CA2943398A1 - Low viscosity antibody compositions - Google Patents

Abstract

The present invention relates generally to the field of pharmaceutical formulations of antibodies. Specifically, the present invention relates to a stable low-viscosity antibody formulation and its pharmaceutical preparation.

Description

LOW VISCOSITY ANTIBODY COMPOSITIONS
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical formulations of antibodies.
Specifically, the present invention relates to a low viscosity liquid antibody formulation and its pharmaceutical preparation.
BACKGROUND
Antibody preparations intended for therapeutic or prophylactic use require stabilizers to prevent loss of activity or structural integrity of the protein due to the effects of denaturation, oxidation or aggregation over a period of time during storage and transportation prior to use. These problems are exacerbated at the high concentrations of antibody often desired for therapeutic administration. In addition, formulation constituents, such as sugars, may further exacerbate the self-association tendency of the antibody and high concentrations of these stabilizing excipients can lead to high viscosities.
A major aim in the development of antibody formulations is to maintain antibody solubility, stability and potency of its antigen binding. It is particularly desirable to avoid antibody self-association, aggregates, and particulates in solution which would require sterile filtration before use for intravenous or subcutaneous injection and limit route of administration.
Antibody aggregates can cause pain and anaphylactoid side effects when the formulation containing them is intravenously injected. Moreover, self-associated antibodies and aggregates present increased difficulties for subcutaneous (Sc) administration. The ease of injection for sc administration is described as extrusion force, the force required to extrude the composition from the syringe. The viscosity of the liquid composition is directly related to the required extrusion force: more viscous compositions require greater extrusion force.
Alternatively, a larger diameter needle or a longer injection time may be required to administer the desired dose. As a result, high viscosity compositions present a greater risk for pain at the injection site, and thus may negatively impact patient compliance.
Self-associated antibodies exhibit high viscosity and result in difficulty in manufacturing.
Tangential flow filtration is often used in manufacturing for buffer exchange and protein concentration. High viscosity compositions create additional back pressure and shear stress during this process, which can increase the processing time and destabilize the *
. antibody. One solution to self-association of antibody therapeutics is to formulate the therapeutic in a viscosity lowering composition.
Viscosity lowering excipients, surfactants, pH, and cryoprotectant/tonicity agents such as sugars may contribute to overcoming self-association problems. Some viscosity lowering excipients have been explored including arginine, histidine, lysine, and camphor-10-sulfonic acid. Zheng Guo et al., "Structure-Activity Relationship for Hydrophobic Salts as Viscosity-Lowering Excipients for Concentrated Solutions of Monoclonal Antibodies", Pharmaceutical Research, vol. 29, no. 11, June 13, 2012, p.3182-3189. However, a need still exists for lowered viscosity antibody compositions which support high concentrations of 1.0 bioactive antibody in solution and may be suitable for parenteral administration, including intravenous intramuscular, intraperitoneal, intradermal or subcutaneous injection.
SUMMARY
One aspect of the present invention includes pharmaceutical compositions comprising a.
an antibody, wherein the antibody concentration is between about 100 mg/ml to about 400 mg/ml, and b. a viscosity lowering excipient comprising camphorsulfonic acid, sulfosalicylic acid, a salt of camphorsulfonic acid or a salt of sulfosalicylic acid, wherein the viscosity lowering excipient concentration is between about 30 mM to about 200 mM;
wherein the pH of said composition is from about 4.0 to about 9Ø
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A depicts a graph comparing the viscosity of anti-IL-7R antibody formulation at different pH values.
FIG. 16 depicts a graph comparing the viscosity of anti-IL-7R antibody formulation at different pH values.
FIG. 2A depicts a graph comparing the viscosity of anti-IL7R antibody formulation with and without camphorsulfonic acid.

2 =
. FIG. 2B depicts a graph comparing the viscosity of anti-IL7R
antibody formulation with and without camphorsulfonic acid.
FIG. 3 depicts a graph comparing the viscosity of anti-IL7R antibody formulation with a combination of camphorsulfonic acid and arginine, and arginine HCI.
FIG 4 depicts a graph comparing the viscosity of anti-IL7R antibody formulation at varying concentrations of camphorsulfonic acid, camphorsulfonic acid and arginine, and arginine HCI.
FIG. 5 depicts a graph comparing the viscosity of anti-glucagon receptor antibody (XX1) and anti-PCSK9 receptor antibody (XX2) formulations.
1.0 FIG. 6 depicts a graph comparing the viscosity of anti-glucagon receptor antibody (XXI) and anti-PCSK9 receptor antibody (XX2) with camphorsulfonic acid, camphorsulfonic acid and arginine, and arginine HCI.
FIG. 7A depicts a graph comparing the viscosity of anti-glucagon receptor antibody (XXI) and anti-PCSK9 receptor antibody (XX2) with varying levels of camphorsulfonic acid, camphorsulfonic acid and arginine, and arginine HCI.
FIG. 7B depicts a graph cornparing the viscosity of anti-glucagon receptor antibody (XXI) and anti-PCSK9 receptor antibody (XX2) with varying levels of camphorsulfonic acid, camphorsulfonic acid and arginine, and arginine HCI.
DETAILED DESCRIPTION
The present invention may be understood even more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein. Unless stated otherwise, the concentrations listed herein are those concentrations at ambient conditions, [i.e., at 25 C and atmospheric pressure].
Before the present compositions and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The plural and singular should be treated as interchangeable, other than the indication of

3 = number. As used in this specification, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.
The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.
An "antibody" is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (ScFv) and domain antibodies), and fusion proteins comprising an antibody portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.
An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2, which denote differences in the constant region, particularly in the hinge and upper CH2 domain. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Following human IgG1 EU numbering and beginning at the 216 position, the isotypes have the following sequences:
IgG1: EPKSCDKTHTCPPCP
IgG2: ERKCCVE---CPPCP
IgG4: ESKYGPP---CPSCP

4 = As used herein, "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or may be made by recombinant DNA methods such as described in U.S.
Pat.
No. 4,816,567. The monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCafferty et al., 1990, Nature 348:552-554, for example.
A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) that contain hypervariable regions. The identity of the amino acid residues in a particular antibody that make up a CDR can be determined using methods well known in the art. For example, antibody CDRs may be identified as the hypervariable regions originally defined by Kabat et al (Kabat et a/.,1991, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C., N1H Publication No. 91-3242). The positions of the CDRs may also be identified as the structural loop structures described by Chothia and others (Chothia et al., 1989, Nature 342:877-883). Other approaches to CDR

identification include the "AbM definition," which is a compromise between Kabat and Chothia and is derived the Abysis program (www.abysis.org), or the "contact definition" of CDRs based on observed antigen contacts, set forth in MacCallum et al., 1996, J. Mol.
Biol., 262:732-745. North has identified canonical CDR conformations using a different preferred set of CDR definitions (North et al., 2011, J. Mol. Biol, 406: 228-256). In another

5 =
' approach, referred to herein as the "conformational definition" of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding (Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166).
Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs (or other residue of the antibody) may be defined in accordance with any of Kabat, Chothia, North, extended, AbM, contact, and/or conformational definitions.
As known in the art a "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.
The "hinge region" of an antibody consists of a flexible domain that joins the Fab arms to the Fc region.
The antibody of the present invention is selected from the group of monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab')2, Fv, Fc, ScFv etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion (e.g., a domain antibody), humanized antibodies, human antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibody may be murine, rat, human, or any other origin (including chimeric or humanized antibodies). In some embodiments, the antibody can be human but is more preferably humanized. Preferably the antibody is isolated, further preferably it is substantially pure. Where the antibody is an antibody fragment this preferably retains the functional characteristics of the original antibody i.e. the ligand binding and/or antagonist or agonist activity.
b . In one embodiment of the present invention the antibody heavy chain constant region may be from any type of constant region, such as IgG, IgM, IgD, IgA, and IgE; and any isotypes, such as IgGI , IgG2, IgG3, and IgG4. In another embodiment, the antibody is an IgG2 antibody.
According to the present invention, the antibody can comprise the human heavy chain IgG2a constant region. In some embodiments the antibody comprises the human light chain kappa constant region. In some embodiments, the antibody comprises a modified constant region, such as a constant region that is immunologically inert, e.g., does not trigger complement mediated lysis, or does not stimulate antibody-dependent cell mediated cytotoxicity (ADCC). In other embodiments, the constant region is modified as described in Eur. J. Immunol. (1999) 29:2613-2624; PCT publication No. W0099/58572; and/or UK
Patent Application No. 9809951.8. In still other embodiments, the antibody comprises a human heavy chain IgG2a constant region comprising the following mutations:

to S330S331 (amino acid numbering with reference to the wildtype IgG2a sequence), Eur.
J. lmmunol. (1999) 29:2613-2624.
As used herein, the antibody does not necessarily comprise an identical amino acid sequence of the amino acid sequence described herein. An antibody that has a similar amino acid sequence refers to an antibody analog that satisfies at least one of the following: (a) an amino acid sequence that is at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 99%
identical to the amino acid sequence of any of the antibodies or portions of antibodies described herein; (b) an antibody encoded by a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence encoding the antibody of at least about 5 contiguous amino acid residues, at least about 10 contiguous amino acid residues, at least about 15 contiguous amino acid residues, at least about 20 contiguous amino acid residues, at least about 25 contiguous amino acid residues, at least about 40 contiguous amino acid residues, at least about 50 contiguous amino acid residues, at least about 60 contiguous amino residues, at least about 70 contiguous amino acid residues, at least about 80 contiguous amino acid residues, at least about 90 contiguous amino acid residues, at least ..
. about 100 contiguous amino acid residues, at least about 125 contiguous amino acid residues, or at least about 150 contiguous amino acid residues to the amino acid sequences described herein; or (c) an antibody encoded by a nucleotide sequence that is at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 99% identical to the nucleotide sequence encoding the any of the antibodies or portions of antibodies described herein.
To determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., A) identity=number of identical overlapping positions/total number of positions×100%). In one embodiment, the two sequences are the same length.
The determination of percent identity between two sequences can also be accomplished using a mathematical algorithm. One, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc.
Natl. Acad. Sci. U.S.A. 90:5873-5877. Such an algorithm is incorporated into the NBLAST
and XBLAST programs of Altschul et ah, 1990, J. Mol. Biol. 215:403. BLAST
nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the present invention. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score-50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule of the present invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in . Altschul et al, 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id). When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., the NCB1website). Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.
The formulations of the present invention include at least one antibody. In some embodiments, more than one antibody may be present. At least one, at least two, at least three, at least four, at least five, or more, different antibodies may be present. Generally, the two or more different antibodies have complementary activities that do not adversely affect each other. The, or each, antibody can also be used in conjunction with other agents that serve to enhance and/or complement the effectiveness of the antibodies.
In one embodiment of the present invention the concentration of antibody can range from about 50 mg/ml to about 450 mg/ml. In other embodiments, the concentration of antibody is about 50 mg/ml, about 70 mg/ml, about 90 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about 180 mg/ml, about 190 mg/ml, about 200 mg/ml, about 210 mg/ml, about 220 mg/ml, about 230 mg/ml, about 240 mg/ml, about 250 mg/ml, about 260 mg/ml, about 270 mg/ml, about 280 mg/ml, about 290 mg/ml, about 300 mg/ml, about 310 mg/ml, about 320 mg/ml, about 330 mg/ml, about 340 mg/ml, about 350 mg/ml, about 370 mg/ml, about 390 mg/ml, about 400 mg/ml, about 420 mg/ml, or about 450mg/ml. In some embodiments, the concentration of the antibody in the formulation is between about 50 mg/ml and about 400 mg/ml, between about 100 mg/ml and about 400 mg/ml, between about 100 mg/ml and about 350 mg/ml, between about 100 mg/ml and about 300 mg/ml, between about 100 mg/ml and about 250 mg/ml, between about 100 mg/ml and about mg/ml, between about 120 mg/ml and 200 mg/ml, between about 150 mg/ml and about 200 mg/ml, or between about 165 mg/ml and about 215 mg/ml.

' "Isolated" when used to describe the various antibodies disclosed herein, means a polypeptide or antibody that has been identified, separated and/or recovered from a component of its production environment. Contaminant components of its production environment, such as that resulting from recombinant transfected cells, are materials that would typically interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody in the antibody formulation is purified prior to being added to the antibody formulation. The terms "isolate," and "purify" refer to separating the antibody from an impurity or other contaminants in the composition which the antibody resides, e.g., a composition comprising host cell proteins. In some embodiments, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, at least about 99.5%, at least about or 99.9%
(w/w) of an impurity is purified from the antibody.
Throughout the present disclosure, all expressions of percentage, ratio, and the like are "by weight" unless otherwise indicated. As used herein, "by weight" is synonymous with the term "by mass," and indicates that a ratio or percentage defined herein is done according to weight rather than volume, thickness, or some other measure.
"Camphorsulphonic acid" (CSA) means camphor-10-sulphonic acid or the compound of formula CSA. CSA is represented by the chemical formula:
so3H

o CSA
"CSA" includes all hydrate/solvate forms including the anhydrous form as well as the free base form, as well as any salt form. "CSA" includes all enantiomers (e.g., (+)camphorsulphonic acid and (-)camphorsulphonic acid), and any combination of enantiomers (e.g., 50% (+)camphorsulphonic acid and 50% (-)camphorsulphonic acid;

= 90%-100% (+)camphorsulphonic acid and 10 /o-0% (-)camphorsulphonic acid, etc.). In some embodiments, the term "GSA" includes greater than 99% (+)camphorsulphonic acid and less than 1`)/0 (-)camphorsulphonic acid. In some embodiments, the term "GSA"
includes an enantomerically pure (+)camphorsulphonic acid.
s Exemplary pharmaceutically acceptable acid salts may be formed from counterions and include sodium, arginine, lysine, histidine, and include all hydrates, solvates, and enantiomers thereof.
The present invention includes various amounts of GSA. In some embodiments, the amount of GSA is greater than about 5 mM, greater than about 10 mM, greater than about 15 mM, greater than about 20 mM, greater than about 25 mM, greater than about 30 mM, greater than about 35 mM , greater than about 50 mM , greater than about 75 mM
, greater than about 100 mM , greater than about 125 mM , greater than about 150 mM , greater than about 200 mM , greater than about 225 mM , or greater than about 250 mM.
In some embodiments, the amount of GSA in the formulation is between about 5 mM and about 250 mM , between about 10 mM and about 200 mM, between about 20 mM and about 200 mM, between about 30 mM and about 200 mM, between about 30 mM and about 150 mM, or between about 30 mM and about 100 mM.
When present as the GSA salt form, the concentration of GSA and the counterion can be the same or different. For example, a salt of GSA formed with arginine (GSA-Arg) with a concentration of 50mM has a GSA concentration of 50mM and an arginine concentration of 50mM. However, more or less arginine (counterion) could be present, whereby not all of the GSA or counterion is in the salt form.
"Arginine" (Arg) is an amino acid that can be represented by the chemical formula:

Arginine = "Arginine" includes all hydrate/solvate forms including the anhydrous form as well as the free base form, as well as any salt form, including without limitation Arginine hydrochloride (Arg-HCI). Arginine includes all enantiomers (e.g., L-arginine and D-arginine), and any combination of enantiomers (e.g., 50% L-arginine and 50% D-arginine; 90%-100%
L-arginine and 10%-0% D-arginine, etc.). In some embodiments, the term "arginine" includes greater than 99% L-arginine and less than 1% D-arginine. In some embodiments, the term "arginine" includes an enantomerically pure L-arginine. In some embodiments, the arginine is a pharmaceutical grade arginine.
"Histidine" is an amino acid that can be represented by the chemical formula:

N
< I OH

HN
Histidine "Histidine" includes all hydrate/solvate forms including the anhydrous form as well as the free base form, as well as any salt form, including without limitation histidine hydrochloride.
"Histidine" includes all enantiomers (e.g., L-histidine and D-histidine), and any combination of enantiomers (e.g., 50% L- histidine and 50% D- histidine; 90%-100% L-histidine and 10%-0% D- histidine, etc.). In some embodiments, the term "histidine" includes greater than 99% L- histidine and less than 1% D- histidine. In some embodiments, the term "histidine" includes an enantomerically pure L- histidine. In some embodiments, the histidine is a pharmaceutical grade histidine.
"Lysine" is an amino acid that can be represented by the chemical formula:

OH

Lysine "Lysine" includes all hydrate/solvate forms including the anhydrous form as well as the free base form, as well as any salt form, including without limitation lysine hydrochloride.
"Lysine" includes all enantiomers (e.g., L-lysine and D-lysine), and any combination of enantiomers (e.g., 50% L- lysine and 50% D- lysine; 90%-100% L- lysine and 10%-0% D-lysine, etc.). In some embodiments, the term "lysine" includes greater than 99% L- lysine and less than 1 /0 D- lysine. In some embodiments, the term "lysine" includes an enantomerically pure L- lysine. In some embodiments, the lysine is a pharmaceutical grade lysine.
By "chelating agent" is meant an optional composition component that can form at least one bond (e.g., covalent, ionic, or otherwise) to a metal ion. Exemplary chelating agents include aminopolycarboxylic acids, hydroxyaminocarboxylic acids, N-substituted glycines, 2- (2-amino-2-oxocthyl) aminoethane sulfonic acid (BES), deferoxamine (DEF), citric acid, niacinamide, and desoxycholates and mixtures thereof. In one embodiment, the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriamine pentaacetic acid 5 (DTPA), nitrilotriacetic acid (NTA), N-2-acetamido-2-iminodiacetic acid (ADA), bis(aminoethyl)glycolether, N,N,N',N'-tetraacetic acid (EGTA), trans-diaminocyclohexane tetraacetic acid (DCTA), glutamic acid, and aspartic acid, N-hydroxyethyliminodiacetic acid (HIMDA), N,N-bis-hydroxyethylglycine (bicine) and N-(trishydroxymethylmethyl) 10 glycine (tricine), glycylglycine, sodium desoxycholate, ethylenediamine; propylenediamine; diethylenetriamine; triethylenetetraamine (trien), ethylenediaminetetraaceto EDTA; disodium EDTA, calcium EDTA oxalic acid, malate, citric acid, citric acid monohydrate, and trisodium citrate-dihydrate, 8-hydroxyquinolate, amino acids, histidine, cysteine, methionine, peptides, polypeptides, and proteins and mixtures thereof. In another embodiment, the chelating agent is selected from the group consisting of salts of EDTA including dipotassium EDTA, disodium EDTA, EDTA calcium disodium, sodium EDTA, trisodium EDTA, and potassium EDTA; and a suitable salt of deferoxamine (DEF) is deferoxamine mesylate (DFM), or mixtures thereof. Chelating agents used in the invention can be present, where possible, as the free acid or free base form or salt form of the compound, also as an anhydrous, solvated or hydrated form of the compound or corresponding salt.

= The concentration of chelating agent, when present, generally ranges from about 0.01 mg/ml to about 50 mg/ml, from about 0.01 mg/ml to about 10.0 mg/ml, from about 0.01 mg/ml to about 5.0 mg/ml, from about 0.01 mg/ml to about 1.0 mg/ml, or from about 0.01 mg/ml to about 0.3 mg/ml. In another embodiment, the concentration of chelating agent generally ranges from about 0.01 mM to about 2.0 mM, from about 0.01 mM to about 1.5 mM, from about 0.01 mM to about 0.5 mM, from about 0.01 mM to about 0.4 mM, from about 0.01 mM to about 0.2 mM, from about 0.01 mM to about 0.15 mM, from about 0.01 mM to about 0.1 mM, from about 0.01 mM to about 0.09 mM, from about 0.01 mM to about 0.08 mM, from about 0.01 mM to about 0.07 mM, from about 0.01 mM to about 0.06 mM, io from about 0.01 mM to about 0.05 mM, from about 0.01 mM to about 0.04 mM, from about 0.01 mM to about 0.03 mM, from about 0.01 mM to about 0.02 mM or from about 0.005 mM to about 0.01 mM. In another embodiment, the concentration of chelating agent can be about 0.01 mg/ml, 0.02 mg/ml, 0.03 mg/ml, about 0.04 mg/ml, about 0.05 mg/ml, about 0.06 mg/ml, about 0.07 mg/ml, about 0.10 mg/ml, about 0.20 mg/ml.
A "cryoprotectant" is an optional composition component that is a molecule which, when combined with a protein of interest, significantly prevents or reduces chemical and/or physical instability of the protein upon lyophilization and subsequent storage. Exemplary cryoprotectants include sugars and their corresponding sugar alcohols; an amino acid such as monosodium glutamate or histidine; a methylamine such as betaine; a lyotropic salt such as magnesium sulfate; a polyol such as trihydric or higher molecular weight sugar alcohols, e.g. glycerin, dextran, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol;
propylene glycol; polyethylene glycol; Pluronics®; and combinations thereof. Additional exemplary cryoprotectants include glycerin and gelatin, and the sugars mellibiose, melezitose, raffinose, mannotriose and stachyose. Examples of reducing sugars include glucose, maltose, lactose, maltulose, iso-maltulose and lactulose. Examples of non-reducing sugars include non-reducing glycosides of polyhydroxy compounds selected from sugar alcohols and other straight chain polyalcohols including sucrose, dextrose, mannose and trehalose (including all forms of trehalose such as trehalose monohydrate and trehalsoe dihydrate). Example sugar alcohols are monoglycosides, especially those compounds obtained by reduction of disaccharides such as lactose, maltose, lactulose and maltulose. The glycosidic side group can be either glucosidic or galactosidic.
Additional examples of sugar alcohols are glucitol, maltitol, lactitol and iso-maltulose.

. The concentration of the cryoprotectant, when present in the liquid composition, ranges from about 0.1 mg/ml to about 150 mg/ml, from about 0.1 mg/ml to about 100 mg/ml, or from about 1 mg/ml to about 100 mg/ml. In one embodiment, the concentration of the cryoprotectant in the liquid composition is about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, or about 150 mg/ml.
Where the cryoprotectant comprises a salt, the concentration of the salt in the liquid composition ranges from about 1 mg/ml to about 20 mg/ml. Salts that are pharmaceutically acceptable and suitable for this invention include sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. Exemplary salts include sodium chloride and magnesium chloride, magnesium chloride may also improve the antibody stability by protecting the protein from deamidation.
In one embodiment, the salt in the liquid composition is selected from a range of concentrations of any of about 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8, mg/ml, 9 mg/ml, 10 mg/ml, 11 mg/ml, 12 mg/ml, 13 mg/ml, 14 mg/ml, 15 mg/ml, 16 mg/ml, 17 mg/ml, 18 mg/ml, 19 mg/ml and 20 mg/ml.
The term "injection force" is the amount of pressure (in Newtons) required to pass the antibody formulation through a needle. The injection force is correlated with the amount of resistance provided by the antibody formulation when administering the antibody formulation to a subject. The injection force will be dependent on the gauge of the administering needle, as well as temperature. In some embodiments, the antibody formulation has an injection force of less than 15 N, 12 N, 10N, or 8 N when passed through a 27 Ga thin wall PFS needle such as defined in the International Organization for Standardization (ISO) document "Stainless steel needle tubing for the manufacture of medical devices" (ISO 9626:1991) and manufactured by BD Medical, Pharmaceutical Systems (Franklin Lakes, N.J.). In some embodiments, the antibody formulation has an injection force of less than 15 N, 12 N, 10N, or 8 N when passed through a 25 or 26 Gauge needle.

= An "isotonic" formulation is one which has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to about 350 mOsm. The term "hypotonic" describes a formulation with an osmotic pressure below that of human blood. Correspondingly, the term "hypertonic" is used to s describe a formulation with an osmotic pressure above that of human blood. Isotonicity can be measured using a vapor pressure or ice-freezing type osmometer, for example. In one embodiment, the compositions of the present invention are isotonic.
The term "IV bag protectant" refers to the surfactant added to the intravenous bag prior to dilution of the antibody formulation described herein into the intravenous bag. The IV bag protectant can also be added to the intravenous bag prior to addition of other antibody formulations known to those of skill in the art, e.g., a lyophilized antibody formulation.
Surfactants suitable for use as an IV bag protectant will generally be those suitable for use in IV formulations. In some embodiments, the surfactant used in the IV bag protectant is the same buffer used in the antibody formulation. For example, if the antibody formulation comprises polysorbate 80 as a surfactant, then polysorbate 80 would be added to the intravenous bag prior to adding the antibody formulation to the intravenous bag. In some embodiments, the surfactant concentration in the IV bag resulting from addition of the IV
protectant will be about the same or only a portion of the surfactant concentration in the antibody formulation. Knowing the desired final concentration of surfactant in the IV bag, one can formulate the desired concentration of the surfactant in the IV bag protectant.
The term "Koff", as used herein, is intended to refer to the off rate constant for dissociation of an antibody from the antibody/antigen complex. The term "Kd", as used herein, is intended to refer to the dissociation constant of an antibody-antigen interaction. One way of determining the Kd or binding affinity of antibodies to the antigen is by measuring binding affinity of monofunctional Fab fragments of the antibody. To obtain monofunctional Fab fragments, an antibody (for example, IgG) can be cleaved with papain or expressed ) recombinantly. The affinity of a Fab fragment of an antibody can be determined by surface plasmon resonance (BlAc0rC1GM000Tm surface plasmon resonance (SPR) system, BlAcore, INC, Piscaway NJ). CM5 chips can be activated with N-ethyl-N'-(3-dimethylaminopropyI)-carbodiinide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. Human antigen can be diluted into 10 mM sodium acetate pH 4.0 and injected over the activated chip at a concentration of 0.005 mg/mL.
Using variable flow time across the individual chip channels, two ranges of antigen density can be achieved: 100-200 response units (RU) for detailed kinetic studies and for screening assays. Serial dilutions (0.1-10x estimated Kd) of purified Fab samples are injected for 1 min at 100 microliters/min and dissociation times of up to 2 hours are allowed. The concentrations of the Fab proteins are determined by ELISA and/or SDS-PAGE electrophoresis using a Fab of known concentration (as determined by amino acid analysis) as a standard. Kinetic association rates (Icon) and dissociation rates (koff) are obtained simultaneously by fitting the data to a 1:1 Langmuir binding model (Karlsson, R.
Roos, H. Fagerstam, L. Petersson, B. (1994). Methods Enzymology 6.99-110) using the BlAevaluation program. Equilibrium dissociation constant (Kd) values are calculated as koff/kon. This protocol is suitable for use in determining binding affinity of an antibody to any antibody.
The antibody formulations can have different "osmolarity" concentrations.
Methods of measuring osmolarity of antibody formulations are known to those in the art, and can include, e.g., an osmometer (e.g., an Advanced Instrument Inc 2020 freezing point depression osmometer). In some embodiments, the formulation has an osmolarity of between 200 and 600 mosm/kg, between 260 and 500 mosm/kg, or between 300 and mosm/kg. In some embodiments, the formulation does not comprise an osmolyte.
The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or can be safely administered to a subject.
A "pharmaceutically acceptable acid" includes inorganic and organic acids which are non toxic at the concentration and manner in which they are formulated. For example, suitable inorganic acids include hydrochloric, perchloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfonic, sulfinic, sulfanilic, phosphoric, carbonic, etc. Suitable organic acids include straight and branched-chain alkyl, aromatic, cyclic, cyloaliphatic, arylaliphatic, heterocyclic, saturated, unsaturated, mono, di- and tri-carboxylic, including for example, formic, acetic, 2-hydroxyacetic, trifluoroacetic, phenylacetic, trimethylacetic, t-butyl acetic, anthranilic, propanoic, 2-hydroxypropanoic, 2-oxopropanoic, propandioic, cyclopentanepropionic, ' cyclopentane propionic, 3-phenylpropionic, butanoic, butandioic, benzoic, 3-(4-hydroxybenzoyl)benzoic, 2-acetoxy-benzoic, ascorbic, cinnamic, lauryl sulfuric, stearic, muconic, mandelic, succinic, embonic, fumaric, malic, maleic, hydroxymaleic, malonic, lactic, citric, tartaric, glycolic, glyconic, gluconic, pyruvic, glyoxalic, oxalic, mesylic, succinic, salicylic, phthalic, palmoic, palmeic, thiocyanic, methanesulphonic, ethanesulphonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulphonic, 4-chorobenzenesulfonic, napthalene-2-sulphonic, p-toluenesulphonic, camphorsulphonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 4,4'-methylenebis-3-(hydroxy-2-ene-1-carboxylic acid), hydroxynapthoic.
"Pharmaceutically-acceptable bases" include inorganic and organic bases which are non-toxic at the concentration and manner in which they are formulated. For example, suitable bases include those formed from inorganic base forming metals such as lithium, sodium, potassium, magnesium, calcium, ammonium, iron, zinc, copper, manganese, aluminum, N-methylglucamine, morpholine, piperidine and organic nontoxic bases including, primary, secondary and tertiary amine, substituted amines, cyclic amines and basic ion exchange resins, [e.g., N(R')₄ + (where R' is independently H or C_1-4 alkyl, e.g., ammonium, Tris)], for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
Additional pharmaceutically acceptable acids and bases useable with the present invention include those which are derived from the amino acids, for example, histidine, glycine, phenylalanine, aspartic acid, glutamic acid, lysine, arginine and asparagine.
"Pharmaceutically acceptable" buffers and salts, which are an optional composition component, include those derived from both acid and base addition salts of the above indicated acids and bases. According to the present invention, the buffer is used to adjust the pH. In one embodiment of the present invention, the buffer is selected from the group consisting of acetate, succinate, gluconate, citrate, histidine, arginine, acetic acid, phosphate, phosphoric acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic -I ö

acid, ascorbic acid, imidazole, bicarbonate and carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate (EDTA), acetate, malate, imidazole, tris, phosphate, and mixtures thereof.
When present, the concentration of the buffer can range from about 0.1 millimolar (mM) to about 200 mM. In one embodiment, the concentration of the buffer is from about 0.5 mM
to about 200 mM, from about 1 mM to about 100 mM, from about 1 mM to about 65 mM, or from about 1 mM to about 30 mM. In another embodiment, the concentration of the buffer is about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 10 mM, about mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 10 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, or about 100 mM.
According to one embodiment of the present invention, the pH can be in the range of about 4.0 to about 9Ø In another embodiment, the pH is between about 4.5 and about 8.0, between about 5.0 and about 7.5, between about 5.5 and about 7.0, or between about 6.0 15 and 7.5. In another embodiment, the pH is about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about

6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about

7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about

8.6, about 8.7, about 8.8, about 8.9, or about 9Ø
Of note, the inclusion of viscosity lowering excipient (comprising CSA, SSA, CSA salts or SSA salts) in the formulation may allow the antibody to be formualted at a pH
that is impractical without the viscosity lowering excipient. One of skill in the art would expect that self-association is strongest when the antibody is formulated at the pH of the isoelectric point, where the net charge on the antibody is expected to be zero. In some cases, severe self-association may even lead to phase separation, making it impractical to formulate the molecule at a pH near the isoelectric point. The addition of the viscosity lowering excipient in some cases greatly reduce the self-association, which may allow formulation at pH
values which otherwise would be prohibited, and may offer additional benefits with respect = to stability of the antibody. Unexpectedly, the self-association behavior may actually be minimized near the isolectric point of the molecule rather than at higher or lower pH values when a viscosity lowering exipient are included in the formulation.
A "preservative" is a compound which can be added to the formulations herein to reduce bacterial activity. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation. Examples of potential preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long-chain compounds), and benzethonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. In one embodiment, the composition does not include a preservative.
In some embodiments, various components can be omitted from the antibody formulation, or can be "substantially free" of that component. The term "substantially free" as used herein refers to an antibody formulation, said formulation containing less than 0.01%, less than 0.001 /0, less than 0.0005%, less than 0.0003%, or less than 0.0001 /0 of the designated component.
"Sulfosalicyclic acid" (SSA) means the compound represented by the chemical formula:

OH

OH
SSA
"SSA" includes hydrate/solvate forms including the anhydrous form as well as the free base form and any salt form. Exemplary pharmaceutically acceptable acid salts may be formed from counter-ions and include sodium, hydrochloride, arginine, lysine, histidine, and include all hydrates, solvates, and enantiomers thereof.

. The present invention includes various amounts of SSA. In some embodiments, the amount of SSA is greater than about 5 mM, greater than about 10 mM, greater than about 15 mM, greater than about 20 mM, greater than about 25 mM, greater than about 30 mM, greater than about 35 mM , greater than about 50 mM , greater than about 75 mM
, greater than about 100 mM , greater than about 125 mM ,greater than about 150 mM
,greater than about 200 mM , greater than about 225 mM , or greater than about 250 mM.
In some embodiments, the amount of SSA in the formulation is between about 5 mM and about 250 mM, between about 10 mM and about 200 mM, between about 20 mM and about 200 mM, between about 30 mM and about 200 mM, between about 30 mM and about 150 mM, or between about 30 mM and about 100 mM.
"Surfactant" is an optional component to the composition which is a pharmaceutically acceptable agent that reduces the tendency for the formation of bubbles in the formulation during preparation and handling of the formulation and preparation for parenteral administration and especially from stress related to shaking and agitation during preparation and also during shipping. Exemplary surfactants include polysorbates, poloxamers, tritons, sodium dodecyl sulfate, sodium laurel sulfate, sodium octyl glycoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauroamidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium methyl cocoyl-taurate, disodium methyl oleyl- taurate, dihydroxypropyl PEG 5 linoleammonium chloride, polyethylene glycol, polypropylene glycol, and mixtures thereof. In further embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, and mixtures thereof.
When present, the concentration of the surfactant generally ranges from about 0.01 mg/ml to about 5.0 mg/ml, from about 0.01 mg/ml to about 2.0 mg/ml, from about 0.01 mg/ml to about 1.5 mg/ml, from about 0.01 mg/ml to about 1.0 mg/ml, from about 0.01 mg/ml to about 0.5 mg/ml, from about 0.01 mg/ml to about 0.4 mg/ml, from about 0.01 mg/ml to - about 0.3 mg/ml, from about 0.01 mg/ml to about 0.2 mg/ml, from about 0.01 mg/ml to about 0.15 mg/ml, from about 0.01 mg/ml to about 0.1 mg/ml, or from about 0.01 mg/ml, to about 0.05 mg/ml. Furthermore, the concentration of the surfactant is about 0.5 mg/ml, about 0.05 mg/ml about 0.06 mg/ml about 0.07 mg/ml about 0.08 mg/ml about 0.09 mg/ml about 0.1 mg/ml about 0.11 mg/ml about 0.12 mg/ml about 0.13 mg/ml about 0.14 mg/ml about 0.15 mg/ml about 0.16 mg/ml about 0.17 mg/ml about 0.18 mg/ml about 0.19 mg/ml, or about 0.2 mg/ml.
The term "subject" refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar 1.0 animal species. "Edible animals" refers to food-source animals such as cows, pigs, sheep and poultry.
"Viscosity" as used herein may be "kinematic viscosity" or "absolute viscosity." "Kinematic viscosity" is a measure of the resistive flow of a fluid under the influence of gravity. When two fluids of equal volume are placed in identical capillary viscometers and allowed to flow by gravity, a viscous fluid takes longer than a less viscous fluid to flow through the capillary. If one fluid takes 200 seconds to complete its flow and another fluid takes 400 seconds, the second fluid is twice as viscous as the first on a kinematic viscosity scale.
"Absolute viscosity", sometimes called dynamic or simple viscosity, is the product of kinematic viscosity and fluid density: Absolute Viscosity=Kinematic Viscosity x Density The dimension of kinematic viscosity is L2/T where L is a length and T is a time. Commonly, kinematic viscosity is expressed in centistokes (cSt). The SI unit of kinematic viscosity is MM2/s, which is 1 cSt. Absolute viscosity is expressed in units of centipoise (cP). The Si unit of absolute viscosity is the milliPascal-second (mPa-s), where 1 cP=1 mPa-s.
The formulation may be in either aqueous or lyophilized form. In aqueous form, the formulation may have a viscosity of no greater than about 60 cP. In another embodiment, the formulation has a viscosity of no greater than about 50 cP, or no greater than about 40 cP, or no greater than about 30 cP, or no greater than about 20 cP, or no greater than about 15 cP. In some embodiments the composition comprising antibody has a viscosity of between about 1 cP and about 50 cP, between about 1 cP and 40 cP, between about 1 cP
and about 30 cP, between about 1 cP and about 20 cP, between about 1 cP and about 15 cP, or between about 1 cP and about 10 cP at 25 C. In some embodiments, the formulation has a viscosity of about 50 cP, about 45 cP, about 40 cP, about 35 cP, about 30 cP, about 25 cP, about 20 cP, about 15 cP, or about 10 cP, or about 5 cP.
In some embodiments, the formulation has a viscosity of between about 10 cP and 50 cP, between about 10 cP and 30 cP, between about 10 cP and 20 cP, or between about 5 cP
and 15 cP.
The present invention is directed at pharmaceutical compositions that include:
a. an antibody, wherein the antibody concentration is between about 100 mg/ml to about 400 mg/ml, and b. a viscosity lowering excipient comprising camphorsulfonic acid, sulfosalicylic acid, or a salt of camphorsulfonic acid or sulfosalicylic acid, wherein the viscosity lowering excipient concentration is between about 30 mM to about 200 mM;
wherein the pH of said composition is from about 4.0 to about 9Ø
In another embodiment, the composition also includes a pharmaceutically acceptable buffer. In one embodiment, the pharmaceutically acceptable buffer comprises arginine, histidine, tris, phosphate or lysine, or a salt thereof. . In another embodiment, the pharmaceutically acceptable buffer comprises histidine, tris, or phosphate, or a salt thereof.
In another embodiment, the concentration of pharmaceutically acceptable buffer is from about 1.0 to about 200 mM.
In another embodiment, the composition also includes a surfactant. In one embodiment, the surfactant is polysorbate 20 or polysorbate 80. In another embodiment, the concentration of surfactant is from about 0.01 to about 0.3 mg/ml.
In another embodiment, the composition also includes a chelating agent. In one embodiment, the chelating agent is EDTA or disodium EDTA. In another embodiment, the concentration of chelating agent is from about 0.01 to about 0.3 mg/ml.
In another embodiment, the composition also includes a cryoprotectant. In one embodiment, the cryoprotectant is sucrose, dextrose, mannose or trehalose. In another embodiment, the concentration of the cryoprotectant is from about 1 mg/ml to about 100 mg/ml.

In another embodiment, the viscosity lowering agent is (+)camphorsulfonic acid or (-)camphorsulfonic acid or a salt thereof. In another embodiment, the viscosity lowering agent concentration is between about 50 mM to about 150 mM. In another embodiment, the viscosity lowering agent concentration is between about 70 mM to about 110 mM.
In another embodiment, the viscosity lowering agent is a salt of camphorsulfonic acid comprising camphorsulfonic acid and arginine. In another embodiment, the camphorsulfonic acid concentration is between about 50 mM and about 150 mM and the arginine concentration is between about 50 mM and about 150 mM. In another embodiment, the camphor sulfonic acid concentration is between about 70 mM and about 110 mM and the arginine concentration is between about 70 mM and about 110 mM.
In one embodiment, the antibody is a human or humanized monoclonal IgG1, IgG2 or IgG4 antibody. In another embodiment, the antibody is an anti-IL7R, anti-PCSK9 or anti-glucagon receptor antibody.
In another embodiment, the antibody includes a heavy chain comprising one, two or three CDRs selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO:
4, 5, or 6; CDR2 comprising the amino acid sequence shown in SEQ ID NO: 7 or 8;
and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 9, and a light chain comprising one, two or three CDRs selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 10, CDR2 comprising the amino acid sequence shown in SEQ ID NO: 11, and CDR3 comprising the amino acid sequence shown in SEQ ID NO:
12.
In yet another embodiment, the antibody includes an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 2, and an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a light chain variable region amino acid sequence shown in SEQ ID NO: 3.
In yet another embodiment, the antibody includes an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 13, and an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95%
or 98% identical to a light chain amino acid sequence shown in SEQ ID NO: 14.

In yet another embodiment, the antibody includes a variable heavy chain sequence comprising the amino acid sequence shown in SEQ ID NO: 2 and a variable light chain sequence comprising the amino acid sequence shown in SEQ ID NO: 3.
In yet another embodiment, the antibody includes a heavy chain comprising one, two or three CDRs selected from CDR1 comprising the amino acid sequence shown in SEQ
ID
NO: 17, 18 or 19; CDR2 comprising the amino acid sequence shown in SEQ ID NO:
20 or 21; and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 22, and a light chain comprising one, two or three CDRs selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 23, CDR2 comprising the amino acid sequence shown in SEQ ID NO: 24, and CDR3 comprising the amino acid sequence shown in SEQ ID NO:
25.
In yet another embodiment, the antibody includes an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 15, and an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a light chain variable region amino acid sequence shown in SEQ ID NO: 16.
In yet another embodiment, the antibody includes an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 26 or 27, and an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a light chain amino acid sequence shown in SEQ ID
NO: 28.
In yet another embodiment, the antibody includes a variable heavy chain sequence comprising the amino acid sequence shown in SEQ ID NO: 15 and a variable light chain sequence comprising the amino acid sequence shown in SEQ ID NO: 16.
In yet another embodiment, the antibody includes a heavy chain comprising one, two or three CDRs selected from CDR1 comprising the amino acid sequence shown in SEQ
ID
NO: 32, 33, or 34; CDR2 comprising the amino acid sequence shown in SEQ ID NO:
35 or 36; and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 37, and a light chain comprising one, two or three CDRs selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 38, CDR2 comprising the amino acid sequence shown in SEQ ID NO: 39, and CDR3 comprising the amino acid sequence shown in SEQ ID NO:
40.

' In yet another embodiment, the antibody includes an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 41, and an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a light chain variable region amino acid sequence shown in SEQ ID NO: 42.
In yet another embodiment, the antibody includes an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95% or 98% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 30, and an amino acid sequence that is at least 80%, 85%, 90%, 92%, 95%
or 98% identical to a light chain amino acid sequence shown in SEQ ID NO: 31.
In yet another embodiment, the antibody includes a variable heavy chain sequence comprising the amino acid sequence shown in SEQ ID NO: 41 and a variable light chain sequence comprising the amino acid sequence shown in SEQ ID NO: 42.
In another embodiment, the composition is lyophilized. In yet another embodiment, the lyophilized composition is reconstituted and the antibody concentration of the reconstituted composition is between about 250 mg/ml and about 400 mg/ml. In yet another embodiment, the lyophilized composition is reconstituted and the antibody concentration of the reconstituted composition is higher than the antibody concentration before lyophilization. In yet another embodiment, the composition has a viscosity of less than about 50 cP at 25 C. In yet another embodiment, the composition is isotonic.
Preparation of the Antibodies Anti-IL-7R
As used herein, the term "IL-7R" refers to any form of IL-7R and variants thereof that retain at least part of the activity of IL-7R. Unless indicated differently, such as by specific reference to human IL-7R, IL-7R includes all mammalian species of native sequence IL-7R, e.g., human, canine, feline, equine, and bovine. One exemplary human IL-7R
is found as Uniprot Accession Number P16871 (SEQ ID NO: 1).
MTILGTTFGM VFSLLQVVSG ESGYAQNGDL EDAELDDYSF SCYSQLEVNG
SQHSLTCAFE DPDVNTTNLE FEICGALVEV KCLNFRKLQE IYFIETKKFL

LIGKSNICVK VGEKSLTCKK IDLTTIVKPE APFDLSVIYR EGANDFVVTF
NTSHLQKKYV KVLMHDVAYR QEKDENKWTH VNLSSTKLTL LQRKLQPAAM
YEIKVRSIPD HYFKGFWSEW SPSYYFRTPE INNSSGEMDP ILLTISILSF
FSVALLVILA CVLWKKRIKP IVWPSLPDHK KTLEHLCKKP RKNLNVSFNP
ESFLDCQIHR VDDIQARDEV EGFLQDTFPQ QLEESEKQRL GGDVQSPNCP
SEDVVITPES FGRDSSLTCL AGNVSACDAP ILSSSRSLDC RESGKNGPHV
YQDLLLSLGT TNSTLPPPFS LQSGILTLNP VAQGQPILTS LGSNQEEAYV
TMSSFYQNQ (SEQ ID NO: 1) Antagonist IL-7R antibodies encompass antibodies that block, antagonize, suppress or reduce (to any degree including significantly) IL-7R biological activity, including downstream pathways mediated by IL-7R signaling, such interaction with IL-7 and/or elicitation of a cellular response to IL-7. For purpose of the present invention, it will be explicitly understood that the term "antagonist IL-7R antibody"
(interchangeably termed "IL-7R antagonist antibody," "antagonist anti-IL-7R antibody" or "anti-IL-7R
antagonist antibody") encompasses all the previously identified terms, titles, and functional states and characteristics whereby the IL-7R itself, an IL-7R biological activity (including but not limited to interaction with IL-7, its ability to mediate any aspect of phosphorylation of STAT5, phosphatidylinosito1-3-kinase (PI3K)-Akt pathway activation, p27Kip1 downregulation, BcI-2 upregulation, Rb hyperphosphorylation, and CXCR4 upregulation), or the consequences of the biological activity, are substantially nullified, decreased, or neutralized in any meaningful degree. In some embodiments, an antagonist IL-7R

antibody binds IL-7R and prevents interaction with IL-7. Examples of antagonist IL-7R
antibodies are provided herein. Anti-IL-7R antagonist antibodies for use in the invention can be identified or characterized using methods known in the art, whereby reduction, amelioration, or neutralization of an IL-7R biological activity is detected and/or measured.
As used herein, the term "Cl GM" is used to refer to an antibody comprising the amino acid sequence of the heavy chain and light chain variable regions shown in SEQ ID
NO: 2 and SEQ ID NO: 3, respectively.

, C1GM heavy chain variable region:
EVQLVESGGGLVKPGGSLRLSCAASGFTFDDSVMHWVRQAPGKGLEWVSLVGWDGFF
TYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQGDYMGNNWGQGTLVTV
SS (SEQ ID NO: 2) C1GM light chain variable region:
NFMLTQPHSVSESPGKTVTISCTRSSGSIDSSYVQWYQQRPGSSPTTVIYEDDQRPSGVP
DRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYDFHHLVFGGGTKLTVL (SEQ ID NO: 3) The generation and characterization of C1 GM is described in the Examples of W02011/104687, the entire content of which is herein incorporated by reference in its entirety for all purposes. In some embodiments, the term "Cl GM" refers to immunoglobulin encoded by (a) a polynucleotide encoding C1 GM light chain variable region that has a deposit number of ATCC No. PTA-11678, and (b) a polynucleotide encoding C1 GM heavy chain variable region that has a deposit number of ATCC
No. PTA-11679.
In some embodiments, the antibody is an anti-IL-7R antibody that binds IL-7Ra (such as human IL-7Ra) with a high affinity. In some embodiments, high affinity is (a) binding IL-7R
with a KD of less than about 2 nM (such as any of about 1 nM, 800 pM, 600 pM, 400 pM, 200 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30pM, 20pM, 10pM, 5pM
or less).
In some embodiments, antibodies (a) bind IL-7R (such as human IL-7R) with a KD
of less than about 2 nM (such as any of about 1 nM, 800 pM, 600 pM, 400 pM, 200 pM, 100pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30pM, 20pM, 10pM, 5pM or less), and/or a koff of about 4x10-4 S-1.
The epitope(s) that can be bound by the antibody can be continuous or discontinuous. In one embodiment, the antibody binds essentially the same IL-7R epitope as antibody C1GM.
In some embodiments, the antibody can be anti-IL-7R antibody comprising a heavy chain variable region comprising:

(a) a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 4 (GFTFDDSVMH) (extended) or in SEQ ID NO: 5 (DSVMH) (Kabat) or in SEQ ID NO: 6 (GFTFDDS) (Chothia);
(b) a CDR2 comprising the amino acid sequence shown in SEQ ID NO: 7 (LVGWDGFFTYYADSVKG) (Kabat) or in SEQ ID NO: 8 (GWDGFF) (Chothia); and (c) a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 9 (QGDYMGNN).
In some embodiments, the antibody can be an anti-IL-7R antibody comprising a light chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 10 (TRSSGSIDSSYVQ);
(b) a CDR2 comprising the amino acid sequence shown in SEQ ID NO: 11 (EDDQRPS);
and (c) a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 12 (QSYDFHHLV).
In some embodiments, the antibody can be anti-IL-7R antibody comprising three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID
NO: 2.
EVQLVESGGGLVKPGGSLRLSCAASGFTFDDSVMHWVRQAPGKGLEWVSLVGWDGFF
TYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQGDYMGNNWGQGTLVTV
SS (SEQ ID NO: 2) In some embodiments, the antibody can be anti-IL-7R antibody comprising three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID
NO: 3.
NFMLTQPHSVSESPGKTVTISCTRSSGSIDSSYVQWYQQRPGSSPTTVIYEDDQRPSGVP
DRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYDFHHLVFGGGTKLTVL (SEQ ID NO: 3) In some embodiments, the anti-IL-7R antibody may comprise a heavy chain variable region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91`)/0, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO. 2 and/or a light chain variable region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO. 3, wherein the antibody binds specifically to human IL-7Ra.
The anti-IL-7R antibody may comprise a heavy chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 2 and/or may comprise a light chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 3.
The anti-IL-7R antibody may be an antibody comprising the amino acid sequences shown in SEQ ID NOS: 2 and 3.
The anti-IL-7R antibody may comprise a heavy chain region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 13 and / or a light chain region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%
or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 14, wherein the antibody binds specifically to human IL-7Ra.
Heavy chain region sequence EVQLVESGGGLVKPGGSLRLSCAASGFTFDDSVMHWVRQAPGKGLEWVSLVGWDGFF
TYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQGDYMGNNWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK
GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH
EALHNHYTQKSLSLSPGK (SEQ ID NO: 13) Light chain region sequence NFMLTQPHSVSESPGKTVTISCTRSSGSIDSSYVQWYQQRPGSSPTTVIYEDDQRPSGVP
DRFSGSIDSSSNSASLTISGLKTEDEADYYCQSYDFHHLVFGGGTKLTVLQPKAAPSVTLF
PPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL
SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 14) The anti-IL-7R antibody may comprise a heavy chain region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 13 and/or may comprise a light chain region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 14.
The anti-IL-7R antibody may be an antibody comprising the amino acid sequences shown in SEQ ID NOS: 13 and 14.
The anti-IL-7R antibody may compete for IL-7R binding with an anti-IL-7R
antibody as defined herein. The anti-IL-7R antibody may compete for IL-7R binding with an antibody comprising a heavy chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 2 and/or a light chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ
ID NO: 3.
The anti-IL-7R antibody may be a human and affinity matured antibody, C1GM, which specifically binds human IL-7Ra. Antibody 01GM is described in W02011/104687, the content of which is hereby incorporated by reference in its entirety. The amino acid sequences of the heavy chain and light chain variable regions of 01GM are shown in SEQ
ID NOs: 2 and 3, respectively. The CDR portions of antibody 01GM (including Chothia and Kabat CDRs) are diagrammatically depicted in Table 1 of W02011/104687.
Antibody C1 GM is highly potent in blocking IL-7R biological activity.
The anti-IL-7R antibody may also comprise a fragment or a region of the antibody 01GM.
In one embodiment, the fragment is a light chain of the antibody 01GM
comprising the amino acid sequence as shown in SEQ ID NO: 14 herein. In another embodiment, the fragment is a heavy chain of the antibody 01GM comprising the amino acid sequence as shown in SEQ ID NO: 13 herein. In yet another embodiment, the fragment contains one or more variable regions from a light chain and/or a heavy chain of the antibody 01GM. In yet another embodiment, the fragment contains one or more CDRs from a light chain and/or a heavy chain of the antibody 01GM comprising the amino acid sequences as shown in SEQ
ID NOS: 14 and 13, respectively, herein.
In some embodiments, the antibody may comprise any one or more of the following: a) one or more (one, two, three, four, five, or six) CDR(s) derived from antibody 01GM shown in SEQ ID NOs: 4-12. In some embodiments, the CDRs may be Kabat CDRs, Chothia CDRs, or a combination of Kabat and Chothia CDRs (termed "extended" or "combined"
CDRs herein). In some embodiments, the polypeptides comprise any of the CDR
configurations (including combinations, variants, etc.) described herein.
In some embodiments of the present invention the C-terminal lysine of the heavy chain of any of the anti-IL-7R antibodies described herein is deleted. In various cases the heavy and/or light chain of the anti-IL-7R antibodies described herein may optionally include a signal sequence.
In another embodiment, the antibody may be selected from an anti-IL-7R
antibody known in the art, such as antibodies described in, for example without limitation, any of the following published PCT applications: W02011/104687 (including, for example without limitation, any of the antibodies listed in Table 1), WO/2011/094259 (including, for example without limitation, antibodies H3L4, BPC4401, BPC4398, BPC1142, BPC4399, BPC4402, BPC4403, and BPC1142), WO/2013/056984 (including, for example without limitation, antibodies MD707-1, MD707-2, MD707-3, MD707-4, MD707-5, MD707-6, MD707-9, MD707-12, and MD707-13), and W02010/017468 (including, for example without limitation, antibodies 9B7, R34.34, 6A3 and 1A11). The antibody may bind to the same epitope as an anti-IL-7R antibody known in the art and/or may compete for binding to IL-7R
with such an antibody.
Anti-Glucagon Receptor As used herein, the term "Glucagon Receptor" refers to any form of glucagon receptor and variants thereof that retain at least part of the activity of the glucagon receptor. Unless indicated differently, such as by specific reference to human glucagon receptor, glucagon . receptor includes all mammalian species of native sequence glucagon receptor, e.g., human, canine, feline, equine, and bovine. One exemplary human glucagon receptor is found as Uniprot Accession Number P47871 (SEQ ID NO: 29).
MPPCQPQRPLLLLLLLLACQPQVPSAQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNR
TFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRD
ASQCQMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHA
NLFASFVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANY
CWLLVEGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSN
DNMGFWWILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVH
EVVFAFVTDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLG
KVLWEERNTSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF
(SEQ ID NO: 29) As used herein, an "anti-glucagon receptor antagonist antibody" refers to an antibody that is able to inhibit glucagon receptor biological activity and/or downstream events(s) mediated by glucagon receptor. Anti-glucagon receptor antagonist antibodies encompass antibodies that block, antagonize, suppress or reduce (to any degree including significantly) glucagon receptor biological activity, including downstream events mediated by glucagon receptor, such glucagon binding and downstream signaling, adenylate cyclase activation, increased levels of intracellular cAMP, glycogenolysis stimulation, gluconeogenesis activation, glycogenesis inhibition, glycolysis inhibition, and hepatic glucose production. For purposes of the present invention, it will be explicitly understood that the term "anti-glucagon receptor antagonist antibody" (interchangeably termed "antagonist glucagon receptor antibody", "antagonist anti-glucagon receptor antibody" or "glucagon receptor antagonist antibody") encompasses all the previously identified terms, titles, and functional states and characteristics whereby the glucagon receptor itself, a glucagon receptor biological activity (including but not limited to its ability to bind glucagon, increase intracellular cAMP, stimulate glycogenolysis, activate gluconeogenesis, and promote relase of hepatic glucose), or the consequences of the biological activity, are substantially nullified, decreased, or neutralized in any meaningful degree.
In some embodiments, an anti-glucagon receptor antagonist antibody binds glucagon receptor and , lowers plasma glucose levels. Examples of anti-glucagon receptor antagonist antibodies are provided herein.
As used herein, the term "mAb5" is used to refer to an antibody comprising the amino acid sequence of the heavy chain and light chain variable regions shown in SEQ ID
NO: 15 and SEQ ID NO: 16, respectively.
mAb5 heavy chain variable region:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFSVHWVRQAPGQGLEWMGWINTETDET
SYADDFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCVKSRYWSYGPPDYWGQGTTV
TVSS (SEQ ID NO: 15) 1.13 mAb5 light chain variable region:
DIQMTQSPSSLSASVGDRVTITCQASQNIRTAVVWYQQKPGKAPKLLIYLASNRHSGVPS
RFSGSGSGTDFTFTISSLQPEDIATYYCLQHWTYPFTFGGGTKVEIK (SEQ ID NO: 16) The generation and characterization of mAb5 is described in the Examples of W02014/181229, the entire content of which is herein incorporated by reference in its entirety for all purposes. In some embodiments, the term "mAb5" refers to immunoglobulin encoded by (a) a polynucleotide encoding mAb5 light chain variable region that has a deposit number of ATCC No. PTA-120164 and (b) a polynucleotide encoding mAb5 heavy chain variable region that has a deposit number of ATCC No. PTA-120165.
In some embodiments, the antibody is an anti- glucagon receptor antibody that binds glucagon receptor (such as human glucagon receptor) with a high affinity. In some embodiments, high affinity is (a) binding IL-7R with a KD of less than about 2 nM (such as any of about 1 nM, 800 pM, 600 pM, 400 pM, 200 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30pM, 20pM, 10pM, 5pM or less).
In some embodiments, antibodies (a) bind glucagon receptor (such as human glucagon receptor) with a KD of less than about 2 nM (such as any of about 1 nM, 800 pM, 600 pM, 400 pM, 200 pM, 100pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30pM, 20pM, 10pM, 5pM or less), and/or a koff of about 4x10-4 s-1.

=
. The epitope(s) that can be bound by the antibody can be continuous or discontinuous. In one embodiment, the antibody binds essentially the same glucagon receptor epitope as antibody mAb5.
In some embodiments, the antibody can be anti- glucagon receptor antibody comprising a heavy chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 17 (GYTFTDFSVH) (extended) or in SEQ ID NO: 18 (GYTFTDF) (Chothia) or in SEQ ID
NO:
19 (DFSVH) (Kabat);
(b) a CDR2 comprising the amino acid sequence shown in SEQ ID NO: 20 (NTETDE) (Chothia) or in SEQ ID NO: 21 (WINTETDETSYADDFKG) (Kabat); and (c) a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 22 (SRYWSYGPPDY).
In some embodiments, the antibody can be an anti-glucagon receptor antibody comprising a light chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 23 (QASQNIRTAVV);
(b) a CDR2 comprising the amino acid sequence shown in SEQ ID NO: 24 (LASNRHS);
and (c) a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 25 (LQHWTYPFT).
In some embodiments, the antibody can be anti-glucagon receptor antibody comprising three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 15.
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFSVHWVRQAPGQGLEWMGWINTETDET
SYADDFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCVKSRYWSYGPPDYVVGQGTTV
TVSS (SEQ ID NO: 15) In some embodiments, the antibody can be anti-glucagon receptor antibody comprising three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 16.
DIQMTQSPSSLSASVGDRVTITCQASQNIRTAVVWYQQKPGKAPKWYLASNRHSGVPS
RFSGSGSGTDFTFTISSLQPEDIATYYCLQHWTYPFTFGGGTKVEIK (SEQ ID NO: 16) In some embodiments, the anti-glucagon receptor antibody may comprise a heavy chain variable region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO. 15 and/or a light chain variable region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91 A, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO. 16, wherein the antibody binds specifically to human glucagon receptor.
The anti-glucagon receptor antibody may comprise a heavy chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ
ID NO: 15 and/or may comprise a light chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 16.
The anti-glucagon receptor antibody may be an antibody comprising the amino acid sequences shown in SEQ ID NOS: 15 and 16.
The anti-glucagon receptor antibody may comprise a heavy chain region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 26 and / or a light chain region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91 A), 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 28, wherein the antibody binds specifically to human glucagon receptor.
The amino acid sequence of mAb5 full-length heavy chain (SEQ ID NO: 26) is shown below:

=
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFSVHWVRQAPGQGLEWMGWINTETDET
SYADDFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCVKSRYWSYGPPDYWGQGTTV
TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVA
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQ
FNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSI EKTISKTKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 26) The amino acid sequence of mAb5 full-length heavy chain without the C-terminal lysine (SEQ ID NO: 27) is shown below:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFSVHWVRQAPGQGLEWMGWINTETDET
SYADDFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCVKSRYWSYGPPDYWGQGTTV
TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVA
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQ
FNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS
RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 88) (SEQ ID NO: 27) The amino acid sequence of mAb5 full-length light chain (SEQ ID NO: 28) is shown below:
DIQMTQSPSSLSASVG DRVTITCQASQ NI RTAVVWYQQKPGKAPKLLIYLASN RHSGVPS
RFSGSGSGTDFTFTISSLQPEDIATYYCLQHWTYPFTFGGGTKVEIKRTVAAPSVFIFPPSD
EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 28) The anti-glucagon receptor antibody may comprise a heavy chain region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 26 and/or may comprise a light chain region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 28.
The anti-glucagon receptor antibody may be an antibody comprising the amino acid sequences shown in SEQ ID NOS: 26 and 28.

The anti-glucagon receptor antibody may compete for glucagon receptor binding with an anti-glucagon receptor antibody as defined herein. The anti-glucagon receptor antibody may compete for glucagon receptor binding with an antibody comprising a heavy chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 15 and/or a light chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 16.
The anti-glucagon receptor antibody may be a human and affinity matured antibody, mAb5, which specifically binds human glucagon receptor. Antibody mAb5 is described in W02014/181229, the content of which is hereby incorporated by reference in its entirety for all purposes. The amino acid sequences of the heavy chain and light chain variable regions of mAb5 are shown in SEQ ID NOs: 15 and 16, respectively. The CDR portions of antibody mAb5 (including Chothia and Kabat CDRs) are diagrammatically depicted in Table 1A of W02014/181229. Antibody mAb5 is highly potent in blocking glucagon receptor biological activity.
The anti-glucagon receptor antibody may also comprise a fragment or a region of the antibody mAb5. In one embodiment, the fragment is a light chain of the antibody mAb5 comprising the amino acid sequence as shown in SEQ ID NO: 28 herein. In another embodiment, the fragment is a heavy chain of the antibody mAb5 comprising the amino acid sequence as shown in SEQ ID NO: 26 herein. In yet another embodiment, the fragment contains one or more variable regions from a light chain and/or a heavy chain of the antibody mAb5. In yet another embodiment, the fragment contains one or more CDRs from a light chain and/or a heavy chain of the antibody mAb5 comprising the amino acid sequences as shown in SEQ ID NOS: 28 and 26, respectively, herein.
In some embodiments, the antibody may comprise any one or more of the following: a) one or more (one, two, three, four, five, or six) CDR(s) derived from antibody mAb5 shown in SEQ ID NOs: 17-25. In some embodiments, the CDRs may be Kabat CDRs, Chothia CDRs, or a combination of Kabat and Chothia CDRs (termed "extended" or "combined"
CDRs herein). In some embodiments, the polypeptides comprise any of the CDR
configurations (including combinations, variants, etc.) described herein.

In some embodiments of the present invention the C-terminal lysine of the heavy chain of any of the anti-glucagon receptor antibodies described herein is deleted, as in SEQ ID NO.
27. In various cases the heavy and/or light chain of the anti-glucagon receptor antibodies described herein may optionally include a signal sequence.
In another embodiment, the antibody may be selected from an anti-glucagon receptor antibody known in the art, such as antibodies described in, for example without limitation, any of the following published PCT applications: W02014/181229 (including, for example without limitation, any of the antibodies listed in Tables 1A and 1B
including, for example without limitation antibodies mAb1, mAb2, mAb3, mAb4, mAb5, mAb6, H2-A8, H2-A11, H2-C8, H2-E7, H2-F10, H2-F11, H3-05, H3-C10, H3-F5, H3-H9, H2-A11-H3-1, H2-A11-H3-2, H2-A11-H3-3, H2-A11-H3-4, H2-C8-H3-1, H2-C8-H3-2, H2-C8-H3-3, H2-C8-H3-4, H2-E7-H3-1, H2-E7-H3-2, H2-E7-H3-3, H2-E7-H3-4, FF1, FF2, FF3, FF4, FF2-H2WT, FF2-H2RG, FF2-H3RY, and FF2-H2WT-H3RY); W02012/071372; W02011/030935;
W02013/059531; and W02013/081993. The antibody may bind to the same epitope as an anti-glucagon receptor antibody known in the art and/or may compete for binding to glucagon receptor with such an antibody.

As used herein, the term "PCSK9" refers to any form of PCSK9 and variants thereof that retain at least part of the activity of PCSK9. Unless indicated differently, such as by specific reference to human PCSK9, PCSK9 includes all mammalian species of native sequence PCSK9, e.g., human, canine, feline, equine, and bovine. One exemplary human PCSK9 is found as Uniprot Accession Number Q8NBP7. (SEQ ID NO: 43) MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED
GLAEAPEHGT TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA
QAARRGYLTK ILHVFHGLLP GFLVKMSGDL LELALKLPHV DYIEEDSSVF
AQSIPWNLER ITPPRYRADE YQPPDGGSLV EVYLLDTSIQ SDHREIEGRV
MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG VAKGASMRSL
RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA
CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT
LGTNFGRCVD LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML

_ ` SAEPELTLAE LRQRLIHFSA KDVINEAWFP EDQRVLTPNL VAALPPSTHG
AGWQLFCRTV WSAHSGPTRM ATAVARCAPD EELLSCSSFS RSGKRRGERM
EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP PAEASMGTRV
HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC
CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV
DNTCVVRSRD VSTTGSTSEG AVTAVAICCR SRHLAQASQE LQ (SEQ ID NO: 43) As used herein, a "PCSK9 antagonist" refers to an antibody, peptide, or aptamer that is able to inhibit PCSK9 biological activity and/or downstream pathway(s) mediated by PCSK9 signaling, including PCSK9-mediated down-regulation of the LDLR, and mediated decrease in LDL blood clearance. A PCSK9 antagonist antibody encompasses antibodies that block, antagonize, suppress or reduce (to any degree including significantly) PCSK9 biological activity, including downstream pathways mediated by PCSK9 signaling, such as LDLR interaction and/or elicitation of a cellular response to PCSK9. For purpose of the present invention, it will be explicitly understood that the term "PCSK9 antagonist antibody" encompasses all the previously identified terms, titles, and functional states and characteristics whereby the PCSK9 itself, a PCSK9 biological activity (including but not limited to its ability to mediate any aspect of interaction with the LDLR, down regulation of LDLR, and decreased blood LDL clearance), or the consequences of the biological activity, are substantially nullified, decreased, or neutralized in any meaningful degree. In some embodiments, a PCSK9 antagonist antibody binds and prevents interaction with the LDLR. Examples of PCSK9 antagonist antibodies are provided herein.
As used herein, the term "L1 L3" is used to refer to an antibody comprising the amino acid sequence of the heavy chain and light chain variable regions shown in SEQ ID
NO: 41 and SEQ ID NO: 42, respectively.
L1 L3 heavy chain variable region:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGEISPFGGRT
NYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARERPLYASDLWGQGTTVTVS
S (SEQ ID NO: 41) =
, L1L3 light chain variable region:
DIQMTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYSASYRYTGVPSR
FSGSGSGTDFTFTISSLQPEDIATYYCQQRYSLWRTFGQGTKLEIK (SEQ ID NO: 42) The generation and characterization of L1L3 is described in the Examples of W02010/029513, the entire content of which is herein incorporated by reference in its entirety for all purposes. In some embodiments, the term "L1L3" refers to immunoglobulin encoded by (a) a polynucleotide encoding L1L3 light chain variable region that has a deposit number of ATCC No. PTA-10303 and (b) a polynucleotide encoding L1L3 heavy chain variable region that has a deposit number of ATCC No. PTA-10302.
In some embodiments, the antibody is an anti-PCSK9 antibody that binds PCSK9 receptor (such as human PCSK9 receptor) with a high affinity. In some embodiments, high affinity is (a) bindingPCSK9 receptor with a KD of less than about 2 nM (such as any of about 1 nM, 800 pM, 600 pM, 400 pM, 200 pM, 100 pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30pM, 20pM, 10pM, 5pM or less).
In some embodiments, antibodies (a) bind PCSK9 receptor (such as human PCSK9 receptor) with a KD of less than about 2 nM (such as any of about 1 nM, 800 pM, 600 pM, 400 pM, 200 pM, 100pM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40pM, 30pM, 20pM, 10pM, 5pM or less), and/or a koff of about 4x10-4 s-1.
The epitope(s) that can be bound by the antibody can be continuous or discontinuous. In one embodiment, the antibody binds essentially the same PCSK9 receptor epitope as antibody L1L3.
In some embodiments, the antibody can be anti-PCSK9 receptor antibody comprising a heavy chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 32 (GYTFTSYYMH) (extended) or in SEQ ID NO: 33 (GYTFTSY) (Chothia) or in SEQ ID
NO:
34 (SYYMH) (Kabat);
(b) a CDR2 comprising the amino acid sequence shown in SEQ ID NO: 35 (EISPFGGRTNYNEKFKS) (Kabat) or in SEQ ID NO: 36 (SPFGGR) (Chothia); and . (C) a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 37 (ERPLYASDL).
In some embodiments, the antibody can be an anti-PCSK9 receptor antibody comprising a light chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 38 (RASQGISSALA);
(b) a CDR2 comprising the amino acid sequence shown in SEQ ID NO: 39 (SASYRYT);
and (c) a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 40 (QQRYSLWRT).
io In some embodiments, the antibody can be anti-PCSK9 antibody comprising three CDRs from a heavy chain variable region comprising the amino acid sequence shown in SEQ ID
NO: 41.
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGEISPFGGRT
NYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARERPLYASDLWGQGTTVTVS
S (SEQ ID NO: 41) In some embodiments, the antibody can be anti-PCSK9 receptor antibody comprising three CDRs from a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 42.
DIQMTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYSASYRYTGVPSR
FSGSGSGTDFTFTISSLQPEDIATYYCQQRYSLWRTFGQGTKLEIK (SEQ ID NO: 42) In some embodiments, the anti-PCSK9 receptor antibody may comprise a heavy chain variable region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO. 41 and/or a light chain variable region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91`)/0, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO. 42, wherein the antibody binds specifically to human PCSK9 receptor.

The anti-PCSK9 receptor antibody may comprise a heavy chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO:

and/or may comprise a light chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 42.
The anti-PCSK9 receptor antibody may be an antibody comprising the amino acid sequences shown in SEQ ID NOS: 41 and 42.
The anti-PCSK9 receptor antibody may comprise a heavy chain region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91`)/0, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 30 and / or a light chain region comprising an amino acid sequence of any of at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 31, wherein the antibody binds specifically to human PCSK9 receptor.
The amino acid sequence of Li L3 full-length heavy chain (SEQ ID NO: 30) is shown below:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGEISPFGGRT
NYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARERPLYASDLWGQGTTVTVS
SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNST
FRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 30) The amino acid sequence of Li L3 full-length light chain (SEQ ID NO: 31) is shown below:
DIQMTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYSASYRYTGVPSR
FSGSGSGTDFTFTISSLQPEDIATYYCQQRYSLWRTFGQGTKLEIKRTVAAPSVFIFPPSD
EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 31) The anti- PCSK9 receptor antibody may comprise a heavy chain region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 30 and/or may comprise a light chain region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 31.
The anti-PCSK9 receptor antibody may be an antibody comprising the amino acid sequences shown in SEQ ID NOS: 30 and 31.
The anti-PCSK9 receptor antibody may compete for PCSK9 receptor binding with an anti-PCSK9 receptor antibody as defined herein. The anti- PCSK9 receptor antibody may compete for PCSK9 receptor binding with an antibody comprising a heavy chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 41 and/or a light chain variable region comprising the amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 42.
The anti-PCSK9 receptor antibody may be a human and affinity matured antibody, Li L3, which specifically binds human PCSK9 receptor. Antibody Li L3 is described in W02010/029513, the content of which is hereby incorporated by reference in its entirety for all purposes. The amino acid sequences of the heavy chain and light chain variable regions of Li L3 are shown in SEQ ID NOs: 41 and 42, respectively. The CDR portions of antibody Li L3 (including Chothia and Kabat CDRs) are diagrammatically depicted in Table 7 of W02010/029513. Antibody Li L3 is highly potent in blocking PCSK9 receptor biological activity.
The anti-PCSK9 receptor antibody may also comprise a fragment or a region of the antibody Li L3. In one embodiment, the fragment is a light chain of the antibody Li L3 comprising the amino acid sequence as shown in SEQ ID NO: 31 herein. In another embodiment, the fragment is a heavy chain of the antibody Li L3 comprising the amino acid sequence as shown in SEQ ID NO: 30 herein. In yet another embodiment, the fragment contains one or more variable regions from a light chain and/or a heavy chain of the antibody Li L3. In yet another embodiment, the fragment contains one or more CDRs from a light chain and/or a heavy chain of the antibody Li L3 comprising the amino acid sequences as shown in SEQ ID NOS: 31 and 30, respectively, herein.

, .
, In some embodiments, the antibody may comprise any one or more of the following: a) one or more (one, two, three, four, five, or six) CDR(s) derived from antibody Li L3 shown in SEQ ID NOs: 32-40. In some embodiments, the CDRs may be Kabat CDRs, Chothia CDRs, or a combination of Kabat and Chothia CDRs (termed "extended" or "combined"
CDRs herein). In some embodiments, the polypeptides comprise any of the CDR
configurations (including combinations, variants, etc.) described herein.
In some embodiments of the present invention the C-terminal lysine of the heavy chain of any of the anti-PCSK9 receptor antibodies described herein is deleted. In various cases the heavy and/or light chain of the anti-PCSK9 receptor antibodies described herein may optionally include a signal sequence.
In some embodiments, the anti-PCSK9 receptor antibody is alirocumab (PRALUENTTm);
evolocumab (REPATHATm); REGN728; LGT209; RG7652; LY3015014; J16, L1L3 (bococizumab); 31H4, 11F1, 12H11, 8A3, 8A1, or 3C4 (see, e.g., US8,030,457);

(see, e.g., US8,062,640); or 1D05 (see, e.g., US8,188,234). In some embodiments, the anti-PCSK9 antibody is bococizumab, alirocumab (PRALUENTTm), or evolocumab (REPATHATm). The antibody may bind to the same epitope as an anti-PCSK9 receptor antibody known in the art and/or may compete for binding to PCSK9 receptor with such an antibody.
Preparation of the Formulations In preparing the compositions of the present invention, the antibody and camphorsulfonic acid or sulfosalicyclic acid are mixed together and the pH of the mixture is measured and if necessary, adjusted with the use of a buffer or basic component. Other optional components may also be added to the mixture including one or more surfactants, chelating agents, and cryopretectants. Following mixture of the entire composition, the formulation may be utilized in the liquid state, or lyophilized. Many different freeze-dryers are available for this purpose such as Hu1150.TM. (Hull, USA) or GT20.TM. (Leybold-Heraeus, Germany) freeze-dryers. Freeze-drying is accomplished by freezing the formulation and subsequently subliming ice from the frozen content at a temperature suitable for primary drying. Under this condition, the product temperature is below the eutectic point or the collapse temperature of the formulation. Typically, the shelf temperature for the primary drying will range from about -30 to 25 C (provided the product remains frozen during primary drying) at a suitable pressure, ranging typically from about 50 to 250 mTorr. The formulation, size and type of the container holding the sample (e.g., glass vial) and the volume of liquid will mainly dictate the time required for drying, which can range from a few hours to several days (e.g. 40-60 hrs). Optionally, a secondary drying stage may also be performed s depending upon the desired residual moisture level in the product. The temperature at which the secondary drying is carried out ranges from about 0-40 C, depending primarily on the type and size of container and the type of protein employed. For example, the shelf temperature throughout the entire water removal phase of lyophilization may be from about 15-30 C (e.g., about 200C). The time and pressure required for secondary drying will be that which produces a suitable lyophilized cake, dependent, e.g., on the temperature and other parameters. The secondary drying time is dictated by the desired residual moisture level in the product and typically takes at least about 5 hours (e.g. 10-15 hours). The pressure may be the same as that employed during the primary drying step.
Freeze-drying conditions can be varied depending on the formulation and vial size.
The formulations described herein may also be prepared as reconstituted lyophilized formulations. The compositions described herein are lyophilized and then reconstituted to produce the reduced-viscosity stable liquid formulations of the invention. In this particular embodiment, after preparation of the antibody of interest as described above, a "pre-lyophilized formulation" is produced. The amount of antibody present in the pre-lyophilized formulation is determined taking into account the desired dose volumes and mode(s) of administration. For example, the concentration of an antibody in the pre-lyophilized formulation and in the reconstituted formulation can be as described previously, and may differ such that the reconstituted formulation may have an increased antibody concentration as compared to the pre-lyophilized formulation. A
"reconstituted" formulation is one which has been prepared by dissolving a lyophilized formulation in a diluent such that the antibody is distributed throughout the reconstituted formulation. The reconstituted formulation may be suitable for administration (e.g. parenteral administration) to a subject and, in certain embodiments of the invention, may be one which is suitable for subcutaneous administration.
The "diluent" of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation, a such as a formulation reconstituted after lyophilization. Exemplary diluents include sterile water, bacteriostatic water for injection (BWFI or WFI), a pH buffered solution (e.g.
phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution. In an alternative embodiment, diluents can include aqueous solutions of salts and/or buffers and/or surfactants.
Reconstitution generally takes place at a temperature of about 25 C to ensure complete hydration, although other temperatures may be employed as desired. The time required for reconstitution will depend, e.g., on the type of diluent, amount of excipient(s) and protein. In one embodiment, the reconstituted formulation has less than 3000 particles per vial which are less than 10 pm per vial and 300 particles per vial which are less than 25 pm per vial for vials containing less than 100 mL of solution.
Route of Administration The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g. injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends on the intended mode of administration. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One intended mode of administration is parenteral (e.g. intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial, intralesional or intraarticular routes).
Liposomes containing compounds of the invention may be prepared by methods known in the art, such as described in US4485045 and US4544545. Liposomes with enhanced circulation time are disclosed in US5013556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

a , Suitable emulsions may be prepared using commercially available fat emulsions, such as lntralipidTM, LiposynTM, InfonutrolTm, LipofundinTM and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1.0pm, particularly 0.1 and 0.5pm, and have a pH in the range of 5.5 to 8Ø
The emulsion compositions may be those prepared by mixing a compound of the invention with lntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).
Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides (US3773919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-hydroxybutyric acid.

e The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
Formulations of the invention may be placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
In some embodiments, the formulations may be administered to a subject by subcutaneous (i.e. beneath the skin) administration. For such purposes, the formulation may be injected using a syringe. However, other devices for administration of the formulation are available such as injection devices (e.g. the Inject-ease.TM. and Genject.TM. devices);
injector pens (such as the GenPen.TM.); auto-injector devices, needleless devices (e.g.
MediJector.TM.
and BioJector.TM.); and subcutaneous patch delivery systems.
In another embodiment of the invention, an article of manufacture is provided which contains the formulation and preferably provides instructions for its use. The article of manufacture comprises a container. Suitable containers include, for example, bottles, vials (e.g. dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic.
The container holds the formulation and the label on, or associated with, the container may indicate directions for reconstitution and/or use. The label may further indicate that the formulation is useful or intended for subcutaneous administration. The container holding the formulation may be a multi-use vial, which allows for repeat administrations (e.g. from 2-6 administrations) of the reconstituted formulation. The article of manufacture may further comprise a second container comprising a suitable diluent (e.g. BWFI). Upon mixing of the diluent and the lyophilized formulation, the final protein concentration in the reconstituted formulation will generally be at least 50 mg/ml. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

EXAMPLES
Unless specified otherwise, starting materials are generally available from commercial sources such as Sigma-Aldrich Corp. (St. Louis, MO), Fisher Chemical (Pittsburgh, PA), Avantor Performance Materials (Center Valley, PA) MP Biomedicals (Santa Ana, CA) Promega Corp. (Madison, WI), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), AstraZeneca Pharmaceuticals (London, England), and Accela ChemBio (San Diego, CA).
General Experimental Procedures 1.0 The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art.
Such techniques are explained fully in the literature, such as, Molecular Cloning:
A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press;
Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press;
Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A.
Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-1998) J. Wiley and Sons;
Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D.M.
Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M.
Miller and M.P. Cabs, eds., 1987); Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994);
Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); lmmunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P.
Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989);
Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995).

' Procedures Example 1. Anti-IL-7R antibody formulation 1 This example illustrates the viscosity of high concentration anti-IL-7R
antibody formulations.
Formulation 1 was amenable to achieve concentrations of approximately 50-70 mg/mL
C1GM antibody (in 20 mM histidine, 85 g/L sucrose, 0.05 g/L disodium EDTA
dihydrate, 0.2 g/L polysorbate-80, pH 5.8), with suitable stability characteristics.
Studies were conducted to evaluate impact of pH change (below and above isoelectric point, pl). The drug product was formulated as a lyophilized powder for reconstitution with sWFI (Table 1). Viscosity was evaluated using an Anton-Paar rheometer in cone-plate configuration, at 25 C. The sample size was approximately 81 pL. The samples were measured with a constant shear rate (898 s-1).
Table 1 Component Formulation 1 Antibody C1GM 0-200 mg/mL
L-histidine 20mM
Sucrose 85 g/L
Disodium EDTA 0.05 g/L
Polysorbate 80 0.2 g/L
Arginine HCI n/a WFI q.s. 1.0 mL
pH 5.0 0.5 Presentation lyophilized, 100mg/vial (= 2mL
solution after reconstitution) = High viscosity was observed at both pH 5.0 and 5.8 (FIGS. 1A and 1B:
viscosity of formulation at pH 5.8 and pH 5.0 (A) up to approximately 200 mg/mL C1GM; (B) y-axis scale limited to 100 cP).
Example 2. Anti-IL-7R antibody formulations with camphorsulfonic acid.
This example illustrates the impact of camphor-10-sulfonic acid (also described as camphorsulfonic acid or CSA) on viscosity in a new anti-IL-7R antibody formulation, formulation 2.
A study was conducted to assess the viscosity of formulation 2. Formulation 2, shown in 3.0 Table 2 below, includes 200 mM CSA. Due to the acidic nature of CSA, nearly an equimolar amount of NaOH was used to neutralize the acid and bring the pH of the formulation to 7Ø Therefore, sodium ions are also present in this formulation at approximately 200 mM.
Table 2 Component Formulation 2 Antibody Cl GM 99 to 171.6 mg/mL
L-histidine 15mM
Camphorsulfonic 200 mM
Acid WFI q.s. 1.0 mL
pH 7.0 Presentation Liquid or lyophilized Viscosity was evaluated using an Anton-Paar rheometer in cone-plate configuration, at C. The sample size was approximately 81 pL. The samples were measured with a = constant shear rate (898 s-1). Viscosity data are summarized in Table 3 below and FIG. 2A
and 2B.
Table 3 Antibody concentration Viscosity at 25 C
Formulation (mg/mL) (cP) 179.1 506.3 Formulation 1, 151.8 221.8 pH 5 116.1 89.5 101.4 55.1 171.6 13.1 Formulation 2 with 200 141.7 7.5 mM GSA, pH 7.0 116.1 4.4 99 3.2 Viscosity of formulation 2 containing 200 mM CSA showed significantly reduced viscosity, i.e., approximately 20-40 fold reduction in viscosity, compared to formulation 1 across concentrations tested (Table 3 and FIG. 2A and 2B). For example, at about 100 mg/ml antibody, viscosity of formulation 2 was 3.2 cP, compared to viscosity of formulation 1, which was 55.1 cp, a 17.2 fold reduction. At about 116 mg/ml antibody, viscosity of 1.0 formulation 2 was 4.4 cP, compared to viscosity of formulation 1, which was 89.5 cP, a 20.3 fold reduction. At about 145 mg/ml antibody, viscosity of formulation 2 was 7.5 cP, compared to viscosity of formulation 1, which was 221.8 cP, a 29.6 fold reduction. At about 175 mg/ml antibody, viscosity of formulation 2 was 13.1 cP, compared to viscosity of formulation 1, which was 506.3 cP, a 38.6 fold reduction. Of note, viscosity reduction on a fold basis increases as antibody concentration increases.
These results demonstrate the inclusion of GSA significantly reduces viscosity of an anti-IL-7R antibody formulation. Formulation 2, which contains 200 mM GSA and has pH
7, allows Cl GM protein concentrations of greater than 170 mg/mL with suitable viscosity behavior.
This was not possible for 01GM in formulation 1 because of high viscosity.

' Example 3. Impact of counterion on viscosity reduction ,.
This example illustrates how varying the counterion ion for GSA can also impact viscosity.
As indicated in Example 2, NaOH was used to neutralize the acidic nature of GSA in creating formulation 2, and bring the pH of the formulation to 7Ø Therefore, sodium ions are also present in this formulation at approximately 200 mM. Alternatively, other molecules basic in nature may be utilized to neutralize the acidic nature of GSA, effectively forming a salt of GSA. One such species is arginine (Arg).
Formulation 3, shown in the table below, includes 200 mM GSA and 200 mM
arginine. The basic nature of the arginine largely neutralizes the acidic nature of the CSA, and minimal acid or base needs to be added to adjust the pH to 7.0, avoiding the introduction of additional ionic species. For the purpose of comparison, Formulation 4 utilizes 200 mM
arginine-HCI (Arg-HCl).
Table 4 Component Formulation 3 Formulation 4 Antibody 01GM 109 to 189 mg/mL 151 to 202 mg/mL
L-histidine 20 mM 20 mM
Camphorsulfonic 200 mM N/A
Acid L-Arginine 200 mM N/A
L-Arginine HOP N/A 200 mM
WFI q.s. 1.0 mL q.s. 1.0 nnL
pH 7.0 7.0 Presentation Liquid or lyophilized Liquid or lyophilized Viscosity was evaluated using an Anton-Paar rheometer in cone-plate configuration, at C. The sample size was approximately 81 pL. The samples were measured with a ' constant shear rate (898 s-1). Viscosity data are summarized in Table 5 below and FIG. 3.
Table 5 Antibody concentration Viscosity at 25 C
Formulation (mg/mL) (cP) 189 17.3 Formulation 3 with 200 163 9.4 mM CSA and 200 mM 146 6.45 Arg, pH 7.0 126 4.61 106 3.35 202 53.6 Formulation 4 with 200 174 31.6 mM Arg-HCI, pH 7.0 151 15.7 These results demonstrate that the choice of counter-ion used together with CSA also has an impact on viscosity. With the correct choice of counter-ion, a synergistic effect can occur, resulting in a greater viscosity reduction than is observed for the individual components. The viscosity values for the CSA-Arg combination used in Formulation 3 are lower than what is observed for the CSA based Formulation 2 and far lower than what is observed for the Arg-HCI based Formulation 4. Thus, combinations of CSA with an appropriate counter-ion are particularly advantageous to achieve viscosity reduction.
Formulation 3, which contains 200 mM CSA-Arg and has pH 7, allows 01GM protein concentrations of greater than 190 mg/mL with suitable viscosity behavior.
This was not possible for 01GM in Formulation 1 because of high viscosity, and offers further improvements over both Formulations 2 and 4.
Example 4. Impact of excipient concentration on viscosity This example illustrates the impact of varying excipient concentration on viscosity in an anti-IL-7R antibody formulation.
Excipient concentrations of CSA and Arginine in Formulations 2-4 were reduced to either 100 mM or 50 mM. Viscosities of these formulations were evaluated at pH 7 using an Anton-Paar rheometer in cone-plate configuration, at 25 C. The sample size was approximately 81 pL. The samples were measured with a constant shear rate (898 s-1).
Results are summarized in FIG. 4 and Table 6.
Table 6 Antibody concentration Viscosity at 25 C
Formulation (mg/mL) (cP) Formulation 3 with 100 178 42.6 mM CSA and 100 mM 155 22.6 Arg, pH 7.0 132 11.9 Formulation 3 with 50 196 136.7 mM CSA and 50 mM 166 58.9 Arg, pH 7.0 146 28.7 Formulation 2 with 100 150 29.6 mM CSA pH 7.0 131 14.2 189 194.8 Formulation 2 with 50 163 46.0 mM CSA pH 7.0 131 26.6 191 81.2 Formulation 4 with 100 177 45.9 mM Arg-HCI pH 7.0 139 16.2 195 170.9 Formulation 4 with 50 174 66.5 mM Arg-HCI pH 7.0 145 32.2 Lower amounts of excipients led to higher viscosities than observed for the 200 mM
excipients used previously. However, reduction of excipient levels may be necessary to develop formulations which are roughly isotonic and suitable for parenteral injection. In particular, additional excipients not included in Formulations 2-4, such as cryoprotectants, surfactants, and chelating agents, may be necessary to include in the formulation, and will contribute to the tonicity of the formulation. Therefore, reduction of CSA and Arg levels may be required to allow these other excipients to be included in the formulation.
Even at lower ' levels of CSA and Arg, formulations of CI GM that include these excipients have significantly lower viscosity than formulations without these excipients.
These results demonstrate that CSA-Arg appears to provide some robust protection against viscosity increases over the range of the ionic strength of the formulation.
Example 5. Viscosity Reduction by Camphorsulfonic acid and CSA-Arg formulations of other antibodies This example illustrates the impact of camphorsulfonic acid (CSA) and CSA-Arg on viscosity new formulations of mAb5 and Li L3 antibodies.
Formulations of mAb5 and Li L3 antibodies listed in Table 7 exhibited high viscosity at high io concentrations, as shown in Figure 5 (XX1 is mAb5 antibody and XX2 is Li L3 antibody) and Table 8 Table 7 Component Formulation of mAb5 Formulation of Antibody 0-200 mg/mL 0-200 mg/mL
L-histidine 20 mM 20 mM
Sucrose 50 g/L 0 g/L
Disodium EDTA 0.05 g/L 0 g/L
Polysorbate 80 0.2 g/L 0 g/L
WFI q.s. 1.0 mL
q.s. 1.0 mL
pH 5.8 0.5 5.5 0.5 Presentation Liquid or lyophilized Liquid or lyophilized ' Table 8 Antibody concentration Viscosity at 25 C
Formulation (mg/mL) (cP) 132 33.5 126 28.8 Formulation of mAb5 102 10.9 83 5.8 61 3.1 Antibody concentration Viscosity at 20 C
(mg/mL) (cP) 193 82.4 185 55.1 Formulation of Li L3 166 23.6 146 11.0 124 5.9 102 3.4 In an effort to lower viscosity of these formulations, mAb5 and Li L3 were reformulated with the above formulations by adding 200 mM Arginine HCI, 200 mM GSA, or 200 mM
GSA-Arg. Viscosity was evaluated using an Anton-Paar rheonneter in cone-plate configuration, at 25 C. The sample size was approximately 81 pL. The samples were measured with a constant shear rate (898 s-1). Viscosity data are summarized in Table 9 below and FIG. 6 (XX1 is mAb5 antibody and XX2 is L1L3 antibody).

' Table 9 s I
mAb5 Antibody Viscosity L1L3 Antibody Viscosity concentration at 25 C
concentration at 25 C
Formulation (mg/mL) (cP) (mg/mL) (cP) 198 144.8 187 53.9 200 mM Arg-HCI 180 54.5 149 16.4 151 32.1 133 11.4 222 169.2 196 35.0 175 38.5 173 16.3 200 mM CSA 148 15.2 142 8.1 121 7.7 121 4.7 100 4.6 105 3.7 262 144.6 244 75.3 204 26.1 220 39.4 153 9.3 187 22.3 200 mM CSA-Arg 137 5.7 150 7.0 102 3.6 115 3.7 2.8 The data show that Arg, CSA, and CSA-Arg formulations are all effective in reducing the viscosity of formulations of mAb5 and Li L3 antibodies. As was observed for formulations of the 01GM antibody, the CSA-Arg combination offers the most effective reduction of viscosity for the mAb5 and Li L3 antibody formulations.
Formulations containing 200 mM CSA-Arg at pH 7.0 allows mAb5 protein concentrations of greater than 195 mg/mL, and L1L3 protein concentrations of greater than 185 mg/mL, with suitable viscosity behaviors. This was not possible for mAb5 and Li L3 antibodies without the excipients because of high viscosity.

' Example 6. Impact of excipient concentration on viscosity for other antibodies.
, This example illustrates the impact of varying excipient concentration on viscosity on mAb5 and Li L3 antibody formulations.
Excipient concentrations of GSA and Arginine were reduced to either 100 mM or 50 mM
from the previous level of 200 mM. Viscosities of these formulations were evaluated at pH
7 using an Anton-Paar rheometer in cone-plate configuration, at 25 C. The sample size was approximately 81 pL. The samples were measured with a constant shear rate (898 s-1). Results are summarized in FIG. 7A and 7B (XX1 is mAb5 antibody and XX2 is antibody) and Table 10.
Lower amounts of excipients led to higher viscosities than observed for the 200 mM
excipients. Even at lower levels of GSA and Arg, formulations of mAb5 and Li L3 that include these excipients have significantly lower viscosity than formulations without these excipients. These results demonstrate that CSA-arginine appears to provide some robust protection against viscosity increases over the range of the ionic strength of the formulation for a variety of antibodies.

, Table 10 , mAb5 Antibody Viscosity Ll L3 Antibody Viscosity concentration at 25 C
concentration at 25 C
Formulation (mg/mL) (cP) (mg/mL) (cP) 203 220.8 173 93.6 100 mM Arg-HCI 167 67.6 158 32.2 145 29.1 133 22.1 188 125.9 237 192.9 100 mM CSA 179 52.4 201 55.2 30.0 186 1541.1 184 40.8 100 mM CSA-Arg 176 369.6 157 17.6 157 149.8 135 7.6 211 1093.7 168 171.8 50 mM Arg-HCI 180 251.4 159 47.5 162 109.8 135 23.0 188 581.1 201 90.0 50 mM CSA 167 194.5 168 36.2 147 89.1 138 23.4 131 140.3 183 57.4 , 50 mM CSA-Arg N/A N/A 150 18.9 10.9 Example 7. Impact of hinge region structure on viscosity This example illustrates the impact of the choice of hinge region structure on the viscosity of a formulation of monoclonal antibodies.
Monoclonal antibodies with identical CDR regions but differing hinge regions were produced and characterized using methods known in the art. Identical CDR
regions were incorporated into frameworks of the IgG1, IgG2, and IgG4 subtypes, and referred to as IgG1, IgG2, and IgG4, respectively. The IgG4 contained a hinge stabilizing S228P mutation (serine at position 228 of the heavy chain is replaced with proline).

Each antibody was formulated at 130 mg/mL in 20 mM histidine, 85 g/L sucrose, 0.05 g/L disodium EDTA dihydrate, 0.2 g/L polysorbate-80, pH 5.8. Viscosity of these formulations was evaluated using an Anton-Paar rheometer in cone-plate configuration, at 25 C. The sample size was approximately 81 pL. The samples were measured with a constant shear rate (898 s-1). Viscosity data are summarized in Table 11.
Table 11 Viscosity at 25 C
Antibody subtype (cP) IgG1 5.24 IgG2 5.89 IgG4 6.95 The data show that the choice of hinge region structure can impact viscosity for an otherwise identical monoclonal antibody. IgG1 exhibits the lowest viscosity, followed by IgG2, and the hinge stabilized IgG4. The data indicate that the flexibility of the hinge region may impact viscosity. These results demonstrate that proper selection or design of the hinge region of an antibody can result in lower viscosity antibody formulations.
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for all purposes.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification including the examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

SEQUENCE LISTING IN ELECTRONIC FORM
In accordance with Section 111(1) of the Patent Rules, this description contains a sequence listing in electronic form in ASCII text format (file:

Seq 31-AUG-16 v1 .b1/41).
A copy of the sequence listing in electronic form is available from the Canadian Intellectual Property Office.
The sequences in the sequence listing in electronic form are reproduced in the following table.
SEQUENCE TABLE
<110> Pfizer Inc.
<120> Low Viscosity Antibody Compositions <130> 72222-956 <150> US 62/235638 <151> 2015-10-01 <150> US 62/324482 <151> 2016-04-19 <160> 43 <170> PatentIn version 3.5 <210> 1 <211> 459 <212> PRT
<213> Homo sapiens <400> 1 Met Thr Ile Leu Gly Thr Thr Phe Gly Met Val Phe Ser Leu Leu Gin Val Val Ser Gly Glu Ser Gly Tyr Ala Gin Asn Gly Asp Leu Glu Asp Ala Glu Leu Asp Asp Tyr Ser Phe Ser Cys Tyr Ser Gin Leu Glu Val Asn Gly Ser Gin His Ser Leu Thr Cys Ala Phe Glu Asp Pro Asp Val Asn Thr Thr Asn Leu Glu Phe Glu Ile Cys Gly Ala Leu Val Glu Val Lys Cys Leu Asn Phe Arg Lys Leu Gin Glu Ile Tyr Phe Ile Glu Thr Lys Lys Phe Leu Leu Ile Gly Lys Ser Asn Ile Cys Val Lys Val Gly Glu Lys Ser Leu Thr Cys Lys Lys Ile Asp Leu Thr Thr Ile Val Lys Pro Glu Ala Pro Phe Asp Leu Ser Val Ile Tyr Arg Glu Gly Ala Asn Asp Phe Val Val Thr Phe Asn Thr Ser His Leu Gin Lys Lys Tyr Val Lys Val Leu Met His Asp Val Ala Tyr Arg Gin Glu Lys Asp Glu Asn Lys Trp Thr His Val Asn Leu Ser Ser Thr Lys Leu Thr Leu Leu Gin Arg Lys Leu Gin Pro Ala Ala Met Tyr Glu Ile Lys Val Arg Ser Ile Pro Asp His Tyr Phe Lys Gly Phe Trp Ser Glu Trp Ser Pro Ser Tyr Tyr Phe Arg Thr Pro Giu Ile Asn Asn Ser Ser Gly Glu Met Asp Pro Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe Ser Val Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gin Ile His Arg Val Asp Asp Ile Gin Ala Arg Asp Glu Val Glu Gly Phe Leu Gin Asp Thr Phe Pro Gin Gin Leu Glu Glu Ser Glu Lys Gin Arg Leu Gly Gly Asp Val Gin Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly Pro His Val Tyr Gin Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gin'Ser Gly Ile Leu Thr Leu Asn Pro Val Ala Gin Gly Gin Pro Ile Leu Thr Ser Leu Gly Ser Asn Gin Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gin Asn Gin <210> 2 <211> 117 <212> PRT
<213> Homo sapiens <400> 2 = Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Ser Val Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Leu Val Gly Trp Asp Gly Phe Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gin Gly Asp Tyr Met Gly Asn Asn Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser <210> 3 <211> 110 <212> PRT
<213> Homo sapiens <400> 3 Asn Phe Met Leu Thr Gin Pro His Ser Val Ser Glu Ser Pro Gly Lys Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Asp Ser Ser Tyr Val Gin Trp Tyr Gin Gin Arg Pro Gly Ser Ser Pro Thr Thr Val Ile Tyr Glu Asp Asp Gin Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gin Ser Tyr Asp Phe His His Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu <210> 4 <211> 10 <212> PRT
<213> Homo sapiens <400> 4 Gly Phe Thr Phe Asp Asp Ser Val Met His <210> 5 <211> 5 <212> PRT
<213> Homo sapiens <400> 5 Asp Ser Val Met His <210> 6 <211> 7 <212> PRT
<213> Homo sapiens <400> 6 Sly She Thr She Asp Asp Ser <210> V
<211> 16 <212> PRT
<213> Homo sapiens <400> 7 Leu Val Sly Trp Asp Sly Phe She Thr Tyr Tyr Ala Asp Ser Val Lys <210> 8 <211> 6 <212> PRT
<213> Homo sapiens <400> 8 Sly Trp Asp Sly Phe She <210> 9 <211> 8 <212> PRT
<213> Homo sapiens <400> 9 Gln Gly Asp Tyr Met Sly Asn Asn <210> 10 <211> 13 <212> PRT
<213> Homo sapiens <400> 10 Thr Arg Ser Ser Sly Ser Ile Asp Ser Ser Tyr Val Gln <210> 11 <211> 7 <212> PRT
<213> Homo sapiens <400> 11 Glu Asp Asp Gin Arg Pro Ser <210> 12 <211> 9 <212> PRT
<213> Homo sapiens <400> 12 Gin Ser Tyr Asp Phe His His Leu Val <210> 13 <211> 432 <212> PRT
<213> Homo sapiens <400> 13 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Ser Val Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Leu Val Gly Trp Asp Gly Phe Phe Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gin Gly Asp Tyr Met Gly Asn Asn Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Vol Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Vol Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys <210> 14 <211> 215 <212> PRT
<213> Homo sapiens <400> 14 Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Asp Ser Ser Tyr Val Gin Trp Tyr Gln Gln Arg Pro Gly Ser Ser Pro Thr Thr Val Ile Tyr Glu Asp Asp Gln Arg Pro Ser Gly Vol Pro Asp Arg Phe Ser Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Phe His His Leu Vol Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Vol Thr Vol Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Vol Glu Thr Thr Thr Pro Ser Lys Gin Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gin Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser <210> 15 <211> 120 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 15 Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Ser Val His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Glu Thr Asp Glu Thr Ser Tyr Ala Asp Asp Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Val Lys Ser Arg Tyr Trp Ser Tyr Gly Pro Pro Asp Tyr Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser <210> 16 <211> 107 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 16 Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gin Ala Ser Gin Asn Ile Arg Thr Ala Val Val Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Arg His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gin Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gin His Trp Thr Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys <210> 17 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 17 ,Ply Tyr Thr Phe Thr Asp Phe Ser Val His <210> 18 <211> 7 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 18 Ply Tyr Thr Phe Thr Asp Phe <210> 19 <211> 5 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 19 Asp Phe Ser Val His <210> 20 <211> 6 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 20 Asn Thr Glu Thr Asp Glu <210> 21 <211> 17 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 21 Trp Ile Asn Thr Glu Thr Asp Glu Thr Ser Tyr Ala Asp Asp Phe Lys Gly <210> 22 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 22 Ser Arg Tyr Trp Ser Tyr Gly Pro Pro Asp Tyr <210> 23 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 23 Gin Ala Ser Gin Asn Ile Arg Thr Ala Vol Val <210> 24 <211> 7 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 24 Leu Ala Ser Asn Arg His Ser <210> 25 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 25 Leu Gin His Trp Thr Tyr Pro Phe Thr <210> 26 <211> 446 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 26 Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Ser Vol His Trp Vol Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Glu Thr Asp Glu Thr Ser Tyr Ala Asp Asp Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Val Lys Ser Arg Tyr Trp Ser Tyr Gly Pro Pro Asp Tyr Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Vol Thr Vol Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Vol His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Vol Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Vol Thr Cys Val Vol Val Asp Val Ser His Glu Asp Pro Glu Vol Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Vol Ser Val Leu Thr Val Vol His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Vol Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys <210> 27 <211> 445 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 27 Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Ser Val His Trp Val Arg Gin Ala Pro Gly Gin Gly Lou Glu Trp Met Gly Trp Ile Asn Thr Glu Thr Asp Glu Thr Ser Tyr Ala Asp Asp Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Lou Per Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Val Lys Ser Arg Tyr Trp Ser Tyr Gly Pro Pro Asp Tyr Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Giu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Per Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Vol Pro Per Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly <210> 28 <211> 214 <212> PRT
<213> Artificial Sequence <220>
<223> Humanized antibody sequence <400> 28 Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gin Ala Ser Gin Asn Ile Arg Thr Ala Val Val Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Arg His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gin Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Lou Gin His Trp Thr Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Lou Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr = 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys <210> 29 <211> 477 <212> PRT
<213> Homo sapiens <400> 29 Met Pro Pro Cys Gin Pro Gin Arg Pro Leu Leu Leu Leu Leu Lou Leu Leu Ala Cys Gin Pro Gin Val Pro Ser Ala Gin Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp Gin Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala Asn Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His Lys Val Gin His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gin Trp Val Arg Gly Pro Arg Gly Gin Pro Trp Arg Asp Ala Ser Gin Cys Gin Met Asp Gly Glu Glu Ile Glu Val Gin Lys Giu Val Ala Lys Met Tyr Ser Ser Phe Gin Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly Ala Leu Leu Leu Ala Lou Ala Ile Leu Gly Gly Lou Ser Lys Leu His Cys Thr Arg Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu Lys Ala Ser Ser Val Leu Val Ile Asp Gly Leu Lou Arg Thr Arg Tyr Ser Gin Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gin Tyr Gly Ile Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu His Asn Leu Lou Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser Leu Tyr Lou Gly Ile Giy Trp Gly Ala Pro Met Leu Phe Val Val Pro Trp Ala Val Val Lys Cys Leu Phe Glu Asn Val Gin Cys Trp Thr Ser Asn Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala Ile Leu Ile Asn Phe Phe Ile Phe Val Arg Ile Val Gin Lou Leu Val Ala Lys Leu Arg Ala Arg Gin Met His His Thr Asp Tyr Lys Phe Arg Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gin Gly Thr Leu Arg Ser Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gin Gly Leu Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gin Ser Glu Leu Arg Arg Arg Trp His Arg Trp Arg Leu Gly Lys Val Leu Trp Glu Glu Arg Asn Thr Ser Asn His Arg Ala Ser Ser Ser Pro Gly His Gly Pro Pro Ser Lys Glu Leu Gin Phe Gly Arg Gly Gly Gly Ser Gin Asp Ser Ser Ala Glu Thr Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala Glu Ser Pro Phe <210> 30 <211> 444 <212> PRT
<213> Artificial Sequence <220>
<223> HUMANIZED L1L3 HEAVY CHAIN
<400> 30 Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly Glu Ile Ser Pro Phe Gly Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Arg Pro Leu Tyr Ala Ser Asp Leu Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Her Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Vol Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Vol Vol Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Her Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys <210> 31 <211> 214 <212> PRT
<213> Artificial Sequence <220>
<223> HUMANIZED L1L3 LIGHT CHAIN
<400> 31 Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Vol Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Gly Ile Ser Ser Ala Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gin Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gin Gin Arg Tyr Ser Leu Trp Arg Thr Phe Gly Gin Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Tie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Clu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys <210> 32 <211> 10 <212> PRT
<213> Artificial Sequence <220>
<223> Synthetic <400> 32 Gly Tyr Thr Phe Thr Ser Tyr Tyr Met His <210> 33 <211> 7 <212> PRT
<213> Artificial Sequence <220>
<223> Synthetic <400> 33 Gly Tyr Thr Phe Thr Ser Tyr <210> 34 <211> 5 <212> PRT
<213> Artificial Sequence <220>
<223> VARIABLE HEAVY CHAIN CDR
<400> 34 Ser Tyr Tyr Met His <210> 35 <211> 17 <212> PRT
<213> Artificial Sequence <220>
<223> VARIABLE HEAVY CHAIN CDR
<400> 35 Glu Ile Ser Pro Phe Gly Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys Ser <210> 36 <211> 6 <212> PRT
<213> Artificial Sequence <220>
<223> Synthetic <400> 36 Ser Pro Phe Gly Gly Arg <210> 37 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> VARIABLE HEAVY CHAIN CDR
<400> 37 Glu Arg Pro Leu Tyr Ala Ser Asp Leu <210> 38 <211> 11 <212> PRT
<213> Artificial Sequence <220>
<223> VARIABLE LIGHT CHAIN CDR
<400> 38 Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala <210> 39 <211> 7 <212> PRT
<213> Artificial Sequence <220>
<223> VARIABLE LIGHT CHAIN CDR

<400> 39 Ser Ala Ser Tyr Arg Tyr Thr <210> 40 <211> 9 <212> PRT
<213> Artificial Sequence <220>
<223> VARIABLE LIGHT CHAIN CDR
<400> 40 Gin Gin Arg Tyr Ser Leu Trp Arg Thr <210> 41 <211> 120 <212> PRT
<213> Homo sapiens <400> 41 Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly Glu Ile Ser Pro Phe Gly Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Arg Pro Leu Tyr Ala Ser Asp Lou Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser <210> 42 <211> 107 <212> PRT
<213> Homo sapiens <400> 42 Asp Ile Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Gly Ile Ser Ser Ala Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Lou Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gin Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gin Gin Arg Tyr Ser Leu Trp Arg Thr Phe Gly Gin Gly Thr Lys Leu Glu Ile Lys <210> 43 <211> 108 <212> PRT
<213> Mus musculus <400> 43 Asp Ile Val Met Thr Gin Ser Gin Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gin Asn Val Gly Thr Asn Val Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ser Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Leu Ser Glu Asp Leu Ala Giu Tyr Phe Cys Gin Gin Phe Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

Claims (35)

What is claimed is:

1. A pharmaceutical composition comprising;
a. an antibody, wherein the antibody concentration is between about 100 mg/m1 to about 400 mg/ml, and b. a viscosity lowering excipient comprising camphorsulfonic acid, sulfosalicylic acid, a salt of camphorsulfonic acid, or a salt of sulfosalicylic acid, wherein the viscosity lowering excipient concentration is between about 30 mM to about 200 mM, wherein the pH of said composition is from about 4.0 to about 9Ø

2. The composition of claim 1 wherein the antibody is a human or humanized monoclonal lgG1, lgG2 or lgG4 antibody.

3. The composition of claim 1 or 2 wherein the composition further comprises a pharmaceutically acceptable buffer.

4. The composition of claim 3 wherein the pharmaceutically acceptable buffer comprises histidine, tris, phosphate, or a salt thereof.

5. The composition of claim 3 or 4 wherein the concentration of pharmaceutically acceptable buffer is from about 1.0 to about 200 mM.

6. The composition of any one of claims 1-5 wherein the composition further comprises a surfactant.

7. The composition of claim 6 wherein the surfactant is polysorbate 20 or polysorbate 80.

8. The composition of claim 6 or 7 wherein the concentration of surfactant is from about 0.01 to about 0.3 mg/ml.

9. The composition of any one of claims 1-8 wherein the composition further comprises a chelating agent.

10. The composition of claim 9 wherein the chelating agent is EDTA or disodium EDTA.

11. The composition of claim 9 or 10 wherein the concentration of chelating agent is from about 0.01 to about 0.3 mg/ml.

12. The composition of any one of claims 1-8 wherein the composition further comprises a cryoprotectant.

13. The composition of claim 12 wherein the cryoprotectant is sucrose, dextrose, mannose or trehalose.

14. The composition according to claim 12 or 13, wherein the concentration of the cryoprotectant is from about 1 mg/ml to about 100 mg/ml.

15. The composition of any one of claims 1-14 wherein the viscosity lowering agent is a salt of camphorsulfonic acid comprising camphorsulfonic acid and arginine .

16. The composition of claim 15 wherein the camphorsulfonic acid concentration is between about 50 mM and about 150 mM and the arginine concentration is between about 50 mM and about 150 mM.

17. The composition of claim 16 wherein the camphor sulfonic acid concentration is between about 70 mM and about 110 mM and the arginine concentration is between about 70 mM and about 110 mM.

18. The composition according to any one of claims 1 to 17 wherein the antibody comprises a heavy chain comprising at least one CDR selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 4, 5, or 6; CDR2 comprising the amino acid sequence shown in SEQ ID NO: 7 or 8; and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 9, and a light chain comprising at least one CDR selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 10, CDR2 comprising the amino acid sequence shown in SEQ ID NO: 11, and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 12.

19. The composition according to any one of claims 1 to 17 wherein the antibody comprises an amino acid sequence that is at least 85% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 2, and an amino acid sequence that is at least 85% identical to a light chain variable region amino acid sequence shown in SEQ
ID NO: 3.

20. The composition according to any one of claims 1 to 17 wherein the antibody comprises an amino acid sequence that is at least 85% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 13, and an amino acid sequence that is at least 85%
identical to a light chain amino acid sequence shown in SEQ ID NO: 14.

21. The composition according to any one of claims 1 to 17 wherein the antibody comprises a variable heavy chain sequence comprising the amino acid sequence shown in SEQ ID NO: 2 and a variable light chain sequence comprising the amino acid sequence shown in SEQ ID NO: 3.

22. The composition according to any one of claims 1 to 17 wherein the antibody comprises a heavy chain comprising at least one CDR selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 17, 18 or 19; CDR2 comprising the amino acid sequence shown in SEQ ID NO: 20 or 21; and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 22, and a light chain comprising at least one CDR

selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 23, comprising the amino acid sequence shown in SEQ ID NO: 24, and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 25.

23. The composition according to any one of claims 1 to 17 wherein the antibody comprises an amino acid sequence that is at least 85% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 15, and an amino acid sequence that is at least 85% identical to a light chain variable region amino acid sequence shown in SEQ
ID NO: 16.

24. The composition according to any one of claims 1 to 17 wherein the antibody comprises an amino acid sequence that is at least 85% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 26 or 27, and an amino acid sequence that is at least 85% identical to a light chain amino acid sequence shown in SEQ ID NO: 28.

25. The composition according to any one of claims 1 to 17 wherein the antibody comprises a variable heavy chain sequence comprising the amino acid sequence shown in SEQ ID NO: 15 and a variable light chain sequence comprising the amino acid sequence shown in SEQ ID NO: 16.

26. The composition according to any one of claims 1 to 17 wherein the antibody comprises a heavy chain comprising at least one CDR selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 32, 33, or 34; CDR2 comprising the amino acid sequence shown in SEQ ID NO: 35 or 36; and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 37, and a light chain comprising at least one CDR

selected from CDR1 comprising the amino acid sequence shown in SEQ ID NO: 38, comprising the amino acid sequence shown in SEQ ID NO: 39, and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 40.

27. The composition according to any one of claims 1 to 17 wherein the antibody comprises an amino acid sequence that is at least 85% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 41, and an amino acid sequence that is at least 85% identical to a light chain variable region amino acid sequence shown in SEQ
ID NO: 42.

28. The composition according to any one of claims 1 to 17 wherein the antibody comprises an amino acid sequence that is at least 85% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 30, and an amino acid sequence that is at least 85%
identical to a light chain amino acid sequence shown in SEQ ID NO: 31.

29. The composition according to any one of claims 1 to 17 wherein the antibody comprises a variable heavy chain sequence comprising the amino acid sequence shown in SEQ ID NO: 41 and a variable light chain sequence comprising the amino acid sequence shown in SEQ ID NO: 42.

30. The composition according to any one of claims 1 to 29 wherein the composition is lyophilized.

31. The composition according to claim 30 wherein the lyophilized composition is reconstituted and the antibody concentration of the reconstituted composition is between about 250 mg/ml and about 400 mg/ml.

32. The composition according to any one of claims 1 to 31 wherein the composition has a viscosity of less than about 50 cP at 25°C.

33. The composition according to any one of claims 1 to 32 wherein the antibody hinge region increases flexibility of the antibody.

34. The composition according to claim 33 wherein the antibody has lowered viscosity.

35. The composition according to any one of claims 1 to 34 wherein the antibody is an IgG4 subtype comprising S228P in the antibody hinge region.