High-concentration anti-IL13R antibody formulation

Abstract

A stable, high-concentration formulation of an anti-IL13R antibody or antigen-binding fragment thereof. Use of the formulation for treatment, e.g., for treating an inflammatory or autoimmune disease, e.g., atopic dermatitis, is also provided.

Description

[Technical Field]

[0001] The present disclosure relates to highly concentrated formulations of anti-IL13R antibodies or antigen-binding fragments thereof, methods of treatment using the formulations, particularly for the conditions disclosed herein, and processes for making the formulations. [Background technology]

[0002] IL-13 has been associated with various conditions, including, but not limited to, various respiratory and allergic disorders, fibrosis, scleroderma, inflammatory bowel disease, and certain cancers (see, e.g., Wynn, TA, 2003 Annu. Rev. Immunol. 21:425-456; Terabe et al., 2000 Nat Immunol. 1 (6): 515-520; Fuss et al., 2004 J. Clin. Invest. 113 (10): 1490-1497; Simms et al., 2002 Curr. Opin. Rheumatol. 14 (6): 717-722; and Hasegawa et al., 1997 J. Rheumatol. 24 (2): 328-332). Therefore, IL-13 is an attractive target for the treatment of such diseases.

[0003] One possible way to inhibit IL-13 activity is to block the binding of IL-13 to its receptor, IL-13R, by using an antibody specific for IL-13R, such as an antibody specific for IL-13Rα1. Effective antibody antagonists against IL-13Rα1 may also block IL-13 binding and prevent heterodimerization between IL-4Ra and IL-13Rα1. Such antibodies could inhibit both IL-13 and IL-4 signaling through the type II receptor, while sparing IL-4 signaling through the type I receptor. Signaling through the type I receptor is essential during the induction phase of the immune response, during which Th2 cells differentiate. Because T cells do not express IL-13Rα1, the type II receptor does not play any role in Th2 differentiation. Therefore, IL-13Rα1 antibodies should not affect the overall Th1 / Th2 balance. Signaling through the type II IL-4 / IL-13 receptor is important during the effector-A stage of the immune response during the establishment of allergic inflammation. Therefore, blockade of the type II receptor should have beneficial effects on many asthma symptoms and other IL-13R-mediated conditions and should therefore be an effective disease-modifying agent.

[0004] Antibodies (both monoclonal and polyclonal) against IL-13Rα1 have been described in the art, e.g., WO 97 / 15663, WO 03 / 80675; WO 03 / 46009; WO 06 / 072564; Gauchat et al, 1998 Eur. J. Immunol. 28:4286-4298; Gauchat et al, 2000 Eur. J. Immunol. 30:3157-3164; Clement et al, 1997 Cytokine 9(11):959 (Meeting Abstract); Ogata et al, 1998 J. Biol. Chem. 273:9864-9871; Graber et al, 1998 Eur. J. Immunol. 28:4286-4298;C. Vermot-Desroches et al, 2000 Tissue Antigens 5(Supp. l):52-53 (Meeting Abstract);Poudrier et al, 2000 Eur. 13:75-84; Cancino-Diaz et al, 2002 J. Invest Dermatol. 119:1114-1120; and Krause et al, 2006 Mol. Immunol. 43:1799-1807.

[0005] One particularly promising anti-IL-13Rα1 antibody is CSL334 (formerly known as ASLAN004 and now called ebrasakimab), which is described in WO 2008 / 060813 as antibody 10G5-6. Ebrasakimab has been shown to bind to human IL-13Rα1 with high affinity (e.g., Kd may be 500 pM). ASLAN004 has been shown to effectively antagonize IL-13 function through inhibition of IL-13 binding to its receptor, IL-13Rα1, and inhibit IL-13- and IL-4-induced eotaxin release in NHDF cells, IL-13- and IL-4-induced STAT6 phosphorylation in NHDF cells, and IL-13-stimulated TARC release in blood or peripheral blood mononuclear cells.

[0006] Antibodies such as ebrasakimab must be formulated at high concentrations to allow the desired dose to be administered in humans in as small a volume as possible. High-concentration formulations pose unique challenges because phenomena such as phase separation can be observed. Aggregation is also a common feature at high antibody concentrations. However, formulations must contain very high levels of "monomeric" antibody molecules, e.g., 99% monomer or greater. Furthermore, formulations must be stable during storage. Ebrasakimab appears to have hydrophobic moieties in its protein that, for example, interact with hydrophobic interaction columns unless the salt concentration is high. This hypothetical hydrophobic moiety adds additional complexity to formulating antibodies and preventing aggregation. Aggregate and particle formation in parenteral formulations can be extremely dangerous to patients and must be avoided. Therefore, the antibodies of the present disclosure are particularly difficult to formulate. In particular, formulation optimization is required to maintain viscosity at an acceptably low level for a formulation suitable for subcutaneous injection, i.e., in the 20-25 cP range, e.g., close to the target viscosity of 20 cP.

[0007] Previous studies have suggested that adding high concentrations of arginine, e.g., 200 mM or more of arginine-HCl, to the formulation can significantly reduce the viscosity of highly concentrated anti-IL13R antibody formulations. However, maintaining viscosity within the target range of 20–25 cP is particularly challenging for ultra-high-concentration formulations with antibody concentrations exceeding 175 mg / ml, such as 200 mg / ml or more.

[0008] Therefore, optimized formulations are needed to address these issues and / or to maximize the shelf life, delivery, potency and effectiveness of the formulation.

[0009] The present invention uses tryptophan in the formulation. Without wishing to be bound by theory, the inventors hypothesize that this amino acid in the formulation may stabilize the hydrophobic portion of the antibody, thereby reducing aggregation of the antibody molecules.

[0010] Thus, the present disclosure provides highly concentrated antibody formulations in which the formulated antibody is substantially monomeric and has a viscosity that is acceptable for administration to a patient, e.g., a human patient. Summary of the Invention

[0011] The present disclosure is summarized in the following paragraphs: 1. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: 175 to 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml, 225 mg / ml, 230 mg / ml, 235 mg / ml, 240 mg / ml, 245 mg / ml or 250 mg / ml, in particular 190 mg / ml, 200 mg / ml, 210 mg / ml, 225 mg / ml or 250 mg / ml, for example 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; 5–100 mM tryptophan (15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38mM, 39mM, 40mM, 41mM, 42mM, 43mM, 44mM, 45mM, 46mM, 47mM, 48mM, 49mM, 50mM, 5 1mM, 52mM, 53mM, 54mM, 55mM, 56mM, 57mM, 58mM, 59mM, 60mM, 61mM, 62mM, 63mM, 64 mM, 65 mM, 66 mM, 67 mM, 68 mM, 69 mM, 70 mM, 71 mM, 72 mM, 73 mM, 74 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM or 100 mM), for example with 15 to 75 mM tryptophan, for example with 15 to 60 mM, in particular with 25 to 50 mM tryptophan, for example with 20 mM, 50 mM or 80 mM tryptophan; 140-290 mM arginine (including 150 mM or 151-290 mM), for example, 160-290 mM arginine (such as Arg-HCl or Arg-Glu), for example, 160 mM, 165 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM , 220mM, 225mM, 230mM, 235mM, 240mM, 245mM, 250mM, 255mM, 260mM, 265mM, 270mM, 275mM, 280mM, 285mM or 290mM, in particular 150mM, 185mM, 215mM, 225mM, 250mM, 260mM or 280mM arginine; 0.01 to 0.03% of a non-ionic surfactant (such as a polysorbate), for example 0.01 to 0.03% w / w, for example 0.01%, 0.015%, 0.020%, 0.025% or 0.030%, in particular 0.02% w / w; a buffer (such as a histidine buffer), for example a 15-55 mM buffer (25 mM or 26-55 mM), for example a 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM or 55 mM histidine buffer; In particular, 20 mM, 35 mM or 50 mM histidine buffer Including, the pH of the formulation is in the range of 5.5 to 7.2 (including 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0), for example in the range of 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 5.8, 6.3, 6.4, 6.5, 6.6, 6.7 or 6.8, formulation.

[0012] 2. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: 175 to 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml or 225 mg / ml, in particular 200 mg / ml, 225 mg / ml or 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 15-75 mM tryptophan, e.g. 15-60 mM, especially 25-50 mM tryptophan; 160 to 290 mM arginine (such as Arg-HCl or Arg-Glu), for example 160 mM, 165 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM, 270 mM, 275 mM, 280 mM, 285 mM or 290 mM, in particular 200 mM, 210 mM, 225 mM, 235 mM, 250 mM or 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, the pH of the formulation is in the range of 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.4; formulation.

[0013] 3. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: 175 to 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml or 225 mg / ml, in particular 200 mg / ml, 225 mg / ml or 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 15-75 mM tryptophan, e.g. 15-60 mM, especially 25-50 mM tryptophan; 175 to 270 mM arginine (such as Arg-HCl or Arg-Glu), for example 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 200 mM, 210 mM, 225 mM, 235 mM, 250 mM or 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, the pH of the formulation is in the range of 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.4; formulation.

[0014] 4. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: 175 to 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml or 225 mg / ml, in particular 200 mg / ml, 225 mg / ml or 250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 15-75 mM tryptophan, e.g. 15-60 mM, especially 25-50 mM tryptophan; 190-270 mM arginine (such as Arg-HCl or Arg-Glu), for example 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 200 mM, 210 mM, 225 mM, 235 mM, 250 mM or 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, the pH of the formulation is in the range of 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.4; formulation.

[0015] 5. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: 190 to 210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, particularly 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 25 to 75 mM tryptophan, for example 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM or 75 mM tryptophan, in particular 25 to 50 mM tryptophan; 175 to 270 mM arginine (such as Arg-HCl or Arg-Glu), for example 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 200 mM, 210 mM, 225 mM, 235 mM, 250 mM or 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, the pH of the formulation is in the range of 6.3 to 6.7, for example 6.3, 6.4, 6.5, 6.6, 6.7, in particular 6.4, 6.5 or 6.6; formulation.

[0016] 6. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: 190 to 210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, particularly 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 25-60 mM tryptophan, e.g., 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, or 60 mM tryptophan, especially 25-50 mM tryptophan; 175 to 270 mM arginine (such as Arg-HCl or Arg-Glu), for example 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 200 mM, 210 mM, 225 mM, 235 mM, 250 mM or 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, The pH of the formulation is in the range of 6.4 to 6.6, for example 6.4, 6.5 or 6.6; formulation.

[0017] 7. The formulation of any one of paragraphs 1 to 6, comprising 190 to 210 mg / ml, such as 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml or 210 mg / ml of an anti-IL13R antibody or binding fragment thereof.

[0018] 8. The formulation of any one of paragraphs 1 to 7, comprising 200 mg / ml of an anti-IL13R antibody or antigen-binding fragment thereof.

[0019] 9. The formulation of any one of paragraphs 1 to 8, comprising 20 to 80 mM tryptophan.

[0020] 10. The formulation of any one of paragraphs 1 to 9, comprising 15 to 55 mM tryptophan, for example 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM or 55 mM tryptophan.

[0021] 11. The formulation of any one of paragraphs 1 to 9, comprising 25 to 60 mM tryptophan, for example 25 mM, 30 mM, 40 mM, 45 mM, 50 mM, 55 mM or 60 mM tryptophan.

[0022] 12. The formulation of any one of paragraphs 1 to 11, comprising 20 mM, 50 mM or 80 mM tryptophan, for example 80 mM tryptophan.

[0023] 13. The formulation of any one of paragraphs 1-12, comprising 25 mM or 50 mM tryptophan.

[0024] 14. The formulation of any one of paragraphs 1-13, comprising 50 mM tryptophan.

[0025] 15. The formulation of any one of paragraphs 1 to 14, comprising 150 to 280 mM arginine, such as 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM, 270 mM, 275 mM, or 280 mM arginine.

[0026] 16. The formulation of any one of paragraphs 1 to 14, comprising 185 to 260 mM arginine, such as 185 mM, 195 mM, 205 mM, 215 mM, 225 mM, 235 mM, 245 mM, 255 mM, or 260 mM arginine.

[0027] 17. The formulation of any one of paragraphs 1 to 16, comprising 200 to 260 mM arginine, such as 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, or 260 mM arginine.

[0028] 18. The formulation of any one of paragraphs 1-17, comprising 150 mM, 185 mM, 215 mM, 225 mM, 260 mM, or 280 mM arginine.

[0029] 19. The formulation of any one of paragraphs 1-18, comprising 200 mM, 210 mM, 225 mM, 235 mM, 250 mM, or 260 mM arginine.

[0030] 20. The formulation of any one of paragraphs 1-19, comprising 185 mM, 215 mM, 225 mM, or 260 mM arginine.

[0031] 21. The formulation of any one of paragraphs 1 to 20, wherein the arginine is Arg-HCl.

[0032] 22. The formulation of any one of paragraphs 1 to 21, further comprising phenylalanine.

[0033] 23. 25-175 mM phenylalanine, e.g., 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM 23. The formulation of paragraph 22, comprising 1 mM or 175 mM phenylalanine, such as 50 to 150 mM phenylalanine, such as 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM or 150 mM phenylalanine.

[0034] 24. A formulation according to paragraph 22 or 23, comprising 50 mM, 75 mM, 100 mM, 125 mM or 150 mM phenylalanine, such as 75 mM, 125 mM or 150 mM phenylalanine, in particular 150 mM phenylalanine.

[0035] 25. The formulation of any one of paragraphs 1 to 24, further comprising creatine, e.g., creatine monohydrate.

[0036] 26. The formulation of paragraph 25 comprising 50 to 125 mM creatine monohydrate, such as 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM or 125 mM creatine monohydrate, such as 75 to 100 mM creatine monohydrate, such as 75 mM, 80 mM, 85 mM, 90 mM, 95 mM or 100 mM creatine monohydrate.

[0037] 27. The formulation of paragraph 26, comprising 75 mM or 100 mM creatine monohydrate.

[0038] 28. The formulation of any one of paragraphs 1 to 27, comprising 20 to 50 mM histidine buffer, for example 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM or 50 mM, for example 20 mM or 50 mM histidine buffer.

[0039] 29. The formulation of any one of paragraphs 1 to 28, comprising a 20 mM histidine buffer.

[0040] 30. The formulation of any one of paragraphs 1 to 28, comprising a 50 mM histidine buffer.

[0041] 31. The formulation of any one of paragraphs 1 to 30, further comprising CaCl2, for example 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, or 70 mM CaCl2.

[0042] 32. The formulation of any one of paragraphs 1 to 31, comprising 50 mM CaCl2.

[0043] 33. The osmolality of the formulation is in the range of 500-700 mOsmo / kg, e.g., 500 mOsmo / kg, 510 mOsmo / kg, 520 mOsmo / kg, 530 mOsmo / kg, 540 mOsmo / kg, 550 mOsmo / kg, 560 mOsmo / kg, 570 mOsmo / kg, 580 mOsmo / kg, 590 mOsmo / kg, 600 mOsmo / kg, 610 mOsmo / kg, 620 mOsmo / kg, 630 mOsmo / kg, 640 mOsmo / kg, 650 mOsmo / kg, 660 mOsmo / kg, 33. The formulation of any one of paragraphs 1 to 32, wherein the saturation dose is 575 to 625 mOsmo / kg, such as 575 mOsmo / kg, 580 mOsmo / kg, 585 mOsmo / kg, 590 mOsmo / kg, 595 mOsmo / kg, 600 mOsmo / kg, 605 mOsmo / kg, 610 mOsmo / kg, 615 mOsmo / kg, 620 mOsmo / kg or 625 mOsmo / kg.

[0044] 34. The formulation of any one of paragraphs 1 to 33, wherein the osmolality of the formulation is 595 mOsmo / kg or 600 mOsmo / kg.

[0045] 35. The formulation of any one of paragraphs 1 to 34, further comprising 50 to 200 mM sugar, e.g., 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, e.g., 180 mM sugar.

[0046] 36. The formulation of any one of paragraphs 1 to 35, comprising 180 mM sugar.

[0047] 37. The formulation of paragraph 35 or 36, wherein the sugar is selected from mannitol, sorbitol, dextrose, galactose, fructose, lactose, trehalose, and sucrose.

[0048] 38. The formulation of any one of paragraphs 35 to 37, wherein the sugar is sucrose.

[0049] 39. A formulation according to any one of claims 1 to 38, comprising 0.02% w / w of a non-ionic surfactant.

[0050] 40. The formulation of any one of paragraphs 1 to 39, wherein the nonionic surfactant is a polysorbate, e.g., polysorbate 20, 40, 60, or 80.

[0051] 41. The formulation of any one of paragraphs 1 to 40, wherein the nonionic surfactant is polysorbate 80.

[0052] 42. The formulation of any one of paragraphs 1 to 40, wherein the nonionic surfactant is polysorbate 20.

[0053] 43. The formulation of any one of paragraphs 1 to 42, which does not contain NaCl.

[0054] 44. A formulation according to any one of paragraphs 1 to 42 comprising 50 to 150 mM NaCl, e.g., 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, e.g., 62.5 mM or 140 mM NaCl.

[0055] 45. A formulation according to any one of paragraphs 1 to 44, having a viscosity in the range of 10 to 30 cP (mPa.s), for example 10 cP, 11 cP, 12 cP, 13 cP, 14 cP, 15 cP, 16 cP, 17 cP, 18 cP, 19 cP, 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, 25 cP, 26 cP, 27 cP, 28 cP, 29 cP or 30 cP, for example 15 to 25 cP, in particular 20 cP.

[0056] 46. ​​The formulation of any one of paragraphs 1 to 45, having a viscosity in the range of 15 to 25 cP, e.g., 15 cP, 20 cP, or 25 cP.

[0057] 47. The formulation of any one of paragraphs 1-45, having a viscosity of less than 25 cP, e.g., 25 cP, 24 cP, 23 cP, 22 cP, 21 cP, or 20 cP.

[0058] 48. The formulation of any one of paragraphs 1 to 47, having a pH in the range of 5.8 to 6.8, e.g., 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.

[0059] 49. The formulation of any one of paragraphs 1 to 48, having a pH selected from the group including 5.8, 6.3, 6.5, 6.7 and 6.8, for example 5.8, 6.7 or 6.8.

[0060] 50. The formulation of any one of paragraphs 1 to 47, having a pH in the range of 6.3 to 6.7, for example 6.3, 6.4, 6.5, 6.6 or 6.7.

[0061] 51. The formulation of any one of paragraphs 1 to 47, having a pH in the range of 6.4 to 6.7, for example 6.4, 6.5, 6.6 or 6.7.

[0062] 52. With 260 mM arginine-HCl; with 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.5, for example 6.4. 52. The formulation of any one of paragraphs 1 to 51.

[0063] 53. 225 mM Arg-HCl; 75 mM phenylalanine, with 50 mM tryptophan; 0.02% Polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.5, for example 6.4. 52. The formulation of any one of paragraphs 1 to 51.

[0064] 54. 200 mM Arg-HCl; 125 mM phenylalanine, with 50 mM tryptophan; 0.02% Polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.5, for example 6.4. 52. The formulation of any one of paragraphs 1 to 51.

[0065] 55. 225 mM Arg-HCl; 100 mM phenylalanine, with 25 mM tryptophan; 0.02% Polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.5, for example 6.4. 52. The formulation of any one of paragraphs 1 to 51.

[0066] 56. With 260 mM arginine-HCl; with 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5 or 6.6; 41. The formulation of any one of paragraphs 1 to 40.

[0067] 57. With 225 mM arginine-HCl; with 75 mM phenylalanine; with 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5 or 6.6; 52. The formulation of any one of paragraphs 1 to 51.

[0068] 58. With 215 mM arginine-HCl; with 125 mM phenylalanine; with 20 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 comprising or consisting of The pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5 or 6.6 52. The formulation of any one of paragraphs 1 to 51.

[0069] 59. With 185 mM arginine-HCl; with 150 mM phenylalanine; with 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 comprises or consists of, The pH of the formulation is 6.3 to 6.7, for example 6.4 or 6.5; 52. The formulation of any one of paragraphs 1 to 51.

[0070] 60. The formulation of any one of paragraphs 52 to 59, comprising 190 to 210 mg / ml, for example 200 mg / ml, of anti-IL13R antibody.

[0071] 61. The formulation of any one of paragraphs 1 to 60, wherein the anti-IL-13R antibody or antigen-binding fragment thereof is an anti-IL13Rα1 antibody.

[0072] 62. The formulation of any one of paragraphs 1 to 61, wherein the anti-IL-13R antibody or antigen-binding fragment thereof binds to the epitope FFYQ.

[0073] 63. The formulation of any one of paragraphs 1 to 62, wherein the anti-IL-13R antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10.

[0074] 64. The formulation of any one of paragraphs 1 to 63, wherein the anti-IL-13R antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto.

[0075] 65. The formulation of any one of paragraphs 1 to 64, wherein the anti-IL-13R antibody or antigen-binding fragment thereof comprises a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

[0076] 66. The formulation of any one of paragraphs 1 to 65, wherein the anti-IL-13R antibody or antigen-binding fragment thereof comprises a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto.

[0077] 67. The formulation of any one of paragraphs 1 to 66, wherein the anti-IL-13R antibody or antigen-binding fragment thereof comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

[0078] 68. The formulation of any one of paragraphs 1 to 67, wherein the anti-IL13R antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto.

[0079] 69. The formulation of any one of paragraphs 1 to 68, wherein the anti-IL13R antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51 and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53.

[0080] 70. The formulation of any one of paragraphs 1 to 69, wherein the anti-IL13R antibody or antigen-binding fragment thereof is a human antibody.

[0081] 71. The formulation of any one of paragraphs 1 to 70, wherein the anti-IL13R antibody is ebrasakimab (ASLAN004).

[0082] 72. Formulation 1, containing 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 5.8; Formulation 2, containing 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 6.8; Formulation 3, containing 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 5.8; Formulation 4, containing 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 5.8; Formulation 5, containing 200 mg / ml ebrasakimab, 50 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.3; Formulation 6, containing 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 7, containing 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 8, containing 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 5.8; Formulation 9, containing 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.3; Formulation 10, containing 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 5.8; Formulation 11, containing 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 12, containing 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.3; Formulation 13, containing 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 14, containing 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 5.8; Formulation 15, containing 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.3; Formulation 16, containing 200 mg / ml ebrasakimab, 35 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 5.8; Formulation 17, containing 200 mg / ml ebrasakimab, 20 mM histidine, 215 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 18, containing 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 5.8; Formulation 19, containing 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.3; Formulation 20, containing 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 21, containing 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 22, containing 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, with a formulation pH of pH 6.8; Formulation 23, containing 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 5.8; Formulation 24, comprising 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; and Formulation 25, containing 200 mg / ml ebrasakimab, 35 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, with a formulation pH of 6.8. 72. The formulation of any one of paragraphs 1 to 71, wherein the formulation is selected from the group comprising:

[0083] 73. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 5.8 (Formulation 1).

[0084] 74. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 6.8 (Formulation 2).

[0085] 75. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 5.8 (Formulation 3).

[0086] 76. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 5.8 (Formulation 4).

[0087] 77. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3 (Formulation 5).

[0088] 78. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 6).

[0089] 79. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 7).

[0090] 80. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8 (Formulation 8).

[0091] 81. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3 (Formulation 9).

[0092] 82. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 2, wherein the pH of the formulation is pH 5.8 (Formulation 10).

[0093] 83. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 11).

[0094] 84. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3 (Formulation 12).

[0095] 85. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 13).

[0096] 86. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8 (Formulation 14).

[0097] 87. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3 (Formulation 15).

[0098] 88. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 35 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8 (Formulation 16).

[0099] 89. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 215 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 17).

[0100] 90. The formulation of any one of paragraphs 1-72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8 (Formulation 18).

[0101] 91. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3 (Formulation 19).

[0102] 92. The formulation of any one of paragraphs 1-72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 20).

[0103] 93. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 21).

[0104] 94. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 22).

[0105] 95. The formulation of any one of paragraphs 1 to 72, comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8 (Formulation 23).

[0106] 96. The formulation of any one of paragraphs 1-72, comprising 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8 (Formulation 24).

[0107] 97. The formulation of any one of paragraphs 1-72, comprising 200 mg / ml ebrasakimab, 35 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8 (Formulation 25).

[0108] 98. The formulation of any one of paragraphs 1 to 97, which is stable at refrigerator temperatures, for example below 8°C, for example between 2 and 8°C, such as 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, in particular 4°C.

[0109] 99. The formulation of any one of paragraphs 1 to 98, which is stable at room temperature, e.g., 15 to 25°C, e.g., 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C or 25°C, in particular 25°C.

[0110] 100. The formulation of any one of paragraphs 1 to 99, which is stable for at least 1 month, e.g., at least 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months.

[0111] 101. The formulation of any one of paragraphs 1 to 100, which is stable at refrigerator temperature, e.g., 4°C, for at least 6 months.

[0112] 102. The formulation of any one of paragraphs 1 to 101, which is stable at room temperature, e.g., 25°C, for at least 6 months.

[0113] 103. A formulation according to any one of paragraphs 1 to 102 for use in treatment.

[0114] 104. The formulation of paragraph 103 for use in treating an inflammatory or autoimmune disease, such as chronic inflammation.

[0115] 105. The formulation of paragraph 104, wherein the inflammation is selected from the group comprising fibrosis (including pulmonary fibrosis, e.g., cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis; liver fibrosis, e.g., cirrhosis; heart diseases, e.g., atrial fibrosis, endomyocardial fibrosis, old myocardial infarction; arthrofibrosis; Dupuytren's contracture; keloid fibrosis; mediastinal fibrosis; myelofibrosis; nephrogenic systemic fibrosis; retroperitoneal fibrosis; and scleroderma), Hodgkin's disease, ulcerative colitis, Crohn's disease, atopic dermatitis, eosinophilic esophagitis, allergic rhinitis, asthma and chronic lung diseases (including chronic obstructive pulmonary disease), in particular asthma.

[0116] 106. A formulation described in any one of paragraphs 1 to 105 for use in the treatment of atopic dermatitis.

[0117] 107. Use of a formulation according to any one of paragraphs 1 to 102 in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease, such as chronic inflammation.

[0118] 108. Use of a formulation according to paragraph 107 in the manufacture of a medicament for the treatment of a condition selected from the group comprising fibrosis (including pulmonary fibrosis, such as cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis; hepatic fibrosis, such as cirrhosis of the liver; heart disease, such as atrial fibrosis, endomyocardial fibrosis, old myocardial infarction; arthrofibrosis; Dupuytren's contracture; keloid fibrosis; mediastinal fibrosis; myelofibrosis; nephrogenic systemic fibrosis; retroperitoneal fibrosis; and scleroderma), Hodgkin's disease, ulcerative colitis, Crohn's disease, atopic dermatitis, eosinophilic esophagitis, allergic rhinitis, asthma and chronic lung disease (including chronic obstructive pulmonary disease), Sézary syndrome, in particular asthma.

[0119] 109. Use of a formulation according to paragraph 107 or 108 in the manufacture of a medicament for the treatment of atopic dermatitis.

[0120] 110. A method of treatment comprising administering a therapeutically effective amount of the formulation described in any one of paragraphs 1 to 102.

[0121] 111. A method for treating inflammation (such as chronic inflammation) or an autoimmune disease, comprising administering an effective amount of a formulation described in any one of paragraphs 1 to 102.

[0122] 112. The method of paragraph 111, wherein the method is for the treatment of a condition selected from the group comprising fibrosis (including pulmonary fibrosis, such as cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis; cirrhosis of the liver; heart disease, e.g. atrial fibrosis, endomyocardial fibrosis, old myocardial infarction; hepatic fibrosis, such as arthrofibrosis; Dupuytren's contracture; keloid fibrosis; mediastinal fibrosis; myelofibrosis; nephrogenic systemic fibrosis; retroperitoneal fibrosis; and scleroderma), Hodgkin's disease, ulcerative colitis, Crohn's disease, atopic dermatitis, eosinophilic esophagitis, allergic rhinitis, asthma and chronic lung disease (including chronic obstructive pulmonary disease), particularly asthma.

[0123] 113. The method of any one of paragraphs 110 to 112, for the treatment of atopic dermatitis.

[0124] In one embodiment, a formulation of the present disclosure comprises arginine, phenylalanine, and tryptophan.

[0125] In one embodiment, the patient is a human.

[0126] In one embodiment, the formulations of the present disclosure are physically stable, eg, exhibit no / minimal aggregation.

[0127] In one embodiment, the formulations of the present disclosure are chemically stable, eg, have no / minimal deamination.

[0128] In one embodiment, the formulations of the present disclosure are thermally stable.

[0129] The present inventors have optimized the formulations of the present disclosure and established that IL-13R antibodies, such as ebrasakimab, are best suited for formulation within a limited range of parameters. The formulations of the present disclosure are highly monomeric, e.g., at least 98% monomeric (e.g., 98-99.5% monomeric), even when formulated at high antibody concentrations. The formulations of the present disclosure also have good viscosity at high antibody concentrations.

[0130] The presently disclosed anti-IL13R antibody formulations are particularly suitable for stable long-term storage of anti-IL13R antibodies. In one embodiment, the formulations are stored at a temperature ranging from 2 to 8°C, e.g., 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, or 8°C, e.g., 4°C.

[0131] Moreover, the formulations are suitably stable, e.g., in some embodiments, no change in monomer or less than a 0.5% loss in monomer was observed when stored for 90 days at 4° C. or 25° C. In contrast, Dupixent® (dupilumab) can only be stored for a maximum of 14 days at 25° C. Accelerated "stress test" studies at 40° C., e.g., using titration, also show that formulations of the present disclosure are stable over a 60-day period.

[0132] In one embodiment, certain formulations of the present disclosure have 1% or less protein aggregation when stored for 90 days, for example, at temperatures ranging from 2 to 25° C. In one embodiment, a formulation of the present disclosure has 1% or less protein aggregation when stored for 90 days at 4° C. In one embodiment, a formulation of the present disclosure has 1% or less protein aggregation when stored for 90 days at 25° C.

[0133] Thus, in one embodiment, a formulation of the present disclosure is stable at refrigerator temperature, e.g., 8°C or below, e.g., 2-8°C, e.g., 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, particularly 4°C. In another embodiment, a formulation of the present disclosure is stable at room temperature, e.g., 15-25°C, e.g., 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C, particularly 25°C. Thus, in one embodiment, the formulation is stable at 4°C. In another embodiment, the formulation is stable at 25°C.

[0134] In one embodiment, the formulations of the present disclosure are stable for at least 1 month, e.g., 28, 29, 30, or 31 days. In one embodiment, the formulations of the present disclosure are stable for at least 2 months or at least 60 days. In one embodiment, the formulations are stable for at least 3 months or at least 90 days. In one embodiment, the formulations are stable for at least 6 months. In one embodiment, the formulations are stable for at least 12 months. In one embodiment, the formulations are stable for at least 18 months. In one embodiment, the formulations are stable for at least 24 months. In one embodiment, the formulations are stable for at least 30 months. In one embodiment, the formulations are stable for at least 36 months.

[0135] In one embodiment, a formulation of the present disclosure is stable for at least 1 month, e.g., 28, 29, 30, or 31 days, at room temperature, e.g., 15-25°C, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, particularly 25°C. In one embodiment, a formulation of the present disclosure is stable for at least 60 days at room temperature, e.g., 15-25°C, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, particularly 25°C. In one embodiment, a formulation is stable for at least 90 days at room temperature, e.g., 15-25°C, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, particularly 25°C. In one embodiment, the formulation is stable for at least 6 months at room temperature, e.g., 15-25°C, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, in particular 25°C. In one embodiment, the formulation is stable for at least 12 months at room temperature, e.g., 15-25°C, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, in particular 25°C. In one embodiment, the formulation is stable for at least 18 months at room temperature, e.g., 15-25°C, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, in particular 25°C. In one embodiment, the formulation is stable for at least 24 months at room temperature, e.g., 15-25°C, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, in particular 25°C. In one embodiment, the formulation is stable for at least 30 months at room temperature, e.g., 15-25°C, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, in particular 25°C. In one embodiment, the formulation is stable for at least 36 months at room temperature, e.g., 15-25°C, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25°C, in particular 25°C.

[0136] In one embodiment, a formulation of the present disclosure is stable at refrigerator temperatures, e.g., 8°C or below, e.g., 2-8°C, e.g., 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, particularly 4°C, for at least 1 month, e.g., 28 days, 29 days, 30 days, or 31 days. In one embodiment, a formulation of the present disclosure is stable at refrigerator temperatures, e.g., 8°C or below, e.g., 2-8°C, e.g., 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, particularly 4°C, for at least 60 days. In one embodiment, a formulation is stable at refrigerator temperatures, e.g., 8°C or below, e.g., 2-8°C, e.g., 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, particularly 4°C, for at least 90 days. In one embodiment, the formulation is stable for at least 6 months at refrigerator temperatures, for example at or below 8°C, for example 2-8°C, for example 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, in particular 4°C. In one embodiment, the formulation is stable for at least 12 months at refrigerator temperatures, for example at or below 8°C, for example 2-8°C, for example 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, in particular 4°C. In one embodiment, the formulation is stable for at least 18 months at refrigerator temperatures, for example at or below 8°C, for example 2-8°C, for example 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, in particular 4°C. In one embodiment, the formulation is stable for at least 24 months. In one embodiment, the formulation is stable for at least 30 months at refrigerator temperatures, for example at or below 8° C., for example between 2 and 8° C., for example 8° C., 7° C., 6° C., 5° C., 4° C., 3° ​​C., 2° C., or 1° C., in particular 4° C. In one embodiment, the formulation is stable for at least 36 months at refrigerator temperatures, for example at or below 8° C., for example between 2 and 8° C., for example 8° C., 7° C., 6° C., 5° C., 4° C., 3° ​​C., 2° C., or 1° C., in particular 4° C.

[0137] A combination of characteristics of the formulations of the present disclosure, including pH, contribute to the stabilization of the IL-13 receptor antibody or binding fragment thereof.

[0138] In particular, the inventors have established that the addition of tryptophan to high-concentration anti-IL13R antibody formulations results in a dramatic reduction in viscosity, enabling ultra-high concentration formulations containing 200 mg / ml or more of anti-IL13R antibody to achieve a viscosity of, for example, 20 cP, within the target range of 20-25 cP.

[0139] In one embodiment, a formulation of the present disclosure has a viscosity in the range of 10-30 cP, e.g., 11 cP, 12 cP, 13 cP, 14 cP, 15 cP, 16 cP, 17 cP, 18 cP, 19 cP, 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, 25 cP, 26 cP, 27 cP, 28 cP, 29 cP, or 30 cP (centipoise), e.g., 20 cP, e.g., at ambient temperature. In one embodiment, a formulation has a viscosity in the range of 10-25 cP, e.g., 10 cP, 11 cP, 12 cP, 13 cP, 14 cP, 15 cP, 16 cP, 17 cP, 18 cP, 19 cP, 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, or 25 cP. In one embodiment, the formulation has a viscosity in the range of 15-25 cP, e.g., 15 cP, 16 cP, 17 cP, 18 cP, 19 cP, 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, or 25 cP. In one embodiment, the formulation has a viscosity in the range of 20-25 cP, e.g., 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, or 25 cP. In one embodiment, the formulation has a viscosity of less than 25 cP, e.g., 25 cP, 24 cP, 23 cP, 22 cP, 21 cP, 20 cP, 19 cP, 18 cP, 17 cP, 16 cP, or 15 cP. Surprisingly, the viscosity of the formulations of the present disclosure is relatively low, even at high antibody concentrations.

[0140] In one embodiment, viscosity is measured using a viscometer, such as a rotational viscometer, an electromagnetic ball rotational (EMS) viscometer, or a Stabinger viscometer. In one embodiment, viscosity is measured using a rheometer, such as a shear rheometer, a dynamic shear rheometer, an extensional rheometer, or a capillary rheometer. In one embodiment, viscosity is measured using a Kinexus-ultra+ rheometer (Netsch).

[0141] In one embodiment, the osmolality of the formulation is in the range of 510-575 mOsmo / kg, for example 520-570 mOsmo / kg, for example 520 mOsmo / kg, 525 mOsmo / kg, 530 mOsmo / kg, 535 mOsmo / kg, 540 mOsmo / kg, 545 mOsmo / kg, 550 mOsmo / kg, 555 mOsmo / kg, 560 mOsmo / kg, 565 mOsmo / kg, 570 mOsmo / kg or 575 mOsmo / kg. In one embodiment, the osmolality of the formulation is in the range of 500-600 mOsmo / kg, e.g., 500 mOsmo / kg, 505 mOsmo / kg, 510 mOsmo / kg, 515 mOsmo / kg, 520 mOsmo / kg, 525 mOsmo / kg, 530 mOsmo / kg, 535 mOsmo / kg, 540 mOsmo / kg, 545 mOsmo / kg, 550 mOsmo / kg, 555 mOsmo / kg, 560 mOsmo / kg, 565 mOsmo / kg, 570 mOsmo / kg, 575 mOsmo / kg, 580 mOsmo / kg, 585 mOsmo / kg, 590 mOsmo / kg, 595 mOsmo / kg, or 600 mOsmo / kg. In one embodiment, the osmolality of the formulation is in the range of 550-600 mOsmo / kg, e.g., 550 mOsmo / kg, 555 mOsmo / kg, 560 mOsmo / kg, 565 mOsmo / kg, 570 mOsmo / kg, 575 mOsmo / kg, 580 mOsmo / kg, 585 mOsmo / kg, 590 mOsmo / kg, 595 mOsmo / kg or 600 mOsmo / kg.

[0142] In one embodiment, the formulation contains 175-250 mg / ml, e.g., 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml, 225 mg / ml, 230 mg / ml, 235 mg / ml, 240 mg / ml, 245 mg / ml or 250 mg / ml or antigen-binding fragment thereof, e.g., 175 to 225 mg / ml, e.g., 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml, or 225 mg / ml of the anti-IL13Rα1 antibody or antigen-binding fragment thereof. In one embodiment, the formulation contains 200 mg / ml or more, e.g., 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml, or 225 mg / ml of the anti-IL13Rα1 antibody or antigen-binding fragment thereof. In one embodiment, the formulation comprises 190 mg / ml to 210 mg / ml, e.g., 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, of the anti-IL13Rα1 antibody or antigen-binding fragment thereof. In one embodiment, the formulation comprises about 200 mg / ml of the anti-IL13Rα1 antibody or antigen-binding fragment thereof, e.g., 200 mg / ml of the anti-IL13Rα1 antibody. In one embodiment, the formulation comprises 195 mg / ml of the anti-IL13Rα1 antibody or antigen-binding fragment thereof. In one embodiment, the formulation comprises 190 mg / ml of the anti-IL13Rα1 antibody or antigen-binding fragment thereof.

[0143] In one embodiment, the anti-IL13Rα1 antibody or binding fragment thereof comprises a heavy chain variable region comprising a CDRH1 having the sequence set forth in SEQ ID NO: 1, a CDRH2 having the sequence set forth in SEQ ID NO: 3, and a CDRH3 having the sequence set forth in SEQ ID NO: 30, and a light chain variable region comprising a CDRL1 having the sequence set forth in SEQ ID NO: 31, a CDRL2 having the sequence set forth in SEQ ID NO: 32, and a CDRL3 having the sequence set forth in SEQ ID NO: 33.

[0144] In one embodiment, the anti-IL13Rα1 antibody or binding fragment thereof comprises a VH domain having the sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto. In one embodiment, the antibody or binding fragment thereof comprises a VL domain having the sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto.

[0145] In one embodiment, the anti-IL13Rα1 antibody or binding fragment thereof comprises a VH domain having the sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain having the sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto. In one embodiment, the anti-IL13Rα1 antibody or binding fragment thereof comprises a VH domain having the sequence set forth in SEQ ID NO: 51, and a VL domain having the sequence set forth in SEQ ID NO: 53.

[0146] In one embodiment, the anti-IL13Rα1 antibody or binding fragment thereof is ebrasakimab (ASLAN004).

[0147] In one embodiment, the formulation contains 100 mM or less tryptophan, for example, 100 mM, 95 mM, 90 mM, 85 mM, 80 mM, 75 mM, 70 mM, 65 mM, 60 mM, 55 mM, or 50 mM tryptophan. In one embodiment, the formulation contains 90 mM or less tryptophan, for example, 90 mM, 85 mM, 80 mM, 75 mM, 70 mM, 65 mM, 60 mM, 55 mM, or 50 mM tryptophan. In one embodiment, the formulation contains 80 mM or less tryptophan, for example, 80 mM, 75 mM, 70 mM, 65 mM, 60 mM, 55 mM, or 50 mM tryptophan. In one embodiment, the formulation contains 70 mM or less tryptophan, for example, 70 mM, 65 mM, 60 mM, 55 mM, or 50 mM tryptophan. In one embodiment, the formulation contains 60 mM or less tryptophan, e.g., 60 mM, 55 mM, 50 mM, 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, or 20 mM tryptophan. In one embodiment, the formulation contains 50 mM or less tryptophan, e.g., 50 mM, 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, or 20 mM tryptophan.

[0148] The formulations of the present disclosure contain a minimum level of 5 mM tryptophan.

[0149] In one embodiment, the formulation contains 5-100 mM tryptophan, e.g., 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, or 100 mM tryptophan. In one embodiment, the formulation contains 10-90 mM tryptophan, e.g., 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, or 90 mM tryptophan. In one embodiment, the formulation contains 15-85 mM tryptophan, e.g., 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM tryptophan. In one embodiment, the formulation contains 20-80 mM tryptophan, e.g., 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, or 80 mM tryptophan. In one embodiment, the formulation contains 25-75 mM tryptophan, e.g., 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, or 75 mM tryptophan. In one embodiment, the formulation contains 20-70 mM tryptophan, e.g., 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, or 80 mM tryptophan. In one embodiment, the formulation contains 20-60 mM tryptophan, e.g., 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, or 60 mM tryptophan.

[0150] In one embodiment, the formulation contains 20-55 mM tryptophan, e.g., 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, or 55 mM tryptophan. In one embodiment, the formulation contains 25-50 mM tryptophan, e.g., 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM tryptophan. In one embodiment, the formulation contains 20 mM tryptophan. In one embodiment, the formulation contains 25 mM tryptophan. In another embodiment, the formulation contains 50 mM tryptophan. In one embodiment, the formulation contains 80 mM tryptophan.

[0151] The tryptophan in the formulations of the present invention may be used as a salt, for example, the potassium salt or the sodium salt.

[0152] In one embodiment, tryptophan is not used as the salt.

[0153] In one embodiment, the tryptophan is L-tryptophan.

[0154] In one embodiment, the formulation comprises 290 mM or less arginine, for example 290 mM, 285 mM, 280 mM, 275 mM, 270 mM, 265 mM, 260 mM, 255 mM, 250 mM, 245 mM, 240 mM, 235 mM, 230 mM, 225 mM, 220 mM, 215 mM, 210 mM, 205 mM or 200 mM arginine. In one embodiment, the formulation contains 280 mM or less arginine, e.g., 280 mM, 275 mM, 270 mM, 265 mM, 260 mM, 255 mM, 250 mM, 245 mM, 240 mM, 235 mM, 230 mM, 225 mM, 220 mM, 215 mM, 210 mM, 205 mM, or 200 mM arginine. In one embodiment, the formulation contains 270 mM or less arginine, e.g., 270 mM, 265 mM, 260 mM, 255 mM, 250 mM, 245 mM, 240 mM, 235 mM, 230 mM, 225 mM, 220 mM, 215 mM, 210 mM, 205 mM, or 200 mM arginine. In one embodiment, the formulation comprises 260 mM or less arginine, for example 260 mM, 255 mM, 250 mM, 245 mM, 240 mM, 235 mM, 230 mM, 225 mM, 220 mM, 215 mM, 210 mM, 205 mM or 200 mM arginine.

[0155] The formulations of the present disclosure contain at least 140 mM arginine.

[0156] In one embodiment, the formulation comprises 140-290 mM arginine, e.g., 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM, 270 mM, 275 mM, 280 mM, 285 mM, or 290 mM arginine. In one embodiment, the formulation comprises 150-280 nM arginine, for example 150 nM, 155 nM, 160 nM, 165 nM, 170 nM, 175 nM, 180 nM, 185 nM, 190 nM, 195 nM, 200 nM, 205 nM, 210 nM, 215 nM, 220 nM, 225 nM, 230 nM, 235 nM, 240 nM, 245 nM, 250 nM, 255 nM, 260 nM, 265 nM, 270 nM, 275 nM or 280 nM arginine. In one embodiment, the formulation comprises 160-270 nM arginine, for example 160 nM, 165 nM, 170 nM, 175 nM, 180 nM, 185 nM, 190 nM, 195 nM, 200 nM, 205 nM, 210 nM, 215 nM, 220 nM, 225 nM, 230 nM, 235 nM, 240 nM, 245 nM, 250 nM, 255 nM, 260 nM, 265 nM or 270 nM arginine. In one embodiment, the formulation comprises 175-265 nM arginine, for example 175 nM, 180 nM, 185 nM, 190 nM, 195 nM, 200 nM, 205 nM, 210 nM, 215 nM, 220 nM, 225 nM, 230 nM, 235 nM, 240 nM, 245 nM, 250 nM, 255 nM, 260 nM or 265 nM arginine.

[0157] In one embodiment, the formulation contains 185-260 mM arginine, e.g., arginine-HCl, e.g., 185 mM, 195 mM, 205 mM, 215 mM, 225 mM, 235 mM, 245 mM, 255 mM, or 260 mM arginine. In one embodiment, the formulation contains 190-250 nM arginine, e.g., 190 nM, 195 nM, 200 nM, 205 nM, 210 nM, 215 nM, 220 nM, 225 nM, 230 nM, 235 nM, 240 nM, 245 nM, or 250 nM arginine. In one embodiment, the formulation contains 200-260 mM arginine, e.g., 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, or 260 mM arginine. In one embodiment, the formulation contains 175-195 mM arginine, e.g., 175 mM, 180 mM, 185 mM, 190 mM, or 195 mM arginine. In one embodiment, the formulation contains 250-270 mM arginine, e.g., 250 mM, 255 mM, 260 mM, 265 mM, or 270 mM arginine.

[0158] In one embodiment, the formulation comprises 150 mM, 215 mM, 260 mM, or 280 mM arginine. In one embodiment, the formulation comprises 200 mM, 210 mM, 225 mM, 235 mM, 250 mM, or 260 mM arginine. In one embodiment, the formulation comprises 185 mM arginine. In one embodiment, the formulation comprises 150 mM arginine. In one embodiment, the formulation comprises 200 mM arginine. In one embodiment, the formulation comprises 210 mM arginine. In one embodiment, the formulation comprises 215 mM arginine. In one embodiment, the formulation comprises 225 mM arginine. In one embodiment, the formulation comprises 235 mM arginine. In one embodiment, the formulation comprises 250 mM arginine. In one embodiment, the formulation comprises 260 mM arginine. In one embodiment, the formulation comprises 280 mM arginine.

[0159] In one embodiment, the arginine is Arg-HCl. In another embodiment, the arginine is Arg-Glu. In one embodiment, the arginine is L-arginine. Accordingly, in one embodiment, the formulation comprises 185-260 mM Arg-HCl. In one embodiment, the formulation comprises 200-260 mM Arg-HCl. In one embodiment, the formulation comprises 200 mM, 210 mM, 225 mM, 235 mM, 250 mM, or 260 mM Arg-HCl. In one embodiment, the formulation comprises 185 mM Arg-HCl. In one embodiment, the formulation comprises 200 mM Arg-HCl. In one embodiment, the formulation comprises 210 mM Arg-HCl. In one embodiment, the formulation comprises 215 mM Arg-HCl. In one embodiment, the formulation comprises 225 mM Arg-HCl. In one embodiment, the formulation comprises 235 mM Arg-HCl. In one embodiment, the formulation comprises 250 mM Arg-HCl. In one embodiment, the formulation comprises 260 mM Arg-HCl.

[0160] In one embodiment, the formulation comprises 0.01-0.03% non-ionic surfactant, for example 0.01%, 0.015%, 0.02%, 0.025%, or 0.030%, particularly 0.02%. In one embodiment, the formulation comprises 0.01-0.03%, for example 0.01%, 0.015%, 0.02%, 0.025%, or 0.030%, particularly 0.02%, volume per volume (v / v) of non-ionic surfactant. In one embodiment, the formulation comprises 0.01-0.03%, for example 0.01%, 0.015%, 0.02%, 0.025%, or 0.030%, particularly 0.02%, weight per volume (w / v) of non-ionic surfactant. In one embodiment, the formulation comprises 0.01 to 0.03%, for example 0.01%, 0.015%, 0.02%, 0.025% or 0.030%, especially 0.02%, weight per weight (w / w) of non-ionic surfactant. In one embodiment, the formulation comprises 0.02% w / w non-ionic surfactant.

[0161] In one embodiment, the non-ionic surfactant is a polysorbate, e.g., polysorbate 20, 40, 60, or 80, e.g., 20 or 80. In one embodiment, the non-ionic surfactant is polysorbate 80. Thus, in one embodiment, the formulation comprises 0.01-0.03%, e.g., 0.02% (e.g., as % w / w, % w / v, % v / w, or % v / v) polysorbate 80. In one embodiment, the formulation comprises 0.02% w / w polysorbate 80. In one embodiment, the non-ionic surfactant is polysorbate 20 (Tween 20). Thus, in one embodiment, the formulation comprises 0.01-0.03%, for example 0.010%, 0.015%, 0.020%, 0.025% or 0.030% (e.g., as % w / w, % w / v, % v / w or % v / v) polysorbate 20. In one embodiment, the formulation comprises 0.02% w / w polysorbate 20.

[0162] In one embodiment, the pH of the formulation is in the range of 5.5 to 7.2, e.g., 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, or 7.2. In one embodiment, the pH of the formulation is in the range of 5.7 to 7.0, e.g., 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In one embodiment, the pH is in the range of 5.8 to 6.8, e.g., 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8. In one embodiment, the pH of the formulation is in the range of 6.0 to 7.0, e.g., 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In one embodiment, the pH of the formulation is in the range of 6.2 to 6.8, e.g., 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.

[0163] In one embodiment, the pH is 6.8 or less, for example, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, or 6.0. In one embodiment, the pH is 6.7 or less, for example, 6.7, 6.6, 6.5, 6.4, 6.3, 6.1, 6.1, or 6.0. In one embodiment, the pH is 6.6 or less, for example, 6.6, 6.5, 6.4, 6.3, 6.1, 6.1, or 6.0. In one embodiment, the pH is 6.5 or less, for example, 6.5, 6.4, 6.3, 6.1, 6.1, or 6.0. In one embodiment, the pH is in the range of 6.3 to 6.7, for example, 6.3, 6.4, 6.5, 6.6, or 6.7. In one embodiment, the pH is 6.3 to 6.5, for example, 6.3, 6.4, or 6.5, for example, 6.4. In one embodiment, the pH is 6.4 to 6.6, for example, 6.4, 6.5, or 6.6. In one embodiment, the pH is 6.5 to 6.7, for example, 6.5, 6.6, or 6.7. In one embodiment, the pH is 5.8, 6.3, 6.5, 6.6, 6.7, or 6.8. In one embodiment, the pH is 5.8. In one embodiment, the pH is 6.3. In one embodiment, the pH is 6.4. In one embodiment, the pH is 6.5. In one embodiment, the pH is 6.6. In one embodiment, the pH is 6.7. In one embodiment, the pH is 6.8.

[0164] In one embodiment, the formulation further comprises phenylalanine, for example 45-90 mM phenylalanine, for example 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM or 90 mM phenylalanine. In one embodiment, the formulation further comprises 25-175 mM phenylalanine, such as 50-150 mM phenylalanine, for example 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 103 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM or 150 mM phenylalanine. In one embodiment, the formulation comprises 65 to 160 mM phenylalanine, for example 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM or 160 mM phenylalanine. In one embodiment, the formulation comprises 75-150 mM phenylalanine, e.g., 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM phenylalanine. In one embodiment, the formulation comprises 115-160 mM phenylalanine, e.g., 125-150 mM phenylalanine, e.g., 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, or 150 mM phenylalanine. In one embodiment, the formulation comprises 50 mM, 75 mM, 100 mM, 125 mM or 150 mM phenylalanine, such as 75 mM, 125 mM or 150 mM phenylalanine.

[0165] In one embodiment, the formulation comprises 50 mM, 75 mM, or 80 mM phenylalanine. In one embodiment, the formulation comprises 50 mM phenylalanine. In one embodiment, the formulation comprises 75 mM phenylalanine. In one embodiment, the formulation comprises 80 mM phenylalanine. In one embodiment, the formulation comprises 125 mM phenylalanine. In one embodiment, the formulation comprises 150 mM phenylalanine.

[0166] In one embodiment, the formulation further comprises creatine, such as creatine monohydrate, creatine ethyl ester, creatine hydrochloride, buffered creatine, or creatine magnesium chelate. In one embodiment, the formulation comprises creatine monohydrate. In one embodiment, the formulation comprises 50-125 mM creatine, such as 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, or 125 mM creatine. In one embodiment, the formulation comprises 75-100 mM creatine, such as 75-100 mM creatine monohydrate. In one embodiment, the formulation comprises 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, or 100 mM creatine, e.g., 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, or 100 mM creatine monohydrate. In one embodiment, the formulation comprises 75 mM creatine monohydrate. In one embodiment, the formulation comprises 100 mM creatine monohydrate.

[0167] In one embodiment, the formulation comprises a 15-55 mM histidine buffer, e.g., 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, or 55 mM histidine buffer. In one embodiment, the formulation comprises a 20-50 mM histidine buffer, e.g., 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM histidine buffer, e.g., 20 mM or 50 mM histidine buffer. In one embodiment, the formulation comprises a 25-50 mM histidine buffer, e.g., 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM histidine buffer. In one embodiment, the formulation comprises a 35-50 mM histidine buffer, for example, a 35 mM, 40 mM, 45 mM, or 50 mM histidine buffer. In one embodiment, the formulation comprises a 20 mM, 35 mM, or 50 mM histidine buffer. In one embodiment, the formulation comprises a 20 mM histidine buffer. In one embodiment, the formulation comprises a 35 mM histidine buffer. In another embodiment, the formulation comprises a 50 mM histidine buffer.

[0168] In one embodiment, the formulation does not include a phosphate buffer, such as a sodium phosphate buffer or a potassium phosphate buffer.

[0169] In one embodiment, the formulation further comprises CaCl, e.g., 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, or 60 mM CaCl. In one embodiment, the formulation comprises 50 mM CaCl.

[0170] In one embodiment, the formulation does not include CaCl2.

[0171] In one embodiment, the formulation of the present disclosure does not include NaCl and / or KCl.

[0172] In one embodiment, the formulation further comprises 50-200 mM sugar, e.g., 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM sugar. In one embodiment, the formulation comprises 180 mM sugar. In one embodiment, the sugar is selected from mannitol, sorbitol, dextrose, galactose, fructose, lactose, trehalose, and sucrose. In one embodiment, the sugar is sucrose. Thus, in one embodiment, the formulation comprises 180 mM sucrose.

[0173] In one embodiment, the formulations of the present disclosure do not include sugars, particularly sugars disclosed herein, such as sucrose.

[0174] In one embodiment, a parenteral formulation (particularly a liquid formulation) is provided, for example, for infusion or injection. In one embodiment, the liquid parenteral formulation is provided as a concentrate for dilution with an injectable liquid, for example, glucose for injection, saline, or water. In one embodiment, the liquid parenteral formulation is provided at a final concentration for administration without dilution, for example, for injection or infusion.

[0175] In one embodiment, the antibody or binding fragment used in the formulation of the present disclosure is a monoclonal antibody.

[0176] In one embodiment, the antibody or binding fragment used in the formulation of the present disclosure is a human antibody. In one embodiment, the antibody or binding fragment used in the formulation of the present disclosure is a chimeric antibody or a humanized antibody.

[0177] In one embodiment, the formulation is not F2 in Figure 1. In one embodiment, the formulation is not F4 in Figure 1. In one embodiment, the formulation is not F7 in Figure 1. In one embodiment, the formulation is not F9 in Figure 1. In one embodiment, the formulation is not F10 in Figure 1.

[0178] In one embodiment, the formulation comprises: 190 to 210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, particularly 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 40-60 mM tryptophan, e.g., 40 mM, 45 mM, 50 mM, 55 mM, or 60 mM tryptophan, especially 50 mM tryptophan; 175-270 mM arginine (such as Arg-HCl or Arg-Glu), for example 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 185 mM, 215 mM, 225 mM, or 260 mM, 200 mM, 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, The pH of the formulation is in the range of 6.3 to 6.7, for example 6.3, 6.4, 6.5, 6.6, 6.7, in particular 6.4, 6.5 or 6.6.

[0179] In one embodiment, the formulation comprises: 190 to 210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, particularly 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 40-60 mM tryptophan, e.g., 40 mM, 45 mM, 50 mM, 55 mM, or 60 mM tryptophan, especially 50 mM tryptophan; 250-270 mM arginine (such as Arg-HCl or Arg-Glu), for example 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, The pH of the formulation is in the range of 6.3 to 6.7, for example 6.3, 6.4, 6.5, 6.6, 6.7, in particular 6.4, 6.5 or 6.6.

[0180] In one embodiment, the formulation comprises: 190 to 210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, particularly 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 40-60 mM tryptophan, e.g., 40 mM, 45 mM, 50 mM, 55 mM, or 60 mM tryptophan, especially 50 mM tryptophan; 175-195 mM arginine (such as Arg-HCl or Arg-Glu), for example 175 mM, 180 mM, 185 mM, 190 mM or 195 mM, in particular 185 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of a non-ionic surfactant; Buffer solutions (such as histidine buffer solutions) Including, The pH of the formulation is in the range of 6.3 to 6.7, for example 6.3, 6.4, 6.5, 6.6, 6.7, in particular 6.4, 6.5 or 6.6.

[0181] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 260 mM arginine-HCl; 50 mM tryptophan; and 0.02% non-ionic surfactant; and the pH of the formulation is 6.4.

[0182] In one embodiment, the formulation contains 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 225 mM Arg-HCl; 75 mM phenylalanine; 50 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.4.

[0183] In one embodiment, the formulation contains 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 200 mM Arg-HCl; 125 mM phenylalanine; 50 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.4.

[0184] In one embodiment, the formulation contains 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 225 mM Arg-HCl; 100 mM phenylalanine; 25 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.4.

[0185] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 260 mM arginine-HCl; 50 mM tryptophan; and 0.02% non-ionic surfactant; and the pH of the formulation is 6.3 to 6.7, for example 6.4 or 6.5.

[0186] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 225 mM arginine-HCl; 75 mM phenylalanine; 50 mM tryptophan; and 0.02% non-ionic surfactant; and the pH of the formulation is 6.3 to 6.7, for example 6.4 or 6.5.

[0187] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 215 mM arginine-HCl; 125 mM phenylalanine; 20 mM tryptophan; and 0.02% non-ionic surfactant; and the pH of the formulation is 6.3 to 6.7, for example 6.4 or 6.5.

[0188] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 185 mM arginine-HCl; 150 mM phenylalanine; 50 mM tryptophan; and 0.02% non-ionic surfactant; and the pH of the formulation is 6.3 to 6.7, for example 6.4 or 6.5.

[0189] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 260 mM arginine-HCl; 50 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5, or 6.6.

[0190] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 225 mM arginine-HCl; 75 mM phenylalanine; 50 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5, or 6.6.

[0191] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 215 mM arginine-HCl; 125 mM phenylalanine; 20 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5, or 6.6.

[0192] In one embodiment, the formulation comprises 190 to 210 mg / ml, for example 200 mg / ml, of an anti-IL13R antibody or antigen-binding fragment thereof (wherein the anti-IL13R antibody comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto); 185 mM arginine-HCl; 150 mM phenylalanine; 50 mM tryptophan; and 0.02% polysorbate 20; and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5, or 6.6.

[0193] In one embodiment, the formulation is manufactured and / or filled under nitrogen.

[0194] In one embodiment, the formulation is filled into an opaque vial, for example, an amber vial that blocks light.

[0195] Detailed Disclosure As used herein, long-term refers to a period of at least 6 months, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months.In one embodiment, the formulation of the present disclosure is stored for at least 12 months, for example, 12, 18 and 24 months.

[0196] Nonionic surfactant used herein refers to surfactant that has covalently bonded oxygen-containing hydrophilic group that is connected to hydrophobic philic structure.The example of nonionic surfactant is ethoxylate, for example fatty alcohol ethoxylate (narrow range ethoxylate, such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether), alkylphenol ethoxylate (such as nonoxynol and Triton X-100), fatty acid ethoxylate, ethoxylated amine and / or fatty acid amide (such as polyethoxylated tallow amine, cocamide monoethanolamine and cocamide diethanolamine), end-blocked ethoxylate (such as poloxamers); fatty acid ester of polyhydroxy compound; fatty acid ester of glycerol (such as glycerol monostearate and glycerol monolaurate); fatty acid ester of sorbitol (such as sorbitan monolaurate, sorbitan monostearate and sorbitan tristearate); Tween Tweens such as 20, 40, 60 or 80; fatty acid esters of sucrose; alkyl polyglucosides (such as decyl glucoside, lauryl glucoside and octyl glucoside); and polysorbates (such as polysorbate 20, 40, 60 or 80).

[0197] Thus, in one embodiment, the nonionic surfactant is selected from the group comprising ethoxylates; fatty acid esters of polyhydroxy compounds; fatty acid esters of glycerol; fatty acid esters of sorbitol; Tweens; fatty acid esters of sucrose; alkyl polyglucosides; and polysorbates.

[0198] As used herein, parenteral formulation refers to a formulation that is not designed to be delivered through the GI tract. Typical parenteral administration routes include injection (including bolus injection), implantation or infusion. In one embodiment, the formulation is provided in a form for bolus administration.

[0199] In one embodiment, the parenteral formulation is administered intravenously. In one embodiment, the parenteral formulation is administered subcutaneously.

[0200] As used herein, injection refers to the administration of a liquid formulation into the body via a syringe or syringe pump. Injections include intravenous, subcutaneous, or intramuscular administration. Injections generally occur over a short period of time, e.g., 5 minutes or less. However, injections can be administered slowly or continuously, e.g., using a syringe pump. Injections generally involve the administration of smaller volumes than an infusion. In one embodiment, injections are administered as a slow infusion, e.g., over a period of 1.5 to 30 minutes. As used herein, slow infusion refers to manual injection using a syringe. In one embodiment, a single dose of less than 100 ml of the formulation, e.g., 30 ml, is administered, e.g., via a syringe pump.

[0201] In one embodiment, the dose of the anti-IL13R antibody or antigen-binding fragment thereof, e.g., ebrasakimab, is 100 to 600 mg, e.g., 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg. In one embodiment, the dose is 300 mg. In one embodiment, the dose is 400 mg. In one embodiment, the dose is 500 mg. In one embodiment, the dose is 600 mg.

[0202] Advantageously, the high-concentration formulations of the present disclosure contain 175-250 mg / ml, e.g., 190-210 mg / ml, particularly 200 mg / ml, of an anti-IL-13R antibody or antigen-binding fragment thereof. Subcutaneous injections are generally limited to a maximum volume of 2 ml. Thus, the present high-concentration formulations allow for the administration of high doses, e.g., 400 mg or 500 mg, via a single subcutaneous injection.

[0203] Thus, in one embodiment, the dose is administered by subcutaneous injection, for example, by multiple or single subcutaneous injections. In one embodiment, the dose is administered by single subcutaneous injection. In one embodiment, the dosage is less than 4 ml, for example, 4 ml, 3.5 ml, 3.0 ml, 2.5 ml, 2.0 ml, 1.5 ml, 1 ml, or 0.5 ml. In one embodiment, the dosage is 2 ml or less, for example, 2.0 ml, 1.5 ml, or 0.5 ml. In one embodiment, the dosage is 2 ml. In one embodiment, the dosage is 1.5 ml. In one embodiment, the dosage is 1.0 ml. In one embodiment, the dosage is 0.5 ml.

[0204] In one embodiment, a 500 mg dose is administered by a single subcutaneous injection. In one embodiment, a 400 mg dose is administered by a single subcutaneous injection. In one embodiment, a 300 mg dose is administered by a single subcutaneous injection. In one embodiment, a 200 mg dose is administered by a single subcutaneous injection. In one embodiment, a 100 mg dose is administered by a single subcutaneous injection.

[0205] In one embodiment, a 400 mg dose is administered by a single 2 ml subcutaneous injection.

[0206] As used herein, infusion refers to the administration of a fluid by a drip infusion machine, infusion pump, or equivalent device. In one embodiment, the infusion is administered over a period of 1 to 120 minutes (e.g., 1 to 5 minutes), such as about 1 minute, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 65 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, or 120 minutes.

[0207] Anti-IL13R antibody As used herein, interleukin-13 receptor (IL-13R) is a type I cytokine receptor that binds to interleukin-13. It consists of two subunits, encoded by IL13Rα1 and IL4R, respectively. These two genes encode the proteins IL-13Rα1 and IL-4Rα, which form dimers with IL-13 bound to the IL-13Rα1 chain, with IL-4Rα stabilizing this interaction. Due to the presence of the IL4R subunit, IL13R can also trigger IL-4 signal transduction. In both cases, this occurs via activation of the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway, leading to the phosphorylation of STAT6. Human IL-13Rα1 has the Uniprot number P3597.

[0208] IL-13Rα2, previously referred to as IL-13R and IL-13Rα, is another receptor that can bind IL-13. However, in contrast to IL-13Rα1, this protein binds IL-13 with high affinity, but it does not bind IL-4. Human IL-13Rα2 has the Uniprot number Q14627.

[0209] As used herein, an anti-IL13R antibody refers to an antibody having specificity for IL13R, e.g., IL13Rα1 or IL13Rα2. In one embodiment, an anti-IL13R antibody of the present disclosure is specific for IL13Rα1. In one embodiment, the anti-IL13R antibody binds to an epitope comprising the amino acid sequence FFYQ.

[0210] The anti-IL13R antibodies of the present disclosure may comprise an intact antibody molecule having full-length heavy and light chains or binding fragments thereof, including, but not limited to, Fab, modified Fab, Fab', F(ab')2, Fv, single domain antibodies (such as VH, VL, VHH, IgNAR V domains), scFv, bivalent, trivalent or tetravalent antibodies, bis-scFv, diabodies, triabodies, tetrabodies, and epitope-binding fragments of any of the above (see, e.g., Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews-Online 2(3), 209-217).

[0211] Methods for generating and producing these antibody fragments are well known in the art (see, for example, Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). Other antibody fragments for use in the present invention include the Fab and Fab' fragments described in WO 2005 / 003169, WO 2005 / 003170, and WO 2005 / 003171. Other antibody fragments for use in the present invention include the Fab-Fv and Fab-dsFv fragments described in WO 2010 / 035012, as well as antibody fragments comprising these fragments. Multivalent antibodies may comprise multiple specificities or may be monospecific (see, for example, WO 92 / 22853 and WO 05 / 113605).

[0212] Antibodies and fragments thereof for use in the present disclosure may be from any species, including, for example, mouse, rat, shark, rabbit, pig, hamster, camel, llama, goat, or human. Chimeric antibodies have non-human variable regions and human constant regions.

[0213] Antibodies or binding fragments for use in the present invention can be from any class (e.g., IgG, IgE, IgM, IgD, or IgA) or subclass of immunoglobulin molecule. In one embodiment, the antibody used in this disclosure is an IgG4 or IgG4 with the 241P mutation.

[0214] In one embodiment, the antibody or binding fragment used in the formulation of the present disclosure has an affinity of 5 nM or more (higher affinities are lower numbers), such as 500 pM, for example 250 pM or more, particularly 125 pM or less.

[0215] In one embodiment, CDRH1 is the amino acid sequence GYSFTSYWIG (SEQ ID NO: 1).

[0216] In one embodiment, CDRH2 is the amino acid sequence VIYPGDSYTR (SEQ ID NO: 2).

[0217] In one embodiment, CDRH3 has the formula: SEQ ID NO: 3 X1Pro Asn Trp Gly X6X7Asp X9 and X1 represents Phe, Met, Gln, Leu or Val; X6 represents Ser or Ala, X7 represents Phe, Leu, Ala or Met; X9 represents Tyr, Gln, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn, or Gly.

[0218] In one embodiment, the IL13-R1α1 antibody or binding fragment used in the formulation of the present disclosure comprises a CDRH3 independently selected from SEQ ID NOs: 4-30.

[0219] In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3.

[0220] In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0221] In one embodiment, an anti-IL13R antibody or binding fragment used in this disclosure comprises a CDRH3 having the amino acid sequence MPNWGSLDH (SEQ ID NO: 10).

[0222] In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:1, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:10.

[0223] In one embodiment, CDRL1 is the amino acid sequence RASQSISSSYLA SEQ ID NO:31.

[0224] In one embodiment, CDRL2 is the amino acid sequence GASSRAT SEQ ID NO:32.

[0225] In one embodiment, CDL3 has the formula: SEQ ID NO: 33 Gln X2X3X4X5 and X2 represents Gln, Arg, Met, Ser, Thr or Val; X3 represents Tyr or Val, X4 represents Glu, Ala, Gly or Ser, X5 represents Thr, Ala or Ser.

[0226] In one embodiment, the IL-13Rα1 antibody used in the formulation of the present disclosure comprises a CDRL3 independently selected from SEQ ID NOs: 34-47.

[0227] In one embodiment, the anti-IL13R antibody or binding fragment used in this disclosure comprises a CDL3 having the amino acid sequence QQYAS (SEQ ID NO: 45).

[0228] In one embodiment, an anti-IL13R antibody or binding fragment used in the present disclosure comprises a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

[0229] In one embodiment, the IL-13Rα1 antibody used in the formulation of the present disclosure comprises a CDRL3 independently selected from the sequence comprising SEQ ID NOs: 34-47.

[0230] In one embodiment, CDRL3 comprises the amino acid sequence set forth in SEQ ID NO:33.

[0231] In one embodiment, the VH regions are independently selected from the group comprising: SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51 and a sequence at least 95% identical to any one of these.

[0232] SEQ ID NO:51 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly Val Ile Tyr Pro Gly Asp Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Met Pro Asn Trp Gly Ser Leu Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

[0233] In one embodiment, the VL is independently selected from a sequence from the group consisting of SEQ ID NO: 52, SEQ ID NO: 53 and SEQ ID NO: 54 and a sequence at least 95% identical to any one of these (*K is deleted in post-translational modifications).

[0234] SEQ ID NO:53 EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYASFGQGTKVEI*

[0235] In one embodiment, the VH sequence is SEQ ID NO:48 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VH sequence is SEQ ID NO:49 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VH sequence is SEQ ID NO:50 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VH sequence is SEQ ID NO:51 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:52, SEQ ID NO:53, or SEQ ID NO:54 (or a sequence at least 95% identical to any one of these). In one embodiment, the VL sequence is SEQ ID NO:52 (or a sequence at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence at least 95% identical to any one of these). In one embodiment, the VL sequence is SEQ ID NO:53 (or a sequence at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence at least 95% identical to any one of these). In one embodiment, the VL sequence is SEQ ID NO:54 (or a sequence at least 95% identical thereto), and the VH sequence is SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, or SEQ ID NO:51 (or a sequence at least 95% identical thereto). In one embodiment, the VH sequence is SEQ ID NO:51 (or a sequence at least 95% identical thereto), and the VL sequence is SEQ ID NO:53 (or a sequence at least 95% identical thereto).

[0236] As used herein, a variable region refers to the region in an antibody chain comprising the CDRs and an appropriate framework.

[0237] In one embodiment, the heavy chain comprises a sequence independently selected from the group comprising SEQ ID NOs: 55, 56, 57, 58, 59, 60 and a sequence at least 95% identical to any one of these (*K is deleted in a post-translational modification).

[0238] In one embodiment, the light chain is independently selected from the group comprising SEQ ID NO: 61; SEQ ID NO: 62; SEQ ID NO: 63 and a sequence at least 95% identical to any one of these.

[0239] In one embodiment, the heavy chains are independently selected from SEQ ID NOs: 55, 56, 57, 58, 59 and 60 (or a sequence at least 95% identical to any one of these), and the light chains are independently selected from SEQ ID NOs: 61, 62 and 63 (or a sequence at least 95% identical to any one of these).

[0240] In one embodiment, the heavy chain is SEQ ID NO:55 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NOs:61 or 62 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:56 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NOs:61 or 62 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:57 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NOs:62 or 63 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:58 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NOs:61, 62 and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:59 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NOs:61, 62, and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:60 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NOs:61, 61, and 63 (or a sequence at least 95% identical to any one of these). In one embodiment, the heavy chain is SEQ ID NO:58 or 60 (or a sequence at least 95% identical to any one of these) and the light chain has the sequence set forth in SEQ ID NO:61 (or a sequence at least 95% identical thereto). In one embodiment, the heavy chain is SEQ ID NO:58 (or a sequence at least 95% identical to any one of these) and the light chain has the sequence set forth in SEQ ID NO:61 (or a sequence at least 95% identical thereto). In one embodiment, the heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical to any one of these) and the light chain has the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).

[0241] In one embodiment, the anti-IL13R antibody is ebrasakimab (formerly known as ASLAN004).

[0242] As used herein, Derived from refers to the fact that the sequence employed, or a sequence highly similar to the sequence employed, was obtained from the original genetic material, e.g., the light or heavy chain of an antibody.

[0243] As used herein, "at least 95% identical" is intended to refer to an amino acid sequence that is 95% or more identical to a reference sequence over its entire length, e.g., 96%, 97%, 98% or 99% identical. Software programs can be used to calculate the percentage of identity.

[0244] In one embodiment, the antibodies or binding fragments thereof used in the formulations of the present disclosure are humanized.

[0245] As used herein, humanized (including CDR-grafted antibodies) refers to molecules having one or more complementarity-determining regions (CDRs) from a non-human species and framework regions from a human immunoglobulin molecule (see, e.g., U.S. Pat. No. 5,585,089; WO 91 / 09967). It will be recognized that only the specificity-determining residues of the CDRs need to be transferred, rather than the entire CDR (see, e.g., Kashmiri et al., 2005, Methods, 36, 25-34). A humanized antibody may optionally further comprise one or more framework residues from the non-human species from which the CDRs were derived. For a review, see Vaughan et al., Nature Biotechnology, 16, 535-539, 1998.

[0246] When CDRs or specificity-determining residues are grafted, any suitable acceptor variable region framework sequence may be used, taking into account the class / type of the donor antibody from which the CDRs are derived, including mouse, primate, and human framework regions. Examples of human frameworks that can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY, and POM (Kabat et al., supra). For example, KOL and NEWM can be used for the heavy chain, REI can be used for the light chain, and EU, LAY, and POM can be used for both the heavy and light chains. Alternatively, human germline sequences can be used, which are available at http: / / vbase.mrc-cpe.cam.ac.uk / .

[0247] In the humanized antibodies used in the present invention, the acceptor heavy and light chains do not necessarily have to be derived from the same antibody, but may, if desired, comprise composite chains having framework regions derived from different chains.

[0248] The framework regions need not have the exact same sequence as those of the acceptor antibody. For example, unusual residues can be changed to more frequently occurring residues for that class or type of acceptor chain. Alternatively, selected residues in the acceptor framework regions can be changed so that they correspond to residues found at the same positions in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such changes should be kept to the minimum necessary to restore the affinity of the donor antibody. Protocols for selecting residues in acceptor framework regions that may need to be changed are described in WO 91 / 09967.

[0249] In one embodiment, the anti-IL13R antibodies of the present disclosure are fully human antibodies, in particular one or more variable domains are fully human antibodies.

[0250] A fully human molecule is one in which the variable and constant regions (if present) of both the heavy and light chains are all of human origin or substantially identical to sequences of human origin, although not necessarily from the same antibody. Examples of fully human antibodies can include, for example, antibodies produced by the phage display methods described above and antibodies produced in mice in which the genes for the variable and, optionally, constant regions of mouse immunoglobulins have been replaced by their human counterparts, as generally described, for example, in EP 0 546 073, U.S. Pat. No. 5,545,806, U.S. Pat. No. 5,569,825, U.S. Pat. No. 5,625,126, U.S. Pat. No. 5,633,425, U.S. Pat. No. 5,661,016, U.S. Pat. No. 5,770,429, EP 0 438 474, and EP 0 463 151.

[0251] As used herein, constant region is intended to refer to the portion of the constant region located in a heavy chain between two variable domains, e.g., between non-cognate variable domains. Thus, the presently disclosed anti-IL13R antibodies can comprise one or more constant regions, e.g., naturally occurring constant domains or naturally occurring domain derivatives.

[0252] As used herein, a derivative of a naturally occurring domain is intended to refer to one in which one, two, three, four or five amino acids in the naturally occurring sequence have been substituted or deleted to optimize the properties of the domain, for example, by eliminating undesirable properties, while retaining the characteristic function of the domain.

[0253] If necessary, the antibody for use in the present invention may be conjugated to one or more effector molecules. It will be recognized that the effector molecule may comprise a single effector molecule or two or more molecules linked to form a single moiety that can be attached to the antibody of the present invention. If it is desired to obtain an antibody fragment linked to an effector molecule, this can be prepared by standard chemical or recombinant DNA procedures, and the antibody fragment is linked to the effector molecule directly or via a coupling agent. Techniques for conjugating effector molecules to antibodies are well known in the art (see Hellstrom et al., Controlled Drug Delivery, 2nd Ed., Robinson et al., eds., 1987, pp. 623-53; Thorpe et al., 1982, Immunol. Rev., 62:119-58 and Dubowchik et al., 1999, Pharmacology and Therapeutics, 83, 67-123). Exemplary chemical procedures include, for example, those described in WO 93 / 06231, WO 92 / 22583, WO 89 / 00195, WO 89 / 01476 and WO 03031581. Alternatively, where the effector molecule is a protein or polypeptide, attachment may be achieved using recombinant DNA procedures, for example as described in WO 86 / 01533 and EP 0392745.

[0254] The term effector molecule as used herein includes, for example, biologically active proteins, such as enzymes, other antibodies or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof, such as DNA, RNA and fragments thereof, radionuclides, in particular radioactive iodides, radioisotopes, chelated metals, nanoparticles and reporter groups, such as fluorescent compounds or compounds that can be detected by NMR or ESR spectroscopy.

[0255] Other effector molecules can include detectable substances, such as those useful in diagnosis. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances, bioluminescent substances, radionuclides, positron-emitting metals (for use in positron emission tomography), and non-radioactive paramagnetic metal ions. For metal ions that can be conjugated to antibodies for use in diagnosis, see generally U.S. Patent No. 4,741,900. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin, and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; and suitable radionuclides include 125I, 131I, 111In, and 99Tc.

[0256] In another example, the effector molecule may extend the half-life of the antibody in vivo, and / or reduce the immunogenicity of the antibody, and / or enhance delivery of the antibody across the epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumin, albumin-binding proteins, or albumin-binding compounds such as those described in WO 05 / 117984. When the effector molecule is a polymer, it may generally be a synthetic or naturally occurring polymer, such as an optionally substituted linear or branched polyalkylene, polyalkenylene, or polyoxyalkylene polymer, or a branched or unbranched polysaccharide, such as a homopolysaccharide or heteropolysaccharide.

[0257] Particular optional substituents that may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.

[0258] Specific examples of synthetic polymers include optionally substituted linear or branched poly(ethylene glycol), poly(propylene glycol), poly(vinyl alcohol) or derivatives thereof, particularly optionally substituted poly(ethylene glycol), such as methoxypoly(ethylene glycol), or derivatives thereof. Specific naturally occurring polymers include lactose, amylose, dextran, glycogen, or derivatives thereof.

[0259] As used herein, "derivative" is intended to include reactive derivatives, e.g., thiol-selective reactive groups such as maleimides. The reactive group may be linked to the polymer directly or via a linker segment. It will be recognized that the residue of such a group may form part of the product as the linking group between the antibody fragment and the polymer.

[0260] Suitable polymers include polyalkylene polymers, such as poly(ethylene glycol) or, in particular, methoxypoly(ethylene glycol) or derivatives thereof, especially having a molecular weight in the range of about 15,000 Da to about 40,000 Da.

[0261] In one example, an antibody for use in the present invention is attached to a poly(ethylene glycol) (PEG) moiety. In a particular example, the antibody is an antibody fragment, and the PEG molecule can be attached via any available amino acid side chain or terminal amino acid functional group located in the antibody fragment, such as any free amino, imino, thiol, hydroxyl, or carboxyl group. Such amino acids may occur naturally in the antibody fragment or may be incorporated into the fragment using recombinant DNA methods (see, e.g., U.S. Pat. Nos. 5,219,996; 5,667,425; WO 98 / 25971; WO 2008 / 038024). In one example, the antibody molecule of the present invention is a modified Fab fragment, and the modification is the addition of one or more amino acids to the C-terminus of its heavy chain to allow for the attachment of an effector molecule. Suitably, the additional amino acids form a modified hinge region containing one or more cysteine ​​residues to which an effector molecule may be attached. Multiple sites can be used to attach two or more PEG molecules.

[0262] In one embodiment, the presently disclosed formulation is suitable for use in the treatment of chronic inflammatory conditions.Examples of chronic inflammatory conditions include, but are not limited to, atopic dermatitis, asthma, rheumatoid arthritis, psoriatic arthritis, lupus, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, diabetes such as type 1 or type 2 diabetes, ankylosing spondylitis, gout, myositis, scleroderma, Sjogren's syndrome, endometriosis and vasculitis.Therefore, in one embodiment, the patient to be treated has a chronic inflammatory condition selected from the group comprising atopic dermatitis, asthma, rheumatoid arthritis, psoriatic arthritis, lupus, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, diabetes such as type 1 or type 2 diabetes, ankylosing spondylitis, gout, myositis, scleroderma, Sjogren's syndrome, endometriosis and vasculitis.

[0263] In one embodiment, the formulation is for use in the treatment of atopic dermatitis, such as moderate to severe atopic dermatitis. In one embodiment, the formulation is for use in the treatment of pruritus.

[0264] In patients with cancer, such as breast cancer, cancer-related lymphedema (BCRL), the formulations of the present disclosure may prevent lymphedema-related effects, such as fibrosis, hyperkeratosis, fibroadipose tissue deposition, fluid retention, swelling of the hands and feet, loss of skin elasticity, and pain. By reducing excess volume, the formulations may improve lymphatic, e.g., limb, function.

[0265] The development of lymphedema after lymphatic injury is associated with tissue inflammation, infiltration of CD4+ cells, and their differentiation into the type 2 helper T cell (Th2) phenotype. Th2 cells produce IL-4 and IL-13, which play an important role in the development of lymphedema-associated symptoms and other Th2-mediated diseases.

[0266] In one embodiment, the formulations herein are administered in combination with another treatment.

[0267] As used herein, "in combination" is intended to include when an anti-IL13R antibody is administered prior to or concurrently with another treatment.

[0268] As used herein, a therapeutic dose refers to an amount of an anti-IL13R antibody, e.g., ebrasakimab (ASLAN004), that is adequate to achieve the intended therapeutic effect when used in an appropriate treatment regimen, e.g., ameliorate a disease symptom or condition, particularly without causing dose-limiting side effects. An appropriate therapeutic dose is generally a balance between therapeutic effect and tolerable toxicity, e.g., side effects and toxicity are acceptable given the benefits achieved by the treatment.

[0269] In one embodiment, a formulation according to the present disclosure (including formulations containing same) is administered monthly, for example, in a treatment cycle or as maintenance therapy.

[0270] In the context of this specification, "comprising" should be interpreted as "including." Embodiments of the invention comprising certain features / elements are also intended to extend to alternative embodiments "consisting of" or "consisting essentially of" the associated elements / features. Where technically appropriate, embodiments of the invention may be combined.

[0271] Technical references, such as patents and applications, are incorporated herein by reference.

[0272] Any embodiment specifically and explicitly described herein may form the basis of a disclaimer either alone or in combination with one or more additional embodiments.

[0273] The subject headings herein are used to divide the document into sections and are not intended to be used to interpret the meaning of the disclosure provided herein.

[0274] This application claims priority from U.S. Patent No. 63 / 373,566, filed August 26, 2022, SG10202260455R, filed December 15, 2022, and SG10202301153T, filed April 25, 2023, all of which are incorporated herein by reference and any may be used to correct any errors herein.

[0275] The background contains technical information and can be used as a basis for modification.

[0276] Individual values ​​in the examples may be extracted and combined with the general elements of this disclosure, i.e., used as a specific basis for modification without reference to other features of the examples.

[0277] The invention will now be further described, by way of example only, by way of the following examples. [Brief explanation of the drawings]

[0278] [Figure 1] Table showing the composition of the tested formulations, including theoretical osmolality. [Figure 2] Flowchart showing the experimental design, including an overview of how the formulations were prepared. [Figure 3] Photograph of the formulation for visual inspection. [Figure 4] Table showing the measured pH, osmolality and protein concentration of the formulations tested. [Figure 5] Table showing viscosity measurements of the formulations tested. F7-R and F8-R are replicate measurements of F7 and F8, respectively. [Figure 6] Graph showing the viscosity (at room temperature) of the formulations tested. [Figure 7] Table showing the composition of the formulations tested in round 2 screening. [Figure 8] Flowchart showing the experimental design, including an overview of how the formulations were prepared for the Round 2 screening formulations. [Figure 9] Photograph of formulations from round 2 screening for visual inspection. [Figure 10] Table showing the pH, osmolality, and protein concentration of formulations from round 2 screening. Protein stock concentrations were measured by three analysts using 16 individual 2-fold diluted protein stock solutions by Solo VPE. Measured protein stock concentrations ranged from 190 to 210 mg / mL, averaging 203 ± 7 mg / mL at the 95% confidence level. In round 1, the average protein concentration was slightly lower at 200 mg / mL. [Figure 11] Table showing viscosity measurements of formulations from round 2 screening. [Figure 12] Graph showing formulation viscosity results from round 2 screening. [Figure 13] Table showing the composition of formulations from round 2 screening selected for stability testing. Formulation 3 was tested at both target concentrations of 195 mg / ml and 200 mg / ml. [Figure 14A]Photograph of the formulation at T=0 for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 14B] Photograph of formulation at T=4 weeks at 4°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 14C] Photograph of formulation at T=4 weeks at 25°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 14D] Photograph of formulation at T=4 weeks at 40°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 15A] Table summarizing the results of visual inspection of the formulations at T=0 week. Color swatches according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 15B] Table summarizing the results of visual inspection of the formulations at T=4 weeks at 4°C. Color swatches according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 15C] Table summarizing the results of visual inspection of the formulations at T=4 weeks at 25°C. Color swatches according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 15D] Table summarizing the results of visual inspection of formulations at T=4 weeks at 40°C. Color swatches according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 16] Photograph showing a comparison of the color of the current formulation versus the previous ebrasakimab formulation (WP3B). [Figure 17] Table showing the pH of the formulation at T=4 weeks versus T=0 weeks. [Figure 18]Table showing reverse-phase high performance liquid chromatography (RP-HPLC) concentrations of formulations at T=4 weeks versus T=0 weeks. *Concentrations for T=0, vortex, and 5xF / T were adjusted by correcting the concentration of the stock standard solution used for the standard curve from 100 mg / mL to 105.2 mg / mL. The concentrated stock standard solution (BDS from JHL) was measured by SoloVPE to be 105.2 mg / mL instead of 100 mg / mL. [Figure 19] Viscosity curves of formulations with increasing ebrasakimab concentrations (Tangential Flow Filtration (TFF) diluted samples). JHL formulation = previous ebrasakimab formulation with good viscosity up to 100 mg / ml concentration. [Figure 20] Graph and table showing viscosity results of formulations at T=4 weeks vs. T=0. *Concentration of F@ is approximately 212 mg / ml. [Figure 21A] Graphs and tables showing size exclusion high performance liquid chromatography (SE-HPLC) results of formulations at T=0. [Figure 21B] Graph and table showing SE-HPLC results of formulations at T=4 weeks at 4° C. [Figure 21C] Graph and table showing SE-HPLC results of formulations at T=4 weeks at 25° C. [Figure 21D] Graph and table showing SE-HPLC results of formulations at T=4 weeks at 40° C. [Figure 22] Graph summarizing SE-HPLC results - % monomer and % soluble aggregates of formulations at T=4 weeks vs. T=0. [Figure 23] Graph summarizing the physical stability of the currently claimed formulation versus the previous ebrasakimab formulation (WP3B) based on SE-HPLC results. *F3-195 is 195 mg / mL. [Figure 24A] Graph and table showing cation exchange high performance liquid chromatography (CEX-HPLC) results of formulations at T=0. [Figure 24B] Graph and table showing CEX-HPLC results of formulations at T=4 weeks at 4° C. [Figure 24C]Graph and table showing CEX-HPLC results of formulations at T=4 weeks at 25° C. [Figure 24D] Graph and table showing CEX-HPLC results of formulations at T=4 weeks at 40° C. [Figure 25] Graph summarizing the chemical stability of the currently claimed formulation based on CEX-HPLC results. [Figure 26A] Graph showing microflow imaging (MFI) analysis results for particle size range >5 pM - an indicator of physical stability and quality. All samples were diluted to 20 mg / ml with the corresponding formulation buffer for MFI analysis. MFI particle counts were based on the average of two measurements. [Figure 26B] Graph showing results from non-sphericity (non-SPH) analysis of particle size range >5 pM - an indicator of physical stability and quality. All samples were diluted to 20 mg / ml with the corresponding formulation buffer for MFI analysis. MFI particle counts were based on the average of two measurements. Non-sphericity analysis: aspect ratio <0.75. [Figure 27A] Graph comparing MFI and non-SPH analysis results of this formulation with the previous ebrasakimab formulation (WP3B) for the size range >10 pM. [Figure 27B] Graph comparing MFI and non-SPH analysis results of this formulation with the previous ebrasakimab formulation (WP3B) for the size range >25 pM. [Figure 28A] Photograph of formulation at T=8 weeks at 4°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 28B] Photograph of formulation at T=8 weeks at 25°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 28C] Photograph of formulation at T=8 weeks at 40°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 29A]Table summarizing the results of visual inspection of formulations at T=8 weeks at 4°C. TNTC=Not Countable. Color swatch according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 29B] Table summarizing the results of visual inspection of formulations at T=8 weeks at 25°C. TNTC=Not Countable. Color swatch according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 29C] Table summarizing the results of visual inspection of formulations at T=8 weeks at 40°C. Color swatches according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 30] Table showing the pH of the formulations at T=8 weeks versus T=4 weeks and T=0. [Figure 31] Table showing concentrations by RP-HPLC of formulations at T=8 weeks vs. T=4 weeks and T=0. *Concentrations for T=0, stirred, and 5xF / T were corrected by correcting the concentration of the stock standard solution used for the standard curve from 100 mg / mL to 105.2 mg / mL. The concentrated stock standard solution was measured by SoloVPE to be 105.2 mg / mL instead of 100 mg / mL. [Figure 32] Table showing the osmolality (vapor pressure) of the formulations at T=8 weeks versus T=4 weeks and T=0. [Figure 33] Graph and table showing viscosity results of formulations at T=8 weeks versus T=4 weeks and T=0. [Figure 34A] Graph and table showing SE-HPLC results of formulations at T=8 weeks at 4° C. [Figure 34B] Graph and table showing SE-HPLC results for formulations at T=8 weeks at 25° C. [Figure 35A] Graph summarizing SE-HPLC results of formulations at T=8 weeks at 4° C. [Figure 35B] Graph summarizing SE-HPLC results for formulations at T=8 weeks at 25° C. [Figure 36A] Graph and table showing CEX-HPLC results of formulations at T=8 weeks at 4° C. [Figure 36B]Graph and table showing CEX-HPLC results of formulations at T=8 weeks at 25° C. [Figure 37A] Graph summarizing CEX-HPLC results of formulations at T=8 weeks at 4° C. [Figure 37B] Graph summarizing CEX-HPLC results for formulations at T=8 weeks at 25° C. [Figure 38A] Graph showing MFI and non-SPH analysis results of formulations at T=8 weeks vs. T=4 weeks and T=0 for >5 pM. [Figure 38B] Graph showing MFI and non-SPH analysis results of formulations at T=8 weeks vs. T=4 weeks and T=0 for >10 pM. [Figure 38C] Graph showing MFI and non-SPH analysis results of formulations at T=8 weeks vs. T=4 weeks and T=0 for >25 pM. [Figure 39A] Photograph of formulation at T=26 weeks at 4°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 39B] Photograph of formulation at T=26 weeks at 25°C for visual inspection. Color swatch with Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 40A] Table summarizing the results of visual inspection of formulations at T=26 weeks at 4°C. TNTC=Not Countable. Color swatch according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 40B] Table summarizing the results of visual inspection of formulations at T=26 weeks at 25°C. TNTC=Not Countable. Color swatch according to Ph Eur (Sigma-Aldrich 86293-1SET-F). [Figure 41] Table showing the pH of the formulations at T=26 weeks, T=8 weeks, T=4 weeks and T=0. [Figure 42]Table showing RP-HPLC concentrations of formulations at T=26 weeks, T=8 weeks, T=4 weeks, and T=0. *Concentrations for T=0, stirred, and 5xF / T were corrected by correcting the concentration of the stock standard solution used for the standard curve from 100 mg / mL to 105.2 mg / mL. The concentrated stock standard solution was measured by SoloVPE to be 105.2 mg / mL instead of 100 mg / mL. [Figure 43] Table showing the osmolality (vapor pressure) of the formulations at T=26 weeks, T=8 weeks, T=4 weeks and T=0. [Figure 44] Graph and table showing viscosity results for formulations at T=26 weeks, T=8 weeks, T=4 weeks and T=0. [Figure 45A] Graph and table showing SE-HPLC results for formulations at T=26 weeks at 4° C. [Figure 45B] Graph and table showing SE-HPLC results for formulations at T=26 weeks at 25° C. [Figure 46A] Graph summarizing SE-HPLC results for formulations at T=26 weeks at 4° C. [Figure 46B] Graph summarizing SE-HPLC results for formulations at T=26 weeks at 25° C. [Figure 47A] Graph and table showing CEX-HPLC results of formulations at T=26 weeks at 4° C. [Figure 47B] Graph and table showing CEX-HPLC results for formulations at T=26 weeks at 25° C. [Figure 48A] Graph summarizing CEX-HPLC results for formulations at T=26 weeks at 4° C. [Figure 48B] Graph summarizing CEX-HPLC results for formulations at T=26 weeks at 25° C. [Figure 49A] Table showing MFI analysis results of formulations at T=26 weeks at 4° C. All samples were diluted to 20 mg / mL with the corresponding formulation buffer for MFI analysis. MFI particle count: average of two measurements, non-spherical: aspect ratio <0.75. [Figure 49B]Table showing MFI analysis results for formulations at T=26 weeks at 25° C. All samples were diluted to 20 mg / mL with the corresponding formulation buffer for MFI analysis. MFI particle count: average of two measurements, non-spherical: aspect ratio <0.75. [Figure 50A] Graph showing MFI and non-SPH analysis results of formulations at T=26 weeks, T=8 weeks, T=4 weeks, and T=0 weeks for >5 pM. All samples were diluted to 20 mg / mL with the corresponding formulation buffer for MFI analysis. MFI particle count: average of two measurements; non-spherical: aspect ratio <0.75. [Figure 50B] Graph showing MFI and non-SPH analysis results of formulations at T=26 weeks, T=8 weeks, T=4 weeks, and T=0 weeks for >25 pM. All samples were diluted to 20 mg / mL with the corresponding formulation buffer for MFI analysis. MFI particle count: average of two measurements; non-spherical: aspect ratio <0.75. DETAILED DESCRIPTION OF THE INVENTION

[0279] Example Example 1 - Production and Testing of a High Concentration 200mg / ml Anti-IL13R Ebrasakimab (ASLAN004) Formulation - Round 1 Screening Figure 1 shows the composition of the 10 formulations tested. The formulations were prepared according to the method shown in Figure 2.

[0280] Briefly, 60 ml of ASLAN004 (Ebrasakimab) Drug Product Standard (DS) was dialyzed in 200 mM arginine-HCl and the pH was adjusted to 6.5. The dialyzed protein was then concentrated to approximately 200 mg / ml, and 10% polysorbate 80 solution was added to a final concentration of 0.02% w / w. An appropriate amount of solid excipient (e.g., creatine monohydrate) was prepared, and 1.5 ml of approximately 200 mg / ml Ebrasakimab stock solution was added to the solid excipient in a glass vial. The vial was gently shaken overnight at room temperature, after which the solution was filtered through a 0.2 μm filter.

[0281] The formulations were then subjected to various tests and measurements, such as visual inspection, measurement of pH, osmolality and viscosity.

[0282] The test results are shown in FIGS.

[0283] Figure 3 shows photographs of the formulations. As can be seen, all formulations tested were clear and particle-free, i.e., there was no evidence of significant aggregation.

[0284] Figure 4 shows the measured pH, osmolality, and concentration of ebrasakimab in the formulations. All formulations had a pH of 6.4, an osmolality of approximately 550 mOsm / kg (measurements ranged from 520 to 566 mOsm / kg), and an ebrasakimab concentration of approximately 200 mg / ml (measurements ranged from 192 to 205 mg / ml). This result suggests that these formulations had comparable pH, osmolality, and antibody concentration, meaning that these formulations were suitable for comparative experiments.

[0285] Figures 5 and 6 show the results of viscosity measurements. All formulations successfully achieved a viscosity of 25 cP. Specifically, formulations containing tryptophan, such as formulations F5, F6, F7, and F8, achieved a viscosity of less than 20 cP.

[0286] The above results therefore clearly demonstrate the suitability of the currently claimed high concentration anti-IL13R antibody formulations, such as 200 mg / ml ebrasakimab.

[0287] Example 2 - Round 2 Formulation Screening In the first round of viscosity screening, six formulations were found to be at or below the target viscosity of 20 cP. A second round of viscosity screening was therefore performed to confirm the results from round 1 and to test three new formulation candidates.

[0288] Table 1 below shows the six formulations selected from round 1 screening and their new names assigned in round 2 screening.

[0289] [Table 1]

[0290] Figure 7 shows the compositions of the formulations tested in Round 2 screening. Formulations F7, F8, and F9 are new formulation candidates. F10 is a previously developed ebrasakimab formulation, F46, at 200 mg / ml. The composition of F46 is shown in Table 2 below. This formulation was included as a control for comparison with the currently claimed formulation.

[0291] All formulations were successfully prepared using the same protocol as in Round 1. Details of the preparation method are shown in Figure 8. The formulations were subjected to various tests and measurements following Round 1 screening, such as visual inspection, pH, osmolality and viscosity measurements.

[0292] The results of round 2 screening are shown in Figures 9 to 12.

[0293] Figures 9 and 10 show the visual inspection, pH, and osmolality results of the round 2 screening. The pH, osmolality, and visual appearance of all formulations were found to be acceptable for viscosity testing. Specifically, all formulations were free of visible particles. The control formulation F10 (F46), however, appeared slightly opaque compared to the newly developed formulations.

[0294] Figures 11 and 12 show the results of viscosity measurements from the Round 2 screening. The measured viscosity of the standard (see Figure 12) was found to be 1.4 cP above the expected value (31.4 cP vs. 30 cP), but within the acceptable error range. The viscosity of the F10 formulation was previously measured to be 29.5 cP (n=1) at 200 mg / mL. This formulation was found to be 31.9 cP (n=3) at 203 mg / mL in this screening, suggesting that the method used to measure viscosity is reliable.

[0295] Overall, all formulations except F10 had good viscosities close to or below the target of 20 cP. In particular, formulations with a combination of Arg, Phe, and Trp tended to perform best. All Round 2 formulations are therefore expected to be injectable at room temperature.

[0296] The protein concentration in round 2 was slightly higher than in round 1 (average 203 mg / mL compared to 200 mg / mL in round 1), which may explain the slight increase in viscosity (-1 to 2 cP) of the same formulations tested in round 1.

[0297] The new formulation candidates (F7, F8, F9) are also promising as a small further reduction in viscosity was achieved with F7 and F9 compared to the other round 2 formulations.

[0298] Example 3 - Stability Study Results at 4 Weeks Based on the Round 2 screening results, five formulations were selected for preliminary stability studies, the compositions of which are shown in Figure 13. Formulation 3 was tested at both target ebrasakimab concentrations of 195 mg / ml (F3-195) and 200 mg / ml (F3-200).

[0299] The formulations were stored in vials at either 4°C, 25°C (room temperature), or 40°C (accelerated heat stress conditions) and subjected to various tests after 4 weeks of storage (T=4 weeks). The results of the tests are shown in Figures 14-27.

[0300] Figures 14-16 show the results of visual inspection. There are no signs of visible particle formation in any of the formulations, even after exposure to accelerated heat stress conditions. Formulations stored at 40°C (see Figures 14D and 15D) showed signs of yellowing, with formulations F2, which lacks tryptophan, and F7, which has 20 mM Trp instead of 50 mM Trp, showing slightly less yellowing. Figure 16 shows a comparison of the five current formulations versus a previous ebrasakimab formulation (WP3B). Details of the composition of the previous formulation are provided in Table 2 below.

[0301] [Table 2]

[0302] There was no sign of yellowing in any of the formulations under normal storage conditions, including the WP3B formulation stored at 40° C. Therefore, we believe that the yellowing is likely due to the decomposition of Trp at elevated temperatures.

[0303] Figures 21 and 22 show SE-HPLC results indicating the rate of aggregation, which in turn indicates the physical stability of the formulations. The SE-HPLC results suggest that there were no significant differences between the formulations in the rate of aggregation. All five formulations perform favorably compared to the previous ebrasakimab formulation (WP3B).

[0304] Figures 24 and 25 show the CEX-HPLC results, which indicate the extent of deamination, which in turn indicates the chemical stability of the formulations. These results suggest that there was no significant difference in the rate of chemical degradation (deamination) between the formulations. Unfortunately, the five formulations could not be compared to the previous ebrasakimab formulation (WP3B) because T=4 week data from these formulations was not available.

[0305] Figures 26 and 27 show the results of microflow imaging (MFI) and non-sphericity (non-SPH) analysis. These tests demonstrate the tendency of the formulations to form subvisible particles (SVPs), which in turn indicates the physical stability and quality of the formulations. These results suggest that formulations F2 and F7 exhibit a greater tendency for particle formation. The remaining formulations are highly resistant to particle formation during storage at normal storage temperatures and accelerated stress conditions.

[0306] Importantly, the USP 788 specification for subvisible particles requires no more than 6000 particles / container at >10 pM and no more than 600 particles / container at >25 pM. These results suggest that all formulations tested, including those exposed to accelerated stress conditions, meet the USP 788 specification.

[0307] Overall, the 4-week stability results suggest that formulations with 50 mM Trp are less viscous and more stable (fewer subvisible particles) than those with less or no Trp.

[0308] In summary, based on the 4-week stability data, the new 200 mg / mL formulation shows promising stability compared to the previously developed formulation.

[0309] Example 4 - Stability Study Results at Week 8 After 8 weeks of storage (T=8 weeks), the stability of the five formulations was further evaluated by performing tests similar to those described in Example 3. The results of the tests are shown in Figures 28-38.

[0310] Figures 28-29 show the results of the visual inspection. Compared to the results from week 4, numerous particulates were now visible in formulation F2 when stored at 4° C. and in formulations F2 and F7 when stored at 25° C. The remaining formulations were free of visible particles.

[0311] Figures 30-32 show the pH, concentration, and osmolality of the formulations as measured at T=0, T=4 weeks, and T=8 weeks. These results show that there was no significant change in pH, concentration, and osmolality over the 8-week study period, suggesting that formulations of these embodiments remain stable.

[0312] Figure 33 shows the viscosity results of the formulations as measured at T=0, T=4 weeks, and T=8 weeks. With the exception of formulation F2, all other formulations had viscosity measurements close to or below the target of 20 cP at 8 weeks when stored at 4°C and 25°C. Formulation F3 had the best viscosity, with the 195 mg / ml formulation (F3-195) continuing to exhibit a viscosity below 20 cP even under accelerated stress conditions (40°C).

[0313] Figures 34-35 show the SE-HPLC results at T=8 weeks. These results suggest that all formulations had excellent aggregation stability at 8 weeks when stored at 4°C. When stored at 25°C, all formulations except for formulation F7 showed little loss of purity at 8 weeks.

[0314] Figures 36-37 show the CEX-HPLC results at T=8 weeks. These results suggest that all formulations had excellent chemical stability at 8 weeks when stored at 4°C. When stored at 25°C, all formulations had comparable chemical stability after 8 weeks of storage.

[0315] Figures 38A-38C show the results of MFI and non-SPH analysis. In the >5 pM size range, formulation F2 showed the greatest increase in subvisible particles (SVPs), followed by formulation F7, consistent with the results from T=4 weeks. Visual observation suggests that the SVP content of formulations F2 and F7 strongly correlates with the formation of visible particles (see Figures 28-29). At 8 weeks, formulation F4 also showed an increase in SVP content. A similar stability ranking was also observed for SVPs in the >10 μM and >25 μM size ranges.

[0316] Surprisingly, F3 and F9 showed little increase in SVP content in any size range, a result rarely observed in preparations due to the high sensitivity of the assay.

[0317] In summary, at the 8 week time point, superior formulations are beginning to emerge from the list of five formulation candidates - both F3 and F9 show promising stability combined with acceptable viscosity.

[0318] The presence and concentration of tryptophan appears to be important, as the formulation without Trp (F2) was the least stable during storage compared to the other formulations with 50 mM Trp, and the formulation with 20 mM Trp (F7) had even lower stability. The HPLC data also appear to suggest that at 8 weeks, the overall stability (in terms of both physical and chemical stability) of the 200 mg / mL ebrasakimab formulation was comparable to the previously developed 100 mg / mL ebrasakimab formulation (JHL formulation).

[0319] Importantly, the stability of formulation F3 was demonstrated at both 195 mg / mL and 200 mg / mL, which increases the confidence in the results. Therefore, based on robust stability data, simplicity, and lack of repellency, formulation F3 (20 mM His, 260 mM Arg, 50 mM Trp, 0.02% PS20) appears to be the preferred formulation candidate going forward.

[0320] Example 5 - Stability Study Results at 6 Months (26 Weeks) After 26 weeks of storage (T=26 weeks), the stability of the five formulations was further evaluated by performing tests similar to those described in Example 4. The results of the tests are shown in Figures 39-50.

[0321] Figures 39-40 show the results of the visual inspection. Compared to the eight results, numerous particulates were now visible in both Formulations F2 and F7 when stored at 4° C. and Formulations F2, F4, and F7 when stored at 25° C. The remaining formulations were free of visible particles.

[0322] Figures 41-43 show the pH, concentration, and osmolality of the formulations as measured at T=0, T=4 weeks, T=8 weeks, and T=26 weeks. These results show that there was no significant change in pH, concentration, and osmolality over the 26-week study period, indicating that formulations of these embodiments remain stable.

[0323] Figure 44 shows the viscosity results for the formulations when measured at T=0, T=4 weeks, T=8 weeks, and T=26 weeks. With the exception of Formulation F2, all other formulations had viscosity measurements close to or below the target of 20 cP at 8 weeks when stored at 4°C and 25°C. Formulation F3 continued to have the best viscosity.

[0324] Figures 45-46 show the SE-HPLC results at T=26 weeks. These results suggest that only formulation F7 exhibited a significant decrease in purity at 26 weeks when stored at 4°C. When stored at 25°C, all formulations except formulation F7 showed minimal decrease in purity at 26 weeks.

[0325] Figures 47-48 show the CEX-HPLC results at T=26 weeks. These results suggest that all formulations had excellent chemical stability at 26 weeks when stored at 4°C. When stored at 25°C, all formulations had similar chemical stability after 26 weeks of storage.

[0326] Figures 49-50 show the results of the MFI and non-SPH analysis. In the >5 pM size range, formulation F2 showed the greatest increase in subvisible particles (SVPs), followed by formulation F7, consistent with the results from T=8 weeks.

[0327] In summary, at 26 weeks, these results indicate that formulations F3 and F9 continue to have the best stability. Impressively, there was no sign of visible particle formation in F3 and F9, even after prolonged exposure to accelerated heat stress conditions (25°C).

[0328] The viscosity of all formulations remains stable after 6 months of storage at 2-8°C and 25°C.

[0329] No significant difference was observed in the rate of chemical degradation (deamination) between F3 and F9. F3 and F9 also show a very low tendency for particle formation. SVP content suggests a strong correlation with the formation of visible particles (see, for example, F2 and F7).

[0330] In conclusion, the stability results at T=26 weeks further support formulation F3 as the lead formulation, given its excellent stability at 4°C and even at 25°C.

[0331] Example 6 - Formulation 1 Formulation 1 contains 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 5.8.

[0332] Example 7 - Formulation 2 Formulation 2 contains 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0333] Example 8 – Formulation 3 Formulation 3 contains 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 5.8.

[0334] Example 9 – Formulation 4 Formulation 4 contains 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 5.8.

[0335] Example 10 – Formulation 5 Formulation 5 contains 200 mg / ml ebrasakimab, 50 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.3.

[0336] Example 11 – Formulation 6 Formulation 6 contains 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0337] Example 12 - Formulation 7 Formulation 7 contains 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0338] Example 13 - Formulation 8 Formulation 8 contains 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 5.8.

[0339] Example 14 – Formulation 9 Formulation 9 contains 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.3.

[0340] Example 15 – Formulation 10 Formulation 10 contains 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 5.8.

[0341] Example 16 - Formulation 11 Formulation 11 contains 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0342] Example 17 - Formulation 12 Formulation 12 contains 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.3.

[0343] Example 18 – Formulation 13 Formulation 13 was 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 50 mM tryptophan, 0.02% Tween 20, and the pH of the formulation was 6.8.

[0344] Example 19 – Formulation 14 Formulation 14 is 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, 0.02% Tween 20, and the pH of the formulation is 5.8.

[0345] Example 20 - Formulation 15 Formulation 15 contains 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.3.

[0346] Example 21 – Formulation 16 Formulation 16 is 200 mg / ml ebrasakimab, 35 mM histidine, 150 mM arginine, 80 mM tryptophan, 0.02% Tween 20, and the pH of the formulation is 5.8.

[0347] Example 22 – Formulation 17 Formulation 17 contains 200 mg / ml ebrasakimab, 20 mM histidine, 215 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0348] Example 23 - Formulation 18 Formulation 18 is 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 80 mM tryptophan, 0.02% Tween 20, and the pH of the formulation is 5.8.

[0349] Example 24 – Formulation 19 Formulation 19 contains 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.3.

[0350] Example 25 – Formulation 20 Formulation 20 contains 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0351] Example 26 – Formulation 21 Formulation 21 contains 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0352] Example 27 – Formulation 22 Formulation 22 contains 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0353] Example 28 – Formulation 23 Formulation 23 was 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation was 5.8.

[0354] Example 29 – Formulation 24 Formulation 24 is 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 20 mM tryptophan, 0.02% Tween 20, and the pH of the formulation is 5.8.

[0355] Example 30 - Formulation 25 Formulation 25 contains 200 mg / ml ebrasakimab, 35 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, and the pH of the formulation is 6.8.

[0356] Example 31 – Design of Experiments (DOE) Study The objective of the design of experiments (DOE) study was to evaluate the effect of excipients on the viscosity of ebrasakimab at a 200 mg / mL concentration to determine the optimal formulation design space.

[0357] Materials and Methods Table 3 below details the bulk drug substance (BDS) and formulation parameters.

[0358] [Table 3]

[0359] The 25 formulations listed above in Examples 5-30 will be prepared for the DOE study. The complete list of formulations for the DOE study is shown below in Table 4. Four parameters will be tested: 1. pH 5.8-6.8 2. Histidine concentration: 20-50mM 3. Arginine concentration: 150-280nM 4. Tryptophan concentration: 20-80mM

[0360] [Table 4]

[0361] Sample handling and preparation process 1. Transfer an appropriate amount (35 mL) of BDS to a Spectra / Pro1 dialysis membrane (MWCO 6-8 kD) and first dialyze against 2 x 1000 L of 20 mM histidine, 200 mM arginine at pH 6.5 to remove the sucrose in the buffer. The drug product (DP) formulation contains 0.02% Tween 20, while the dialysis buffer does not contain Tween 20, so a surfactant must be added after dialysis / ultrafiltration. Adjust the pH for lower and higher pH formulations by adding appropriate amounts of 1 M HCl and / or NaOH. 2. Concentrate the dialyzed protein sample to approximately 200 mg / mL by ultrafiltration using an Amicon Ultra-15 30,000 MWCO centrifugal concentrator at 3000 RPM using a Beckman 6KR refrigerated centrifuge. 3. Determine the protein concentration in solution using SoloVPE (A 280 ) to determine the protein concentration. If the protein concentration is below the target value, the bulk solution is further concentrated by ultrafiltration until the target concentration is reached. If the protein concentration is above 205 mg / mL, an appropriate amount of formulation buffer (20 mM histidine, 200 mM Arg at pH 6.5) can be added to reach the target concentration. Once the concentration of the dialyzed bulk drug substance is confirmed to be approximately 200 mg / mL, an appropriate amount of 10% resorbate 20 (PS20) is added to the protein solution so that the final protein solution contains approximately 200 mg / mL ebrasakimab at pH 6.5, 20 mM histidine, 200 mM arginine, and 0.02% PS20. 4. Protein concentration is checked again after adding PS20. 5. Aliquot the concentrated protein solution into 25 separate 2 mL glass vials containing the solid excipients listed in Table 3 to reach the target formulation parameters listed in Table 4. Add the concentrated protein solution to the excipient solids in each individual vial, then mix by gently pipetting / swirling up and down (do not vortex the sample). 6. After the solid excipients have completely dissolved and formed a homogeneous solution, leave the sample at 4-8°C overnight to allow any air bubbles to settle. 7. The next day, each sample is visually inspected on a light box and photographs of the samples are taken against a black and white background to document the physical appearance of the sample, with particular attention to the level of turbidity and the presence of particles. Only formulations without visible particulates and / or phase separation are used for further testing. 8. Following visual inspection, samples that pass inspection are transferred to 1.5 mL Eppendorf tubes and then spun down in a centrifuge at 10K RPM for 10 minutes to remove any air bubbles before further analysis. 9. The supernatant from each sample is carefully removed and then analyzed by various assays in the following order: 1. pH; 2. Osmolality; 3. Viscosity.

[0362] The acceptance criteria is ±0.1 for pH. The osmolality must deviate by less than 10% from the theoretical osmolality value. If a formulation does not meet the specifications for pH or target osmolality, the sample is not submitted for viscosity measurement. Instead, the formulation is reformulated until it meets all target formulation parameters and specifications.

[0363] Analysis of samples The samples are evaluated using the analytical techniques and in the order shown in Table 5 below.

[0364] [Table 5]

[0365] At the end of the experiment, a DoE analysis is performed with one response (viscosity), with a target viscosity of 20 cP.

[0366] The optimal formulation design space is identified, along with the key formulation parameters that affect viscosity and any interactions between these parameters. Expected outputs include Pareto plots, 3D displays of the data, and 2D contour plots showing the optimal design space for response.

[0367] Pareto chart: gives the ranking of the variables tested (i.e., pH, histidine concentration, arginine concentration, and tryptophan concentration). The analysis suggests which formulation variables are most important.

[0368] 3D response surface plots: Showing the effect under various conditions. Revealing the relative performance of different formulations under the same experimental set of conditions, providing an empirical view of the design space.

[0369] Optimization plot: Helps identify formulations that truly optimize viscosity of ebrasakimab 200 mg / ml formulations.

[0370] Danny Chou et al, Formulation and Development Review Sep / October 2016, Automated and rapid methods to assess quality and stability of biologies: recent developments and practical ways to implement them in formulation development, includes a review of DOE approaches and summarizes the types of data outputs that can be generated and how the data can be used to determine the optimal design space.

[0371] High-concentration accelerated stability testing After successful completion of viscosity screening, all formulations that meet the target viscosity (20 cP) are further evaluated in stability studies. Samples are analyzed using the assays and conditions shown in Table 6.

[0372] [Table 6]

Claims

1. 1. A highly concentrated formulation of an anti-IL-13R antibody or antigen-binding fragment thereof, comprising: with 175-250 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, for example 175 mg / ml, 180 mg / ml, 185 mg / ml, 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, 210 mg / ml, 215 mg / ml, 220 mg / ml, 225 mg / ml, 230 mg / ml, 235 mg / ml, 240 mg / ml, 245 mg / ml or 250 mg / ml, in particular 190 mg / ml, 200 mg / ml, 210 mg / ml, 225 mg / ml or 250 mg / ml, for example 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; 5-100 mM tryptophan (15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM, 41 mM, 42 mM, 43 mM, 44 mM, 45 mM, 46 mM, 47 mM, 48 mM, 49 mM, 50 mM, 51 mM, 52 mM, 53 mM, 54 mM, 55 mM, 56 mM, 57 mM, 58 mM, 59 mM, 60 mM, 61 mM, 62 mM, 63 mM, 64 mM, 65 mM, 66 mM, 67 mM, 68 mM, 69 mM, 70 mM, 71 mM, 72 mM, 73 mM, 74 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 101 mM, 102 mM, 103 mM, 104 mM, 105 mM, 106 mM, 107 mM, 108 mM, 109 mM, 110 mM, 111 mM, 11 8mM, 39mM, 40mM, 41mM, 42mM, 43mM, 44mM, 45mM, 46mM, 47mM, 48mM, 49mM, 50mM, 51 mM, 52mM, 53mM, 54mM, 55mM, 56mM, 57mM, 58mM, 59mM, 60mM, 61mM, 62mM, 63mM, 64mM , 65 mM, 66 mM, 67 mM, 68 mM, 69 mM, 70 mM, 71 mM, 72 mM, 73 mM, 74 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM or 100 mM), for example 15 to 75 mM tryptophan, for example 15 to 60 mM, in particular 25 to 50 mM tryptophan, for example 20 mM, 50 mM or 80 mM tryptophan; 140-290 mM arginine, for example 160-290 mM arginine (such as Arg-HCl or Arg-Glu), for example 160 mM, 165 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM , 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM, 270 mM, 275 mM, 280 mM, 285 mM or 290 mM, in particular 150 mM, 185 mM, 215 mM, 225 mM, 250 mM, 260 mM or 280 mM arginine; 0.01 to 0.03% of a non-ionic surfactant (such as a polysorbate), for example 0.01 to 0.03%, for example 0.01%, 0.015%, 0.020%, 0.025% or 0.030%, especially 0.02% w / w; a buffer (such as a histidine buffer), for example a 15-55 mM buffer, for example a 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM or 55 mM histidine buffer; in particular a 20 mM, 35 mM or 50 mM histidine buffer and the pH of the formulation is in the range of 5.5 to 7.2, for example 6.0 to 7.0, for example 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 5.8, 6.3, 6.4, 6.5, 6.6, 6.7 or 6.8; formulation.

2. with 190-210 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof, e.g., 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml, or 210 mg / ml, particularly 200 mg / ml of an anti-IL-13R antibody or antigen-binding fragment thereof; with 25 to 60 mM tryptophan, for example 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, or 60 mM tryptophan, in particular 25 to 50 mM tryptophan; 175-270 mM arginine (such as Arg-HCl or Arg-Glu), for example 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, 220 mM, 225 mM, 230 mM, 235 mM, 240 mM, 245 mM, 250 mM, 255 mM, 260 mM, 265 mM or 270 mM, in particular 200 mM, 210 mM, 225 mM, 235 mM, 250 mM or 260 mM arginine; 0.01 to 0.03% of a non-ionic surfactant, for example 0.01 to 0.03% w / w, for example 0.02% w / w of polysorbate 20 or polysorbate 80; a buffer (such as a histidine buffer, e.g., 20 mM histidine buffer); and the pH of the formulation is in the range of 6.4 to 6.6, for example 6.4, 6.5 or 6.6; The formulation of claim 1.

3. 3. The formulation of claim 1 or 2, comprising 190-210 mg / ml, such as 190 mg / ml, 195 mg / ml, 200 mg / ml, 205 mg / ml or 210 mg / ml of an anti-IL13R antibody or binding fragment thereof.

4. 4. The formulation of claim 1, comprising 200 mg / ml of an anti-IL13R antibody or antigen-binding fragment thereof.

5. 5. A formulation according to any one of claims 1 to 4, comprising 15 to 55 mM tryptophan, such as 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM or 55 mM tryptophan.

6. 6. The formulation of claim 1, comprising 20 mM or 50 mM tryptophan.

7. 7. A formulation according to any one of claims 1 to 6, comprising 185 to 260 mM arginine, such as 185 mM, 195 mM, 205 mM, 215 mM, 225 mM, 235 mM, 245 mM, 255 mM or 260 mM arginine.

8. 8. The formulation of claim 1, comprising 185 mM, 215 mM, 225 mM or 260 mM arginine.

9. 9. A formulation according to any one of claims 1 to 8, comprising 260 mM arginine, such as 260 mM arginine-HCl.

10. 25-175 mM phenylalanine, for example 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM or 1 10. A formulation according to any one of claims 1 to 9 comprising 75 mM phenylalanine, such as 50 to 150 mM phenylalanine, such as 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM or 150 mM phenylalanine.

11. 11. A formulation according to any one of claims 1 to 10, comprising 50 mM, 75 mM, 100 mM, 125 mM or 150 mM phenylalanine, such as 75 mM, 125 mM or 150 mM phenylalanine, in particular 150 mM phenylalanine.

12. 12. A formulation according to any one of claims 1 to 11, comprising 20-50 mM histidine buffer, such as 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM or 50 mM, for example 20 mM or 50 mM histidine buffer.

13. 13. The formulation of any one of claims 1 to 12, comprising 20 mM histidine buffer.

14. 14. A formulation according to any one of claims 1 to 13, comprising 0.02% w / w of a non-ionic surfactant.

15. 5. A formulation according to any one of claims 1 to 4, wherein the non-ionic surfactant is a polysorbate, such as polysorbate 20, 40, 60 or 80, in particular 80.

16. 16. The formulation of any one of claims 1 to 15, wherein the non-ionic surfactant is polysorbate 20.

17. 17. A formulation according to any one of claims 1 to 16, having a viscosity in the range of 10 to 30 cP (mPa.s), e.g. 10 cP, 11 cP, 12 cP, 13 cP, 14 cP, 15 cP, 16 cP, 17 cP, 18 cP, 19 cP, 20 cP, 21 cP, 22 cP, 23 cP, 24 cP, 25 cP, 26 cP, 27 cP, 28 cP, 29 cP or 30 cP, e.g. 15 to 25 cP, in particular 20 cP.

18. 18. A formulation according to any preceding claim, having a pH in the range of 6.4 to 6.7, such as 6.4, 6.5, 6.6 or 6.

7.

19. 260 mM arginine-HCl; 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5 or 6.6; 19. A formulation according to any one of claims 1 to 18.

20. 225 mM arginine-HCl; 75 mM phenylalanine; 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5 or 6.6; 19. A formulation according to any one of claims 1 to 18.

21. 215 mM arginine-HCl; 125 mM phenylalanine; 20 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 and the pH of the formulation is 6.3 to 6.7, for example 6.4, 6.5 or 6.6; 19. A formulation according to any one of claims 1 to 18.

22. 185 mM arginine-HCl; 150 mM phenylalanine; 50 mM tryptophan; 0.02% non-ionic surfactant, e.g., polysorbate 20 and the pH of the formulation is 6.3 to 6.7, for example 6.4 or 6.5; 19. A formulation according to any one of claims 1 to 18.

23. 23. The formulation of any one of claims 1 to 22, wherein the anti-IL13R antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 51, or a sequence at least 95% identical thereto, and a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 53, or a sequence at least 95% identical thereto.

24. 24. The formulation of any one of claims 1 to 23, wherein the anti-IL13R antibody is ebrasakimab (ASLAN004).

25. Formulation 1 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 5.8; Formulation 2 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 6.8; Formulation 3 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 5.8; Formulation 4 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 5.8; Formulation 5 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3; Formulation 6 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 7 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 8 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; Formulation 9 comprising 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3; Formulation 10 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; Formulation 11 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 12 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3; Formulation 13 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 14 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; Formulation 15 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3; Formulation 16 comprising 200 mg / ml ebrasakimab, 35 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; Formulation 17 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 215 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 18 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 280 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; Formulation 19 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.3; Formulation 20 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 260 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 21 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 22 comprising 200 mg / ml ebrasakimab, 20 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 6.8; Formulation 23 comprising 200 mg / ml ebrasakimab, 50 mM histidine, 150 mM arginine, 50 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; Formulation 24 comprising 200 mg / ml ebrasakimab, 35 mM histidine, 280 mM arginine, 20 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is pH 5.8; and Formulation 25 comprising 200 mg / ml ebrasakimab, 35 mM histidine, 215 mM arginine, 80 mM tryptophan, and 0.02% Tween 20, wherein the pH of the formulation is 6.

8.

2. The formulation of claim 1, selected from the group comprising:

26. 26. The formulation of any one of claims 1 to 25, which is stable at refrigerator temperature, for example below 8°C, such as 2-8°C, for example 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, or 1°C, in particular 4°C.

27. 27. A formulation according to any one of claims 1 to 26 which is stable at room temperature, for example 15 to 25°C, such as 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C or 25°C, in particular 25°C.

28. 28. The formulation of any one of claims 1 to 27, which is stable for at least 1 month, such as at least 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months or 36 months.

29. 29. A formulation according to any one of claims 1 to 28 for use in treatment, such as for use in the treatment of inflammation or an autoimmune disease, such as for treating chronic inflammation.

30. 30. A formulation according to any one of claims 1 to 29 for use in the treatment of atopic dermatitis.

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