 0.13 T04 0.19 0.16 0.14 0.10 0.10 0.03 TOS 0.16 0.19 0.11 025 0.15 0.11 T12 NP* 022 0.15 0.17 0.14 0.11 FZT Tinidal 0.10 0.09 0.08 0.12 0.10 0.13 T04 025 - - - - - TOS - 021 0.12 0.13 0.09 0.11 ATT Tinidal 0.10 0.09 0.08 0.12 0.10 0.13 T04 0.15 020 0.11 0.14 0.10 0.10 Determination of protein concentration by UV at 280 nm The samples were diluted to a nominal concentration of 20 mg / ml and then to a nominal concentration of 0.5 mg / ml with filtered deionized water. The concentration was determined IF-2019-00825794- APN-ANP#INPI Page 56 of 115 using an absorbance at 280 nm combined with a standard curve on a 96-well UV-transparent flat-bottom plate with an extinction coefficient of 1.56 ml / (mg * cm) using a Molecular Devices M5 plate reader (sample volume 5: 100 μA). No obvious trends of decrease or increase could be observed in these data throughout the study (Table 6A). Table 6A Condition is Time Point in weeks s Formulations 1 2 3 4 5 6 5 °CT starts 1 162.8 171.1 170.5 168.7 174.8 169.2 T04 159.0 196.2 208.4 193.6 195.8 192.2 T08 150.9 177.7 191.8 169.9 179.0 178.1 T12 — 141.9 158.9 136.8 144.5 150.9 25 °C / 60%RH T starts 1 162.8 171.1 170.5 168.7 174.8 169.2 T04 162.9 196.1 206.0 189.6 210.9 185.3 IF-2019-00825794- APN-ANP#INPI Page 57 of 115 T08 165.6 189.1 203.1 177.1 196.4 180.8 T12 — 195.1 162.9 152.6 197.8 165.6 35 °C / 75%RH T starts 1 162.8 171.1 170.5 168.7 174.8 169.2 T04 169.1 195.0 217.5 192.9 205.0 181.4 T08 168.8 208.4 191.4 182.0 200.0 211.6 T12 — 184.3 163.2 160.0 186.2 168.8 FZT T starts 1 162.8 171.1 170.5 168.7 174.8 169.2 T04 160.1 — — — — — T08 — 176.5 188.9 175.8 187.0 182.7 AFT T starts 1 162.8 171.1 170.5 168.7 174.8 169.2 Q04 169.2 177.2 183.0 177.3 176.2 178.8 pH measurement The pH was determined using a Mettler Toledo S47 pH meter at 23-25 ​​°C. No dilution was performed prior to the 5th measurement. IF-2019-00825794- APN-ANP#INPI Page 58 of 115 For samples stored at 5 °C, during the course of the study, the pH value for all formulations was within 0.2 pH units of the initial value (Table 6B Table 6B Buffers 1A 2 3 4 5 6 537 535 5.75 5.49 5.70 533 Additions Time period ea semi iax Formulations 1 2 3 4 5 6 5°C Temp 536 535 5.89 531 5.76 536 TM 5.60 534 5.92 534 5.76 NP* TOS 5.74 536 5.90 538 5.77 537 T12 NI* 535 5.91 5.69 5.76 535 25°C / 60%RH Tiaidal 536 535 5.89 531 5.76 536 TM 8.39 535 5.88 5.89 5.76 5.49 TOS 8.17 5.63 5.96 6.07 5.79 5.68 T12 NI* NP 5.96 636 NP* NP* 35°CV75íiRH Tmicial 536 535 5.89 531 5.76 536 TM 7.48 535 5.90 630 5.76 538 TOS 8.66 5.71 6.00 NP* 5.87 5.90 T12 NT* NP* 6.44 8.25 NP* 5.62 FZT Tiaidal 536 535 5.89 531 5.76 536 TM 536 - - - - - TOS - 535 5.90 5 60 5.78 537 AFT Tiaidal 536 535 5.89 531 576 536 TM 533 536 5.89 539 5.77 537 IF-2019-00825794- APN-ANP#INPI Page 59 of 115 a: No sample remaining on the plate; b: Formulation 1 had to be prepared again, which alters the collection time at T12. For formulation 3, the initial pH value was 0.14, which is 5 times higher than the buffer alone, suggesting that the antibody in this buffer increases the pH value. For formulations 1 and 4, even though the pH was within 0.2 pH units of the initial value, there appeared to be a trend showing a gradual increase over 2 and 3 months, respectively, which was not observed in the other formulations. For samples stored at 25°C during the study, the pH value for formulations 2, 3, 5, and 6 was within 0.2 pH units. For formulations 2, 5, and 6, the pH could not be determined because no sample remained at T12. For samples stored at 25°C, for formulations 1 and 4, a significant increase in pH was observed from T04 onward at 25°C and 35°C, suggesting sample degradation or contamination.For the samples stored at 35 °C, formulations 2, 5, and 6 showed pH values ​​within 0.2 pH units of the initial value, with one out-of-trend value observed at T0 8 for formulation 6. As no samples remained for measurement at T12 for formulations 2 and 5, no conclusions could be drawn regarding the possibility of a pH increase with 60. IF-2019-00825794- APN-ANP#INPI Page 60 of 115 time, since the values ​​are still within 0.2 pH units of the initial value. Formulation 3 in T12 shows an abnormal increase in pH. Size exclusion chromatography The analyses were performed on sample aliquots diluted to 5 mg / ml in filtered mobile phase (0.2 M Na phosphate, pH 7.0) using an Agilent 1200 series HPLC with a 96-well autosampler. The analyses were performed as follows: • Sample load: 50 pL (250 pg) at 5 mg / ml • Column: Tosoh BioScience TSK Gel G3000 SWXL, 250 Å, 5 pm, 7.8 x 300 mM (Part number: 8541) • Eluent A: 0.2 M sodium phosphate, pH 7.0 • Flow rate: 1 ml / min • Detection: UV (Wavelength: 280 nm, Resolution: 8 nm, Reference: Off) • Column temperature: 25 °C • Sample temperature: 4 °C • Gradient: Isocratic • Maximum pressure: 70 bar • Run time: 15 min • Post-run time: 5 min The data analysis was performed using Empower 2 software. IF-2019-00825794- APN-ANP#INPI Page 61 of 115 The % increase of HMW species by SEC for formulation 1 to 6 compared to the reference formulations DS (Anti-IL-17A / F Ab at 80 mg / ml in 20 mM histidine, 250 mM sorbitol, 0.02% polysorbate 80, pH 6.0) and DP (same as DS but packaged in a glass vial) is shown in Table 7. For samples stored at 5 °C, after 12 weeks, formulations 2, 4, 5, and 6 show a similar degree of aggregation to formulations DS and DP, while formulation 3 shows a greater increase in aggregation than formulations DS and DP. Fragment generation is minimal for formulations 2, 3, 5, and 6 (data not shown). For samples stored at 25 °C, formulation 3 performed best; however, all formulations performed worse than formulations DS and DP. All formulations showed an increase in fragmentation levels (data not shown). Formulation 2 showed a decrease in the percentage of HMW species over 12 weeks and a significant increase in fragmentation. For samples stored at 35 °C, formulation 6 performed best; however, all formulations performed worse than formulations DS and IF-2019-00825794- APN-ANP#INPI Page 62 of 115 DP. All formulations show an increase in fragmentation levels (data not shown). Table 7 Conditions Formulations Time points in weeks T04 T08 T12 5 °C 1 0.21 0.36 NP 2 0.22 0.18 0.44 3 0.62 0.59 1.03 4 0.14 0.06 0.31 5 0.38 0.38 0.62 6 0.12 0.16 0.38 DS 0.20 0.50 0.70 DP 0.00 0.20 0.40 25 °C / 60%RH 1 3.88 3.04 NP 2 1.00 0.76 -0.36 3 1.87 2.23 2.47 4 1.58 2.56 4.64 5 1 / 71 2.09 3.09 6 1.13 1.39 1.93 DS 0.80 1.30 1.70 DP 0.40 0.90 1.30 35 °C / 75%RH 1 3.44 4.66 NP 2 2.21 2.49 3.29 3 3.49 3.70 4.59 IF-2019-00825794- APN-ANP#INPI Page 63 of 115 4 4.75 6.41 7.82 5 3.15 4.19 5.11 6 2.08 3.06 3.19 40°C / 75%RH DP 1.60 2.60 3.80 ICE Capillary electrophoresis with imaging was performed using a Protein Simple iCE3 system. The analyses were performed as follows: Formulations 1 to 6 were diluted to a nominal concentration of 20 mg / mL and then to a concentration of 2 mg / mL (using the concentration determined by A280) with filtered deionized water. The 10 assays were performed on samples at 0.2 mg / mL (1 / 10 dilution in the master mix of the 2 mg / mL samples). A master mix was prepared with the following components (Table 8): Table 8 DI Water 1% MC Farmalitos 3-10 Marker pl 4.65 Marker pl 9.50 100 pL 70 pL 8 pL 1 pL 1 pL The focusing parameters were as follows: 1 minute at 1500 volts followed by 6 minutes at 3000 volts. The results are reported in Table 9A (% of IF-2019-00825794- APN-ANP#INPI Page 64 of 115 acidic species) and in Table 9B (% of basic species). At 5 °C, no significant changes in the % of acidic species can be observed under all conditions and formulations, with values ​​within 2-3%. For samples stored at 25 °C, an increase in the percentage of acid species was observed for all formulations over 12 weeks, with formulations 1 and 4 showing a significant increase. This observation is likely related to the pH increase observed in these formulations after initial mixing. For samples stored at 35 °C, a significant increase in the % of acid species is observed after the initial mixing and subsequent time points for all formulations; formulation 4 shows the greatest increase at 12 weeks. Freeze / thaw stress does not affect the % of acid species in any of the formulations. Regarding the % of basic species, at 5 °C, no significant changes were observed in the formulations and time points. For samples stored at 25 °C, formulations 3, 5 and 6 show a slight increase in the % of basic species over time, and formulations 1 and 4 show a more significant increase in basic species (approximately 2.5%). IF-2019-00825794- APN-ANP#INPI Page 65 of 115 For samples stored at 35 °C, all formulations showed an increase in the percentage of basic species, with formulation 3 showing the smallest increase. Freeze-thaw stress did not affect the percentage of the five basic species in any of the formulations. Table 9 Conditions Panto of time ea weeks Formulations 1 2 3 4 5 6 5°C Tinidal 59.80 5739 57.11 57.72 57.56 56 63 T04 56.69 58.42 59.06 57.82 60.45 59 30 TOS 60.09 5726 5735 58.14 59.81 5638 T12 NP* 59.70 5937 59.76 59.71 59 02 25°C / 60iRH Tmicial 59.80 5739 57.11 57.72 57.56 56 63 T04 65.12 6126 5999 65.11 60.12 60.46 TOS 68.07 6338 59.99 6952 60.05 6235 T12 NP* 55.16 6237 7595 NP* 6355 35°C / 75*»RH Tinidal 59.80 5739 57.11 57.72 5756 56 63 T04 6820 67.65 64.48 69.15 6439 6634 TOS 67.79 71.74 67.76 7929 68.77 7124 T12 NP* 75.11 71.43 87.65 NP* 83.81 FZT Tinidal 59.80 5739 57.11 57.72 57.56 56.63 T04 5721 - - - - - TOS - 57.83 58.71 58.02 58.00 57.93 AFT Tinidal 59.80 5739 57.11 57.72 5756 56.63 T04 58.32 57.41 57.63 57.87 5755 58.14 a: not available b: no sample left to analyze IF-2019-00825794- APN-ANP#INPI Page 66 of 115 Board 9B Additions Point of time in weeks Formulations 1 2 3 4 5 6 5°C Initial T 2.67 2.23 2.34 2.15 2.16 2.28 T04 2.42 2.53 2.62 2.76 2.83 2.83 TOS 2.97 2.25 2.19 2.70 2.10 2.33 τη NP* 2.77 2.19 2.45 Z41 2.44 25°C760íiRH Initial T 2.67 2.23 2.34 2.15 2.16 2.28 T04 3 20 328 3(M 339 327 3.49 TOS 524 3.92 2.90 434 3.10 2.42 T12 NP1 18.61 2.89 4.80 NP* 2.90 35°C / 75HRII Tiinitial 2.67 223 2.34 2.15 2.16 228 T04 3.64 429 3.56 3.64 4.00 4.10 TOS 521 4.75 3.53 5.48 420 4.14 T12 NP* 6.09 3.40 5.02 NP* 5.13 t leato Tinicial 2.67 223 234 2.15 2.16 228 T04 2.48 - - - - - TOS - 2.51 239 3.16 226 2.69 FZT fast Tinicial 2.67 2.23 2.34 2.15 2.16 228 T04 237 2.63 2.49 228 236 224 a: not available b: no sample left to analyze Intrinsic fluorescence IF-2019-00825794- APN-ANP#INPI Page 67 of 115 The analysis was performed on 100 µA of sample from each formulation at 0.5 mg / ml antibody. This method is based on the intrinsic fluorescent properties of Trp. Trp is known to fluoresce strongly at 340 nm when excited at 280 nm and protected from water; Trp exposed to water fluoresces weakly. This property can be used to assess protein stability. As the protein begins to unfold, protected Trp molecules are exposed to water, resulting in reduced fluorescence. As the protein aggregates and more Trp molecules are protected, fluorescence should increase. The method was carried out on a 96-well, flat-bottomed, opaque black fluorescence plate using the M5 Molecular Devices plate reader (read from above, without shaking) with an excitation wavelength of 280 nm and an emission wavelength of 310 nm to 370 nm, with 6 flashes per reading.The blank plate was water and the reference standard was 5x reference standard at 0.5 mg / ml. The results were normalized for concentration against the reference standard and reported as a response factor (Table 11) using the following calculation:. ((FLU / Concentration) / reference standard FLU)*100 At 5 °C, for 12 weeks, formulations 2 and 3 show a smaller increase in the response factor than formulations 4, 5, and 6, suggesting that the molecule is 68 IF-2019-00825794- APN-ANP#INPI Page 68 of 115 shows formulations 2 and 3 less susceptible to aggregation (Table 10). For all formulations 2 through 6, there is a significant increase in T04, which is also observed under the other conditions. One possible explanation for this could be an increased susceptibility to aggregation in all formulations 2 through 6 after 1 month, which may be reversible (non-covalent aggregation) since the effect is much less pronounced at later time points. However, as the effect is similar under all conditions, and a smaller effect would be expected at lower temperatures, this observation appears to be an outlier, since all T04 measurements are higher. This could also be related to an error in preparation or measurement. At 25 °C, over 12 weeks, formulation 2 showed the smallest increase in the response factor compared to formulations 3, 4, 5, and 6, suggesting that the molecule is less susceptible to aggregation for this formulation. At 35 °C, over 12 weeks, formulations 2 and 4 showed the smallest increase in the response factor compared to formulations 3, 5, and 6, suggesting that the molecule is less susceptible to aggregation for formulations 2 and 4. After slow and rapid freeze / thaw stress, formulations 2, 4, and 6 show less increase in 69 IF-2019-00825794- APN-ANP#INPI Page 69 of 115 the response factor that formulations 3 and 5 suggest that the molecule is less susceptible to aggregation for formulations 2, 4 and 6. In the case of formulation 1, the response factor 5 decreases after slow and rapid freeze / thaw stress, as well as after 12 weeks under all conditions, which may be related to protein unfolding in this formulation. It should be noted that it is unknown at what point the magnitude of the 10 change in the response factor becomes significant enough to differentiate between formulations. Consequently, it is difficult to evaluate the performance of formulations based solely on intrinsic fluorescence, as this does not correlate with SEC data. IF-2019-00825794- APN-ANP#INPI Page 70 of 115 Table 10 Conditions Time Point in weeks Formulations 1 2 3 4 5 6 5°C T04 -13.89 87.46 8936 9756 99.41 10229 TOS -8.17 17.74 34 65 2822 40.17 20 01 T12 NP1 3538 40.12 4539 53.86 4530 25°C / 60HRH T04 -35 66 58 60 88.02 59 88 8820 65.40 TOS -2635 10.10 2728 16.17 3354 18.20 T12 NP* 1455 41.61 3124 3022 32.76 35°C / 75HRH T04 -2125 9328 78.42 8927 93.71 104.94 T08 -39.64 3.63 33.48 5.05 23.62 126 T12 NP* 1858 42 65 17.48 34.17 2955 FZT T04 -17.49 - - — - - TOS - 17.51 ​​35.80 21.76 39.94 22.19 ATT T04 -1659 2334 3723 2537 4639 26.76 Dynamic scattering of light The analyses were performed on sample aliquots diluted to approximately 5 mg / ml in the relevant filtered buffers without polysorbate 80 or sucrose (where these excipients are part of the formulation) using a Malvern Zetasizer APS with a 96-well plate autosampler. The analyses were performed as indicated in Table 11 with a scattering angle of 90° and an upper size range limit of 0.5 µm. IF-2019-00825794- APN-ANP#INPI Page 71 of 115 Table 11 Parameter Standard size (60 µm) Protein sample Material Latex Protein Solvent Water Water Temperature 25 °C 25 °C Equilibrium time 120 sec 120 sec Sampling rate Default Default Cleaning Vigorous wash3 Vigorous wash3 Measurement duration Automatic Automatic Number of measurements 3 5 Extended duration for large particles — Yes Relaxation time multiplier — 1,000,000 Automatic attenuation selection Yes Yes Data processing General purpose Protein analysis a: Rinse solvent: filtered deionized water; wash solvent: NaOH IF-2019-00825794- APN-ANP#INPI Page 72 of 115 The parameters considered from the DLS measurements were the % monomer and % Pd (polydispersity) by intensity distribution. The % monomer is not strictly speaking monomer, since DLS cannot differentiate between molecules unless they are at least six times larger than the monomer. The % Pd indicates whether the distribution is monodisperse; however, the technique may not be able to detect dimer species. According to the manufacturer's literature, a distribution with a % Pd of less than 23% is monodisperse, less than 28% is nearly monodisperse, and more than 28% is polydisperse. At the initial temperature, the percentage of monomer by intensity distribution is low (below approximately 80%) for all formulations (data not shown) except for formulation 1 (above 90%). Throughout the entire study at 5 °C, the values ​​are between approximately 82 and 98% for formulations 2 to 6, except for formulation 3, for which the observed values ​​are approximately 66–68%. At 25 °C, formulations 1, 3, and 4 are the worst performers, with the percentage of monomer by intensity change falling below 80% after the initial temperature for formulations 1 and 3, and below 4 for formulation 4. At 35 °C, formulations 1, 3, and 4 are the worst performers, with the percentage of monomer by intensity change falling to 73%. IF-2019-00825794- APN-ANP#INPI Page 73 of 115 values ​​£ 80% after the initial time point. For formulation 5, this change occurs after T04. Regarding the % Pd, at 5 °C and 25 °C, no real trends can be observed across the conditions and formulations, with all values ​​below 23%, indicating monodisperse distributions. At 35 °C, although the % Pd is below 23%, an increasing trend can be observed in all formulations. Differential scanning fluorimetry The method was carried out by Thermofluor using an Applied BioSystem 7500 rapid real-time PCR oven. The basis of this method is that when proteins are subjected to temperature increases, they begin to unfold. A dye (the dye is inactivated in an aqueous environment but not in a nonpolar environment) is added to the protein, and as unfolding occurs, the dye binds to the exposed hydrophobic regions and emits a fluorescence response that is detected by the PCR oven's detector. Different regions of the protein have different thermal stabilities; therefore, they will unfold at different temperatures. The temperature at which unfolding occurs is known as the midpoint of thermal denaturation. IF-2019-00825794- APN-ANP#INPI Page 74 of 115 The higher the temperature, the greater the thermal stability of the protein in a specific environment. All samples were diluted to 0.12 mg / ml using the relevant formulation buffer. Five preparations were made, each replicated in quadruplicate. Since the effects of polysorbate 20, PEG3350, and benzyl alcohol were unknown, the following measurements were performed: Formulation 1 was measured diluted in formulation buffer with and without PEG3350. Formulations 2 and 4 were measured diluted in a formulation buffer with and without PS20. Formulation 3 was measured diluted in formulation buffer with and without benzyl alcohol. Formulations 5 and 6 were measured in their respective formulation buffers. 15. The dye solution was prepared by mixing 2 pL of 1000X protein heat exchange dye with 250 ul of deionized water to obtain an 8X protein heat exchange dye solution. The preparation of the sample for the test is as indicated in Table 12A. IF-2019-00825794- APN-ANP#INPI Page 75 of 115 Table 12A Component Volume (pL) Protein Heat Shift Buffer 5 Sample at 0.12 mg / ml 12.5 Protein Heat Shift Dye 8X 2.5 Samples were prepared in triplicate on a 96-well Applied Biosystems MicroAmp Fast Optical plate and sealed with an Applied Biosystems MicroAmp Optical adhesive film. Protein Thermal Shift software was used for data analysis. Only Tm2 could be determined automatically. Tml was estimated manually using the first derivative of the thermogram. To differentiate the formulations by DSF, the difference in Tm should be greater than 2 °C (Table 12B). The results indicated that, at least by DSF, all formulations are similar. IF-2019-00825794- APN-ANP#INPI Page 76 of 115 Tal □la 12B Formulations Tmla Tm2b 1 70-72 74.5 2 70-72 75.0 3 70-72 75.2 4 70-72 74.7 5 70-72 75.2 6 70-72 75.2 a: First shoulder of the derivative; b: First main peak of the derivative Ossiasolarity The analyses were performed on an advanced Model 3320 Micro-Ositometer using freezing point depression according to the manufacturer's protocol. Samples were measured in triplicate. Formulations 1 and 6 are below 10,240 mOsm / kg, which is not suitable for subcutaneous injection (Table 13). Table 13 Formulation Osmolarity in mOsm / kg 1 168 2 255 3 251 IF-2019-00825794- APN-ANP#INPI Page 77 of 115 4 408 5 391 6 173 Goo The analyses were performed on 76 pL sample aliquots using a TA Instruments DHR-1 rheometer with a steady-state detection flow sweep method. The geometry used was a 20 mm, 1.99 °C cone with a solvent trap containing diionized water to reduce material evaporation during measurement. For the steady-state detection flow sweep method, viscosity was averaged across all points where steady state was reached (acceptance criteria: less than or equal to 5% RSD between points). Steady-state flow sweep Temperature: 25 °C Soaking time: 10 sec Sweep: logarithmic Shear rate: 2.9 to 287.9 ​​s-1 Points per decade: 5 Steady state detection: yes Maximum balancing time: 180 s IF-2019-00825794- APN-ANP#INPI Page 78 of 115 Sample period: 25 s % tolerance: 5 Consecutive within: 3 Speed ​​controlled: motor in auto mode Data acquisition: 'save display point' Step termination; none All formulations other than formulation 6 were considered adequate (Table 14). Table 14 Formulations Viscosity at 25 °C in cP (steady state flow sweep) 1 13.5 2 13.6 3 12.8 4 14.0 5 12.8 6 a a: failed. Conclusions IF-2019-00825794- APN-ANP#INPI Page 79 of 115 SEC and DLS have been identified as the differentiation assays. Considering the SEC at 5 °C, formulation 3 shows an increased aggregation rate over 12 weeks; however, the B22 value is similar to formulations 4 and 5. Furthermore, formulation 2 has a higher B22 value (3.5) than formulations 4, 5, and 6 (2.8-2.9) and does not perform better than formulations 4, 5, and 6, while formulation 6 has a negative B22, which would be synonymous with net protein-protein attraction leading to a greater propensity for aggregation, with a performance similar to that of 2, 4, and 5. Considering DLS, when stored at 5 °C, formulation 6 appeared to perform better than formulation 3, which had the worst performance. Protein self-association is known to be primarily related to colloidal stability, while the formation of partially unfolded intermediates is primarily related to conformational stability. However, these two aggregation pathways are sometimes difficult to distinguish. Often, relative B22 values ​​do not indicate a tendency toward aggregation, as similar B22 values ​​could be obtained under different solution conditions, regardless of the different aggregation tendencies. IF-2019-00825794- APN-ANP#INPI Page 80 of 115 aggregation or the conditions in which the measured B22s were more negative than those that showed less propensity to aggregation (Bajaj, H., Sharma, VK and Kalonia, DS, 2004, Biophys. J. 87 (6), 4048-4054). In the case of the anti-IL-17A / F antibody exemplified herein, the selection approach using B22 values ​​does not correlate with the aggregation behavior of this molecule at 160 mg / ml. This could be due to the fact that the aggregation mechanisms are different at 1 mg / ml and 160 mg / ml or that the tendency of protein self-association is not what primarily governs the degradation / aggregation of this molecule. Furthermore, formulations 1 and 6 are below the threshold of 240 mOsm / kg. Formulations with osmolarity below this value are not suitable for subcutaneous injection; therefore, they were not included in any further long-term stability assessment. Formulation 3 was also excluded due to its aggregation rate over 12 weeks. EXAMPLE 3: Aggregation studies 1 To evaluate the kinetics of the formation of HMW species of anti-IL-17A / F antibody according to the invention, it was studied in 2 formulation buffers: A: 20 mM histidine, 250 mM sorbitol pH 6.0 and IF-2019-00825794- APN-ANP#INPI Page 81 of 115 B: 55 mM sodium acetate, 220 mM glycine, pH 5.0 at 4 different concentrations (80, 120, 160 and 200 mg / ml) of antibody and polysorbate 80 (0.02, 0.03, 0.04 and 0.05%, according to the antibody concentration) by SEC for 3 months with numerous time points at 3 storage conditions (5 °C, 25 °C / 60%RH and 35 °C / 75%RH) of HMW species formation. The anti-IL-17A / F antibody according to the invention was in an original buffer of 20 mM histidine, 250 mM sorbitol pH 6.0 at approximately 88 mg / ml, so the buffer swap was only performed to buffer B without polysorbate 80 using Vivaflow 50 cassettes with a PES membrane and an MWCO of 30 kDa. Three cycles of 2 volumes of buffer formulation B were performed. The antibody in formulation buffers A and B was concentrated to nominal values ​​of 120 mg / ml, 160 mg / ml, and 200 mg / ml. Concentration values ​​outside 5% of the target value were adjusted with the relevant buffer. Concentrations were measured using the SoloVPE (C. Technologies Variable Path Extension System connected to a Cary50 spectrophotometer) with an extinction coefficient of 1.56 at 280 nm. All prepared formulations were sterile filtered using Steriflip tubes with a 0.22 pm PVDF membrane, except formulation B at 200 mg / ml where 82 IF-2019-00825794- APN-ANP#INPI Page 82 of 115. The PES membrane was used after the PVDF membrane became blocked. The sample in formulation A at 200 mg / ml was filtered more easily using PVDF membrane filters, while the sample in formulation B at 200 mg / ml was filtered more easily using PES membrane filters. All formulations were enriched with the relevant amount of polysorbate 80 to obtain the values ​​listed in Table 15. This was done in a laminar flow hood. Table 15 Formulations PS80 Concentration (%w / v) Formulations A and B at 80 mg / ml 0.02 Formulations A and B at 120 mg / ml 0.03 Formulations A and B at 160 mg / ml 0.04 Formulations A and B at 200 mg / ml 0.05 Three 2 ml vials with a fill volume of 1 ml were prepared for each formulation at each concentration. At each time point, the vials were transferred to a laminar flow hood and 2 x 10 μA aliquots were taken. IF-2019-00825794- APN-ANP#INPI Page 83 of 115 per sample for analysis by SEC followed by sealing the vial and placing it under the required storage conditions. The reduction in headspace at the last time point may not affect the study results, as the total volume taken from 1 vial was only 260 pL. Storage was performed at 5 °C, 25 °C / 60% RH, and 35 °C / 75% RH at baseline, and on days 1, 2, 3, 4, 5, 7, 10, 14, 18, 28, 42, 56, and 84. An additional measurement was taken at 168 days for formulation B only at 160 mg / ml. Size exclusion chromatography The analyses were performed on sample aliquots diluted to 5 mg / ml in filtered mobile phase (0.2 M Na phosphate, pH 7.0) using an Agilent 1200 series HPLC with a 96-well autosampler. The analyses were performed as follows: Sample load: 50 pL (250 pg) at 5 mg / ml Column: Tosoh BioScience TSK Gel G3000 SWXL, 250Á, 5pm, 7.8x300 mM Eluent A: 0.2 M sodium phosphate, pH 7.0 Flow rate: 1 ml / min Detection: UV (Wavelength: 280 nm, Resolution: 8 nm, Reference: Off) Column temperature: 25 °C IF-2019-00825794- APN-ANP#INPI Page 84 of 115 Sample temperature: 4 °C; Gradient: Isocratic; Maximum pressure: 70 bar; Run time: 15 min; Post-time: 5 min The data analysis was performed using Empower 2 software. The aggregation rates reported in Tables 16 and 17 refer to the average monthly rate increase for each formulation, based on the aggregation measured after 3 months or after 6 months, compared to that of T0. At all concentrations, formulations B showed the best performance with the lowest aggregation rate over time at 5 °C (Table 16). Furthermore, after 6 months, the formulation with 55 mM sodium acetate, 220 mM glycine, 0.04% (w / v) PS80 at pH 5.0 with an anti-IL-17A / F Ab concentration of 160 mg / mL showed a similar aggregation rate to the DP formulation or the rate after 3 months of the formulation with an anti-IL-17A / F Ab concentration of 80 mg / mL in 20 mM histidine, 250 mM sorbitol, 0.02% (w / v) PS80 at pH 6.0 at 5 °C (Table 16). There was no significant percentage increase in LMW species over time at 5 °C (data not shown). Table 16 Formulation 1 Antibody concentration Rate after 3 months Rate after 6 months IF-2019-00825794- APN-ANP#INPI Page 85 of 115 (mg / ml) A 80 0.10 NP B 0.08 NP A 120 0.18 NP B 0.13 NP A 160 0.25 NP B 0.17 0.10 A 200 0.33 NP B 0.21 NP DP 80 0.13 0.10 DS 80 0.23 0.17 At 25 °C, for each concentration, formulations A and B show a comparable aggregation rate over time (Table 17). However, formulation B shows a slightly greater propensity to fragment over time at 25 °C, resulting in formulation A being the best-performing formulation at 25 °C for all concentrations (data not shown). In particular, at 25 °C, the IL17A / F anti-antibody exemplified in the formulation A (55 mM Na acetate, 220 mM glycine, PS80 0.04% (w / v) pH 5.0 at 160 mg / ml shows a slightly higher aggregation rate than when formulated in histidine (20 mM), sorbitol (250 mM, PS80 0.02% (w / v) pH 6.0 at 80 mg / ml) (Table 17). IF-2019-00825794- APN-ANP#INPI Page 86 of 115 compare with the DP and the DS (prepared as in the example 2), both formulations showed a higher aggregation rate at 160 mg / ml and 200 mg / ml, while at 80 mg / ml and 120 mg / ml formulation B shows a similar aggregation rate to that of the DP and DS material. Table 17 Formulation Antibody Concentration (mg / ml) Rate after 3 months Rate after 6 months A 80 0.34 NP B 0.37 NP A 120 0.56 NP B 0.59 NP A 160 0.77 NP B 0.79 0.62 A 200 0.97 NP B 0.97 NP DP 80 0.43 0.30 DS 80 0.57 0.37 At 35 °C, at all concentrations, formulations A performed better over time with a lower aggregation and fragmentation rate (Table shows the % of HMW species). In particular, the IF-2019-00825794- APN-ANP#INPI Page 87 of 115. Formulation A at 160 mg / ml exhibits a similar aggregation rate to DP at 80 mg / ml at 40°C (data not shown). DS and DP were prepared as in Example 2. Table 18 Formulation Concentration (mg / ml) days 0 1 2 3 4 7 10 14 18 28 42 56 84 168 A Oβ 1.37 1.44 1.47 1.55 1.58 1.68 1.78 1.97 2.08 2.16 2.68 2.88 3.43 NP B 1.17 1.27 1.32 1.40 1.41 1.53 1.69 1.88 2.11 2.21 3.13 3.60 4.75 NP A 120 1.56 1.78 1.87 2.04 2.04 2.3 2.43 2.69 2.90 3.05 3.76 4.05 4 .80 NP B 1.36 1.57 1.64 1.77 1.79 2.04 2.23 2.53 2.84 2.95 4.24 4.84 6 .36 NP A 160 1.73 2.10 2.27 2.45 2.52 2.84 3.04 3.37 3.61 3.84 4.66 5.01 5 .92 NP B 1.49 1.77 1.89 2.03 2.13 2.38 2.64 2.99 3.36 3.49 5.07 5.76 7 .53 12.14 A 200 1.97 2.49 2.68 2.95 3.04 3.43 3.65 4.07 4.40 4.69 5.67 6.12 7 .24 NP B 1.70 2.10 2.25 2.43 2.53 2.88 3.2 3.66 4.12 4.25 6.47 7.37 9 .59 NP EXAMPLE 4: Aggregation Study 2 Given the aggregation rate shown by formulation B with 160 mg / ml of anti-IL-17A / F antibody at 5 °C and 25 °C / 60% RH on DS and DP material (prepared as in Example 2), a second aggregation study was performed to validate the results of the first study (Example 3) using an unaged anti-IL-17A / F antibody. Only the formulation of 55 mM sodium acetate, 220 mM glycine, pH 5.0 with 0.02%, 0.03%, 0.04%, or 0.05% (w / v) PS80 (PS80 concentration dependent on antibody concentration) was investigated at four different antibody concentrations (80 mg / ml, 120 mg / ml, 88 mg / ml, 120 mg / ml, 15 ... IF-2019-00825794- APN-ANP#INPI Page 88 of 115 mg) / ml, 160 mg / ml and 200 mg / ml) under 3 storage conditions (5 °C, 25 °C / 60% RH, 35 °C / 75% RH). As in aggregation study 1, SEC was used to investigate the sample for 3 months. After 3 months, the 160 mg / ml formulation still performed well enough to be considered for long-term stability evaluation; therefore, this formulation was also tested at 6 months. The preparation, buffer and vial storage, and SEC methodology were as described in Example 3. The aggregation rates reported in Tables 19B, 20B, and 2IB refer to the average monthly rate increase for each formulation, based on the aggregation measured after 3 months or after 6 months, compared to that of T0. The results of aggregation study 2 confirm the results of aggregation study 1 at 5 °C (Table 19a % of HMW species and % of LMW species - Table 19B, comparison of the aggregation rate of studies 1 and 2), at 25 °C / 60% RH (Table 20A, % of HMW species and % of LMW species - Table 20B, comparison of the aggregation rate of studies 1 and 2) and 35 °C / 75% RH (Table 21a, % of HMW species and % of LMW species - Table 21B, comparison of the aggregation rate of studies 1 and 2). IF-2019-00825794- APN-ANP#INPI Page 89 of 115 Table 19A % of HMW species Concentration (mg / ml) days 0 7 14 21 28 56 84 168 80 0.76 0.77 0.79 0.80 0.85 0.87 0.94 1.02 120 0.90 NP 0.96 0.96 1.02 1.10 1.18 1.31 160 1.00 1.03 1.08 1.12 1.21 1.28 1.41 1.58 200 1.09 1.14 1.22 1.25 1.32 1.48 1.60 1.78 % of LMW species Concentration (mg / ml) days 0 7 14 21 28 56 84 168 80 0.65 0.68 0.69 0.75 0.66 0.69 0.72 0.78 120 0.59 NP 0.64 0.66 0.64 0.69 0.73 0.79 160 0.62 0.69 0.73 0.70 0.63 0.70 0.74 0.77 200 0.58 0.70 0.69 0.72 0.68 0.67 0.74 0.82 TabJ La 19B Aggregation Study Antibody Concentration (mg / ml) Rate after 3 months Rate after 6 months 1 80 0.08 NP 2 0.06 0.04 1 120 0.13 NP 2 0.09 0.07 1 160 0.17 0.10 2 0.14 0.10 IF-2019-00825794- APN-ANP#INPI Page 90 of 115 1 200 0.21 NP 2 0.17 0.12 DP 80 0.13 0.10 DS 80 0.23 0.17 Table 20A % of BMW species Concentration (mg / ml) days 0 7 14 21 28 56 84 168 80 0.76 0.88 0.99 1.05 1.16 1.41 1.69 2.30 120 0.90 1.12 1.29 1.38 1.51 1.92 2.28 3.10 160 1.00 1.34 1.61 1.77 1.96 2.51 2.96 4.05 200 1.09 1.54 1.85 2.00 2.20 2.82 3.32 4.53 % of LMW species Concentration (mg / ml) days 0 7 14 21 28 56 84 168 80 0.65 0.78 0.90 0.99 1.04 1.39 1.88 2.54 120 0.59 0.77 0.84 0.98 0.96 1.32 1.82 2.46 160 0.62 0.77 0.81 0.94 0.98 1.37 1.79 2.54 200 0.58 0.78 0.89 0.95 0.99 1.36 1.80 2.31 Table 2OB Aggregation study Antibody concentration (mg / ml) Rate after 3 months Rate after 6 months 1 80 0.37 NP 2 0.31 0.26 1 120 0.59 NP IF-2019-00825794- APN-ANP#INPI Page 91 of 115 2 0.46 0.37 1 160 0.79 0.62 2 0.65 0.51 1 200 0.97 NP 2 0.74 0.57 DP 80 0.43 0.30 DS 80 0.57 0.37 The results shown in Tables 19B, 20B and 2IB show that in aggregation study 2 (performed with fresh antibody material) the aggregation and fragmentation rate was slightly lower than in aggregation study 1. Table 21A % of species RMW Concentration (mg / ml) days 0 7 14 21 28 56 84 168 80 0 / 76 1.14 1 / 45 1.66 1.91 2.85 3.85 6.60 120 0.90 1 / 45 1.93 2.21 2.54 3.80 4.95 8.15 160 1.00 1.85 2.45 2.83 3.23 4.71 6.11 9.91 200 1.09 2.10 2.77 3.17 3.64 5.24 6.74 10.81 % of species LMH 0 M *0 *** _ 0 CU q Bd u ® <e v B dias IF-2019-00825794- APN-ANP#INPI Page 92 of 115 0 7 14 21 28 56 84 168 80 0.65 0.98 1.34 1.62 1.82 2.99 4.08 6.66 120 0.59 0.98 1.35 1.58 1.78 2.94 4.05 6.41 160 0.62 0.94 1.32 1.60 1.74 2.85 3.87 6.21 200 0.58 0.96 1.30 1.86 1.74 2.80 3.78 5.95 Table 21B Aggregation Study Antibody Concentration (mg / ml) Rate after 3 months Rate after 6 months 1 80 1.19 NP 2 1.03 0.97 1 120 1.67 NP 2 1.35 1.21 1 160 2.01 1.78 2 1.70 1.49 1 200 2.63 NP 2 1.88 1.62 DP 80 1.27a 1.02a DS 80 1.19 NP a: at 40 °C / 75% RH EXAMPLE 5: Long-term stability study In consideration of the results of both aggregation studies (examples 3 and 4) and the additive selection study at 160 mg / ml (example 2), the following formulations were selected for long-term stability evaluation (Table 22). All formulations comprised 160 mg / ml of anti-IL-17A / F Ab IF-2019-00825794- APN-ANP#INPI Page 93 of 115 exemplified herein and were also subjected to 5 freeze / thaw cycles. Table 22 A Sodium citrate 40 mM, K2HPO4 50 mM, Sucrose 75 mM, PS20 0.00044% (w / v), pH 5.6 Formulation 2 examples 1 and 2 B Sodium citrate 40 mM, K2HPO4 25 mM, Sucrose 100 mM, PS20 0.00022% (w / v), pH 5.5 Formulation 4 examples 1 and 2 C Sodium acetate 40 mM, K2HPO4 25 mM, Sucrose 125 mM pH 5.7 Formulation 5 examples 1 and 2 D Sodium acetate 55 mM, 220 mM glycine, 0.04% (w / v) PS80, pH 5.0 Formulation B examples 3 and 4 E Histidine 20 mM, sorbitol 250 mM, 0.04% PS80, pH 6.0 formulation A examples 3 and 4 During formulation preparation, the buffer exchange cycle for formulations A, B, and C took longer than for formulation E (approximately 90 minutes for formulations A and B and 50 minutes for formulation E). Formulations A and B behaved similarly, and both were cloudy during the buffer exchange and concentration steps. Furthermore, the color for each of these formulations was cloudy and milky. Formulation C was also cloudy during the 94 IF-2019-00825794- APN-ANP#INPI Page 94 of 115 buffer exchange and concentration stages. There were no notable differences for formulations D and E, although E appeared to concentrate and filter better compared to the other formulations. Osmolarity (measured with Precision System Multi-Osmetter 2430), viscosity (measured with Anton Paar automatic viscosity meter), pH (Mettler Toledo SevenMulti), visual appearance, absorbance at 280 nm (Agilent 8453 spectrophotometer), SDS-PAGE analysis, cIEF (measured with Protein Simple ICE280 system, see Example 2), binding activity (measured with a GE Healthcare Biacore T100 system), subvisible particle analysis by light obscuration (Hach Lange HIAC 9703 system), CEX-HPLC, and SEC-HPLC were performed over a 6-month period (viscosity and osmolarity were measured only at time point 0) at time points 0, 1 month, 2 months, 3 months, 4 months, and 6 months. Unless otherwise specified, the methods were as described in Example 2.After a six-month time point, only samples of formulation D were evaluated. For all formulations, a sample fill volume of 1.0 mL was used. For the freeze-thaw study, all formulations were stored at -70 °C for 12 hours and then stored at room temperature until completely thawed (2 hours). This was repeated for a total of 5 freeze-thaw cycles. IF-2019-00825794- APN-ANP#INPI Page 95 of 115 Goo Viscosity was measured using an Anton Paar automated viscometer. Viscosity values ​​for formulations A through E were analyzed at time zero. All formulations showed viscosity values ​​ranging from 2.3 to 17.3 cP. Samples were evaluated at room temperature (approximately 25.00 ± 0.01 °C). Osmolarity Osmolarity was determined using a Precision Systems Multi-Osmetter 2430. No dilution was performed. Osmolarity was analyzed at time zero for all formulations. Osmolarity values ​​ranged from 316 mOsm / kg to 450 mOsm / kg. pH The pH was measured at 25 °C using a Mettler Toledo sevenMulti pH meter. No dilution was performed. The pH was analyzed for each formulation at each data point. During the first 6 months of stability, the pH of formulations A and B at each time point was 5.5 ± 0.1, the pH of formulation C was 5.7 ± 0.1, and the pH of formulation E was 6.2 ± 0.2. Over the 12 months of stability, the pH of formulation D was 5.1. IF-2019-00825794- APN-ANP#INPI Page 96 of 115 No change in pH was observed for any of the five formulations evaluated during the freeze-thaw study compared to time zero. Aspect At each time point during the 12-month stability period, which included freezing and thawing, the appearance of each formulation was evaluated. For all formulations during the first 6 months of stability, the appearance was a clear, yellowish-brown solution, free of visible particles. After 4 months, the appearance was determined to be a clear, yellowish liquid, also free of visible particles. The observed change in the appearance of all formulations can be attributed to analyst variability. As such, there were no differences between the formulations during the 12-month stability period. Absorbance at 280 nm Protein concentrations were determined using an Agilent 8453 spectrophotometer. Samples were diluted gravimetrically to 0.5 mg / ml in their respective lamps. Before the analysis of each formulation, the system was used as a blank using a formulation buffer. 97 IF-2019-00825794- APN-ANP#INPI Page 97 of 115 showed clear trends for the freeze-thaw study or during the course of the 12-month stability study, suggesting that any observed changes in concentration were within the variability of the assay. No consistent decrease in concentration was observed for any of the 5 formulations. SDS-PAGE SDS-PAGE analysis was performed using a 4-20% Tris-Glycine gel with 3 pg (non-reducing conditions with IAA) or 4 pg (reducing conditions with DTT) per lane load. Denaturation was performed by incubating samples at 70 °C for 5 minutes. The stain used was colloidal blue. Stability analyses of the samples using reduced SDS-PAGE showed no trend (increasing or decreasing) in the % of heavy chains (HC) + light chains (LC) for any of the formulations, except for measurements taken under accelerated and stressed conditions. A decrease in the % of HC + LC was observed in all formulations under the 25 °C / 60% RH condition, with a greater decrease observed in the formulations at 40 °C / 75% RH. For each of the formulations under these conditions, the formation of a new species was observed. IF-2019-00825794- APN-ANP#INPI Page 98 of 115 No change was observed in any of the formulations evaluated during the freeze-thaw study. Stability analyses of the samples using non-reduced SDSPAGE showed an overall decrease in the percentage of IgG observed across all formulations and conditions. The greatest decrease in the percentage of IgG was observed for formulations stored at 25 °C / 60% RH and 40 °C / 75% RH. Aggregate formation was particularly evident in formulation D at 40 °C / 75% RH. No changes were observed in any of the formulations evaluated during the freeze-thaw study. CIEF The percentage of the main peak area for formulations stored at -70 °C and 2–8 °C showed little to no change during the 12-month stability period. A decrease in the percentage of the main peak area was observed for all formulations stored at 25 °C / 60% RH, with a greater decrease observed when stored at 40 °C / 75% RH. This decrease was slightly greater in formulation D and slightly less in formulation E. For all formulations, no changes in the % of acid species were observed at -70 °C and 2–8 °C. An increase in the % of acid species was observed for formulation 99 IF-2019-00825794- APN-ANP#INPI Page 99 of 115 stored at 25 °C / 60% RH and 40 °C / 75% RH. For formulation D, there was a slightly greater increase in the % of acid species observed at 25 °C / 60% RH. At 40 °C / 75% RH, formulations B and D showed a slightly greater increase in the % of acid species, while formulation E showed a slightly smaller increase. No significant changes were observed in the percentage of basic species for formulations stored at -70 °C and 2–8 °C. A slight increase was observed in formulations stored at 25 °C / 60% RH, with an even greater increase in the percentage of basic species observed in formulation A stored at 40 °C / 75% RH. At the 2-month time point, there was a loss of resolution due to capillary issues, causing a decrease in the percentage of basic species for all formulations and conditions. For all time points, there was greater variability in the percentage of basic species. No changes were observed in the main acidic or basic species in the freeze-thaw formulations A to E. Biacore The binding of IL-17A and IL-17F was measured using a Biacore T100 (GE Healthcare). All experiments were performed at 25 °C. The Affinipure F (ab')2 fragment was immobilized. IF-2019-00825794- APN-ANP#INPI Page 100 of 115 Goat anti-human IgG, specific for the Fe fragment (Jackson ImmunoResearch, category # 109-006-098, lot # 83295) was injected onto a CM5 sensor chip (Biacore AB, category # BR1000-14, different chips used from lot # 10030608) via amine coupling chemistry to a capture level of approximately 7000 response units (RUs). HBS-EP buffer (HEPES 10 mM pH 7.4, NaCl 0.15 M, EDTA 3 mM, surfactant P20 0.005%, GE Healthcare) was used as the running buffer with a flow rate of 10 pL / min. A 10 pL injection of each antibody sample at 0.5 pg / ml was used for capture. Recombinant human IL-17A (R&D Systems, catalog number 317-ILB) and IL-17F (R&D Systems, catalog number 1335-IL) were titrated against captured anti-IL17AF antibody at doubling dilutions of 10 nM to 2.5 nM and 10 nM to 1.25 nM respectively at a flow rate of 30 pL / min.The surface was regenerated at a flow rate of 10 pl / min by an injection of 10 pl of 40 mM HC1, followed by an injection of 5 pl of 5 mM NaOH. Double-referenced background subtraction bonding curves were analyzed using BIA evaluation software (version 3.2) following standard procedures. Kinetic parameters were determined from the fitting algorithm (Langmuir Biacore 1:1 bond fitting). No trends were observed in joining activity during 101 IF-2019-00825794- APN-ANP#INPI Page 101 of 115 The first 12 months of stability showed no significant changes, suggesting that the changes in KD were within the expected range of the assay. An evaluation of the freeze-thaw study samples was performed in parallel with the 1-month stability samples. No changes were observed in these samples, and the slight changes in KD were within the expected range of the assay. Size exclusion chromatography SEC was performed on sample aliquots diluted to 1 mg / ml in filtered eluent A using an Agilent 1200 series system with the following parameters: • Sample load: 20 pL (20 pg) at 1 mg / ml • Column: Tosoh BioScience TSK Gel G3000 SWXL, 250 Å, 5 pm, 7.8 x 300 mM (Part number: 8541) • Eluent A: 0.05 M NajHPCU, 0.25 M NaCl, pH 7.2 • Flow rate: 0.5 ml / min • Detection: UV (Wavelength: 280 nm, Resolution: 8 nm, Reference: Off) • Column temperature: 20 ± 5 °C • Sample temperature: 6 ± 2 °C • Gradient: Isocratic • Maximum pressure: 70 bar • Run time: 35 min 102 IF-2019-00825794- APN-ANP#INPI Page 102 of 115 For all formulations, no change was observed in the percentage of the main peak at -70 °C, and a slight change was observed at a 2–8 °C reduction. A decrease in the percentage of the main peak was observed for all formulations stored at 25 °C / 60% RH, and an even greater decrease for formulations stored at 40 °C / 75% RH. Overall, formulation D showed the greatest decrease in the percentage of the main peak during 6 months of stability at 25 °C / 60% RH and 3 months of stability at 40 °C / 75% RH. No significant changes were observed in the percentage of MW and LMW species in any formulation stored at -70 °C. There was a slight increase in the percentage of HMW, but no notable change was observed in the percentage of LMW for formulations stored at 2–8 °C. During the six-month stability period, the aggregation rate was lower for formulations A, B, and D compared to formulations C and E. An increase in both HMW and LMW species was observed under the conditions of 25 °C / 60% RH and 40 °C / 75% RH. Formulation D showed the greatest increase in both HMW and LMW species during the six-month stability period at 25 °C / 60% RH and during the three-month stability period at 40 °C / 75% RH. No changes were observed in any of the formulations evaluated during the freeze-thaw study. 103 IF-2019-00825794- APN-ANP#INPI Page 103 of 115 cation exchange chromatography CEX was performed on sample aliquots diluted in 1 mg / ml in eluent A using an Agilent 1100 system with the following parameters: Sample load: 20 pL (20 pg) Column: BioMAb, NP5, PK, 4.6*250mm #Agilent 5190-2407 Eluent A: 10 mM sodium phosphate pH6.0 Eluent B: 10 mM sodium phosphate, 1 M NaCl, pH 6.0 Flow rate: 1 ml / min Wavelength: 220 nm bandwidth 8 nm / 220 nm bandwidth 8 nm, reference 360 ​​nm bandwidth 100, slot 4 nm Peak width: 0.1 min (2s) Column temperature: 25 °C Sample temperature: 4 °C Gradient: Time (min) %B 4015 40.02100 45100 45,022 602 104 IF-2019-00825794-APN-ANP#INPI Page 104 of 115 For all formulations and conditions during the 12-month stability period, there were no changes in the percentage of the main peak area for the -70 °C or 2–8 °C conditions. A decrease was observed at 25 °C / 60% RH and an even greater decrease under the stress condition of 40 °C / 75% RH. At 25 °C / 60% RH, all formulations behaved similarly within the variability of the assay. At 40 °C / 75% RH, formulations A, B, C, and D behaved similarly, with formulation E showing a smaller decrease. The percentage area for acidic and basic species did not change during the 12-month study for formulations stored at -70 °C and 2–8 °C. However, the decrease in the percentage of the main peak for formulations stored at 25 °C / 60% RH and 40 °C / 75% RH corresponds primarily to an increase in the percentage area of ​​acidic species, with a smaller increase observed in the percentage area of ​​basic species. All formulations behaved similarly within the assay variability. The CEX method has high variability: 5% for acidic species and 9% for basic species. No changes were observed for the freeze-thaw stress samples in the main peak %, acid %, or base % area. 105 IF-2019-00825794- APN-ANP#INPI Page 105 of 115 HIAC Analysis of subvisible particles by light obscuration was performed using a HACK Lange HIAC9703 system by diluting 200 pL of sample in 1000 pL of WFI. Two 500 pL extractions were analyzed for 2, 5, 10, and 25 pm particles, and the data from the second extraction were corrected for dilution (results multiplied by 5) and reported as particles / ml. The results were relatively consistent over the course of 12 months, with differences occurring due to variability within the trial. No changes were observed in the freeze-thaw stress samples. Conclusions When samples were stored at 2–8 °C, only the SEC results showed any differentiation between formulations. All formulations showed similar low levels of fragmentation; however, formulations A, B, and D showed the lowest aggregation throughout the study, with D showing the lowest initial level of HMW species. The SEC results, combined with processing observations, lead to the conclusion that, given the formulation's shelf life is intended for 5 °C and not under 106 conditions IF-2019-00825794- APN-ANP#INPI Page 106 of 115 similar to those used in accelerated or stress studies, formulation D performed best at 2-8 °C followed by formulation E, also in light of the fact that formulation D at 160 mg / ml of anti-IL-17A / F Ab had a comparable profile to the DP of 80 mg / ml and reduced processing problems. Example 6: Robustness test study of selected formulations over 3 months A Design of Experiments (DoE) was generated using a fractional factorial design with 3 center points using SAS JMP statistical software version 11. This was intended as a primary test of the following formulation variables by testing for main effects and interactions over 12 weeks under two conditions: 5 ± 3 °C and 25 ± 2 °C / 60% RH. • Acetate concentration (55 mM ± 20%) • Glycine concentration (220 mM ± 20%) • Polysorbate 80 concentration (0.04% ± 0.02%) • pH (4.9 ± 0.3) • Protein concentration (160 ± 15%) The formulations comprising the antiIL17A / F antibody exemplified herein were prepared as detailed in Table 23. Formulation 20 was added to evaluate the impact on stability of low concentrations of proteins and excipients. 107 IF-2019-00825794- APN-ANP#INPI Page 107 of 115 formulations were prepared by buffer-exchange of the anti-IL17A / F antibody exemplified herein at 50 mg / ml in the relevant formulation detailed in Table 23 without PS80. Seven cycles were performed before the protein concentration was adjusted to the desired concentration indicated in Table 23. Formulation 20 was prepared by diluting formulation 9. A 10% PS80 stock solution was used to enrich each formulation to the desired PS80 concentration detailed in Table 23. Table 23 Formulations Cone, Desired Protein Conc, Measured Acetate (mM) Glycine (mM) Polysorbate 80 (w / v) Osmolarity DF Buffer pH Measured pH 24.0°C pH Change F1 160 160.0 55 220 0.04 350 4.90 5.02 0.12 F2 136 138.2 66 264 0.02 405 5.21 5.28 0.07 F3 136 135.8 66 176 0.02 291 4.60 4.75 0.15 F4 136 134.8 44 176 0.06 262 4.60 4.80 0.21 F5 184 186.4 44 176 0.06 310 5.20 5.35 0.15 F6 184 168.1 66 264 0.02 432 4.60 4.81 0.21 F7 136 135.1 44 264 0.06 363 5.21 5.31 0.10 F8 136 134.8 66 264 0.06 377 4.61 4.76 0.15 F9 136 134.4 44 176 0.02 277 5.20 5.31 0.10 FIO 184 190.3 44 264 0.06 398 4.60 4.90 0.30 FU 136 137.0 44 264 0.02 354 4.61 4.84 0.23 F12 184 184.5 44 176 0.02 293 4.60 4.88 0.28 F13 184 185.8 44 264 0.02 402 5.20 5.35 0.15 F14 184 187.1 66 264 0.06 442 5.21 5.30 0.08 108 IF-2019-00825794- APN-ANP#INPI Page 108 of 115 F15 160 161.9 55 220 0.04 349 4.90 5.05 0.15 F16 160 160.3 55 220 0.04 344 4.90 5.04 0.14 F17 136 137.2 66 176 0.06 311 5.18 5.25 0.07 F18 184 184.5 66 176 0.06 326 4.60 4.81 0.21 F19 184 184.3 66 176 0.02 355 5.20 5.31 0.11 F20 68 69.9 44 176 0.02 262 5.20 5.26 0.06 After sterile filtration, 1 ml of each formulation was transferred to 2 ml Schott Type 1 glass vials sealed with Flurotec-coated Westar stoppers and Tru-Edge flip-off seals for initial testing and storage at 5 ± 3°C and 25 ± 2°C / 60 ± 5% RH. The pH and osmolarity detailed in Table 23 were measured at initial T, while the visual assessment, as well as the SEC and ICE, were performed at 4, 8, and 12 weeks (T12w). An SEC was performed on aliquots diluted to 1 mg / ml in the filtered eluent A (0.05 M Na2HPO4, 0.25 M NaCl, pH 7.2) using an Agilent 1200 series system with the following parameters: • Sample load: 20 pL (20 pg) at 1 mg / ml • Column: Tosoh BioScience TSK Gel G3000 SWXL, 250 Å, 5 pm, 7.8 x 300 mM (Part number: 8541) • Flow rate: 0.5 ml / min • Detection: UV (Wavelength: 280 nm, Resolution: 8 nm, Reference: Off) • Column temperature: 20 ± 5 °C • Sample temperature: 6 ± 2 °C 109 IF-2019-00825794- APN-ANP#INPI Page 109 of 115 • Gradient: Isocratic • Maximum pressure: 70 bar • Run time: 35 min The data analysis was performed using the 5 Empower 3 software. For all formulations, no significant changes in the % of LMW species were observed in all formulations stored at 5 °C, but an increase was observed for all formulations when stored at 25 °C. As expected, an increase in the % of BMW species was observed over 12 weeks in all formulations, and formulations stored at 25 °C showed a more pronounced increase than those stored at 5 °C (Table 24). Table 24 Formulation is T12w SEC % BMW Delta in 3M T12wSE C % Mono Delta in 3M T12w SEC % LMW Delta in 3M 5 °C F1 2.39 0.65 96.53 -0.76 1.08 0.11 F2 2.38 0.65 96.57 -0.75 1.05 0.10 F3 2.06 0.55 96.86 -0.66 1.08 0.12 F4 2.02 0.50 96.90 -0.61 1.09 0.11 F5 2.88 0.81 96.06 -0.91 1.06 0.09 F6 2.41 0.71 96.50 -0.83 1.09 0.12 110 IF-2019-00825794- APN-ANP#INPI Page 110 of 115 F7 2.38 0.65 96.54 -0.79 1.08 0.14 F8 1.99 0.49 96.93 -0.58 1.08 0.09 F9 2.42 0.66 96.52 -0.76 1.06 0.10 F1O 2.50 0.73 96.43 -0.82 1.06 0.09 Fil 1.99 0.50 96.92 -0.61 1.08 0.10 F12 2.47 0.72 96.46 -0.82 1.07 0.09 F13 2.78 0.86 96.18 -0.93 1.05 0.08 F14 2.87 0.86 96.07 -0.94 1.06 0.08 F15 2.30 0.60 96.64 -0.69 1.06 0.09 F16 2.37 0.65 96.57 -0.74 1.05 0.08 F17 2.41 0.65 96.53 -0.74 1.06 0.09 F18 2.44 0.69 96.47 -0.79 1.09 0.10 F19 2.93 0.90 96.01 -0.99 1.06 0.09 F20 1.85 0.39 97.07 -0.51 1.08 0.12 25 °C Fl 4.21 2.47 93.56 -3.73 2.23 1.26 F2 4.43 2.70 93.60 -3.72 1.97 1.02 F3 3.45 1.94 93.89 -3.63 2.66 1.70 F4 3.38 1.86 94.13 -3.38 2.49 1.51 F5 5.11 3.04 93.00 -3.97 1.88 0.91 F6 4.56 2.86 92.81 -4.52 2.63 1.66 F7 4.30 2.57 93.73 -3.60 1.97 1.03 F8 3.54 2.04 93.80 -3.71 2.66 1.67 F9 4.15 2.39 93.90 -3.38 1.95 0.99 111 IF-2019-00825794- APN-ANP#INPI Page 111 of 115 FIO 4.68 2.91 92.91 -4.34 2.41 1.44 FU 3.50 2.01 94.01 -3.52 2.48 1.50 F12 4.44 2.69 93.21 -4.07 2.35 1.37 F13 5.43 3.51 92.67 -4.44 1.91 0.94 F14 5.43 3.42 92.65 -4.36 1.92 0.94 F15 4.23 2.53 93.59 -3.74 2.18 1.21 F16 4.39 2.67 93.44 -3.87 2.17 1.20 F17 4.12 2.36 93.90 -3.37 1.99 1.02 F18 4.43 2.68 93.02 -4.24 2.55 1.56 F19 5.30 3.27 92.78 -4.22 1.92 0.95 F20 4.21 2.47 93.56 -3.73 2.23 1.26 Capillary electrophoresis with imaging was performed using a Protein Simple iCE3 system. The analyses were performed as follows: The samples were diluted to a nominal concentration of 20 mg / ml and then to a concentration of 2 mg / ml with filtered deionized water. Assays were performed on 0.2 mg / ml samples (1 / 10 dilution in the master mix of the 2 mg / ml samples). A master mix was prepared with the following 10 components (Table 25). 112 IF-2019-00825794- APN-ANP#INPI Page 112 of 115 Table 25 1% MC Fannalitos 3-10 pl marker 4.65 pl marker 9.50 Urea 4 M 70pL 8 pL 1 pL 1 pL 100 pL The focusing parameters were as follows: 1 minute at 1500 volts followed by 6 minutes at 3000 volts. As shown in Table 26, for all formulations, no significant changes were observed in the % of acidic and % of basic species for formulations stored at 5 °C. Regarding the % of HMW species, formulations stored at 25 °C showed a more pronounced increase in both acidic and basic species than those stored at 5 °C (Table 26). Table 26 formulation 4.1 1 O NJ F4 49.9 O) o 1 45.8 0.7 CXI mo 1 113 IF-2019-00825794- APN-ANP#INPI Page 113 of 115 F5 50,5 0,2 45,5 -0,6 4,1 0,4 F6 50,2 0,3 45,7 -0,2 4,1 -0,1 F7 50,3 0,1 45,7 0,1 4,1 -0,3 F8 49,6 -0,4 45,9 0,5 4,4 -0,1 F9 50,2 0,9 46,0 -0,5 3,9 -0,4 FIO 50,5 0,4 45,1 -0,7 4,4 0,3 Fil 50,4 0,5 45,5 -0,6 4,2 0,1 F12 50,4 1,4 45,3 -1,4 4,3 0,0 F13 50,2 ‘ 1,3 45,6 -1,1 4,2 -0,2 F14 50,5 0,6 45,3 -0,5 4,2 -0,1 F15 50,0 0,3 45,6 -0,5 4,4 0,2 F16 50,3 1,2 45,7 -1,0 4,1 -0,2 F17 50,0 1,2 46,1 -0,9 4,0 -0,3 F18 49,8 -0,3 46,0 0,2 4,2 0,2 F19 50,5 0,6 45,4 -0,3 4,2 -0,3 F20 49,9 -0,8 45,9 0,8 4,2 0,0 25 °C Fl 55,34 5,79 39,4 -7,0 5,3 1,2 F2 55,99 6,39 39,3 1 Ch 4,7 0,2 F3 54,13 4,75 39,9 -6,3 in 1,6 F4 54,99 4,88 39,3 co m I 5,7 1,0 F5 55,75 5,50 39,7 -6,4 4,6 0,9 F6 54,90 5,01 39,2 -6,8 5,9 1,8 F7 56,50 6,39 38,6 -6,9 4,9 0,5 114 IF-2019-00825794- APN-ANP#INPI Página 114 de 115 F8 55.21 5.13 38.9 1 σι in r 1.4 F9 55.53 6.23 39.6 σ» KO I 4.9 0.6 FIO 55.34 5.24 39.1 -6.7 5.6 1.5 Fil 55.33 5.52 38.9 -7.2 5.8 1.7 F12 54.66 5.73 39.3 “7.4 6.0 1.7 F13 56.05 7.14 39.5 “7.3 4.5 0.1 F14 56.08 6.17 39.2 -6.6 4.7 0.4 F15 55.11 5.37 39.6 in KO 1 5.3 1.1 F16 54.66 5.54 40.0 -6.7 Ui GJ 1.1 F17 55.30 6.50 39.8 7.2 O in 0.7 F18 54.20 4.10 39.6 CM KO 1 6.2 2.1 F19 55.09 5.20 39.6 -6.1 5.3 0.9 F20 54.89 4.27 40.2 -4.9 4.9 0.6 115 IF-2019-00825794- APN-ANP#INPI Page 115 of 115 Argentine Republic - National Executive Branch 2019 - Year of Exports Additional Signature Sheet Graphic Report Number: IF-2019-00825 794-APN-ANP#INPI CITY OF BUENOS AIRES Friday, January 4, 2019 Reference: 20180103417 The document was imported by the GEDO system with a total of 115 page(s). Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=EGESTION DOCUMENTAL ELECTRONICA - GDE, c=AR, o=MINISTERIO DE MODERNIZACION, ou=SECRETARIA DE MODERNIZACION ADMINISTRATIVA, serialNumber=CUIT 30715117564 Date: 2019.01.04 20:51:31 -03'00' Mariela Flavia Gonnet Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=EGEST10N DOCUMENTAL ELECTRONICA - GDE, c=AR, o=MINISTERIO DE MODERNIZACION, ou=SECRETARIA DE ADMINISTRATIVE MODERNIZATION, serialNumber=CUIT 30715117564 Date: 2019.01.04 20:51:32 -03'00'

Claims

1. A pharmaceutical composition characterized in that it comprises: a. 120 mg / ml to 180 mg / ml of an antibody, or an antigen-binding fragment thereof, specifically binding to human IL-17A and human IL-17F and having a heavy-chain variable region comprising SEQ ID NO: 1 and a light-chain variable region comprising SEQ ID NO: 2; b. 40 mM to 90 mM of acetate; c. 160 mM to 300 mM of glycine; d. 0.02% to 0.06% of polysorbate 80; and having a pH of 4.6 to 5.

5. Nine claims follow.