FORMULATIONS FOR ANTI-N3pGlu AMYLOID BETA ANTIBODIES

Abstract

The present disclosure is related to stable pharmaceutical formulations comprising an anti-N3pGlu amyloid beta (Aβ) antibody that specifically binds to or targets N3pGlu Aβ. In certain embodiments, the formulations contain, in addition to the antibody, a buffer, a tonicity modifier, an antioxidant, and a surfactant.

Description

ATTORNEY DOCKET NO: 30762_WO -1- FORMULATIONS FOR ANTI-N3pGlu AMYLOID BETA ANTIBODIES FIELD OF THE INVENTION

[0001] The present invention relates to stable therapeutic antibody formulations. More specifically, the present invention relates to pharmaceutical formulations comprising an anti-N3pGlu Amyloid β (Aβ) antibody that specifically binds to N3pGlu Aβ. SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “30762” created May 3, 2024, and is 14 kilobytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety. BACKGROUND

[0003] The exploration of antibodies for therapeutic applications has led to their widespread use in disease treatment and prevention. The process typically involves administering a pharmaceutical formulation of the therapeutic antibody to patients in need. However, the formulation of these antibodies into pharmaceutical compositions suitable for different administration routes (including subcutaneous, intramuscular, intravenous, and intraperitoneal) presents significant challenges due to the multifaceted approaches that may be taken while accounting for properties needed for therapeutic viability, such as, patient administration, manufacturability, distribution, and storage stability.

[0004] Formulating therapeutic macromolecules like antibodies is a complex task that necessitates careful consideration of numerous factors. The formulation must not only be suitable for patient administration but also ensure the stability of the macromolecules during storage and use. For instance, therapeutic antibodies are sometimes prone to oxidation, degradation, aggregation, or unwanted chemical modifications unless appropriately formulated. The stability of an antibody in a formulation is contingent on the types, quantities, and ratios of the excipients used, often resulting in a multivariate and highly unpredictable problem.

[0005] Beyond stability, other factors such as the solution’s viscosity, the maximum antibody concentration that the formulation can accommodate, and the formulation’s visual appeal must be considered. Thus, formulating a therapeutic antibody demands meticulous attentionATTORNEY DOCKET NO: 30762_WO -2- to achieve a stable formulation with sufficient antibody concentration, appropriate viscosity, and other properties that facilitate convenient patient administration.

[0006] Each component of the formulation, its concentration, its ratio relative to other components, and its characteristics can influence the formulation’s suitability for manufacturing, distribution, and storage, among other essential functional characteristics. Consequently, while a specific adjustment may enhance one aspect of the formulation, it may detrimentally affect others. For instance, while surfactants can confer beneficial properties to an antibody formulation, including a surfactant such as polysorbates can lead to degradation, loss in efficacy, or even particle formation (see, e.g., Weber, Johanna, et al., “Oxidation of Polysorbates–An Underestimated Degradation Pathway?” International Journal of Pharmaceutics: X (2023): 100202).

[0007] Predicting the impact of modifying an individual component, its concentration, or its ratio relative to other components on the properties of a pharmaceutical formulation of an antibody remains a formidable challenge. Optimization of one property (e.g., concentration of an excipient) can lead to unfavorable changes in other properties. This complexity is further compounded by the virtually limitless number of different formulation components, such as buffers and excipients, and their possible concentrations.

[0008] The present disclosure provides pharmaceutical formulations of anti-N3pGlu Aβ antibodies (i.e., antibodies that bind to or target N3pGlu Aβ), reduce plaque (Aβ1-42) in vivo, and, in some instances, exhibit reduced immunogenicity. These anti-N3pGlu Aβ antibodies may also demonstrate reduced non-specific binding to plasma proteins. Additionally, these antibodies may provide a reduced predicted T-Dependent Ab Response, increased antibody half-life, and an improved safety profile for a potential human therapeutic with pharmacokinetics for a better dosing schedule.

[0009] The anti-N3pGlu Aβ antibodies of the present disclosure are often difficult to formulate because of the stringent requirements for formulation and administration. Although anti-N3pGlu Aβ antibodies are known for their use in treatment of Alzheimer’s disease, there remains a need in the art for novel pharmaceutical formulations comprising the antibodies that are, e.g., sufficiently stable (e.g., not prone to oxidation), provide adequate efficacy against Alzheimer’s disease without causing significant side effects, and suitable for administration to patients.ATTORNEY DOCKET NO: 30762_WO -3- SUMMARY OF THE INVENTION

[0010] This invention pertains to antibodies that bind or target human N3pGlu amyloid beta (Aβ) peptide, their pharmaceutical formulations, and their use in treating diseases associated with Aβ peptide, its variants, or its aberrant accumulation, such as Alzheimer’s disease.

[0011] It was observed that the anti-N3pGlu Aβ antibodies disclosed herein are prone to oxidation (e.g., during storage). In one aspect, this application reveals certain unique and unexpected characteristics of the anti-N3pGlu antibody formulations discussed here and the methods by which these formulations address the issue of oxidation during storage. In another aspect, the present disclosure relates to formulations that address issues such as high concentration of antibody and related viscosity, aggregation, injection site reaction, and injection site pain.

[0012] Oxidation renders the antibody and its formulation less desirable for several critical reasons. For example, potential alterations to the antibody due to oxidation could impact the potency of the antibody or its formulation, thereby affecting the precision and consistency of the doses administered to patients (e.g., in clinical trials or during treatment). These issues pose significant obstacles to delivering the intended therapeutic dose of the antibody to the patient. Therefore, there is a need for a pharmaceutical formulation containing the antibodies disclosed herein that offers enhanced stability suitable for manufacturing, distribution, storage, and patient administration.

[0013] The current disclosure meets this need by offering pharmaceutical formulations of the anti-N3pGlu Aβ antibodies with enhanced properties. For instance, the disclosure relates to the development of pharmaceutical formulations containing antibodies that show decreased oxidation over time during storage.

[0014] It was discovered that an increased concentration of the antibody disclosed herein (e.g., remternetug) results in a decrease in antibody oxidation. This finding is counterintuitive, as a higher antibody concentration is typically expected to contain a higher concentration or number of impurities that could enhance oxidation. Therefore, in contrast to conventional wisdom, aspects of the disclosure relate to pharmaceutical solutions containing high concentrations of antibodies that demonstrate improved stability, including enhanced stability. In some embodiments, the stability is enhanced over weeks, months, or years when stored at temperatures ranging from about 5ºC to about 35ºC, such as at 5ºC, 25ºC, or 35ºC.ATTORNEY DOCKET NO: 30762_WO -4-

[0015] Another important consideration for the antibody formulations of the present invention is to maintain the viscosity of the formulation (e.g., for formulations that have high concentrations of the N3pGlu Aβ antibody) such that 1) the antibody is not oxidized, 2) the formulation can deliver appropriate dose of the antibody to the patient via, e.g., an autoinjector. The mechanical components of an autoinjector can only handle a certain level of viscosity and there are often limitations on the volume of formulation that can be included in the autoinjector. In some embodiments, the antibody formulation is such that it can be administered via autoinjectors. The present invention also provides for convenient delivery of dose(s) to the patient via subcutaneous administration. Certain other aspects of the present invention provide for administration of the subcutaneous dose via a syringe or an autoinjector. In some embodiments, the viscosity of the antibody formulation is not suitable for subcutaneous administration using injectors (e.g., pre-filled syringe or autoinjector). Accordingly, the viscosity of the antibody formulation must be modified such that it may be administered using injectors. In some embodiments, certain excipients are added to the pharmaceutical formulations to reduce the viscosity of the formulation. In some embodiments, the excipient is a viscosity reducer, e.g., L-Arginine HCl.

[0016] In some embodiments, the formulation of the present invention is for subcutaneous administration. Some aspects of the present invention are related to pharmaceutical formulations that do not cause injection site reaction or pain to the patients. In some embodiments, the formulation of the present invention is for subcutaneous administration and it does not cause pain.

[0017] In some embodiments, the pharmaceutical formulation of the present invention is used for intravenous administration. Some aspects of the present invention are related to pharmaceutical formulations that do not cause injection site reaction or pain to the patients. In some embodiments, the pharmaceutical formulation of the present invention is used for intravenous administration without causing injection site reaction or pain.

[0018] The pharmaceutical formulation of the present invention, in some embodiments, ensures the stability of the antibody and its suitability for manufacturing, distribution, and storage, especially for therapeutic antibodies delivered in high doses (e.g., for subcutaneous administration or intravenous administration) and / or antibodies that have demonstrated challenging stability characteristics including oxidation or aggregation.

[0019] Changes in the amount of charge variants of an antibody may indicate oxidation or an increase in the rate of oxidation of the antibody. Also, an increase in certain chargeATTORNEY DOCKET NO: 30762_WO -5- variants over time may indicate that certain post-translational modifications are occurring within that antibody during manufacturing, distribution, and storage. In some embodiments, the formulation is such that it does not lead to change in the concentration of charge variants of the antibody. This is important as the antibody of the present invention (e.g., remternetug) is prone to oxidation and thus reduction in potency.

[0020] In some aspects the present disclosure relates to a pharmaceutical formulation comprising an antibody of the disclosure (e.g., remternetug), a buffering agent, a viscosity reducer, an antioxidant, a surfactant, and an optional excipient. Aspects of the disclosure also relate to pharmaceutical formulations comprising an antibody of the disclosure (e.g., remternetug), a buffer, a viscosity reducer, a surfactant, and an optional excipient that exhibit one or more of improved antibody stability, improved formulation stability, improved purity, improved antibody solubility, improved potency, reduced pain in a patient upon / during administration, and suitability for intended therapeutic benefit. In one aspect, the present disclosure is related to a pharmaceutical formulation comprising: (a) an anti- N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 has an amino acid sequence of SEQ ID NO.1, HCDR2 has an amino acid sequence of SEQ ID NO: 2, HCDR3 has an amino acid sequence of SEQ ID NO: 3, LCDR1 has an amino acid sequence of SEQ ID NO: 4, LCDR2 has an amino acid sequence of SEQ ID NO: 5, and LCDR3 has an amino acid sequence of SEQ ID NO: 6; (b) a buffering agent; (c) a viscosity reducer; (d) optionally, an antioxidant; and (e) optionally, a surfactant comprising polysorbate 80 (PS80); wherein the formulation has a pH range from about 5.3 to about 6.3.

[0021] In one aspect, the present disclosure is related to a pharmaceutical formulation comprising: (a) an anti-N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 has an amino acid sequence of SEQ ID NO. 1, HCDR2 has an amino acid sequence of SEQ ID NO: 2, HCDR3 has an amino acid sequence of SEQ ID NO: 3, LCDR1 has an amino acid sequence of SEQ ID NO: 4, LCDR2 has an amino acid sequence of SEQ ID NO: 5, and LCDR3 has an amino acid sequence of SEQ ID NO: 6; (b) histidine buffer; (c) L-Arginine HCl; (d) L-Methionine; andATTORNEY DOCKET NO: 30762_WO -6- (e) polysorbate 80 (PS80); wherein the formulation has a pH range from about 5.3 to about 6.3.

[0022] In some embodiments, the pharmaceutical formulation is such that: a) the % oxidation of light chain (LC) Tryptophan 32 amino acid residue of the antibody is i) no more than about 5% when tested based on Fenton stress test or ii) not more than about 7% when tested based on AAPH stress test; b) the % oxidation of heavy chain (HC) Methionine 257 amino acid residue of the antibody is i) no more than about 5% when tested based on Fenton stress test or ii) not more than about 4% when tested based on AAPH stress test; c) the % oxidation of heavy chain (HC) Methionine 433 amino acid residue of the antibody is i) no more than about 2% when tested based on Fenton stress test or ii) not more than about 2% when tested based on AAPH stress test; d) the formulation has at least 95% Fc purity after 14 days of 316 stainless steel exposure or at least 96% LC purity after 14 days of 316 stainless steel exposure; and / or e) the formulation has at least about 40% of main charge variant of the antibody after 2 months at 35º C.

[0023] Aspects of the disclosure also relate to pharmaceutical formulations suitable for administration to human patients for the treatment or prevention of a disease. Pharmaceutical formulations of antibodies disclosed herein are useful in treating a disease characterized by deposition of Aβ, including, but not limited to, Alzheimer’s disease (AD) (including, but not limited to, preclinical AD, prodromal AD, mild AD, moderate AD, and severe AD), Down’s syndrome, and cerebral amyloid angiopathy. Aspects of the disclosure also relate to kits comprising the pharmaceutical formulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 shows the RP-HPLC oxidation results. The solid black bars show Lc peak, and the striped bars show the Fc peak. The concentration of methionine on X-axis is represented in mM (e.g., from 0 mM to 20 mM and 10 mM in a syringe). DETAILED DESCRIPTION

[0025] The disclosed compositions and processes may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is also to be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to beATTORNEY DOCKET NO: 30762_WO -7- limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0026] Some aspects of the present invention are related to antibodies targeting N3pGlu Aβ and their pharmaceutically acceptable formulations. Anti-N3pGlu Aβ antibodies are known in the art and have applications in treating or preventing disease, such as, Alzheimer’s disease. One of ordinary skill in the art will appreciate and recognize that anti-N3pGlu Aβ antibodies are identified and disclosed (along with methods for making and using such antibodies) in U.S. Patent No. 10,647,759 B2 and US Patent No. 11,078,261 (which are hereby incorporated by reference in their entireties).

[0027] For example, remternetug, which is disclosed in U.S. Patent No. 10,647,759, is an antibody directed towards N3pGlu Aβ that is present only in brain amyloid plaques. As used herein, “remternetug” refers to an anti-N3pGlu Aβ antibody comprising a light chain (LC), wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and a heavy chain (HC), wherein the HC comprises the amino acid sequence SEQ ID NO: 9.

[0028] In one aspect, the present invention is related to a pharmaceutical formulation comprising: (a) an anti-N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 has an amino acid sequence of SEQ ID NO. 1, HCDR2 has an amino acid sequence of SEQ ID NO: 2, HCDR3 has an amino acid sequence of SEQ ID NO: 3, LCDR1 has an amino acid sequence of SEQ ID NO: 4, LCDR2 has an amino acid sequence of SEQ ID NO: 5, and LCDR3 has an amino acid sequence of SEQ ID NO: 6; (b) a buffering agent; (c) a viscosity reducer; (d) optionally, an antioxidant; and (e) optionally, a surfactant; wherein the formulation has a pH range from about 5.3 to about 6.3.

[0029] In another aspect, the present invention is related to a pharmaceutical formulation comprising: (a) an anti-N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 has an amino acid sequence of SEQ ID NO. 1, HCDR2 has an amino acid sequence of SEQ ID NO: 2, HCDR3 has an amino acid sequence of SEQ ID NO: 3, LCDR1 has an amino acid sequence of SEQ ID NO: 4,ATTORNEY DOCKET NO: 30762_WO -8- LCDR2 has an amino acid sequence of SEQ ID NO: 5, and LCDR3 has an amino acid sequence of SEQ ID NO: 6; (b) a buffering agent; and (c) a viscosity reducer. In some embodiments, the pharmaceutical formulation further comprises an antioxidant. In some embodiments, the pharmaceutical formulation further comprises a surfactant. In some embodiments, the pharmaceutical formulation further comprises an antioxidant and a surfactant. In some embodiments, the formulation has a pH in the range of from about 5.3 to about 6.3.

[0030] In some embodiments, the pharmaceutical formulation comprises an antibody comprising a HCVR comprising an amino acid sequence of SEQ ID NO: 7 and a LCVR comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 10.

[0031] Pharmaceutical formulations of antibodies according to the disclosure can be prepared using the anti-N3pGlu Aβ antibodies disclosed herein. In some embodiments, a monoclonal anti-N3pGlu Aβ antibody is purified. In some embodiments, a monoclonal anti- N3pGlu Aβ antibody is subjected to one or more purification methods, e.g., as described in “Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (Feb.28, 1997).

[0032] In some embodiments, a purification scheme of the antibody comprises one or more of the following: (a) production techniques that prevent the introduction of, and / or that eliminate, contaminants, including but not limited to animal proteins and materials, DNA, endotoxins, pyrogens, culture media constituents, components that may leach from columns, and viruses; (b) incorporation of one or more steps known to remove or inactivate retroviruses in excess of an endogenous particle load (where applicable), including, but not limited to, one or more robust virus removal / inactivation operations, which are those operations that have been shown to work well under a variety of conditions (e.g., pH or ionic strength of column buffers) with a variety of monoclonal antibodies (e.g., low pH, heat, solvent and / or detergent treatments, and filtration); (c) demonstration of the ability of the purification scheme to remove adventitious agents and other contaminants, by means of a clearance study; (d) limits that are prospectively set on the number of times a purification component (e.g., a chromatography column) can be reused; (e) saving of retention samples from each production so that side-by-side comparisons may be made to determine productATTORNEY DOCKET NO: 30762_WO -9- comparability; and (f) a description of the design features of purification room(s), HVAC, and other support systems, equipment, transfers, and personnel.

[0033] In some embodiments, the anti-N3pGlu Aβ antibody used in the present invention has been purified to be free of non-immunoglobulin (Ig) contaminants or to contain less than 5% non-Ig contaminants by weight, less than 4% non-Ig contaminants by weight, less than 3% non-Ig contaminants by weight, less than 2% non-Ig contaminants by weight, or less than 1% non-Ig contaminants by weight. In some embodiments, the anti- N3pGlu Aβ antibody from which a pharmaceutical formulation of an antibody is prepared is not fragmented, not aggregated, and / or otherwise not modified (e.g., by loss of carbohydrate side chains or other post-translational modifications).

[0034] In some embodiments, the anti-N3pGlu Aβ antibody of the present invention is subjected to tests for one or more of the following: (a) protein quantity; (b) potency; (c) purity (e.g., as determined by electrophoretic migration of the antibody in both native and reduced states on polyacrylamide gels, with comparison to a reference standard); (d) sterility; (e) one or more tests for endotoxins (e.g., a Limulus Amebocyte Lysate (LAL) assay); (f) an identity test; (g) moisture, where appropriate; (h) preservative, where appropriate; (i) excipients, where appropriate; and (j) pH, where appropriate.

[0035] In some embodiments, the anti-N3pGlu Aβ antibody is subjected to one or more tests for stability. For example, in some embodiments, the anti-N3pGlu Aβ antibody is subjected to a stability testing program that includes tests for one or more of (a) physico- chemical integrity (e.g., fragmentation and / or aggregation), (b) potency, (c) sterility, (d) moisture (where appropriate); (e) pH (where appropriate); and (f) preservative stability (where appropriate). In some embodiments, the anti-N3pGlu Aβ antibody is subjected to one or more tests for assuring biological activity or potency (e.g., quantitative in vitro potency assays).

[0036] In some embodiments, the antibody is present in a pharmaceutical formulation at a concentration of from 0.1 mg / ml to 1,000 mg / ml, such as from about 1 mg / ml to about 500 mg / ml, from about 1 mg / ml to about 400 mg / ml, from about 1 mg / ml to about 300 mg / ml, from about 1 mg / ml to about 200 mg / ml, from about 1 mg / ml to about 150 mg / ml, from about 1 mg / ml to about 100 mg / ml, from about 1 mg / ml to about 50 mg / ml, from about 1 mg / ml to about 40 mg / ml, from about 100 mg / ml to about 300 mg / ml (such as 200 mg / ml), from about 150 mg / ml to about 250 mg / ml, from about 125 mg / ml to about 275 mg / ml, from about 5 mg / ml to about 75 mg / ml, from about 5 mg / ml to about 50 mg / ml, from aboutATTORNEY DOCKET NO: 30762_WO -10- 10 mg / ml to about 30 mg / ml, from about 10 mg / ml to about 25 mg / ml, or from about 15 mg / ml to about 20 mg / ml, such as 15 mg / ml, 10 mg / ml, 20 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 250 mg / ml, or 300 mg / ml. In some embodiments, the antibody concentration is from about 1 mg / ml to about 30 mg / ml. In some embodiments, the pharmaceutical formulation includes the antibody of the present invention, and the antibody concentration is about 20 mg / ml. In some embodiments, the pharmaceutical formulation includes the antibody of the present invention, and the antibody concentration is from about 100 mg / ml to about 250 mg / ml. In some embodiments, the pharmaceutical formulation includes the antibody of the present invention, and the antibody concentration is from about 100 mg / ml to about 200 mg / ml. In some embodiments, the pharmaceutical formulation includes the antibody of the present invention, and the antibody concentration is about 200 mg / ml.

[0037] In some embodiments, the pharmaceutical formulations of the present invention include a buffering agent. In some embodiments, the buffering agent is histidine. In some embodiments, the buffering agent is histidine buffer, and the concentration of histidine buffer is from about 2.5 mM to about 10 mM. In some embodiments, the histidine buffer concentration is about 5 mM.

[0038] In some embodiments, the pharmaceutical formulation of the present disclosure includes a viscosity reducer. In some embodiments, the viscosity reducer leads to reduction in viscosity of the formulation, particularly in formulations where the viscosity is not appropriate for administration via, e.g., an injection. In some embodiments, the viscosity reducer is L-Arginine HCl. In some embodiments, the viscosity reducer also functions as a tonicity agent. In some embodiments, the viscosity reducer is L-Arginine, and its concentration is from about 100 to about 150 mM. In some embodiments, the concentration of L-Arginine is about 120 mM in the formulation.

[0039] In some embodiments, the pharmaceutical formulation of the present disclosure includes an antioxidant to provide protection against oxidation of the antibody or fragments / components thereof. In some embodiments, the pharmaceutical formulation of present disclosure includes an antioxidant wherein the antioxidant is L-Methionine. In some embodiments, the antioxidant is L-Methionine, and its concentration is about 10 mM. In some embodiments, the antioxidant is L-Methionine, and its concentration is from about 1 mM to about 20 mM. In some embodiments, the antioxidant is L-Methionine, and its concentration is from about 5 mM to about 20 mM. In some embodiments, the antioxidantATTORNEY DOCKET NO: 30762_WO -11- is L-Methionine, and its concentration is about 1 mM, about 2 mM, about 3 mM, about 5 mM, about 10 mM, about 15 mM, or about 20 mM.

[0040] In some embodiments, the pharmaceutical formulation of the present disclosure includes a surfactant. In some embodiments, the pharmaceutical formulation of present disclosure includes the surfactant wherein the surfactant is polysorbate 80 (PS80). In some embodiments, the surfactant is PS80, and its concentration is from about 0.01% w / v to about 0.08% w / v. In some embodiments, the PS80 concentration in the pharmaceutical formulation of the present disclosure is about 0.04%w / v.

[0041] In some embodiments of a pharmaceutical formulation according to the disclosure, the pH of the solution is from about 5.0 to about 7.0, from about 5.2 to about 6.4, from about 5.3 to about 6.3, from about 5.5 to about 7.5, from about 5.5 to about 6.5, from about 5.75 to about 6.25, from about 5.8 to about 6.2, or from about 5.9 to about 6.1. In some embodiments, the pH of the solution is about 5.3, about 5.4, about 5.5, about 6.3, about 6.4, about 6.5, or about 7.0. In some embodiments, the pH of the solution is 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, or about 6.3. In some embodiments, the pH of the pharmaceutical formulation is about 5.8. In some embodiments, the pH of the pharmaceutical formulation is about 5.9. In some embodiments, the pH of the pharmaceutical formulation is about 6.0.

[0042] In some embodiments of the present disclosure, the pharmaceutical formulation comprises (a) about 200 mg / ml of the antibody, (b) about 5 mM of histidine as the buffering agent, (c) about 120 mM of L-Arginine HCl, (d) about 10 mM of L-Methionine, and (e) about 0.04% w / v of PS80; at a pH of about 5.8. In some embodiments, the pharmaceutical formulation is as shown in Table 1 or Table 2 below: Table 1: Remternetug Formulation (for subcutaneous administration) Component Type Final Conc. Table 2: Remternetug Formulation (for intravenous administration) Component Type Final Conc.ATTORNEY DOCKET NO: 30762_WO -12- Histidine Buffering Agent 5 mM L-Arginine HCl Tonicity modifier and viscosity 120 mM [00travenous administration or ii) subcutaneous administration to a patient. In some embodiments, the pharmaceutical formulation is for intravenous administration after a 5X dilution such that each component of the formulation is diluted 5X. In some embodiments, the pharmaceutical formulation is for intravenous administration after a 10X dilution such that each component of the formulation is diluted 10X. In some embodiments, the pharmaceutical formulation is for intravenous administration after a 20X dilution such that each component of the formulation is diluted 20X. In some embodiments, the pharmaceutical formulation is for intravenous administration after a 30X dilution such that each component of the formulation is diluted 30X. In some embodiments, the pharmaceutical formulation is for intravenous administration after a 40X dilution such that each component of the formulation is diluted 40X. In some embodiments, the pharmaceutical formulation is for intravenous administration after from about 2X to about 40X dilution. In some embodiments, the pharmaceutical formulation is for intravenous administration after from about 5X to about 30X dilution.

[0044] In some embodiments, the pharmaceutical formulation is formulated such that it does not cause severe pain to a patient based on visual analog scale upon subcutaneous administration. In some embodiments, the pharmaceutical formulation is formulated such that it does not cause moderate pain to a patient based on visual analog scale upon subcutaneous administration.

[0045] In some embodiments, the pharmaceutical formulation is in the form of a stock solution, wherein the stock solution is used for making the pharmaceutical formulation of the present invention in a downstream step. In some embodiments, the pharmaceutical formulation is in the form of a stock solution, wherein the stock solution is used for transporting the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation includes: (a) from about 225 mg / ml to about 275 mg / ml of the antibody, (b) about 5 mM Histidine, (c) about 120 mM Arginine HCl, (d) about 0.04 % w / v PS80, wherein the formulation has a pH of about 5.8.ATTORNEY DOCKET NO: 30762_WO -13-

[0046] In some embodiments, the pharmaceutical formulation of the present disclosure has total aggregates of no more than about 8.0%. In some embodiments, the pharmaceutical formulation of the present disclosure has total aggregates of no more than about 1.8%, about 4.0%, about 5.0%, about 6%, or about 7%. In some embodiments, the formulation has total aggregates of no more than about 1.8%.

[0047] In some embodiments, the antibody of the present invention is prone to oxidation of certain residues, which may render the antibody unsuitable for manufacturing, distribution, and storage. Certain pharmaceutical formulations of the antibodies allow for a reduction in the oxidation levels of the antibody upon storage, and these formulations are surprisingly suitable for manufacturing, distribution, and storage, as well as maintaining the essential functional characteristics of the antibodies for therapeutic use.

[0048] Some features are considered important to maintain the best outcomes for manufacturing, distribution, and storage, as well as for maintaining the essential functional characteristics of the antibodies for therapeutic use. These features include, e.g. a. the level of oxidation at Tryptophan 32 of the light chain (SEQ ID NO: 10); b. the level of oxidation at Methionine 257 of the heavy chain (SEQ ID NO: 9); c. the level of oxidation at Methionine 433 of the heavy chain (SEQ ID NO: 9); d. the concentration of charge variants; e. the concentration of acidic and / or basic charge variants; and / or f. the concentration of the antibody and the viscosity of the formulation.

[0049] In some embodiments, the antibody of the present invention is oxidized at light chain (LC) Tryptophan 32 amino acid residue wherein the LC has an amino acid sequence of SEQ ID NO: 10. In some embodiments, the pharmaceutical formulation of the present invention is such that the % oxidation of light chain (LC) Tryptophan 32 amino acid residue is i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 10% when tested based on AAPH stress test at 35ºC for 2 weeks. In some embodiments, the % oxidation of LC Tryptophan 32 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 7% when tested based on AAPH stress test at 35ºC for 2 weeks.

[0050] In some embodiments, the antibody of the present invention is oxidized at heavy chain Methionine 257 amino acid residue wherein the HC has an amino acid sequence of SEQ ID NO: 9. In some embodiments, the % oxidation of heavy chain Methionine 257 amino acid residue is i) not more than about 8% when tested based on Fenton stress test atATTORNEY DOCKET NO: 30762_WO -14- 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks. In some embodiments, the % oxidation of HC Methionine 257 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 4% when tested based on AAPH stress test at 35ºC for 2 weeks.

[0051] In some embodiments, the antibody of the present invention is oxidized at heavy chain Methionine 433 amino acid residue wherein the HC has an amino acid sequence of SEQ ID NO: 9. In some embodiments, the % oxidation of HC Methionine 433 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks. In some embodiments, the % oxidation of HC Methionine 433 amino acid residue is i) not more than about 2% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 2% when tested based on AAPH stress test at 35ºC for 2 weeks.

[0052] In some embodiments, the pharmaceutical formulation is such that the % oxidation: a) of LC Tryptophan 32 amino acid residue is: i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 10% when tested based on AAPH stress test at 35ºC for 2 weeks; b) of HC Methionine 257 amino acid residue is i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks; and / or c) of HC Methionine 433 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks.

[0053] In some embodiments, the pharmaceutical formulation is such that the % oxidation: a) of LC Tryptophan 32 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 7% when tested based on AAPH stress test at 35ºC for 2 weeks; b) of HC Methionine 257 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 4% when tested based on AAPH stress test at 35ºC for 2 weeks; and / orATTORNEY DOCKET NO: 30762_WO -15- c) of HC Methionine 433 amino acid residue is i) not more than about 2% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 2% when tested based on AAPH stress test at 35ºC for 2 weeks.

[0054] In some embodiments, the pharmaceutical formulation of the present invention is such that the formulation has at least about 40% of main charge variant of the antibody after 2 months at 35º C. In some embodiments, the formulation has at least about 50% of main charge variant of the antibody after 2 months at 35º C. In some embodiments, the formulation has at least about 59% of main charge variant of the antibody after 2 months at 35º C.

[0055] In some embodiments, the formulation has no more than 50% of acidic variants of the antibody after 2 months at 35°C. In some embodiments, the formulation has no more than 35% of acidic variants of the antibody after 2 months at 35°C.

[0056] In some embodiments, the formulation has no more than 20% of basic variants of the antibody after 2 months at 35°C. In some embodiments, the formulation has no more than 10% of basic variants of the antibody after 2 months at 35°C.

[0057] In some embodiments, the pharmaceutical formulation of the present disclosure has viscosity less than about 5 cP to about 25 cP. In some embodiments, the pharmaceutical formulation of the present disclosure has viscosity less than about 5 cP, 10 cP, 15 cP, or 20 cP.

[0058] In some embodiments, the pharmaceutical formulation of the present invention comprises: (a) about 200 mg / ml of an anti-N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 has an amino acid sequence of SEQ ID NO: 1, HCDR2 has an amino acid sequence of SEQ ID NO: 2, HCDR3 has an amino acid sequence of SEQ ID NO: 3, LCDR1 has an amino acid sequence of SEQ ID NO: 4, LCDR2 has an amino acid sequence of SEQ ID NO: 5, and LCDR3 has an amino acid sequence of SEQ ID NO: 6; (b) about 5 mM histidine buffer, wherein the formulation is at a pH about 5.8, (c) about 120 mM L-Arginine HCl; (d) about 10 mM L-Methionine; (d) about 0.04% w / v PS-80. In some embodiments, the formulation is such that:ATTORNEY DOCKET NO: 30762_WO -16- (a) the % oxidation of light chain (LC) Tryptophan 32 amino acid residue is i) no more than about 5% when tested based on Fenton stress test or ii) not more than about 7% when tested based on AAPH stress test; (b) the % oxidation of heavy chain (HC) Methionine 257 amino acid residue is i) no more than about 5% when tested based on Fenton stress test or ii) not more than about 4% when tested based on AAPH stress test; (c) the % oxidation of heavy chain (HC) Methionine 433 amino acid residue is i) no more than about 2% when tested based on Fenton stress test or ii) not more than about 2% when tested based on AAPH stress test; (d) the formulation has at least 95% Fc purity after 14 days of 316 stainless steel exposure or at least 96% LC purity after 14 days of 316 stainless steel exposure; and / or (e) the formulation has at least about 40% of main charge variant of the antibody after 2 months at 35º C.

[0059] In some embodiments, the pharmaceutical formulation of the present disclosure has no more than 35% of acidic variants of the antibody after 2 months at 35°C. In some embodiments, the pharmaceutical has no more than 10% of basic variants of the antibody after 2 months at 35°C.

[0060] The pharmaceutical formulations of the present invention may be contained within any container suitable for storage of medicines and other therapeutic compositions. For example, the pharmaceutical formulations may be contained within a sealed and sterilized plastic or glass container having a defined volume such as a vial, ampule, syringe, cartridge, or bottle. Different types of vials can be used to contain the formulations of the present invention including, e.g., clear, and opaque (e.g., amber) glass or plastic vials. Likewise, any type of syringe can be used to contain or administer the pharmaceutical formulations of the present invention. The pharmaceutical formulations of the present invention, according to certain embodiments, may be contained within a syringe that comprises a coated plunger, or within a vial that is sealed with a coated rubber stopper. In some embodiments, the pharmaceutical formulation of the present disclosure is contained in a container. The container can be, e.g., a vial or a syringe. In some embodiments, the container is a prefilled syringe. In some embodiments, the pharmaceutical formulation of the present disclosure is contained in an autoinjector.ATTORNEY DOCKET NO: 30762_WO -17-

[0061] An aspect of the present disclosure is related to a kit including the pharmaceutical formulation of the present disclosure, a container, and instructions. In some embodiments, the container is a vial, a cartridge, or a syringe. In some embodiments, the kit includes a prefilled syringe filled with the pharmaceutical formulation. In some embodiments, the kit includes an autoinjector or a prefilled syringe.

[0062] The pharmaceutical formulations can be administered to a patient by parenteral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or percutaneous, mucosal, nasal, pulmonary, or oral administration. Numerous reusable pens or autoinjector delivery devices can be used to subcutaneously deliver the pharmaceutical formulations of the present invention.

[0063] In certain embodiments, the pharmaceutical formulation of any of the preceding aspects is contained in a sterile glass vial and is administered as an IV infusion. In certain embodiments, the present invention provides an autoinjector comprising any of the pharmaceutical formulations described herein. In some embodiments, the present invention provides an autoinjector comprising a pharmaceutical formulation comprising about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, or about 300 mg / ml of the anti-N3pGlu Aβ antibody of the present invention wherein the antibody is, optionally, formulated as described herein.

[0064] In certain embodiments, the present invention provides a prefilled syringe comprising any of the pharmaceutical formulations described herein. In some embodiments, the present invention provides a prefilled syringe comprising a pharmaceutical formulation comprising about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, or about 300 mg / ml of the anti-N3pGlu Aβ antibody of the present invention wherein the antibody is, optionally, formulated as described herein.

[0065] In one embodiment, the pharmaceutical formulation containing about 200 mg / ml of the anti-N3pGlu Aβ antibody is administered in a volume of about 2 ml in a prefilled syringe or an autoinjector. In one embodiment, the pharmaceutical formulation containing about 200 mg / ml of the anti-N3pGlu Aβ antibody is administered in a volume of about 1 ml in a prefilled syringe or autoinjector.

[0066] In some embodiments, the pharmaceutical formulations of the present invention are diluted before administration to a patient in need thereof. In some embodiments, the pharmaceutical formulation is for intravenous administration and is diluted 5X or 10X. In some embodiments, the pharmaceutical formulation is for intravenous administration and isATTORNEY DOCKET NO: 30762_WO -18- diluted 5X or 10X in the IV bag. In some embodiments, the pharmaceutical formulation is administered such that the total dose of the anti-N3pGlu Aβ antibody administered to the patient is 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, or 3000 mg.

[0067] Aspects of the disclosure relate to treating a disease characterized by deposition of amyloid beta (Aβ) and / or a disease characterized by amyloid beta (Aβ) deposits. In some embodiments, the disclosure pertains to a method of treating a disease characterized by deposition of amyloid beta (Aβ) and / or a disease characterized by amyloid beta (Aβ) deposits by administering a therapeutically effective amount of a pharmaceutical formulation according to the disclosure to a patient in need thereof.

[0068] As used herein, the terms “disease characterized by deposition of amyloid beta (Aβ)” or a “disease characterized by amyloid beta (Aβ) deposits” are used interchangeably and refer to a disease that is pathologically characterized by Aβ deposits in the brain or in brain vasculature. This includes diseases such as Alzheimer’s disease (AD), Down’s syndrome, and cerebral amyloid angiopathy. In some embodiments, the Alzheimer’s disease is mild cognitive impairment (MCI), preclinical AD, prodromal AD, mild AD, moderate AD, or severe AD. In some embodiments, a method of treating a disease characterized by deposition of amyloid beta (Aβ) and / or a disease characterized by amyloid beta (Aβ) deposits according to the disclosure comprises administering a pharmaceutical formulation according to the disclosure obtained from a vessel according to the disclosure to a patient in need thereof.

[0069] The pharmaceutical formulations of the present invention are useful, inter alia, for the treatment, prevention or amelioration of a disease characterized by deposition of amyloid beta (Aβ). Exemplary, non-limiting diseases and disorders that can be treated or prevented by the administration of the pharmaceutical formulations of the present invention include Alzheimer’s disease (AD), Down’s syndrome, and cerebral amyloid angiopathy. In some embodiments, Alzheimer’s disease is preclinical AD, prodromal AD, mild AD, moderate AD, or severe AD.

[0070] As used herein, the term “pharmaceutical” refers to a composition that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of subjects (e.g., human beings) without excessive toxicity, irritation, allergic response, and / or other problems or complications, commensurate with a reasonable benefit / risk ratio.ATTORNEY DOCKET NO: 30762_WO -19-

[0071] As used herein, the term “about” refers to a difference of ± 10% of the stated value. In some embodiments, the term “about” refers to a difference of ± 5% of the stated value. In some embodiments, the term “about” refers to a difference of or ± 1% of the stated value.

[0072] As used herein, the expression “pharmaceutical formulation” means a combination of at least one active ingredient (e.g., a macromolecule, compound, etc. which can exert a biological effect in a human or non-human animal), and at least one inactive ingredient which, when combined with the active ingredient or one or more additional inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. The term “formulation,” as used herein, means “pharmaceutical formulation” unless specifically indicated otherwise.

[0073] As used herein, an “antibody” is an immunoglobulin molecule comprising two HC and two LC interconnected by disulfide bonds. The amino terminal portion of each LC and HC includes a variable region responsible for antigen recognition via the complementarity determining regions (CDRs) contained therein. The CDRs are interspersed with regions that are more conserved, termed framework regions. Assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies of the present disclosure is based on the following: Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)), and North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)). Following the above method, the CDRs of the antibodies of the present disclosure were determined.

[0074] Unless specifically indicated otherwise, the term “antibody,” as used herein, shall be understood to encompass complete antibody molecules as well as antigen-binding fragments thereof. The term “antigen-binding portion” or “antigen-binding fragment” of an antibody (or simply “antibody portion” or “antibody fragment”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to or target human N3pGlu Aβ or a portion thereof.

[0075] An “isolated antibody” as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds human N3pGlu Aβ is substantially free of antibodies that specifically bind antigens other than human N3pGlu Aβ).ATTORNEY DOCKET NO: 30762_WO -20-

[0076] The term “specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.

[0077] In some embodiments, the antibodies of the present disclosure are monoclonal antibodies (“mAbs”). Monoclonal antibodies can be produced, for example, by hybridoma technologies, recombinant technologies, phage display technologies, synthetic technologies, e.g., CDR-grafting, or combinations of such or other technologies known in the art. The monoclonal antibodies of the present disclosure are human or humanized. Humanized antibodies can be engineered to contain one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from ImunoGeneTics (INGT) via their website, http: / / imgt.cines.fr, or from The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001, ISBN 012441351. Techniques for generating human or humanized antibodies are well known in the art. In another embodiment of the present disclosure, the antibody, or the nucleic acid encoding the same, is provided in isolated form. As used herein, the term “isolated” refers to a protein, peptide or nucleic acid that is not found in nature and is free or substantially free from other macromolecular species found in a cellular environment. “Substantially free,” as used herein, means the protein, peptide or nucleic acid of interest comprises more than 80% (on a molar basis) of the macromolecular species present, preferably more than 90% and more preferably more than 95%.

[0078] The anti-N3pGlu Aβ antibody of the present disclosure is administered as a pharmaceutical composition. The pharmaceutical composition comprising an antibody of the present disclosure can be administered to a subject at risk for, or exhibiting, diseases or disorders as described herein by parental routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular). Subcutaneous and intravenous routes are preferred. In some embodiment, the anti-N3pGlu Aβ antibody is administered by intravenous infusion. In some embodiment, the anti-N3pGlu Aβ antibody is administered subcutaneously.

[0079] The terms “treatment,” “treating” or “to treat” and the like include restraining, slowing, or stopping the progression or severity of an existing symptom, condition, disease, or disorder in a subject. The term “subject” refers to a human.ATTORNEY DOCKET NO: 30762_WO -21-

[0080] The term “prevention” means prophylactic administration of the antibody of the present disclosure to an asymptomatic subject or a subject with pre-clinical Alzheimer’s disease to prevent onset or progression of the disease.

[0081] The terms “subject” and “patient” are used interchangeably in the present disclosure.

[0082] As used herein, “methods of treatment” are equally applicable to use of a composition for treating the diseases or disorders described herein and / or compositions for use and / or uses in the manufacture of a medicaments for treating the diseases or disorders described herein.

[0083] As used herein, it is to be understood that a “buffer” or a “buffering agent” is an agent that acts to regulate the pH of a composition, but a “buffer” may also provide other functions in a composition (e.g., affecting the tonicity of the composition). In some embodiments, a “buffer” may be a “buffer system.” The term “a single buffer system” as used herein is to be understood to refer to an agent that acts to regulate the pH of a composition, wherein the agent comprises two or more components, such as an acid compound and its conjugate base. In some embodiments, the buffer comprises an organic acid, an inorganic acid, an amino acid, and / or combinations thereof. In some embodiments, the buffer comprises a salt of an organic acid, a salt of an inorganic acid, and an amino acid, and / or combinations thereof. Non-limiting examples of organic acids include citric acid, acetic acid, tartaric acid, succinic acid, and glutamic acid. Non-limiting examples of inorganic acids include hydrochloric acid and phosphoric acid. Non-limiting examples of amino acids include arginine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, aspartic acid. In some embodiments, the buffer comprises citric acid or a salt thereof, acetic acid or a salt thereof, succinic acid or a salt thereof, phosphoric acid or a salt thereof, arginine or a salt thereof, lysine or a salt thereof, histidine or a salt thereof, ornithine or a salt thereof, isoleucine or a salt thereof, leucine or a salt thereof, alanine or a salt thereof, glycine or a salt thereof, glutamic acid or a salt thereof, and aspartic acid or a salt thereof. In some embodiments, the buffer comprises histidine or a salt thereof.

[0084] As used herein, the term “tonicity agent” denotes pharmaceutically acceptable excipient used to modulate the tonicity of a formulation. Tonicity in general relates to the osmotic pressure of a solution usually relative to that of human blood serum. The formulation can be hypotonic, isotonic, or hypertonic. A formulation is typically preferably isotonic. An isotonic formulation is liquid, or liquid reconstituted from a solid form, e.g. from a lyophilized form and denotes a solution having the same tonicity as some otherATTORNEY DOCKET NO: 30762_WO -22- solution with which it is compared, such as physiologic salt solution and the blood serum. Preferred tonicity agents are sodium chloride, trehalose, sucrose, or arginine. In some embodiments, the tonicity agent is a sugar, an amino acid, a salt, and / or combinations thereof. In some embodiments, the tonicity agent is selected from a monosaccharide, a disaccharide, a polysaccharide, and / or combinations thereof. In some embodiments, the tonicity agent is chosen from sodium chloride, arginine or a salt thereof, lysine or a salt thereof, histidine or a salt thereof, methionine or a salt thereof, ornithine or a salt thereof, isoleucine or a salt thereof, leucine or a salt thereof, alanine or a salt thereof, glycine or a salt thereof, glutamic acid, aspartic acid, sucrose, fructose, glucose, maltose, trehalose, galactose, mannose, sorbose, lactose, mannitol, lactitol, maltitol, and combinations thereof. In some embodiments, the tonicity agent is sodium chloride. In some embodiments, the tonicity agent is sucrose.

[0085] “Viscosity reducer” as used herein may be used to reduce the “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. For example, 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). In some embodiments, the viscosity reducer is arginine, glycine, sodium chloride, lysine, histidine, proline, or betaine (see, e.g., Proj, Matic, et al., “Discovery of Compounds with Viscosity-reducing Effects on Biopharmaceutical Formulations with Monoclonal Antibodies,” Computational and Structural Biotechnology Journal 20 (2022): 5420-5429). In some embodiments, the viscosity reducer can also function as a tonicity agent. Some examples of agents that may act as a viscosity reducer and tonicity agent are arginine, glycine, sodium chloride, lysine, and / or betaine.

[0086] The term “surfactant” as used herein denotes a pharmaceutically acceptable excipient which is used to protect protein formulations against mechanical stresses like agitation and shearing. In some embodiments, the surfactant is selected from poloxamers, polysorbates, polyoxyethylene alkyl ethers (Brij), alkylphenylpolyoxyethylene ethers (Triton-X), and sodium dodecyl sulphate (SDS). In some embodiments, the surfactants areATTORNEY DOCKET NO: 30762_WO -23- polysorbates and poloxamers. In some embodiments, the surfactant is selected from polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, poloxamer 188, and combinations thereof. In some embodiments, the surfactant is selected from polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a poloxamer, and combinations thereof. In some embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate (also known as, polysorbate 80 or PS80).

[0087] The term “antioxidant” denotes pharmaceutically acceptable excipients, which prevent oxidation of the active pharmaceutical ingredient or antibody. This includes chelating agents, reactive oxygen scavengers and chain terminators. In some embodiments, the antioxidant is selected from EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), p-amino benzoic acid, glutathione, cysteine, methionine, and N-acetyl cysteine.

[0088] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. EXAMPLES

[0089] The following non-limiting examples are offered for purposes of illustration, not limitation. Abbreviations and Definitions AAPH – 2,2'-Azobis(2-amidinopropane) dihydrochloride ACN – Acetonitrile AI – Auto-Injector API – Active pharmaceutical ingredient CEX – Cation Exchange Chromatography cIEF – Capillary Isoelectric Focusing DLS – Dynamic Light Scattering DTT – DithiothreitolATTORNEY DOCKET NO: 30762_WO -24- BDS – Bulk Drug substance, starting material for the process DSC – Differential Scanning Calorimetry EDTA – Ethylenediaminetetraacetic acid EP – European Pharmacopoeia HPLC – High Performance Liquid Chromatography IPA – Isopropanol; isopropyl alcohol LC / MS – Liquid Chromatography / Mass Spectrometry MFI – Microflow Imaging PDS – Pharmaceutical Development Services RH – Relative Humidity RP-HPLC – Reversed Phase High Performance Liquid Chromatography SDS – Sodium Dodecyl Sulfate SEC – Size-Exclusion Chromatography TC – Thermo Couples TFA – Trifluoroacetic acid Tris – Tris(hydroxymethyl)aminomethane USP – United States Pharmacopoeia Table 3: Materials Material Vendor Vendor Part No. Quality GradeATTORNEY DOCKET NO: 30762_WO -25- 20 mm serum West 19700021 N / A stoppers Pharmaceutical i PATTORNEY DOCKET NO: 30762_WO -26- Iron (III) Sigma 31232-500G N / A Chloride h EATTORNEY DOCKET NO: 30762_WO -27- Tosoh TSKgel Sigma 08541 N / A G3000SWxl, 7.8Equipment Manufacturer Model HPLC S t A il t 1100 / 1200Example 1: Pre-formulation Study / Formulation Development for Phase 1

[0090] A pre-formulation study to evaluate the chemical and physical stability with respect to pH and buffer types was conducted for the anti-N3pGlu Aβ antibody (i.e., remternetug). Four buffer types (acetate, histidine, citrate, and succinate, used in the forms of sodium acetate / acetic acid; histidine and histidine monohydrochloride; sodium citrate dihydrate and citric acid anhydrous; sodium succinate and succinic acid) were evaluated by screening each of the buffers at several pH values, ranging from 4.5 to 6.5, as appropriate for each bufferATTORNEY DOCKET NO: 30762_WO -28- system. Formulations were prepared by dialysis into 10 mM acetate at pH 4.5, 5, and 5.5; 10mM citrate at pH 5.5, 6, and 6.5; and 10 mM histidine at pH 5.5, 6, and 6.5. Each formulated sample was diluted to 4 mg / ml with appropriate buffers, filtered through 0.22 µm filters, and filled into glass vials with elastomeric stoppers. Each formulation was subjected to thermal stress at 5°C (RH typically <50% during refrigeration, but the RH was not controlled or monitored in this study), 25°C / 60% RH, and 40°C / 75% RH for 8 weeks. Samples were then analyzed by SEC (Size Exclusion Chromatography) and icIEF to assess formulation stability (Table 5). Table 5: SEC and icIEF Results for 4 mg / ml Remternetug Formulation in Different Buffer Types and at Different pH After Storage for 8 Weeks at 40°C / 75% RH. SEC icIEF al ts

[0091] The % total aggregates and % total fragments was the lowest in the 10 mM histidine buffer. Likewise, the remternetug formulation in 10 mM histidine buffer had the smallestATTORNEY DOCKET NO: 30762_WO -29- increase in % total acidic variants. The optimal formulation pH based on the data from this study was between 5.5 and 6.

[0092] A subsequent stability study was carried out to assess excipient effect on remternetug stability. The formulations, at pH 5.8, comprise either 14 mg / ml or 35 mg / ml remternetug, 10 mM histidine, either 100 mM glycine / 180mM mannitol or 280 mM sucrose, and either polysorbate 80 (PS80) or poloxamer 188 (P188). Formulations were prepared by dialyzing into the respective formulation matrix, diluting to the appropriate remternetug concentration with formulation matrix, spiking in the appropriate level of polysorbate 80 or poloxamer 188 from stock solutions, 0.22 µm filtration, and filling the formulations in glass vials. The vials were then stored at 5°C, 25°C / 60%RH, and 40°C / 75%RH for 8 weeks. The total % of aggregates, monomer, and fragments was determined by SEC, and subvisible particles were counted using MFI, as depicted in Table 6. Table 6: Comparison of SEC Data and Subvisible Particulate Data Between Remternetug Formulations with Different Excipients and / or Remternetug Concentrations after 8 weeks at 40°C / 75% RH. SEC MFI F l i ≥ 2 ≥ Ci lar n, mATTORNEY DOCKET NO: 30762_WO -30- • 0.04% (w / v) PS80 • pH 5.8, , the % total observed aggregates were lowest in formulations containing 100 mM glycine and 180 mM mannitol, but higher in the formulation containing 280 mM sucrose. Even though the % monomer had the highest purity in the P188-containing formulation, the P188- containing formulation was susceptible to an increase in subvisible particulate matter. Based on this data, a formulation containing 20 mg / ml remternetug, 10 mM histidine, 100 mM glycine, 180 mM mannitol, 0.04% (w / v) PS80, at a target pH of 5.8 was used in phase 1 clinical trials. Example 2: High Concentration Screening and Prototype Study

[0094] Phase 1 clinical trials (CTs) were carried out using a formulation containing 20 mg / ml remternetug, 10 mM histidine, 180 mM mannitol, 100 mM glycine, and 0.04% (w / v) PS80 at a target pH of 5.8.

[0095] Stability analysis of the phase 1 formulation showed that remternetug was prone to oxidation leading to a decrease in potency. To give extra options for patients, remternetug was reformulated into a high concentration formulation to enable the delivery of high doses via subcutaneous injection using autoinjector device or an enhanced prefilled syringe.In addition, a formulation for intravenous infusion was needed for clinical trials and possible commercialization. Development studies were designed and conducted to enable a single formulation capable of meeting the needs of both the SC (subcutaneous) and IV (intravenous) formulations.

[0096] For subcutaneous administration, it is important for the solution viscosity of the drug product formulation to not exceed the capabilities of the final delivery device and to be low enough to be user-friendly for the end-user (See e.g., PharmaceuticalATTORNEY DOCKET NO: 30762_WO -31- Technology, Pharmaceutical Technology-04-02-2018, Volume 42, Issue 4, pages:30–33). During development of high concentration for remternetug an excipient screening was performed to determine excipient’s effect on the viscosity of drug product formulation. Remternetug API (Active Pharmaceutical Ingredient) was buffer exchanged and concentrated to ~300 mg / ml in a 5 mM histidine, 50 mM arginine HCl matrix at a pH ~6. Excipients were then added from stock solutions to the remternetug solution so that the final matrices were 250 mg / ml remternetug, 5 mM histidine, 50 mM arginine HCl, plus 50 mM of each respective excipient. The pH of these solutions was titrated to 5.5. The viscosity of each solution was then measured at 20°C using a Rheosense VROC®Initium viscometer (results depicted in Table 7). Table 7: Excipient Effect on 250 mg / ml Remternetug Solution Viscosity at 20°C Measured E i i remternetug i i P 2 °C

[0097] Under conditions described above, Arginine showed the largest impact on viscosity reduction of the 250 mg / ml remternetug formulation. All other excipients assessed in this study (NaCl, glycine, lysine, mannitol, and proline) increased the viscosity of the remternetug solution. Use of NaCl is not optimal because it has the potential to cause injection site pain.

[0098] A subsequent study was performed to assess the chemical and physical thermal stability of remternetug formulations at 200 and 225 mg / ml in a base matrix of 5 mM histidine and 125 mM arginine HCl. Formulations were diluted to 200 or 225 mg / ml with stock solutions containing the relevant formulation excipients and titrated to the target pH, where necessary. The formulations were then 0.22 µm filtered and filled into glass vials. Formulations were stored for 2 months at 35°C. Samples were then tested for aggregateATTORNEY DOCKET NO: 30762_WO -32- growth using SEC and for changes in charge variant distribution using CEX. Results are described in Tables 8 and 9. Table 8: SEC Results Comparing Remternetug Formulations After 2 months at 35°C Remternetug ration Excipients Surfactant pH % % concent Total Aggregates MonomerTable 9: CEX Results Comparing Remternetug Formulations After 2 months at 35°C. Remternetug % Total % % Total n ntrtin E i int S rf tnt H Aidi Min B i tsATTORNEY DOCKET NO: 30762_WO -33- 125 mM arginine l

[0099] Un er con t ons escr e a ove, t e remternetug ormu at on conta n ng 5 mM histidine, 125 mM arginine HCl, 10 mM methionine, and 0.04% (w / v) PS80 at pH 5.8 contained the lowest % total aggregates and the lowest % total acidic variants.

[0100] It has previously been reported that the choice of surfactant in a solution formulation may impact syringe functionality (See., e.g., Wang, Tingting, et al., “Impact of surfactants on the functionality of prefilled syringes,” Journal of Pharmaceutical Sciences 109.11 (2020): 3413-3422). A study was conducted to elucidate the impact that polysorbate 80 and poloxamer 188 may have on the functionality of a glass syringe filled with a 200 mg / ml remternetug formulation containing 5 histidine, 120 mM arginine HCl, and 10 mM methionine at pH 5.8. Remternetug API was diluted to 200 mg / ml using a stock solution containing the relevant formulation excipients. The solution was then 0.22 µm filtered and filled into 2 ml glass syringes. The filled syringes were then placed on stability for 4 weeks at 35°C. Syringe glide force was measured immediately after syringe filling and after 4 weeks of storage. The results of syringe glide force functionality are depicted in Table 10. Table 10: Syringe Glide Force at time 0 and 4 Weeks After Syringe Fill. Time Point / Glide ForceATTORNEY DOCKET NO: 30762_WO -34- 0.04% (w / v) 4 weeks / 35°C 20.94 Polysorbate 80(w / v) polysorbate 80 or 0.04% (w / v) poloxamer 188 did not have an impact on the glide force of glass syringe filled with the 200 mg / ml formulation containing 5 mM histidine, 120 mM arginine HCl, and 10 mM methionine at pH 5.8. Example 3: Antioxidant Stabilization Study

[0102] Stability of remternetug formulations is evaluated in an antioxidant stabilization study. The formulations, at pH 5.8, comprise 100 mg / ml remternetug, 0.04% polysorbate 80 (PS80), and 10 mM histidine buffer, and are tested with and without the presence of 10 mM methionine. Formulations are prepared by dialysis into a pH 5.8, 10 mM histidine buffer, followed by addition of excipients using stock solutions, stored in glass vials with elastomeric stoppers, and subjected to a range of stress conditions. Stress conditions include storage at 35º C for 2 weeks in the presence of 10 ppm Fe3+and 5 ppm H2O2(Fenton stress), as well as storage for 2 weeks at 35oC in the presence of 100 µg / ml of AAPH (AAPH stress). Both Fenton stress and AAPH stress are known to be relevant stress test conditions for pharmaceutical formulations (See, e.g., Schöneich, Christian, “Primary Processes of Free Radical Formation in Pharmaceutical Formulations of Therapeutic Proteins,” Biomolecules 13.7 (2023): 1142 and Cioc, Răzvan C., et al., “Formation of N-nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies,” Organic Process Research & Development 27.10 (2023): 1736- 1750). Samples are analyzed by LC / MS Peptide Mapping, specifically analyzing oxidation at residues known to be susceptible to oxidation, including W32, M257, and M433, as shown in Table 11. Table 11: Comparison of Oxidation for 100 mg / ml Remternetug Formulations between Formulations with and without 10 mM Methionine. Fenton stress (% oxidation) AAPH stress (% oxidation) neATTORNEY DOCKET NO: 30762_WO -35-and M433 was higher in formulation, which does not contain methionine, compared to formulation which contains 10 mM methionine.

[0104] Stability of remternetug formulations is also evaluated in a second antioxidant stabilization study. The formulations, at pH 5.8, comprise 200 mg / ml remternetug, 0.04% polysorbate 80, 5 mM histidine buffer, 125 mM arginine, and are tested with either no antioxidant, 10 mM methionine, 1 mM citrate, or 50 µM EDTA. Formulations are prepared by dialysis into a pH 5.8, 5 mM histidine buffer, followed by addition of excipients using stock solutions, stored in glass vials with elastomeric stoppers, and subjected to a range of stress conditions. Stress conditions include storage at 35oC for 2 weeks in the presence of 10 ppm Fe3+and 5 ppm hydrogen peroxide (Fenton stress), as well as storage for 2 weeks at 35oC in the presence of 100 µg / ml of AAPH. Samples are then analyzed by LC / MS Peptide Mapping, specifically analyzing oxidation at residues known to be susceptible to oxidation, including W32, M257, and M433, as shown in Table 12. Table 12: Comparison of Oxidation for 200 mg / ml Remternetug Formulations Between Formulations with and without 10 mM Methionine. Fenton stress AAPH stress A

[0105] Under conditions as described above, the percent oxidation at W32, M257, and M433 was higher in formulation, which does not contain an antioxidant, compared toATTORNEY DOCKET NO: 30762_WO -36- formulation which contains 10 mM methionine. In some cases, addition of 1 mM citrate or 50 µM EDTA also provides a stabilization effect with respect to oxidation. However, the effect is not as consistent or pronounced, particularly for oxidation of M257 and M433. Additionally, use of citrate or EDTA introduces additional undesirable properties for a pharmaceutical formulation. Specifically, use of citrate introduces risk of pain on injection (Shi, Galen H., et al., “Subcutaneous Injection Site Pain of Formulation Matrices,” Pharmaceutical Research 38.5 (2021): 779-793) of a subcutaneous formulation, and use of EDTA introduces risk of nitrosamine contamination (see, e.g., Cioc, Răzvan C., et al., “Formation of N-nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies,” Organic Process Research & Development 27.10 (2023): 1736-1750), which carries significant toxicology risk.

[0106] Under conditions as described above, the percent oxidation at W32, M257, and M433 was higher in formulation at 100 mg / ml as compared to formulation at 200 mg / ml. Example 4: Stainless-steel Compatibility Study

[0107] Exposure to stainless steel is known to induce oxidation in antibody formulations containing histidine and polysorbate 80 (see, e.g., Gopalrathnam, Ganapathy, et al., “Impact of Stainless-steel Exposure on the Oxidation of Polysorbate 80 in Histidine Placebo and Active Monoclonal Antibody Formulation,” PDA Journal of Pharmaceutical Science and Technology 72.2 (2018): 163-175). To assess the impact of stainless-steel exposure on the remternetug formulation, the drug product at 20 mg / ml and 200 mg / ml remternetug concentration was exposed to 316 stainless steel for 14 days at a worst-case surface area to volume ratio. After 14 days of exposure, the solution was removed from the stainless steel and filled into glass vials. Vials were then incubated at 25°C for 0.5, 1, 2, and 3 months. At each timepoint, the formulation stability was monitored by peptide mapping using LC / MS and a reverse phased HPLC method capable of detecting oxidation to the fragment crystallizable (Fc) region and light chain (LC) regions of remternetug. These results are described in Tables 13 and 14. Table 13: Reversed-Phased HPLC Results after 1 and 2 Months Post-stainless-steel Exposure. Formulation Timepoint % Fc Purity % LC PurityATTORNEY DOCKET NO: 30762_WO -37- 2 months 92.8 89.7 Initial 96.7 97.8y Post-stainless-steel Exposure. % M257 Formulation Timepoint % W32 oxidation oxidation

[0108] Under cond t ons as descr bed above, t e resu ts prov ded in Tables 11 and 12 demonstrate that the 200 mg / ml remternetug formulation is less susceptible to degradation from stainless steel exposure than a 20 mg / ml formulation. The 200 mg / ml formulation retains Fc and LC peak purity and known susceptible amino acid residues (e.g., W32 and M257) are less oxidized following stainless-steel exposure as compared to the 20 mg / ml formulation. Example 5: Peroxide Spiking Study

[0109] It is well known that hydrogen peroxide may induce degradation in monoclonal antibodies (see, e.g., Agrawal, Neeraj J., et al., “Prediction of the Hydrogen Peroxide– induced Methionine Oxidation Propensity in Monoclonal Antibodies,” Journal of Pharmaceutical Sciences 107.5 (2018): 1282-1289). Hydrogen peroxide is used as a sanitizing agent during drug product manufacturing, so it is critical to know if the drug product formulation is susceptible to hydrogen peroxide exposure. A spiking study was performed to assess the susceptibility of the remternetug formulation to degradation via exposure to hydrogen peroxide. Increasing concentrations (0 ppm, 0.2 ppm, 0.4 ppm, 0.6 ppm, 1 ppm) of hydrogen peroxide were spiked into remternetug drug product formulation. Samples were stressed for 2 months at 30°C. Stability was then monitored using a reversed-ATTORNEY DOCKET NO: 30762_WO -38- phase HPLC method capable of detecting oxidation at the fragment crystallizable (Fc) and light chain (LC) regions of remternetug. Results are depicted in Table 15. Table 15: Comparison of Oxidation for the 200 mg / ml Remternetug Formulation Spiked with Increasing Concentration of Hydrogen Peroxide. RP-HPLC Concentration of Timepoint % Fc % LC[ ] n er con ons as escr e a ove, ere was no c ange n either % Fc or % LC purity using RP-HPLC. There is a minimal risk of degradation due to hydrogen peroxide exposure when remternetug is formulated in the 200 mg / ml formulation with methionine (Table 15). Example 6: Photostability Study of Remternetug Formulations

[0111] The photostability of remternetug formulation (as shown above in Tables 1 and 2) is evaluated in a light exposure study. The literature shows that exposure to light can lead to modification of amino acid residues and aggregation of proteins (see e.g., Rathore, Nitin, and Rahul S. Rajan, “Current Perspectives on Stability of Protein Drug Products During Formulation, Fill and Finish Operations,” Biotechnology Progress 24.3 (2008): 504- 514). The remternetug formulation comprises 200 mg / ml remternetug, 10 mM histidine buffer at a pH of 5.8, 125 mM arginine HCl, 0.04% polysorbate 80, and are tested with and without the presence of 10 mM methionine. The formulations were filled into glass vials with elastomeric stoppers and subjected to 240,000 lux-hours of visible light and 40 W- hrs / m2of UV (Ultraviolet) light using a Caron 7450 photo chamber.20 Klux of visible light and 20 Watt-hr / m2were maintained by the photo chamber lamps during the exposure. Dark controls of each formulation were wrapped in aluminum foil and were also subjected to light exposure along with the exposed vials. Samples were then analyzed by SEC to determine aggregate levels following the light exposure; results are depicted in Table 16.ATTORNEY DOCKET NO: 30762_WO -39- Table 16: Comparison of Total Aggregates as Determined by SEC Following Exposure to Visible and UV Light Formulation % Total Aggregates following light exposure

[0112] U, hionine in the remternetug formulation reduced the growth of % aggregates as determined by SEC as compared to a similar formulation without methionine. Example 7: Buffer Matrix Pain Study

[0113] Subcutaneously administered drugs should be carefully formulated to minimize localized pain at the injection site. Components of a formulation that may impact injection site pain are buffer types, tonicity modifiers, pH, and osmolality (see, e.g., Shi, Galen H., et al., “Subcutaneous Injection Site Pain of Formulation Matrices,” Pharmaceutical Research 38.5 (2021): 779-793). At the time of development, data could not be found to confirm whether the use of methionine in a subcutaneously administered solution would or would not cause pain. To assess the potential for the remternetug formulation matrix (5 mM histidine, 120 mM arginine HCl, 10 mM methionine, 0.04% PS80 at pH 5.8) to cause injection site pain, the matrix was extemporaneously prepared and administered to patients via subcutaneous injection. No injections of formulations containing remternetug were studied; only the formulation matrix was examined. The clinical trial participants used a visual analogue scale (VAS; see, e.g., Thong, Ivan SK, et al., “The Validity of Pain Intensity Measures: What do the NRS, VAS, VRS, and FPS-R Measure?” Scandinavian Journal of Pain 18.1 (2018): 99-107) to describe the level of pain experienced post-injection. The pain level was categorized in three groups: mild pain, moderate pain, and severe pain. High-level results of the buffer matrix pain study are described in Table 17. Table 17: VAS Scores for Injection Site Pain Experienced Following Subcutaneous Injection of Remternetug Formulation Matrix and a Citrate Buffer Formulation Containing NaCl Buffer Matrix Mild Pain Moderate Pain Severe PainATTORNEY DOCKET NO: 30762_WO -40- Citrate / NaCl / sucrose 76% 20% 4% matrixd mild pain following subcutaneous injection of the remternetug formulation matrix. In contrast, a citrate buffer formulation containing sodium chloride and sucrose at pH 6 resulted in 4% of trial participants experiencing severe pain, 20% of trial participants experiencing moderate pain, and 76% of trial participants experiencing mild pain. Results from this study supported the matrix choice for the remternetug formulation.

[0115] Studies show that the antibodies do not contribute to pain when included in the subcutaneous formulation. Example 8: Methionine Range Study

[0116] The stability of remternetug drug product formulations was evaluated in a study in which increasing concentrations of methionine (up to 20 mM) were included in the formulation. Formulations were prepared by diluting a remternetug drug substance stock solution with a 5 mM histidine, 120 mM arginine HCl, pH 5.8 buffer solution containing a sufficient amount of methionine to prepare either a 0 mM, 5 mM, 10 mM, or 20 mM methionine concentration in the final drug product. Remternetug drug product solutions were subjected to the following forced degradation conditions: 1) Thermal stress at 40°C for 4 weeks 2) 40 ppm Fe3+ + 20 ppm H2O2 spiking, 40°C for 4 weeks 3) 300 µg / ml AAPH, 40°C for 4 weeks 4) 200% ICH Q1b light exposure (2.4 million lux-hours of visible light and 400 Watt-hrs / m2 of ultraviolet light)

[0117] The drug product solutions were filtered and filled into either 5 ml type 1 glass vials or 2.25 ml glass semi-finished syringes. Light exposure experiments were conducted after the drug product solutions were filled into the vials and syringes. Following the forced degradation, samples were analyzed using subunit RP-HPLC to compare oxidation to the light chain (LC) and Fc subunits.

[0118] Under conditions as described above, the highest amounts of oxidation were detected under the 300 µg / ml AAPH and 200% ICH Q1b light exposure conditions in the vial format. Results (see Figure 1) show that the inclusion of methionine in the formulation provides protection to remternetug, as evidenced by maintaining higher LC and Fc subunitATTORNEY DOCKET NO: 30762_WO -41- purity. The remternetug syringe drug products with 10 mM methionine showed no oxidation. Increasing the concentration of methionine in the formulation for the vial drug product did offer slightly increased protection to remternetug, however due to the exaggerated forced degradation conditions in this study 10 mM methionine was deemed appropriate for the final formulation. Example 9: Remternetug Drug Product Demonstration Batch Stability

[0119] The stability of remternetug drug product formulation is monitored and evaluated following manufacture of demonstration batches for both syringe and vial presentations. The syringe demonstration batch was manufactured at scale on the same manufacturing line intended for production of phase 3 clinical trial drug product supply, using the same semi- finished syringe container-closure system. The vial demonstration batch was manufactured at a reduced lab scale, using representative processing conditions and the same vial container-closure system used for phase 3 clinical trial drug product supply. Syringes and vials from these batches were placed on stability for 9 months at 5°C, 25°C, and 35°C. Remternetug critical quality attributes were monitored for any adverse stability such as aggregation, oxidation, and acidic variants (see Table 18 below). Table 18: Critical Quality Attributes Timepoint Total % Total Acidic % Lc subunit % Fc subunit Aggregates Variants purity purityATTORNEY DOCKET NO: 30762_WO -42-

[0120] Under conditions as described above, all analytical test results showed acceptable stability at nominal storage conditions (5°C) as well as accelerate and stressed conditions (25°C and 35°C, respectively). Results indicate that the remternetug formulation is not undergoing undesirable levels of aggregation, acidic variants growth, or oxidation. Example 10: Tungsten Study

[0121] During the glass syringe barrel manufacturing process, tungsten pins are used to make the syringe opening in the glass. Residual tungsten and tungstate species may remain the syringe after this forming process. Published reports (Liu, Wei, et al., “Root Cause Analysis of Tungsten-induced Protein Aggregation in Pre-filled Syringes,” PDA Journal of Pharmaceutical Science and Technology 64.1 (2010): 11-19) have demonstrated potential protein instabilities due to interactions with different tungsten species and protein. To assess any incompatibilities with remternetug and tungsten, stock solutions of tungsten oxide (IV) and tungsten oxide (VI) were spiked into remternetug drug product solution at 0.5 ppm and 5 ppm. A non-spiked drug product was also prepared to act as a control. These solutions were then filled with 5 ml glass vials and placed on stability for 3 months at 25°C. Drug product stability was monitored using SEC, CEX, and RP-HPLC. Refer to Table 19 for the analytical results from this study. Table 19: Remternetug Stability After 3 months Storage at 25°C Following Spiking with Tungsten Oxides Concentration % Total CEX RP-HPLC of tungsten Aggregates % Total % Main % Total % LC % FC

[0122] A study was conducted to determine the compatibility between remternetug drug product and silicone oil. Silicone oil is present on glass syringe barrels to provide lubrication to aid in dose delivery. Any incompatibilities between proteins and silicone oil may resultATTORNEY DOCKET NO: 30762_WO -43- in protein aggregation (Jones, Latoya S., Allyn Kaufmann, and C. Russell Middaugh, “Silicone Oil Induced Aggregation of Proteins,” Journal of Pharmaceutical Sciences 94.4 (2005): 918-927). To test the compatibility between silicone oil and remternetug drug product, a silicone: water emulsion was prepared and then spiked into drug product solution at final silicone oil concentrations of 0, 0.3, and 0.7 mg / ml. Vials containing the spiked drug product solution were placed on stability for 1 month at 35°C. Samples were tested for total aggregates using SEC. Refer to Table 20 for the analytical results from this study. Table 20: Remternetug Stability After 1 month Storage at 35°C Following Spiking of Silicone Oil Spiked Concentration % Total Aggregates, of Silicone Oil SEChe stability of remternetug drug product was not impacted by either spiking of tungsten (IV) oxide and tungsten (VI) oxide up to 5 ppm; or spiking of silicone oil up to 0.7 mg / ml as compared to control (non-spiked) remternetug drug product. General Methods Used in Examples 1-10

[0124] The following describes general methods and conditions used in the Examples. Table 21: icIEF (Imaged Capillary Isoelectric Focusing) Conditions Principle Methodology that separates proteins based on their isoelectric int 3 n n dATTORNEY DOCKET NO: 30762_WO -44- 1% (v / v) 9.46 pI marker, 10 mM arginine, and 0.035% (v / v) water.Instrument High Performance Liquid Chromatograph (HPLC) equipped with a UV detector, column heater, and an autosamplerTable 23: CEX Conditions Instrument High Performance Liquid Chromatograph (HPLC) equipped with a UV detector column heater and an autosam ler l,ATTORNEY DOCKET NO: 30762_WO -45-

[0125] Samples are injected onto the column at 100% mobile phase A. Charge variants are eluted from the column using a gradient of 0% mobile phase B to 35% mobile phase B over 37 minutes. Glide Force

[0126] Utilizes a Zwick standard test system which measures the force (in Newtons) necessary to initiate plunger movement on the prefilled syringe (break loose force) and the maximum force required to sustain plunger movement (glide force). Force measurements are performed with a calibrated load cell. Syringes are placed into the Zwick test system. The syringe plunger is depressed at a linear rate, and the force is recorded. This procedure is described in USP <382>. LC / MS Peptide Mapping

[0127] The LC / MS peptide map was performed on a Vanquish UPLC and Thermo Q Extractive HF-X MS. LC separation occurred using a Waters Acquity UPLC BEH C18 column (300 Angstrom, 1.7 µm, 2.1 mm (about 0.08 in) x 150 mm) and applying a gradient of 0.05% TFA (trifluoracetic acid) in water (mobile phase A) and 0.04% TFA in acetonitrile (mobile phase B). MFI

[0128] Protein Simple Micro-Flow Imaging Microscope, model DPA 4200 or 5200 was used in the MFI analysis. One ml (about 0.03 oz) of sample is used for analysis. The sample flows through the instrument’s flow cell. Particles that pass through the flow cell are imaged, counted, and characterized (based on size and morphology). RP-oxidation HPLC Method Conditions

[0129] Principle: Enzymatic digestion and chemical reduction followed by reversed phase HPLC with UV detection. This method is stability indicating.

[0130] HPLC column: Phenomenex Aeris Widepore XB-C18, 4.6 mm x 250 mm, 3.6 µm, Part No.00G-4482-E0.

[0131] Mobile Phase A: 0.1% TFA in 10 / 90 IPA / H2O solution; Mobile Phase B: 0.1% TFA in 10 / 90 IPA / ACN solution

[0132] Sample preparation: dilute samples to 5 mg / ml in 10mM Tris-HCl, pH 8.0. Add FabRICATOR enzyme and digest sample at 37°C for 3 hours. Add guanidine, EDTA, Tris, and DTT. Incubate at 37°C for 45 minutes. Analysis by RP-HPLC. Table 24:ATTORNEY DOCKET NO: 30762_WO -46- PARAMETER SETTING Column 60°C

[0133] If the peaks elute too early or too late as compared to the expected profile, the mobile phase composition may be universally adjusted by increasing or decreasing the % B in the mobile phase by up to 2%. For example, the % Mobile Phase B could be decreased by 1-2% if Fc peak begins eluting < 10.0 minutes.

[0134] The adjusted gradient program used in this example would be as shown in Table 25: Table 25: Al di Ti M bil Ph M bilATTORNEY DOCKET NO: 30762_WO -47- 42 75 25 47 75 25ATTORNEY DOCKET NO: 30762_WO -48- SEQUENCES The following nucleic and / or amino acid sequences of the antibody (Remternetug) of the present disclosure are provided below for reference. Antibody (Remternetug), HCDR1 (SEQ ID NO: 1) AASGFTFSSYPMS Antibody, HCDR2 (SEQ ID NO: 2) AISGSGGSTYYADSVKG Antibody, HCDR3 (SEQ ID NO: 3) AREGGSGSYYNGFDY Antibody, LCDR1 (SEQ ID NO: 4) RASQSLGNWLA Antibody, LCDR2 (SEQ ID NO: 5) YQASTLES Antibody, LCDR3 (SEQ ID NO: 6) QHYKGSFWT Antibody, HCVR (SEQ ID NO: 7) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGG STYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDY WGQGTLVTVSS Antibody, LCVR (SEQ ID NO: 8) DIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLES GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIK Antibody, Heavy Chain (SEQ ID NO: 9) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGG STYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG Antibody, Light Chain (SEQ ID NO: 10)ATTORNEY DOCKET NO: 30762_WO -49- DIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLES GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Exemplified DNA for Expressing Antibody Heavy Chain (SEQ ID NO: 11) gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcaccttta gcagctatcctatgagctgggtccgccaggctccagggaaggggctggagtgggtctcagctattagtggtagtggtggtagcaca tactacgcagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgaga gccgaggacacggccgtatattactgtgcgagagaggggggctcagggagttattataacggctttgattattggggccagggaac cctggtcaccgtctcctcagcctccaccaagggcccatcggtcttcccgctagcaccctcctccaagagcacctctgggggcacag cggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgca caccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagac ctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacat gcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctccc ggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtgga ggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcacca ggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagcc aaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggacgagctgaccaagaaccaggtcagcctgacctg cctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcc ccccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctc atgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt Exemplified DNA for Expressing Antibody Light Chain (SEQ ID NO: 12) Gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtcttg gtaactggttggcctggtatcagcagaaaccagggaaagcccctaaactcctgatctatcaggcgtctactttagaatctggggtccc atcaagattcagcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgcc aacattataaaggttctttttggacgttcggccaagggaccaaggtggaaatcaaacggaccgtggctgcaccatctgtcttcatcttc ccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtg gaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcag cagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcc cgtcacaaagagcttcaacaggggagagtgc

Claims

ATTORNEY DOCKET NO: 30762_WO -50- What is claimed is:

1. A pharmaceutical formulation comprising: (a) an anti-N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 comprises an amino acid sequence of SEQ ID NO. 1, HCDR2 comprises an amino acid sequence of SEQ ID NO: 2, HCDR3 comprises an amino acid sequence of SEQ ID NO: 3, LCDR1 comprises an amino acid sequence of SEQ ID NO: 4, LCDR2 comprises an amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises an amino acid sequence of SEQ ID NO: 6; (b) a buffering agent; (c) a viscosity reducer; (d) optionally, an antioxidant; and (e) optionally, a surfactant comprising polysorbate 80 (PS80); wherein the formulation has a pH range from about 5.3 to about 6.

3.

2. The pharmaceutical formulation of claim 1, wherein the antibody comprises a HCVR comprising an amino acid sequence of SEQ ID NO: 7 and a LCVR comprising an amino acid sequence of SEQ ID NO:

8.

3. The pharmaceutical formulation of claim 1, wherein the antibody comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO:

10.

4. The pharmaceutical formulation of claim 1, wherein the antibody concentration is from about 1 mg / ml to about 30 mg / ml.

5. The pharmaceutical formulation of claim 4, wherein the antibody concentration is about 20 mg / ml.

6. The pharmaceutical formulation of claim 1, wherein the antibody concentration is from about 100 mg / ml to about 250 mg / ml.ATTORNEY DOCKET NO: 30762_WO -51- 7. The pharmaceutical formulation of claim 6, wherein the antibody concentration is about 100 mg / ml or about 200 mg / ml.

8. The pharmaceutical formulation of any one of claims 1 - 7, wherein the buffering agent comprises histidine.

9. The pharmaceutical formulation of claim 8, wherein the histidine buffer concentration is from about 2.5 mM to about 10 mM.

10. The pharmaceutical formulation of claim 9, wherein the histidine buffer concentration is about 5 mM.

11. The pharmaceutical formulation of any one of claims 1 - 10, wherein the viscosity reducer comprises L-Arginine HCl.

12. The pharmaceutical formulation of claim 11, wherein the viscosity reducer also functions as a tonicity agent.

13. The pharmaceutical formulation of claim 11, wherein the L-Arginine HCl concentration is from about 100 to about 150 mM.

14. The pharmaceutical formulation of claim 13, wherein the L-Arginine HCl concentration is about 120 mM.

15. The pharmaceutical formulation of any one of claims 1 - 14, wherein the antioxidant comprises L-Methionine.

16. The pharmaceutical formulation of claim 15, wherein the L-Methionine concentration is from about 5 mM to about 20 mM.

17. The pharmaceutical formulation of claim 15, wherein the L-Methionine concentration is about 10 mM.

18. The pharmaceutical formulation of any one of claims 1 - 17, wherein the surfactant comprises polysorbate 80 (PS80).

19. The pharmaceutical formulation of claim 18, wherein the PS80 concentration is from about 0.01% w / v to about 0.08% w / v.

20. The pharmaceutical formulation of claim 19, wherein the PS80 concentration is about 0.04% w / v.ATTORNEY DOCKET NO: 30762_WO -52- 21. The pharmaceutical formulation of any one of claims 1-20, wherein the pH of the formulation is about 5.

8.

22. The pharmaceutical formulation of anyone of claims 1-3 comprising: (a) about 200 mg / ml of the antibody, (b) about 5 mM of histidine, (c) about 120 mM of L-Arginine HCl, (d) about 10 mM of L-Methionine, and (e) about 0.04% w / v of PS80; at pH of about 5.

8.

23. The pharmaceutical formulation of claim 22, wherein the pharmaceutical formulation is for i) intravenous administration or ii) subcutaneous administration.

24. The pharmaceutical formulation of claim 22, wherein the pharmaceutical formulation is for intravenous administration after 10X dilution or 5X dilution.

25. The pharmaceutical formulation according to claim 22, wherein subcutaneous administration of the formulation does not cause severe pain to a patient based on visual analog scale.

26. The pharmaceutical formulation of any one of claims above, wherein the formulation has total aggregates of no more than about 8.0%.

27. The pharmaceutical formulation of any one of claims above, wherein the formulation has total aggregates of no more than about 1.8%, about 4.0%, about 5.0%, about 6%, or about 7%.

28. The pharmaceutical formulation of any one of claims above, wherein the formulation has total aggregates of no more than about 1.8%.

29. The pharmaceutical formulation of any one of claims above, wherein the % oxidation of light chain (LC) Tryptophan 32 amino acid residue is i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 10% when tested based on AAPH stress test at 35ºC for 2 weeks.ATTORNEY DOCKET NO: 30762_WO -53- 30. The pharmaceutical formulation of claim 29, wherein the % oxidation of LC Tryptophan 32 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 7% when tested based on AAPH stress test at 35ºC for 2 weeks.

31. The pharmaceutical formulation of any one of claims above, wherein the % oxidation of heavy chain (HC) Methionine 257 amino acid residue is i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks.

32. The pharmaceutical formulation of claim 31, wherein the % oxidation of HC Methionine 257 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 4% when tested based on AAPH stress test at 35ºC for 2 weeks.

33. The pharmaceutical formulation of any one of claims above, wherein the % oxidation of HC Methionine 433 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks.

34. The pharmaceutical formulation of claim 33, wherein the % oxidation of HC Methionine 433 amino acid residue is i) not more than about 2% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 2% when tested based on AAPH stress test at 35ºC for 2 weeks.

35. The pharmaceutical formulation of any one of claims 1-3, wherein the % oxidation i) of LC Tryptophan 32 amino acid residue is i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 10% when tested based on AAPH stress test at 35ºC for 2 weeks; ii) of HC Methionine 257 amino acid residue is i) not more than about 8% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks; and iii) of HC Methionine 433 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 5% when tested based on AAPH stress test at 35ºC for 2 weeks.ATTORNEY DOCKET NO: 30762_WO -54- 36. The pharmaceutical formulation of any one of claims 1-3, wherein the % oxidation i) of LC Tryptophan 32 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 7% when tested based on AAPH stress test at 35ºC for 2 weeks; ii) of HC Methionine 257 amino acid residue is i) not more than about 5% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 4% when tested based on AAPH stress test at 35ºC for 2 weeks; and iii) of HC Methionine 433 amino acid residue is i) not more than about 2% when tested based on Fenton stress test at 35ºC for 2 weeks or ii) not more than about 2% when tested based on AAPH stress test at 35ºC for 2 weeks.

37. The pharmaceutical formulation of any one of claims above, wherein the formulation has viscosity less than about 5 cP to about 25 cP.

38. The pharmaceutical formulation of claim 37, wherein the formulation has viscosity less than about 5 cP, 10 cP, 15 cP, or 20 cP.

39. The pharmaceutical formulation of any one of claims above, wherein the formulation has at least about 40% of main charge variant of the antibody after 2 months at 35º C.

40. The pharmaceutical formulation of claim 39, wherein the formulation has at least about 50% of main charge variant of the antibody after 2 months at 35º C.

41. The pharmaceutical formulation of claim 39, wherein the formulation has at least about 59% of main charge variant of the antibody after 2 months at 35º C.

42. The pharmaceutical formulation of any one of claims above, wherein the formulation has no more than 50% of acidic variants of the antibody after 2 months at 35°C.

43. The pharmaceutical formulation of claim 42, wherein the formulation has no more than 35% of acidic variants of the antibody after 2 months at 35°C.

44. The pharmaceutical formulation of claim 42, wherein the formulation has no more than 20% of basic variants of the antibody after 2 months at 35°C.

45. The pharmaceutical formulation of claim 42, wherein the formulation has no more than 10% of basic variants of the antibody after 2 months at 35°C.

46. A pharmaceutical formulation comprising:ATTORNEY DOCKET NO: 30762_WO -55- (a) about 200 mg / ml of an anti-N3pGlu Aβ antibody comprising a heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and a light chain variable region (LCVR) comprising three light chain CDRs (LCDR1, LCDR2 and LCDR3) wherein HCDR1 comprises an amino acid sequence of SEQ ID NO. 1, HCDR2 comprises an amino acid sequence of SEQ ID NO: 2, HCDR3 comprises an amino acid sequence of SEQ ID NO: 3, LCDR1 comprises an amino acid sequence of SEQ ID NO: 4, LCDR2 comprises an amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises an amino acid sequence of SEQ ID NO: 6; (b) about 5 mM histidine buffer, pH about 5.8, (c) about 120 mM L-Arginine HCl, (d) about 10 mM L-Methionine, (d) about 0.04% w / v PS-80; wherein: (i) the % oxidation of light chain (LC) Tryptophan 32 amino acid residue is i) no more than about 5% when tested based on Fenton stress test or ii) not more than about 7% when tested based on AAPH stress test; ii) the % oxidation of heavy chain (HC) Methionine 257 amino acid residue is i) no more than about 5% when tested based on Fenton stress test or ii) not more than about 4% when tested based on AAPH stress test; iii) the % oxidation of heavy chain (HC) Methionine 433 amino acid residue is i) no more than about 2% when tested based on Fenton stress test or ii) not more than about 2% when tested based on AAPH stress test; (iv) the formulation has at least 95% Fc purity after 14 days of 316 stainless steel exposure or at least 96% LC purity after 14 days of 316 stainless steel exposure; and / or (v) the formulation has at least about 40% of main charge variant of the antibody after 2 months at 35º C.

47. The pharmaceutical formulation of claim 46, wherein the formulation has no more than 35% of acidic variants of the antibody after 2 months at 35°C.ATTORNEY DOCKET NO: 30762_WO -56- 48. The pharmaceutical formulation of claim 46, wherein the formulation has no more than 10% of basic variants of the antibody after 2 months at 35°C.

49. A pharmaceutical formulation of any one of claims above, wherein said formulation is contained in a container.

50. The pharmaceutical formulation of claim 49, wherein the container is a vial, a cartridge, a syringe, a prefilled syringe, or an autoinjector.

51. A kit comprising a pharmaceutical formulation of any one of claims above, a container, and instructions.

52. The kit of claim 51, wherein the container is a vial, a syringe, a cartridge, a prefilled syringe, or an autoinjector.

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