US 20150071922A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0071922 A1 Larson et al. (43) Pub. Date: Mar. 12, 2015

(54) LIQUID PROTEIN FORMULATIONS application No. 61/946,436, ?led on Feb. 28, 2014, CONTAINING IONIC LIQUIDS provisional application No. 61/943,197, ?led on Feb. 21, 2014, provisional application No. 61/940,227, (71) Applicant: Arsia Therapeutics, Inc., Waltham, MA ?led on Feb. 14, 2014, provisional application No. (Us) 61/876,621, ?led on Sep. 11,2013. (72) Inventors: Alyssa M. Larson, Dana Point, CA Publication Classi?cation (US); Kevin Love, Boston, MA (US); Alisha K. Weight, Mill Creek, WA (US); (51) Int. Cl. Alan Crane, Waban, MA (US); Robert A61K 47/06 (2006.01) S. Langer, NeWton, MA (US); A61K 39/395 (2006.01) Alexander M. Klibanov, Boston, MA (52) U.S. Cl. (Us) CPC ...... A61K 47/06 (2013.01); A61K39/395 (2013.01) (21) App1.No.: 14/4s4,053 USPC ...... 424/1331 (22) Filed: Sep. 11, 2014 (57) ABSTRACT Concentrated, low-viscosity, low-volume liquid pharmaceu Related U.S. Application Data tical formulations of proteins have been developed. Such (60) Provisional application No. 62/030,521, ?led on Jul. formulations can be rapidly and conveniently administered 29, 2014, provisional application No. 62/026,497, by subcutaneous or intramuscular injection, rather than by ?led on Jul. 18, 2014, provisional application No. lengthy intravenous infusion. These formulations include 62/008,050, ?led on Jun. 5, 2014, provisional applica low-molecular-weight and/or high-molecular-weight pro tion No. 61/988,005, ?led on May 2, 2014, provisional teins, such as mAbs, and viscosity-reducing ionic liquids. US 2015/0071922 A1 Mar. 12, 2015

LIQUID PROTEIN FORMULATIONS cause pain at the site of inj ection, are often imprecise, and/or CONTAINING IONIC LIQUIDS may have decreased chemical and/or physical stability. [0005] These characteristics result in manufacturing, stor CROSS-REFERENCE TO RELATED age, and usage requirements that can be challenging to APPLICATIONS achieve, in particular for formulations having high concen trations of high-molecular-weight proteins, such as mAbs. [0001] This application claims priority to and the bene?t of All protein therapeutics to some extent are subject to physical U.S. Provisional Application No. 62/030,521, ?led Jul. 29, and chemical instability, such as aggregation, denaturation, 2014, entitled “Low- Viscosity Protein Formulations Contain crosslinking, deamidation, isomerization, oxidation, and ing Hydrophobic Salts;” U.S. Provisional Application No. clipping (Wang et al., J. Pharm. Sci. 9611-26, 2007). Thus, 62/026,497, ?led Jul. 18, 2014, entitled “Low- Viscosity Pro optimal formulation development is paramount in the devel tein Formulations Containing GRAS Viscosity-Reducing opment of commercially viable protein pharmaceuticals. Agents,"’ U.S. Provisional Application No. 62/008,050, ?led [0006] High protein concentrations pose challenges relat Jun. 5, 2014, entitled “Low-Viscosity Protein Formulations ing to the physical and chemical stability of the protein, as Containing Ionic Liquids,"’ U.S. Provisional Application No. well as dif?culty with manufacture, storage, and delivery of 61/988,005, ?led May 2, 2014, entitled “Low- Viscosity Pro the protein formulation. One problem is the tendency of pro tein Formulations Containing Organophosphates,"’ U.S. Pro teins to aggregate and form particulates during processing visional Application No. 61/946,436, ?led Feb. 28, 2014, and/or storage, which makes manipulations during further entitled “Concentrated, Low- Viscosity In?iximab Formula processing and/or delivery dif?cult. Concentration-depen tions;” U.S. Provisional Application No. 61/943,197, ?led dent degradation and/ or aggregation are major challenges in Feb. 21, 2014, entitled “Concentrated, Low- Viscosity, High developing protein formulations at higher concentrations. In Molecular-Weight-Protein Formulations;” U.S. Provisional addition to the potential for non-native protein aggregation Application No. 61/940,227, ?led Feb. 14, 2014, entitled and particulate formation, reversible self-association in aque “Concentrated, Low- Viscosity High-Molecular-Weight Pro ous solutions may occur, which contributes to, among other tein Formulations,"’ and U.S. Provisional Application No. things, increased viscosity that complicates delivery by inj ec 61,876,621, ?led Sep. 11, 2013, entitled “Concentrated, tion. (See, for example, Steven J. Shire et al., J. Pharm. Sci. Low- Viscosity, High-Molecular- Weight Protein Formula 93:1390-1402, 2004.) Increased viscosity is one of the key tions,” the disclosures of which are expressly incorporated challenges encountered in concentrated protein compositions hereby by reference. affecting both production processes and the ability to readily deliver such compositions by conventional means. (See, for FIELD OF THE INVENTION example, I. Jezek et al., Advanced Drug Delivery Reviews [0002] The invention is generally in the ?eld of injectable 63:1107-1117, 2011.) low-viscosity pharmaceutical formulations of highly concen [0007] Highly viscous liquid formulations are dif?cult to trated proteins and methods of making and using thereof. manufacture, draw into a syringe, and inject subcutaneously or intramuscularly. The use of force in manipulating the vis BACKGROUND OF THE INVENTION cous formulations can lead to excessive frothing, which may further denature and inactivate the therapeutically active pro [0003] Monoclonal antibodies (mAbs) are important pro tein. High viscosity solutions also require larger diameter tein-based therapeutics for treating various human diseases needles for injection and produce more pain at the injection such as cancer, infectious diseases, in?ammation, and site. autoimmune diseases. More than 20 mAb products have been [0008] Currently available commercial mAb products approved by the U.S. Food and Drug Administration (FDA), administered by SC or IM injection are usually formulated in and approximately 20% of all biopharmaceuticals currently aqueous buffers, such as a phosphate or L-histidine buffer, being evaluated in clinical trials are mAbs (Daugherty et al., with excipients or surfactants, such as mannitol, sucrose, Adv. DrugDeliv. Rev. 58:686-706, 2006; and Buss et al., Curr. lactose, trehalose, POLOXAMER® (nonionic triblock Opinion in Pharmacol. 121615-622, 2012). copolymers composed of a central hydrophobic chain of [0004] mAb-based therapies are usually administered polyoxypropylene (poly(propylene oxide)) ?anked by two repeatedly over an extended period of time and require sev hydrophilic chains of polyoxyethylene (poly(ethylene eral mg/kg dosing. Antibody solutions or suspensions can be oxide))) or POLYSORBATE® 80 (PEG(80)sorbitan mono administered via parenteral routes, such as by intravenous laurate), to prevent aggregation and improve stability. (IV) infusions, and subcutaneous (SC) or intramuscular (IM) Reported antibody concentrations formulated as described injections. The SC or IM routes reduce the treatment cost, above are typically up to about 100 mg/mL (Wang et al., J. increase patient compliance, and improve convenience for Pharm. Sci. 9611-26, 2007). patients and healthcare providers during administration com [0009] U.S. Pat. No. 7,758,860 describes reducing the vis pared to the IV route. To be effective and pharrnaceutically cosity in formulations of low-molecular-weight proteins acceptable, parenteral formulations should preferably be ster using a buffer and a viscosity-reducing inorganic salt, such as ile, stable, injectable (e.g., via a syringe), and non-irritating at calcium chloride or magnesium chloride. These same salts, the site of injection, in compliance with FDA guidelines. however, showed little effect on the viscosity of a high-mo Because of the small volumes required for subcutaneous lecular-weight antibody (IMA-638) formulation. As (usually under about 2 mL) and intramuscular (usually under described in U.S. Pat. No. 7,666,413, the viscosity ofaqueous about 5 mL) injections, these routes of administration for formulations of high-molecular-weight proteins has been high-dose protein therapies require concentrated protein reduced by the addition of such salts as arginine hydrochlo solutions. These high concentrations often result in very vis ride, sodium thiocyanate, ammonium thiocyanate, ammo cous formulations that are dif?cult to administer by injection, nium sulfate, ammonium chloride, calcium chloride, Zinc US 2015/0071922 A1 Mar. 12, 2015

chloride, or sodium acetate in a concentration of greater than pharmaceutically important mAbs, on the other hand, can about 100 mM or, as described in US. Pat. No. 7,740,842, by exceed 1,000 cP at therapeutically relevant concentrations. addition of organic or inorganic acids. However, these salts do [0014] It is not a trivial matter to control aggregation and not reduce the viscosity to a desired level and in some cases viscosity in high-concentration mAb solutions (EP 2538973). make the formulation so acidic that it is likely to cause pain at This is evidenced by the few mAb products currently on the the site of injection. market as high-concentration formulations (>100 mg/mL) [0010] US. Pat. No. 7,666,413 describes reduced-viscosity (EP 2538973). formulations containing speci?c salts and a reconstituted [0015] The references cited above demonstrate that while anti-IgE mAb, but with a maximum antibody concentration many groups have attempted to prepare low -viscosity formu of only up to about 140 mg/mL. US. Pat. No. 7,740,842 lations of mAbs and other therapeutically important proteins, describes E25 anti-IgE mAb formulations containing acetate/ a truly useful formulation for many proteins has not yet been acetic acid buffer with antibody concentrations up to 257 achieved. Notably, many of the above reports employ agents mg/mL. The addition of salts such as NaCl, CaClZ, or MgCl2 for which safety and toxicity pro?les have not been fully was demonstrated to decrease the dynamic viscosity under established. These formulations would therefore face a higher high-shear conditions; however, at low-shear the salts pro regulatory burden prior to approval than formulations con duced an undesirable and dramatic increase in the dynamic taining compounds known to be safe. Indeed, even if a com viscosity. Additionally, inorganic salts such as NaCl may pound were to be shown to substantially reduce viscosity, the lower solution viscosity and/or decrease aggregation (EP compound may ultimately be unsuitable for use in a formu 1981824). lation intended for injection into a human. [0011] Non-aqueous antibody or protein formulations have [0016] Many pharmaceutically important high-molecular also been described. WO2006/071693 describes a non-aque weight proteins, such as mAbs, are currently administered via ous suspension of up to 100 mg/mL mAb in a formulation IV infusions in order to deliver therapeutically effective having a viscosity enhancer (polyvinylpyrrolidone, PVP) and amounts of protein due to problems with high viscosity and a solvent (benzyl benzoate or PEG 400). WO2004/089335 other properties of concentrated solutions of large proteins. describes 100 mg/mL non-aqueous lysozyme suspension for For example, to provide a therapeutically effective amount of mulations containing PVP, glycofurol, benzyl benzoate, ben many high-molecular-weight proteins, such as mAbs, in vol zyl alcohol, or PEG 400. US2008/0226689A1 describes 100 umes less than about 2 mL, protein concentrations greater mg/mL human growth hormone (hGH) single phase, three than 150 mg/mL are often required. vehicle component (polymer, surfactant, and a solvent), non [0017] It is, therefore, an object of the present invention to aqueous, viscous formulations. US. Pat. No. 6,730,328 provide concentrated, low-viscosity liquid formulations of describes non-aqueous, hydrophobic, non-polar vehicles of pharmaceutically important proteins, especially high-mo low reactivity, such as per?uorodecalin, for protein formula lecular-weight proteins, such as mAbs. tions. These formulations are non-optimal and have high [0018] It is a further object of the present invention to viscosities that impair processing, manufacturing and injec provide concentrated low-viscosity liquid formulations of tion; lead to the presence of multiple vehicle components in proteins, especially high-molecular-weight proteins, such as the formulations; and present potential regulatory challenges mAbs, capable of delivering therapeutically effective associated with using polymers not yet approved by the FDA. amounts of these proteins in volumes useful for SC and IM [0012] Alternative non-aqueous protein or antibody formu injections. lations have been described using organic solvents, such as [0019] It is a further object of the present invention to benzyl benzoate (Miller et al., Langmuir 26:1067-1074, provide the concentrated liquid formulations of proteins, 2010), benzyl acetate, ethanol, or methyl ethyl ketone (Srini especially high-molecular-weight proteins, such as mAbs, vasan et al., Pharm. Res. 30:1749-1757, 2013). In both with low viscosities that can improve injectability and/or instances, viscosities of less than 50 centipoise (cP) were patient compliance, convenience, and comfort. achieved upon formulation at protein concentrations of at [0020] It is also an object of the present invention to provide least about 200 mg/mL. US. Pat. No. 6,252,055 describes methods for making and storing concentrated, low-viscosity mAb formulations with concentrations ranging from 100 formulations of proteins, especially high-molecular-weight mg/mL up to 257 mg/mL. Formulations with concentrations proteins, such as mAbs. greater than about 189 mg/mL demonstrated dramatically [0021] It is an additional object of the present invention to increased viscosities, low recovery rates, and dif?culty in provide methods of administering low-viscosity, concen processing. US. Patent Application Publication No. 2012/ trated liquid formulations of proteins, especially high-mo 0230982 describes antibody formulations with concentra lecular-weight proteins, such as mAbs. tions of 100 mg/mL to 200 mg/mL. None of these formula tions are low enough viscosity for ease of injection. [0022] It is an additional object of the present invention to provide methods for processing reduced-viscosity, high-con [0013] Du and Klibanov (Biotechnology and Bioengineer centration biologics with concentration and ?ltration tech ing 108:632-636, 2011) described reduced viscosity of con niques known to those skilled in the art. centrated aqueous solutions of bovine serum albumin with a maximum concentration up to 400 mg/mL and bovine SUMMARY OF THE INVENTION gamma globulin with a maximum concentration up to 300 mg/mL. Guo et al. (Pharmaceutical Research 29:3102-3109, [0023] Concentrated, low-viscosity, low-volume liquid 2012) described low-viscosity aqueous solutions of four pharmaceutical formulations of proteins have been devel model mAbs achieved using hydrophobic salts. The mAb oped. Such formulations can be rapidly and conveniently formulation employed by Guo had an initial viscosity, prior to administered by subcutaneous or intramuscular injection, adding salts, no greater than 73 cP. The viscosities of many rather than by lengthy intravenous infusion. These formula US 2015/0071922 A1 Mar. 12, 2015

tions include low-molecular-weight and/or high-molecular be an antibody, such as a mAb, or a PEGylated or otherwise weight proteins, such as mAbs, and viscosity-reducing ionic a derivatized form thereof. Preferred mAbs include natali liquids. Zumab (TYSABRI®), cetuximab (ERBITUX®), bevaci [0024] The concentration of proteins is between about 10 Zumab (AVASTIN®), trastuzumab (HERCEPTIN®), in?ix mg/mL and about 5,000 mg/mL, more preferably from about imab (REMICADE®), rituximab (RITUXAN®), 100 mg/mL to about 2,000 mg/mL. In some embodiments, panitumumab (VECTIBIX®), ofatumumab (ARZERRA®), the concentration of proteins is between about 100 mg/mL to and biosimilars thereof. The high-molecular weight protein, about 500 mg/mL, more preferably from about 300 mg/mL to optionally PEGylated, can be an enzyme. Other proteins and about 500 mg/mL. Formulations containing proteins and vis mixtures of proteins may also be formulated to reduce their cosity-reducing ionic liquids are stable when stored at a tem viscosity. perature of 40 C., for a period of at least one month, preferably [0028] In some embodiments, the protein and viscosity at least two months, and most preferably at least three months. reducing ionic liquid(s) are provided in a lyophilized dosage The viscosity of the formulation is less than about 75 cP, unit, sized for reconstitution with a sterile aqueous pharma preferably below 50 cP, and most preferably below 20 cP at ceutically acceptable vehicle, to yield the concentrated low about 250 C. In some embodiments, the viscosity is less than viscosity liquid formulations. The presence of the viscosity about 15 cP or even less than or about 10 cP at about 250 C. In reducing ionic liquid(s) facilitates and/ or accelerates the certain embodiments, the viscosity of the formulation is about reconstitution of the lyophilized dosage unit compared to a 10 cP. Formulations containing proteins and ionic liquids lyophilized dosage unit not containing a viscosity-reducing typically are measured at shear rates from about 0.6 s‘1 to ionic liquid. about 450 s_l, and preferably from about 2 s'1 to about 400 [0029] Methods are provided herein for preparing concen s_1, when measured using a cone and plate viscometer. For trated, low-viscosity liquid formulations of high-molecular mulations containing proteins and viscosity-reducing ionic weight proteins such as mAbs, as well as methods for storing liquids typically are measured at shear rates from about 3 s—1 the low-viscosity, high-concentration protein formulations, to about 55,000 s_l, and preferably from about 20 s'1 to about and for administration thereof to patients. In another embodi 2,000 s_l, when measured using a micro?uidic viscometer. ment, the viscosity-reducing ionic liquid is added to facilitate [0025] The viscosity of the protein formulation is reduced processing (e.g., pumping, concentration, and/ or ?ltration) by the presence of one or more viscosity-reducing ionic liquid by reducing the viscosity of the protein solutions. (s). Unless speci?cally stated otherwise, the term “ionic liq uid” includes both single compounds and mixtures of more DETAILED DESCRIPTION OF THE INVENTION than one ionic liquid. It is preferred that the viscosity-reduc ing ionic liquid(s) is present in the formulation at a concen I. De?nitions tration less than about 1.0 M, preferably less than about 0.50 [0030] The term “protein,” as generally used herein, refers M, more preferably less than about 0.30 M, and most prefer to a polymer of amino acids linked to each other by peptide ably less than about 0.15 M. The formulations can have a bonds to form a polypeptide for which the chain length is viscosity that is at least about 30% less, preferably at least suf?cient to produce at least a detectable tertiary structure. about 50% less, most preferably at least about 75% less, than Proteins having a molecular weight (expressed in kDa the viscosity of the corresponding formulation under the wherein “Da” stands for “Daltons” and 1 kDa:1,000 Da) same conditions except for replacement of the viscosity-re greater than about 100 kDa may be designated “high-molecu ducing ionic liquid with an appropriate buffer or salt of about lar-weight proteins,” whereas proteins having a molecular the same concentration. In some embodiments, a low-viscos weight less than about 100 kDa may be designated “low ity formulation is provided where the viscosity of the corre molecular-weight proteins.” The term “low-molecular sponding formulation without the viscosity-reducing ionic weight protein” excludes small peptides lacking the requisite liquid is greater than about 200 cP, greater than about 500 cP, of at least tertiary structure necessary to be considered a or even above about 1,000 cP. In a preferred embodiment, the protein. Protein molecular weight may be determined using shear rate of the formulation is at least about 0.5 s_l, when standard methods known to one skilled in the art, including, measured using a cone and plate viscometer or at least about but not limited to, mass spectrometry (e.g., ESI, MALDI) or 1.0 s_l, when measured using a micro?uidic viscometer. calculation from known amino acid sequences and glycosy [0026] The pharmaceutically acceptable liquid formula lation. Proteins can be naturally occurring or non-naturally tions contain one or more ionic liquids in an effective amount occurring, synthetic, or semi-synthetic. to signi?cantly reduce the viscosity of the protein, e. g., mAb [0031] “Essentially pure protein(s)” and “substantially formulation. Representative ionic liquids include 4-(3-butyl pure protein(s)” are used interchangeably herein and refer to 1-imidazolio)-1-butane sulfonate (BIM), 1-butyl-3-meth a composition comprising at least about 90% by weight pure ylimidazolium methanesulfonate (BMI Mes), 1-ethyl-1-me protein, preferably at least about 95% pure protein by weight. thylmorpholinium methylcarbonate, (EMMC) and 1 -butyl-1 - “Essentially homogeneous” and “substantially homoge methylpyrrolidinium chloride (BMP Chloride), at neous” are used interchangeably herein and refer to a com concentrations preferably between about 0.10 and about 0.50 position wherein at least about 90% by weight of the protein M, equivalent to about 20-150 mg/mL. The resultant formu present is a combination of the monomer and reversible di lations can exhibit Newtonian ?ow characteristics. and oligo-meric associates (not irreversible aggregates), pref [0027] For embodiments in which the protein is a “high erably at least about 95%. molecular-weight protein”, the “high-molecular-weight pro [0032] The term “antibody,” as generally used herein, tein,” may have a molecular weight between about 100 kDa broadly covers mAbs (including full-length antibodies which and about 1,000 kDa, preferably between about 120 kDa and have an immunoglobulin Fc region), antibody compositions about 500 kDa, and most preferably between about 120 kDa with polyepitopic speci?city, bispeci?c antibodies, diabod and about 250 kDa. The high-molecular-weight protein can ies, and single-chain antibody molecules, as well as antibody US 2015/0071922 A1 Mar. 12, 2015

fragments (e.g., Fab, Fab', F(ab')2, and Fv), single domain and another ?uid takes 400 s, the second ?uid is called twice antibodies, multivalent single domain antibodies, Fab fusion as viscous as the ?rst on a kinematic viscosity scale. The proteins, and fusions thereof. dimension of kinematic viscosity is length2/time. Commonly, [0033] The term “monoclonal antibody” or “mAb,” as gen kinematic viscosity is expressed in centiStokes (cSt). The SI erally used herein, refers to an antibody obtained from a unit of kinematic viscosity is mm2/ s, which is equal to 1 cSt. population of substantially homogeneous antibodies, i.e., the The “absolute viscosity,” sometimes called “dynamic viscos individual antibodies comprising the population are identical, ity” or “simple viscosity,” is the product of kinematic viscos except for possible naturally occurring mutations that may be ity and ?uid density. Absolute viscosity is expressed in units present in minor amounts. Monoclonal antibodies are highly of centipoise (cP). The SI unit of absolute viscosity is the speci?c, being directed against a single epitope. These are milliPascal-second (mPa-s), where 1 cP:1 mPa-s. Viscosity typically synthesized by culturing hybridoma cells, as may be measured by using, for example, a viscometer at a described by Kohler et al. (Nature 256: 495, 1975), or may be given shear rate or multiple shear rates. An “extrapolated made by recombinant DNA methods (see, e. g., US. Pat. No. zero-shear” viscosity can be determined by creating a best ?t 4,816,567), or isolated from phage antibody libraries using line of the four highest-shear points on a plot of absolute the techniques described in Clackson et al. (Nature 352: 624 viscosity versus shear rate, and linearly extrapolating viscos 628, 1991) and Marks et al. (J. Mol. Biol. 222: 581-597, ity back to zero-shear. Alternatively, for a Newtonian ?uid, 1991), for example. As used herein, “mAbs” speci?cally viscosity can be determined by averaging viscosity values at include derivatized antibodies, antibody-drug conjugates, multiple shear rates. Viscosity can also be measured using a and “chimeric” antibodies in which a portion of the heavy micro?uidic viscometer at single or multiple shear rates (also and/or light chain is identical with or homologous to corre called ?ow rates), wherein absolute viscosity is derived from sponding sequences in antibodies derived from a particular a change in pressure as a liquid ?ows through a channel. species or belonging to a particular antibody class or subclass, Viscosity equals shear stress over shear rate. Viscosities mea while the remainder of the chain(s) is (are) identical with or sured with micro?uidic viscometers can, in some embodi homologous to corresponding sequences in antibodies ments, be directly compared to extrapolated zero-shear vis derived from another species or belonging to another anti cosities, for example those extrapolated from viscosities body class or subclass, as well as fragments of such antibod measured at multiple shear rates using a cone and plate vis ies, so long as they exhibit the desired biological activity cometer. (US. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. [0038] “Shear rate” refers to the rate of change of velocity Sci. USA 81:6851-6855, 1984). at which one layer of ?uid passes over an adjacent layer. The [0034] An “antibody fragment” comprises a portion of an velocity gradient is the rate of change of velocity with dis intact antibody, including the antigen binding and/ or the vari tance from the plates. This simple case shows the uniform able region of the intact antibody. Examples of antibody velocity gradient with shear rate (vl—v2)/h in units of (cm/ fragments include Fab, Fab', F(ab')2, and Fv fragments; dia sec)/(cm):1/sec. Hence, shear rate units are reciprocal sec bodies; linear antibodies (see US. Pat. No. 5,641,870; Zapata onds or, in general, reciprocal time. For a micro?uidic vis et al., Protein Eng. 8:1057-1062, 1995); single-chain anti cometer, change in pressure and ?ow rate are related to shear body molecules; multivalent single domain antibodies; and rate. “Shear rate” refers to the speed with which a material is multispeci?c antibodies formed from antibody fragments. deformed. Formulations containing proteins and viscosity [0035] “Humanized” forms of non-human (e.g., murine) lowering agents are typically measured at shear rates ranging antibodies are chimeric immunoglobulins, immunoglobulin from about 0.5 s'1 to about 200 s'1 when measured using a chains, or fragments thereof (such as Fv, Fab, Fab', F(ab')2, or cone and plate viscometer and a spindle appropriately chosen other antigen-binding subsequences of antibodies) of mostly by one skilled in the art to accurately measure viscosities in human sequences, which contain minimal sequences derived the viscosity range of the sample of interest (i.e., a sample of from non-human immunoglobulin. (See, e.g., Jones et al., 20 cP is most accurately measured on a CPE40 spindle a?ixed Nature 321:522-525, 1986; Reichmann et al., Nature 332: to a DV2T viscometer (Brook?eld)); greater than about 20 s—1 323-329, 1988; and Presta, Curr. Op. Struct. Biol. 2:593-596, to about 3,000 s‘1 when measured using a micro?uidic vis 1 992 .) cometer. [0036] “Rheology” refers to the study of the deformation [0039] For classical “Newtonian” ?uids, as generally used and ?ow of matter. herein, viscosity is essentially independent of shear rate. For [0037] “Viscosity” refers to the resistance of a substance “non-Newtonian ?uids,” however, viscosity either decreases (typically a liquid) to ?ow. Viscosity is related to the concept or increases with increasing shear rate, e.g., the ?uids are of shear force; it can be understood as the effect of different “shear thinning” or “shear thickening”, respectively. In the layers of the ?uid exerting shearing force on each other, or on case of concentrated (i.e., high-concentration) protein solu other surfaces, as they move against each other. There are tions, this may manifest as pseudoplastic shear-thinning several measures of viscosity. The units of viscosity are behavior, i.e., a decrease in viscosity with shear rate. Ns/m2, known as Pascal-seconds (Pa-s). Viscosity can be [0040] The term “chemical stability,” as generally used “kinematic” or “absolute”. Kinematic viscosity is a measure herein, refers to the ability of the protein components in a of the rate at which momentum is transferred through a ?uid. formulation to resist degradation via chemical pathways, It is measured in Stokes (St). The kinematic viscosity is a such as oxidation, deamidation, or hydrolysis. A protein for measure of the resistive ?ow of a ?uid under the in?uence of mulation is typically considered chemically stable if less than gravity. When two ?uids of equal volume and differing vis about 5% of the components are degraded after 24 months at cosity are placed in identical capillary viscometers and 4° C. allowed to ?ow by gravity, the more viscous ?uid takes longer [0041] The term “physical stability,” as generally used than the less viscous ?uid to ?ow through the capillary. If, for herein, refers to the ability of a protein formulation to resist example, one ?uid takes 200 seconds (s) to complete its ?ow physical deterioration, such as aggregation. A formulation US 2015/0071922 A1 Mar. 12, 2015

that is physically stable forms only an acceptable percentage subsequent storage. Exemplary lyoprotectants include sugars of irreversible aggregates (e.g., dimers, trimers, or other and their corresponding sugar alcohols, such as sucrose, lac aggregates) of the bioactive protein agent. The presence of tose, trehalose, dextran, erythritol, arabitol, xylitol, sorbitol, aggregates may be assessed in a number of ways, including by and mannitol; amino acids, such as arginine or histidine; measuring the average particle size of the proteins in the lyotropic salts, such as magnesium sulfate; polyols, such as formulation by means of dynamic light scattering. A formu propylene glycol, glycerol, poly(ethylene glycol), or poly lation is considered physically stable if less than about 5% (propylene glycol); and combinations thereof. Additional irreversible aggregates are formed after 24 months at 4° C. exemplary lyoprotectants include gelatin, dextrins, modi?ed Acceptable levels of aggregated contaminants ideally would starch, and carboxymethyl cellulose. Preferred sugar alcohols be less than about 2%. Levels as low as about 0.2% are are those compounds obtained by reduction of mono- and achievable, although approximately 1% is more typical. di-saccharides, such as lactose, trehalose, maltose, lactulose, [0042] The term “stable formulation,” as generally used and maltulose. Additional examples of sugar alcohols are herein, means that a formulation is both chemically stable and glucitol, maltitol, lactitol and isomaltulose. The lyoprotectant physically stable. A stable formulation may be one in which is generally added to the pre-lyophilized formulation in a more than about 95% of the bioactive protein molecules “lyoprotecting amount.” This means that, following lyo retain bioactivity in a formulation after 24 months of storage philization of the protein in the presence of the lyoprotecting at 4° C., or equivalent solution conditions at an elevated amount of the lyoprotectant, the protein essentially retains its temperature, such as one month storage at 40° C. Various physical and chemical stability and integrity. analytical techniques for measuring protein stability are [0047] A “diluent” or “carrier,” as generally used herein, is available in the art and are reviewed, for example, in Peptide a pharmaceutically acceptable (i.e., safe and non-toxic for and Protein Drug Delivery, 247-301, Vincent Lee, Ed., Mar administration to a human or another mammal) and useful cel Dekker, Inc., New York, N.Y. (1991) and Jones, A., Adv. ingredient for the preparation of a liquid formulation, such as Drug Delivery Revs. 10:29-90, 1993. Stability can be mea an aqueous formulation reconstituted after lyophilization. sured at a selected temperature for a certain time period. For Exemplary diluents include sterile water, bacteriostatic water rapid screening, for example, the formulation may be kept at for injection (BWFI), a pH buffered solution (e. g., phosphate 40° C., for 2 weeks to one month, at which time residual buffered saline), sterile saline solution, Ringer’s solution or biological activity is measured and compared to the initial dextrose solution, and combinations thereof. condition to assess stability. When the formulation is to be stored at 2° C.-8° C., generally the formulation should be [0048] A “preservative” is a compound which can be added stable at 30° C. or 40° C. for at least one month and/ or stable to the formulations herein to reduce contamination by and/or at 2° C.-8° C. for at least 2 years. When the formulation is to action of bacteria, fungi, or another infectious agent. The be stored at room temperature, about 25° C., generally the addition of a preservative may, for example, facilitate the formulation should be stable for at least 2 years at about 25° production of a multi-use (multiple-dose) formulation. C. and/or stable at 40° C. for at least about 6 months. The Examples of potential preservatives include octadecyldim extent of aggregation following lyophilization and storage ethylbenzylammonium chloride, hexamethonium chloride, can be used as an indicator of protein stability. In some benzalkonium chloride (a mixture of alkylbenzyldimethy embodiments, the stability is assessed by measuring the par lammonium chlorides in which the alkyl groups are long ticle size of the proteins in the formulation. In some embodi chained), and benzethonium chloride. Other types of preser ments, stability may be assessed by measuring the activity of vatives include aromatic alcohols such as phenol, butyl and a formulation using standard biological activity or binding benzyl alcohol, alkyl parabens such as methyl or propyl para assays well within the abilities of one ordinarily skilled in the ben, catechol, resorcinol, cyclohexanol, 3-pentanol, and art. m-cresol. [0043] The term protein “particle size,” as generally used [0049] A “bulking agent,” as generally used herein, is a herein, means the average diameter of the predominant popu compound which adds mass to a lyophilized mixture and lation of bioactive molecule particulates, or particle size dis contributes to the physical structure of the lyophilized cake tributions thereof, in a formulation as determined by using (e.g. facilitates the production of an essentially uniform lyo well known particle sizing instruments, for example, dynamic philized cake which maintains an open pore structure). Exem light scattering, SEC (size exclusion chromatography), or plary bulking agents include mannitol, glycine, lactose, other methods known to one ordinarily skilled in the art. modi?ed starch, poly(ethylene glycol), and sorbitol. [0044] The term “concentrated” or “high-concentration”, [0050] A “therapeutically effective amount” is the lowest as generally used herein, describes liquid formulations hav concentration required to effect a measurable improvement or ing a ?nal concentration of protein greater than about 10 prevention of any symptom or a particular condition or dis mg/mL, preferably greater than about 50 mg/mL, more pref order, to effect a measurable enhancement of life expectancy, erably greater than about 100 mg/mL, still more preferably or to generally improve patient quality of life. The therapeu greater than about 200 mg/mL, or most preferably greater tically effective amount is dependent upon the speci?c bio than about 250 mg/mL. logically active molecule and the speci?c condition or disor [0045] A “reconstituted formulation,” as generally used der to be treated. Therapeutically effective amounts of many herein, refers to a formulation which has been prepared by proteins, such as the mAbs described herein, are well known dissolving a dry powder, lyophilized, spray-dried or solvent in the art. The therapeutically effective amounts of proteins precipitated protein in a diluent, such that the protein is dis not yet established or for treating speci?c disorders with solved or dispersed in aqueous solution for administration. known proteins, such as mAbs, to be clinically applied to treat [0046] A “lyoprotectant” is a substance which, when com additional disorders may be determined by standard tech bined with a protein, signi?cantly reduces chemical and/or niques which are well within the craft of a skilled artisan, such physical instability of the protein upon lyophilization and/or as a physician. US 2015/0071922 A1 Mar. 12, 2015

[0051] The term “inj ectability” or “syringeability,” as gen [0054] The term “reduced-viscosity formulation,” as gen erally used herein, refers to the injection performance of a erally used herein, refers to a liquid formulation having a high pharmaceutical formulation through a syringe equipped with concentration of a high-molecular-weight protein, such as a an 18-32 gauge needle, optionally thin walled. Injectability mAb, or a low-molecular-weight protein that is modi?ed by depends upon factors such as pressure or force required for the presence of one or more additives to lower the viscosity, as injection, evenness of ?ow, aspiration qualities, and freedom compared to a corresponding formulation that does not con from clogging. Inj ectability of the liquid pharmaceutical for tain the viscosity-lowering additive(s). mulations may be assessed by comparing the injection force [0055] The term “osmolarity,” as generally used herein, of a reduced-viscosity formulation to a standard formulation refers to the total number of dissolved components per liter. without added viscosity-lowering agents. The reduction in Osmolarity is similar to molarity but includes the total num the injection force of the formulation containing a viscosity ber of moles of dissolved species in solution. An osmolarity lowering agent re?ects improved injectability of that formu of 1 Osm/L means there is 1 mole of dissolved components lation. The reduced viscosity formulations have improved per L of solution. Some solutes, such as ionic solutes that dissociate in solution, will contribute more than 1 mole of injectability when the injection force is reduced by at least dissolved components per mole of solute in the solution. For 10%, preferably by at least 30%, more preferably by at least example, NaCl dissociates into Na+ and Cl‘ in solution and 50%, and most preferably by at least 75% when compared to thus provides 2 moles of dissolved components per 1 mole of a standard formulation having the same concentration of pro dissolved NaCl in solution. Physiological osmolarity is typi tein under otherwise the same conditions, except for replace cally in the range of about 280 mOsm/ L to about 310 mOsm/ ment of the viscosity-lowering agent with an appropriate L. buffer of about the same concentration. Alternatively, inject ability of the liquid pharmaceutical formulations may be [0056] The term “tonicity,” as generally used herein, refers to the osmotic pres sure gradient resulting from the separation assessed by comparing the time required to inject the same of two solutions by a semi-permeable membrane. In particu volume, such as 0.5 mL, or more preferably about 1 mL, of different liquid protein formulations when the syringe is lar, tonicity is used to describe the osmotic pressure created across a cell membrane when a cell is exposed to an external depressed with the same force. solution. Solutes that can cross the cellular membrane do not [0052] The term “injection force,” as generally used herein, contribute to the ?nal osmotic pressure gradient. Only those refers to the force required to push a given liquid formulation dissolved species that do not cross the cell membrane will through a given syringe equipped with a given needle gauge at contribute to osmotic pressure differences and thus tonicity. a given injection speed. The inj ection force is typically [0057] The term “hypertonic,” as generally used herein, reported in Newtons. For example, the injection force may be refers to a solution with a higher concentration of solutes than measured as the force required to push a liquid formulation is present on the inside of the cell. When a cell is immersed through a 1 mL plastic syringe having a 0.25 inch inside into a hypertonic solution, the tendency is for water to ?ow diameter, equipped with a 0.50 inch 27 gauge needle at a 250 out of the cell in order to balance the concentration of the mm/min injection speed. Testing equipment can be used to solutes. measure the injection force. When measured under the same [0058] The term “hypotonic,” as generally used herein, conditions, a formulation with lower viscosity will generally refers to a solution with a lower concentration of solutes than require an overall lower injection force. is present on the inside of the cell. When a cell is immersed [0053] The “viscosity gradient,” as used herein, refers to into a hypotonic solution, water ?ows into the cell in order to the rate of change of the viscosity of a protein solution as balance the concentration of the solutes. protein concentration increases. The viscosity gradient can be [0059] The term “isotonic,” as generally used herein, refers approximated from a plot of the viscosity as a function of the to a solution wherein the osmotic pressure gradient across the protein concentration for a series of formulations that are cell membrane is essentially balanced. An isotonic formula otherwise the same but have different protein concentrations. tion is one which has essentially the same osmotic pressure as The viscosity increases approximately exponentially with human blood. Isotonic formulations will generally have an increasing protein concentration. The viscosity gradient at a osmotic pressure from about 250 mOsm/kg to 350 mOsm/kg. speci?c protein concentration can be approximated from the [0060] The term “liquid formulation,” as used herein, is a slope of a line tangent to the plot of viscosity as a function of protein that is either supplied in an acceptable pharmaceutical protein concentration. The viscosity gradient can be approxi diluent or one that is reconstituted in an acceptable pharma mated from a linear approximation to the plot of viscosity as ceutical diluent prior to administration to the patient. a function of any protein concentration or over a narrow [0061] The terms “branded” and “reference,” when used to window of protein concentrations. In some embodiments a refer to a protein or biologic, are used interchangeably herein formulation is said to have a decreased viscosity gradient if, to mean the single biological product licensed under section when the viscosity as a function of protein concentration is 351(a) of the Us. Public Health Service Act (42 U.S.C. approximated as an exponential function, the exponent of the §262). exponential function is smaller than the exponent obtained for [0062] The term “biosimilar,” as used herein, is generally the otherwise same formulation without the viscosity-lower used interchangeably with “a generic equivalent” or “follow ing agent. In a similar manner, a formulation can be said to on.” For example, a “biosimilar mAb” refers to a subsequent have a lower/higher viscosity gradient when compared to a version of an innovator’s mAb typically made by a different second formulation if the exponent for the formulation is company. “Biosimilar” when used in reference to a branded lower/higher than the exponent for the second formulation. protein or branded biologic can refer to a biological product The viscosity gradient can be numerically approximated from evaluated against the branded protein or branded biologic and a plot of the viscosity as a function of protein concentration by licensed under section 351(k) of the Us. Public Health Ser other methods known to the skilled formulation researchers. vice Act (42 U.S.C. §262). A biosimilar mAb can be one that US 2015/0071922 A1 Mar. 12, 2015

satis?es one or more guidelines adopted May 30, 2012 by the succinic, sulfuric, tartaric acid, p-toluenesulfonic and the Committee for Medicinal Products for Human Use (CHMP) like. Suitable positively charged counterions include sodium, of the European Medicines Agency and published by the potassium, lithium, calcium and magnesium. European Union as “Guideline on similar biological medici [0067] As used herein, the term “ionic liquid” refers to a nal products containing monoclonal antibodiesinon-clini crystalline or amorphous salt, zwitterion, or mixture thereof cal and clinical issues” (Document Reference EMA/CHMP/ that is a liquid at or near temperatures where most conven BMWP/403543/2010). tional salts are solids: at less than 200° C., preferably less than [0063] Biosimilars can be produced by microbial cells 100° C. or more preferably less than 80° C. Some ionic liquids (prokaryotic, eukaryotic), cell lines of human or animal ori have melting temperatures around room temperature, e.g. gin (e.g., mammalian, avian, insect), or tissues derived from between 10° C. and 40° C., or between 15° C. and 35° C. The animals or plants. The expression construct for a proposed term “zwitterion” is used herein to describe an overall neu biosimilar product will generally encode the same primary trally charged molecule which carries formal positive and amino acid sequence as its reference product. Minor modi? negative charges on different chemical groups in the mol cations, such as N- or C-terminal truncations that will not ecule. Examples of ionic liquids are described in Riduan et have an effect on safety, purity, or potency, may be present. al., Chem. Soc. Rev., 42:9055-9070, 2013; Rantwijk et al., [0064] A biosimilar mAb is similar to the reference mAb Chem. Rev., 107:2757-2785, 2007; Earle et al., Pure Appl. physiochemically or biologically both in terms of safety and Chem., 72(7):1391-1398, 2000; and Sheldon et al., Green ef?cacy. The biosimilar mAb can be evaluated against a ref Chem., 4:147-151, 2002. erence mAb using one or more in vitro studies including [0068] As used herein, the term “organophosphate” refers assays detailing binding to target antigen(s); binding to iso to a compound containing one or more phosphoryl groups at forms of the Fc gamma receptors (FcyRI, FcyRII, and least one of which is covalently connected to an organic group FcyRIII), FcRn, and complement (C1q); Fab-associated through a phosphoester bond. functions (e.g. neutralization of a soluble ligand, receptor [0069] As used herein, a “water soluble organic dye” is an activation or blockade); or Fc-associated functions (e.g. anti organic molecule having a molar solubility of at least 0.001 M body-dependent cell-mediated cytotoxicity, complement-de at 25° C. and pH 7, and that absorbs certain wavelengths of pendent cytotoxicity, complement activation). In vitro com light, preferably in the visible-to-infrared portion of the elec parisons may be combined with in vivo data demonstrating tromagnetic spectrum, while possibly transmitting or re?ect similarity of pharmacokinetics, pharrnacodynamics, and/or ing other wavelengths of light. safety. Clinical evaluations of a biosimilar mAb against a [0070] As used herein, the term “chalcogen” refers to reference mAb can include comparisons of pharmacokinetic Group 16 elements, including oxygen, sulfur and selenium, in properties (e.g. AUCO_W, AUCO_t, Cmax, tmax, Ctrough); phar any oxidation state. For instance, unless speci?ed otherwise, macodynamic endpoints; or similarity of clinical ef?cacy the term “chalcogen” also include S02. (e.g. using randomized, parallel group comparative clinical [0071] As used herein, the term “alkyl group” refers to trials). The quality comparison between a biosimilar mAb straight-chain, branched-chain and cyclic hydrocarbon and a reference mAb can be evaluated using established pro groups. Unless speci?ed otherwise, the term alkyl group cedures, including those described in the “Guideline on simi embraces hydrocarbon groups containing one or more double lar biological medicinal products containing biotechnology or triple bonds. An alkyl group containing at least one ring derived proteins as active substance: Quality issues” (EMEA/ system is a “cycloalkyl” group. An alkyl group containing at CHMP/BWP/49348/2005), and the “Guideline on least one double bond is an “alkenyl group,” and an alkyl development, production, characterization and speci?cations group containing at least one triple bond is an “alkynyl for monoclonal antibodies and related substances” (EMEA/ group.” CHMP/ BWP/ 1 57653/ 2007). [0072] As used herein, the term “aryl” refers to aromatic [0065] Differences between a biosimilar mAb and a refer carbon ring systems, including fused ring systems. In an ence mAb can include post-translational modi?cation, e. g. by “aryl” group, each of the atoms that form the ring are carbon attaching to the mAb other biochemical groups such as a atoms. phosphate, various lipids and carbohydrates; by proteolytic [0073] As used herein, the term “heteroaryl” refers to aro cleavage following translation; by changing the chemical matic ring systems, including fused ring systems, wherein at nature of an amino acid (e. g., formylation); or by many other least one of the atoms that form the ring is a heteroatom. mechanisms. Other post-translational modi?cations can be a [0074] As used herein, the term “heterocycle” refers to ring consequence of manufacturing process operationsifor systems that, including fused ring systems, that are not aro example, glycation may occur with exposure of the product to matic, wherein at least one of the atoms that forms the ring is reducing sugars. In other cases, storage conditions may be a heteroatom. permissive for certain degradation pathways such as oxida [0075] As used herein, a “heteroatom” is any non-carbon or tion, deamidation, or aggregation. As all of these product non-hydrogen atom. Preferred heteroatoms include oxygen, related variants may be included in a biosimilar mAb. sulfur, and nitrogen. Exemplary heteroaryl and heterocyclyl [0066] As used herein, the term “pharmaceutically accept rings include: benzimidazolyl, benzofuranyl, benzothiofura able salts” refers to salts prepared from pharmaceutically nyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benz acceptable non-toxic acids and bases, including inorganic thiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, ben acids and bases, and organic acids and bases. Suitable non zisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, toxic acids include inorganic and organic acids such as acetic, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydro benzenesulfonic, benzoic, camphorsulfonic, citric, ethane quinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3b]tet sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydro rahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazoli chloric, isethionic, lactic, maleic, malic, mandelic, methane nyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, sulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, US 2015/0071922 A1 Mar. 12, 2015

isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, iso of one or more ionic liquids permits the preparation of for quinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, mulations having a viscosity less than or about 80 cP, prefer morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxa ably less than or about 50 cP, even more preferably less than diazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadia about 20 cP, or most preferably less than or about 10 cP, when zolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, measured at 250 C. pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenaZinyl, [0080] In some embodiments, the aqueous protein formu phenothiaZinyl, phenoxathinyl, phenovainyl, phthalaZinyl, lations have a viscosity that is at least about 30% less than the piperaZinyl, piperidinyl, piperidonyl, 4-piperidonyl, pipero analogous formulation without the ionic liquid(s), when mea nyl, pteridinyl, purinyl, pyranyl, pyraZinyl, pyrazolidinyl, sured under the same conditions. In other embodiments, the pyrazolinyl, pyrazolyl, pyridaZinyl, pyridooxazole, pyri formulations have a viscosity that is 40% less, 50% less, 60% doimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, less, 70% less, 80% less, 90% less, or even more than 90% pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, less than the analogous formulation without the viscosity quinolinyl, 4H-quinoliZinyl, quinoxalinyl, quinuclidinyl, tet reducing ionic liquid(s). In a preferred embodiment, the for rahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinoli mulation contains a therapeutically effective amount of the nyl, tetrazolyl, 6H-1,2,5-thiadiaZinyl, 1,2,3-thiadiazolyl, 1,2, one or more high-molecular-weight proteins, such as mAbs, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3 ,4-thiadiazolyl, in a volume of less than about 2 mL, preferably less than about thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoox 1 mL, or more preferably less than about 0.75 mL. azolyl, thienoimidazolyl, thiophenyl, and xanthenyl. [0081] The reduced-viscosity formulations have improved injectability and require less injection force compared to the II. Formulations analogous formulation without the viscosity-reducing ionic [0076] Biocompatible, low-viscosity protein solutions, liquid (e.g., in phosphate buffer) under otherwise the same such as those of mAbs, can be used to deliver therapeutically conditions. In some embodiments, the force of injection is effective amounts of proteins in volumes useful for subcuta decreased by more than about 20%, more than about 30%, neous (SC) and intramuscular (IM) injections, typically less more than about 40%, more than about 50%, or more than than or about 2 mL for SC and less than or about 5 mL for IM, about 2 fold, as compared to standard formulations without more preferably less than or about 1 mL for SC and less than the viscosity-reducing ionic liquid(s) under otherwise the or about 3 mL for IM. The proteins can generally have any same injection conditions. In some embodiments, the formu molecular weight, although in some embodiments high-mo lations possess “Newtonian ?ow characteristics,” de?ned as lecular-weight proteins are preferred. In other embodiments having viscosity which is substantially independent of shear the proteins are low-molecular-weight proteins. rate. The protein formulations can be readily injected through [0077] Formulations may have protein concentrations needles of about 18-32 gauge. Preferred needle gauges for the between about 10 mg/mL and about 5,000 mg/mL. The for delivery of the low-viscosity formulations include 27, 29, and mulations, including mAb formulations, may have a protein 31 gauge, optionally thin walled. concentration greater than 100 mg/mL, preferably greater [0082] The formulations may contain one or more addi than 150 mg/mL, more preferably greater than about 175 tional excipients, such as buffers, surfactants, sugars and mg/ml, even more preferably greater than about 200 mg/mL, sugar alcohols, other polyols, preservatives, antioxidants, and even more preferably greater than about 225 mg/mL, even chelating agents. The formulations have a pH and osmolarity more preferably greater than about 250 mg/mL, and most suitable for administration without causing signi?cant preferably greater than or about 300 mg/mL. In the absence of adverse side effects. In some embodiments, the concentrated, a viscosity-reducing ionic liquid, the viscosity of a protein low-viscosity formulations have a pH between 5 and 8, formulation increases exponentially as the concentration is between 5.5 and 7.6, between 6.0 and 7.6, between 6.8 and increased. Such protein formulations, in the absence of a 7.6, or between 5.5 and 6.5. viscosity-reducing ionic liquids, may have viscosities greater [0083] The low-viscosity protein formulations can allow than 100 cP, greater than 150 cP, greater than 200 cP, greater for greater ?exibility in formulation development. The low than 300 cP, greater than 500 cP, or even greater than 1,000 cP, viscosity formulations can exhibit changes in viscosity that when measured at 25° C. Such formulations are often unsuit are less dependent upon the protein concentration as com able for SC or IM injection. The use of one or more viscosity pared to the otherwise same formulation without the viscos reducing ionic liquids permits the preparation of formulations ity-reducing ionic liquid. The low-viscosity protein formula having a viscosity less than or about 100 cP, preferably less tions can allow for increased concentrations and decreased than or about 75 cP, more preferably less than or about 50 cP, dosage frequencies of the protein. In some embodiments the even more preferably less than or about 30 cP, even more low-viscosity protein formulations contain 2 or more, 3 or preferably less than or about 20 cP, or most preferably less more, or 4 or more different proteins. For example, combina than or about 10 cP, when measured at 250 C. tions of 2 or more mAbs can be provided in a single low [0078] Although the viscosity-reducing ionic liquids may viscosity protein formulation. be used to lower the viscosity of concentrated protein formu [0084] Because protein (such as mAb) formulations may be lations, they may be used in less-concentrated formulations as administered to patients at higher protein concentrations than well. In some embodiments, formulations may have protein otherwise similar protein formulations not containing a vis concentrations between about 10 mg/mL and about 100 cosity-reducing ionic liquid, the dosing frequency of the pro mg/mL. The formulations may have a protein concentration tein can be reduced. For instance, proteins previously requir greater than about 20 mg/mL, greater than about 40 mg/mL, ing once daily administration may be administered once or greater than about 80 mg/mL. every two days, every three days, or even less frequently when [0079] For certain proteins, formulations not having an the proteins are formulated with viscosity-lowering agents. ionic liquid may have viscosities greater than about 20 cP, Proteins which currently require multiple administrations on greater than about 50 cP, or greater than about 80 cP. The use the same day (either at the same time or at different times of US 2015/0071922 Al Mar. 12, 2015

the day) may be administered in fewer injections per day. In protein concentration can be increased to a greater degree some instances, the frequency may be reduced to a single before an exponential increase in viscosity is observed. injection once a day. By increasing the dosage administered [0090] A. Proteins per injection multiple-fold the dosing frequency can be [0091] Any protein can be formulated, including recombi decreased, for example from once every 2 weeks to once nant, isolated, or synthetic proteins, glycoproteins, or lipo every 6 weeks. proteins. These may be antibodies (including antibody frag [0085] In some embodiments, the liquid formulations have ments and recombinant antibodies), enzymes, growth factors a physiological osmolarity, for example, between about 280 or hormones, immunomodi?ers, antiinfectives, antiprolifera mOsm/L to about 310 mOsm/L. In some embodiments, the tives, vaccines, or other therapeutic, prophylactic, or diagnos liquid formulations have an osmolarity greater than about 250 tic proteins. In certain embodiments, the protein has a mOsm/ L, greater than about 300 mOsm/ L, greater than about molecular weight greater than about 150 kDa, greater than 350 mOsm/L, greater than about 400 mOsm/L, or greater 160 kDa, greater than 170 kDa, greater than 180 kDa, greater than about 500 mOsm/L. In some embodiments, the formu than 190 kDa or even greater than 200 kDa. lations have an osmolarity of about 200 mOsm/L to about [0092] In certain embodiments, the protein can be a PEGy 2,000 mOsm/L or about 300 mOsm/L to about 1,000 mOsm/ lated protein. The term “PEGylated protein,” as used herein, L. In some embodiments, the liquid formulations are essen refers to a protein having one or more poly(ethylene glycol) tially isotonic to human blood. The liquid formulations can in or other stealth polymer groups covalently attached thereto, some cases be hypertonic. optionally through a chemical linker that may be different [0086] The additives, including the viscosity-reducing from the one or more polymer groups. PEGylated proteins are ionic liquid(s), can be included in any amount to achieve the characterized by their typically reduced renal ?ltration, desired viscosity levels of the liquid formulation, as long as decreased uptake by the reticuloendothelial system, and the amounts are not toxic or otherwise harmful, and do not diminished enzymatic degradation leading to, for example, substantially interfere with the chemical and/or physical sta prolonged half-lives and enhanced bioavailability. Stealth bility of the formulation. The viscosity-reducing ionic liquid polymers include poly(ethylene glycol); polypropylene gly (s) in some embodiments can be independently present in a col); poly(amino acid) polymers such as poly(glutamic acid), concentration less than about 1.0 M, preferably less than poly(hydroxyethyl-L-asparagine), and poly(hydroxethyl-L about 0.50 M, less than or equal to about 0.30 M or less than glutamine); poly(glycerol); poly(2-oxazoline) polymers such or equal to 0.15 M. Especially preferred concentrations as poly(2-methyl-2-oxazoline) and poly(2-ethyl-2-oxazo include about 0.15 M and about 0.30 M. For some embodi line); poly(acrylamide); poly(vinyl idone); poly(N-(2-hy ments having two or more viscosity-reducing ionic liquids, droxypropyl)methacrylamide); and copolymers and mixtures the agents are preferably, but not necessarily, present at the thereof. In preferred embodiments the stealth polymer in a same concentration. PEGylated protein is poly(ethylene glycol) or a copolymer [0087] The viscosity-reducing ionic liquid(s) permit faster thereof PEGylated proteins can be randomly PEGylated, i.e. reconstitution of a lyophilized dosage unit. The dosage unit is having one or more stealth polymers covalently attached at a lyophilized cake of protein, viscosity-reducing ionic liquid non-speci?c site(s) on the protein, or can be PEGylated in a (s) and other excipients, to which water, saline or another site-speci?c manner by covalently attaching the stealth poly pharmaceutically acceptable ?uid is added. In the absence of mer to speci?c site(s) on the protein. Site-speci?c PEGylation viscosity-reducing ionic liquids, periods of 10 minutes or can be accomplished, for example, using activated stealth more are often required in order to completely dissolve the polymers having one or more reactive functional groups. lyophilized cake at high protein concentration. When the Examples are described, for instance, in Hoffman et al., lyophilized cake contains one or more viscosity-reducing Progress in Polymer Science, 321922-932, 2007. ionic liquid, the period required to completely dissolve the [0093] In the preferred embodiment, the protein is high cake is often reduced by a factor of two, ?ve or even ten. In molecular-weight and an antibody, most preferably a mAb, certain embodiments, less than one minute is required to and has a high viscosity in aqueous buffered solution when completely dissolve a lyophilized cake containing greater concentrated suf?ciently to inject a therapeutically effective than or about 150, 200 or even 300 mg/mL of protein. amount in a volume not exceeding 1.0 to 2.0 mL for SC and [0088] The low-viscosity protein formulations allow for 3.0 to 5.0 mL for IM administration. High-molecular-weight greater ?exibility in formulation development. The low-vis proteins can include those described in Scolnik, mAbs 1:179 cosity formulations exhibit a viscosity that changes less with 184, 2009; Beck, mAbs 3:107-110, 2011; Baumann, Curr. increasing protein concentrations as compared to the other Drug Melh. 7:15-21, 2006; or Federici, Biologicals 41 : 131 wise same formulation without the ionic liquid(s). The low 147, 2013. The proteins for use in the formulations described viscosity protein formulations exhibit a decreased viscosity herein are preferably essentially pure and essentially homo gradient as compared to the otherwise same formulation geneous (i.e., substantially free from contaminating proteins without the ionic liquid. and/or irreversible aggregates thereof). [0089] The viscosity gradient of the protein formulation [0094] Preferred mAbs herein include natalizumab may be 2-fold less, 3-fold less, or even more than 3-fold less (TYSABRI®), cetuximab (ERBITUX®), bevacizumab than the viscosity gradient of the otherwise same protein (AVASTIN®), trastuzumab (HERCEPTIN®), in?iximab formulation without the viscosity-reducing ionic liquid(s). (REMICADE®), rituximab (RITUXAN®), panitumumab The viscosity gradient of the protein formulation may be less (V ECTIBIX®), ofatumumab (ARZERRA®), and biosimi than 2.0 cP mL/mg, less than 1.5 cP mL/mg, less than 1.0 cP lars thereof. Exemplary high-molecular-weight proteins can mL/mg, less than 0.8 cP mL/mg, less than 0.6 cP mL/mg, or include tocilizumab (ACTEMRA®), alemtuzumab (mar less than 0.2 cP mL/mg for a protein formulation having a keted under several trade names), brodalumab (developed by protein concentration between 10 mg/mL and 2,000 mg/mL. Amgen, Inc (“Amgen”)), denosumab (PROLIA® and By reducing the viscosity gradient of the formulation, the XGEVA®), and biosimilars thereof. US 2015/0071922 A1 Mar. 12, 2015

[0095] Exemplary molecular targets for antibodies [0101] Cetuximab is an epidermal growth factor receptor described herein include CD proteins, such as CD3, CD4, (EGFR) inhibitor used for the treatment of metastatic col CD8, CD19, CD20 and CD34; members of the HER receptor orectal cancer and head and neck cancer. Cetuximab is a family such as the EGF receptor, HER2, HER3 or HER4 chimeric (mouse/human) mAb typically given by IV infu receptor; cell adhesion molecules, such as LEA-1, Mol, sion. Cetuximab is marketed for IV use only under the trade p150,95, VLA-4, ICAM-1, VCAM, and (xv/[33 integrin, name ERBITUX® by Bristol-Myers Squibb Company including either 0t or [3 subunits thereof (e.g., anti-CD11a, (North America; “Bristol-Myers Squibb”), Eli Lilly and anti-CD18, or anti-CD11b antibodies); growth factors, such Company (North America; “Eli Lilly”), and Merck KGaA. as VEGF; IgE; blood group antigens; ?k2/?t3 receptor; obe ERBITUX® is produced in mammalian (murine myeloma) sity (OB) receptor; protein C; PCSK9; etc. cell culture. Each single-use, 50-mL vial of ERBITUX® [0096] Antibody Therapeutics Currently on the Market contains 100 mg of cetuximab at a concentration of 2 mg/mL and is formulated in a preservative-free solution containing [0097] Many protein therapeutics currently on the market, 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate especially antibodies as de?ned herein, are administered via dibasic heptahydrate, 0.42 mg/mL sodium phosphate IV infusions due to high dosing requirements. Formulations monobasic monohydrate, and water for IV Injection, USP. can include one of the antibody therapeutics currently on the market or a biosimilar thereof. Some protein therapeutics [0102] Cetuximab is indicated for the treatment of patients currently on the market are not high-molecular-weight, but with epidermal growth factor receptor (EGFR)-expressing, are still administered via IV infusion because high doses are KRAS wild-type metastatic colorectal cancer (mCRC), in needed for therapeutic ef?cacy. In some embodiments, liquid combination with chemotherapy, and as a single agent in formulations are provided of these low-molecular-weight patients who have failed oxaliplatin- and irinotecan-based therapy or who are intolerant to irinotecan. Cetuximab is proteins as de?ned herein with concentrations to deliver indicated for the treatment of patients with squamous cell therapeutically effective amounts for SC or IM injections. carcinoma of the head and neck in combination with plati [0098] Antibody therapeutics currently on the market num-based chemotherapy for the ?rst-line treatment of recur include belimumab (BENLYSTA®), golimumab (SIMPONI rent and/or metastatic disease and in combination with radia ARIA®), abciximab (REOPRO®), the combination of tosi tion therapy for locally advanced disease. Approximately tumomab and iodine-131 tositumomab, marketed as 75% of patients with metastatic colorectal cancer have an BEXXAR®, alemtuzumab (CAMPATH®), palivizumab EGFR-expressing tumor and are, therefore, considered eli (SYNAGIS®), basiliximab (SIMULECT®), ado-trastu gible for treatment with cetuximab or panitumumab, accord zumab emtansine (KADCYLA®), pertuzumab (PER ing to FDA guidelines. JETA®), capromab pendetide (PROSTASCINT KIT®), [0103] As used herein, the term “cetuximab” includes the caclizumab (ZENAPAX®), ibritumomab tiuxetan (ZEVA mAb known under the International Nonproprietary Name LIN®), eculizumab (SOLIRIS®), ipilimumab (YERVOY®), “CETUXIMAB” or an antigen binding portion thereof. muromonab-CD3 (ORTHOCLONE OKT3®), raxibacumab, Cetuximab includes antibodies described in US. Pat. No. nimotuzumab (THERACIM®), brentuximab vedotin (AD 6,217,866. Cetuximab includes the active agent in products CETRIS®), adalimumab (HUMIRA®), golimumab (SIM marketed under the trade name ERBITUX® and biosimilar PONI®), palivizumab (SYNAGIS®), omalizumab products thereof. Biosimilars of ERBITUX® can include (XOLAIR®), and ustekinumab (STELARA®). those currently being developed by Amgen, AlphaMab Co., [0099] Natalizumab, a humanized mAb against the cell Ltd. (“AlphaMab”), and Actavis plc (“Actavis”). adhesion molecule (x4-integrin, is used in the treatment of [0104] Bevacizumab, a humanized mAb that inhibits vas multiple sclerosis and Crohn’s disease. Previously marketed cular endothelial growth factorA (V EGF-A), acts as an anti under the trade name ANTEGREN®, natalizumab is cur angiogenic agent. It is marketed under the trade name AVAS rently co-marketed as TYSABRI® by Biogen Idec (“Bio TIN® by Genentech, Inc. (“Genentech”) and F. Hoffmann gen”) and Elan Corp. (“Elan”) TYSABRI® is produced in La Roche, LTD (“Roche”). It is licensed to treat various murine myeloma cells. Each 15 mL dose contains 300 mg cancers, including colorectal, lung, breast (outside the US. natalizumab; 123 mg sodium chloride, USP; 17.0 mg sodium A.), glioblastoma (USA. only), kidney and ovarian. AVAS phosphate, monobasic, monohydrate, USP; 7.24 mg sodium TIN® was approved by the FDA in 2004 for use in metastatic phosphate, dibasic, heptahydrate, USP; 3.0 mg polysorbate colorectal cancer when used with standard chemotherapy 80, USP/NF, in water for IV injection, USP at pH 6.1 . Natali treatment (as ?rst-line treatment) and with 5-?uorouracil Zumab is typically administered by monthly intravenous (IV) based therapy for second-line metastatic colorectal cancer. In infusions and has been proven effective in treating the symp 2006, the FDA approved AVASTIN® for use in ?rst-line toms of both multiple sclerosis and Crohn’s disease, as well advanced non-squamous non-small cell lung cancer in com as for preventing relapse, vision loss, cognitive decline, and bination with carboplatin/paclitaxel chemotherapy. AVAS signi?cantly improving patient’s quality of life. TIN® is given as an IV infusion every three weeks at the dose [0100] As used herein, the term “natalizuma ” includes the of either 15 mg/kg or 7.5 mg/kg. The higher dose is usually mAb against the cell adhesion molecule (x4-integrin known given with carboplatin-based chemotherapy, whereas the under the International Nonproprietary Name “NATALI lower dose is given with cisplatin-based chemotherapy. In ZUMAB” or an antigen binding portion thereof. Natalizumab 2009, the FDA approved AVASTIN® for use in metastatic includes antibodies described in US. Pat. No. 5,840,299, renal cell carcinoma (a form of kidney cancer). The FDA also US. Pat. No. 6,033,665, US. Pat. No. 6,602,503, US. Pat. granted accelerated approval of AVASTIN® for the treatment No. 5,168,062, US. Pat. No. 5,385,839, and US. Pat. No. of recurrent glioblastoma multiforme in 2009. Treatment for 5,730,978. Natalizumab includes the active agent in products initial growth is still in phase III clinical trial. marketed under the trade name TYSABRI® by Biogen Idec [0105] The National Comprehensive Cancer Network and Elan Corporation or a biosimilar product thereof. (“NCCN”) recommends bevacizumab as standard ?rst-line US 2015/0071922 A1 Mar. 12, 2015

treatment in combination with any platinum-based chemo by Celltrion, Inc. (“Celltrion”), and INFLECTRATM, devel therapy, followed by maintenance bevacizumab until disease oped by Hospira Inc., UK, have been recommended for regu progression. The NCCN updated its Clinical Practice Guide latory approval in Europe. Celltrion has submitted a ?ling for lines for Oncology (N CCN Guidelines) for Breast Cancer in REMSIMATM to the FDA. In?iximab is currently adminis 2010 to af?rm the recommendation regarding the use of beva tered via IV infusion at doses ranging from about 3 mg/kg to cizumab (AVASTIN®, Genentech/Roche) in the treatment of about 10 mg/kg. metastatic breast cancer. [0111] In?iximab contains approximately 30% murine [0106] As used herein, the term “bevacizumab” includes variable region amino acid sequence, which confers antigen the mAb that inhibits vascular endothelial growth factor A binding speci?city to human TNFG. The remaining 70% cor (VEGF-A) known under the International Nonproprietary respond to a human IgG1 heavy chain constant region and a Name/Common Name “BEVACIZUMAB” or an antigen human kappa light chain constant region. In?iximab has high binding portion thereof. Bevacizumab is described in US. af?nity for human TNFG, which is a cytokine with multiple Pat. No. 6,054,297. Bevacizumab includes the active agent in biologic actions including mediation of in?ammatory products marketed under the trade name AVASTIN® and responses and modulation of the immune system. biosimilar products thereof. Biosimilars of AVASTIN® can [0112] In?iximab is a recombinant antibody generally pro include those currently being developed by Amgen, Actavis, duced and secreted from mouse myeloma cells (SP2/0 cells). AlphaMab, and P?zer, Inc (“P?zer”). Biosimilars of AVAS The antibody is currently manufactured by continuous perfu TIN® can include the biosimilar known as BCD-021 pro sion cell culture. The in?iximab monoclonal antibody is duced by Biocad and currently in clinical trials in the US. expressed using chimeric antibody genes consisting of the [0107] Trastuzumab is a mAb that interferes with the variable region sequences cloned from the murine anti-TNFa HER2/neu receptor. Trastuzumab is marketed under the trade hybridoma A2, and human antibody constant region name HERCEPTIN® by Genentech, Inc. HERCEPTIN® is sequences supplied by the plasmid expression vectors. Gen produced by a mammalian cell (Chinese Hamster Ovary eration of the murine anti-TNFa hybridoma is performed by (CHO)) line. HERCEPTIN® is a sterile, white to pale-yellow, immunization of BALB/c mice with puri?ed recombinant preservative-free lyophilized powder for IV administration. human TNFa. The heavy and light chain vector constructs are Each HERCEPTIN® vial contains 440 mg trastuzumab, 9.9 linearized and transfected into the Sp2/0 cells by electropo mg L-histidine HCl, 6.4 mg L-histidine, 400 mg a,a-trehalose ration. Standard puri?cation steps can include chromato dihydrate, and 1.8 mg polysorbate 20, USP. Reconstitution graphic puri?cation, viral inactivation, nano?ltration, and with 20 mL water yields a multi-dose solution containing 21 ultra?ltration/dia?ltration. mg/mL trastuzumab. HERCEPTIN® is currently adminis [0113] As used herein, the term “in?iximab” includes the tered via IV infusion as often as weekly and at a dosage chimeric mouse/human monoclonal antibody known under ranging from about 2 mg/kg to about 8 mg/kg. the International Nonproprietary Name “INFLIXIMAB” or [0108] Trastuzumab is mainly used to treat certain breast an antigen binding portion thereof. In?iximab neutralizes the cancers. The HER2 gene is ampli?ed in 20-30% of early biological activity of TNFO. by binding with high af?nity to stage breast cancers, which makes it overexpress epidermal the soluble and transmembrane forms of TNFO. and inhibits growth factor (EGF) receptors in the cell membrane. Trastu binding of TNFO. with its receptors. In?iximab is described in zumab is generally administered as a maintenance therapy for US. Pat. No. 5,698,195. The term “In?iximab” includes the patients with HER2-positive breast cancer, typically for one active agent in products marketed or proposed to be marketed year post-chemotherapy. Trastuzumab is currently adminis under the trade names REMICADE® by multiple entities; tered via IV infusion as often as weekly and at a dosage REMSIMATM by Celltrion and INFLECTRATM by Hospira, ranging from about 2 mg/kg to about 8 mg/kg. Inc (“Hospira”). In?iximab is supplied as a sterile lyophilized [0109] As used herein, the term “trastuzumab” includes the cake for reconstitution and dilution. Each vial of in?iximab mAb that interferes with the HER2/neu receptor known under contains 100 mg in?iximab and excipients such as monobasic the International Nonproprietary Name/Common Name sodium phosphate monohydrate, dibasic sodium phosphate “TRASTUZUMAB” or an antigen binding portion thereof. dihydrate, sucrose, and polysorbate 80. Trastuzumab is described in US. Pat. No. 5,821,337. Trastu [0114] Denosumab (PROLIA® and XGEVA®) is a human zumab includes the active agent in products marketed under mAbiand the ?rst RANKL inhibitoriapproved for use in the trade name HERCEPTIN® and biosimilars thereof. The postmenopausal women with risk of osteoporosis and term “trastuzumab” includes the active agent in biosimilar patients with bone metastases from solid tumors. Denosumab HERCEPTIN® products marketed under the trade names is in Phase II trials for the treatment of rheumatoid arthritis. HERTRAZ® by Mylan, Inc. (“Mylan”) and CANMAB® by [0115] Panitumumab is a fully human mAb approved by Biocon, Ltd. (“Biocon”). Trastuzumab can include the active the FDA for treatment of EGFR-expressing metastatic cancer agent in biosimilar HERCEPTIN® products being developed with disease progression. Panitumumab is marketed under by Amgen and by PlantForm Corporation, Canada. the trade name VECTIBIX® by Amgen. VECTIBIX® is [0110] In?iximab is a mAb against tumor necrosis factor packaged as a 20 mg/ml panitumumab concentrate in 5 ml, 10 alpha (TNF-(x) used to treat autoimmune diseases. It is mar ml, and 15 ml vials for IV infusion. When prepared according keted under the trade name REMICADE® by Janssen Global to the packaging instructions, the ?nal panitumumab concen Services, LLC (“Janssen”) in the U.S., Mitsubishi Tanabe tration does not exceed 10 mg/ml. VECTIBIX® is adminis Pharma in Japan, Xian Janssen in China, and Merck & Co tered at a dosage of 6 mg/kg every 14 days as an intravenous (“Merck”); elsewhere. In?iximab is a chimeric mouse/human infusion. As used herein, the term “panitumumab” includes monoclonal antibody with a high molecular weight of the anti-human epidermal growth factor receptor known by approximately 144 kDa. In some embodiments, the formula the International Nonproprietary Name “PANITU tions contain a biosimilar of REMICADE®, such as REM MUMAB.” The term “panitumumab” includes the active SIMATM or INFLECTRATM. Both REMSIMATM, developed agent in products marketed under the trade name US 2015/0071922 A1 Mar. 12, 2015

VECTIBIX® by Amgen and biosimilars thereof. The term is FDA-approved for treating chronic lymphocytic leukemia “panitumumab” includes monoclonal antibodies described in and has also shown potential in treating Follicular non US. Pat. No. 6,235,883. The term “panitumumab” includes Hodgkin’s lymphoma, Diffuse large B cell lymphoma, rheu the active agent in biosimilar VECTIBIX® products, includ matoid arthritis, and relapsing remitting multiple sclerosis. ing biosimilar VECTIBIX® being developed by BioXpress, Ofatumumab has a molecular weight of about 149 kDa. It is SA (“BioXpress”). currently administered by IV infusion at an initial dose of 300 [0116] Belimumab (BENLYSTA®) is a human mAb with a mg, followed by weekly infusions of 2,000 mg. As used molecular weight of about 151.8 kDa that inhibits B-cell herein, the term “ofatumumab” includes the anti-CD20 mAb activating factor (BAFF). Belimumab is approved in the known by the International Nonproprietary Name “OFATU United States, Canada, and Europe for treatment of systemic MUMAB.” The term “ofatumumab” includes the active agent lupus erythematosus. Belimumab is currently administered to in products marketed under the trade name ARZERRA® and lupus patients by IV infusion at a 10 mg/kg dosage. A high biosimilars thereof. The term “ofatumumab” includes the molecular-weight, low-viscosity protein formulation can active agent in biosimilarARZERRA® products being devel include Belimumab, preferably in a concentration of about oped by BioExpress. High-molecular-weight, low-viscosity 400 mg/mL to about 1,000 mg/mL. The preferred ranges are liquid protein formulations can include ofatumumab, prefer calculated based upon body weight of 40-100 kg (approxi ably in a concentration of about 300 mg/mL to about 2,000 mately 80-220 lbs) in a 1 mL volume. mg/mL. [0117] Abciximab (REOPRO®) is manufactured by Jans [0122] Trastuzumab emtansine (in the U.S., ado-trastu sen Biologics BV and distributed by Eli Lilly & Company zumab emtansine, marketed as KADCYLA®) is an antibody (“Eli Lilly”). Abciximab is a Fab fragment of the chimeric drug conjugate consisting of the mAb trastuzumab linked to human-murine monoclonal antibody 7E3. Abciximab binds the cytotoxic agent mertansine (DM1®). Trastuzumab, to the glycoprotein (GP) IIb/IIIa receptor of human platelets described above, stops growth of cancer cells by binding to and inhibits platelet aggregation by preventing the binding of the HER2/neu receptor, whereas mertansine enters cells and ?brinogen, von Willebrand factor, and other adhesive mol destroys them by binding to tubulin. In the United States, ecules. It also binds to vitronectin (0W[33) receptor found on trastuzumab emtansine was approved speci?cally for treat platelets and vessel wall endothelial and smooth muscle cells. ment of recurring HER2-positive metastatic breast cancer. Abciximab is a platelet aggregation inhibitor mainly used Multiple Phase III trials of trastuzumab emtansine are during and after coronary artery procedures. Abciximab is planned or ongoing in 2014. Trastuzumab emtansine is cur administered via IV infusion, ?rst in a bolus of 0.25 mg/kg rently administered by IV infusion of 3.6 mg/kg. High-mo and followed by continuous IV infusion of 0.125 mcg/kg/ lecular-weight, low-viscosity liquid formulations can include minute for 12 hours. trastuzumab emtansine, preferably in a concentration of [0118] Tositumomab (BEXXAR®) is a drug for the treat about 144 mg/mL to about 360 mg/mL. ment of follicular lymphoma. It is an IgG2a anti-CD20 mAb [0123] Pertuzumab (PERJETA®) is a mAb that inhibits derived from immortalized mouse cells. Tositumomab is HER2 dimerization. Pertuzumab received FDA approval for administered in sequential infusions: cold mAb followed by the treatment of HER2-positive metastatic breast cancer in iodine (131I) tositumomab, the same antibody covalently 2012. The currently recommended dosage of Pertuzumab is bound to the radionuclide iodine-131. Clinical trials have 420 mg to 840 mg by IV infusion. High-molecular-weight, established the ef?cacy of the tositumomab/iodine tositumo low-viscosity liquid formulations can include pertuzumab, mab regimen in patients with relapsed refractory follicular preferably in a concentration of about 420 mg/mL to about lymphoma. BEXXAR® is currently administered at a dose of 840 mg/mL. 450 mg via IV infusion. [0124] Daclizumab is a humanized anti-CD25 mAb and is [0119] Alemtuzumab (marketed as CAMPATH®, MAB used to prevent rejection in organ transplantation, especially CAMPATH®, or CAMPATH-1H® and currently under fur in kidney transplants. The drug is also under investigation for ther development as LEMTRADA®) is a mAb used in the the treatment of multiple sclerosis. Daclizumab has a molecu treatment of chronic lymphocytic leukemia (CLL), cutaneous lar weight of about 143 kDa. Daclizumab was marketed in the T-cell lymphoma (CTCL), and T-cell lymphoma. It is also US. by Hoffmann-La Roche, Ltd. (“Roche”) as ZENAPAX® used under clinical trial protocols for treatment of some and administered by IV infusion of 1 mg/kg. Daclizumab autoimmune diseases, such as multiple sclerosis. Alemtu High-Yield Process (DAC HYP; BIIB019; Biogen Idec zumab has a weight of approximately 145.5 kDa. It is admin (“Biogen”) andAbeie, Inc. (“Abeie”)) is in phase III clini istered in daily IV infusions of 30 mg for patients with B-cell cal trials as a 150 mg, once-monthly subcutaneous injection chronic lymphocytic leukemia. to treat relapsing, remitting multiple-sclerosis. High-molecu [0120] Palivizumab (SYNAGIS®) is a humanized mAb lar-weight, low-viscosity liquid formulations can include directed against an epitope in the A antigenic site of the F daclizumab, preferably in a concentration of about 40 mg/mL protein of respiratory syncytial virus. In two Phase III clinical to about 300 mg/mL. trials in the pediatric population, palivizumab reduced the [0125] Eculizumab (SOLIRIS®) is a humanized mAb risk of ho spitalization due to respiratory syncytial virus infec approved for the treatment of rare blood diseases, such as tion by 55% and 45%. Palivizumab is dosed once a month via paroxysmal nocturnal hemoglobinuria and atypical IM injection of 15 mg/kg. hemolytic uremic syndrome. Eculizumab, with a molecular [0121] Ofatumumab is a human anti-CD20 mAb which weight of about 148 kDa, is being developed by Alexion appears to inhibit early-stage B lymphocyte activation. Ofa Pharmaceuticals, Inc (“Alexion”). It is administered by IV tumumab is marketed under the trade name ARZERRA® by infusion in the amount of about 600 mg to about 1,200 mg. GlaxoSmithKline, plc (“GlaxoSmithKline”). ARZERRA® High-molecular-weight, low-viscosity liquid formulations is distributed in single-use vials containing 100 mg/ 5 mL and can include eculizumab, preferably in a concentration of 1,000 mg/ 50 mL ofatumumab for IV infusion. Ofatumumab about 500 mg/mL to about 1,200 mg/mL. US 2015/0071922 A1 Mar. 12, 2015

[0126] Tocilizumab (ACTEMRA®) is a humanized mAb mg weekly. High-molecular-weight, low-viscosity liquid for against the interleukin-6 receptor. It is an immunosuppressive mulations can include nimotuzumab, preferably in a concen drug, mainly for the treatment of rheumatoid arthritis (RA) tration of about 200 mg/mL. and systemic juvenile idiopathic arthritis, a severe form of RA [0133] Brentuximab vedotin (ADCETRIS®) is an anti in children. Tocilizumab is commonly administered by IV body-drug conjugate directed to the protein CD30, expressed infusion in doses of about 6 mg/kg to about 8 mg/kg. High in classical Hodgkin’s lymphoma and systemic anaplastic molecular-weight, low-viscosity liquid formulations can large cell lymphoma. It is administered by IV infusion of include tocilizumab, preferably in a concentration of about about 1.8 mg/kg. High-molecular-weight, low-viscosity liq 240 mg/mL to about 800 mg/mL. uid formulations can include brentuximab vedotin, prefer [0127] Rituximab (RITUXAN®) is a chimeric anti-CD20 ably in a concentration of about 80 mg/mL to about 200 mAb used to treat a variety of diseases characterized by mg/mL. excessive numbers of B cells, overactive B cells, or dysfunc [0134] Itolizumab (ALZUMAB®) is a humanized IgG1 tional B cells. Rituximab is used to treat cancers of the white mAb developed by Biocon. Itolizumab completed successful blood system, such as leukemias and lymphomas, including Phase III studies in patients with moderate to severe psoriasis. Hodgkin’s lymphoma and its lymphocyte-predominant sub Itolizumab has received marketing approval in India; an type. It has been shown to be an effective rheumatoid arthritis application for FDA approval has not been submitted. treatment. Rituximab is widely used off-label to treat dif?cult [0135] Obinutuzumab (GAZYVA®), originally developed cases of multiple sclerosis, systemic lupus erythematosus, by Roche and being further developed under a collaboration and autoimmune anemias. agreement with Biogen is a humanized anti-CD20 mAb approved for treatment of chronic lymphocytic leukemia. It is [0128] Rituximab is jointly marketed in the Us. under the also being investigated in Phase III clinical trials for patients trade name RITUXAN® by Biogen and Genentech and out with various lymphomas. Dosages of about 1,000 mg are side the U.S. under the trade name MABTHERA® by Roche. being administered via IV infusion. RITUXAN® is distributed in single-use vials containing 100 [0136] Certolizumab pegol (CIMZIA®) is a recombinant, mg/ 10 mL and 500 mg/ 50 mL. RITUXAN® is typically humanized antibody Fab' fragment, with speci?city for administered by IV infusion of about 375 mg/m2. The term human tumor necrosis factor alpha (TNFG), conjugated to an “rituximab,” as used herein, includes the anti-CD20 mAb approximately 40 kDa polyethylene glycol known under the International Nonproprietary Name/Com (PEG2MAL40K). The molecular weight of certolizumab mon Name “RITUXIMAB.” Rituximab includes mAbs pegol is approximately 91 kDa. described in US. Pat. No. 5,736,137. Rituximab includes the [0137] Other antibody therapeutics that can be formulated active agent in products marketed under the trade name RIT with viscosity-lowering ionic liquids include CT-P6 from UXAN® and MABTHERA® and biosimilars thereof. Celltrion, Inc. (Celltrion). [0129] High-molecular-weight, low-viscosity liquid for [0138] Antibody Therapeutics in Late-Stage Trials and mulations can include rituximab, preferably in a concentra Development tion of about 475 mg/mL to about 875 mg/mL (approximated [0139] The progression of antibody therapeutics to late using a body surface area range of 1.3 to 2.3 square meters, stage clinical development and regulatory review are pro derived from the Mo steller formula for persons ranging from ceeding at a rapid pace. In 2014, there are more than 300 5 ft, 40 kg to 6 ft, 100 kg). Concentrations are calculated for mAbs in clinical trials and 30 commercially-sponsored anti a 1 mL formulation. body therapeutics undergoing evaluation in late-stage stud [0130] Ipilimumab is a human mAb developed by Bristol ies. First marketing applications for two mAbs (vedolizumab Myers Squibb Company (“Bristol-Myers Squibb”). Mar and ramucirumab) were recently submitted to the FDA. keted as YERVOY®, it is used for the treatment of melanoma Amgen is currently sponsoring multiple ongoing Phase III and is also undergoing clinical trials for the treatment of trials on the use of brodalumab in patients with plaque pso non-small cell lung carcinoma (NSCLC), small cell lung riasis, with additional trials planned or recruiting patients. cancer (SCLC), and metastatic hormone-refractory prostate XBiotech, Inc. has sponsored two Phase I clinical trials of cancer. Ipilimumab is currently administered by IV infusion MABp1 (Xilonix) for patients with advanced cancer or type-2 of 3 mg/kg. High-molecular-weight, low-viscosity liquid for diabetes. Additional trials of MABp1 are recruiting patients. mulations can include ipilimumab, preferably in a concentra Multiple trials are sponsored by MedImmune, LLC (“Med tion of about 120 mg/mL to about 300 mg/mL. Immune”) and underway or recruiting patients for the treat ment of leukemia with moxetumomab pasudotox. Long-term [0131] Raxibacumab (ABthrax®) is a human mAb safety and ef?cacy studies are underway for the use of til intended for the prophylaxis and treatment of inhaled anthrax. drakizumab for the treatment of chronic plaque psoriasis. It is currently administered by IV infusion. The suggested Multiple phase II trials have recently completed for the use of dosage in adults and children over 50 kg is 40 mg/kg. High rilotumumab for the treatment of various cancers. molecular-weight, low-viscosity liquid formulations can [0140] At least 28 mAbs are high-molecular-weight pro include raxibacumab, preferably in a concentration of about teins currently in or having recently completed Phase III 1,000 mg/mL to about 4,000 mg/mL. studies for the treatment of in?ammatory or immunological [0132] Nimotuzumab (THERACIM®, BIOMAB EGFR®, disorders, cancers, high cholesterol, osteoporosis, Alzhe THERALOC®, CIMAher®) is a humanized mAb with a imer’s disease, and infectious diseases. The mAbs in or hav molecular weight of about 151 kDa used to treat squamous ing recently completed Phase III trials include AMG 145, cell carcinomas of the head and neck, recurrent or refractory elotuzumab, epratuzumab, farletuzumab (MORAb-003), high-grade malignant glioma, anaplastic astrocytomas, glio gantenerumab (RG1450), gevokizumab, inotuzumab ozo blastomas, and diffuse intrinsic pontine glioma. Nimotu gamicin, itolizumab, ixekizumab, lebrikizumab, mepoli zumab is typically administered by IV infusion of about 200 zumab, naptumomab estafenatox, necitumumab, nivolumab, US 2015/0071922 A1 Mar. 12, 2015

ocrelizumab, onartuzumab, racotumomab, ramucirumab, monoclonal antibody developed jointly by Amgen and Astra reslizumab, romosozumab, sarilumab, secukinumab, siruku Zeneca and currently in Phase I trials for treatment of lupus. mab, solanezumab, tabalumab, and vedolizumab. A mAb Likewise, AMG 729 is a humanized mAb developed by mixture (actoxumab and bezlotoxumab) is also being evalu Amgen and currently in Phase I trials for the treatment of ated in Phase III trials. See, e.g., Reichert, MAbs 511-4, 2013. lupus and rheumatoid arthritis. In addition, AMG 110 is a [0141] Vedolizumab is a mAb being developed by Millen mAb for epithelial cell adhesion molecule; AMG 157, jointly nium Pharmaceuticals, Inc (“Millennium”; a subsidiary of developed by Amgen and AstraZeneca, is a human mAb Takeda Pharmaceuticals Company, Ltd. (“Takeda”)). Ved currently in Phase I for the treatment of asthma; AMG 167 is olizumab was found safe and highly effective for inducing a humanized mAb that has been evaluated in multiple Phase and maintaining clinical remission in patients with moderate I trials for the treatment of osteopenia; AMG 334, having to severe ulcerative colitis. Phase III clinical trials showed it completed Phase I dosing studies and currently in in Phase II to meet the objectives of inducing a clinical response and studies for the treatment of migraines and hot ?ashes, is a maintaining remission in Crohn’s and ulcerative colitis human mAb that inhibits Calcitonin Gene-Related Peptide; patients. Studies evaluating long-term clinical outcomes AMG 780 is a human anti-angiopoietin mAb that inhibits the show close to 60% of patients achieving clinical remission. A interaction between the endothelial cell-selective Tie2 recep common dose of vedolizumab are 6 mg/kg by IV infusion. tor and its ligands Angl and Ang2, and recently completed [0142] Ramucirumab is a human mAb being developed for Phase I trials as a cancer treatment; AMG 811 is a human the treatment of solid tumors. Phase III clinical trials are monoclonal antibody that inhibits interferon gamma being ongoing for the treatment of breast cancer, metastatic gastric investigated as a treatment for systemic lupus erythemato sus; adenocarcinoma, non-small cell lung cancer, and other types AMG 820 is a human mAb that inhibits c-fms and decreases of cancer. Ramucirumab, in some Phase III trials, is admin tumor associated macrophage (TAM) function and is being istered at about 8 mg/kg via IV infusion. investigated as a cancer treatment; AMG 181, jointly devel [0143] Rilotumumab is a human mAb that inhibits the oped by Amgen andAstraZeneca, is a human mAb that inhib action of hepatocyte growth factor/ scatter factor. Developed its the action of alpha4/beta7 and is in Phase II trials as a by Amgen, it is in Phase III trials as a treatment for solid treatment for ulcerative colitis and Crohn’s disease. tumors. An open Phase III study of rilotumumab treatment in [0151] Many mAbs are currently in clinical trials for the patients with advanced or metastatic esophageal cancer will treatment of autoimmune disorders. These mAbs can be administer rilotumumab at about 15 mg/kg via IV infusion. included in low-viscosity, high-molecular-weight liquid for [0144] Evolocumab (AMG 145), also developed by mulations. RG7624 is a fully human mAb designed to spe Amgen, is a mAb that binds to PCSK9. Evolocumab is indi ci?cally and selectively bind to the human interleukin-17 cated for hypercholesterolemia and hyperlipidemia. family of cytokines. A Phase I clinical trial evaluating [0145] Alirocumab (REGN727) is a human mAb from RG7624 for autoimmune disease is ongoing. BIIB033 is an Regeneron Pharmaceuticals, Inc. (“Regeneron”) and Sano? anti-LINGO-l mAb by Biogen currently in Phase II trials for Aventis US. LLC (“Sano?”), indicated for hypercholester treating multiple sclerosis. olemia and acute coronary syndrome. [0152] High-molecular-weight proteins also can include [0146] Naptumomab estafenatox, AER-217620 from AGS-009, a mAb targeting IFN-alpha developed by Argos Active Biotech AB (“Active Biotech”) is a mAb indicated for Therapeutics, Inc. that recently completed phase I trials for renal cell carcinoma. the treatment of lupus. Patients are administered up to 30 [0147] Racotumomab from CIMAB, SA (“CIMAB”); mg/kg of AGS-009 via IV infusion. BT-061, developed by Laboratorio Elea S.A.C.I.F.y A. is a mAb indicated for non Abeie, is in Phase II trials for patients with rheumatoid small cell lung cancer. arthritis. Certolizumab pegol (CIMZIA®) is a mAb in Phase [0148] Other antibodies which may be formulated with II trials for ankylosing spondylitis and juvenile rheumatoid viscosity-lowering ionic liquids include bococizumab (PF arthritis. Clazakizumab, an anti-IL6 mAb, is in Phase II trials 0495061 5) and tanezumab; ganitumab, blinatumomab, treba by Bristol-Myers Squibb. nanib from Amgen; Anthrax immune globulin from Cangene [0153] CNTO-136 (sirukumab) and CNTO-1959 are Corporation; teplizumab from MacroGenics, Inc.; MK-3222, mABs having recently completed Phase II and Phase III trials MK-6072 from Merck & Co (“Merck”); girentuximab from by Janssen. Daclizumab (previously marketed as ZENA Wilex AG; RIGScan from Navidea Biopharmaceuticals PAX® by Roche) is currently in or has recently completed (“Navidea”); PF-05280014 from P?zer; SA237 from Chugai multiple Phase III trials by Abeie for the treatment of mul Pharmaceutical Co. Ltd. (“Chugai”); guselkumab from Jan tiple sclerosis. Epratuzumab is a humanized mAb in Phase III ssen/Johnson and Johnson Services, Inc. (“1&1”); Antithrom trials for the treatment of lupus. Canakinumab (ILARIS®) is bin Gamma (KW-3357) from Kyowa; and CT-PlO from Cell a human mAb targeted at interleukin-1 beta. It was approved trion. for the treatment of cryopyrin-associated periodic syn [0149] Antibodies in Early-Stage Clinical Trials dromes. Canakinumab is in Phase I trials as a possible treat [0150] Many mAbs have recently entered, or are entering, ment for chronic obstructive pulmonary disease, gout and clinical trials. They can include proteins currently adminis coronary artery disease. Mavrilimumab is a human mAb tered via IV infusion, preferably those having a molecular designed for the treatment of rheumatoid arthritis. Discov weight greater than about 120 kDa, typically from about 140 ered as CAM-3001 by Cambridge Antibody Technology, kDa to about 180 kDa. They can also include such high mavrilimumab is being developed by MedImmune. molecular-weight proteins such as Albumin-conjugated [0154] MEDI-546 are MEDI-570 are mAbs currently in drugs or peptides that are also entering clinical trials or have Phase I and Phase II trials by AstraZeneca for the treatment of been approved by the FDA. Many mAbs from Amgen are lupus. MEDI-546 is administered in the Phase II study by currently in clinical trials. These can be high-molecular regular IV infusions of 300-1,000 mg. MEDI-55l, another weight proteins, for example, AMG 557, which is a human mAb being developed by AstraZeneca for numerous indica US 2015/0071922 A1 Mar. 12, 2015

tions, is also currently administered by IV infusion. NN8209, International, Inc. (“Baxter”), BAY 79-4620 and BAY a mAb blocking the C5aR receptor being developed by Novo 20-101 12 from Bayer HealthCare AG, BHQ880 from Novar Nordisk A/S (“Novo Nordisk”), has completed a Phase II tis AG, 212-Pb-TCMCtrastuzumab from AREVA Med, dosing study for treatment of rheumatoid arthritis. NN8210 is AbGn-7 from AbGenomics International Inc., and ABIO another antiC5aR mAb being developed by Novo Nordisk 0501 (TALL-104) from Abiogen Pharma S.p.A. and currently is in Phase I trials. IPH2201 (NN8765) is a [0160] Other antibody therapeutics that can be formulated humanized mAb targeting NKG2A being developed by Novo with viscosity-lowering ionic liquids include alzumab, Nordisk to treat patients with in?ammatory conditions and GA101, daratumumab, siltuximab, ALX-0061, ALX-0962, autoimmune diseases. NN8765 recently completed Phase I ALX-0761, bimagumab (BYM338), CT-011 (pidilizumab), trials. actoxumab/bezlotoxumab (MK-3515A), MK-3475 (pem [0155] Olokizumab is a humanized mAb that potently tar brolizumab), dalotuzumab (MK-0646), icrucumab (IMC gets the cytokine IL-6. IL-6 is involved in several autoim 18F1, LY3012212), AMG 139 (MEDI2070), SAR339658, mune and in?ammatory pathways. Olokizumab has com dupilumab (REGN668), SAR156597, SAR256212, pleted Phase II trials for the treatment of rheumatoid arthritis. SAR2793 56, SAR3419, SAR153192 (REGN421, enoti Otelixizumab, also known as TRX4, is a mAb, which is being cumab), SAR3 07746 (nesvacumab), SAR650984, developed for the treatment of type 1 diabetes, rheumatoid SAR566658, SAR391786, SAR228810, SAR252067, SGN arthritis, and other autoimmune diseases. Ozoralizumab is a CD19A, SGN-CD33A, SGN-LIV1A, ASG 15ME, Anti humanized mAb that has completed Phase II trials. LINGO, BIIB037, ALXN1007, teprotumumab, concizumab, [0156] P?zer currently has Phase I trials for the mAbs anrukinzumab (IMA-638), ponezumab (PF-04360365), PD-360324 and PF-04236921 for the treatment of lupus. A PF-03446962, PF-06252616, etrolizumab (RG7413), quili rituximab biosimilar, PF-05280586, has been developed by zumab, ranibizumab, lampalizumab, onclacumab, gen P?zer and is in Phase 1/ Phase II trials for rheumatoid arthritis. tenerumab, crenezumab (RG7412), IMC-RON8 (nama [0157] Rontalizumab is a humanized mAb being developed tumab), tremelimumab, vantictumab, eemcizumab, by Genentech. It recently completed Phase II trials for the ozanezumab, mapatumumab, tralokinumab, XmAb5871, treatment of lupus. SAR113244 (anti-CXCR5) is a mAb by XmAb7195, cixutumumab (LY3012217), LY2541546 Sano? in Phase I trials. Sifalimumab (anti-IFN-alpha mAb) is (blosozumab), olaratumab (LY3012207), MEDI4893, a mAb in Phase II trials for the treatment of lupus. MED1573, MEDIO639, MEDI3617, MEDI4736, [0158] A high-molecular-weight low-viscosity liquid for MEDI6469, MEDIO680, MED15872, PF-05236812 (AAB mulation can include one of the mAbs in early stage clinical 003), PF-05082566, BI 1034020, RG7116, RG7356, development for treating various blood disorders. For RG7155, RG7212, RG7599, RG7636, RG7221, RG7652 example, Belimumab (BENLYSTA®) has recently com (MPSK3169A), RG7686, HuMaxTFADC, MOR103, pleted Phase I trials for patients with vasculitis. Other mAbs BT061, MOR208, OMP59R5 (anti-notch 2/3), VAY736, in early-stage trials for blood disorders include BI-655075 MOR202, BAY94-9343, LJM716, OMP52M51, from Boehringer Ingelheim GmbH “Boehringer Ingelheim”, GSK933776, GSK249320, GSK1070806, NN8828, CEP ferroportin mAb and hepcidin mAb from Eli Lily, and SelG1 37250/KHK2804 AGS-16M8F, AGS-16C3F, LY3016859, from Selexys Pharmaceuticals, Corp. (“Selexys”). LY2495655, LY2875358, and LY2812176. [0159] One or more mAbs in early-stage development for [0161] Other early stage mAbs that can be formulated with treating various cancers and related conditions can be viscosity-lowering ionic liquids include benralizumab, included in a low-viscosity, high-molecular-weight liquid MEDI-8968, anifrolumab, MEDI7183, sifalimumab, MEDI formulation. United Therapeutics, Corporation has two 575, tralokinumab from AstraZeneca and MedImmune; mAbs in Phase I trials, 8H9 mAb and ch14.18 mAb. The BAN2401 from Biogen Idec/Eisai Co. LTD (“Eisai”)/Bio mAbs ABT-806, enavatuzumab, and volociximab from Arctic Neuroscience AB; CDP7657 an anti-CD40L monova Abeie are in early-stage development. Actinium Pharma lent pegylated Fab antibody fragment, STX-100 an anti-avB6 ceuticals, Inc has conducted early-stage trials for the mAbs mAb, BIIB059,Anti-TWEAK (BIIB023), and BIIB022 from Actimab-A (M195 mAb), anti-CD45 mAb, and Iomab-B. Biogen; fulranumab from Janssen and Amgen; BI-204/ Seattle Genetics, Inc. (“Seattle Genetics”) has several mAbs RG7418 from BioInvent Intemational/Genentech; BT-062 in early-stage trials for cancer and related conditions, includ (indatuximab ravtansine) from Biotest Pharmaceuticals Cor ing anti-CD22 ADC (RG7593; pinatuzumab vedotin), anti poration; XmAb from Boehringer Ingelheim/Xencor; anti CD79b ADC (RG7596), anti-STEAPl ADC (RG7450), IP10 from Bristol-Myers Squibb; J 591 Lu-177 from BZL ASG-5ME and ASG-22ME from Agensys, Inc. (“Agensys”) Biologics LLC; CDX-011 (glembatumumab vedotin), CDX the antibody-drug conjugate RG7458, and vorsetuzumab 0401 from Celldex Therapeutics; foravirumab from Crucell; mafodotin. The early-stage cancer therapeutics from Genen tigatuzumab from Daiichi Sankyo Company Limited; tech can be included in low-viscosity formulations, including MORAb-004, MORAb-009 (amatuximab) from Eisai; ALT-836, the antibody-drug conjugates RG7600 and LY2382770 from Eli Lilly; DI17E6 from EMD Serono Inc; DEDN6526A, anti-CD22 ADC (RG7593), anti-EGFL7 mAb zanolimumab from Emergent BioSolutions, Inc.; FG-3019 (RG7414), anti-HER3/EGFR DAF mAb (RG7597), anti-PD from FibroGen, Inc.; catumaxomab from Fresenius SE & Co. L1 mAb (RG7446), DFRF4539A, an MINT1526A. Bristol KGaA; pateclizumab, rontalizumab from Genentech; fresoli Myers Squibb is developing early-stage mAbs for cancer mumab from Genzyme & Sano?; GS-6624 (simtuzumab) therapeutics, including those identi?ed as anti-CXCR4, anti from Gilead; CNTO-328, bapineuzumab (AAB-001), car PD-L1, IL-21 (BMS-982470), lirilumab, and urelumab (anti lumab, CNTO-136 from Janssen; KB003 from KaloBios CD137). Other mAbs in early-stage trials as cancer therapeu Pharmaceuticals, Inc.; ASKP1240 from Kyowa; RN-307 tics include APN301 (hu14.18-IL2) from Apeiron Biologics from Labrys Biologics Inc.; ecromeximab from Life Science AG, AV-203 from AVEO Pharmaceuticals, Inc. (“AVEO”), Pharmaceuticals; LY2495655, LY2928057, LY3015014, AVX701 and AVX901 from AlphaVax, BAX-69 from Baxter LY2951742 from Eli Lilly; MBL-HCVl from MassBiolog US 2015/0071922 A1 Mar. 12, 2015

ics; AME-133v from MENTRIK Biotech, LLC; abituzumab axy Biotech LLC; IMGB853, IMGN529 from ImmunoGen from Merck KGaA; MM-121 from Merrimack Pharmaceuti Inc.; CNTO-5, CNTO-5825 from Janssen; KD-247 from cals, Inc.; MCS110, QAX576, QBX258, QGE031 from Kaketsuken; KB004 from KaloBios Pharmaceuticals; Novartis AG; HCD122 from Novartis AG and XOMA Cor MGA271, MGAH22 from MacroGenics, Inc.; XmAb5574 poration (“XOMA”); NN8555 from Novo Nordisk; bavitux from MorphoSys AG/Xencor; ensituximab (NPC-1C) from imab, cotara from Peregrine Pharmaceuticals, Inc.; PSMA Neogenix Oncology, Inc.; LFA102 from Novartis AG and ADC from Progenies Pharmaceuticals, Inc.; oregovomab XOMA; ATI355 from Novartis AG; SAN-300 from Santarus from Quest Pharrnatech, Inc.; fasinumab (REGN475), Inc.; SelG1 from Selexys; HuM195/rGel from Targa Thera REGN1033, SAR231893, REGN846 from Regeneron; peutics, Corp.; VX15 from Teva Pharmaceuticals, Industries RG7160, CIM331, RG7745 from Roche; ibalizumab (TMB Ltd. (“Teva”) and Vaccinex Inc.; TCN-202 from Theraclone 355) from TaiMed Biologics Inc.; TCN-032 from Theraclone Sciences; XmAb2513, XmAb5872 from Xencor; XOMA 3AB from XOMA and National Institute for Allergy and Sciences; TRC105 from TRACON Pharmaceuticals, Inc.; Infectious Diseases; neuroblastoma antibody vaccine from UB-421 from United Biomedical Inc.; VB4-845 from Viven MabVax Therapeutics; Cytolin from CytoDyn, Inc .; Thravixa tia Bio, Inc.; ABT-1 10 fromAbeie; Caplacizumab, Ozorali from Emergent BioSolutions Inc.; and FE 301 from Cyto zumab from Ablynx; PRO 140 from CytoDyn, Inc.; GS vance Biologics; rabies mAb from Janssen and Sano?; ?u CDA1, MDX-1388 from Medarex, Inc.; AMG 827, AMG mAb from Janssen and partly funded by National Institutes of 888 from Amgen; ublituximab from TG Therapeutics Inc.; Health; MB-003 and ZMapp from Mapp Biopharmaceutical, TOL101 from Tolera Therapeutics, Inc.; huN901-DM1 (lor Inc.; and ZMAb from Defyrus Inc. votuzumab mertansine) from ImmunoGen Inc.; epratuzumab [0162] Other Protein Therapeutics Y-90/veltuzumab combination (IMMU-102) from Immuno medics, Inc.; anti-?brin mAb/3B6/22 Tc-99m from Agenix, [0163] The protein can be an enzyme, a fusion protein, a stealth or pegylated protein, vaccine or otherwise a biologi Limited; ALD403 from Alder Biopharmaceuticals, Inc.; RN6G/PF-04382923 from P?zer; CG201 from CG Thera cally active protein (or protein mixture). The term “enzyme,” peutics, Inc.; KBOOl-A from KaloBios Pharmaceuticals/ as used herein, refers to the protein or functional fragment thereof that catalyzes a biochemical transformation of a target Sano?; KRN-23 from Kyowa.;Y-90 hPAM 4 from Immuno molecule to a desired product. medics, Inc.; Tarextumab from Morphosys AG & OncoMed Pharmaceuticals, Inc.; LFG316 from Morphosys AG & [0164] Enzymes as drugs have at least two important fea Novartis AG; CNTO3157, CNTO6785 from Morphosys AG tures, namely i) often bind and act on their targets with high & Jannsen; RG6013 from Roche & Chugai; MM-111 from af?nity and speci?city, and ii) are catalytic and convert mul tiple target molecules to the desired products. In certain Merrimack Pharmaceuticals, Inc. (“Merrimack”); GSK2862277 from GlaxoSmithKline; AMG 282, AMG 172, embodiments, the protein can be PEGylated, as de?ned AMG 595, AMG 745, AMG 761 from Amgen; BVX-20 from herein. Biocon; CT-P19, CT-P24, CT-P25, CT-P26, CT-P27, CT-P4 [0165] The term “fusion protein,” as used herein, refers to a protein that is created from two different genes encoding for from Celltrion; GSK284933, GSK2398852, GSK2618960, two separate proteins. Fusion proteins are generally produced GSK1223249, GSK933776A from GlaxoSmithKline; ane tumab ravtansine from Morphosys AG & Bayer AG; through recombinant DNA techniques known to those skilled BI-836845 from Morphosys AG & Boehringer Ingelheim; in the art. Two proteins (or protein fragments) are fused NOV-7, NOV-8 from Morphosys AG & Novartis AG; together covalently and exhibit properties from both parent MM-302, MM-310, MM-141, MM-131, MM-151 from Mer proteins. rimack, RG7882 from Roche & Seattle Genetics; RG7841 [0166] There are a number of fusion proteins that are on the from Roche/Genentech; PF-06410293, PF-06438179, market. PF-06439535, PF-04605412, PF-05280586 from P?zer; [0167] ENBREL® (Etanercept), is a fusion protein mar RG7716, RG7936, gentenerumab, RG7444 from Roche; keted by Amgen that competitively inhibits TNF. MEDI-547, MEDI-565, MEDIl814, MEDI4920, [0168] ELOCTATE®, Antihemophilic Factor (Recombi MEDI8897, MEDI-4212, MEDI-5117, MEDI-7814 from nant), Fc Fusion Protein, is a recombinant DNA derived, Astrazeneca; ulocuplumab, PCSK9 adnectin from Bristol antihemophilic factor indicated in adults and children with Myers Squibb; FPA009, FPA145 from FivePrime Therapeu Hemophilia A (congenital Factor VIII de?ciency) for control tics, Inc.; GS-5745 from Gilead; BIW-8962, KHK4083, and prevention of bleeding episodes, perioperative manage KHK6640 from Kyowa Hakko Kirin; MM-141 from Merck ment, routine prophylaxis to prevent or reduce the frequency KGaA; REGN1154, REGN1193, REGN1400, REGN1500, ofbleeding episodes. REGN1908-1909, REGN2009, REGN2176-3, REGN728 [0169] EYLEA® (a?ibercept) is a recombinant fusion pro from Regeneron; SAR307746 from Sano?; SGN-CD70A tein consisting of portions of human VEGF receptors 1 and 2 from Seattle Genetics; ALX-0141, ALX-0171 from Ablynx; extracellular domains fused to the Fc portion of human IgG1 milatuzumab-DOX, milatuzumab, TF2, from Immunomed formulated as an iso-osmotic solution for intravitreal admin ics, Inc.; MLN0264 from Millennium; ABT-981 from istration. EYLEA (a?ibercept) is a recombinant fusion pro Abeie; AbGn-168H from AbGenomics International Inc.; tein consisting of portions of human VEGF receptors 1 and 2 ?clatuzumab from AVEO; BI-505 from BioInvent Interna extracellular domains fused to the Fc portion of human IgG1 tional; CDX-1127, CDX-301 from Celldex Therapeutics; formulated as an iso-osmotic solution for intravitreal admin CLT-008 from Cellerant Therapeutics Inc.; VGX-100 from istration. A?ibercept is a dimeric glycoprotein with a protein Circadian; U3-1565 from Daiichi Sankyo Company Limited; molecular weight of 97 kilodaltons (kDa) and contains gly DKN-Ol from Dekkun Corp.; ?anvotumab (TYRP1 protein), cosylation, constituting an additional 15% of the total IL-1[3 antibody, IMC-CS4 from Eli Lilly; VEGFR3 mAb, molecular mass, resulting in a total molecular weight of 1 15 IMC-TR1 (LY3022859) from Eli Lilly and ImClone, LLC; kDa. A?ibercept is produced in recombinant Chinese hamster Anthim from Elusys Therapeutics Inc.; HuL2G7 from Gal ovary (CHO) cells, marketed by Regeneron. US 2015/0071922 A1 Mar. 12, 2015

[0170] ALPROLIXTM, Coagulation Factor IX (Recombi weight every other week by IV infusion. Other lysosomal nant), Fc Fusion Protein, is a recombinant DNA derived, enzymes can also be used. For example, the protein can be a coagulation Factor IX concentrate is indicated in adults and Lysosomal enzyme as described in US 2012/0148556. children with hemophilia B for control and prevention of [0177] Rasburicase (ELITEK®) is a recombinant urate bleeding episodes, perioperative management, routine pro oxidase indicated for initial management of plasma uric acid phylaxis to prevent or reduce the frequency of bleeding epi levels in pediatric and adult patients with leukemia, lym sodes. phoma, and solid tumor malignancies who are receiving anti [0171] Pegloticase (KRYSTEXXA®) is a drug for the cancer therapy expected to result in tumor lysis and subse treatment of severe, treatment-refractory, chronic gout, devel quent elevation of plasma uric acid. ELITEK® is oped by Savient Pharmaceuticals, Inc. and is the ?rst drug administered by daily IV infusion at a dosage of 0.2 mg/kg. approved for this indication. Pegloticase is a pegylated [0178] Imiglucerase (CEREZYME®) is a recombinant recombinant porcine-like uricase with a molecular weight of analogue of human [3-glucocerebrosidase. Initial dosages about 497 kDa. Pegloticase is currently administered by IV range from 2.5 U/kg body weight 3 times a week to 60 U/kg infusions of about 8 mg/kg. High-molecular-weight, low once every 2 weeks. CEREZYME® is administered by IV viscosity liquid formulations can include pegloticase, prefer infusion. ably in a concentration of about 300 mg/mL to about 800 [0179] Abraxane, paclitaxel-conjugated albumin, is mg/mL. approved for metastatic breast cancer, non-small cell lung [0172] Alteplase (ACTIVASE®) is a tissue plasminogen cancer, and late stage pancreatic cancer. activator produced by recombinant DNA technology. It is a [0180] Taliglucerase alfa (ELEYSO®) is a hydrolytic lyso puri?ed glycoprotein comprising 527 amino acids and syn somal glucocerebroside-speci?c enzyme indicated for long thesized using the complementary DNA (cDNA) for natural term enzyme replacement therapy for Type 1 Gaucher dis human tissue-type plasminogen activator obtained from a ease. The recommended dose is 60 U/kg of body weight human melanoma cell line. Alteplase is administered via IV administered once every 2 weeks via intravenous infusion. infusion of about 100 mg immediately following symptoms [0181] Laronidase (ALDURAZYME®) is a polymorphic of a stroke. In some embodiments, low-viscosity formula variant of the human enzyme (x-L-iduronidase that is pro tions are provided containing alteplase, preferably in a con duced via CHO cell line. The recommended dosage regimen centration of about 100 mg/mL. of ALDURAZYME® is 0.58 mg/kg administered once [0173] Glucarpidase (V ORAXAZE®) is a FDA-approved weekly as an intravenous infusion. drug for the treatment of elevated levels of methotrexate [0182] Elosufase alfa (V IMIZIM®) is a human N-acetyl (de?ned as at least 1 micromol/ L) during treatment of cancer galactosamine-6-sulfatase produced by CHO cell line by patients who have impaired kidney function. Glucarpidase is BioMarin Pharmaceuticals Inc (“BioMarin”). It was administered via IV in a single dose of about 50 IU/kg. In approved by the FDA on Feb. 14, 2014 for the treatment of some embodiments, low-viscosity formulations are provided Mucopolysaccharidosis Type IVA. It is administered weekly containing glucarpidase. via intravenous infusion at a dosage of 2 mg/kg. [0174] Alglucosidase alfa (LUMIZYME®) is an enzyme [0183] Other biologics which may be formulated with vis replacement therapy orphan drug for treatment of Pompe cosity-lowering ionic liquids include asparaginase erwinia disease (glycogen storage disease type II), a rare lysosomal chrysanthemi (ERWINAZE®), incobotulinumtoxin A (XE storage disorder. It has a molecular weight of about 106 kDa OMIN®), EPOGEN® (epoetin Alfa), PROCRIT® (epoetin and is currently administered by IV infusions of about 20 Alfa), ARANESP® (darbepoetin alfa), ORENCIA® (abata mg/kg. In some embodiments, a low-viscosity pharmaceuti cept), BATASERON® (interferon beta-1b), NAGLA cal formulation of alglucosidase alfa is provided, preferably ZYME® (galsulfase); ELAPRASE® (Idursulfase); MYO with a concentration of about 100 mg/mL to about 2,000 ZYME® (LUMIZYME®, algucosidase alfa); VPRIV® mg/mL. (velaglucerase), abobotulinumtoxinA (DYSPORT®); BAX [0175] Pegdamase bovine (ADAGEN®) is a modi?ed 326, Octocog alfa from Baxter; Syncria from GlaxoSmith enzyme used for enzyme replacement therapy for the treat Kline; liprotamase from Eli Lilly; Xia?ex (collagenase ment of severe combined immunode?ciency disease (SCID) clostridium histolyticum) from Auxilium and BioSpeci?cs associated with a de?ciency of adenosine deaminase. Technologies Corp.; anakinra from Swedish Orphan Biovit Pegdamase bovine is a conjugate of numerous strands of rum AB; metreleptin from Bristol-Myers Squibb; Avonex, monomethoxypolyethylene glycol (PEG), molecular weight Plegridy (BIIB017) from Biogen; NN1841, NN7008 from 5,000 Da, covalently attached to adenosine deaminase Novo Nordisk; KRN321 (darbepoetin alfa), AMG531 (romi enzyme that has been derived from bovine intestine. plostim), KRN125 (peg?lgrastim), KW-0761 (mogamuli [0176] (x-Galactosidase is a lysosomal enzyme that cataly zumab) from Kyowa; IB1001 from Inspiration Biopharma ses the hydrolysis of the glycolipid, globotriaosylceramide ceuticals; Iprivask from Canyon Pharmaceuticals Group. (GL-3), to galactose and ceramide dihexoside. Fabry disease [0184] Protein Therapeutics in Development is a rare inheritable lysosomal storage disease characterized [0185] Versartis, Inc.’s VRS-317 is a recombinant human by subnormal enzymatic activity of (x-Galactosidase and growth hormone (hGH) fusion protein utilizing the XTEN resultant accumulation of GL-3. Agalsidase alfa (REPLA half-life extension technology. It aims to reduce the fre GAL®) is a human (x-galactosidase A enzyme produced by a quency of hGH injections necessary for patients with hGH human cell line. Agalsidase beta (FABRAZYME®) is a de?ciency. VRS-3 17 has completed a Phase II study, compar recombinant human (x-galactosidase expressed in a CHO cell ing its ef?cacy to daily injections of non-derivatized hGH, line. Replagal is administered at a dose of 0.2 mg/kg every with positive results. Phase III studies are planned. other week by intravenous infusion for the treatment of Fabry [0186] Vibriolysin is a proteolytic enzyme secreted by the disease and, off label, for the treatment of Gaucher disease. Gram-negative marine microorganism, Vzbrio proleolylicus. FABRAZYME® is administered at a dose of 1.0 mg/kg body This endoprotease has speci?c af?nity for the hydrophobic US 2015/0071922 A1 Mar. 12, 2015

regions of proteins and is capable of cleaving proteins adja cept (ACE-011) from Celgene Corporation; PRAME immu cent to hydrophobic amino acids. Vibriolysin is currently notherapeutic from GlaxoSmithKline; Plovamer acetate (PI being investigated by Biomarin for the cleaning and/ or treat 2301) from Merck KGaA; PREMIPLEX (607) from Shire; ment of burns. Vibriolysin formulations are described in BMN-701 from BioMarin; Ontak from Eisai; rHuPH20/in patent WO 02/092014. sulin from Halozyme, Inc.; PB-1023 from PhaseBio Pharma [0187] PEG-PAL (PEGylated recombinant phenylalanine ceuticals, Inc.; ALV-003 from Alvine Pharmaceuticals Inc. ammonia lyase or “PAL”) is an investigational enzyme sub and Abbvie; NN8717 from Novo Nordisk; PRT-201 from stitution therapy for the treatment of phenylketonuria (PKU), Protean Therapeutics Inc.; PEGPH20 from Halozyme, Inc.; an inherited metabolic disease caused by a de?ciency of the Amevive® alefacept from Astellas Pharma Inc.; F-627 from enzyme phenylalanine hydroxylase (PAH). PEG-PAL is Regeneron; AGN-214868 (senrebotase) from Allergan, Inc.; being developed as a potential treatment for patients Whose BAX-817 from Baxter; PRT4445 from Portola Pharmaceuti blood phenylalanine (Phe) levels are not adequately con cals, Inc.; VEN100 from Ventria Bioscience; Onconase/ran trolled by KUVAN®. PEG-PAL is noW in Phase 2 clinical pirnase from Tamir Biotechnology Inc.; interferon alpha-2b development to treat patients Who do not adequately respond infusion from Medtronic, Inc; sebelipase alfa from Synageva to KUVAN®. BioPharma; IRX-2 from IRX Therapeutics, Inc; [0188] Other protein therapeutics Which may be formulated GSK2586881 from GlaxoSmithKline; SI-6603 from Seika With viscosity-lowering ionic liquids include Alprolix/ gaku Corporation; ALXN1101, asfotase alfa from Alexion; rFIXFc, Eloctate/rFVIIIFc, BMN-190; BMN-250; SHP611, SHP609 (Elaprase, idursulfase) from Shire; Lamazyme; Galazyme; ZA-011; Sebelipase alfa; SBC-103; PF-04856884, PF-05280602 from P?zer; ACE-031, Dal and HGT-1110. Additionally, fusion-proteins containing the antercept from Acceleron Pharma; ALT-801 from Altor Bio XTEN half life extension technology including, but not lim Science Corp.; BA-210 from BioAxone Biosciences, Inc.; ited to: VRS -3 1 7 GH-XTEN; Factor VIIa, Factor VIII, Factor WT1 immunotherapeutic from GlaxoSmithKline; IX; PF05280602, VRS-859; Exenatide-XTEN; AMX-256; GZ402666 from Sano?; MSB0010445, Atacicept from GLP2-2G/XTEN; and AMX-179 Folate-XTEN-DMI can be Merck KGaA; Leukine (sargramostim) from Bayer AG; formulated With viscosity-lowering ionic liquids. KUR-211 from Baxter; ?broblast growth factor-1 from Car [0189] Other late-stage protein therapeutics Which can be dioVascular BioTherapeutics Inc.; SPI-2012 from Hanmi formulated With viscosity-lowering ionic liquids include Pharmaceuticals Co., LTD/ Spectrum Pharmaceuticals; FGF CM-AT from CureMark LLC; NN7999, NN7088, Lira 18 (sprifermin) from Merck KGaA; MK-1293 from Merck; glutide (NN8022), NN9211, Semaglutide (NN9535) from interferon-alpha-2b from HanAll Biopharma; CYT107 from Novo Nordisk; AMG 386, Filgrastim fromAmgen; CSL-654, Cytheris SA; RT001 from Revance Therapeutics, Inc.; Factor VIII from CSL Behring; LA-EP2006 (peg?lgrastim MEDI6012 from AztraZeneca; E2609 from Biogen; BMN bio similar) from Novartis AG; Multikine (leukocyte interleu 190, BMN-270 from BioMarin; ACE-661 from Acceleron kin) from CEL-SCI Corporation; LY2605541, Teriparatide Pharma; AMG 876 from Amgen; GSK3052230 from Glaxo (recombinant PTH 1-34) from Eli Lilly; NU-100 from Nuron SmithKline; RG7813 from Roche; SAR342434, Lantus from Biotech, Inc.; Calaspargase Pegol from Sigma-Tau Pharma Sano?; AZ01 fromAllozyne Inc. ; ARX424 fromAmbrx, Inc.; ceuticals, Inc.; ADI-PEG-20 from Polaris Pharmaceuticals, FP-1040, FP-1039 from FivePrime Therapeutics, Inc.; ATX MS-1467 from Merck KGaA; XTEN fusion proteins from Inc.; BMN-110, BMN-702 from BioMarin; NGR-TNF from Molmed S.p.A.; recombinant human C1 esterase inhibitor Amunix Operating Inc.; entolimod (CBLB502) from Cleve from Pharming Group/Santarus Inc.; Somatropin biosimilar land BioLabs, Inc.; HGT2310 from Shire; HM10760A from from LG Life Sciences LTD; Natpara from NPS Pharmaceu Hanmi Pharmaceuticals Co., LTD; ALXNl 102/ALXN1 103 ticals, Inc.; ART123 from Asahi Kasei Corporation; BAX from Alexion; CSL-689, CSL-627 from CSL Behring; glial 111 from Baxter; OBI-1 from Inspiration Biopharmaceuti growth factor 2 from Acorda Therapeutics, Inc.; NX001 from cals; Wilate from Octapharma AG; Talactoferrin alfa from Nephrx Corporation; NN8640, NN1436, NN1953, NN9926, Agennix AG; Desmoteplase from Lundbeck; Cinryze from NN9927, NN9928 from Novo Nordisk; NHS-IL 12 from Shire; RG7421 and Roche and Exelixis, Inc.; Midostaurin EMD Serono; 3K3A-APC from ZZ Biotech LLC; PB-1046 (PKC412) from Novartis AG; Damoctocog alfa pegol, BAY from PhaseBio Pharmaceuticals, Inc.; RU-101 from R-Tech 86-6150, BAY 94-9027 from Bayer AG; Peginterferon Ueno, Ltd.; insulin lispro/BC106 from Adocia; h1-con1 from lambda-1a, Nuloj ix (Belatacept) from Bristol-Myers Squibb; Iconic Therapeutics, Inc.; PRT-105 from Protalix BioThera Pergoveris, Corifollitropin alfa (MK-8962) from Merck peutics, Inc.; PF-04856883, CVX-096 from P?zer; ACP-501 KGaA; recombinant coagulation Factor IX Fc fusion protein fromAlphaCore Pharma LLC; BAX-855 from Baxter; CDX (rFIXFc; BIIB029) and recombinant coagulation Factor VIII 1 135 from Celldex Therapeutics; PRM-151 from Promedior, Fc fusion protein (rFVIIIFc; BIIB031) from Biogen; and Inc.; TS01 from Thrombolytic Science International; TT-173 Myalept from AstraZeneca. from Thrombotargets Corp.; OBI-139 from Quintessence Biosciences, Inc.; Vatelizumab, GBR500, GBR600, [0190] Other early stage protein biologics Which can be GBR830, and GBR900 from Glenmark Pharmaceuticals; and formulated With viscosity-lowering water ionic liquids CYT-6091 from Cytimmune Sciences, Inc. include Alferon LDO from Hemispherx BioPharma, Inc.; SL-401 from Stemline Therapeutics, Inc.; PRX-102 from [0191] Other Biologic Agents Protalix Biotherapeutics, Inc.; KTP-001 from Kaketsuken/ [0192] Other biologic drugs that can be formulated With Teij in Pharma Limited; Vericiguat from BayerAG; BMN-l 1 1 viscosity-lowering ionic liquids include PF-05285401, from BioMarin; ACC-001 (PF-05236806) from Janssen; PF-05231023, RN317 (PF-05335810), PF-06263507, LY2510924, LY2944876 from Eli Lilly; NN9924 from Novo PF-05230907, Dekavil, PF-06342674, PF06252616, Nordisk; INGAP peptide from Exsulin; ABT-122 from RG7598, RG7842, RG7624d, OMP54F28, GSK1995057, Abbvie; AZD9412 from AstraZeneca; NEUBLASTIN BAY1179470, IMC-3G3, IMC-18F1, IMC-35C, IMC (BG00010) from Biogen; Luspatercept (ACE-536), Sotater 20D7S, PF-06480605, PF-06647263, PF-06650808, US 2015/0071922 A1 Mar. 12, 2015

PF-05335810 (RN317) PD-0360324, PF-00547659 from P?zer; MK-8237 from Merck; BI033 from Biogen; @/ GZ402665, SAR438584/REGN2222 from Sano?; IMC 18Fl; and Icrucumab, IMC-3G3 from ImClone LLC; Ryzo deg, Tresiba, Xultophy from Novo Nordisk; Toujeo (U300), o .61 LixiLan, Lyxumia (lixisenatide) from Sano?; MAGE-A3 N H immunotherapeutic from GlaxoSmithKline; Tecemotide from Merck KGaA; Sereleaxin (RLX03 0) from Novartis AG; K/\ O Erythropoietin; Peg?lgrastim; LY2963016, Dulaglutide (LY2182965) from Eli Lilly; and Insulin Glargine from Boe Derivatives of BMI Mes can be obtained, for example, by hringer Ingelheim. substituting the methanesulfonate constituent for other [0193] B. Ionic Liquids anionic constituents, replacing one or more carbons with a [0194] The viscosity of liquid protein formulations, includ heteroatom, replacing the N-butyl or N-methyl group with ing low-molecular-weight and/ or high-molecular-weight one or more higher-order N-alkyl groups, attaching addi proteins, is reduced by the addition of one or more viscosity tional substituents to one or more carbon atoms, or a combi reducing ionic liquids. The pharmaceutical formulations may nation thereof. Exemplary anionic constituents are described be converted from non-Newtonian to Newtonian ?uids by the above. Exemplary heteroatoms include N, O, P, and S. Exem addition of an effective amount of one or more viscosity plary higher-order N-alkyl groups include substituted and reducing ionic liquids. unsubstituted N-alkyl and N-heteroalkyl groups containing Ionic Liquid Salts from 1 to 30 carbon atoms, preferably from 1 to 12 carbon [0195] atoms. Examples of higher-order N-alkyl groups include [0196] The ionic liquid can be a salt. Representative ionic N-ethyl, N-propyl, N-butyl, N-sec-butyl, and N-tert-butyl. liquid salts include salts with imidazolium cations, including Additional substituents can include hydroxyl and substituted N,N-dialkyl-imidazoliums. Ionic liquids include salts with and unsubstituted alkoxy, heteroalkoxy, alkyl, aryl, aralkyl, N-alkylated unsaturated or saturated nitrogen-containing het aryloxy, aralkyloxy, heteroalkyl, alkenyl, and alkynyl groups erocyclic cations, including N-alkylpyridinium salts, N-alky having from 1 to 30, preferably from 3 to 20 carbon atoms. lpyrrolidinium salts, and N-alkylpiperidinium salts. In pre [0199] The ionic liquid can be l-butyl-l-methylpyrroli ferred embodiments, the ionic liquid is pharmaceutically acceptable and miscible with water. dinium chloride (BMP chloride) having the structure shown below or a derivative thereof. [0197] In some embodiments, the ionic liquid contains a cationic constituent having a cationic heterocyclic group with one or more alkyl, heteroalkyl, alkenyl, or alkynyl substitu ents having from 2 to 50 carbon atoms, from 3 to 30 carbon atoms, or from 4 to 12 carbon atoms. Suitable anionic con i 99> 016 stituents include halide ions, sulfate, sulfonate, sul?te, sul? nate, phosphate, phosphonate, phosphite, phosphonite, car /L/\ bonate, and carboxylate anions optionally substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic groups, preferably having from 1 to 20 or from Derivatives of BMP chloride can be obtained, for example, by 1 to 12 carbon atoms. Exemplary anionic constituents include substituting the chloride constituent for other anionic con chloride, bromide, methylphosphate, methyl-ethyl-phos stituents, replacing one or more ring carbons with a heteroa phate, methylsulfate, methylsulfonate, formate, acetate, tom, replacing the N,N-butyl-methyl group with one or more butyrate, citrate, carbonate, methyl carbonate, and lactate. higher-order N,N-dialkyl groups, attaching one or more addi The cationic heterocyclic group can be saturated or unsatur tional substituents to a carbon atom, or a combination thereof. ated. Saturated cationic heterocyclic groups include pyrroli Exemplary anionic constituents include those described dinium, oxazolidinium, piperidinium, piperaZinium, mor above. Exemplary heteroatoms include N, O, P, and S. Exem pholinium, thiomorpholinium, and azepanium groups, and plary higher-order N,N-dialkyl groups include linear, the like. Unsaturated cationic heterocyclic groups include branched, and cyclic N-alkyl and N-heteroalkyl groups con pyrrolinium, imidazolinium, 1,2,3-triazolium, 1,2,4-triazo taining from 2 to 30 carbon atoms, preferably from 3 to 12 lium, thiazolium, 1,2,4-dithiazolium, 1,4,2-dithiazolium, tet carbon atoms. Examples of higher-order N,N-dialkyl groups razolium, pyrazolinium, oxazolinium, pyridinium, and aze include N-ethyl-N-methyl; N-isopropyl-N-methyl; N-butyl pinium groups, and the like. The cationic heterocyclic group N-methyl; N,N-diethyl; N-ethyl-N-isopropyl; N,N-diisopro can be a fused ring structure having two, three, four, or more pyl groups, and the like. Additional substituents can include fused rings. The cationic heterocyclic group can be a bicyclic hydroxyl, and substituted and unsubstituted alkoxy, het cationic heterocycle, such as benzoxazolium, benzothiazo eroalkoxy, alkyl, heteroalkyl, aryl, aryloxy, aralkyl, aralky lium, benzotriazolium, benZimidazolium, and indolium loxy, alkenyl, and alkynyl groups having from 1 to 30, pref groups, and the like. The cationic heterocyclic group can be erably from 3 to 20 carbon atoms. substituted with one or more additional substituents, includ [0200] In some embodiments, the ionic liquid contains a ing hydroxyl and substituted and unsubstituted alkoxy, het cationic constituent having a structure according to Formula eroalkoxy, alkyl, heteroalkyl, alkenyl, and alkynyl groups I where each occurrence of R1 is independently selected from having from 1 to 30, preferably from 3 to 20 carbon atoms. hydrogen and substituted and unsubstituted alkyl, het [0198] The ionic liquid can be l-butyl-3-methylimidazo eroalkyl, aryl, aralkyl, alkenyl, and alkynyl groups having lium methanesulfonate (BMI Mes) having the structure from 1 to 30 carbon atoms, from 3 to 20 carbon atoms, or from shown below or a derivative thereof. 4 to 12 carbon atoms; where each occurrence of R2 is inde