Methods for treating or preventing thyroxine transporter mediated amyloidosis

Abstract

Provided herein are anti-TTR antibody dosing regimens useful for the treatment of thyroxine transporter amyloid cardiomyopathy (ATTR-CM) in adult patients. In an embodiment, the patient is treated with an anti-TTR antibody comprising NI006 / ALXN2220.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 383,807 and European Application No. EP 22 207 651.5, both filed on November 15, 2022, and European Application No. EP 23 020175.8, filed on April 6, 2023. The entire contents of the above-referenced patent applications are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to methods of treating or preventing transthyretin-mediated amyloidosis (ATTR). Background Art

[0003] Systemic amyloidosis is an infiltrative disease caused by the progressive deposition of amyloid fibrils in organs such as the heart, liver and pancreas. For cardiac amyloidosis, the most common forms include immunoglobulin light chain and transthyretin amyloidosis. Currently approved drugs stabilize or block the production of amyloid precursors to prevent further amyloid deposition. This approach, while reducing cell damage and disease progression, does not remove existing amyloid deposits and leads to recovery of affected organ function, thereby improving quality of life and survival rates. Therapeutic strategies based on monoclonal antibodies that can selectively bind to amyloid deposits and induce their removal can represent a key treatment method for systemic amyloidosis (such as cardiac amyloidosis).

[0004] Attempts have been made to develop drugs that promote the degradation and reabsorption of amyloid deposits at the tissue level. For example, antibodies that bind to serum amyloid (SAP, a plasma glycoprotein produced by hepatocytes that represents one of the scaffolding proteins for amyloid deposits in all tissues) have been studied. However, a Phase II study (NCT03044353) in patients with cardiac amyloidosis was prematurely terminated due to a clear change in the benefit / risk profile in this type of patient.

[0005] Transthyretin (TTR) is a soluble protein involved in the transport of thyroid hormone and retinol in the body. TTR is secreted by the liver in the blood and by the choroid plexus in the cerebrospinal fluid, and is also expressed in specific tissues such as pancreatic α cells and the retinal epithelium.

[0006] Under specific conditions that have not yet been elucidated and may include acidic pH, oxidative stress, and local factors, the TTR protein adopts a misfolded, misassembled, and / or aggregated TTR conformation and becomes toxic, which may lead to transthyretin-mediated amyloidosis (ATTR).

[0007] Antibodies (e.g., human antibodies) that target misfolded, misassembled, and / or aggregated TTR have been developed. There is a need for improved methods (e.g., antibody dosing regimens) suitable for treating or preventing ATTR in a subject that have an acceptable benefit / risk profile and are preferably as convenient to administer / apply as possible to the subject and the physician.

[0008] According to the invention, a solution to the above-mentioned problem is provided by the embodiments characterized in the claims as well as by the embodiments disclosed in the description and recited in the clauses preceding the claims. Summary of the Invention

[0009] Specifically provided herein are methods and related dosing regimens for treating or preventing wild-type or hereditary transthyretin-mediated amyloidosis (ATTR), such as ATTR-CM, which is an ATTR amyloidosis that causes cardiomyopathy (CM). More particularly, the present invention provides an anti-transthyretin (TTR) antibody for use in a method of treating ATTR in a subject in need of such treatment, wherein the method comprises administering the antibody at a dose of: (a) 2000 mg to 2500 mg for a patient weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg); (b) 3000 mg to 3500 mg for a patient weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg); or (c) 4000 mg to 5000 mg for a patient weighing 100 kg or more (≥100 kg).

[0010] As shown in Example 1, the anti-TTR antibody used in accordance with the present invention (exemplarily shown as ALXN2220, also referred to as NI006) was shown to be safe and well tolerated by human patients and to deplete amyloid transthyretin deposits from cardiac tissue by antibody-dependent cellular phagocytosis (ADCP) in a dose-dependent and time-dependent manner, with the most significant effect at doses greater than 10 mg / kg when administered once every four weeks. In addition, the antibody was administered at a maximum dose of 60 mg / kg body weight every 28 days without any drug-related serious adverse events; see ClinicalTrials.gov ID NCT04360434 and Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250, each of which is incorporated herein by reference. As further shown in Example 1, data from bone scintigraphy and MRI indicated that doses of 30 mg / kg and 60 mg / kg reduced cardiac amyloid deposition by a median of 12.8% and 25.6% compared to baseline at 4 months; at 12 months, the median reductions were 30.7% and 50.7%, respectively. In the same patients, NT-proBNP decreased by 78.2% and 72.2% at 12 months. Because NT-proBNP concentrations typically increase in untreated ATTR-CM patients and are strongly associated with patient mortality, this data demonstrates the usefulness of the anti-TTR antibodies of the present disclosure in treating and / or preventing ATTR-CM in human patients.

[0011] Although it has been shown that ATTR immunotherapy with anti-TTR antibodies is possible, the weight-adjusted dosing regimen used in clinical trials has proven inappropriate in clinical practice because weight-adjusted dosing is complex and prone to errors, such as when measuring body weight, calculating the appropriate dose to be administered, and withdrawing the corresponding volume of drug from the vial. Furthermore, this approach generates significant drug waste, which corresponds to the amount of drug remaining in the vial that is not administered to the patient.

[0012] Therefore, based on the results of a phase 1 clinical trial, a 14-day repeat-dose GLP toxicity study, and PK modeling, a new dosing regimen, namely, weight-graded fixed-dose, has been developed to overcome the above-mentioned shortcomings.

[0013] In this case, a PK / PD model was established and a safe and effective fixed dose in the range of 2000 mg to 5000 mg has been calculated; see Example 5. In this case, single and repeated dose PK studies in rats confirmed the pharmacokinetic (PK) profile of the IgG1 molecule. Taking all of this into account, a weight-adjusted fixed dose has been calculated, wherein a dose in the range of 2000 mg to 2500 mg for patients weighing equal to or greater than 40 kg (≥40 kg) to less than 60 kg (<60 kg), a dose in the range of 3000 mg to 3500 mg for patients weighing equal to or greater than 60 kg (≥60 kg) to less than 100 kg (<100 kg), and a dose in the range of 4000 mg to 5000 mg for patients weighing equal to or greater than 100 kg (≥100 kg) have been calculated to be safe and effective. Accordingly, the present invention relates to an anti-transthyretin (TTR) antibody for use in a method of treating transthyretin-mediated amyloidosis (ATTR) in a subject in need of such treatment, wherein the method comprises administering the antibody at a dose of: (a) 2000 mg to 2500 mg for a patient weighing equal to or greater than 40 kg (≥40 kg) to less than 60 kg (<60 kg); (b) 3000 mg to 3500 mg for a patient weighing equal to or greater than 60 kg (≥60 kg) to less than 100 kg (<100 kg); or (c) 4000 mg to 5000 mg for a patient weighing equal to or greater than 100 kg (≥100 kg).

[0014] More specifically, in an initial embodiment, the following doses were proposed: 5000 mg if body weight ≥ 100 kg; 3500 mg if 60 kg ≤ body weight < 100 kg; and 2500 mg if body weight < 60 kg, administered via IV every 28 days (q4w). Those weight-graded fixed doses were further optimized to ensure administration of the full amount of drug present in each vial and eliminate residual volume and corresponding drug waste, while maintaining the same predicted efficacy, and were calculated to yield the following: 2400 mg for patients weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg); 3200 mg for patients weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg); or 4800 mg for patients weighing 100 kg or more (≥100 kg); see Example 6. Thus, in a preferred embodiment, the antibody is administered at a dose of 2400 mg to patients weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg), at a dose of 3200 mg to patients weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg), or at a dose of 4800 mg to patients weighing 100 kg or more (≥100 kg). These fixed doses are used in the Phase 3 clinical trial protocol (CTP) as outlined in Example 8. As exemplified in the CTP, one concept for monitoring during the administration of study drug and the post-infusion observation period includes monitoring heart rate, blood pressure, and oxygen saturation, as well as ECG assessments, at screening and before and after infusion at Weeks 1, 3, 12, and approximately every 12 weeks thereafter.

[0015] As mentioned above, the antibody ALXN2220 / NI006 has been used as a drug substance in the clinical trials mentioned in Example 1. The parent antibody of NI006 was first described in WO 2015 / 092077A1 (designated antibody NI-301.37F1) and Michalon et al., Nat. Commun. 12 (2021), 3142 (designated antibody NI301A). As disclosed in WO 2015 / 092077A1, NI006 (NI-301.37F1) is characterized in particular by binding to aggregated human wild-type thyroxine transthyretin (wtATTR), which is present in Figures 2 to 4 and Figure 7 3 to 6, and further described in the last paragraph of page 46. In addition, WO 2015 / 092077A1 discloses that NI006 (NI-301.37F1) does not bind to monomers and dimers of human native thyroxine translocon (TTR), as shown in Examples 5 and 6. Figure 4As shown. This binding spectrum is advantageous because the antibody selectively binds to aggregated wtTTR, thus allowing ostensibly to consider not only the treatment of hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as familial amyloid polyneuropathy, FAP), which is caused by mutations in the gene encoding TTR, but also the treatment of wild-type transthyretin amyloidosis (wtATTR), known as senile systemic amyloidosis (SSA). In addition, the antibody does not pose the risk of interfering with the assembly of natural monomers into physiological tetramers. The antibody has been modified by comprising in its variable region or binding domain the complementary determining regions (CDRs) and the variable heavy chain (V H ) and variable light chain (V L ) are described, these chains respectively have WO 2015 / 092077A1 Figure 1 C and Figure 1 The amino acid sequence depicted in M. The disclosure of U.S. Patent No. 10,344,080 is incorporated by reference to the relevant portions thereof (e.g., the sequences of VHCDR1-3 and VLCDR1-3, including the sequences of the VH and VL chains).

[0016] In principle, any anti-TTR antibody that recognizes amyloidogenic forms of TTR, i.e., aggregated TTR species, and preferably human aggregated TTR, but does not bind to physiological TTR species, can be used according to the present invention. Preferably, the anti-TTR antibody used according to the present invention is NI006 / ALXN2220 or an equivalent antibody that substantially has the TTR binding profile of NI006 and is preferably of human origin. For example, WO 2015 / 092077A1 discloses two additional human antibodies that exhibit such binding profiles (i.e., antibodies NI-301.59F1 and NI-301.35G11), as well as two human antibodies NI-301.28B3 and NI301.12D3 that have substantially the same epitope as NI006 (NI-301.37F7). More preferably, the equivalent antibody is derived from the human antibody NI-301.37F1, as characterized in WO 2015 / 092077 A1 and Michalon et al., Nat Commun. 12 (2021), 3142; see also above.

[0017] Thus, in one embodiment, the antibodies or antigen-binding fragments used according to the present invention comprise a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDR1-3, the sequences of which are shown in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, the sequences of which are shown in SEQ ID NOs: 4-6, wherein the anti-TTR antibody or antigen-binding fragment thereof comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8.

[0018] In some embodiments, the VH region comprises an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO:7, and the VL comprises an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO:8.

[0019] In some embodiments, the VH region comprises an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO: 11, and the VL comprises an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO: 12.

[0020] Preferably, the VH region comprises the amino acid sequence of SEQ ID NO: 7 and the VL comprises the amino acid of SEQ ID NO: 8, or the VH region comprises the amino acid sequence of SEQ ID NO: 11 and the VL comprises the amino acid of SEQ ID NO: 8 or 12, preferably SEQ ID NO: 8.

[0021] To avoid the development of "anti-drug antibodies" (ADA) in subjects administered the antibodies described herein, the antibodies are preferably human or humanized antibodies, typically human IgG, and most preferably human IgGl. In a preferred embodiment, the antibody is of the human IgG1m3 allotype.

[0022] The antibody NI006 / ALXN2220 used in accordance with the present invention is a fully human IgG1m3 allotype antibody and, therefore, comprises the amino acid sequence of a human constant heavy chain (HC) as exemplified in SEQ ID NO:9 and the corresponding human constant light chain (LC), here a kappa light chain, as exemplified in SEQ ID NO:10. As further explained below, the IgG antibody is prepared as a tetramer consisting of the HC and two disulfide-linked light LC chains. The theoretical molecular weight of the antibody NI006 / ALXN2220 is 144.2 kDa, and the weights determined by mass spectrometry (MS) are 144.2 kDa (deglycosylated) and 147.0 kDa to 147.6 kDa (intact IgG1).

[0023] Antibody NI006 / ALXN2220 has been produced in Chinese Hamster Ovary (CHO)-K1 cells. CHO cells are the most widely used mammalian cells for producing recombinant monoclonal antibodies due to their ability to undergo post-translational modifications (PTMs) to antibody molecules, which also commonly occur in humans. Through genetic manipulation by mutagenesis, different CHO daughter cells with improved quality have been established. Among these variants are CHO-K1, CHO-S, CHO-DXB11, and CHO-DG44. Thus, in one embodiment, the antibodies used according to the present invention are produced in CHO cells, preferably in the CHO-K1 cell line, and purified from the cell culture medium for further use.

[0024] As shown in Example 7, the major PTMs identified in antibody NI006 / ALXN2220 are modification of the N-terminal glutamine to pyroglutamate, deletion of the C-terminal lysine, and N-glycosylation in the HC. In this case, an N-glycosylation site was identified at position 300 (HC N300, SEQ ID NO: 9). Thus, in one embodiment, the antibody used according to the present invention lacks the C-terminal lysine, i.e., the antibody undergoes C-terminal lysine cleavage. In particular, the C-terminal lysine as shown in SEQ ID NO: 9 is removed from the heavy chain of the antibody, preferably from each heavy chain of the antibody. Alternatively, the N-terminal glutamine is modified to pyroglutamate, i.e., the heavy chain of the antibody as shown in SEQ ID NO: 9 undergoes N-terminal glutaminyl cyclization. The sequence, i.e., the sequence of the heavy chain comprising cyclic pyroglutamate and lacking an N-terminal glutamate, is shown in SEQ ID NO: 14.

[0025] Alternatively, the heavy chain of the antibody used according to the present invention lacks the C-terminal lysine and the glutamine at the N-terminus is modified to pyroglutamic acid. The sequence, i.e., the sequence of the heavy chain with a truncated C-terminal lysine and containing cyclic pyroglutamic acid and no N-terminal glutamic acid, is shown in SEQ ID NO: 15.

[0026] Additionally or alternatively, the antibody is glycosylated, particularly N-glycosylated. More particularly, the heavy chain of the antibody is glycosylated, and even more particularly N300 of the heavy chain.

[0027] In a preferred embodiment, the anti-TTR antibody used according to the invention lacks a C-terminal cysteine, has a modified glutamine as pyroglutamate at the N-terminus, and comprises at least one N-glycosylation site.

[0028] Therefore, in a preferred embodiment, the antibody used according to the present invention is composed of two heavy chains having SEQ ID NO: 9 and two light chains having SEQ ID NO: 10, wherein in the heavy chain, the glutamine at the N-terminus is modified to pyroglutamic acid, the C-terminal lysine is deleted, and the heavy chain is N-glycosylated. In other words, the antibody used according to the present invention is preferably composed of two heavy chains having SEQ ID NO: 15 and two light chains having SEQ ID NO: 10, and wherein the heavy chain is N-glycosylated.

[0029] As described above, the anti-TTR antibodies used according to the present invention deplete amyloid thyroxine transporter from cardiac tissue in a dose-dependent and time-dependent manner. Thus, in some embodiments, ATTR amyloidosis leads to cardiomyopathy (CM), and thus, in a preferred embodiment, the subject treated according to the present invention suffers from ATTR amyloidosis with CM (ATTR-CM). In a preferred embodiment, the subject to be treated suffers from variant ATTR (ATTRv / hATTR) or wild-type ATTR-CM (wATTR). Even more preferably, the subject to be treated suffers from variant ATTR-CM (ATTRv-CM / hATTR-CM) or wild-type ATTR-CM (wATTR-CM).

[0030] In some embodiments, the subject suffers from ATTR polyneuropathy (ATTR-PN). In some embodiments, the subject suffers from familial amyloid polyneuropathy (FAP). In some embodiments, the subject suffers from familial amyloid cardiomyopathy (FAC). In some embodiments, the subject suffers from senile systemic amyloidosis (SSA). In some embodiments, the subject suffers from systemic familial amyloidosis. In some embodiments, the subject suffers from leptomeningeal / central nervous system (CNS) amyloidosis. In some embodiments, the subject suffers from Alzheimer's disease. In some embodiments, the subject suffers from TTR-related ocular amyloidosis. In some embodiments, the subject suffers from TTR-related renal amyloidosis. In some embodiments, the subject suffers from TTR-related hyperthyroxinemia. In some embodiments, the subject suffers from TTR-related ligamentous amyloidosis, including carpal tunnel syndrome. In some embodiments, the subject suffers from rotator cuff tear and lumbar spinal stenosis. In some embodiments, the subject suffers from preeclampsia.

[0031] In some embodiments, the subject is diagnosed with hereditary ATTR-CM due to a known pathogenic TTR mutation.

[0032] In some embodiments, the subject has sporadic, wild-type ATTR-CM (WT-ATTR-CM) (e.g., a wild-type ATTR gene that encodes a TTR protein that forms deposits in the heart) and has a negative genetic test for a TTR mutation.

[0033] Preferably, the diagnosis is based on the presence of symptomatic ATTR, preferably ATTR-CM, or on an NT-proBNP level >2000 pg / mL. The use of NT-proBNP as a biomarker in ATTR is well established in the art, and a staging system with a cutoff of 3000 pg / mL for NT-proBNP has been developed based on the level of this biomarker (combined with the level of cardiac troponin T (cTnT) (Grogan et al., J Am Coll Cardiol 68 (2016), 1014–1020) or with estimated glomerular filtration rate (eGFR) (Gillmore et al., European Heart Journal 39 (2018), 2799–2806); see also Perfetto et al., Internal and Emergency Medicine 17 (2022), 957–969. Thus, depending on the level of cTnT and eGFR, and considering only the level of NT-proBNP, a subject has grade I, II, and III cardiac ATTR. Therefore, the subject to be treated preferably has symptoms of ATTR (preferably ATTR-CM) and / or has an NT-proBNP level >2000 pg / mL.

[0034] Additionally or alternatively, the subject is an adult subject, in particular an adult subject, preferably a subject who is 18 years or older but less than 90 years (≥18 years to ≤90 years).

[0035] Thus, the therapeutic regimens of the present invention may be used to treat subjects with any or all of the mentioned indications / characteristics.

[0036] In one embodiment, treatment of a human subject with an antibody for use according to the invention results in a lower cardiac amyloid burden and / or a composite endpoint of all-cause mortality (ACM) and total cardiovascular (CV) clinical events and / or heart failure (HF) events. In some embodiments, treatment with an anti-TTR antibody according to the methods of the invention results in a dose-dependent and time-dependent reduction in cardiac amyloid burden in the patient of at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60% or more, e.g., about 70%, about 80%, about 90%, after a specified duration of treatment (e.g., 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 21 months, or 24 months or longer, e.g., 48 months).

[0037] Preferably, the treatment, i.e., administration of the dosing regimen, of the present invention improves at least one of:

[0038] (a) symptomatic, functional, and health-related quality of life (QoL), as measured by the change from baseline in the Kansas City Cardiomyopathy Questionnaire Global Summary (KCCQ-OS) score;

[0039] (b) time to cardiovascular (CV)-related death;

[0040] (c) six-minute walk test (6MWT) scores compared with baseline;

[0041] (d) rates of cardiovascular (CV) clinical events; and

[0042] (e) Time to all-cause mortality (ACM).

[0043] In one embodiment, treatment

[0044] (a) reduce the subject's NT-proBNP level compared to baseline;

[0045] (b) reduce the rate of heart failure (HF) events;

[0046] (c) reducing the incidence of intensive oral diuretic therapy, optionally including outpatient intensive oral diuretic therapy;

[0047] (d) reduce the incidence of disease-modifying therapy changes;

[0048] (e) reduce the incidence of hospitalization due to atrial fibrillation;

[0049] (f) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score after 24 months of study treatment;

[0050] (g) change from baseline in the six-minute walk test (6MWT) after 24 months of study treatment;

[0051] (h) changes from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia disease stages and NYHA classification;

[0052] (i) induce changes in GLS relative to baseline;

[0053] (j) induced changes in stroke volume relative to baseline;

[0054] (k) elicit changes in echocardiographic parameters of interest relative to baseline;

[0055] (l) causing changes in hs-cTnT relative to baseline;

[0056] (m) causing changes relative to baseline in DPD / PYP / HMDP cardiac scintigraphic cardiac uptake and / or cMRI-derived ECV, T1, and T2 maps;

[0057] (n) Causes a change in eGFR relative to baseline

[0058] (o) cause a change from baseline in the EQ-5D-5L score and / or cause a change from baseline in the SF-36 score;

[0059] (p) causing a change relative to baseline in a marker selected from the group consisting of CRP, IL11b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin; preferably, a change relative to baseline in a marker of CRP;

[0060] (q) causing a change relative to baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6;

[0061] (r) causing a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4;

[0062] (s) cause changes from baseline in: (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or sNFL level; and / or

[0063] (t) Causes a change from baseline in the NIS and / or causes a change in the NC study.

[0064] In some embodiments, an antibody for use according to the invention is administered to a subject once every four weeks (q4w).

[0065] In some embodiments, the antibody for use according to the present invention is administered to the subject intravenously (IV), preferably via IV infusion, ie the method of treatment as defined above comprises administering the antibody to the subject intravenously (IV), preferably via IV infusion.

[0066] In some embodiments, the antibody for use according to the invention is administered for at least 24 months, preferably at least 48 months, ie the method of treatment comprises administering the antibody for at least 24 months, preferably at least 48 months.

[0067] In some embodiments, the antibody for use according to the present invention is administered as a weight-graded fixed dose, preferably as a fixed dose as defined above, based on the patient's recorded weight, wherein the recording of body weight is performed within 30 days of the planned administration, wherein the dose is administered intravenously (IV) every four weeks (q4w), i.e., the method comprises administering the antibody as a weight-graded fixed dose, preferably as a fixed dose as defined above, based on the patient's recorded weight, wherein the recording of body weight is performed within 30 days of the planned administration, wherein the dose is administered intravenously (IV) every four weeks (q4w).

[0068] In pharmacological studies (Michalon, 2021), NI006 / ALXN2220 was shown to activate immune cells by binding to Fcγ receptors. Using different in vitro and in vivo models, it has been demonstrated that NI006 / ALXN2220 triggers the elimination of ATTR fibrils from patient samples in a dose-dependent and time-dependent manner through immune-driven phagocytic clearance. Thus, NI006 / ALXN2220 induces antibody-mediated phagocytosis of ATTR fibrils by phagocytic immune cells (such as macrophages), leading to the clearance of ATTR deposits from tissues.

[0069] Thus, in some embodiments, the antibodies used in accordance with the present invention trigger elimination of ATTR fibrils from patient samples in a dose-dependent and time-dependent manner via immune-driven phagocytic clearance.

[0070] In the Phase 1 study NI006-101, once-monthly NI006 / ALXN2220 treatment was generally safe and well tolerated in adult patients with ATTR-CM up to the highest dose tested (i.e., 60 mg / kg IV q4w). The NI006 / ALXN2220 PK profile was considered dose-proportional, providing sustained antibody levels and compatible with monthly dosing. In this study, two different methods were used to estimate the amount of ATTR deposits in the heart: quantification of cardiac tracer uptake in the heart by scintigraphy or quantification of ECV by cMRI. These two PD measurements represent cardiac amyloid burden and are used to estimate baseline amyloid burden and changes over time during clinical studies. NI006 / ALXN2220 showed a dose-dependent and time-dependent reduction of cardiac amyloid burden of up to approximately 51% at 60 mg / kg at 12 months. Thus, preferably, the elimination of ATTR fibrils by anti-TTR antibody treatment is measured via cardiac tracer uptake scintigraphy or quantification of ECV with cMRI; see Phase 1 study NI006-101. More preferably, treatment of patients with anti-TTR antibodies results in a dose-dependent and time-dependent reduction in cardiac amyloid burden of up to about 51% at 12 months, preferably wherein the dose administered to the patient corresponds to about 60 mg / kg. Thus, in some embodiments, treatment with anti-TTR antibodies according to the methods of the present invention results in a dose-dependent and time-dependent reduction in cardiac amyloid burden in patients of at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60% or more, e.g., about 70%, about 80%, about 90%, after a specified duration of treatment (e.g., 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 21 months, or 24 months or longer, e.g., 48 months).

[0071] In some embodiments, the patient to be treated with the antibody according to the present invention is a male or female subject who

[0072] (1) ATTR-CM with a wild-type or variant TTR genotype confirmed by a central diagnosis based on evidence of cardiac amyloidosis by echocardiography or cMRI and one of the following:

[0073] a. Endomyocardial biopsy with confirmatory TTR amyloid typing by immunohistochemistry or mass spectrometry; or

[0074] b. Grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTcPYP, or 99mTc HMDP) in the absence of monoclonal gammopathy; or

[0075] c. In the presence of monoclonal gammopathy, grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and confirmatory TTR amyloid typing in non-cardiac tissues by immunohistochemistry or mass spectrometry;

[0076] (2) Willingness to undergo genetic testing for mutations in the TTR gene during screening if genetic testing has not been performed previously or if genetic results are unavailable

[0077] (3) Echocardiography at screening showed end-diastolic ventricular septal wall thickness ≥11 mm for women or ≥12 mm for men

[0078] (4) NT-proBNP > 2000 pg / mL measured by the central laboratory at screening

[0079] (5) treated with loop diuretics for at least 30 days before screening;

[0080] (6) A history of heart failure documented by one of the following events within 1 year before screening:

[0081] a. Hospitalization for heart failure

[0082] b. Urgent heart failure visit

[0083] c. Episodes of volume overload documented by NT-proBNP > 2000 pg / mL (or equivalent BNP)

[0084] (7) New York Heart Association (NYHA) class II-IV at screening; and / or

[0085] (8) Have a life expectancy of at least 6 months based on the judgment of a clinician.

[0086] As outlined in European patent application EP 22 207 645.7 and U.S. provisional applications 63 / 383,803 and 63 / 503,286, and in detail in International application entitled “Pharmaceutical compositions for treating or preventing transthyretin-mediated amyloidosis” filed on November 15, 2023 (Attorney Docket No. NE30A100 / P-WO), the contents of which are incorporated herein by reference, it has been found that a formulation comprising 50 mg / mL of antibody (i.e., ALXN2220 / NI006) in 20 mM histidine buffer at pH 5.8, 80 mg / mL or 65 mg / mL sucrose, and 0.3 mg / mL polysorbate 80 is particularly suitable for ensuring long-term stability of the drug product. Therefore, a formulation comprising 50 mg / mL of the antibody (ie, ALXN2220 / NI006) in 20 mM histidine buffer at pH 5.8, 80 mg / mL sucrose, and 0.3 mg / mL polysorbate 80 has been used in clinical trials as described in the Examples below.

[0087] Thus, in some embodiments, the antibodies for use according to the present invention are administered as a pharmaceutical formulation at 50 mg / mL in 20 mM histidine buffer (e.g., L-histidine and L-histidine monohydrochloride), 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80 at pH 5.8. Alternatively, the antibodies for use according to the present invention are administered as a pharmaceutical formulation at 50 mg / mL in 20 mM histidine buffer (e.g., L-histidine and L-histidine monohydrochloride), 65 mg / mL sucrose, 0.3 mg / mL polysorbate 80 at pH 5.8.

[0088] Preferably, the antibody for use according to the present invention is administered to the patient as an intravenous (IV) infusion, with the initial administration being within 2 hours and subsequent administrations being within 1 hour, i.e., the method comprises administering the antibody to the patient as an intravenous (IV) infusion, with the initial administration being within 2 hours and subsequent administrations being within 1 hour.

[0089] In some embodiments, the subject has been previously treated with and / or is concurrently receiving a disease-modifying agent selected from a TTR silencing agent and a TTR stabilizer. For example, a TTR tetramer stabilizer can be diflunisal, tamifluanil ( or ) or Acoramidis (AG10). Currently, tafamidis, which acts as an oral disease-modifying treatment, is the only approved drug treatment that specifically targets wild-type and inherited forms of ATTR-CM. According to the present invention, ALXN2220 activity was shown to be maintained in the presence of tafamidis.

[0090] In some embodiments, the antibody for use according to the present invention is administered for up to 24 months according to the intervention infusion schedule provided in Table 25. Preferably, after the 24-month treatment period, the antibody for use according to the present invention is administered as a subsequent treatment according to the intervention infusion schedule of Table 26. Thus, in one embodiment, the method comprises administering the antibody for up to 24 months according to the intervention infusion schedule provided in Table 25, and preferably, after the 24-month treatment period, the antibody is administered as a subsequent treatment according to the intervention infusion schedule of Table 26.

[0091] As shown in the Examples, treatment with the anti-TTR antibody resulted in a reduction in median amyloid when the antibody was administered at doses of 30 mg / kg and 60 mg / kg in patients, and based on PK modeling, the same reduction in amyloid would be expected to occur at a fixed dose. Thus, in some embodiments, when the anti-TTR antibody is used according to the present invention, treatment with the antibody results in a reduction in median amyloid when the antibody is administered at a dose corresponding to a 30 mg / kg to 60 mg / kg dose in patients. Preferably, efficacy of treatment is measured using endomyocardial biopsy, including intraepidermal nerve fiber density (IENFD) and / or sweat gland nerve fiber density (SGNFD).

[0092] In some embodiments, patients are stratified based on:

[0093] (1) prior treatment with a disease-modifying agent, wherein the disease-modifying agent is selected from (a) a TTR silencing agent, optionally in combination with a TTR stabilizer; (b) a TTR stabilizer alone; and (c)

[0094] No TTR stabilizer or TTR silencing agent treatment;

[0095] (2) TTR genotype, including ATTR variant (ATTRv) or ATTR wild type (ATTRwt); or

[0096] (3) Disease severity based on cardiac biomarker levels, including NT-

[0097] proBNP>3000 pg / mL and NT-proBNP≤3000 pg / mL, optionally together with pre- and post-treatment high-sensitivity cardiac troponin C (hs-cTnT) levels.

[0098] In addition, to monitor the efficacy of treatment, serum biomarker levels can be monitored before and after treatment with the antibodies used according to the present invention. In particular, in some embodiments, the biomarkers are selected from: (a) complement factors selected from C3 and C4, and CRP; (b) proinflammatory cytokines selected from IL1b, IL6, IL8, IFNg and TNF-α; (c) anti-inflammatory cytokines selected from IL10, IL1RA; (d) positive acute phase proteins selected from SAA and ferritin; (e) PICP; (f) PIIINP; (g) CITP; (h) PRO-C6; and (i) plasma NNTTR, or a combination thereof.

[0099] definition

[0100] For the avoidance of any doubt, it is emphasized that the expressions "in some embodiments," "in certain embodiments," "in some cases," "in some instances," "in some aspects," "in further embodiments," "in one embodiment," "in further aspects," "in a first aspect," "in a second aspect," etc. are used and mean that any embodiment described therein should be read in light of each of the features of those embodiments in combination, and the disclosure must be treated in the same manner as if the combination of features of those embodiments and aspects were set forth in one embodiment. The same is true for any combination of embodiments and features exemplified in the appended claims and examples, which are also intended to be combined with the features of the corresponding embodiments disclosed in the specification, where only for consistency and brevity the embodiments are characterized by dependencies, and indeed each combination of embodiments and features that might be interpreted due to dependency(ies) must be considered as literally disclosed and not as a choice between different options. In this context, one skilled in the art will understand that the embodiments and features disclosed in the examples are intended to be generalizable to any anti-TTR antibody and equivalents having substantially the same properties.

[0101] As used herein, the term "about" refers to a value of ±10% of the stated value; preferably ±5%.

[0102] In conjunction with the present invention, the term "and / or" is to be understood as meaning that all members of the group connected by the term "and / or" are disclosed cumulatively in any combination, alternately with one another and in each case are disclosed one another. For the expression "A, B and / or C", this means that the following disclosure is to be understood thereunder: a) A or B or C; or b) (A and B); or c) (A and C); or d) (B and C); or e) (A and B and C).

[0103] As used herein, the term "antibody" includes its corresponding binding fragments, and the dosages mentioned herein refer to NI006 with a molecular weight of approximately 147 kDa for the intact IgG1 antibody. Therefore, if an antibody with a significantly different MW is used, the dosage can be adjusted accordingly. Similarly, if an antibody with a lower or longer serum half-life is used, for example due to altered glycosylation and / or modifications such as pegylation, the dosage and dosing interval can be recalculated, respectively.

[0104] As used herein, the term "pharmaceutical composition" refers to a mixture containing a therapeutic agent (e.g., an anti-TTR antibody described herein), optionally in combination with one or more pharmaceutically acceptable excipients, diluents, and / or carriers. For example, a pharmaceutical composition is formulated for administration to a subject, such as a mammal, e.g., a human, to prevent, treat, or manage a particular disease or condition that affects or may affect the subject (e.g., ATTR, such as ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and preeclampsia).

[0105] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects, such as mammals (e.g., humans), without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0106] As used herein, the expressions "capable of binding" and "binds to" refer to the ability of an antibody to bind to, for example, aggregated TTR under experimental conditions, such as in an ELISA assay.

[0107] As used herein, the term "between" is inclusive.

[0108] " sequence identity percentage (%) " with respect to reference polynucleotide or peptide sequence is defined as after alignment sequence and, if necessary, introducing breach to realize maximum sequence identity percentage, the nucleic acid or amino acid identical with the nucleic acid in the reference polynucleotide or peptide sequence in the candidate sequence or amino acid percentage.Comparison for determining nucleic acid or amino acid sequence identity percentage can realize in the various ways within the capabilities of those skilled in the art, for example, using the computer software available to the public, such as BLAST, BLAST-2 or Megalign software. Those skilled in the art can determine the appropriate parameters for alignment sequence, be included in any algorithm required for maximum comparison on the total length of the sequence compared. For example, sequence comparison computer program BLAST can be used to generate sequence identity percentage values. As an illustration, given nucleic acid or amino acid sequence A is relative to given nucleic acid or amino acid sequence B, and A and B or A are to B's sequence identity percentage (it can alternatively be expressed as given nucleic acid or amino acid sequence A relative to given nucleic acid or amino acid sequence B, and A and B or A have specific sequence identity percentage to B) and calculates as follows:

[0109] 100 multiplied by (fraction X / Y)

[0110] wherein X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program's alignment of A and B, and wherein Y is the total number of nucleic acids in B. It will be understood that when the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not equal the percent sequence identity of B to A.

[0111] As used herein, the term "treatment" refers to therapeutic treatment and prophylactic or preventative measures, wherein the goal is to prevent or slow (mitigate) the progression of undesirable physiological changes or conditions, such as heart defects. Beneficial or desired clinical results include, but are not limited to, alleviating symptoms, reducing the extent of the disease, stabilizing the disease state (i.e., not worsening), delaying or slowing disease progression, improving or alleviating the disease state, and detectable or undetectable relief (whether partial or complete). "Treatment" can also mean extending survival (e.g., extending the survival of a human subject with ATTR by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more years, e.g., the lifetime of the subject) compared to the expected survival if not receiving treatment. Those in need of treatment include those already suffering from a condition or disorder, as well as those susceptible to a condition or disorder or those whose manifestations are to be prevented.

[0112] As used herein, the term "loading dose" refers to a dose of about 600 mg to 4000 mg (e.g., 2400 mg, 2500 mg, 3000 mg, 3200 mg, or 3500 mg) of an antibody that increases the blood (e.g., serum or plasma) concentration of the subject to the desired therapeutic level for the subject being treated (e.g., ≥1 μg / mL, e.g., ≥1 μg / mL, ≥2.5 μg / mL, ≥5 μg / mL, ≥10 μg / mL, ≥20 μg / mL, ≥30 μg / mL, ≥40 μg / mL, ≥50 μg / mL, ≥60 μg / mL, ≥70 μg / mL, ≥80 μg / mL, ≥90 μg / mL, ≥100 μg / mL, ≥1 10μg / mL, ≥120μg / mL, ≥130μg / mL, ≥140μg / mL, ≥150μg / mL, ≥160μg / mL, ≥170μg / mL, ≥180μg / mL, ≥190μg / mL, ≥200μg / mL, ≥210μg / mL, ≥220μg / mL, ≥230μg / mL, ≥240μg / mL, ≥250μg / mL, ≥260μg / mL, ≥270μg / mL, ≥280μg / mL, ≥290μg / mL, ≥300μg / mL, ≥310μg / mL, ≥320μg / mL, ≥330μg / mL, ≥340μg / mL, ≥350μg / mL, ≥ 360μg / mL, ≥370μg / mL, ≥380μg / mL, ≥390μg / mL, ≥400μg / mL, ≥410μg / mL, ≥420μg / mL, ≥430μg / mL, ≥440μg / mL, ≥450μg / mL, ≥460μg / mL, ≥470μg / mL, ≥480μ g / mL, ≥490μg / mL, ≥500μg / mL, ≥510μg / mL, ≥520μg / mL, ≥530μg / mL, ≥540μg / mL, ≥550μg / mL, ≥560μg / mL, ≥570μg / mL, ≥580μg / mL, ≥590μg / mL, ≥600μg / mL, ≥610μg / mL, ≥620μg / mL, ≥630μg / mL, ≥640μg / mL, ≥650μg / mL, ≥660μg / mL, ≥670μg / mL, ≥680μg / mL, ≥690μg / mL, ≥700μg / mL, ≥710μg / mL, ≥720μg / mL, ≥730μ g / mL, ≥740μg / mL, ≥750μg / mL, ≥760μg / mL, ≥770μg / mL, ≥780μg / mL, ≥790μg / mL, ≥800μg / mL, ≥810μg / mL, ≥820μg / mL, ≥830μg / mL, ≥840μg / mL, ≥850μg / mL,≥860μg / mL, ≥870μg / mL, ≥880μg / mL, ≥890μg / mL, ≥900μg / mL, ≥910μg / mL, ≥920μg / mL, ≥930μg / mL, ≥940μg / mL, ≥950μg / mL, ≥960μg / mL, ≥970μg / mL, ≥980μg / mL, ≥990μg / mL, ≥1000μg / mL or more). For example, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) loading doses can be administered to a subject weekly (e.g., every 7 days), every other week (e.g., every two weeks or every 14 days), monthly (e.g., every 28 days ± 7 days), or every other month (e.g., every two months, e.g., every 56 days ± 7 days) prior to administering a maintenance dose (e.g., a first maintenance dose or any subsequent maintenance dose) to the subject.

[0113] As used herein, the term "maintenance dose" refers to a dose of about 600 mg to 6000 mg (e.g., 2500 mg, 3000 mg, 3500 mg, or 5000 mg, and 2400 mg, 3200 mg, or 4800 mg, respectively) or 10 mg / kg to 60 mg / kg (e.g., 10 mg / kg, 30 mg / kg, or 60 mg / kg) of an antibody that maintains a desired minimum blood (e.g., serum or plasma) concentration of the antibody. For example, it is desirable to maintain ≥1 μg / mL (e.g., ≥1 μg / mL, ≥2.5 μg / mL, ≥5 μg / mL, ≥10 μg / mL, ≥20 μg / mL, ≥30 μg / mL, ≥40 μg / mL, ≥50 μg / mL, ≥60 μg / mL, ≥70 μg / mL, ≥80 μg / mL, ≥90 μg / mL, ≥100 μg / mL, ≥110 μg / mL, ≥120 μg / mL, ≥130 μg / mL, ≥140 μg / mL, ≥150 μg / mL, ≥160 μg / mL, ≥170 μg / mL, ≥180 μg / mL, ≥190 μg / mL, ≥200 μg / mL, ≥210 μg / mL, ≥220 μg / mL, ≥230 μg / mL, ≥240 μg / mL, ≥250 μg / mL, ≥260 μg / mL, ≥270 μg / mL, ≥280 μg / mL, ≥290 μg / mL, ≥300 μg / mL, ≥310 μg / mL, ≥320 μg / mL, ≥330 μg / mL, ≥340 μg / mL 160μg / mL, ≥170μg / mL, ≥180μg / mL, ≥190μg / mL, ≥200μg / mL, ≥210μg / mL, ≥220μg / mL, ≥230μg / mL, ≥240μg / mL, ≥250μg / mL, ≥260μg / mL, ≥270μg / mL, ≥280μg / mL, ≥290μg / mL, ≥300μg / mL, ≥310μg / mL, ≥320μg / mL, ≥330μg / mL, ≥340μg / mL, ≥350μg / mL, ≥360μg / mL, ≥ 370μg / mL, ≥380μg / mL, ≥390μg / mL, ≥400μg / mL, ≥410μg / mL, ≥420μg / mL, ≥430μg / mL, ≥440μg / mL, ≥450μg / mL, ≥460μg / mL, ≥470μ g / mL, ≥480μg / mL, ≥490μg / mL, ≥500μg / mL, ≥510μg / mL, ≥520μg / mL, ≥530μg / mL, ≥540μg / mL, ≥550μg / mL, ≥560μg / mL, ≥570μg / mL, ≥580μg / mL, ≥590μg / mL, ≥600μg / mL, ≥610μg / mL, ≥620μg / mL, ≥630μg / mL, ≥640μg / mL, ≥650μg / mL, ≥660μg / mL, ≥670μg / mL, ≥680μ g / mL, ≥690μg / mL, ≥700μg / mL, ≥710μg / mL, ≥720μg / mL, ≥730μg / mL, ≥740μg / mL, ≥750μg / mL, ≥760μg / mL, ≥770μg / mL, ≥780μg / mL,≥790μg / mL, ≥800μg / mL, ≥810μg / mL, ≥820μg / mL, ≥830μg / mL, ≥840μg / mL, ≥850μg / mL, ≥860μg / mL, ≥870μg / mL, ≥880μg / mL, ≥890μg / mL, ≥900μ g / mL, ≥910 μg / mL, ≥920 μg / mL, ≥930 μg / mL, ≥940 μg / mL, ≥950 μg / mL, ≥960 μg / mL, ≥970 μg / mL, ≥980 μg / mL, ≥990 μg / mL, ≥1000 μg / mL or higher). The maintenance dose can be administered to the subject at a certain concentration (e.g., 10 mg / kg-60 mg / kg, such as 10 mg / kg, 30 mg / kg or 60 mg / kg) or a fixed dose (e.g., about 600 mg to 4000 mg, such as 2400 mg, 2500 mg, 3000 mg or 3200 mg), preferably, the dose is lower than the loading dose previously administered to the same subject or subject of the same weight class. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figure 1 is a schematic diagram illustrating an exemplary dosing schedule. The red outlined box indicates the single ascending dose (SAD) phase for each of Cohorts 1 to 6, as further described in Example 1. The blue outlined box indicates the multiple ascending dose (MAD) phase for each of Cohorts 1 to 6, as further described in Example 1. The green-filled cells labeled DEC in the table are exemplary time periods during which a data evaluation committee, etc., reviews the safety and / or therapeutic efficacy of the subjects before and after a given administration.

[0115] Figure 2 is a schematic diagram showing exemplary dosing regimens for the open-label extension (OLE) phase of each of Cohorts 1 through 6, as further described in Example 1. The green-filled cells labeled DEC in the table are exemplary time periods during which a data review committee, etc., will review subjects for safety and / or therapeutic efficacy before and after designated administration.

[0116] Figure 3 is a schematic diagram illustrating an exemplary dosing schedule. The red outlined box indicates the single ascending dose (SAD) phase of Cohort 7, as further described in Example 1. The blue outlined box indicates the multiple ascending dose (MAD) phase of Cohort 7, as further described in Example 1. The green outlined box indicates the open-label extension (OLE) phase of Cohort 7, as further described in Example 1. The green-filled cells labeled DEC in the table are exemplary time periods during which a data evaluation committee, etc., reviews the safety and / or therapeutic efficacy of the subjects before and after the designated administration.

[0117] Figure 4 Shown are scintigraphic images (A) and serial midventricular ECV images (B) visualizing depletion of amyloid thyroxine transporter by NI006 / ALXN2220 in ATTR-CM. Figure 4 (A) Serial bone scintigraphy at baseline, 4 months (after completion of double-blind SAD / MAD), and 12 months (after completion of OLE) is shown for one patient randomized to NI006 / ALXN2220 and one patient randomized to placebo. Quantification of cardiac tracer uptake is expressed as the cardiac / whole body ratio (H / WB ratio in %). Cumulative administered NI006 / ALXN2220 dose (in g) and NI006 / ALXN2220 exposure (AUC in mg / mL per day) for each imaging time point after baseline are provided. Figure 4 (B) Serial mid-ventricular ECV images at baseline, 4 months, and 12 months are shown for one patient randomized to NI006 / ALXN2220 and one patient randomized to placebo. Quantification of cardiac amyloid deposition is expressed by ECV measurements (in %). The individual cumulative administered NI006 / ALXN2220 dose (in g) and NI006 / ALXN2220 exposure (in mg / mL per day) at the post-baseline imaging time point are provided.

[0118] Figure 5 Shown are graphs visualizing changes in cardiac amyloid burden, specifically the relative change from baseline in cardiac amyloid (RCFB) derived from quantification of serial bone scintigraphy (triangles) and MRI (dots). Figure 5 (A) Shown are the RCFB for each assigned NI006 / ALXN2220 dose cohort and placebo at 4 and 12 months. Figure 5 (B) Shown are the RCFB at 4 and 12 months for patients assigned to NI006 / ALXN2220 in relation to their individual cumulative NI006 / ALXN2220 exposure.

[0119] Figure 6 Shown are graphs visualizing cardiac amyloid changes in placebo switchers at 12 months, specifically relative change from baseline in cardiac amyloid (RCFB) derived from quantification of serial bone scintigraphy (triangles) and MRI (dots) of patients randomized to placebo. Figure 6 (A) shows RCFB at 4 months and at 12 months after switching to NI006 / ALXN2220 during the open-label extension phase. Figure 6(B) Shown are the RCFB at 12 months for patients randomized to placebo but switched to NI006 / ALXN2220 in relation to their individual cumulative NI006 / ALXN2220 exposure at 12 months.

[0120] Figure 7 Shown are graphs visualizing changes in cardiac biomarkers and echocardiographic parameters, particularly relative changes from baseline in cardiac biomarkers and echocardiographic parameters after 12 months of treatment with NI006 / ALXN2220. Figure 7 (A) Shown are the relative change from baseline (RCFB) in NT-proBNP and troponin T for each assigned NI006 / ALXN2220 dose cohort (top) and the relationship to each patient's individual cumulative NI006 / ALXN2220 exposure at 12 months (bottom). Figure 7 (B) Shown are the absolute changes from baseline (ACFB) in echocardiographic indices of cardiac structure (end-diastolic volume, ED-IVS), systolic function (left ventricular ejection fraction, LVEF, left ventricular systolic volume and left ventricular diastolic volume, LVESV and LVEDV), and diastolic function (left atrial volume, LAV and E / e' ratio).

[0121] Figure 8 The 95th percentile of serum NI006 / ALXN2220 predicted after a single dose is shown. max ( Figure 8 (A)) and median AUC 28天 Visualization diagram. 1000 simulations were performed according to dose and body weight. Observe individual C max And simulate individual AUC 28天 .

[0122] Figure 9 The predicted serum NI006 / ALXN2220 95th percentile C at steady state (9 q4w doses) is shown. max ( Figure 9 (A)) and median AUC 28天 ( Figure 9 (B) Visualization of the plot. 1000 simulations were performed according to dose and body weight. Observe individual C max And simulate individual AUC 28天 .

[0123] Figure 10Figure 3: Study schematic for the Phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of the amyloid-depleting agent ALXN2220 in adult participants with transthyretin amyloid cardiomyopathy (ATTR-CM). a Participants will receive standard of care, as determined by treating and study physicians, which may include conventional heart failure therapies and approved disease-modifying agents for ATTR amyloidosis. b Randomization will be stratified according to three factors: current treatment with a disease-modifying agent (TTR silencer ± TTR stabilizer vs. TTR stabilizer alone vs. no TTR silencer and TTR stabilizer), TTR genotype (variant vs. wild-type), and disease severity based on cardiac biomarkers (NT-proBNP > 3000 pg / mL vs. NT-proBNP ≤ 3000 pg / mL). c Safety follow-up will be conducted for up to 120 days after the last dose of study intervention. DETAILED DESCRIPTION

[0124] The present invention relates to a method for treating or preventing diseases associated with transthyretin-mediated amyloidosis (ATTR). Specifically, the present invention relates to a method for treating patients with transthyretin-mediated amyloidosis (ATTR) (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia). Human anti-thyroxine transtransferrin (TTR) antibodies for use in a method of treating or preventing a subject suffering from or at risk of suffering from a disorder or condition such as leukemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tears, and lumbar spinal stenosis), and preeclampsia, which antibodies are capable of binding to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof and do not substantially recognize physiological TTR species, wherein the method comprises administering the anti-TTR antibody or a pharmaceutical composition thereof at a dosing regimen as described herein. These methods provide for reduction of cardiac amyloid deposits in the heart. The dosing regimens described herein can provide favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties, for example, allowing for dosing of the anti-TTR antibody at a frequency of about monthly (e.g., once every 28 days ± 7 days and once every 4 weeks, respectively), and reducing the level of cardiac amyloid (e.g., misfolded TTR protein) deposits in the heart. Thus, the therapeutic regimens described herein can confer surprisingly beneficial therapeutic and prophylactic effects on subjects having or at risk of having a disease associated with ATTR (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and pre-eclampsia).

[0125] In particular, in one embodiment, the method comprises administering the antibody at a dosing regimen that results in a sustained (e.g., for a period of time, such as about 1 day to about 1 week, about 1 day to about 30 days, e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 day, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days) plasma concentration of the antibody in the subject of ≥ 1 μg / mL (e.g., about 1 μg / mL to about 1000 μg / mL).

[0126] In some embodiments, the antibody is administered to a subject at a concentration that results in a sustained plasma concentration of the antibody in the range of 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL, about 2.5 μg / mL, about 5 μg / mL, about 10 μg / mL, about 20 μg / mL, about 30 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, about 100 μg / mL, about 110 μg / mL, about 120 μg / mL, about 130 μg / mL, about 140 μg / mL, about 150 μg / mL, about 160 μg / mL, about 170 μg / mL, about 180 μg / mL, about 190 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 90 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 410 μg / mL, about 420 μg / mL, about 430 μg / mL, about 440 μg / mL, about 450 μg / mL, about 460 μg / mL, about 470 μg / mL, about 480 μg / mL, about 490 μg / mL, about 500 μg / mL, about 510 μg / mL, about 520 μg / mL, about 530 μg / mL, about 540 μg / mL, about 550 μg / mL, about 560 μg / mL, about 570 μg / mL, about 580 μg / mL, about 590 μg / mL, about 600 μg / mL, about 610 μg / mL, about 620 μg / mL, about 630 μg / mL, about 640 μg / mL, about 650 μg / mL, about 660 μg / mL, about 670 μg / mL, about 680 μg / mL, about 690 μg / mL, about 700 μg / mL, about 710 μg / mL, about 720 μg / mL, about 730 μg / mL, about 740 μg / mL, about 750 μg / mL, about 760 μg / mL, about 770 μg / mL, about 780 μg / mL, about 790 μg / mL, about 800 μg / mL, about 810 μg / mL, about 820 μg / mL, about 830 μg / mL, about 840 μg / mL, about 850 μg / mL, about 860 μg / mL, about 870 μg / mL, about 880 μg / mL, about 890 μg / mL, about 900 μg / mL, about 910 μg / mL, about 920 μg / mL, about 930 μg / mL,In some embodiments, the antibody is administered with a dosage regimen of about 10 μg / mL to about 75 μg / mL (e.g., about 10 μg / mL to about 50 μg / mL, about 20 μg / mL to about 60 μg / mL, or about 50 μg / mL to about 75 μg / mL) resulting in a sustained plasma concentration of the antibody. Alternatively, the antibody is administered with a dosage regimen of 20 μg / mL to about 200 μg / mL (e.g., about 20 μg / mL to about 100 μg / mL, about 50 μg / mL to about 150 μg / mL, or about 75 μg / mL to about 175 μg / mL) resulting in a sustained plasma concentration of the antibody. Alternatively, the antibody is administered at a dosing regimen that results in a sustained blood concentration of the antibody of 100 μg / mL to about 800 μg / mL (e.g., about 140 μg / mL to about 700 μg / mL, about 200 μg / mL to about 600 μg / mL, or about 400 μg / mL to about 800 μg / mL). For example, the trough concentration of the antibody in an approximately 40 kg to 140 kg subject receiving about 10 mg / kg of the antibody once a month is about 20 μg / mL to 100 μg / mL. In another embodiment, the trough concentration of the antibody in an approximately 40 kg to 140 kg subject receiving about 60 mg / kg of the antibody once a month is about 140 μg / mL to 700 μg / mL.

[0127] The invention further relates to a human anti-transthyretin (TTR) antibody that binds to mutated, misfolded, misassembled and / or aggregated TTR species and / or fragments thereof, and does not substantially recognize physiological TTR species, for use in treating or preventing a subject having or at risk of having transthyretin-mediated amyloidosis (ATTR) by administering the antibody at a dosing regimen that results in a sustained plasma concentration of the antibody in the subject with an area under the curve (AUC) of about 2,000 μg*day / mL to about 100,000 μg*day / mL, e.g., at least 30,000 μg*day / mL (e.g., the area under the plasma drug concentration-time curve in the subject after, e.g., 17 weeks to 50 weeks of treatment / dosing).

[0128] In some embodiments, the anti-TTR antibody is administered at a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., the area under the plasma drug concentration-time curve in a subject after 17 weeks of treatment / dosing) of about 2,000 μg*day / mL to about 50,000 μg*day / mL (e.g., about 2,000 μg*day / mL, about 2,500 μg*day / mL, about 3,000 μg*day / mL, about 3,500 μg*day / mL, about 4,000 μg*day / mL, about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 12,000 μg*day / mL, about 13,000 μg*day / mL, about 14,000 μg*day / mL, about 15,000 μg*day / mL, about 16,000 μg*day / mL, about 17,000 μg*day / mL, about 18,000 μg*day / mL, about 19,000 μg*day / mL, about 20,000 μg*day / mL, about 21,000 μg*day / mL, about 23,000 μg*day / mL, about 24,000 μg*day / mL, about 25,000 μg*day / mL, about 26,000 μg*day / mL, about 27,000 μg*day / mL, about 28,000 μg*day / mL, about 29,000 μg*day / mL, about 3 00 μg*day / mL, about 4,000 μg*day / mL, about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about 40,000 μg*day / mL, or about 50,000 μg*day / mL).

[0129] Alternatively, the anti-TTR antibody is administered at a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., the area under the plasma drug concentration-time curve in a subject after 50 weeks of treatment / dosing) of about 2,500 μg*day / mL to about 100,000 μg*day / mL, about 5,000 μg*day / mL to about 100,000 μg*day / mL, or about 10,000 μg*day / mL to about 100,000 μg*day / mL (e.g., about 2,500 μg*day / mL, about 3,000 μg*day / mL, about 3,500 μg*day / mL, about 4,000 μg*day / mL, about 5,000 μg*day / mL, or about 10,000 μg*day / mL to about 100,000 μg*day / mL in a subject). , about 80,000 μg*day / mL, about 90,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about 40,000 μg*day / mL, about 50,000 μg*day / mL, about 60,000 μg*day / mL, about 70,000 μg*day / mL, about 80,000 μg*day / mL, about 90,000 μg*day / mL or about 100,000 μg*day / mL).

[0130] In some embodiments, administration of an anti-TTR antibody according to the invention can be used for long-term treatment and / or for subsequent treatment after an initial higher dose and amyloid removal (e.g., at a dose sufficient to achieve a sustained plasma concentration of about 1 μg / mL, 2.5 μg / mL, or 5 μg / mL).

[0131] In a preferred embodiment, the anti-TTR antibody for use according to the invention is administered at a dose of about 0.3 mg / kg to about 60 mg / kg (e.g., 0.3 mg / kg to 60 mg / kg, 0.3 mg / kg to 30 mg / kg, 0.3 mg / kg to 1 mg / kg, 1 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, or 50 mg / kg to 60 mg / kg).

[0132] Alternatively, the anti-TTR antibodies used according to the invention are administered at a dose of about 0.3 mg / kg to about 30 mg / kg (e.g., 0.3 mg / kg to 20 mg / kg, 0.3 mg / kg to 10 mg / kg, 1 mg / kg to 15 mg / kg, 5 mg / kg to 15 mg / kg, 15 mg / kg to 20 mg / kg, 15 mg / kg to 25 mg / kg, or 25 mg / kg to 30 mg / kg).

[0133] In some embodiments, the anti-TTR antibody is administered at a dose of about 0.3 mg / kg.

[0134] In some embodiments, the anti-TTR antibody is administered at a dose of about 1 mg / kg.

[0135] In some embodiments, the anti-TTR antibody is administered at a dose of about 3 mg / kg.

[0136] In some embodiments, the anti-TTR antibody is administered at a dose of about 10 mg / kg.

[0137] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0138] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg to about 80 mg / kg (e.g., 30 mg / kg to 40 mg / kg, 30 mg / kg to 50 mg / kg, 30 mg / kg to 60 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 40 mg / kg to 60 mg / kg, 40 mg / kg to 70 mg / kg, 40 mg / kg to 80 mg / kg, 50 mg / kg to 60 mg / kg, 50 mg / kg to 70 mg / kg, or 50 mg / kg to 80 mg / kg).

[0139] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0140] In some embodiments, the anti-TTR antibody is administered at a dose of about 40 mg / kg.

[0141] In some embodiments, the anti-TTR antibody is administered at a dose of about 50 mg / kg.

[0142] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0143] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg and results in a sustained plasma concentration of the antibody in the subject of about 50 μg / mL.

[0144] In some embodiments, the anti-TTR antibody is administered at a dose of about 10 mg / kg and results in a sustained plasma concentration of the antibody in the subject of about 20 μg / mL to about 100 μg / mL.

[0145] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg and results in a sustained plasma concentration of the antibody in the subject of about 65 μg / mL to about 350 μg / mL.

[0146] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg and results in a sustained plasma concentration of the antibody in the subject of about 140 μg / mL to about 700 μg / mL.

[0147] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0148] In some embodiments, anti-TTR is first administered at a dose of about 0.3 mg / kg to about 10 mg / kg (e.g., about 0.3 mg / kg to 1 mg / kg, 0.5 mg / kg to 2 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 3 mg / kg to 8 mg / kg, 5 mg / kg to 10 mg / kg, or 8 mg / kg to 10 mg / kg).

[0149] In some embodiments, the anti-TTR antibody is further administered at a maintenance dose of about 10 mg / kg to about 60 mg / kg (e.g., 10 mg / kg to 20 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 20 mg / kg to 50 mg / kg, or 30 mg / kg to 60 mg / kg). In a preferred embodiment of the invention, the anti-TTR antibody is administered initially at a dose of about 0.3 mg / kg to about 10 mg / kg (e.g., about 0.3 mg / kg to 1 mg / kg, 0.5 mg / kg to 2 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 3 mg / kg to 8 mg / kg, 5 mg / kg to 10 mg / kg, or 8 mg / kg to 10 mg / kg) and further administered at a maintenance dose of about 10 mg / kg to about 60 mg / kg (e.g., 10 mg / kg to 20 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 20 mg / kg to 50 mg / kg, or 30 mg / kg to 60 mg / kg).

[0150] As described above, the anti-TTR antibodies used according to the present invention deplete amyloid thyroxine transporter from cardiac tissue in a dose- and time-dependent manner, with the most significant effect at doses greater than 10 mg / kg when administered once every four weeks. Thus, in a preferred embodiment, the anti-TTR antibody is administered at a dose greater than 10 mg / kg, such as 10 mg / kg to 100 mg / kg, preferably 10 mg / kg to 60 mg / kg, more preferably 30 mg / kg or 60 mg / kg, preferably wherein the antibody is administered once every four weeks (q4w). Furthermore, data from bone scintigraphy and MRI indicated that doses of 30 mg / kg and 60 mg / kg reduced cardiac amyloid deposition by a median of 12.8% and 25.6% compared to baseline at 4 months; at 12 months, the median reductions were 30.7% and 50.7%, respectively. In the same patients, NT-proBNP was reduced by 78.2% and 72.2% at 12 months.

[0151] Therefore, in another preferred embodiment of the invention, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0152] In another preferred embodiment of the invention, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0153] Thus, the treatment or prevention method according to the invention preferably comprises administering the antibody at a dose of greater than 10 mg / kg, such as from 10 mg / kg to 100 mg / kg, preferably from 10 mg / kg to 60 mg / kg, more preferably at a dose of 30 mg / kg or 60 mg / kg, preferably wherein the antibody is administered once every 4 weeks (q4w).

[0154] Based on the results of the mg / kg doses in the safety and efficacy studies, modeling was performed to calculate a fixed dose that is more convenient to administer and is therefore a preferred embodiment of the present invention. In particular, a PK / PD model was established and a safe and effective fixed dose in the range of 600 mg to 7500 mg was calculated; see Examples 5 and 6.

[0155] Thus, in one embodiment of the invention, the anti-TTR antibody is administered at a dosage of about 600 mg to about 7500 mg (e.g., 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 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, mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 500 0mg, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6050mg, 6100mg , 6150mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 63 In some embodiments, the maintenance dose is about 2500 mg, for example, preferably 2400 mg. In another preferred embodiment, the maintenance dose is about 3000 mg. In a most preferred embodiment, the maintenance dose is about 3500 mg, for example, preferably 3200 mg.

[0156] In some embodiments, an anti-TTR antibody is administered at a dosage of about 600 mg to about 7500 mg (e.g., 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 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, 260 0mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800mg, 3900mg or 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5 100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6050mg, 6100mg, 615 0mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 6350mg , 6400 mg, 6450 mg, 6500 mg, 6550 mg, 6600 mg, 6650 mg, 6700 mg, 6750 mg, 6800 mg, 6850 mg, 6900 mg, 6950 mg, 7000 mg, 7050 mg, 7100 mg, 7150 mg, 7200 mg, 7250 mg, 7300 mg, 7350 mg, 7400 mg, 7450 mg or 7500 mg).

[0157] Preferably, the anti-TTR antibody is administered with a loading dose of about 600 mg to about 4000 mg (e.g., 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 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, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, or 4000 mg).

[0158] In a preferred embodiment, the loading dose is about 2500 mg, such as preferably 2400 mg. In another preferred embodiment, the loading dose is about 3000 mg. In a most preferred embodiment, the loading dose is about 3500 mg, such as preferably 2400 mg.

[0159] Preferably, according to the present invention, the anti-TTR antibody is administered at a maintenance dose of about 600 mg to about 7500 mg, prior to which the anti-TTR antibody is administered at a loading dose of about 600 mg to about 7500 mg, preferably about 600 mg to about 4000 mg. In an optional embodiment, the loading dose is administered every other week for up to two months prior to the maintenance dose.

[0160] In further preferred embodiments, the maintenance or loading dose of the anti-TTR antibody is about 3000 mg, more preferably about 3500 mg, and most preferably about 3200 mg.

[0161] In further preferred embodiments, the maintenance and loading doses of the anti-TTR antibody are about 3000 mg, more preferably about 3500 mg, and most preferably about 3200 mg.

[0162] In some embodiments of the invention, anti-TTR is administered at a dosage of 600 mg to 7500 mg (e.g., 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 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, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 600 600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 380 0mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000m g, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6050mg, 6100mg, 6150mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 63 In a preferred embodiment, the dosage is about 2500 mg, 3000 mg, 3500 mg or 5000 mg, i.e., preferably a dosage of 2200 mg, 3200 mg or 4800 mg.

[0163] Using the above PK / PD model, it was further found that a fixed dose (but dependent on the patient's weight) was most conducive to achieving the safest and most effective treatment; see Figure 8 and Figure 9 And Example 5.

[0164] Thus, in one embodiment of the invention, the anti-TTR antibody is administered at a dose of 2000 mg to 2500 mg to a patient weighing about 40 kg to about ≤60 kg. In one embodiment, the anti-TTR antibody is administered at a dose of 2000 mg or 2500 mg to a patient weighing about 40 kg to about ≤60 kg. In a preferred embodiment, the anti-TTR antibody is administered at a dose of 2500 mg to a patient weighing about 40 kg to about ≤60 kg. In one embodiment of the invention, the anti-TTR antibody is administered at a dose of 3000 mg to 3500 mg to a patient weighing about ≥60 kg to about 100 kg. In one embodiment, the anti-TTR antibody is administered at a dose of 3000 mg or 3500 mg to a patient weighing about ≥60 kg to about 100 kg. In a preferred embodiment, the anti-TTR antibody is administered at a dose of 3500 mg to a patient weighing about ≥60 kg to about 100 kg. In one embodiment of the invention, the anti-TTR antibody is administered to a patient weighing about ≤100 kg at a dose of 4000 mg to 5000 mg. In one embodiment, the anti-TTR antibody is administered to a patient weighing about ≤100 kg at a dose of 4000 mg, 4500 mg, or 5000 mg. In a preferred embodiment, the anti-TTR antibody is administered to a patient weighing about ≤100 kg at a dose of 4000 mg or 5000 mg, and most preferably, the anti-TTR antibody is administered to a patient weighing about ≤100 kg at a dose of 5000 mg.

[0165] As explained in Example 6, based on data from the Phase I clinical trial, the above-described PK / PD model has been further refined to ensure administration of the full amount of drug present in each vial and eliminate residual amounts and corresponding drug waste, while maintaining the same desired level of efficacy. Specifically, the PK / PD model has been used to develop slightly lower fixed doses, which also improve patient convenience because lower amounts of drug are administered and infused separately. These fixed doses were used in the Phase III clinical trial, as outlined in Example 8.

[0166] Thus, in a preferred embodiment of the invention, the anti-TTR antibody is administered to a patient weighing approximately ≥40 kg to <60 kg at a dose ranging from 2200 mg to 2700 mg (inclusive). In a preferred embodiment, the anti-TTR antibody is administered to a patient weighing approximately ≥40 kg to <60 kg at a dose of 2400 mg. In one embodiment of the invention, the anti-TTR antibody is administered to a patient weighing approximately ≥60 kg to <100 kg at a dose of 3000 mg to 3500 mg. In a preferred embodiment, the anti-TTR antibody is administered to a patient weighing approximately ≥60 kg to <100 kg at a dose of 3200 mg. In one embodiment of the invention, the anti-TTR antibody is administered to a patient weighing approximately ≤100 kg at a dose of 4400 mg to 5200 mg. In a preferred embodiment, the anti-TTR antibody is administered to a patient weighing approximately ≤100 kg at a dose of 4800 mg.

[0167] In some embodiments, the anti-TTR antibody is administered to the subject once every 3 to 56 days, preferably once every 3 to 35 days, e.g., once every 7 to 35 days, e.g., once every 21 to 35 days (e.g., 22 to 34 days, 23 to 33 days, 24 to 32 days, 25 to 31 days, 23 to 33 days, or 27 to 35 days). In some embodiments, the anti-TTR antibody is administered once a week via subcutaneous infusion or continuous infusion via a pump.

[0168] In some embodiments, the anti-TTR antibody is administered to the subject once every 28 to 35 days (e.g., 28 to 30 days, 29 to 34 days, 30 to 33 days, or 30 to 32 days).

[0169] In some embodiments, the anti-TTR antibody is administered to the subject once every 28 days.

[0170] In some embodiments, the anti-TTR antibody is administered to the subject once every 35 days. In preferred embodiments, the anti-TTR antibody is administered to the subject once every 28 days. Preferably, the anti-TTR antibody is administered once every 4 weeks (q4w).

[0171] Thus, in one embodiment, the anti-TTR antibody is administered once every 28 days at a dose of 30 mg / kg.

[0172] In one embodiment, the anti-TTR antibody is administered once every 35 days at a dose of 30 mg / kg.

[0173] In one embodiment, the anti-TTR antibody is administered once every 4 weeks (q4w) at a dose of 30 mg / kg.

[0174] In one embodiment, the anti-TTR antibody is administered once every 28 days at a dose of 60 mg / kg.

[0175] In one embodiment, the anti-TTR antibody is administered once every 35 days at a dose of 60 mg / kg.

[0176] In one embodiment, the anti-TTR antibody is administered once every 4 weeks (q4w) at a dose of 60 mg / kg.

[0177] In one embodiment, the anti-TTR antibody is administered at a dose of 2500 mg once every 28 days to a patient weighing 40 kg to ≤ 60 kg.

[0178] In one embodiment, the anti-TTR antibody is administered at a dose of 2500 mg once every 35 days to a patient weighing 40 kg to ≤ 60 kg.

[0179] In one embodiment, the anti-TTR antibody is administered at a dose of 2500 mg once every 4 weeks (q4w) to patients weighing 40 kg to ≤60 kg.

[0180] In one embodiment, the anti-TTR antibody is administered at a dose of 2400 mg once every 28 days to a patient weighing 40 kg to ≤ 60 kg.

[0181] In one embodiment, the anti-TTR antibody is administered at a dose of 2400 mg once every 35 days to a patient weighing 40 kg to ≤ 60 kg.

[0182] In one embodiment, the anti-TTR antibody is administered at a dose of 2400 mg once every 4 weeks (q4w) to patients weighing 40 kg to ≤ 60 kg.

[0183] In one embodiment, the anti-TTR antibody is administered at a dose of 3500 mg once every 28 days to patients weighing ≥60 kg to 100 kg.

[0184] In one embodiment, the anti-TTR antibody is administered at a dose of 3500 mg once every 35 days to patients weighing ≥60 kg to 100 kg.

[0185] In one embodiment, the anti-TTR antibody is administered at a dose of 3500 mg once every 4 weeks (q4w) to patients weighing ≥60 kg to 100 kg.

[0186] In one embodiment, the anti-TTR antibody is administered at a dose of 3200 mg once every 28 days to patients weighing ≥60 kg to 100 kg.

[0187] In one embodiment, the anti-TTR antibody is administered at a dose of 3200 mg once every 35 days to patients weighing ≥60 kg to 100 kg.

[0188] In one embodiment, the anti-TTR antibody is administered at a dose of 3200 mg once every 4 weeks (q4w) to patients weighing ≥60 kg to 100 kg.

[0189] In one embodiment, the anti-TTR antibody is administered at a dose of 5000 mg once every 28 days to patients weighing ≥ 100 kg.

[0190] In one embodiment, the anti-TTR antibody is administered at a dose of 5000 mg once every 35 days to patients weighing ≥ 100 kg.

[0191] In one embodiment, the anti-TTR antibody is administered at a dose of 5000 mg once every 4 weeks (q4w) to patients weighing ≥ 100 kg.

[0192] In one embodiment, the anti-TTR antibody is administered at a dose of 4800 mg once every 28 days to patients weighing ≥ 100 kg.

[0193] In one embodiment, the anti-TTR antibody is administered at a dose of 4800 mg once every 35 days to patients weighing ≥ 100 kg.

[0194] In one embodiment, the anti-TTR antibody is administered at a dose of 4800 mg once every 4 weeks (q4w) to patients weighing ≥100 kg.

[0195] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months to 30 months (e.g., 4 months to 12 months, 8 months to 16 months, 12 months to 20 months, 16 months to 24 months, or 20 months to 30 months).

[0196] In some embodiments, the anti-TTR antibody is administered to the subject for about 12 months to 18 months (e.g., 12 months to 15 months, 13 months to 16 months, 14 months to 17 months, or 15 months to 18 months).

[0197] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months.

[0198] In some embodiments, the anti-TTR antibody is administered to the subject for about 11 months.

[0199] In some embodiments, the anti-TTR antibody is administered to the subject for about 24 months to 48 months, but at least 24 months.

[0200] In some embodiments, the anti-TTR antibody is administered to a subject at a dose of about 30 mg / kg or 60 mg / kg for about 12 months to 18 months (e.g., 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months).

[0201] In some embodiments, the anti-TTR antibody is administered to a subject at a dose of about 30 mg / kg to 60 mg / kg once every 21 to 35 days for about 12 months to 18 months (e.g., about 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months).

[0202] In some embodiments, a loading dose is administered once every other week for up to two months prior to administration of a maintenance dose. In some embodiments, the maintenance dose is lower than the loading dose.

[0203] In some embodiments, the anti-TTR antibody is administered for up to 24 months according to the intervention infusion (i.e., intravenous administration of the anti-ATTR antibody) schedule provided in Table 25. In additional embodiments, after the 24-month treatment period, the anti-TTR antibody is administered as a subsequent treatment according to the intervention infusion schedule of Table 26.

[0204] In some embodiments, the plasma concentration of the anti-TTR antibody is maintained at about 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL to about 100 μg / mL, about 2.5 μg / mL to about 125 μg / mL, about 5 μg / mL to about 150 μg / mL, about 10 μg / mL to about 200 μg / mL, about 65 μg / mL to about 350 μg / mL, about 20 μg / mL to about 200 μg / mL, about 20 μg / mL to about 100 μg / mL, about 50 μg / mL to about 150 μg / mL, or about 75 μg / mL to about 175 μg / mL, about 100 μg / mL to about 800 μg / mL, about 140 μg / mL to about 700 μg / mL, about 200 μg / mL to about 600 μg / mL, or about 400 μg / mL to about 800 μg / mL).For example, about 10 μg / mL, about 20 μg / mL, about 30 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, about 100 μg / mL, about 110 μg / mL, about 120 μg / mL, about 130 μg / mL, about 140 μg / mL, about 150 μg / mL, about 160 μg / mL, about 170 μg / mL, about 180 μg / mL, about 190 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL. / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 410 μg / mL, about 420 μg / mL, about 430 μg / mL, about 440 μg / mL, about 450 μg / mL, about 460 μg / mL, about 470 μg / mL, about 480 μg / mL, about 490 μg / mL, about 500 μg / mL, about 510 μg / mL g / mL, about 520 μg / mL, about 530 μg / mL, about 540 μg / mL, about 550 μg / mL, about 560 μg / mL, about 570 μg / mL, about 580 μg / mL, about 590 μg / mL, about 600 μg / mL, about 610 μg / mL, about 620 μg / mL, about 630 μg / mL, about 640 μg / mL, about 650 μg / mL, about 660 μg / mL, about 670 μg / mL, about 680 μg / mL, about 690 μg / mL, about 700 μg / mL, about 710 μg / mL, about 720 μg / mL, about 730 μg / mL, about 740 μg / mL, about 750 μg / mL, about 760 about 900 μg / mL, about 910 μg / mL, about 920 μg / mL, about 930 μg / mL, about 940 μg / mL, about 950 μg / mL, about 960 μg / mL, about 970 μg / mL, about 980 μg / mL, about 990 μg / mL, or about 1000 μg / mL),For about 1 day to about 30 days (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days).

[0205] In some embodiments, the plasma concentration is maintained at about 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL to about 100 μg / mL, about 2.5 μg / mL to about 125 μg / mL, about 5 μg / mL to about 150 μg / mL, about 10 μg / mL to about 200 μg / mL, about 65 μg / mL to about 350 μg / mL, about 20 μg / mL to about 200 μg / mL, about 20 μg / mL to about 100 μg / mL, about 50 μg / mL to about 150 μg / mL, or about 75 μg / mL to about 175 μg / mL, about 100 μg / mL to about 800 μg / mL, about 140 μg / mL to about 700 μg / mL, about 200 μg / mL to about 600 μg / mL, or about 400 μg / mL to about 800 μg / mL,For example, about 10 μg / mL, about 20 μg / mL, about 30 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, about 100 μg / mL, about 110 μg / mL, about 120 μg / mL, about 130 μg / mL, about 140 μg / mL, about 150 μg / mL, about 160 μg / mL, about 170 μg / mL, about 180 μg / mL, about 190 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL. / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 410 μg / mL, about 420 μg / mL, about 430 μg / mL, about 440 μg / mL, about 450 μg / mL, about 460 μg / mL, about 470 μg / mL, about 480 μg / mL, about 490 μg / mL, about 500 μg / mL, about 510 μg / mL g / mL, about 520 μg / mL, about 530 μg / mL, about 540 μg / mL, about 550 μg / mL, about 560 μg / mL, about 570 μg / mL, about 580 μg / mL, about 590 μg / mL, about 600 μg / mL, about 610 μg / mL, about 620 μg / mL, about 630 μg / mL, about 640 μg / mL, about 650 μg / mL, about 660 μg / mL, about 670 μg / mL, about 680 μg / mL, about 690 μg / mL, about 700 μg / mL, about 710 μg / mL, about 720 μg / mL, about 730 μg / mL, about 740 μg / mL, about 750 μg / mL, about 760 about 900 μg / mL, about 910 μg / mL, about 920 μg / mL, about 930 μg / mL, about 940 μg / mL, about 950 μg / mL, about 960 μg / mL, about 970 μg / mL, about 980 μg / mL, about 990 μg / mL, or about 1000 μg / mL),Lasts from about 1 day to about 1 week.

[0206] In some embodiments, administration of an anti-TTR antibody or antigen-binding fragment thereof is monitored by measuring the level of at least one biomarker, e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP) or a fragment thereof. Additionally or alternatively, administration of an anti-TTR antibody is monitored by measuring the level of one or more biomarkers, e.g., cardiac troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) or a fragment thereof. These biomarkers, particularly NT-proBNP and / or fragments thereof, are recognized in the art as useful for monitoring the progress of ATTR treatment; see, e.g., Perfetto et al., Internal and Emergency Medicine 17 (2022), 957–969 (incorporated herein by reference).

[0207] Thus, in one embodiment, a decrease in the level of a biomarker is indicative of therapeutic efficacy.

[0208] In some embodiments, the subject has an N-terminal pro-b-type natriuretic peptide (NT-proBNP) level of about 300 pg / mL to about 20,000 pg / mL before undergoing the treatment methods described herein. In some embodiments, the subject has an N-terminal pro-b-type natriuretic peptide (NT-proBNP) level of about 0 pg / mL to about 300 pg / mL after undergoing the treatment methods described herein.

[0209] In some embodiments, the subject has a cardiac troponin T (TnT) level of about 10 pg / mL to about 200 pg / mL before undergoing the treatment methods described herein. In some embodiments, the subject has a cardiac troponin T (TnT) level of 0 pg / mL to about 10 pg / mL after undergoing the treatment methods described herein. In a preferred embodiment, the subject has an N-terminal pro-b-type natriuretic peptide (NT-proBNP) level of >2000 pg / mL.

[0210] In one embodiment of the invention, administration of an anti-TTR antibody according to the invention is further accompanied by determining the level of C-reactive protein (CRP), wherein a dose-dependent, transient (e.g., lasting from about 1 day to about 14 days, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days) increase in CRP levels is indicative of target immune activation and efficacy of treatment. Thus, CRP can be used as a biomarker, and a dose-dependent, transient increase in CRP levels is indicative of target immune activation and efficacy of treatment.

[0211] In some embodiments, administration of an anti-TTR antibody results in a reduction in cardiac amyloid burden, as determined, for example, by magnetic resonance imaging (MRI).

[0212] In some embodiments, administration of the anti-TTR antibody results in a reduction in heart mass, e.g., as measured by echocardiography or cardiac MRI.

[0213] In some embodiments, administration of an anti-TTR antibody results in improved cardiovascular function (e.g., diastolic myocardial relaxation, atrioventricular (AV) flow, global longitudinal strain (GLS), ventricular ejection fraction, or end-diastolic volume), e.g., as assessed by echocardiography. For example, echocardiography can be used to measure the ratio of the early diastolic mitral inflow velocity to the early diastolic mitral annular motion velocity (E / e' ratio) to assess cardiovascular function.

[0214] Clinical trial analysis conducted within the scope of the present invention surprisingly revealed that after administration of 30 mg / kg or 60 mg / kg of anti-TTR antibody to patients, cardiac amyloid deposition was reduced (see Example 1) and CRP levels transiently increased in a dose-dependent manner. Furthermore, it was shown for the first time that therapeutic intervention resulted in substantial and sustained amyloid depletion, supporting preclinical data demonstrating the ability of NI006 / ALXN2220 to induce transthyretin amyloid degradation. While not being bound by a particular mechanism or theory, this TTR amyloid degradation effect of NI006 / ALXN2220 may be mediated through recruitment of phagocytes via its Fc-effector function.

[0215] Therefore, due to this observation, CRP can serve as a biomarker for monitoring the success of treatment of amyloidosis, particularly for monitoring the depletion of TTR via phagocytosis to treat amyloidosis. This effect is particularly significant after the first administration of the antibody. The transient CRP response observed with anti-TTR antibodies is mostly asymptomatic. CRP is a cyclic pentameric protein found in plasma, the circulating concentration of which increases, for example, in response to inflammation. The amino acid sequence of CRP is publicly available, see, for example, UniProt Reference: P02741CRP_HUMAN. Early CRP kinetics have been described as a possible therapeutic biomarker to predict the response to the first-line immune checkpoint blockade (IO) combination therapy for metastatic renal cell carcinoma (mRCC); see Klümper et al., Clinical & Translational Immunology 10 (2021), e1358. However, the observation that CRP kinetics is accompanied by phagocytosis to remove amyloid in a transient and dose-dependent manner has not been reported or proposed before.

[0216] Thus, in a further aspect, the present invention relates to CRP as a biomarker for targeting immune activation and / or for monitoring the efficacy of a treatment for an amyloidosis, preferably a systemic amyloidosis, preferably ATTR, most preferably ATTR-CM. In another preferred embodiment, CRP is used as a biomarker for monitoring the treatment of an amyloidosis, preferably a systemic amyloidosis, preferably ATTR, most preferably ATTR-CM, wherein the treatment is performed by depleting TTR via phagocytosis. More particularly, the present invention relates to the use of CRP as a biomarker for targeting immune activation and / or for monitoring the efficacy of a treatment for the above-mentioned amyloidosis, such as ATTR, preferably ATTR-CM, with an amyloid depletion agent, such as a therapeutic agent capable of depleting amyloid deposits, preferably cardiac amyloid deposits, preferably via phagocytosis. In a preferred embodiment, the therapeutic agent / amyloid depletion agent is an anti-TTR antibody as defined herein.

[0217] In this regard, the present invention further relates to a method for monitoring the efficacy of treating amyloidosis as described above, preferably systemic amyloidosis, more preferably ATTR, and most preferably ATTR-CM, with an amyloid depleting agent (e.g., a therapeutic agent capable of depleting amyloid deposits, preferably cardiac amyloid deposits, preferably via phagocytosis), wherein the method comprises determining the level of CRP in a sample from a subject undergoing treatment, preferably wherein the CRP level is determined at a first time point, e.g., before administration of the amyloid depleting agent, and at least a second time point (e.g., a time point after administration of the amyloid depleting agent), wherein an increase in the CRP level in the sample at the second time point compared to the sample at the first time point indicates efficacy of the treatment. In a preferred embodiment, the second time point is after the first administration of the amyloid depleting agent. In a preferred embodiment, the amyloid depleting agent is anti-TTR, preferably as defined herein, and most preferably formulated as described herein and provided in a specific dose as described herein. The sample can be any tissue or preferably a body fluid, such as blood, in which CRP is present.

[0218] The present invention further relates to a kit comprising reagents for detecting and measuring CRP levels in patient samples, which is particularly useful for monitoring the therapeutic efficacy of therapeutic agents / amyloid depleting agents as described above. In a preferred embodiment, the kit comprises non-immune and / or immune reagents for detecting CRP, such as anti-CRP antibodies, nucleic acid probes, or PC conjugates containing multiple copies of covalently coupled phosphorylcholine (PC) moieties. The kit may also include reagents and / or instructions for use. Preferably, the amyloid depleting agent / therapeutic agent whose efficacy is monitored is an anti-TTR antibody as described herein, and is administered at a specified dose. Means and methods for detecting CRP are known to those skilled in the art.

[0219] The present invention further relates to an article of manufacture, such as a kit, preferably a therapeutic kit, which provides an effective dose of an anti-TTR antibody as described herein, preferably a dose of 30 mg / kg or 60 mg / kg, and a fixed dose of 2500 mg, 3500 mg and 5000 mg, respectively, optionally comprising an agent for delivering said dose, such as in the form of a formulation. Most preferably, the therapeutic kit of the present invention provides a fixed dose of 2400 mg, 3200 mg and / or 4800 mg. Thus, the kit preferably comprises one or more containers, wherein the container comprises a formulation of an anti-TTR antibody as defined above, preferably a formulation of the antibody NI006 / ALXN2022 as defined above by its CDR, VH and VL regions and by its heavy and light chains, respectively, wherein the container comprises 2400 mg, 3200 mg or 4800 mg of the antibody, or multiple doses of the antibody, such as 4800 mg, 6400 mg, 9600 mg or 7200 mg, 9600 mg or 14400 mg, etc. The kit preferably further comprises a device for delivering the antibody to a subject, wherein the device preferably comprises an infusion bag and / or a syringe.

[0220] Thus, the kit may include an anti-TTR antibody, for example, provided in a container such as a vial, optionally an infusion bag to which the antibody is added, optionally an infusion solution and / or a diluent (e.g., a formulation, and more preferably glucose). The kit may also include a means for detecting biomarkers for monitoring therapeutic efficacy, preferably cardiac troponin T (TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and / or C-reactive protein (CRP). Alternatively, the kit of the present invention may also include a means for detecting at least N-terminal pro-B-type natriuretic peptide (NT-proBNP). In one embodiment, the article of manufacture may include an anti-TTR antibody and the above-mentioned kit for detecting CRP.

[0221] The present invention also relates to an article of manufacture comprising one or more containers as defined above for a kit and a label indicating that the antibody is suitable for treating cardiomyopathy due to wild-type or hereditary transthyretin-mediated amyloidosis in adults. Alternatively, the label indicates a dosing regimen according to the present invention, preferably a fixed dose regimen.

[0222] In some embodiments, the anti-TTR antibody or antigen-binding fragment thereof is provided in an aqueous formulation at a concentration of about 25 mg / mL to 200 mg / mL (e.g., 25 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, or 200 mg / mL), and the aqueous solution can be diluted prior to administration. In some embodiments, the anti-TTR antibody is administered at a diluted concentration of about 1 mg / mL to about 50 mg / mL (e.g., about 1 mg / mL to about 42 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 10 mg / mL, such as about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about The invention relates to an aqueous formulation of a pharmaceutical composition comprising: a) about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL) to a subject.

[0223] In some embodiments, the subject has been previously treated with a TTR tetramer stabilizer and / or is concurrently receiving a TTR tetramer stabilizer. For example, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, tafamidis, and aclometrexate (AG10).

[0224] In some embodiments, the anti-TTR antibody is administered to a subject by intravenous infusion in an aqueous formulation, wherein the aqueous formulation has a pH of about 5.0 to 6.5, comprises a histidine buffer, a sugar (such as sucrose), and a surfactant (such as polysorbate 80 (PS80)), and wherein the anti-TTR antibody is present in the aqueous formulation at a concentration of about 25 mg / mL to 125 mg / mL.

[0225] In some embodiments, the aqueous formulation has a pH of about 5.8 and comprises 20 mM histidine (e.g., histidine hydrochloride, e.g., L-histidine and / or L-histidine monohydrochloride), 6.5% weight / volume (w / v) sucrose, and 0.03% PS80 w / v, and wherein the antibody is present in the aqueous formulation at a concentration of about 50 mg / mL or about 100 mg / mL.

[0226] In some embodiments, the aqueous formulation has a pH of about 5.8 and comprises 20 mM histidine (e.g., histidine hydrochloride, e.g., L-histidine and / or L-histidine monohydrochloride), 8% weight / volume (w / v) sucrose, and 0.03% PS80 w / v, and wherein the anti-TTR antibody is present in the aqueous formulation at a concentration of about 50 mg / mL or about 100 mg / mL, preferably about 50 mg / mL.

[0227] In some embodiments, the anti-TTR antibody is administered to the subject in a diluted form including a diluent.

[0228] In some embodiments, the diluent is glucose or a polymer thereof (e.g., the polymer is dextran). Glucose or a polymer thereof (e.g., dextran) can be used as a diluent at a concentration of about 1% w / v, 2% w / v, 3% w / v, 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, or 10% w / v.

[0229] In some embodiments, the infusion line is flushed with a diluent before and after the intravenous infusion.

[0230] In some embodiments, intravenous infusion is performed using a syringe pump or an infusion pump with an infusion syringe. In one embodiment, a total antibody dose of up to 100 mg is administered by infusion, e.g., a syringe pump with an infusion syringe. In one embodiment, a total antibody dose of greater than 100 mg is administered using an infusion pump. In one embodiment, the anti-TTR antibody is diluted into an infusion bag prefilled with a diluent.

[0231] In some embodiments, the infusion syringe includes a minimum administration volume of 10 mL of the aqueous formulation.

[0232] In some embodiments, the total volume of diluted form administered to a subject does not exceed 200 mL (e.g., about 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 55 mL, 60 mL, 65 mL, 70 mL, 75 mL, 80 mL, 85 mL, 90 mL, 95 mL, 100 mL, 105 mL, 110 mL, 115 mL, 120 mL, 125 mL, 130 mL, 135 mL, 140 mL, 145 mL, 150 mL, 155 mL, 160 mL, 165 mL, 170 mL, 175 mL, 180 mL, 185 mL, 190 mL, 195 mL, or 200 mL), including the flush volume. For example, in some embodiments, the total volume of a single administration does not exceed 200 mL.

[0233] In some embodiments, at least for the first infusion, the aqueous formulation is administered within about 2 hours (± 10 minutes).

[0234] In some embodiments, the aqueous formulation is administered within about 1 hour (± 10 minutes).

[0235] In some embodiments, ATTR amyloidosis causes cardiomyopathy (CM), and thus, in a preferred embodiment, the subject treated according to the present invention has ATTR amyloidosis with CM (ATTR-CM). In some embodiments, the subject has ATTR polyneuropathy (ATTR-PN). In some embodiments, the subject has familial amyloid polyneuropathy (FAP). In some embodiments, the subject has familial amyloid cardiomyopathy (FAC). In some embodiments, the subject has senile systemic amyloidosis (SSA). In some embodiments, the subject has systemic familial amyloidosis. In some embodiments, the subject has leptomeningeal / central nervous system (CNS) amyloidosis. In some embodiments, the subject has Alzheimer's disease. In some embodiments, the subject has TTR-related ocular amyloidosis. In some embodiments, the subject has TTR-related renal amyloidosis. In some embodiments, the subject has TTR-related hyperthyroxinemia. In some embodiments, the subject has TTR-related ligamentous amyloidosis, including carpal tunnel syndrome. In some embodiments, the subject has a rotator cuff tear and lumbar spinal stenosis. In some embodiments, the subject has preeclampsia.

[0236] In some embodiments, the subject is diagnosed with hereditary ATTR-CM due to a known pathogenic TTR mutation.

[0237] In some embodiments, the subject has sporadic, wild-type ATTR-CM (WT-ATTR-CM) (e.g., a wild-type ATTR gene that encodes a TTR protein that forms deposits in the heart) and has a negative genetic test for a TTR mutation.

[0238] Preferably, the diagnosis is based on evidence of cardiac amyloidosis by echocardiography or cMRI and one of the following: (a) endomyocardial biopsy with confirmatory TTR amyloid typing by immunohistochemistry or mass spectrometry; or (b) grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) in the absence of a monoclonal gammopathy; or (c) grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and confirmatory TTR amyloid typing in non-cardiac tissues by immunohistochemistry or mass spectrometry in the presence of a monoclonal gammopathy.

[0239] Additionally or alternatively, the subject has a left ventricular ejection fraction (LVEF) of ≥20% (e.g., about 20% to about 60%, e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60%), e.g., as measured by echocardiography, prior to undergoing the treatment methods described herein. In one embodiment, the subject has an LVEF of 50% to 70% (e.g., 50%, 55%, 60%, 65% or 70%) after undergoing the treatment methods described herein (e.g., the subject exhibits an increase in LVEF after treatment relative to the LVEF before treatment).

[0240] Additionally or alternatively, the subject has a left ventricular wall thickness (LVWT) of ≥12 mm (e.g., about 12 mm to about 30 mm, e.g., about 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, or 30 mm) prior to undergoing the treatment methods described herein, e.g., as measured by echocardiography. In one embodiment, the subject has a LVWT of <12 mm (e.g., about 8 mm to about 12 mm, e.g., about 8 mm, 9 mm, 10 mm, 11 mm, or 12 mm) after undergoing the treatment methods described herein.

[0241] Additionally or alternatively, the subject (particularly a female) has an end-diastolic septal wall thickness of ≥ 11 mm (e.g., about 11 mm to about 30 mm, e.g., about 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm or 30 mm) prior to undergoing the treatment methods described herein, or The subject, particularly a male, has an end-diastolic septal wall thickness of ≥12 mm (e.g., about 12 mm to about 30 mm, e.g., about 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm or 30 mm) prior to undergoing the treatment methods described herein, e.g., as measured by echocardiography.

[0242] Additionally or alternatively, the subject (e.g., a female) has an end-diastolic septal wall thickness of <11 mm (e.g., about 8 mm to about 11 mm, e.g., about 8 mm, 9 mm, 10 mm, or 11 mm) after undergoing the treatment methods described herein; or the subject (e.g., a male) has an end-diastolic septal wall thickness of <12 mm (e.g., about 8 mm to about 12 mm, e.g., about 8 mm, 9 mm, 10 mm, 11 mm, or 12 mm) after undergoing the treatment methods described herein.

[0243] Additionally or alternatively, the subject has an NT-proBNP level of about 300 pg / mL to about 20,000 pg / mL prior to undergoing the treatment methods described herein, preferably the subject has an NT-proBNP level of >2000 pg / mL prior to undergoing the treatment methods described herein. The use of NT-proBNP as a biomarker in ATTR is well-established in the art and a staging system with a cutoff value of 3000 pg / mL for NT-proBNP has been developed based on the levels of the biomarker in combination with the levels of cardiac troponin T (cTnT) (Grogan et al., J Am Coll Cardiol 68 (2016), 1014–1020) or with estimated glomerular filtration rate (eGFR) (Gillmore et al., European Heart Journal 39 (2018), 2799–2806); see also Perfetto et al., Internal and Emergency Medicine 17 (2022), 957–969. Thus, depending on the level of cTnT and eGFR, and considering only the level of NT-proBNP, the subjects had grade I, II, and III cardiac ATTR.

[0244] Additionally or alternatively, the subject has a history of heart failure as documented by one of the following events within about 1 year prior to undergoing the treatment methods described herein: (i) hospitalization for heart failure, (ii) emergency heart failure visit, and (iii) an episode of volume overload documented by NT-proBNP > 2000 pg / mL (or equivalent BNP).

[0245] Preferably, the subject is an adult subject.

[0246] Thus, the therapeutic regimens of the present invention can be used to treat subjects with any or all of the aforementioned indications / characteristics. In one embodiment of the invention, the heavy chain variable region of the anti-TTR antibody or antigen-binding fragment thereof used according to the invention comprises an amino acid sequence having about 85% sequence identity (e.g., about 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 7, and the light chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises an amino acid sequence having about 85% sequence identity (e.g., about 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to the amino acid sequence of SEQ ID NO: 8.

[0247] In some embodiments, the heavy chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:7, and the light chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:8.

[0248] In some embodiments, the heavy chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 11, and the light chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 8.

[0249] In some embodiments, the heavy chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 11, and the light chain variable region of the anti-TTR antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 12.

[0250] As described above, the parent antibody NI006 is also described in WO 2015 / 092077A1 (designated antibody NI-301.37F1) and Michalon et al., Nat Commun. 12 (2021), 3142 (designated antibody NI301A) and is capable of binding to a human TTR epitope comprising or consisting of the amino acid sequence TTR41-45 (SEQ ID NO: 51 of WO 2015 / 092077A1). Characterization of the binding properties of the antibody showed that it exhibited high binding affinity for misfolded TTR in the subnanomolar range and was highly selective for the amyloid conformation of TTR, i.e., it selectively bound to disease-associated ATTR aggregates with high affinity and exerted similar binding to wild-type TTR and variant TTR. These are associated with sporadic or hereditary diseases, respectively, and do not bind to physiological TTR monomers. In addition, the anti-TTR antibody bound to ATTR deposits in cardiac tissue obtained from ATTR-CM patients at autopsy. Thus, in one embodiment, the antibodies used according to the present invention are equivalent antibodies to the above-characterized antibodies having a heavy chain variable region and a light chain variable region comprising the amino acids of SEQ ID NO: 7 and SEQ ID NO: 8, which means that the equivalent antibodies have substantially the same binding characteristics as the above-characterized antibodies having a heavy chain variable region and a light chain variable region comprising the amino acids of SEQ ID NO: 7 and SEQ ID NO: 8. In particular, the equivalent antibodies

[0251] (i) binds to a human TTR epitope comprising or consisting of the amino acid sequence TTR41-45,

[0252] (ii) exhibits high binding affinity to misfolded TTR in the subnanomolar range,

[0253] (iii) Highly selective for the amyloid conformation of TTR, i.e., selectively binding to disease-associated ATTR aggregates with high affinity

[0254] (iv) exert similar binding to wild-type TTR and variant TTR.

[0255] (v) does not bind to physiological TTR monomers, and / or

[0256] (vi) Incorporation of ATTR deposits in cardiac tissue obtained at autopsy from ATTR-CM patients.

[0257] In one embodiment, the equivalent antibody exhibits one binding characteristic of the binding characteristics (i) to (vi). In one embodiment, the equivalent antibody exhibits at least two of the listed binding characteristics. In one embodiment, the equivalent antibody exhibits at least three of the listed binding characteristics. In one embodiment, the equivalent antibody exhibits at least four of the listed binding characteristics. In one embodiment, the equivalent antibody exhibits at least five of the listed binding characteristics. In a preferred embodiment, the equivalent antibody exhibits all of the binding characteristics (i) to (vi).

[0258] Antibody NI006 / ALXN2220 is a fully human IgG1m3 allotype antibody and thus comprises the human constant heavy chain (HC) amino acid sequence as exemplified in SEQ ID NO:9 and the corresponding human constant light chain (LC), here a kappa light chain, as exemplified in SEQ ID NO:10.

[0259] As shown in Example 7 and mentioned in detail above, the major PTMs that have been identified in antibody NI006 / ALXN2220 are modification of glutamine at the N-terminus to pyroglutamate, deletion of the C-terminal lysine, and N-glycosylation in the HC. Thus, in a preferred embodiment, the heavy chain of the anti-TTR antibody used according to the present invention lacks the C-terminal cysteine, has a modified glutamine as pyroglutamate at the N-terminus, and comprises at least one N-glycosylation site.

[0260] Another class of anti-TTR antibodies that can be used according to the present invention is described in an international application of Prothena Biosciences Limited (Prothena). In particular, embodiments of the present disclosure relate to the use of Novo Nordisk's anti-TTR antibody NN-6019 (formerly known as PRX004 from Prothena Biosciences) in treating human subjects in need of such treatment, as provided herein. NN-6019 (PRX004) corresponds to and is a humanized form of the antibody 14G8 described in Higaki et al., Amyloid 23 (2016) 86-97, and is disclosed in WO 2016 / 120810A1 and WO 2018 / 007922A2, and more specifically in WO 2019 / 108689A1, the disclosures of which are incorporated by reference. NN-6019 (PRX-004) is an investigational monoclonal antibody designed to specifically target and eliminate the misfolded (toxic) form of TTR amyloid found in ATTR. Therefore, the antibody PRX004 would be another preferred anti-TTR antibody for use in the treatment methods according to the present invention, which specifically recognizes the same epitope as PRX004, namely the amino acid TTR. 89-97 or containing amino acid TTR 101-109 The invention relates to an epitope of a humanized mouse monoclonal antibody 14G8, 9D5, 5A1, and 6C1, which are humanized forms of the mouse monoclonal antibodies 14G8, 9D5, 5A1, and 6C1 originally cloned and disclosed in WO 2016 / 120810A1, WO 2018 / 007924A2, WO 2018 / 007924A2, and WO 2018 / 007923A1, the disclosures of which, including antibody sequences (e.g., full length and / or CDRs thereof) associated with these antibody clones and / or their deposits, are incorporated herein by reference.

[0261] Thus, in one embodiment, the antibody for use according to the present invention is a monoclonal antibody comprising a mature heavy chain variable region comprising the three CDRs of SEQ ID NO: 61 as shown in WO 2019 / 108689A1 and a mature light chain variable region comprising the three CDRs of SEQ ID NO: 70 as shown in WO 2019 / 108689A1, except that positions H52 and L26 by Kabat numbering can each independently be N or S; or a monoclonal antibody comprising a mature heavy chain variable region comprising the three CDRs of SEQ ID NO: 1 as shown in WO 2019 / 108689A1 and a mature light chain variable region comprising the three CDRs of SEQ ID NO: 16 as shown in WO 2019 / 108689A1, in one embodiment, the antibody is characterized in that it comprises a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 65 as shown in WO 2019 / 108689A1 and a mature light chain variable region comprising the three CDRs of SEQ ID NO: 70 as shown in WO 2019 / 108689A1. ID NO: 76. More preferably, the antibody is characterized as described in claims 26 to 35 of WO 2019 / 108689A1, the contents of which are incorporated herein by reference.

[0262] In additional aspects, the invention relates to a TTR tetramer stabilizer for use in a method of treating a subject having or at risk of ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and pre-eclampsia), wherein the subject has been previously and / or is concurrently treated with an anti-TTR antibody according to the invention.

[0263] In some embodiments, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, toflavone, and aclometamide (AG10).

[0264] In another aspect, the present invention relates to a method of treating ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear and lumbar spinal stenosis) and pre-eclampsia) by administering a human anti-TTR antibody to a human subject at a dose of about 0.3 mg / kg to about 100 mg / kg once every 3 to 42 days. The antibody is preferably an antibody as defined above. Thus, preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99% or 100% sequence identity) to SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99% or 100% sequence identity) to SEQ ID NO: 8, or the antibody may be an equivalent antibody having substantially the same binding characteristics as defined below. The heavy chain variable region comprises the CDRs set forth in SEQ ID NOs: 1-3, and the light chain variable region comprises the CDRs set forth in SEQ ID NOs: 4-6. Most preferably, the antibody is a fully human IgG1m3 allotype antibody and thus comprises the human constant heavy chain (HC) amino acid sequence as exemplified in SEQ ID NO: 9 and the corresponding human constant light chain (LC) as exemplified in SEQ ID NO: 10, preferably with the post-translational modifications identified above. The antibody is formulated in the pharmaceutical composition at a concentration of about 10 mg / mL to about 100 mg / mL.

[0265] In some embodiments, the anti-TTR antibody is administered at a dose of about 0.3 mg / kg to about 80 mg / kg (e.g., 0.3 mg / kg to 60 mg / kg, 0.3 mg / kg to 30 mg / kg, 0.3 mg / kg to 1 mg / kg, 1 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 30 mg / kg to 50 mg / kg, 30 mg / kg The present invention also provides a method for the administration of a dose of at least one of the following: (a) administering a dose of at least one of the following: (i) administering a dose of at least one of the following: (a) administering a dose of at least one of the following: (b) administering a dose of at least one of the following: (c) administering a dose of at least one of the following: (d) administering a dose of at least one of the following: (i) administering a dose of at least one of the following: (i) administering a dose of at least one of the following: (i) administering a dose of at least one of the following:

[0266] In some embodiments, the anti-TTR antibody is administered at a dose of about 0.3 mg / kg to about 30 mg / kg (e.g., 0.3 mg / kg to 20 mg / kg, 0.3 mg / kg to 10 mg / kg, 1 mg / kg to 15 mg / kg, 5 mg / kg to 15 mg / kg, 15 mg / kg to 20 mg / kg, 15 mg / kg to 25 mg / kg, or 25 mg / kg to 30 mg / kg).

[0267] In some embodiments, the anti-TTR antibody is administered at a dose of about 0.3 mg / kg.

[0268] In some embodiments, the anti-TTR antibody is administered at a dose of about 1 mg / kg.

[0269] In some embodiments, the anti-TTR antibody is administered at a dose of about 3 mg / kg.

[0270] In some embodiments, the anti-TTR antibody is administered at a dose of about 10 mg / kg.

[0271] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0272] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg to about 60 mg / kg (e.g., 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 30 mg / kg to 50 mg / kg, or 40 mg / kg to 60 mg / kg).

[0273] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg and results in a sustained plasma concentration of the antibody in the subject of about 50 μg / mL.

[0274] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0275] In some embodiments, the anti-TTR antibody is first administered at a dose of about 0.3 mg / kg to about 10 mg / kg (e.g., about 0.3 mg / kg to 1 mg / kg, 0.5 mg / kg to 2 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 3 mg / kg to 8 mg / kg, 5 mg / kg to 10 mg / kg, or 8 mg / kg to 10 mg / kg).

[0276] In some embodiments, the anti-TTR antibody is further administered at a maintenance dose of about 10 mg / kg to about 60 mg / kg (e.g., 10 mg / kg to 20 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 20 mg / kg to 50 mg / kg, or 30 mg / kg to 60 mg / kg).

[0277] In a preferred embodiment of the invention, the anti-TTR antibody is administered initially at a dose of about 0.3 mg / kg to about 10 mg / kg (e.g., about 0.3 mg / kg to 1 mg / kg, 0.5 mg / kg to 2 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 3 mg / kg to 8 mg / kg, 5 mg / kg to 10 mg / kg, or 8 mg / kg to 10 mg / kg) and further administered at a maintenance dose of about 10 mg / kg to about 60 mg / kg (e.g., 10 mg / kg to 20 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 20 mg / kg to 50 mg / kg, or 30 mg / kg to 60 mg / kg).

[0278] In another preferred embodiment, the anti-TTR antibody is administered at a dose of greater than 10 mg / kg, e.g., 10 mg / kg to 100 mg / kg, preferably 10 mg / kg to 60 mg / kg, preferably wherein the antibody is administered once every 4 weeks.

[0279] In another preferred embodiment, the anti-TTR antibody is administered at a dose of about 30 mg / kg, preferably wherein the antibody is administered once every 4 weeks.

[0280] In another preferred embodiment, the anti-TTR antibody is administered at a dose of about 60 mg / kg, preferably wherein the antibody is administered once every 4 weeks.

[0281] In some embodiments, an anti-TTR antibody is administered at a dosage of about 600 mg to about 7500 mg (e.g., 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 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, 2600 mg, 00mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 3800 mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg , 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6050mg, 6100mg, 6 150mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 635 0 mg, 6400 mg, 6450 mg, 6500 mg, 6550 mg, 6600 mg, 6650 mg, 6700 mg, 6750 mg, 6800 mg, 6850 mg, 6900 mg, 6950 mg, 7000 mg, 7050 mg, 7100 mg, 7150 mg, 7200 mg, 7250 mg, 7300 mg, 7350 mg, 7400 mg, 7450 mg or 7500 mg).

[0282] In a preferred embodiment, the maintenance dose is about 2500 mg, such as 2400 mg, about 3000 mg or about 3500 mg, such as 3200 mg.

[0283] In one embodiment of the invention, the anti-TTR antibody is further administered with a loading dose of about 600 mg to about 4000 mg (e.g., 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 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, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, or 4000 mg).

[0284] In a preferred embodiment, the loading dose is about 2500 mg, such as 2400 mg, about 3000 mg or about 3500 mg, such as 3200 mg.

[0285] Preferably, the anti-TTR antibody is administered at a maintenance dose of about 600 mg to about 7500 mg as described above, prior to which the anti-TTR antibody is administered at a loading dose of about 600 mg to about 4000 mg as described above. In an optional embodiment, the loading dose is administered every other week for up to two months prior to the maintenance dose.

[0286] In one embodiment of the invention, the maintenance or loading dose of the anti-TTR antibody is about 3000 mg.

[0287] In one embodiment of the invention, the anti-TTR antibody is administered at a dose of 2000 mg to 2500 mg to a patient weighing about 40 kg to about <60 kg. In one embodiment, the anti-TTR antibody is administered at a dose of 2000 mg or 2500 mg to a patient weighing about 40 kg to about ≤60 kg. In a preferred embodiment, the anti-TTR antibody is administered at a dose of 2500 mg to a patient weighing about 40 kg to about ≤60 kg. In one embodiment of the invention, the anti-TTR antibody is administered at a dose of 3000 mg to 3500 mg to a patient weighing about ≥60 kg to about 100 kg. In one embodiment, the anti-TTR antibody is administered at a dose of 3000 mg or 3500 mg to a patient weighing about ≥60 kg to about 100 kg. In a preferred embodiment, the anti-TTR antibody is administered at a dose of 3500 mg to a patient weighing about ≥60 kg to about 100 kg. In one embodiment of the invention, the anti-TTR antibody is administered to a patient weighing about 100 kg or less at a dose of 4000 mg to 5000 mg. In one embodiment, the anti-TTR antibody is administered to a patient weighing about 100 kg or less at a dose of 4000 mg, 4500 mg, or 5000 mg. In a preferred embodiment, the anti-TTR antibody is administered to a patient weighing about 100 kg or less at a dose of 4000 mg or 5000 mg, and most preferably, the anti-TTR antibody is administered to a patient weighing about 100 kg or less at a dose of 5000 mg.

[0288] In a preferred embodiment of the invention, the anti-TTR antibody is administered to a subject weighing approximately ≥40 kg to <60 kg at a dose ranging from 2200 mg to 2700 mg (inclusive). In a preferred embodiment, the anti-TTR antibody is administered to a subject weighing approximately ≥40 kg to <60 kg at a dose of 2400 mg. In one embodiment of the invention, the anti-TTR antibody is administered to a subject weighing approximately ≥40 kg to <60 kg at a dose ranging from 3000 mg to 3500 mg (inclusive). In a preferred embodiment, the anti-TTR antibody is administered to a subject weighing approximately ≥60 kg to <100 kg at a dose of 3200 mg. In one embodiment of the invention, the anti-TTR antibody is administered to a subject weighing approximately ≤100 kg at a dose ranging from 4400 mg to 5200 mg (inclusive). In a preferred embodiment, the anti-TTR antibody is administered to a subject weighing approximately ≤100 kg at a dose of 4800 mg.

[0289] In some embodiments, the anti-TTR antibody is administered to the subject once every 21 to 35 days (e.g., 22 to 34 days, 23 to 33 days, 24 to 32 days, 25 to 31 days, 23 to 33 days, or 27 to 35 days).

[0290] In some embodiments, the anti-TTR antibody is administered to the subject once every 28 to 35 days (eg, 28 to 30 days, 29 to 34 days, 30 to 33 days, or 30 to 32 days).

[0291] In some embodiments, the anti-TTR antibody is administered to the subject once every 28 days.

[0292] In some embodiments, the anti-TTR antibody is administered to the subject once every 35 days.

[0293] In some embodiments, the anti-TTR antibody is administered to the subject once every 4 weeks (q4w).

[0294] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months to 30 months (e.g., 4 months to 12 months, 8 months to 16 months, 12 months to 20 months, 16 months to 24 months, or 20 months to 30 months).

[0295] In some embodiments, the anti-TTR antibody is administered to the subject for about 12 months to 18 months (e.g., 12 months to 15 months, 13 months to 16 months, 14 months to 17 months, or 15 months to 18 months).

[0296] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months.

[0297] In some embodiments, the anti-TTR antibody is administered to the subject for about 11 months.

[0298] In some embodiments, the anti-TTR antibody is administered to a subject at a dose of about 30 mg / kg for about 12 months to 18 months (e.g., 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months).

[0299] In some embodiments, a loading dose is administered every other week for up to two months prior to administration of a maintenance dose.

[0300] In some embodiments, administration of the anti-TTR antibody results in a sustained plasma concentration of the antibody in the subject of about 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL to about 100 μg / mL, about 2.5 μg / mL to about 125 μg / mL, about 5 μg / mL to about 150 μg / mL, about 10 μg / mL to about 200 μg / mL, about 10 μg / mL to about 50 μg / mL, about 25 μg / mL to about 75 μg / mL, about 50 μg / mL to about 1000 μg / mL).

[0301] In some embodiments, the plasma concentration is maintained at about 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL to about 100 μg / mL, about 2.5 μg / mL to about 125 μg / mL, about 5 μg / mL to about 150 μg / mL, about 10 μg / mL to about 200 μg / mL, about 65 μg / mL to about 350 μg / mL, about 20 μg / mL to about 200 μg / mL, about 20 μg / mL to about 100 μg / mL, about 50 μg / mL to about 150 μg / mL, about 75 μg / mL to about 175 μg / mL, about 100 μg / mL to about 800 μg / mL, about 140 μg / mL to about 700 μg / mL, about 200 μg / mL to about 600 μg / mL, or about 400 μg / mL to about 800 μg / mL,For example, about 10 μg / mL, about 20 μg / mL, about 30 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, about 100 μg / mL, about 110 μg / mL, about 120 μg / mL, about 130 μg / mL, about 140 μg / mL, about 150 μg / mL, about 160 μg / mL, about 170 μg / mL, about 180 μg / mL, about 190 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL. / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 410 μg / mL, about 420 μg / mL, about 430 μg / mL, about 440 μg / mL, about 450 μg / mL, about 460 μg / mL, about 470 μg / mL, about 480 μg / mL, about 490 μg / mL, about 500 μg / mL, about 510 μg / mL g / mL, about 520 μg / mL, about 530 μg / mL, about 540 μg / mL, about 550 μg / mL, about 560 μg / mL, about 570 μg / mL, about 580 μg / mL, about 590 μg / mL, about 600 μg / mL, about 610 μg / mL, about 620 μg / mL, about 630 μg / mL, about 640 μg / mL, about 650 μg / mL, about 660 μg / mL, about 670 μg / mL, about 680 μg / mL, about 690 μg / mL, about 700 μg / mL, about 710 μg / mL, about 720 μg / mL, about 730 μg / mL, about 740 μg / mL, about 750 μg / mL, about 760 about 900 μg / mL, about 910 μg / mL, about 920 μg / mL, about 930 μg / mL, about 940 μg / mL, about 950 μg / mL, about 960 μg / mL, about 970 μg / mL, about 980 μg / mL, about 990 μg / mL, or about 1000 μg / mL),For about 1 day to about 30 days (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days).

[0302] In some embodiments, the plasma concentration is maintained at about 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL to about 100 μg / mL, about 2.5 μg / mL to about 125 μg / mL, about 5 μg / mL to about 150 μg / mL, about 10 μg / mL to about 200 μg / mL, about 65 μg / mL to about 350 μg / mL, about 20 μg / mL to about 200 μg / mL, about 20 μg / mL to about 100 μg / mL, about 50 μg / mL to about 150 μg / mL, about 75 μg / mL to about 175 μg / mL, about 100 μg / mL to about 800 μg / mL, about 140 μg / mL to about 700 μg / mL, about 200 μg / mL to about 600 μg / mL, or about 400 μg / mL to about 800 μg / mL,For example, about 10 μg / mL, about 20 μg / mL, about 30 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, about 100 μg / mL, about 110 μg / mL, about 120 μg / mL, about 130 μg / mL, about 140 μg / mL, about 150 μg / mL, about 160 μg / mL, about 170 μg / mL, about 180 μg / mL, about 190 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL. / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 410 μg / mL, about 420 μg / mL, about 430 μg / mL, about 440 μg / mL, about 450 μg / mL, about 460 μg / mL, about 470 μg / mL, about 480 μg / mL, about 490 μg / mL, about 500 μg / mL, about 510 μg / mL g / mL, about 520 μg / mL, about 530 μg / mL, about 540 μg / mL, about 550 μg / mL, about 560 μg / mL, about 570 μg / mL, about 580 μg / mL, about 590 μg / mL, about 600 μg / mL, about 610 μg / mL, about 620 μg / mL, about 630 μg / mL, about 640 μg / mL, about 650 μg / mL, about 660 μg / mL, about 670 μg / mL, about 680 μg / mL, about 690 μg / mL, about 700 μg / mL, about 710 μg / mL, about 720 μg / mL, about 730 μg / mL, about 740 μg / mL, about 750 μg / mL, about 760 about 900 μg / mL, about 910 μg / mL, about 920 μg / mL, about 930 μg / mL, about 940 μg / mL, about 950 μg / mL, about 960 μg / mL, about 970 μg / mL, about 980 μg / mL, about 990 μg / mL, or about 1000 μg / mL),Lasts from about 1 day to about 1 week.

[0303] In some embodiments, administration of an anti-TTR antibody is monitored by measuring the levels of one or more biomarkers.

[0304] In some embodiments, the marker is a protein marker obtained from serum or plasma of a subject (eg, a patient with ATTR-CM).

[0305] In some embodiments, the biomarkers include cardiac troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), wherein a decrease in the biomarker level indicates the efficacy of the treatment. In a preferred embodiment, the biomarker is at least NT-proBNP. Additionally or alternatively, the biomarker includes C-reactive protein (CRP), wherein an increase in CRP levels, preferably a transient increase in CRP levels in a dose-dependent manner (e.g., from about 1 day to about 14 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days), indicates on-target immune activation and efficacy of the treatment.

[0306] In some embodiments, administration of the anti-TTR antibody or antigen-binding fragment thereof results in a reduction in cardiac amyloid burden and / or a composite endpoint of all-cause mortality (ACM) and total cardiovascular (CV) clinical events and / or heart failure (HF) events.

[0307] In some embodiments, administration of the anti-TTR antibody results in a reduction in heart mass as measured by cardiac magnetic resonance imaging (MRI).

[0308] In some embodiments, treatment with an anti-TTR antibody according to the methods of the invention results in a dose-dependent and time-dependent reduction in cardiac amyloid burden in the patient of at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60% or more, e.g., about 70%, about 80%, about 90%, after a specified duration of treatment (e.g., 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 21 months, or 24 months or longer, e.g., 48 months).

[0309] Preferably, the treatment, i.e., administration of the dosing regimen, of the present invention improves at least one of:

[0310] (a) symptomatic, functional, and health-related quality of life (QoL), as measured by the change from baseline in the Kansas City Cardiomyopathy Questionnaire Global Summary (KCCQ-OS) score;

[0311] (b) time to cardiovascular (CV)-related death;

[0312] (c) six-minute walk test (6MWT) scores compared with baseline;

[0313] (d) rates of cardiovascular (CV) clinical events; and

[0314] (e) Time to all-cause mortality (ACM).

[0315] In one embodiment, treatment

[0316] (a) reduce the subject's NT-proBNP level compared to baseline;

[0317] (b) reduce the rate of heart failure (HF) events;

[0318] (c) reducing the incidence of intensive oral diuretic therapy, optionally including outpatient intensive oral diuretic therapy;

[0319] (d) reduce the incidence of disease-modifying therapy changes;

[0320] (e) reduce the incidence of hospitalization due to atrial fibrillation;

[0321] (f) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score after 24 months of study treatment;

[0322] (g) change from baseline in the six-minute walk test (6MWT) after 24 months of study treatment;

[0323] (h) changes from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia disease stages and NYHA classification;

[0324] (i) induce changes in GLS relative to baseline;

[0325] (j) induced changes in stroke volume relative to baseline;

[0326] (k) elicit changes in echocardiographic parameters of interest relative to baseline;

[0327] (l) causing changes in hs-cTnT relative to baseline;

[0328] (m) causing changes relative to baseline in DPD / PYP / HMDP cardiac scintigraphic cardiac uptake and / or cMRI-derived ECV, T1, and T2 maps;

[0329] (n) Causes a change in eGFR relative to baseline

[0330] (o) cause a change from baseline in the EQ-5D-5L score and / or cause a change from baseline in the SF-36 score;

[0331] (p) causing a change relative to baseline in a marker selected from the group consisting of CRP, IL11b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin; preferably, a change relative to baseline in a marker of CRP;

[0332] (q) causing a change relative to baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6;

[0333] (r) causing a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4;

[0334] (s) cause changes from baseline in: (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or sNFL level; and / or

[0335] (t) Causes a change from baseline in the NIS and / or causes a change in the NC study.

[0336] In some embodiments, administration of an anti-TTR antibody results in improved cardiovascular function (e.g., diastolic myocardial relaxation, atrioventricular (AV) flow, global longitudinal strain (GLS), ventricular ejection fraction, or end-diastolic volume), e.g., as assessed by echocardiography. For example, echocardiography can be used to measure the ratio of the early diastolic mitral inflow velocity to the early diastolic mitral annular motion velocity (E / e' ratio) to assess cardiovascular function.

[0337] In some embodiments, the anti-TTR antibody is provided in an aqueous formulation at a concentration of about 25 mg / mL to 125 mg / mL, which is diluted prior to administration. In some embodiments, the anti-TTR antibody is provided in an aqueous formulation at a concentration of about 1 mg / mL to about 50 mg / mL (e.g., about 1 mg / mL to about 42 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 20 mg / mL, or about 1 mg / mL to about 10 mg / mL, such as about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about The invention relates to an aqueous formulation of a pharmaceutical composition comprising: a) about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL) to a subject.

[0338] In some embodiments, the subject has been previously treated with a TTR tetramer stabilizer and / or is concurrently receiving a TTR tetramer stabilizer.

[0339] In some embodiments, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, toflavone, and aclometamide (AG10).

[0340] In some embodiments, the antibody is administered to a subject by intravenous infusion in an aqueous formulation, wherein the aqueous formulation has a pH of about 5.0 to 6.5, comprises a histidine buffer, a sugar (such as sucrose), and a surfactant (such as polysorbate 80 (PS80)), and the antibody is present in the aqueous formulation at a concentration of about 25 mg / mL to 125 mg / mL.

[0341] In some embodiments, the aqueous formulation has a pH of about 5.8 and comprises 20 mM histidine (e.g., L-histidine and / or L-histidine monohydrochloride), 6.5% weight / volume (w / v) sucrose, 0.03% PS80 w / v, and the antibody is present in the aqueous formulation at a concentration of about 50 mg / mL or 100 mg / mL.

[0342] In some embodiments, the aqueous formulation has a pH of about 5.8 and comprises 20 mM histidine (e.g., L-histidine and / or L-histidine monohydrochloride), 8% weight / volume (w / v) sucrose, 0.03% PS80 w / v, and the antibody is present in the aqueous formulation at a concentration of about 50 mg / mL or 100 mg / mL.

[0343] In some embodiments, the antibody is administered to the subject in a diluted form including a diluent.

[0344] In some embodiments, the diluent is glucose or a polymer thereof (e.g., the polymer is dextran). Glucose or a polymer thereof (e.g., dextran) can be used as a diluent at a concentration of about 1% w / v, 2% w / v, 3% w / v, 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, or 10% w / v.

[0345] In some embodiments, the infusion line is flushed with a diluent before and after the intravenous infusion.

[0346] In some embodiments, intravenous infusion is performed using a syringe pump or an infusion pump with an infusion syringe. In one embodiment, a total antibody dose of up to 100 mg is administered by infusion, e.g., a syringe pump with an infusion syringe. In one embodiment, a total antibody dose of greater than 100 mg is administered using an infusion pump. In one embodiment, the anti-TTR antibody is diluted into an infusion bag prefilled with a diluent.

[0347] In some embodiments, the infusion syringe includes a minimum administration volume of 10 mL of the aqueous formulation.

[0348] In some embodiments, the total volume of the diluted form administered to the subject does not exceed 200 mL (including flush volume).

[0349] In some embodiments, at least for the first infusion, the aqueous formulation is administered within about 2 hours (± 10 minutes).

[0350] In some embodiments, the aqueous formulation is administered within about 1 hour (± 10 minutes).

[0351] In some embodiments, ATTR amyloidosis results in cardiomyopathy (CM).

[0352] In some embodiments, the subject suffers from ATTR amyloidosis with CM (ATTR-CM). In some embodiments, the subject suffers from ATTR polyneuropathy (ATTR-PN). In some embodiments, the subject suffers from familial amyloid polyneuropathy (FAP). In some embodiments, the subject suffers from familial amyloid cardiomyopathy (FAC). In some embodiments, the subject suffers from senile systemic amyloidosis (SSA). In some embodiments, the subject suffers from systemic familial amyloidosis. In some embodiments, the subject suffers from leptomeningeal / central nervous system (CNS) amyloidosis. In some embodiments, the subject suffers from Alzheimer's disease. In some embodiments, the subject suffers from TTR-related ocular amyloidosis. In some embodiments, the subject suffers from TTR-related renal amyloidosis. In some embodiments, the subject suffers from TTR-related hyperthyroxinemia. In some embodiments, the subject suffers from TTR-related ligamentous amyloidosis, including carpal tunnel syndrome. In some embodiments, the subject suffers from rotator cuff tear and lumbar spinal stenosis. In some embodiments, the subject suffers from preeclampsia.

[0353] In some embodiments, the subject is diagnosed with hereditary ATTR-CM due to a known pathogenic TTR mutation.

[0354] In some embodiments, the subject has sporadic WT-ATTR-CM and is negative for genetic testing for a TTR mutation.

[0355] Preferably, the diagnosis is based on evidence of cardiac amyloidosis by echocardiography or cMRI and one of the following: a) endomyocardial biopsy with confirmatory TTR amyloid typing by immunohistochemistry or mass spectrometry; or (b) grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTcHMDP) in the absence of a monoclonal gammopathy; or (c) grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and confirmatory TTR amyloid typing in non-cardiac tissues by immunohistochemistry or mass spectrometry in the presence of a monoclonal gammopathy.

[0356] In some embodiments, the subject has a left ventricular ejection fraction (LVEF) of ≥20% (e.g., from about 20% to about 60%, e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%), e.g., as measured by echocardiography, prior to undergoing the treatment methods described herein. In one embodiment, the subject has an LVEF of 50% to 70% (e.g., 50%, 55%, 60%, 65%, or 70%) after undergoing the treatment methods described herein (e.g., the subject exhibits an increase in LVEF after treatment relative to the LVEF before treatment).

[0357] In some embodiments, the subject has a left ventricular wall thickness (LVWT) of ≥12 mm (e.g., about 12 mm to about 30 mm, e.g., about 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, or 30 mm) prior to undergoing the methods of treatment described herein, e.g., as measured by echocardiography. In one embodiment, the subject has a LVWT of <12 mm (e.g., about 8 mm to about 12 mm, e.g., about 8 mm, 9 mm, 10 mm, 11 mm, or 12 mm) after undergoing the methods of treatment described herein.

[0358] In some embodiments, the subject (particularly a female) has an end-diastolic septal wall thickness of ≥ 11 mm (e.g., from about 11 mm to about 30 mm, e.g., about 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, or 30 mm) prior to undergoing the treatment methods described herein, or The subject (particularly a male) has an end-diastolic ventricular septal wall thickness of ≥12 mm (e.g., about 12 mm to about 30 mm, e.g., about 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm or 30 mm) prior to undergoing the treatment methods described herein, e.g., as measured by echocardiography.

[0359] In some embodiments, a subject (e.g., a female) has an end-diastolic septal wall thickness of <11 mm (e.g., about 8 mm to about 11 mm, e.g., about 8 mm, 9 mm, 10 mm, or 11 mm) after undergoing the treatment methods described herein; or a subject (e.g., a male) has an end-diastolic septal wall thickness of <12 mm (e.g., about 8 mm to about 12 mm, e.g., about 8 mm, 9 mm, 10 mm, 11 mm, or 12 mm) after undergoing the treatment methods described herein.

[0360] In some embodiments, the subject has an N-terminal pro-b-type natriuretic peptide (NT-proBNP) level of about 300 pg / mL to about 20,000 pg / mL before undergoing the treatment methods described herein. In some embodiments, the subject has an N-terminal pro-b-type natriuretic peptide (NT-proBNP) level of about 0 pg / mL to about 300 pg / mL after undergoing the treatment methods described herein, preferably the subject has an NT-proBNP level of >2000 pg / mL before undergoing the treatment methods described herein.

[0361] In some embodiments, the subject has a cardiac troponin T (TnT) level of about 10 pg / mL to about 200 pg / mL before undergoing the treatment methods described herein. In some embodiments, the subject has a cardiac troponin T (TnT) level of about 0 pg / mL to about 10 pg / mL after undergoing the treatment methods described herein.

[0362] In some embodiments, the subject has a history of heart failure as documented by one of the following events within about 1 year prior to undergoing the treatment methods described herein: (i) hospitalization for heart failure, (ii) emergency heart failure visit, and (iii) an episode of volume overload documented by NT-proBNP > 2000 pg / mL (or equivalent BNP).

[0363] In some embodiments, the heavy chain variable region of the anti-TTR antibody used according to the present invention comprises the amino acid sequence of SEQ ID NO: 7 or 11, preferably the amino acid sequence of SEQ ID NO: 11, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8, or the antibody may be an equivalent antibody having substantially the same binding characteristics as defined below. Most preferably, the antibody is a fully human IgG1m3 allotype antibody and thus comprises a human constant heavy chain (HC) amino acid sequence as exemplified in SEQ ID NO: 9 and a corresponding human constant light chain (LC) as exemplified in SEQ ID NO: 10, preferably with the above-identified post-translational modifications, such as the HC amino acid sequence preferably present in SEQ ID NO: 15.

[0364] In some embodiments, the method further comprises administering a TTR tetramer stabilizer. In some embodiments, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, tafamidis, and aclometre (AG10), preferably wherein tafamidis is administered as described above.

[0365] In another aspect, the present invention relates to the use of a human anti-TTR antibody that binds to mutated, misfolded, misassembled and / or aggregated TTR species and / or fragments thereof and does not substantially recognize physiological TTR species for treating or preventing a subject having or at risk of having ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear and lumbar spinal stenosis), and pre-eclampsia) in the preparation of a medicament for treating or preventing a subject having or at risk of having ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear and lumbar spinal stenosis), and pre-eclampsia). As outlined in more detail above, in one embodiment, the anti-TTR antibody is capable of binding to wild-type and mutant TTR aggregates. Additionally or alternatively, the anti-TTR antibody does not bind to physiological TTR tetramers, and more preferably does not bind to wild-type TTR monomers, and preferably does not bind to wild-type TTR dimers. Preferably, the antibody is as defined above.

[0366] The use comprises administering the drug at a dosing regimen that results in a sustained plasma concentration of the antibody in the subject of about 1 μg / mL to about 1000 μg / mL (e.g., about 1 μg / mL to about 100 μg / mL, about 2.5 μg / mL to about 125 μg / mL, about 5 μg / mL to about 150 μg / mL, about 10 μg / mL to about 200 μg / mL, about 65 μg / mL to about 350 μg / mL, about 20 μg / mL to about 200 μg / mL, about 20 μg / mL to about 100 μg / mL, about 50 μg / mL to about 150 μg / mL, about 75 μg / mL to about 175 μg / mL, about 100 μg / mL to about 800 μg / mL, about 140 μg / mL to about 700 μg / mL, about 200 μg / mL to about 600 μg / mL, or about 400 μg / mL to about 800 μg / mL,For example, about 10 μg / mL, about 20 μg / mL, about 30 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, about 100 μg / mL, about 110 μg / mL, about 120 μg / mL, about 130 μg / mL, about 140 μg / mL, about 150 μg / mL, about 160 μg / mL, about 170 μg / mL, about 180 μg / mL, about 190 μg / mL, about 200 μg / mL, about 210 μg / mL, about 220 μg / mL, about 230 μg / mL, about 240 μg / mL, about 250 μg / mL, about 260 μg / mL, about g / mL, about 270 μg / mL, about 280 μg / mL, about 290 μg / mL, about 300 μg / mL, about 310 μg / mL, about 320 μg / mL, about 330 μg / mL, about 340 μg / mL, about 350 μg / mL, about 360 μg / mL, about 370 μg / mL, about 380 μg / mL, about 390 μg / mL, about 400 μg / mL, about 410 μg / mL, about 420 μg / mL, about 430 μg / mL, about 440 μg / mL, about 450 μg / mL, about 460 μg / mL, about 470 μg / mL, about 480 μg / mL, about 490 μg / mL, about 500 μg / mL, about 510 μg / mL, about 520 μg / mL, about 530 μg / mL, about 540 μg / mL, about 550 μg / mL, about 560 μg / mL, about 570 μg / mL, about 580 μg / mL, about 590 μg / mL, about 600 μg / mL, about 610 μg / mL, about 620 μg / mL, about 630 μg / mL, about 640 μg / mL, about 650 μg / mL, about 660 μg / mL, about 670 μg / mL, about 680 μg / mL, about 690 μg / mL, about 700 μg / mL, about 710 μg / mL, about 720 μg / mL, about 730 μg / mL, about 740 μg / mL, about 750 μg / mL, about 760 0 μg / mL, about 770 μg / mL, about 780 μg / mL, about 790 μg / mL, about 800 μg / mL, about 810 μg / mL, about 820 μg / mL, about 830 μg / mL, about 840 μg / mL, about 850 μg / mL, about 860 μg / mL, about 870 μg / mL, about 880 μg / mL, about 890 μg / mL, about 900 μg / mL, about 910 μg / mL, about 920 μg / mL, about 930 μg / mL, about 940 μg / mL, about 950 μg / mL, about 960 μg / mL, about 970 μg / mL, about 980 μg / mL, about 990 μg / mL, or about 1000 μg / mL).

[0367] The present invention further relates to the use of a human anti-TTR antibody that binds to mutated, misfolded, misassembled and / or aggregated TTR species and / or fragments thereof and does not substantially recognize physiological TTR species in the preparation of a medicament for treating or preventing a subject having or at risk of having ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear and lumbar spinal stenosis), and pre-eclampsia). As outlined in more detail above, in one embodiment, the anti-TTR antibody is capable of binding to wild-type and mutant TTR aggregates. Additionally or alternatively, the anti-TTR antibody does not bind to physiological TTR tetramers, and more preferably does not bind to wild-type TTR monomers, and preferably does not bind to wild-type TTR dimers. Preferably, the antibody is as defined above.

[0368] The use comprises administering the drug at a dosing regimen that results in a sustained plasma concentration of the antibody in the subject with an AUC (e.g., the area under the plasma drug concentration-time curve in the subject after, for example, 17 weeks to 50 weeks of treatment / dosing) of about 2,000 μg*day / mL to about 100,000 μg*day / mL, about 2,500 μg*day / mL to about 100,000 μg*day / mL, about 5,000 μg*day / mL to about 100,000 μg*day / mL, or about 10,000 μg*day / mL to about 100,000 μg*day / mL (e.g., about 2,000 μg*day / mL, about 2,500 μg*day / mL, about 3,000 μg*day / mL, about 3,500 μg*day / mL, about 4,000 μg*day / mL, or about 5,000 μg*day / mL to about 100,000 μg*day / mL). 00 μg*day / mL, about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about 40,000 μg*day / mL, about 50,000 μg*day / mL, about 60,000 μg*day / mL, about 70,000 μg*day / mL, about 80,000 μg*day / mL, about 90,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about g*day / mL, about 40,000 μg*day / mL, about 50,000 μg*day / mL, about 60,000 μg*day / mL, about 70,000 μg*day / mL, about 80,000 μg*day / mL, about 90,000 μg*day / mL or about 100,000 μg*day / mL), preferably at least 30,000 μg*day / mL.

[0369] In some embodiments, the anti-TTR antibody is administered at a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., the area under the plasma drug concentration-time curve in a subject after 17 weeks of treatment / dosing) of about 2,000 μg*day / mL to about 50,000 μg*day / mL (e.g., about 2,000 μg*day / mL, about 2,500 μg*day / mL, about 3,000 μg*day / mL, about 3,500 μg*day / mL, about 4,000 μg*day / mL, about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 12,000 μg*day / mL, about 13,000 μg*day / mL, about 14,000 μg*day / mL, about 15,000 μg*day / mL, about 16,000 μg*day / mL, about 17,000 μg*day / mL, about 18,000 μg*day / mL, about 19,000 μg*day / mL, about 20,000 μg*day / mL, about 21,000 μg*day / mL, about 23,000 μg*day / mL, about 24,000 μg*day / mL, about 25,000 μg*day / mL, about 26,000 μg*day / mL, about 27,000 μg*day / mL, about 28,000 μg*day / mL, about 29,000 μg*day / mL, about 3 00 μg*day / mL, about 4,000 μg*day / mL, about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about 40,000 μg*day / mL, or about 50,000 μg*day / mL).

[0370] In some embodiments, the anti-TTR antibody is administered at a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., the area under the plasma drug concentration-time curve in a subject after 50 weeks of treatment / dosing) of about 2,500 μg*day / mL to about 100,000 μg*day / mL, about 5,000 μg*day / mL to about 100,000 μg*day / mL, or about 10,000 μg*day / mL to about 100,000 μg*day / mL (e.g., about 2,500 μg*day / mL, about 3,000 μg*day / mL, about 3,500 μg*day / mL, about 4,000 μg*day / mL, about 5,000 μg*day / mL, or about 6,000 μg*day / mL in a subject). , about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about 40,000 μg*day / mL, about 50,000 μg*day / mL, about 60,000 μg*day / mL, about 70,000 μg*day / mL, about 80,000 μg*day / mL, about 90,000 μg*day / mL or about 100,000 μg*day / mL).

[0371] In some embodiments, administration of anti-TTR antibodies can be used for long-term treatment and / or for subsequent treatment after an initial higher dose and amyloid removal (e.g., at a dose sufficient to achieve a sustained plasma concentration of about 1 μg / mL, 2.5 μg / mL, or 5 μg / mL).

[0372] The present invention further relates to the use of a human anti-TTR antibody in the preparation of a medicament for treating ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), senile systemic amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal / central nervous system (CNS) amyloidosis (including Alzheimer's disease), TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis (including carpal tunnel syndrome, rotator cuff tear and lumbar spinal stenosis), and pre-eclampsia) in a subject in need thereof, wherein:

[0373] (a) the use comprises once every 3 days to 56 days (e.g., every 3 days to about 35 days, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 ​​days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 61 days, 62 days, 63 days, 64 days, 65 days, 66 days, 67 days, 68 days, 69 days, 70 days, 71 days, 72 days, 73 days, 74 days, 75 days, 76 days, 77 days, 78 days, 79 days, 80 days, 81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days or the use comprises administering the drug to the subject once every 3 to 56 days (e.g., every 3 days to about 35 days, such as 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days or 42 days) at a dose of about 0.3 mg / kg to about 100 mg / kg; or the use comprises administering the drug to the subject once every 3 to 56 days (e.g., every 3 days to about 35 days, such as 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days,

[0374] 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days,

[0375] 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days,

[0376] Once every 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days or 42 days), preferably once every 4 weeks (q4w), at a dose of about 600 mg to about 7500 mg, preferably about 2500 mg, 3500 mg or 5000 mg, or about 2400 mg, 3200 mg or 4800 mg, respectively, and

[0377] (b) the antibody or antigen-binding fragment thereof comprises a fragment thereof that is at least 80% (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 11

[0378] The light chain variable region comprises a heavy chain variable region that has at least 80% (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 8.

[0379] 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity, or wherein the antibody is an equivalent antibody with substantially the same binding characteristics as defined herein; see also below. The heavy chain variable region comprises the CDRs shown in SEQ ID NOs: 1-3, and the light chain variable region comprises SEQ ID NO:

[0380] Most preferably, the antibody is a fully human IgG1m3 allotype antibody and thus comprises a human constant heavy chain (HC) as exemplified in SEQ ID NO: 9.

[0381] The amino acid sequence and the corresponding human constant light chain (LC) as exemplified in SEQ ID NO: 10, preferably have the above-identified post-translational modifications. The antibody or antigen-binding fragment thereof is present in the drug at a concentration of about 10 mg / mL to about 125 mg / mL. In some embodiments, the antibody is diluted from a concentrated stock solution before administration. Prior to administration to a subject, the concentration of the drug can be diluted, for example, into a dilution bag.

[0382] Treatment

[0383] Described herein are methods for preventing or treating a subject having or at risk of having a disease associated with ATTR (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and preeclampsia) by administering an anti-TTR antibody.

[0384] The treatment methods described herein provide improved signs of cardiac function (e.g., diastolic myocardial relaxation, atrioventricular (AV) flow, global longitudinal strain (GLS), ventricular ejection fraction, or end-diastolic volume) and a reduction (e.g., ≥5%, ≥10%, ≥20%, ≥30%, ≥40%, ≥60%, ≥80%, ≥90%, ≥100%, ≥110%, ≥120%, ≥180%, ≥130%, ≥160%, ≥170%, ≥180%, ≥190%, ≥200%, ≥200%, ≥200%, ≥300%, ≥300%, ≥400%, ≥500%, ≥600%, ≥180%, ≥190%, ≥200%, ≥200%, ≥3 ...

[0385] ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, ≥35%, ≥40%, ≥45%, ≥50%,

[0386] ≥55%, ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥90%, ≥95% or 100% reduction).

[0387] The methods described herein comprise administering a recombinant anti-TTR antibody that is capable of binding to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof and that does not substantially recognize physiological TTR species as outlined in more detail above. Such methods can treat a subject having or at risk of having a disease associated with ATTR (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and pre-eclampsia) or preventing the subject from having or at risk of having a disease associated with ATTR. The antibodies can be administered at a dosing regimen that results in a blood (e.g., serum or plasma) concentration in a subject that is maintained for a period of time (e.g., from about 1 day to about 1 week, from about 1 day to about 30 days, e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days) as described herein. Sustained blood (e.g., serum or plasma) concentrations can be, for example, at least 1 μg / mL, at least 2.5 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 20 μg / mL, at least 30 μg / mL, at least 40 μg / mL, at least 50 μg / mL, at least 60 μg / mL, at least 70 μg / mL, at least 80 μg / mL, at least 90 μg / mL, at least 100 μg / mL, at least 110 μg / mL, at least 120 μg / mL, at least 130 μg / mL, at least 140 μg / mL, at least 150 μg / mL, at least 160 μg / mL, at least 170 μg / mL, at least 180 μg / mL, at least 190 μg / mL, at least 200 μg / mL. / mL, at least 210 μg / mL, at least 220 μg / mL, at least 230 μg / mL, at least 240 μg / mL, at least 250 μg / mL, at least 260 μg / mL, at least 270 μg / mL, at least 280 μg / mL, at least 290 μg / mL, at least 300 μg / mL, at least 310 μg / mL, at least 320 μg / mL, at least 330 μg / mL, at least 340 μg / mL, at least 350 μg / mL, at least 360 μg / mL, at least 370 μg / mL, at least 380 μg / mL, at least 390 μg / mL, at least 400 μg / mL, at least 410 μg / mL, at least 420 μg / mL, at least 430 μg / mL,At least 440 μg / mL, at least 450 μg / mL, at least 460 μg / mL, at least 470 μg / mL, at least 480 μg / mL, at least 490 μg / mL, at least 500 μg / mL, at least 510 μg / mL, at least 520 μg / mL, at least 530 μg / mL, at least 540 μg / mL, at least 550 μg / mL, at least 560 μg / mL, at least 570 μg / mL, at least 580 μg / mL, at least 590 μg / mL, at least 600 μg / mL, at least 610 μg / mL, at least 620 μg / mL, 0 μg / mL, at least 630 μg / mL, at least 640 μg / mL, at least 650 μg / mL, at least 660 μg / mL, at least 670 μg / mL, at least 680 μg / mL, at least 690 μg / mL, at least 700 μg / mL, at least 710 μg / mL, at least 720 μg / mL, at least 730 μg / mL, at least 740 μg / mL, at least 750 μg / mL, at least 760 μg / mL, at least 770 μg / mL, at least 780 μg / mL, at least 790 μg / mL, at least 800 μg / mL mL, at least 810 μg / mL, at least 820 μg / mL, at least 830 μg / mL, at least 840 μg / mL, at least 850 μg / mL, at least 860 μg / mL, at least 870 μg / mL, at least 880 μg / mL, at least 890 μg / mL, at least 900 μg / mL, at least 910 μg / mL, at least 920 μg / mL, at least 930 μg / mL, at least 940 μg / mL, at least 950 μg / mL, at least 960 μg / mL, at least 970 μg / mL, at least 980 μg / mL, at least 9 The dosage may be at least 990 μg / mL or 1000 μg / mL and may be sustained for at least 3 days to about 42 days (e.g., about 3 days to about 35 days, about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days).

[0388] The antibody can also be administered at a dosing regimen that results in a sustained plasma concentration of the antibody in the subject with an AUC (e.g., the area under the plasma drug concentration-time curve in the subject following treatment / dosing) of about 2,000 μg*day / mL to about 100,000 μg*day / mL, about 2,500 μg*day / mL to about 100,000 μg*day / mL, about 3,000 μg*day / mL to about 100,000 μg*day / mL, about 5,000 μg*day / mL to about 100,000 μg*day / mL, or about 100,000 μg*day / mL. mL or about 10,000 μg*day / mL to about 100,000 μg*day / mL or about 2,000 μg*day / mL to about 50,000 μg*day / mL, about 5,000 μg*day / mL to about 50,000 μg*day / mL or about 10,000 μg*day / mL to about 50,000 μg*day / mL (e.g., about 2,000 μg*day / mL, about 2,500 μg*day / mL, about 3,000 μg*day / mL, about 3,500 μg*day / mL, about 4,000 μg*day / mL, 0 μg*day / mL, about 5,000 μg*day / mL, about 6,000 μg*day / mL, about 7,000 μg*day / mL, about 8,000 μg*day / mL, about 9,000 μg*day / mL, about 10,000 μg*day / mL, about 15,000 μg*day / mL, about 20,000 μg*day / mL, about 30,000 μg*day / mL, about 40,000 μg*day / mL, about 50,000 μg*day / mL, about 60,000 μg*day / mL, about 70,000 μg*day / mL, about 80,000 μg*day / mL, about 90,000 μg*day / mL or about 100,000 μg*day / mL. The sustained plasma concentration of the antibody as measured by AUC can vary depending on the duration of treatment. For example, after 17 weeks of treatment, the AUC is equivalent to about 2,000 μg*day / mL to about 50,000 μg*day / mL, and after 50 weeks of treatment, the AUC is equivalent to about 2,500 μg*day / mL to about 100,000 μg*day / mL.

[0389] A dosing regimen can include administering a dose of about 0.3 mg / kg to about 100 mg / kg (e.g., 0.3 mg / kg to 60 mg / kg, 0.3 mg / kg to 30 mg / kg, 0.3 mg / kg to about 10 mg / kg, 0.3 mg / kg to 1 mg / kg, 1 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 10 mg / kg to 30 mg / kg, 10 mg / kg to 60 mg / kg, 20 mg / kg to 30 mg / kg, 30 mg / kg to 40 mg / kg, 40 mg / kg to 50 mg / kg, 50 mg / kg to 60 mg / kg, 60 mg / kg to 70 mg / kg, 70 mg / kg to 80 mg / kg, 80 mg / kg to 90 mg / kg, or 90 mg / kg to 100 mg / kg) of the antibody or antigen-binding fragment thereof. For example, the antibody can be administered at a dose of about 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg of anti-TTR antibody. More particularly, the dosing regimen can include administering a first starting dose of about 0.3 mg / kg to about 60 mg / kg, about 0.3 mg / kg to about 30 mg / kg, and preferably about 0.3 mg / kg to about 10 mg / kg, and a further maintenance dose of about 10 mg / kg to about 100 mg / kg, about 10 mg / kg to about 80 mg / kg, and preferably about 10 mg / kg to about 60 mg / kg, and most preferably about 30 mg / kg or 60 mg / kg.

[0390] In one embodiment, only a maintenance dose is administered.

[0391] Dosing regimens can also include administering a dose of about 300 mg to about 10,000 mg (e.g., about 600 mg to about 7500 mg, 600 mg to 1000 mg, 600 mg to 2000 mg, 600 mg to 4000 mg, 600 mg to 6000 mg, 1000 mg to 2000 mg, 2000 mg to 3000 mg, 3000 mg to 4000 mg, 4000 mg to 5000 mg, 5000 mg to 6000 mg, 6000 mg to 8000 mg, 8000 mg to 9000 mg, 9000 mg to 10000 mg). For example, the antibody can be administered at a dose of about 3000 mg or 3500 mg of the anti-TTR antibody. More particularly, the dosing regimen may include administering a maintenance dose of about 300 mg to about 10,000 mg, about 600 mg to about 10,000 mg, and preferably about 600 mg to about 7,500 mg. The dosing regimen may also include administering a loading dose of about 300 mg to 6,000 mg, about 600 mg to 5,000 mg, and preferably about 600 mg to 4,000 mg, wherein the loading dose is preferably administered prior to administering the maintenance dose, more preferably administered prior to administering the maintenance dose for up to two months, and most preferably administered prior to administering the maintenance dose for up to two months every other week.

[0392] The dosing regimen can include administering a fixed dose based on the subject's weight. Thus, the dosing regimen can include administering, for example, 2500 mg of anti-TTR antibody to a subject weighing about 40 kg to about ≤ 60 kg, administering, for example, about 3500 mg of anti-TTR antibody to a subject weighing about ≥ 60 kg to about 100 kg, and administering, for example, 5000 mg of anti-TTR antibody to a subject weighing about ≤ 100 kg.

[0393] Preferably, the dosing regimen can include administering, for example, 2400 mg of anti-TTR antibody to a subject weighing about 40 kg to about ≤ 60 kg, administering, for example, about 3200 mg of anti-TTR antibody to a subject weighing about ≥ 60 kg to about 100 kg, and administering, for example, 4800 mg of anti-TTR antibody to a subject weighing about ≤ 100 kg.

[0394] An anti-TTR antibody can be administered to a subject once every 3 to 42 days (e.g., about every 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days), and preferably once every 21 to 35 days, preferably about once every 28 to 35 days, most preferably about once every 28 days or about once every 35 days, and most preferably once every 4 weeks. The anti-TTR antibody can be administered via subcutaneous infusion or continuous infusion via a pump, for example, once a week.

[0395] The anti-TTR antibody is administered to the subject at a dose of about 30 mg / kg for at least 12 months (eg, about 12 months to 18 months, eg, about 12 months).

[0396] Additional details regarding anti-TTR antibodies, dosing regimens (e.g., antibody dosage, frequency of administration, and / or duration of treatment), antibody formulations (e.g., pharmaceutical compositions), subjects to be treated, and how to monitor and assess the efficacy of treatment are described herein.

[0397] Antibody

[0398] As described herein, anti-TTR antibodies can be administered to a subject (e.g., a human) to treat or prevent a disease or condition (e.g., ATTR or ATTR-CM) (e.g., to achieve prevention of the aforementioned diseases). The methods described herein for treating or preventing a disease associated with ATTR (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and preeclampsia) utilize an anti-TTR antibody, e.g., a human anti-TTR antibody. The anti-TTR antibody herein can be one that is capable of binding (e.g., as determined by a dissociation constant (K)). D any antibody that is resistant to (a) mutated, misfolded, misassembled and / or aggregated TTR species and / or fragments thereof, and may not substantially recognize physiological TTR species.

[0399] Preferably, the antibody can be one that exhibits high binding affinity for misfolded TTR in the subnanomolar range, is highly selective for the amyloid conformation of TTR, that is, selectively binds to disease-associated ATTR aggregates with high affinity, and exerts similar binding to wild-type TTR and variant TTR. Any antibody that is associated with sporadic or hereditary diseases, does not bind to physiological TTR monomers, and / or binds to ATTR deposits in cardiac tissue obtained from ATTR-CM patients at autopsy. Binding characteristics can be determined using conventional methods in the art, such as ELISA assays, surface plasmon resonance (SPR) analysis, dot blot analysis, time-course aggregation studies, immunoprecipitation experiments, and immunohistochemistry (IHC), as described, for example, in Michalon et al., Nat Commun. 12 (2021), 3142.

[0400] For example, the anti-TTR antibodies described herein can have different K values ​​for different TTR isoforms. D , such as K for wild-type native TTR D >300 nM, and / or K for denatured TTR D ≤15 nM, such as ≤5 nM, such as ≤2 nM, and / or K for native TTR-V30M D ≤35 nM, e.g., ≤20 nM, for K of native TTR-V122I D ≤5 nM, and / or K for native TTR-L55P D ≤150 nM, for example ≤5 nM, such as ≤2 nM.

[0401] Exemplary heavy chain variable (VH) regions, light chain variable (VL) regions, and complementarity determining regions (CDRs) of anti-TTR antibodies and antigen-binding fragments thereof are shown in Table 1 below. CDR sequences are defined by the Kabat system (bioinf.org.uk / abs / ). SEQ ID NO: 1 (VH-CDR1) represents residues 31-35 (Kabat numbering) of SEQ ID NO: 7 (VH). SEQ ID NO: 2 (VH-CDR2) represents residues 52-67 (Kabat numbering) of SEQ ID NO: 7 (VH). SEQ ID NO: 3 (VH-CDR3) represents residues 100-109 (Kabat numbering) of SEQ ID NO: 7 (VH).

[0402] SEQ ID NO: 4 (VL-CDR1) represents residues 31-35 (Kabat numbering) of SEQ ID NO: 8 (VL). SEQ ID NO: 5 (VL-CDR2) represents residues 52-67 (Kabat numbering) of SEQ ID NO: 8 (VL). SEQ ID NO: 6 (VL-CDR3) represents residues 100-109 (Kabat numbering) of SEQ ID NO: 8 (VL).

[0403] Table 1. Anti-TTR antibody sequences

[0404]

[0405] Table 1. Anti-TTR antibody sequences

[0406]

[0407] CDR = complementarity determining region; VH = heavy chain variable region; VL = light chain variable region, HC = heavy chain; LC = light chain.

[0408] **N-terminal glutamate has been modified to pyroglutamate

[0409] The anti-TTR antibody or antigen-binding fragment thereof may comprise one or more CDR sequences comprising an amino acid sequence having about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and / or SEQ ID NO: 6. In addition, the anti-TTR antibody or antigen-binding fragment thereof may comprise one or more CDR sequences having an amino acid sequence with 1, 2, or 3 mismatches relative to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and / or SEQ ID NO: 6. In a specific example, the anti-TTR antibody or antigen-binding fragment thereof comprises six CDR amino acid sequences that have 100% sequence identity to the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

[0410] The anti-TTR antibody or antigen-binding fragment thereof can have a VH region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In a specific example, the anti-TTR antibody or antigen-binding fragment thereof has a VH region comprising an amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO: 7.

[0411] The anti-TTR antibody or antigen-binding fragment thereof can have a VL region comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In a specific example, the anti-TTR antibody or antigen-binding fragment thereof has a VL region comprising an amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO: 8.

[0412] The anti-TTR antibody or antigen-binding fragment thereof can have a VH region comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 11. In a specific example, the anti-TTR antibody or antigen-binding fragment thereof has a VH region comprising an amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO: 11.

[0413] The anti-TTR antibody or antigen-binding fragment thereof can have a VL region comprising an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 12. In a specific example, the anti-TTR antibody or antigen-binding fragment thereof has a VL region comprising an amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO: 12.

[0414] In some embodiments, the anti-TTR antibody is an anti-TTR antibody described in U.S. Patent Nos. 10,344,080 or 11,180,545 (each of which is incorporated herein by reference in its entirety). The anti-TTR antibody may be an anti-TTR antibody described in U.S. Publication No. US20220144928 (which is incorporated herein by reference in its entirety).

[0415] Also within the scope of the present invention are anti-TTR antibodies and antigen-binding fragments thereof in which specific amino acids have been substituted, deleted, or added. These modifications have no substantial effect on the biological properties of the anti-TTR antibodies (such as binding activity); see also below. For example, the antibodies may have amino acid substitutions in the framework regions (FRs) to improve binding to the antigen. In another example, a number of acceptor framework residues may be replaced with corresponding donor amino acids. The donor framework may be a mature or germline human antibody framework sequence or a consensus sequence. Guidance on how to make phenotypically silent amino acid substitutions is provided, for example, in Bowie et al. (Science, 247: 1306-1310, 1990), Cunningham et al. (Science, 244: 1081-1085, 1989), Ausubel (ed.) (Current Protocols in Molecular Biology, John Wiley and Sons, Inc., 1994), T. Maniatis, E.F. Fritsch and J. Sambrook (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor laboratory, Cold Spring Harbor, NY, 1989), Pearson (Methods Mol. Biol. 243: 307-31, 1994), and Gonnet et al. (Science 256: 1443-45, 1992); each of these references is incorporated herein by reference.

[0416] The variant antibodies or antigen-binding fragments thereof are functionally active and may have, for example, less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5% or about 1% of the amino acids substituted or deleted, while retaining substantially the same immunological properties, including but not limited to binding to TTR, as described herein, i.e., equivalent antibodies having substantially the same binding properties to TTR as the exemplary antibodies comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8, in U.S. Patents 10,344,080 B2 and 11,180,545 B2; see also supra, (corresponding to International Application No. WO 99 / 026664). 2015 / 092077A1, wherein the antibody is designated NI-301.37F1) and in Michalon et al., Nat. Commun. 12 (2021), 3142 (designated antibody NI301A), the antibody is characterized in that (i) it selectively binds to disease-associated ATTR aggregates with high affinity, (ii) it binds to misfolded / aggregated wild-type TTR and variant TTR associated with sporadic and inherited diseases, respectively, and to ATTR deposits in cardiac tissue obtained from ATTR-CM patients at autopsy, but does not substantially bind to native TTR monomers, and importantly, it is able to remove ATTR fibrils by macrophage-mediated phagocytosis. The latter property can be easily tested as described in international application WO 2020 / 094883A1; see also Michalon et al. (2021), supra.

[0417] Antibodies or antigen-binding fragments thereof may also include variants, including, for example, humanized or chimeric antibodies or antigen-binding fragments thereof, analogs, orthologs, homologs, and derivatives of exemplary antibodies that exhibit biological activity, for example, binding of antigens such as TTR. Antibodies may contain one or more amino acid analogs (including, for example, non-naturally occurring amino acids, amino acids that occur naturally only in unrelated biological systems, modified amino acids from mammalian systems, etc.), antibodies with substituted bonds, and other modifications known in the art.

[0418] The anti-TTR antibody fragment may be selected from the group consisting of bis-Fab, Fab, Fab'-SH, Fv, scFv and (Fab')2 fragments.

[0419] In certain embodiments, the anti-TTR antibody is a monoclonal antibody (mAb). The anti-TTR antibody can be a human antibody or a chimeric antibody. The anti-TTR antibody can be an IgG antibody. The anti-TTR antibody can be a recombinant human IgG1 antibody.

[0420] In one embodiment, the human anti-TTR antibody or antigen-binding fragment thereof does not elicit an anti-drug antibody (ADA) response in a human subject. The anti-TTR antibody or antigen-binding fragment thereof can have a VH region comprising an amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO: 7 and a VL region comprising an amino acid sequence having 100% sequence identity to the amino acid sequence of SEQ ID NO: 8.

[0421] In this context, one skilled in the art will recognize that effector function and strength may depend, inter alia, on the IgG class or isotype, and that IgG2 and IgG4 have only reduced effector function compared to IgG1 or IgG3. Thus, in one embodiment, the anti-TTR antibodies described herein may be of the IgG1 or IgG3 class or isotype, such as IgG1. Of course, in addition to using native IgG immunoglobulins, corresponding effector functions may also be genetically engineered; see, for example, Saunders KO (2019) Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life. Front. Immunol. 10: 1296. doi: 10.3389 / fimmu.2019.01296.

[0422] The five main classes of immunoglobulins are IgG, IgM, IgA, IgD, and IgE. These are distinguished by the type of heavy chain found in the molecule. IgG molecules have a heavy chain called a gamma chain; IgM has a μ chain; IgA has an alpha chain; IgE has an epsilon chain; and IgD has a delta chain; see reviews, e.g., Schroeder et al., J. Allergy Clin. Immunol. 125 (2010), S41-S52. In addition, there are different subclasses, with IgA being further divided into subclasses IgA1 and IgA2, and IgG being further divided into subclasses IgG1, IgG2, IgG3, and IgG4. In addition, there are two types of light chains, kappa (κ) and lambda (λ).

[0423] In principle, the antibodies used according to the present invention can be of any class and subclass, respectively, and can comprise any type of light chain, as long as the antibody binds to misfolded and preferably aggregated forms of TTR, and preferably, as long as the binding specificity of the antibody NI-301.37F1 for TTR, as shown in the Examples of WO 2015 / 092077A1, remains qualitatively unaffected, and as long as no side effects occur when the antibody is administered to a patient, where side effects can be determined as described in Example 1. However, it is preferred to use intact IgG antibodies, where the antibody comprises a constant domain. Thus, in one embodiment, the immunoglobulin heavy and / or light chain constant domains present in the antibodies used according to the present invention are of the IgG, IgM, IgA, IgD or IgE type, preferably of the IgG type. In one embodiment, the immunoglobulin heavy and / or light chain constant domains present in the antibodies used according to the invention are of the IgA1, IgA1, IgG1, IgG2, IgG3 or IgG4 subclass, preferably of the IgG1, IgG2, IgG3 or IgG4 subclass, and most preferably of the IgG1 subclass.

[0424] As described above, NI006 / ALXN2220 induces antibody-mediated phagocytosis of ATTR fibrils by phagocytic immune cells (such as macrophages), thereby leading to the clearance of ATTR deposits from tissues. Thus, in one embodiment, the antibody comprises a region equivalent to a human IgG constant region that is capable of mediating phagocytosis, such as an IgA subclass or an engineered Fc region, as described, for example, in Liu et al., Antibodies 9 (2020), 64.

[0425] Recombinant expression of intact human IgG1 antibodies with human or mouse constant domains can be performed essentially as described in the Examples of WO 2015 / 092077 A1. Preferably, the antibody is a monoclonal antibody or is derived from a monoclonal antibody.

[0426] Not only do the four IgG subclasses mentioned above exist, but human heavy and light chain genes also exhibit extensive structural polymorphisms and are closely linked, inherited as haplotypes. Allotypic variants can be immunogenic and cause antibody responses due to allotypic immunity. Therefore, converting allotypes is particularly meaningful for providing non-immunogenic antibody therapeutics. So far, a wide range of allotypes (polymorphisms) are known, but emphasis is placed on the allotypes defined serologically. The allotypes of IgG proteins are defined by the expression of unique epitopes recognized by unique serological reagents. The allotypes expressed on the constant region of the IgG heavy chain are named Gm (genetic marker) together with the subclass (e.g., G1m) and allotype number (or letter) (e.g., G1m1 [or G1m (a)], G3m5 [or G3m (b1)]). Human immunoglobulin allotypes are listed in Table 1 of Jefferis and Lefrance, mAbs 1 (2009), 1-7 and in Table 1 of Irani et al., Molecular Immunology 67 (2015), 171-182. Figure 1 A, the contents of which are incorporated herein by reference. Thus, in one embodiment, the antibody for use according to the present invention is any of the following allotypes, but not limited to the following: G1m1, G1m2, G1m3, G1m17, G2m23, G3m21, G3m28, G3m11, G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1, A2m2, A2m3, Em1, Km1, Km2, and Km3, but preferably G1m2, G1m3, or G1m17, and most preferably G1m3.

[0427] As described above, antibody NI006 / ALXN2220 is a fully human IgG1m3 allotype antibody and is composed of two identical heavy chains of the IgG1 subclass and IgG1m3 allotype. Furthermore, as described above, the original human antibody NI-301.37F1 is of the κ subtype, and thus NI006 / ALXN2220 is composed of two identical light chains of the κ subclass. The sequences of the variable heavy (VH) and variable light (VL) chains of NI006 / ALXN2220 are shown in SEQ ID NOs: 2 and 6, and the sequences of the corresponding human constant regions are known in the art. For example, each isotype, and similar IgG1m3 isotypes, have a unique amino acid sequence in the constant region of their heavy chains; see Jefferis and Lefrance (2009), supra. Thus, in one embodiment, the antibody present in the pharmaceutical formulation of the invention is characterized by two heavy chains, wherein each heavy chain (HC) comprises the amino acid sequence shown in SEQ ID NO: 9; and two light chains, wherein each light chain (LC) comprises the amino acid sequence shown in SEQ ID NO: 10. Each heavy chain consists of 450 amino acid residues, and each light chain consists of 214 amino acid residues. The four chains are stabilized by intrachain and interchain disulfide bonds, wherein the positions of the disulfide bonds identified by Lys-C and trypsin digestion and subsequent LC-MS (see Example 7) are as follows:

[0428] LC:C23-LC:C88

[0429] LC:C134-LC:C194

[0430] LC:C214-HC:C223

[0431] HC:C22-HC:C97

[0432] HC:C147-HC:C203

[0433] HC1:229-HC2:229 and HC1:232-HC2:232

[0434] HC:C264-HC:C324

[0435] HC:C370-HC:C428.

[0436] (Amino acid numbering corresponds to the heavy chain sequence shown in SEQ ID NO: 9)

[0437] Thus, the antibodies used according to the invention may be characterised in that they comprise at least 8 disulfide bridges, preferably at the positions identified above.

[0438] In addition, each heavy chain of antibody NI006 / ALXN2220 contains a single N-linked glycosylation site at Asn300. The N-linked glycosylation structures are primarily fucosylated complex biantennary glycans with either zero galactose residues (GOF) (approximately 49%) or one galactose residue (G1F) (approximately 25%). A detailed glycosylation profile is shown in Example 7. Glycosylation plays a crucial role in the stability, in vivo activity, solubility, serum half-life, and immunogenicity of many therapeutic proteins. N-glycan analysis determines the relative distribution of N-glycans released from glycoproteins and provides insightful information about the safety and efficacy of biotherapeutics.

[0439] Thus, in a preferred embodiment, the antibody for use according to the present invention is an IgG antibody and has an N-glycosylated heavy chain, preferably wherein the N-linked glycosylation site is Asn300, preferably, if expressed, for example, in CHO cells, wherein the antibody comprises an N-linked glycosylation structure that is predominantly glycans with zero galactose residues (GOF) (about 49%) or with one galactose residue (G1F) (about 25%). Most preferably, the antibody has a glycosylation profile as shown in Example 7.

[0440] Furthermore, one or several amino acids at the amino or carboxyl terminus of the light and / or heavy chain, such as the C-terminal lysine of the heavy chain (if present), may be deleted or derivatized in part or all of the molecule.

[0441] Thus, in one embodiment, the antibody present in the pharmaceutical composition of the present invention has a heavy chain that does not contain a C-terminal lysine. For example, in such an embodiment, the C-terminal lysine contained in SEQ ID NO: 9 is deleted. The sequence of such a heavy chain is shown in SEQ ID NO: 13.

[0442] Additionally or alternatively, the antibody has a heavy chain in which the N-terminal glutamine is derivatized, preferably replaced with pyroglutamic acid. This pyroglutamic acid formation is also referred to as N-terminal cyclization. The sequence of such a heavy chain is shown in SEQ ID NO: 14 or SEQ ID NO: 15.

[0443] Most preferably, the antibody has a heavy chain that does not comprise a C-terminal lysine, i.e., the C-terminal lysine has undergone C-terminal lysine cleavage, wherein the glutamine at the N-terminus is replaced by pyroglutamate, i.e., it has undergone N-terminal glutaminyl cyclization (see SEQ ID NO: 15), and which is N-glycosylated.

[0444] The amino acid sequences of the heavy and light chains are shown below:

[0445] QLQLQESGPGLVKPSETLSLTCSVSGGSIISRSSYWGWIRQPPGKGLEWIGGIYHSGNTYDNPSLKSRLTMSVDTSKNQFSLNLRSVTAADTAVYYCARIVPGGDAFDIWGQGTMVTVSS ASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0446] (SEQ ID NO:9, NI006 / ALXN2220, heavy chain amino acid sequence, wherein the amino acids of the constant region are underlined, and wherein the C-terminal lysine (K) is optional and / or the N-terminal glutamine (Q) undergoes intramolecular cyclization, resulting in the formation of pyroglutamate)

[0447] DIQMTQSPSSSLSASVGDRVTIACRASQSVGTYLNWYQQKRGKAPKLLIFAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSSPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0448] (SEQ ID NO: 10, NI006 / ALXN2220, light chain amino acid sequence, wherein the amino acids of the constant region are underlined).

[0449] Furthermore, the theoretical molecular weight of antibody NI006 / ALXN2220 is 144.2 kDa, and the weights determined by mass spectrometry (MS) are 144.2 kDa (deglycosylated) and 147.0 kDa to 147.6 kDa (intact IgG1), respectively. Thus, in one embodiment, the antibody contained in the pharmaceutical composition of the present invention has a molecular weight of about 150 kDa, preferably about 147 kDa.

[0450] Antibody preparations

[0451] Any of the anti-TTR antibodies or antigen-binding fragments thereof described herein and used according to the present invention (e.g., an anti-TTR antibody comprising a VH region having the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 11 and a VL region having the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 12, preferably an anti-TTR antibody comprising a VH region having the amino acid sequence of SEQ ID NO: 11 and a VL region having the amino acid sequence of SEQ ID NO: 8, or an equivalent antibody with substantially the same binding properties, and an anti-TTR antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9, preferably includes the PTMs mentioned above, e.g., an anti-TTR antibody having a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO: 13, 14 or 15, preferably SEQ ID NO: 15, preferably wherein the N-terminus is cyclized and wherein the HC is N-glycosylated, and the light chain comprising the amino acid sequence of SEQ ID NO: 13, 14 or 15, preferably SEQ ID NO: 15, preferably wherein the N-terminus is cyclized and wherein the HC is N-glycosylated, NO:10 amino acid sequence) can be formulated at a concentration of about 1 mg / mL to about 500 mg / mL (e.g., 25 mg / mL to 200 mg / mL, such as 25 mg / mL, 50 mg / mL, 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, or 200 mg / mL). For example, the anti-TTR antibody can be provided in the form of an aqueous formulation (e.g., a pharmaceutical composition) at a concentration of about 10 mg / mL to about 125 mg / mL, such as about 10 mg / mL to about 90 mg / mL, such as about 20 mg / mL to about 80 mg / mL, such as about 25 mg / mL to about 75 mg / mL, such as about 25 mg / mL to about 125 mg / mL. Exemplary antibodies with the same binding specificity, in particular strong binding to misfolded-aggregated TTR but not to physiological TTR monomers, are provided, for example, in WO 2015 / 092077A1, such as antibodies NI-301.59F1 and NI-301.35G11, the contents of which are incorporated herein by reference.

[0452] For example, an anti-TTR antibody is administered at about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, or about 55 mg / mL.

[00145] In some embodiments, an anti-TTR antibody described herein is formulated in an aqueous solution (e.g., a pharmaceutical composition) at about 1 mg / mL, about 20 mg / mL, about 35 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, or about 125 mg / mL.

[0453] In one example, the anti-TTR antibody is provided in a vial (e.g., a glass vial) at a concentration of 50 mg / mL (±12%) or 100 mg / mL (±12%) as an aqueous solution. The total volume of the aqueous solution in the vial can be about 1 mL to about 200 mL, about 1 mL to about 150 mL, about 1 mL to about 100 mL, about 1 mL to about 50 mL, about 5 mL to about 25 mL, about 18 mL to about 22 mL, or about 1 mL to about 10 mL (e.g., about 1 mL to about 2 mL, about 1 mL to about 1.8 mL, about 1 mL to about 1.6 mL, about 1 mL to about 1.4 mL, about 1 mL to about 1.2 mL, about 1.5 mL to about 1.25 mL, about 1.5 mL to about 2 mL, about 1.9 mL to about 1.2 mL, about 2.1 mL to about 2.25 mL), or about 1 mL to about 100 mL (e.g., about 1 mL, about 1.8 mL, about 1.9 mL, about about 24 mL, about 25 mL, about 26 mL, about 27 mL, about 28 mL, about 29 mL, about 30 mL, about 40 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, or about 100 mL). In another example, the total volume of the aqueous solution in the vial will be 2 mL (± 12%), 5 mL (± 12%), 10 mL (± 12%), 15 mL (± 12%), 20 mL (± 12%), 25 mL (± 12%), or 30 mL (± 12%). A subject can receive a quantity of vials sufficient to provide the desired total dose.

[0454] Subjects

[0455] The methods provided herein can be used to treat subjects with ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, preeclampsia, or a known pathogenic TTR mutation (e.g., a mutation that causes amyloidosis). The subject may have sporadic WT-ATTR-CM and be negative for genetic testing for TTR mutations. Genetic testing can be performed by standard laboratory techniques, e.g., DNA or RNA sequencing or protein sequencing using mass spectrometry.

[0456] In some examples, the subject to be treated has previously been treated with a TTR tetramer stabilizer (e.g., diflunisal, toflavone, and aclomide (AG10)). Alternatively, the subject can receive treatment with a TTR tetramer stabilizer (e.g., diflunisal, toflavone, and aclomide (AG10)) concurrently with treatment with an anti-TTR as described herein.

[0457] Administration of an anti-TTR antibody (e.g., at a specific dose, frequency, and / or duration of treatment as described below) can provide a therapeutic or prophylactic effect to a subject. This therapeutic or prophylactic effect of the antibody can result in a sustained blood (e.g., plasma or serum) concentration of the antibody in the subject of ≥1 μg / mL (e.g., ≥1 μg / mL, ≥2.5 μg / mL, ≥5 μg / mL, ≥10 μg / mL, ≥20 μg / mL, ≥30 μg / mL, ≥40 μg / mL, ≥50 μg / mL, ≥60 μg / mL, ≥70 μg / mL, ≥80 μg / mL, ≥90 μg / mL, ≥100 μg / mL, ≥110 μg / mL, ≥120 μg / mL, ≥130 μg / mL, ≥140 μg / mL, ≥150 μg / mL, ≥160 μg / mL, ≥170 μg / mL). , ≥180μg / mL, ≥190μg / mL, ≥200μg / mL, ≥210μg / mL, ≥220μg / mL, ≥230μg / mL, ≥240μg / mL, ≥250μg / mL, ≥260μg / mL, ≥270μg / mL, ≥280μg / mL, ≥290μg / mL, ≥300μg / mL, ≥310μg / mL, ≥320μg / mL, ≥330μg / mL, ≥340μg / mL, ≥350μg / mL, ≥360μg / mL, ≥370μg / mL, ≥380μg / mL, ≥390μg / mL, ≥400μg / mL, ≥410μg / mL, ≥420μg / mL, ≥430μg / mL, ≥440μg / mL, ≥450μg / mL, ≥460μg / mL, ≥470μg / mL, ≥480μg / mL, ≥490μg / mL, ≥500μg / mL, ≥510μg / mL, ≥520μg / mL, ≥530 μg / mL, ≥540μg / mL, ≥550μg / mL, ≥560μg / mL, ≥570μg / mL, ≥580μg / mL, ≥590μg / mL, ≥600μg / mL, ≥610μg / mL, ≥620μg / mL, ≥630μg / mL, ≥640μg / mL, ≥65 0μg / mL, ≥660μg / mL, ≥670μg / mL, ≥680μg / mL, ≥690μg / mL, ≥700μg / mL, ≥710μg / mL, ≥720μg / mL, ≥730μg / mL, ≥740μg / mL, ≥750μg / mL, ≥760μg / mL, ≥ 770μg / mL, ≥780μg / mL, ≥790μg / mL, ≥800μg / mL, ≥810μg / mL, ≥820μg / mL, ≥830μg / mL, ≥840μg / mL, ≥850μg / mL, ≥860μg / mL, ≥870μg / mL, ≥880μg / mL,or higher). In addition, such plasma concentration can continue for any time period (e.g., from about 1 day to about 1 week, from about 1 day to about 30 days, e.g., from about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days). For example, a plasma concentration can continue for 21 to 35 days at a >= 1 μg / mL location. For example, a plasma concentration can continue for 21 to 35 days at a >= 2.5 μg / mL location. For example, a plasma concentration can continue for 21 to 35 days at a >= 5 μg / mL location. For example, a plasma concentration can continue for 21 to 35 days at a >= 10 μg / mL location. Preferably, the indicated plasma concentrations can be sustained for 21 to 35 days, preferably 28 to 35 days, most preferably 28 or 35 days.

[0458] Alternatively, the therapeutic or prophylactic effect of the antibody can result in a sustained plasma concentration of the antibody with an area under the curve (AUC) of ≥2,000 μg*day / mL (e.g., ≥2,000 μg*day / mL, ≥4,000 μg*day / mL, ≥6,000 μg*day / mL, ≥8,000 μg*day / mL, ≥10,000 μg*day / mL, ≥12,000 μg*day / mL, ≥14,000 μg*day / mL, ≥16,000 μg*day / mL, ≥18,000 μg*day / mL, ≥20,000 μg*day / mL , ≥22,000μg*day / mL, ≥24,000μg*day / mL, ≥26,000μg*day / mL, ≥28,000μg*day / mL, ≥30,000μg*day / mL, ≥32,000μg*day / mL, ≥34,000μg*day / mL, ≥36,000μg*day / mL, ≥38,000μg*day / mL, ≥40,000μg*day / mL, ≥42,000μg*day / mL, ≥44,000μg*day / mL, ≥46,000μg*day / mL, ≥48,0 00μg*day / mL, ≥50,000μg*day / mL, ≥52,000μg*day / mL, ≥54,000μg*day / mL, ≥56,000μg*day / mL, ≥58,000μg*day / mL, ≥60,000μg*day / mL, ≥62,000μg*day / mL, ≥64,000μg*day / mL, ≥66,000μg*day / mL, ≥68,000μg*day / mL, ≥70,000μg*day / mL, ≥72,000μg*day / mL, ≥74,000μg*day / mL, ≥76,000 μg*day / mL, ≥78,000 μg*day / mL, ≥80,000 μg*day / mL, ≥82,000 μg*day / mL, ≥84,000 μg*day / mL, ≥86,000 μg*day / mL, ≥88,000 μg*day / mL, ≥90,000 μg*day / mL, ≥92,000 μg*day / mL, ≥94,000 μg*day / mL, ≥96,000 μg*day / mL, ≥98,000 μg*day / mL, ≥100,000 μg*day / mL).

[0459] Monitor and evaluate treatment

[0460] Those skilled in the art (e.g., clinicians) can monitor and assess the efficacy of treatment. Methods for monitoring and assessing the efficacy of treatment are described below.

[0461] For any of the methods described herein, the efficacy of treatment can be assessed or monitored according to standard techniques known in the art. For example, the administration of an anti-TTR antibody or its pharmaceutical composition can be monitored by measuring the level (e.g., mRNA or protein level) of one or more biomarkers (e.g., biomarkers of ATTR). Exemplary biomarkers include cardiac troponin T (TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), C3, C4, IL1b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, serum amyloid A (SAA), ferritin, ATTR, galectin 3 (Gal-3), soluble oncogenic inhibitor 2 (sST2), type 1 procollagen carboxyl-terminal propeptide (PICP), and type III procollagen propeptide (PIIINP). In some embodiments, administration of an anti-TTR antibody is monitored by measuring the level of one or more biomarkers, such as cardiac troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a preferred embodiment, administration of an anti-TTR antibody or a pharmaceutical composition thereof can be monitored by measuring the level (e.g., mRNA or protein level) of N-terminal pro-B-type natriuretic peptide (NT-proBNP).

[0462] In one embodiment, a decrease in the level of a biomarker indicates efficacy of the treatment.

[0463] For example, a subject may have an NT-proBNP level of about 300 pg / mL to about 20,000 pg / mL prior to undergoing a treatment method described herein, and may have a level of about 0 pg / mL to about 300 pg / mL after undergoing a treatment method described herein. Preferably, a subject may have an NT-proBNP level of >2000 pg / mL prior to undergoing a treatment method described herein.

[0464] In another example, a subject can have a TnT level of about 10 pg / mL to about 200 pg / mL prior to undergoing the treatment methods described herein, and can have a level of 0 pg / mL to about 10 pg / mL after undergoing the treatment methods described herein.

[0465] Any reduction (e.g., a 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction) in TnT or NT-proBNP levels (e.g., over time, such as within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or relative to untreated ATTR subjects) indicates therapeutic efficacy. For example, a subject with ATTR or ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or pre-eclampsia can have high levels (e.g., about 300 pg / mL to about 20,000 pg / mL) of NT-proBNP, and these levels can decrease over time in the blood (e.g., plasma or serum) of a subject treated with the methods described herein.

[0466] An increase in CRP levels, particularly a dose-dependent transient (e.g., from about 1 day to about 14 days, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days) increase in CRP levels (e.g., over time or relative to untreated ATTR subjects) also indicates on-target immune activation and efficacy of the treatment.

[0467] Any suitable laboratory technique for determining protein levels of biomarkers (e.g., TnT, NT-proBNP, and CRP) in a sample (e.g., blood, such as plasma or serum) can be used, including but not limited to flow cytometry (FC), fluorescence activated cell sorting (FACS), Western blot, enzyme-linked immunosorbent assay (ELISA), mass spectrometry (MS), immunofluorescence (IF), immunoprecipitation (IP), radioimmunoassay, dot blot, high performance liquid chromatography (HPLC), surface plasmon resonance, spectroscopy, and immunohistochemistry (IHC). Any suitable laboratory technique for determining mRNA expression levels of biomarkers (e.g., TnT, NT-proBNP, and CRP) in a sample can be used, including but not limited to PCR, RT-PCR, qPCR, RT-qPCR, microarray analysis, Northern blot, technology, SAGE and RNA sequencing.

[0468] In order to detect and measure the level of CRP, the above-mentioned test kit can also be used, and the test kit includes a reagent for detecting and measuring the level of CRP in the sample of the patient. As mentioned above, the means and methods for detecting CRP are well known to those skilled in the art; See, for example, the documents cited in paragraphs

[0010] to

[0017] of US2006 / 0246522A1 and US2006 / 0246522A1. Generally speaking, the detection of CRP can be achieved by any suitable method. Exemplary detection methods include immunoassays (for example, by using antibodies specifically binding to CRP), optical methods (for example, confocal and non-confocal microscopy, detection of fluorescence, luminescence, chemifluorescence, absorbance, reflectivity, transmittance and birefringence or refractive index (for example, surface plasmon resonance, ellipsometry, resonant mirror method, grating coupler waveguide method or interferometry)), electrochemical methods (voltammetry and amperometry techniques), atomic force microscopy and radio frequency methods (for example, multipolar resonance spectroscopy). In this case, a standard immunoassay can be used to detect CRP, wherein the immunoassay can be performed in a variety of different formats and generally involves detecting the binding between an anti-biomarker antibody (e.g., an anti-CRP antibody) and its target biomarker antigen (e.g., CRP) in a biological sample obtained from a patient. The immunoassay can be performed in any of a variety of formats, and generally, the assay will measure the reactivity between the anti-biomarker antibody and the patient sample. For example, commercially available kits for detecting CRP are available to technicians, such as ELISA kits, for example, the CRP / C-reactive protein ELISA kit from LifeSpan BioSciences, Seattle, Washington, USA.

[0469] Additional methods for monitoring or evaluating the efficacy of treatment can include monitoring or evaluating the level of cardiac amyloid burden and heart mass in a subject. A subject with an ATTR-related disease (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia) can have ≥20% (e.g., about 20% to about 60%, e.g., 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 400%, 500%, 600%, 700%, 800%, 900%, 1100%, 1200%, 1300%, 1300%, 1 In some embodiments, the present invention relates to a subject having a left ventricular ejection fraction (LVEF) of at least 12 mm (e.g., about 12 mm to about 30 mm, e.g., about 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, or 30 mm) prior to undergoing the treatment methods described herein. A reduction in the level of cardiac amyloid burden or heart mass (e.g., a 5% to 100% reduction relative to a control) indicates therapeutic efficacy of the treatment described herein in the subject. For example, a reduction in left ventricular heart mass of about 5% to about 25% over a treatment period of about 17 weeks to about 50 weeks indicates therapeutic efficacy for the subject. In another example, a reduction in cardiac amyloid burden of about 5% to about 75% over a treatment period of about 17 weeks to about 50 weeks indicates therapeutic efficacy in the subject.Heart mass reduction and cardiac amyloid burden can be measured by cardiac magnetic resonance imaging (MRI).

[0470] Additional examples for monitoring or evaluating the efficacy of treatment may include monitoring and evaluating cardiac function, which can be evaluated by echocardiography. For example, echocardiography can be used to measure systolic function (strain), thickness, and filling pressures, as well as LVEF, left ventricular end-diastolic / end-systolic internal diameter, systolic function, left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), left ventricular diastolic function, right ventricular function, global longitudinal strain, end-diastolic-interventricular septum (ED-IVS), and / or end-diastolic-posterior wall (ED-PW).

[0471] Other readings used to assess treatment efficacy include the 6-minute walk test (6-MWT), the Kansas City Cardiomyopathy Questionnaire (KCCQ), magnetic resonance imaging (MRI), and bone scintigraphy. The 6-MWT is a submaximal exercise test used to assess walking endurance and aerobic capacity. The subject will walk for a total of 6 minutes around a set circular route. The score of the test is the distance the subject walks on a flat, hard surface within 6 minutes (measured in meters and rounded to the nearest decimal point). The KCCQ is a 23-item self-administered questionnaire developed to independently measure the subject's perception of their health status. The questionnaire includes heart failure symptoms, the impact on physical and social functioning, and how their heart failure affects their quality of life during a 2-week recall period. MRI can assess morphological (e.g., LV mass) and functional (e.g., LV ejection fraction, global longitudinal strain) characteristics. Bone scintigraphy can be used to assess the heart retention (HR) / whole body retention (WBR) ratio and the heart retention (HR) / skull retention (SR) ratio.

[0472] Dosage regimen

[0473] Any anti-TTR antibody or pharmaceutical composition thereof used according to the present invention can be administered to a subject in a dosing regimen to treat or prevent ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia in the subject. The dosage, frequency of administration, and / or duration of treatment of the anti-TTR antibody (or fragment thereof or pharmaceutical composition) are described below.

[0474] dose

[0475] For any of the methods described herein, an anti-TTR antibody or pharmaceutical composition thereof can be administered to a subject at a dose (e.g., a maintenance dose and / or a loading dose) of about 0.3 milligrams per kilogram (mg / kg) of body weight to about 100 mg / kg (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, 60 mg / kg, or 100 mg / kg).For example, the anti-TTR antibodies used according to the present invention can be administered at about 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / k g, 31mg / kg, 32mg / kg, 33mg / kg, 34mg / kg, 35mg / kg, 36mg / kg, 37mg / kg, 38mg / kg, 39mg / kg, 40mg / kg, 41mg / kg, 42mg / kg, 43mg / kg, 44mg / kg, 45m g / kg, 46mg / kg, 47mg / kg, 48mg / kg, 49mg / kg, 50mg / kg, 51mg / kg, 52mg / kg, 53mg / kg, 54mg / kg, 55mg / kg, 56mg / kg, 57mg / kg, 58mg / kg, 59mg / kg , 60mg / kg, 61mg / kg, 62mg / kg, 63mg / kg, 64mg / kg, 65mg / kg, 66mg / kg, 67mg / kg, 68mg / kg, 69mg / kg, 70mg / kg, 71mg / kg, 72mg / kg, 73mg / kg, 74mg In some embodiments, the present invention may be administered at a dose (e.g., a maintenance dose and / or a loading dose) of 100 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg, 200 mg / kg,

[0476] More particularly, the anti-TTR antibodies used according to the present invention can be preferably administered to a subject at a starting dose of about 0.3 mg / kg to 10 mg / kg, for example, about 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg or 10 mg / kg. In addition, the anti-TTR antibody used according to the present invention can be further and preferably administered at about 10 mg / kg to about 60 mg / kg, for example, about 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 A maintenance dose of 3 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg or 60 mg / kg was administered to the subject.

[0477] For example, and preferably, the anti-TTR antibody or pharmaceutical composition thereof can be administered at a dose of 30 mg / kg-60 mg / kg, such as 30 mg / kg or 60 mg / kg. The anti-TTR antibody can be administered at a dose of 30 mg / kg. The anti-TTR antibody can be administered at a dose of 60 mg / kg.

[0478] For any of the methods described herein, an anti-TTR antibody or pharmaceutical composition thereof can be administered (e.g., in a dosing regimen) at a dose (e.g., a maintenance dose and / or loading dose) of about 600 mg to about 7500 mg (e.g., 600 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 5000 mg, 6000 mg, 6240 mg, or 7500 mg). For example, an anti-TTR antibody can be administered at about 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg. , 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2 850mg, 2900mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg, 3350mg, 3400mg, 3450mg, 3500mg, 3550mg, 3600 mg, 3650mg, 3700mg, 3750mg, 3800mg, 3850mg, 3900mg, 3950mg, 4000mg, 4050mg, 4100mg, 4150mg, 4200mg, 4250mg, 4300mg, 4350mg , 4400mg, 4450mg, 4500mg, 4550mg, 4600mg, 4650mg, 4700mg, 4750mg, 4800mg, 4850mg, 4900mg, 4950mg, 5000mg, 5050mg, 5100mg, 51 50mg, 5200mg, 5250mg, 5300mg, 5350mg, 5400mg, 5450mg, 5500mg, 5550mg, 5600mg, 5650mg, 5700mg, 5750mg, 5800mg, 5850mg, 5900 mg, 5950mg, 6000mg, 6050mg, 6100mg, 6150mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg,6300 mg, 6350 mg, 6400 mg, 6450 mg, 6500 mg, 6550 mg, 6600 mg, 6650 mg, 6700 mg, 6750 mg, 6800 mg, 6850 mg, 6900 mg, 6950 mg, 7000 mg, 7050 mg, 7100 mg, 7150 mg, 7200 mg, 7250 mg, 7300 mg, 7350 mg, 7400 mg, 7450 mg or 7500 mg is administered as a maintenance dose and / or loading dose.

[0479] More particularly, the anti-TTR antibodies used according to the present invention may preferably be administered at a loading dose of about 600 mg to about 4000 mg (e.g., about 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2500 mg, 2600 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 3000 mg, 3100 mg, 3150 mg, 3200 mg, 3300 mg, 3350 mg, 3400 mg, 3500 mg, 350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg) are administered with a loading dose of 400 mg, 200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg. In one embodiment, the anti-TTR antibody used according to the present invention can be administered at a maintenance dose of preferably about 600 mg to about 7500 mg (e.g., about 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg). , 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 265 0mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg, 3350mg, 3400mg, 3450mg,3500mg, 3550mg, 3600mg, 3650mg, 3700mg, 3750mg, 3800mg, 3850mg, 3900mg, 3950mg, 4000mg, 4 050mg, 4100mg, 4150mg, 4200mg, 4250mg, 4300mg, 4350mg, 4400mg, 4450mg, 4500mg, 4550mg, 460 0mg, 4650mg, 4700mg, 4750mg, 4800mg, 4850mg, 4900mg, 4950mg, 5000mg, 5050mg, 5100mg, 5150m g, 5200mg, 5250mg, 5300mg, 5350mg, 5400mg, 5450mg, 5500mg, 5550mg, 5600mg, 5650mg, 5700mg, 5750mg, 5800mg, 5850mg, 5900mg, 5950mg, 6000mg, 6050mg, 6100mg, 6150mg, 6200mg, 6210mg, 62 20mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 6350mg, 6400mg, 6450 7500 mg, 7600 mg, 7650 mg, 7700 mg, 7750 mg, 7800 mg, 7850 mg, 7900 mg, 7950 mg, 7000 mg, 7050 mg, 7100 mg, 7150 mg, 7200 mg, 7250 mg, 7300 mg, 7350 mg, 7400 mg, 7450 mg, or 7500 mg).

[0480] For example, the anti-TTR antibody or pharmaceutical composition thereof can be administered at a dose of 2000 mg-5000 mg, such as 2400 mg, 2500 mg, 3000 mg, 3200 mg or 3500 mg, preferably 3500 mg or 3200 mg, most preferably 3200 mg.

[0481] Anti-TTR antibodies can be 2000 mg, 2010 mg, 2020 mg, 2030 mg, 2040 mg, 2050 mg, 2060 mg, 2070 mg, 2080 mg, 2090 mg, 2100 mg, 2110 mg, 2120 mg, 2130 mg, 2140 mg, 2150 mg, 2160 mg, 2170 mg, 2180 mg, 2190 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, 2300 mg, 2310 mg, 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg, 2410 mg, 2420 mg, 2430 mg, 2440 mg, 2450 mg, 2460 mg, 2470 mg, 2480 mg, 2490 mg, 2500 mg, 2510 mg, 2520 mg, 2530 mg, 2540 mg, 2550 mg, 2560 mg, 2570 mg, 2580 mg, 2590 mg, 2600 mg, 2610 mg, 2620 mg, 2630 mg, 2640 mg, 2650 mg, 2660 mg, 2670 mg, 2680 mg, 2690 mg, 2700 mg, 2710 mg, 2720 mg, 2730 mg, 2740 mg, 2750 mg, 2760 mg, 2770 mg, 2780 mg, 2790 mg, 2800 mg, 2810 mg, 2820 mg, 2830 mg, 2840 mg, 2850 mg, 2860 mg, 2870 mg, 2880 mg, 2890 mg, 2900 mg, 2910 mg, 2920 mg, 2930 mg, 2940 mg, 2950 mg, 2960 mg, 2970 mg, 2980 mg, 2990 mg, 3000 mg, 3010 mg, 3020 mg, 3030 mg, 3040 mg, 3050 mg, 3060 mg, 3070 mg, 3080 mg, 3090 mg, 3100 mg, 3110 mg, 3120 mg, 3130 mg, 3140 mg, 3150 mg, 3160 mg, 3170 mg, 3180 mg, 3190 mg, 3200 mg, 3210 mg, 3220 mg, 3230 mg, 3240 mg, 3250 mg, 3260 mg, 3270 mg, 3280 mg, 3290 mg, 3300 mg, 3310 mg, 3320 mg, 3330 mg, 3340 mg, 3350 mg, 3360 mg, 3370 mg, 3380 mg, 3390 mg, 3400 mg,3410mg、3420mg、3430mg、3440mg、3450mg、3460mg、3470mg、3480mg、3490mg、3500mg、3510mg、3520mg、3530mg、3540mg、3550mg、3560mg、3570mg、3580mg、3590mg、3600mg、3610mg、3620mg、3630mg、3640mg、3650mg、3660mg、3670mg、3680mg、3690mg、3700mg、3710mg、3720mg、3730mg、3740mg、3750mg、3760mg、3770mg、3780mg、3790mg、3800mg、3810mg、3820mg、3830mg、3840mg、3850mg、3860mg、3870mg、3880mg、3890mg、3900mg、3910mg、3920mg、3930mg、3940mg、3950mg、3960mg、3970mg、3980mg、3990mg、4000mg、4010mg、4020mg、4030mg、4040mg、4050mg、4060mg、4070mg、4080mg、4090mg、4100mg、4110mg、4120mg、4130mg、4140mg、4150mg、4160mg、4170mg、4180mg、4190mg、4200mg、4210mg、4220mg、4230mg、4240mg、4250mg、4260mg、4270mg、4280mg、4290mg、4300mg、4310mg、4320mg、4330mg、4340mg、4350mg、4360mg、4370mg、4380mg、4390mg、4400mg、4410mg、4420mg、4430mg、4440mg、4450mg、4460mg、4470mg、4480mg、4490mg、4500mg、4510mg、4520mg、4530mg、4540mg、4550mg、4560mg、4570mg、4580mg、4590mg、4600mg、4610mg、4620mg、4630mg、4640mg、4650mg、4660mg、4670mg、4680mg、4690mg、4700mg、4710mg、4720mg、4730mg、4740mg、4750mg、4760mg、4770mg、4780mg、4790mg、4800mg、4810mg、4820mg、4830mg、A dose of 4840 mg, 4850 mg, 4860 mg, 4870 mg, 4880 mg, 4890 mg, 4900 mg, 4910 mg, 4920 mg, 4930 mg, 4940 mg, 4950 mg, 4960 mg, 4970 mg, 4980 mg, 4990 mg or 5000 mg (e.g., a maintenance dose and / or a loading dose) is administered.

[0482] Most preferably, as further described above, a fixed dose is administered according to the body weight of the subject to be treated.

[0483] Any dose described herein can be administered to a subject as a maintenance dose and / or a loading dose. For example, a method of treating or preventing a disease associated with ATTR (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia) can include a step of administering an anti-TTR antibody at an initial dose of about 0.3 mg / kg to about 10 mg / kg (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg). In another example, the method can further include the step of administering the anti-TTR antibody at a maintenance dose of about 10 mg / kg to about 60 mg / kg (e.g., 10 mg / kg, 30 mg / kg, or 60 mg / kg) or at a total dose of about 600 mg to about 4000 mg (e.g., 2500 mg or 3000 mg).

[0484] The methods described herein contemplate administering an anti-TTR antibody to a subject more than once (e.g., in multiple doses). For example, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more) doses of an anti-TTR antibody can be administered. Further contemplated herein is an increase (e.g., an increase) in the administered dose. For example, the administration of two or more doses can include one, two, three, four, five, or six increases (e.g., increases) in the dose (e.g., if the subject does not respond or responds insufficiently to a previously administered dose). For example, raising can include an increase of 0.3mg / kg to 1mg / kg, 1mg / kg to 3mg / kg, 3mg / kg to 10mg / kg, 10mg / kg to 30mg / kg or 30mg / kg to 60mg / kg. Raising can occur at any point during the treatment of a subject. When it is determined that the blood (e.g., serum or plasma level) of the antibody is lower than a desired threshold value (e.g., less than 10 μg / mL), raising can be performed.

[0485] In a preferred embodiment, the anti-TTR antibody is administered at a fixed weight-based dosing regimen comprising: (a) 2400 mg for patients weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg); (b) 3200 mg for patients weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg); or (c) 4800 mg for patients weighing 100 kg or more (≥100 kg). Preferably, the weight-based dosing regimen is administered intravenously (IV) to adult patients.

[0486] Frequency and duration of treatment

[0487] For any of the methods described herein, an anti-TTR antibody or pharmaceutical composition thereof can be administered to a subject at a frequency of about once every 3 days to about once every 42 days (e.g., about once every 21 days to about once every 35 days or about once every 28 days to about once every 35 days). For example, an anti-TTR antibody can be administered at a dose described herein (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg, preferably 30 mg / kg or 60 mg / kg, or 2000 mg, 2400 mg, 2500 mg, 3000 mg, 3200 mg, 3500 mg, 4000 mg, 4800 mg, or 5000 mg, preferably 2500 mg, 3500 mg, or 5000 mg, and optimally In some embodiments, the present invention provides an oral administration of at least one bolus (e.g., 150 mg, 150 mg, 150 mg, 150 mg, or 150 mg) approximately every 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days.

[0488] In addition, treatment with an anti-TTR antibody can be administered to a subject for any duration, such as at least 6 months, 12 months, or 18 months (e.g., 1 week to 1 year). For example, an anti-TTR antibody can be administered to a subject for about 4 months to 30 months (e.g., about 4 months to 30 months or 12 months to 18 months). For example, an anti-TTR antibody can be administered to a subject for 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, or 30 months. Alternatively, an anti-TTR antibody can be administered to a subject at the frequencies described above (e.g., about once every 28 days to about once every 35 days) throughout the subject's lifetime.

[0489] Methods of treating or preventing a subject having or at risk of having ATTR, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or pre-eclampsia can utilize any combination of the above-described doses, frequencies, and / or treatment durations.

[0490] In a preferred embodiment, the anti-TTR antibody (eg, ALXN2220) is administered every four weeks (q4w).

[0491] Route of administration

[0492] Administration of the anti-TTR antibody to the subject can be performed, for example, subcutaneously or intravenously (e.g., by intravenous infusion). For example, the anti-TTR antibody can be administered intravenously using a metered syringe or an infusion bag in a syringe pump. If an infusion line is used for administration, the infusion line can be flushed before and / or after infusion of the anti-TTR antibody. An infusion syringe can be used to administer a total antibody dose of up to 100 mg, while an infusion pump is used to administer a total antibody dose of more than 100 mg, optionally using an infusion bag prefilled with a diluent. Glucose or a polymer thereof (such as dextran) can be used as a diluent at a concentration of about 1% w / v, 2% w / v, 3% w / v, 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, or 10% w / v. A diluted form of the anti-TTR antibody (e.g., an aqueous solution) can be administered to a subject with an infusion syringe in a volume of about 10 mL to about 200 mL (e.g., about 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 55 mL, 60 mL, 65 mL, 70 mL, 75 mL, 80 mL, 85 mL, 90 mL, 95 mL, 100 mL, 105 mL, 110 mL, 115 mL, 120 mL, 125 mL, 130 mL, 135 mL, 140 mL, 145 mL, 150 mL, 155 mL, 160 mL, 165 mL, 170 mL, 175 mL, 180 mL, 185 mL, 190 mL, 195 mL, or 200 mL). The anti-TTR antibody in the form of an aqueous solution can be administered within 1 hour to 5 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, for example, 2 hours ± 10 minutes. The first administration of the anti-TTR antibody can be performed, for example, within 2 hours ± 10 minutes, and subsequent administrations can be performed, for example, within about 1 hour ± 10 minutes.

[0493] Preferably, the anti-TTR antibody (eg, ALXN2220) is administered to the patient intravenously (IV) in a 50 mg / ml pharmaceutical formulation using an infusion (eg, a syringe).

[0494] Pharmaceutical composition

[0495] The methods described herein for treating or preventing diseases associated with ATTR (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligamentous amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia) can utilize any anti-TTR antibody as described herein formulated into a pharmaceutical composition. For example, a pharmaceutical composition containing an anti-TTR antibody can be formulated with sucrose, polysorbate 80, and / or a polar excipient, such as a buffer (e.g., histidine). In addition, a pharmaceutical composition containing an anti-TTR antibody can be formulated at a desired pH as described herein (e.g., pH 5.8). A pharmaceutical composition containing an anti-TTR antibody can also include a pharmaceutically acceptable excipient or diluent as described herein.

[0496] The pharmaceutical composition can also include sucrose in an amount of, for example, about 6% w / v to about 9% w / v, about 6% w / v to about 7% w / v, or about 7.5% w / v to about 8.5% weight / volume (w / v) (e.g., about 6% w / v, 6.5% w / v, 7% w / v, 7.5% w / v, 8% w / v, 8.5% w / v, or 9% weight / volume (w / v) sucrose).

[0497] The pharmaceutical composition can also include polysorbate 80 (PS80), for example, in an amount of about 0.001% w / v to about 0.1% w / v (e.g., about 0.001% w / v, 0.005% w / v, 0.01% w / v, 0.05% w / v, or 0.1% w / v PS80).

[0498] The pharmaceutical composition can also include a polar excipient. The polar excipient can be or include, for example, a sugar, a polyol, or an amino acid. Sugar can be, for example, sucrose, trehalose, fructose, lactose, dextrose, or mannitol. A polyol can be, for example, polyethylene glycol or sorbitol. Amino acid can be, for example, one or more of alanine, arginine, aspartic acid, asparagine, carnitine, citrulline, ornithine, glycine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine. In some embodiments, the polar excipient is histidine (for example, L-histidine and / or L-histidine monohydrochloride, or a pharmaceutically acceptable salt thereof). For example, the polar excipient is L-histidine and / or L-histidine monohydrochloride, or a pharmaceutically acceptable salt thereof.

[0499] The pharmaceutical composition can include a polar excipient (e.g., histidine) in an amount of, for example, about 1 mM to about 100 mM (e.g., about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM).

[0500] The pharmaceutical composition can have a pH of about 5.0 to about 8.0 (eg, about 5.5, 6.0, 6.5, 7.0, 7.5, or 8.0).

[0501] Pharmaceutical compositions may contain pharmaceutically acceptable excipients (eg, buffers, carriers, stabilizers, or preservatives) or diluents (eg, saline and aqueous buffer solutions).

[0502] The pharmaceutical composition thereof can be provided as an aqueous solution in a volume of about 1 mL to about 200 mL, about 1 mL to about 150 mL, about 1 mL to about 100 mL, about 1 mL to about 50 mL, about 5 mL to about 25 mL, about 18 mL to about 22 mL, or about 1 mL to about 10 mL (e.g., about 1 mL to about 2 mL, about 1 mL to about 1.8 mL, about 1 mL to about 1.6 mL, about 1 mL to about 1.4 mL, about 1 mL to about 1.2 mL, about 1.5 mL to about 1.25 mL, about 1.5 mL to about 2 mL, about 1.9 mL to about 1.2 mL, about 2.1 mL to about 2.25 mL), or about 1 mL to about 100 mL (e.g., about 1 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL). In some embodiments, the present invention provides a volume of about 1 mL, about 2 mL, about 2.25 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, about 20 mL, about 21 mL, about 22 mL, about 23 mL, about 24 mL, about 25 mL, about 26 mL, about 27 mL, about 28 mL, about 29 mL, about 30 mL, about 40 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, or about 100 mL (e.g., in a vial or other container as described herein).

[0503] The pharmaceutical composition can be any pharmaceutical composition described in a patent application entitled Pharmaceutical Compositions for Treating or Preventing Transthyretin-Mediated Amyloidosis, filed on November 15, 2022, and having application number EP 22 207 645.7 and attorney case number NE30A100 / P-EP (incorporated herein by reference).

[0504] In one example, a pharmaceutical composition containing an antibody is formulated for intravenous or infusion injection and contains the antibody at a concentration of about 50 mg / mL or 100 mg / mL. The pharmaceutical composition comprises 6.5% w / v or 8% weight / unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and a pH of 5.8.

[0505] In one example, a pharmaceutical composition containing an antibody is formulated for intravenous or infusion injection and contains an antibody at a concentration of about 50 mg / mL. The pharmaceutical composition comprises 6.5% weight / unit volume (w / v) sucrose (65 mg / mL sucrose), 0.03% w / v polysorbate 80 (0.3 mg / mL polysorbate 80), 20 mM histidine (1.06 mg / mL L-histidine and 2.78 mg / mL L-histidine monohydrochloride), and a pH of 5.8. The composition can be present in a volume of 2 mL in a container.

[0506] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous or infusion injection and contains the antibody at a concentration of about 50 mg / mL. The pharmaceutical composition comprises 6.5% weight / unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and has a pH of 5.8. The composition can be present in a volume of 20 mL in a container.

[0507] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous injection or infusion and contains the antibody at a concentration of about 50 mg / mL. The pharmaceutical composition comprises 8% w / v sucrose (80 mg / mL sucrose), 0.03% w / v polysorbate 80 (0.3 mg / mL polysorbate 80), 20 mM histidine (1.06 mg / mL L-histidine and 2.78 mg / mL L-histidine monohydrochloride), and a pH of 5.8. The composition can be present in a container in a volume of 2 mL.

[0508] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous injection or infusion and contains the antibody at a concentration of about 50 mg / mL. The pharmaceutical composition comprises 8% w / v sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and has a pH of 5.8. The composition can be present in a volume of 20 mL in a container.

[0509] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous or infusion injection and contains the antibody at a concentration of about 100 mg / mL. The pharmaceutical composition comprises 6.5% weight / unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and has a pH of 5.8. The composition can be present in a volume of 2 mL in a container.

[0510] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous or infusion injection and contains the antibody at a concentration of about 100 mg / mL. The pharmaceutical composition comprises 6.5% weight / unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and has a pH of 5.8. The composition can be present in a volume of 20 mL in a container.

[0511] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous injection or infusion and contains the antibody at a concentration of about 100 mg / mL. The pharmaceutical composition comprises 8% w / v sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and has a pH of 5.8. The composition can be present in a volume of 2 mL in a container.

[0512] In another example, a pharmaceutical composition containing an antibody is formulated for intravenous injection or infusion and contains the antibody at a concentration of about 100 mg / mL. The pharmaceutical composition comprises 8% w / v sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and has a pH of 5.8. The composition can be present in a volume of 20 mL in a container.

[0513] Example

[0514] Example 1. A Phase 1, First-in-Human, Double-Blind, Trial of NI006 in Patients with Amyloid Transthyretin Cardiomyopathy Placebo-controlled, multicenter, single- and multiple-ascending-dose study followed by an open-label extension

[0515] Overall design

[0516] This example describes a randomized, placebo-controlled, double-blind trial that combines a single ascending dose (SAD) phase and a multiple ascending dose (MAD) phase in subjects with amyloid thyroxine transporter (ATTR)-cardiomyopathy (CM), followed by an open-label extension (OLE) phase. The study was designed as a first-in-human study of the safety, tolerability, and exploratory efficacy of single and multiple doses of the antibody NI006, an anti-TTR antibody containing a heavy chain variable (VH) region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable (VL) region having the amino acid sequence of SEQ ID NO: 8, at doses ranging from 0.3 mg / kg to up to 60 mg / kg. NI006 is a recombinant human anti-ATTR monoclonal IgG1 antibody generated based on comprehensive immune repertoire analysis of memory B cell complement from healthy elderly subjects, as described, for example, in WO 2015 / 092077A1 (U.S. Patents 10,344,080; and 11,180,545), where the antibody was designated NI-301.37F1.

[0517] The trial objectives and endpoints are presented in Table 2. During each phase, NI006 or placebo (e.g., control) will be administered to subjects. Subjects who complete the SAD phase will be enrolled in the MAD phase. Subjects who complete the MAD phase will likely continue into the OLE phase with dose escalation. A second open-label extension (OLE2) phase is optional to allow for longer-term treatment at a maximum dose of 30 mg / kg or less. There are several exemplary cohorts of subjects described herein (e.g., Cohort 1 to Cohort 7), each cohort receiving a different dose of anti-TTR antibody or placebo. Exemplary doses of anti-TTR antibody or placebo in milligrams per kilogram (mg / kg) of body weight are: 0.3 mg / kg (Cohort 1), 1 mg / kg (Cohort 2), 3 mg / kg (Cohort 3), 10 mg / kg (Cohort 4), 30 mg / kg (Cohorts 5 and 7), and 60 mg / kg (Cohort 6). Figure 1 (e.g., SAD / MAD of queues 1-6), Figure 2 (OLE of queue 1 - queue 6) and Figure 3 An exemplary trial protocol is provided in (SAD / MAD and OLE for Cohort 7).

[0518] Subjects in Cohorts 1 to 5 may proceed to the second OLE phase (OLE2) by treatment at a maximum dose of 30 mg / kg for up to 10 months.

[0519] The detailed study design conducted in this final dose study is described below:

[0520] The first two patients in each dose cohort (sentinel patients) were randomized 1:1 to receive NI006 or placebo. If no relevant safety signals appeared in the sentinel patients, the four subsequent patients in each cohort were randomized to NI006 or placebo at a ratio of 3:1. After a favorable review of sufficient SAD safety data, the next higher dose cohort was opened. During the combined SAD / MAD phase, patients received a total of four doses of NI006 or placebo q4w. At baseline and 4 months, cardiac imaging was performed to evaluate changes in NI006 and placebo during the SAD / MAD phase. In the event of interruption due to reasons other than suspected drug intoxication during the SAD / MAD phase, replacement patients were recruited. Patients entering the OLE phase were entitled to receive eight NI006q4w administrations, regardless of treatment assignment in the SAD / MAD phase, while still blinded. As new safety information became available from the SAD / MAD phase of the higher dose cohort, patients starting at a lower dose level were adjusted up to the maximum safe dose level at each dose. At the end of the OLE period, at 12 months, cardiac imaging was performed.

[0521] In the first infusion, NI006 was administered as an IV infusion over approximately 2 hours (±10 minutes; except for up to 3 hours at 60 mg / kg). Subsequent infusions were administered over approximately 50-70 minutes. Patients were hospitalized for 4 nights after the SAD administration and the first OLE administration (i.e., the first NI006 administration in patients randomized to placebo), and for 1 to 2 nights after each of the three MAD administrations. All further administrations during the OLE phase were performed as outpatient visits.

[0522] Table 2. Trial objectives and endpoints

[0523]

[0524]

[0525] Patient population

[0526] In this study, 40 patients with wild-type or inherited ATTR-CM (median age 72 years, 97.5% male), chronic heart failure, and baseline NT-proBNP of 766 pg / mL to 5892 pg / mL were enrolled. More specifically, the study population consisted of patients diagnosed with ATTR-CM according to current guidelines (Garcia-Pavia et al., Eur Heart J. 42 (2021), 1554-68; Kittleson et al., Circulation 142 (2020), e7-e22), regardless of the underlying genotype (ATTRv and ATTRwt), with left ventricular wall thickness ≥14 mm, left ventricular ejection fraction (LVEF) ≥40%, NYHA stage I to III, NT-proBNP of 600 pg / mL to 6000 pg / mL, and eGFR>30 mL / min / 1.73 m2. Concomitant treatment with tamiflu was accepted if the dose was stable for at least 30 days before screening. Treatment with other ATTR-specific drugs (including gene silencers) was not permitted. Patients were recruited at six specialized amyloidosis centers in four European countries (Germany, France, Spain, and the Netherlands). The demographic and clinical characteristics of the patients are shown in Table 3.

[0527] Table 3. Demographic and clinical characteristics of patients at baseline

[0528]

[0529]

[0530] *At the French trial site, collection of ethnic background information was not permitted. Positive and negative values ​​are mean ± standard deviation. NT-

[0531] proBNP denotes N-terminal pro-B-type natriuretic peptide, GFR glomerular filtration rate, and NYHA New York Heart Association.

[0532] SAD phase of cohorts 1 to 6

[0533] The treatment regimens described herein begin on the first day that the anti-TTR antibody is administered to the subject, which will be considered Day 1 of the treatment regimen. Days 1 through 29 of the treatment regimen are considered the SAD phase for Cohorts 1 through 6 (e.g., see Figure 1, red box). Subjects from Cohorts 1 to 6 will receive treatment with anti-TTR antibody or placebo on Day 1 of the SAD phase. Cohort 1 will receive 0.3 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase. Cohort 2 will receive 1 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase. Cohort 3 will receive 3 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase. Cohort 4 will receive 10 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase. Cohort 5 will receive 30 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase. Cohort 6 will receive 60 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase.

[0534] MAD phase for cohorts 1 to 6

[0535] Days 30 to 148 of the treatment regimen were considered the MAD phase (e.g., see Figure 1 , blue box). Subjects from Cohorts 1 through 6 who complete the SAD phase will continue into the MAD phase of the trial, which consists of three additional administrations of anti-TTR antibody or placebo starting 35 days after the subject's first treatment with the anti-TTR antibody.

[0536] For example, the subject will be administered an anti-TTR antibody or placebo at the subject's designated dose (e.g., based on their cohort) on day 36 of the treatment regimen, followed by a 28-day ± 2-day treatment interval schedule. For example, cohort 1 will receive 0.3 mg / kg of anti-TTR antibody or placebo on day 36, any day from day 62 to day 66 (e.g., day 64), and any day from day 90 to day 94 (e.g., day 92) of the treatment regimen; cohort 2 will receive 1 mg / kg of anti-TTR antibody or placebo on day 36, any day from day 62 to day 66 (e.g., day 64), and any day from day 90 to day 94 (e.g., day 92) of the treatment regimen; cohort 3 will receive 3 mg / kg of anti-TTR antibody or placebo on day 36, any day from day 62 to day 66 (e.g., day 64), and any day from day 90 to day 94 (e.g., day 92) of the treatment regimen; Cohort 4 will receive 10 mg / kg of anti-TTR antibody or placebo on day 36, any day between day 62 and day 66 (e.g., day 64), and any day between day 90 and day 94 (e.g., day 92) of the treatment regimen; Cohort 5 will receive 30 mg / kg of anti-TTR antibody or placebo on day 36, any day between day 62 and day 66 (e.g., day 64), and any day between day 90 and day 94 (e.g., day 92) of the treatment regimen; and Cohort 6 will receive 60 mg / kg of anti-TTR antibody or placebo on day 36, any day between day 62 and day 66 (e.g., day 64), and any day between day 90 and day 94 (e.g., day 92) of the treatment regimen.

[0537] In another example, the subject will be administered an anti-TTR antibody or placebo at their assigned dose (e.g., based on their cohort) on day 36 of the treatment regimen, followed by a 28 day ± 7 day treatment interval regimen. For example, cohort 1 will receive 0.3 mg / kg of anti-TTR antibody or placebo on day 36, any day from day 57 to day 71 (e.g., day 64), and any day from day 85 to day 99 (e.g., day 92) of the treatment regimen; cohort 2 will receive 1 mg / kg of anti-TTR antibody or placebo on day 36, any day from day 57 to day 71 (e.g., day 64), and any day from day 85 to day 99 (e.g., day 92) of the treatment regimen; cohort 3 will receive 3 mg / kg of anti-TTR antibody or placebo on day 36, any day from day 57 to day 71 (e.g., day 64), and any day from day 85 to day 99 (e.g., day 92) of the treatment regimen; Cohort 4 will receive 10 mg / kg of anti-TTR antibody or placebo on day 36, any day of day 57-day 71 (e.g., day 64), and any day of day 85-day 99 (e.g., day 92) of the treatment regimen; Cohort 5 will receive 30 mg / kg of anti-TTR antibody or placebo on day 36, any day of day 57-day 71 (e.g., day 64), and any day of day 85-day 99 (e.g., day 92) of the treatment regimen; and Cohort 6 will receive 60 mg / kg of anti-TTR antibody or placebo on day 36, any day of day 57-day 71 (e.g., day 64), and any day of day 85-day 99 (e.g., day 92) of the treatment regimen.

[0538] SAD / MAD stage of cohort 7

[0539] The treatment regimens described herein (e.g., see Figure 3 ) begins on the first day that the anti-TTR antibody is administered to the subject, which will be considered Day 1 of the treatment regimen. Days 1 to 28 of the treatment regimen are considered the SAD phase for Cohort 7. Subjects from Cohort 7 will receive treatment with either the anti-TTR antibody or placebo on Day 1 of the SAD phase. For example, Cohort 7 may receive 30 mg / kg of anti-TTR antibody or placebo on Day 1 of the SAD phase.

[0540] Days 29 to 119 of the treatment regimen are considered the MAD phase for Cohort 7. Subjects from Cohort 7 who complete the SAD phase will continue in the MAD phase of the trial, which consists of three additional administrations of anti-TTR antibody or placebo starting 28 days after the subject's first treatment with the anti-TTR antibody.

[0541] For example, the subject will be administered an anti-TTR antibody or placebo at 30 mg / kg on day 29 of the treatment regimen, followed by a treatment interval of 28 days ± 2 days. For example, cohort 7 can receive 30 mg / kg of anti-TTR antibody or placebo on day 29, any day from day 55 to day 59 (e.g., day 57), and any day from day 83 to day 87 (e.g., day 85) of the treatment regimen.

[0542] In another example, the subject will be administered an anti-TTR antibody or placebo at 30 mg / kg on day 29 of the treatment regimen, followed by a 28-day ± 7-day treatment interval regimen. For example, cohort 7 can receive 30 mg / kg of anti-TTR antibody or placebo on day 29, any day from day 50 to day 64 (e.g., day 57), and any day from day 78 to day 92 (e.g., day 85) of the treatment regimen.

[0543] OLE phase for cohorts 1 to 6

[0544] Days 120 to 351 of the treatment regimen were considered the OLE period (e.g., see Figure 2 Subjects from Cohorts 1 through 6 who completed the SAD phase will continue into the OLE phase of the trial. Subjects who received placebo during the SAD and MAD phases may now receive anti-TTR antibody during the OLE phase.

[0545] For subjects who receive placebo during the SAD and MAD phases, the starting dose of the anti-TTR antibody will be at the same dose level as the subject's SAD and MAD phases (e.g., if the subject received 1 mg / kg during the SAD and MAD phases, the subject will receive 1 mg / kg of anti-TTR antibody as the starting dose in the OLE phase), or the highest dose of anti-TTR antibody that was considered safe and well-tolerated at the time of the subject's first treatment in the OLE phase (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg).

[0546] The OLE phase includes eight additional doses of anti-TTR antibody or placebo starting 119 days after the subject's first treatment with the anti-TTR antibody. Subjects will be administered anti-TTR antibody or placebo at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg on day 120 of the treatment regimen, followed by a treatment interval of 28 days ± 2 days or 28 days ± 7 days.

[0547] For example, cohort 7 will receive 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg of anti-TTR antibody or placebo on day 120, any day of day 146-day 150 (e.g., day 148), any day of day 174-day 178 (e.g., day 176), any day of day 202-day 206 (e.g., day 204), any day of day 230-day 234 (e.g., day 232), any day of day 258-day 262 (e.g., day 260), any day of day 286-day 290 (e.g., day 288), and any day of day 314-day 318 (e.g., day 316) of the treatment regimen.

[0548] In another example, cohort 7 will receive 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg of an anti-TTR antibody or placebo on day 120, any day of day 141-155 (e.g., day 148), any day of day 169-183 (e.g., day 176), any day of day 197-211 (e.g., day 204), any day of day 225-239 (e.g., day 232), any day of day 253-267 (e.g., day 260), any day of day 281-295 (e.g., day 288), and any day of day 309-323 (e.g., day 316) of the treatment regimen.

[0549] Administration of the anti-TTR antibody may be up-regulated one or more times during the OLE phase of Cohorts 1 through 6. Up-regulation of the antibody will be performed at one or more treatment intervals: on any day from Day 141 to Day 155 (e.g., on any day from Day 146 to Day 150, e.g., Day 148), on any day from Day 169 to Day 183 (e.g., on any day from Day 174 to Day 178, e.g., Day 176), on any day from Day 197 to Day 211 (e.g., on any day from Day 202 to Day 206, e.g., Day 204), on any day from Day 225 to Day 239 (e.g., on any day from Day 240 to Day 241, e.g., Day 242), on any day from Day 245 to Day 259 (e.g., on any day from Day 250 to Day 251, e.g., Day 253), on any day from Day 251 to Day 259 (e.g., on any day from Day 252 to Day 259, e.g., Day 254), on any day from Day 253 to Day 259 (e.g., on any day from Day 254 to Day 259), on any day from Day 255 to Day 259 (e.g., on any day from Day 256 to Day 250, e.g., Day 253), on any day from Day 257 to Day 259 (e.g., on any day from Day 257 to Day 259 any day of the week (e.g., any day from day 230 to day 234, e.g., day 232), any day from day 253 to day 267 (e.g., any day from day 258 to day 262, e.g., day 260), any day from day 281 to day 295 (e.g., any day from day 286 to day 290, e.g., day 288), and / or any day from day 309 to day 323 (e.g., day 314 to day 318, e.g., day 316).

[0550] Up-titration would include increasing from 0.3 mg / kg to 1 mg / kg, 1 mg / kg to 3 mg / kg, 3 mg / kg to 10 mg / kg, 10 mg / kg to 30 mg / kg, or 30 mg / kg to 60 mg / kg at each treatment interval. For example, up-titration can be performed at each treatment interval. In another example, up-titration can be performed at least once, twice, three times, four times, five times, or six times.

[0551] OLE phase of the 7th cohort

[0552] Days 120 to 232 of the treatment regimen were considered the OLE period for cohort 7 (e.g., Figure 3 ). Subjects from Cohort 7 who complete the MAD phase will continue in the OLE phase of the trial, which includes four additional doses of anti-TTR antibody or placebo starting 119 days after the subject's first treatment with anti-TTR antibody. For example, the subject will be administered anti-TTR antibody or placebo at 30 mg / kg on day 120 of the treatment regimen, followed by a treatment interval of 28 days ± 2 days or 28 days ± 2 days.

[0553] For example, cohort 7 will receive 30 mg / kg of anti-TTR antibody or placebo on day 120, any day from day 146 to day 150 (e.g., day 148), any day from day 174 to day 178 (e.g., day 176), and any day from day 202 to day 206 (e.g., day 204) of the treatment regimen.

[0554] In another example, cohort 7 will receive 30 mg / kg of anti-TTR antibody or placebo on day 120, any day from day 141-day 155 (e.g., day 148), any day from day 169-day 183 (e.g., day 176), and any day from day 197-day 211 (e.g., day 204) of the treatment regimen.

[0555] Extended OLE (OLE+) phase from queue 1 to queue 2

[0556] If a subject from Cohort 1 or Cohort 2 receives 1-7 doses during the OLE phase and therefore does not complete the OLE phase, the subject will enter the extended OLE (OLE+) phase. The OLE+ phase includes one or two additional administrations of anti-TTR antibody starting 28 days ± 2 days after the subject's last treatment with the anti-TTR antibody. For example, 28 days ± 2 days after the subject's last treatment with the anti-TTR antibody, the subject will be administered 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg of anti-TTR antibody, followed by one additional treatment 28 days ± 2 days later or 28 days ± 7 days later. Up-regulation of the anti-TTR antibody is possible, such as from 0.3 mg / kg to 1 mg / kg, 1 mg / kg to 3 mg / kg, 3 mg / kg to 10 mg / kg, 10 mg / kg to 30 mg / kg, or 30 mg / kg to 60 mg / kg. For example, upregulation can occur during the first administration of the OLE+ phase, the second administration of the OLE+ phase, or both.

[0557] OLE2 phase for cohorts 1 to 5

[0558] Subjects from any of Cohorts 1 to 5 who have received at least one (e.g., 1-7) doses in the OLE or OLE+ phase will enter the OLE2 phase, which includes up to 8 additional administrations of anti-TTR antibody. Subjects will be treated with a maximum dose of 30 mg / kg in OLE2. Subjects who were treated with a dose lower than 30 mg / kg prior to starting OLE2 will have to start OLE2 at the last dose level they were treated at in the OLE or OLE+ phase and can be titrated up from one dose level to another monthly (e.g., 28 days ± 2 days or 28 days ± 7 days) (e.g., if a subject's previous dose was 3 mg / kg, the subject will have to start OLE2 at that dose and can then be titrated up to 10 mg / kg on the second OLE2 treatment and then to 30 mg / kg on the third OLE2 treatment). Up-titration would include increasing from 0.3 mg / kg to 1 mg / kg, 1 mg / kg to 3 mg / kg, 3 mg / kg to 10 mg / kg, or 10 mg / kg to 30 mg / kg at each treatment interval. For example, if the subject has no interruption between OLE and OLE2 and is already on a dose of 10 mg / kg or higher at the end of the OLE, the subject can be directly up-titrated to / administered at 30 mg / kg. Up-titration can occur at each treatment interval. In other cases, up-titration can occur at least once, twice, three times, four times, five times, six times, or seven times.

[0559] Application

[0560] Anti-TTR antibody will be administered intravenously using a metered syringe in a syringe pump or an infusion bag. Aqueous anti-TTR antibody formulations should reach room temperature before use. It is recommended that the single-use vial containing anti-TTR antibody be used immediately after opening. Anti-TTR antibody should be clear or slightly opalescent and colorless or pale yellow. Aqueous anti-TTR antibody formulations that are turbid or contain sediment should not be used.

[0561] The initial dose for a subject (e.g., Day 1 of the treatment regimen) will be delivered within approximately 2 hours (±10 minutes). The initial dose for subjects in Cohort 6 will be delivered for a maximum duration of up to 3 hours. If the first infusion is tolerated and there are no hypersensitivity-related adverse events, subsequent infusions for Cohorts 1 to 5 will be delivered within approximately 1 hour (±10 minutes), or for Cohorts 6 and 7, within 60-70 minutes.

[0562] The subject's initial OLE dose (e.g., Day 120 of the treatment regimen) will be delivered within approximately 2 hours (±10 minutes). The initial OLE dose for subjects in Cohort 6 may be delivered for a maximum duration of up to 3 hours.

[0563] The subject's initial dose during OLE2 will be delivered within approximately 2 hours (±10 minutes). All subsequent infusions can be delivered within approximately 1 hour (±10 minutes).

[0564] In the event of reports of infusion site reactions or similar adverse events, the infusion duration of any infusion may be increased by up to 3 hours.

[0565] End of infusion (EOI) was defined as completion of the entire anti-TTR infusion plus flushing of the entire infusion line.

[0566] An adverse event is defined as any untoward medical occurrence in a subject administered a medicinal product (e.g., an anti-TTR antibody) and which does not necessarily have a causal relationship to that treatment. Thus, an adverse event can be any unfavorable or unexpected sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal product (e.g., an anti-TTR antibody), whether or not related to the medicinal product. An adverse event can be any of the following:

[0567] New diseases;

[0568] ● signs or symptoms or worsening of the underlying condition or a concomitant condition during treatment;

[0569] ●Unrelated to participation in a clinical trial or the effects of the medicinal product (e.g., anti-TTR antibody) or comparator;

[0570] ●One or a combination of the above factors

[0571] Dose-limiting toxicity

[0572] The dose-limiting toxicity (DLT) period for safety assessment was defined as 28 calendar days after the subject's first infusion of anti-TTR antibody.

[0573] A DLT was defined as an adverse reaction captured within 28 days of the subject's first dose (based on the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (e.g., Table 4)) and meeting any of the criteria defined below.

[0574] DLT will include:

[0575] 1. Hypersensitivity reactions, including cytokine release syndrome grade 3 and higher;

[0576] 2. Injection site reaction Grade 3 or higher; or

[0577] 3. New / acute onset of the following symptoms most likely attributable to cardiac inflammation due to exposure to anti-TTR antibodies:

[0578] ○ Any of the following:

[0579] Sinus tachycardia grade 3 or higher

[0580] Arrhythmia (atrial fibrillation, supraventricular tachycardia) grade 3 or higher

[0581] Mobitz II

[0582] Signs and symptoms of myocarditis / heart inflammation Grade 3 or higher

[0583] New onset of acute heart failure

[0584] Syncope

[0585] Cardiogenic shock

[0586] Difficulty breathing

[0587] ■Significant ECG abnormalities (ST-segment elevation, complete atrioventricular (AV) block, ventricular tachycardia); and

[0588] ○ Any of the following:

[0589] a) An abrupt decrease in LVEF of more than 10 points from baseline, with an absolute value of <40%; and / or

[0590] b) Troponin increases (100% increase from previous value in the absence of acute renal failure).

[0591] Cardiotoxicity should be evaluated thoroughly, with particular attention to unexpected and unpredictable findings and / or their severity in the context of the subject's medical history and concomitant medications.

[0592] Any other procedures deemed necessary by the treating physician to clarify the presence of a DLT may be performed.

[0593] Table 4. Common Terminology Criteria for Adverse Events [CTCAE] v5.0

[0594]

[0595] ADL = activities of daily living; *Instrumental ADLs include preparing meals, buying groceries or clothes, using the telephone, managing finances, etc.; **Self-care ADLs include bathing, dressing and undressing, self-feeding, toileting, taking medications, and being ambulatory.

[0596] Managing infusion-related reactions

[0597] The following are guidelines for the treatment of infusion-related reactions:

[0598] Mild reactions (redness, mild headache, nausea, mild discomfort, mild weakness)

[0599] ○ Slowly infuse to 1 / 2 the previous rate (not to exceed a maximum infusion time of 3 hours)

[0600] ○ Assess vital signs (blood pressure, pulse rate, oxygen saturation [SpO2]) every 15 minutes

[0601] ○Observe for 30 minutes

[0602] ○ If the response subsides, begin increasing the rate every 15 minutes until the original target rate is reached

[0603] If the reaction recurs, reduce the infusion to the highest previously tolerated rate

[0604] If the reaction persists or worsens, see Moderate Reactions below.

[0605] Moderate reaction (fever, severe headache, wheezing, urticaria, SpO2 <95%, vomiting)

[0606] Stop the infusion

[0607] ○ Draw 3mL of blood from the cannula (process the blood)

[0608] o Connect a new 0.9% NaCl IV bag with new tubing to the cannula and start the infusion at a maintenance rate based on the subject's weight according to local guidelines

[0609] ○Assess vital signs (blood pressure, pulse rate, SpO2) every 5 minutes

[0610] If SpO2 <95%, start supplemental oxygen (mask or nasal, depending on patient age and local guidelines)

[0611] IV diphenhydramine 1 mg / kg body weight (or other antihistamines based on hospital practice and recommended doses)

[0612] For fever or headache, give acetaminophen 500 mg orally (or other nonsteroidal anti-inflammatory drugs [NSAIDs] according to hospital practice and recommended doses)

[0613] ○ Additional medications recommended when necessary and needed (or equivalent / similar medications based on hospital practice and recommended dosages):

[0614] Hydrocortisone 2 mg / kg body weight IV

[0615] Ondansetron 4 mg IV for nausea and vomiting

[0616] Albuterol 5 mg inhaled for wheezing

[0617] ○ If the reaction subsides:

[0618] Wait 30 minutes after IV administration of the drug and then restart the infusion at half the rate at which the reaction occurred (not to exceed a maximum total infusion time of 3 hours)

[0619] Increase the rate every 15 minutes (as tolerated) until the original target rate is reached. If a reaction recurs, repeat the reaction procedure and increase only to the highest previously tolerated rate.

[0620] ○If the reaction persists:

[0621] Consider additional medications listed above

[0622] ○ If the reaction worsens:

[0623] See "Severe Reactions" below

[0624] Severe reactions (allergic reactions)

[0625] Anaphylaxis is a life-threatening medical emergency and should always be treated according to local guidelines and procedures to ensure the quickest, safest, and most effective resolution of the reaction. The following are general recommendations:

[0626] Stop the infusion

[0627] ○ Draw 3mL of blood from the cannula (process the blood)

[0628] o Connect a new 0.9% NaCl IV bag with new tubing to the cannula and start the infusion at a maintenance rate based on the subject's weight according to local guidelines

[0629] ○Assess vital signs (blood pressure, pulse rate, SpO2) every 5 minutes

[0630] If SpO2 <95%, start supplemental oxygen (mask or nasal, depending on patient age and local guidelines)

[0631] Administer epinephrine 0.01 mg / kg body weight intramuscularly (using a 1:1000 dilution or 1 mg / mL, maximum 0.5 mL)

[0632] IV diphenhydramine 1 mg / kg body weight (or other antihistamines based on hospital practice and recommended doses)

[0633] ○ Additional medications recommended when necessary and needed (or equivalent / similar medications based on hospital practice and recommended dosages):

[0634] Hydrocortisone 2 mg / kg body weight IV

[0635] Ondansetron 4 mg IV for nausea and vomiting

[0636] Albuterol 5 mg inhaled for wheezing

[0637] Acetaminophen 500 mg orally (or other NSAID based on hospital practice and recommended dose) for fever or headache

[0638] ○Reaction subsides:

[0639] Do not restart the infusion

[0640] ●Monitor as medically directed

[0641] ○ If the reaction persists or worsens:

[0642] Repeat the above medications as needed and according to label / hospital practice

[0643] ●Continue treatment until the reaction resolves, then monitor as medically directed.

[0644] Pre-infusion medication

[0645] In the event that a subject experiences any type of infusion-related reaction during the trial, premedication with an antihistamine (e.g., diphenhydramine) and / or an antipyretic (e.g., acetaminophen) and / or a corticosteroid (e.g., hydrocortisone 2 mg / kg-4 mg / kg body weight, or equivalent) is recommended 30-60 minutes prior to the infusion. Because the specific medications used may vary by country and institution, this is at the discretion of the healthcare professional. For example, it is recommended that diphenhydramine and acetaminophen be administered prior to the infusion to any subject who has had even a mild infusion reaction.

[0646] Efficacy evaluation

[0647] The following efficacy assessments can be performed on this trial as exploratory readouts.

[0648] 6-minute walk test

[0649] The 6-Minute Walk Test (6-MWT) is a submaximal exercise test used to assess walking endurance and aerobic capacity. The subject will walk around a set circular route for a total of 6 minutes. The test score is the distance the subject walks on a flat, hard surface in 6 minutes (measured in meters and rounded to the nearest decimal point).

[0650] Kansas City Cardiomyopathy Questionnaire

[0651] The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire developed to independently measure subjects' perception of their health status, including heart failure symptoms, impact on physical and social functioning, and how their heart failure affects their quality of life over a 2-week recall period.

[0652] The KCCQ tool quantifies the following six distinct domains and two summary scores:

[0653] The KCCQ symptom domain quantifies the frequency and burden of clinical symptoms in heart failure, including fatigue, shortness of breath, paroxysmal nocturnal dyspnea, and edema / swelling in the subject. The overall symptom score is typically used in analyses; subscale scores for frequency and severity are also available.

[0654] The KCCQ Physical Function domain measures the limitations participants experience in performing daily activities due to their heart failure symptoms. Activities are common, gender-neutral, and generally applicable across cultures, while also meeting a range of exercise requirements.

[0655] • The KCCQ quality of life domains are designed to reflect the subject's assessment of their quality of life in the context of their current heart failure condition.

[0656] The KCCQ Social Limitations domain quantifies the extent to which heart failure symptoms impair a subject's ability to interact in a variety of social activities regardless of gender.

[0657] The KCCQ self-efficacy domain quantifies participants' perceptions of how to prevent worsening heart failure and manage complications if they occur. This scale is not included in the summary score.

[0658] The KCCQ Symptom Stability domain measures recent changes in a subject's symptoms; shortness of breath, fatigue, or swelling. This scale compares the frequency of a subject's heart failure symptoms at the time the KCCQ is completed to their frequency 2 weeks prior. As a measure of change, it is best interpreted as a baseline assessment of the stability of a subject's symptoms at the start of the trial and shortly thereafter.

[0659] As a measure of acute response to treatment. This domain is not included in the summary score.

[0660] ●The clinical summary score includes total symptom and physical function scores corresponding to NYHA class.

[0661] ●Global summary score includes total symptoms, physical function, social limitations, and quality of life scores.

[0662] echocardiography

[0663] A complete echocardiogram may be performed to document systolic function (strain), thickness and filling pressures, and LVEF. A central echocardiogram may include:

[0664] Left ventricular end-diastolic / end-systolic dimensions and systolic function (Simpson's LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV);

[0665] Left ventricular diastolic function—mitral flow—mitral E / A ratio, E / e', maximum left atrial volume or left atrial volume index;

[0666] Right ventricular function – TAPSE and transtricuspid regurgitant systolic gradient

[0667] ● overall longitudinal strain; and / or

[0668] End-diastolic-interventricular septum (ED-IVS) and end-diastolic-posterior wall (ED-PW).

[0669] Magnetic resonance imaging, bone scintigraphy

[0670] One of the following assessments can be performed on each subject.

[0671] Magnetic resonance imaging (MRI) was performed on a subset of participants, including:

[0672] ○ Morphological assessment (eg, LV mass) and functional assessment (eg, LV ejection fraction, global longitudinal strain);

[0673] ○ Native T1 mapping, assessment of extracellular volume after gadolinium administration; and

[0674] ○T2 (inflammation).

[0675] ● Bone scintigraphy using DPD or HMDP in a subset of subjects, including:

[0676] ○ Heart rate retention (HR) / whole body rate retention (WBR) ratio and

[0677] ○ Heart retention (HR) / skull retention (SR) ratio

[0678] The data from these imaging methods will be sent to a central reading provider for central reading.

[0679] Biomarkers

[0680] Biomarkers can be assessed before infusion and at specific time points after infusion during the course of the trial. Serum samples (approximately 12 mL of blood per sample) can be collected during the trial and can be analyzed for novel biomarkers to determine the impact on the course of amyloidosis or other medically relevant conditions and the clinical and biological response to anti-TTR antibodies.

[0681] Biomarkers during the SAD, MAD, and OLE stages may include, but are not limited to:

[0682] ●Indicates cardiac function and cardiac stress:

[0683] Plasma NT-proBNP

[0684] Troponin-T

[0685] Acute phase proteins, complement activation, and inflammatory markers:

[0686] C3, C4, and C-reactive protein (CRP)

[0687] ○IL1b, IL6, IL8, IFNg, TNF-α (proinflammatory cytokines)

[0688] IL10, IL1RA (anti-inflammatory cytokines)

[0689] ○ Serum amyloid A (SAA), ferritin (positive acute phase protein)

[0690] Biomarkers during OLE2 may include, but are not limited to:

[0691] Circulating levels of ATTR

[0692] ●Indicates heart function and cardiac stress

[0693] Plasma NT-proBNP, troponin T or galectin-3 (Gal-3), soluble tumor suppressor 2 (sST2)

[0694] Cardiac fibrosis biomarkers:

[0695] ○Procollagen type 1 carboxyl-terminal propeptide (PICP)

[0696] ○Type III procollagen propeptide (PIIINP)

[0697] Acute phase proteins, complement activation, and inflammatory markers:

[0698] C3, C4, and C-reactive protein (CRP)

[0699] ○IL1b, IL6, IL8, IFNg, TNF-α (proinflammatory cytokines)

[0700] IL10, IL1RA (anti-inflammatory cytokines)

[0701] ○ Serum amyloid A (SAA), ferritin (positive acute phase protein)

[0702] Immunohistochemistry of tissue samples

[0703] Immunohistochemistry (IHC) of cardiac, adipose, or salivary gland biopsies can be performed in a subset of subjects. In OLE2, in the case of salivary gland biopsies, saliva samples will be collected at the time of biopsy.

[0704] Study Results

[0705] After completing the Phase 1 study, the safety and efficacy of the antibody NI006 were evaluated. The primary outcome was generated after all patients in the highest dose group completed the placebo-controlled SAD / MAD phase. Unless otherwise stated, the results are presented for the safety population, i.e., all patients who received at least one dose of the investigational product (NI006 or placebo). All available data from the OLE phase at the time of the analysis data cutoff were included in the analysis. No formal statistical assumptions were tested, and missing data were not interpolated. For descriptive statistics, patients randomized to NI006 were grouped according to their nominal dose cohort at the time of inclusion, while patients taking placebo were pooled from all dose cohorts. Regardless of potential upregulation, the same nominal group assignment was used to summarize the OLE data. Absolute changes (ACFB) or relative changes (RCFB) relative to baseline were calculated. For patients who received placebo during the SAD / MAD phase before switching to NI006 treatment during the OLE period, the pre-OLE baseline was used to calculate the changes during the OLE period. The Kruskal-Wallis test was used to compare ACFB / RCFB between the six dose cohorts and placebo, or between the high-dose cohort (10 mg / kg-60 mg / kg), low-dose cohort (0.3 mg / kg-3 mg / kg) and placebo. Data were analyzed by a contract research organization using Statistical Analysis The data were plotted using R version 9.4 (or later), and the GGplot2 package of R was used to plot the data.

[0706] The following results were obtained.

[0707] As described above, 40 patients with wild-type or inherited ATTR-CM (median age 72 years, 97.5% male), chronic heart failure, and baseline NT-proBNP of 766 pg / mL to 5892 pg / mL were randomized in a 4:2 ratio to six ascending dose cohorts (0.3 mg / kg to 60 mg / kg) and received NI006 or placebo intravenously every four weeks. After four double-blind infusions, participants in the open-label extension phase received eight further doses of NI006, with doses increasing in a stepwise manner.

[0708] NI006 was found to be generally safe and well tolerated up to the highest dose tested. No dose-limiting toxicities or serious adverse reactions occurred. The PK profile was typical for IgG antibodies, and no anti-NI006 antibodies were identified. Data from bone scintigraphy and MRI indicated that doses of 30 mg / kg and 60 mg / kg reduced cardiac amyloid deposits by a median of 12.8% and 25.6%, respectively, compared to baseline at 4 months; at 12 months, the median reductions were 30.7% and 50.7%, respectively. In the same patients, NT-proBNP decreased by 78.2% and 72.2% at 12 months, and echocardiographic parameters indicated improved systolic and diastolic function. Thus, this study demonstrates for the first time that the use of NI006, an anti-TTR antibody, can result in substantial depletion of cardiac transthyretin amyloid, accompanied by reductions in NT-proBNP and signs of improved cardiac function.

[0709] In more detail:

[0710] Patient characteristics

[0711] A total of 40 participants (median age 72 years, range 28 to 87 years, 97.5% male) were enrolled sequentially at dose levels of 0.3 mg / kg to 60 mg / kg, including 4 replacement participants; 27 were randomized to NI006 and 13 were randomized to placebo (Table 3). Most patients presented with ATTRwt-CM (33 / 40, 82.5%) and received concomitant therapy with tamiflu (36 / 40, 90%). Fifteen of the 40 patients (37.5%) had documented symptoms of some degree of polyneuropathy. Based on established markers of ATTR-CM disease severity (NYHA, NAC, and MAYO stage), patients with mild to advanced disease status were enrolled, and the number of advanced patients randomized to NI006 tended to be greater than that of placebo (Table 3). In addition, baseline parameters were well balanced between the different NI006 dose cohorts and placebo, including echocardiographic parameters and estimates of baseline amyloid burden as shown by scintigraphy and cMRI. Trial compliance was high: 85% of patients (34 / 40, including patients who were replaced) received all four scheduled placebo-controlled doses during the SAD / MAD phase, and 97% of eligible patients (34 / 35) were enrolled in the OLE phase after completion of the SAD / MAD phase.

[0712] Safety and tolerability of NI006

[0713] The primary objective of the trial was to determine the safety and tolerability profile of NI006 over the planned dose range of 0.3 mg / kg to 60 mg / kg by studying investigator-reported clinically relevant treatment-emergent adverse events (AEs) and assessing changes in safety markers, including directional echocardiography, close ECG monitoring during administration and hospitalization, and laboratory safety parameters measured locally at the trial site. Blinded safety data were continuously monitored by investigators and the sponsor and reviewed by the Data Evaluation Committee (DEC).

[0714] The results showed that NI006 was generally safe and well tolerated at the highest dose level tested; no patient experienced dose-limiting toxicity, and no serious AEs (SAEs) considered to be related to NI006 occurred (i.e., no serious adverse reactions). Most patients experienced ≥1 AE (38 / 40, 95%) during the SAD / MAD phase, most of which were mild to moderate in intensity (CTCAE grade 1 and 2, 64.9% and 31.4%, respectively), and the overall incidence of non-serious AEs or SAEs was not dose-dependent (see Tables 5 and 6). Two patients (1 placebo, 1 in the 3 mg / kg cohort) reported death during participation in the OLE phase, both of which were attributed to the progression of amyloidosis (see Table 7).

[0715] As expected in this patient population, cardiac disorders, particularly events of heart failure and arrhythmias, were the numerically most frequently observed system organ class (SOC) for AEs.

[0716] The frequency and type of those AEs were similar across dose cohorts, but there was no trend toward a dose-dependent increase in event severity (see Tables 6 and 8). During the SAD / MAD phase, three patients in the 10 mg / kg and 30 mg / kg cohorts reported non-serious AEs of cytokine release syndrome, accompanied by associated increases in cardiac biomarkers. All three patients continued dosing throughout the SAD / MAD and OLE phases without recurrence of AEs. A dose-dependent increase in the incidence of musculoskeletal events (primarily consisting of arthralgia and arthritis events) was observed with increasing dose in the SAD / MAD phase and in patients who switched from placebo in the OLE phase (see Table 7). The majority of these events were of grade 1-2 intensity and did not lead to discontinuation. Two subjects experienced transient asymptomatic decreases in platelet counts, one of whom discontinued due to a non-serious grade 3 thrombocytopenia event. No infusion reactions (IRs) were observed and no other clinically significant values ​​or changes in safety laboratory parameters, vital signs, or ECG parameters relative to baseline were observed.

[0717] Table 5. Summary of AEs in the SAD / MAD phase

[0718]

[0719]

[0720] Numbers represent n patients (% within group) and [n events]. *Subjects were counted only once at the highest CTCAE grade. d / c interruption

[0721] Table 6. Summary of AEs in the SAD / MAD phase by SOC

[0722]

[0723]

[0724] Table 7. Summary of AEs in the Combined SAD / MAD and OLE Phases

[0725]

[0726]

[0727] Numbers represent n patients (% within group) and [n events]. *Subjects were counted only once at the highest CTCAE grade. d / c interruption

[0728] Table 8. Summary of AEs in the Combined SAD / MAD and OLE Phases by SOC

[0729]

[0730]

[0731] PK and immunogenicity profiles

[0732] Throughout the trial, the serum NI006 concentration of all patients was continuously measured using a validated assay. Using individual parameter estimates, the individual total serum NI006 exposure was calculated as the area under the curve (AUC) based on the simulated PK curve. The appearance of anti-drug antibodies was monitored throughout the trial. Regarding immunogenicity analysis, biotinylated and sulfo-tagged NI006 was used as a detection reagent in an electrochemiluminescent immunoassay validated by QPS (Netherlands) to assess the presence of potential anti-drug antibodies. For PK analysis, a sandwich ELISA assay established based on two anti-idiotypic Fab fragments selectively bound to NI006 was used to measure serum NI006 concentration. The lower limit of quantification (LLOQ) was 0.17 μg / mL. Nuventra (Durham, NC, USA) performed non-compartmental analysis (NCA) on serum NI006 concentration versus time data to calculate standard PK parameters, using the validated installed Phoenix WinNonlin 8.2.2 version, using actual blood sampling time and dosing level and utilizing an intravenous (IV) infusion model. Population PK modeling was performed by LYO-X (Switzerland) using a two-compartment model with linear antibody clearance from the central compartment, binding of the antibody to its target ATTR, and elimination of the NI006:ATTR complex in the peripheral compartment. Population PK parameters were estimated using the stochastic approximation of expectation maximization (SAEM) algorithm implemented in Monolix. At 4 and 12 months, individual total serum NI006 exposure was calculated from the simulated PK profiles using individual parameter estimates and the linear trapezoidal rule.

[0733] The NI006 pharmacokinetic profile has been shown to be typical for human IgG with low to moderate inter-subject variability: following a single IV dose, serum NI006 concentrations declined in a biphasic manner with an elimination half-life ranging from 15.5 to 19.2 days. Exposure, as measured by Cmax and AUC, increased in a dose-proportional manner with increasing dose. There was gradual, dose-dependent drug accumulation, which reached a steady state after repeated doses every 4 weeks. Throughout the study, including the OLE, no patient developed anti-drug antibodies (ADA).

[0734] Amyloid depletion

[0735] Amyloid depletion was determined by scintigraphy and cardiac MRI. In particular, for cardiac amyloid imaging, all included patients underwent continuous scintigraphy or cardiac MRI. The choice of imaging mode was independently selected by the researchers for each patient to allow adaptation to individual patient characteristics (e.g., MRI excluding claustrophobia) and local standards of the trial site. For both imaging modes, acquisition was performed according to the unified protocol of the trial site and analyzed by two independent blinded readers in the central imaging core laboratory. In planar scintigraphy, the effect of NI006 on cardiac amyloid burden was estimated using changes in cardiac tracer retention relative to systemic retention (heart / systemic retention ratio, H / WBR ratio). Accordingly, contrast-enhanced cardiac MRI was used to estimate the therapeutic effect of NI006 by changes in the amount of extracellular volume (ECV) in the left ventricle. The relative changes in the results of scintigraphy and MRI imaging and the two imaging modes at 4 months and 12 months were calculated respectively.

[0736] Recording using local scanners at the research center Cardiac MRI . The acquisition protocol was based on the latest guidelines [1-3] and was standardized across all sites during the trial setup phase, and adherence to the laboratory manual was continuously monitored. MRI scans were interpreted by two independent readers (expert radiologists or cardiologists) in the imaging core laboratory using Medis software (Medis, Leiden, The Netherlands). All MRIs were analyzed individually; the central reader was blinded not only to treatment allocation but also to patient identifiers, dose cohorts, and acquisition time points. The MRI acquisition and analysis procedure was similar to the method described by Martinez-Naharro et al. (PMID 28728692): T1 and ECV measurements were performed before and after contrast agent administration, defining the entire left ventricular myocardium at the base and mid-ventricular levels as the region of interest. Both ventricular myocardial and blood T1 measurements were performed in the short-axis view. Information on hematocrit was available. ECV was calculated according to the following formula:

[0737]

[0738] where R1 = 1 / T1 and Δ is the difference between pre-contrast and post-contrast measurements.

[0739] In cases where the two readers disagreed beyond a predefined range of ±10% on key parameters, a consensus read was performed.

[0740] Use at the trial site according to a uniform collection protocol established in the laboratory manual during trial setup. 99m Tc-hydroxy-methylene-diphosphonate (HMDP) or 99mTc-3,3-diphosphono-1,2-propanedicarboxylic acid (DPD) was used as a tracer to collect Bone scintigraphy Adherence to the laboratory manual and image quality were continuously monitored. Planar whole-body images were acquired 3 h after tracer infusion. Interpretation of the acquired images was performed centrally in the imaging core laboratory by two independent nuclear physicians using Syngovia software (Siemens). To calculate the cardiac / whole-body retention ratio (H / WB ratio), potential areas of high tracer retention (e.g., bladder, kidneys, injection site) were considered as areas of rejection in the following formula:

[0741]

[0742] In cases where the two readers disagreed beyond a predefined range of ±10% on key parameters, a consensus read was performed.

[0743] showed that treatment with NI006 significantly reduced cardiac ATTR amyloid deposition in patients with ATTR-CM as measured by both scintigraphy and cMRI as early as 4 months compared to baseline ( Figure 4 ). Continued treatment with NI006 for up to 12 months resulted in further reductions in amyloid deposition. In contrast, patients initially randomized to placebo showed increased cardiac amyloid deposition after 4 months and exhibited a reduction in amyloid burden after 8 months of treatment after switching to NI006 in the OLE. Pooled data from both imaging techniques indicated that doses of 10 mg / kg, 30 mg / kg, or 60 mg / kg reduced cardiac amyloid deposition by a median of 6.9%, 12.8%, and 25.6%, respectively, compared to baseline at 4 months. After an additional 8 months of treatment in the OLE (including some dose increases from 10 mg / kg to 30 mg / kg and from 30 mg / kg to 60 mg / kg), the median reductions in cardiac amyloid burden were 23.6%, 30.7%, and 50.7%, respectively, compared to baseline at 12 months ( Figure 5 ). In individual cases, amyloid reductions of up to 35% absolute ECV or 2.1% H / WB ratio were observed after 12 months of treatment with NI006. At 4 months, the relative changes from baseline were significantly different between the low-dose cohort (0.3 mg / kg-3 mg / kg), the high-dose cohort (10 mg / kg-60 mg / kg), and placebo for both scintigraphy (p=0.011) and MRI (p=0.016). Higher total NI006 exposure, based on individual PK profile simulations to account for unforeseen treatment interruptions (e.g., associated with epidemics) during the OLE and individual uptitration schedules, was associated with higher reductions in cardiac amyloid at 4 months (r=-0.673) and 12 months (r=-0.651) on both imaging modalities ( Figure 5 B). Data from placebo switchers are consistent with and confirm these observations ( Figure 6 ).

[0744] Effects on cardiac biomarkers and echocardiographic parameters

[0745] Changes in cardiac structure and function were investigated by echocardiography and using the plasma biomarkers NT-proBNP and troponin-T. Furthermore, although not supported by the study, global functional capacity and quality of life were investigated using the 6-minute walk test (6MWT) and the Kansas City Cardiomyopathy Questionnaire (KCCQ), respectively. Changes were analyzed at 4 and 12 months. More specifically, standardized echocardiograms were obtained at three time points throughout the trial: at baseline before the first treatment, after completion of the MAD (4 months), and after completion of the OLE (12 months), with full echocardiograms recorded for efficacy analysis. A uniform acquisition protocol was used across all study centers, and analysis was performed centrally at the imaging core laboratory (Biotrial, Rennes, France) by an experienced cardiologist who demonstrated low interreader variability and was blinded to pseudonymous patient ID, treatment assignment, dose cohort, and acquisition time point. Three (sinus rhythm) or five (atrial fibrillation) measurements were performed with the use of EchoPAC CE Medical software (GE Healthcare, Milwaukee, MI, USA), and the average of the three or five measurements was used for further analysis. If the recording did not allow measurement of individual parameters (e.g., poor echogenicity, insufficient number of recorded cycles, suboptimal view), the measurement value was reported as missing.

[0746] In addition, before each of the first five treatment administrations and before discharge, nonstandardized directed echocardiographic examinations were performed by the investigators or an assistant investigator according to local practice to rule out a sudden deterioration of left ventricular systolic function or the development of pericardial effusion.

[0747] showed that at 12 months, plasma biomarkers of cardiac stress and function, NT-proBNP and troponin-T, were reduced in most patients compared with baseline ( Figure 7A) NI006 reduced NT-proBNP in a dose- and time-dependent manner. The greatest reductions in cardiac amyloid burden were observed in the 30 mg / kg or 60 mg / kg dose cohorts, with median relative reductions in NT-proBNP from baseline reaching 78.2% and 72.2% at 12 months. In the 60 mg / kg cohort, median NT-proBNP decreased from 1482 ng / L at baseline to 420 ng / L at 12 months, which was below the study inclusion threshold. Similarly, troponin-T showed greater reductions from baseline at higher total NI006 exposures.

[0748] Patients in the two dose cohorts with the highest amyloid removal (30 mg / kg and 60 mg / kg) also showed signs of treatment benefit in echocardiographic parameters of cardiac structure, systolic, and diastolic function at 12 months ( Figure 7 B): Left ventricular wall thickness decreased (median ED-IVS decrease of 1 mm in both dose cohorts) and LVEF increased (median absolute increase of 12% and 6%, respectively), which appeared to be primarily driven by a decrease in end-systolic volume (LVESV), a decrease in left atrial volume (median decrease of 9 mL and 28 mL), and a decrease in E / e' ratio (median absolute change of -7.6 and -4.7).

[0749] Summary and Discussion

[0750] NI006 can be used to treat transthyretin amyloidosis with cardiomyopathy, regardless of the underlying genotype. In patients diagnosed with ATTR-CM, this first-in-human study showed that NI006 administered IV every 4 weeks for 12 months was generally safe and well tolerated up to the highest dose tested. As determined by two different indicators of cardiac amyloid burden (bone scintigraphy and cardiac MRI), NI006 depleted transthyretin from cardiac tissue in a dose-dependent and time-dependent manner, with the most significant effect a...

Claims

1. An anti-transthyretin (TTR) antibody for use in a method of treating transthyretin-mediated amyloidosis (ATTR) in a subject in need of such treatment, wherein the method comprises administering the antibody at a dose of 2000 mg to 2500 mg for a patient weighing equal to or greater than 40 kg (≥40 kg) to less than 60 kg (<60 kg); (b) 3000 mg to 3500 mg for a patient weighing equal to or greater than 60 kg (≥60 kg) to less than 100 kg (<100 kg); or (c) 4000 mg to 5000 mg for a patient weighing equal to or greater than 100 kg (≥100 kg), wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs1-3 and light chain CDRs1-3, the sequences of the heavy chain CDRs1-3 being set forth in SEQ ID NOs:1-3, respectively, and the sequences of the light chain CDRs1-3 being set forth in SEQ ID NOs:4-6, wherein the anti-TTR antibody comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO:

8.

2. The antibody for use according to claim 1, wherein the antibody is administered at a dose of: (a) 2400 mg for patients weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg); (b) 3200 mg for patients weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg); or (c) 4800 mg for patients weighing 100 kg or more (≥100 kg).

3. The antibody for use according to claim 1 or 2, wherein the antibody comprises a human Ig constant region.

4. The antibody for use according to any one of claims 1 to 3, wherein the antibody comprises a human IgG constant region, preferably wherein the antibody comprises a human IgG1 constant region comprising an antibody heavy chain constant region of the human IgG1m3 allotype.

5. The antibody for use according to any one of claims 1 to 4, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 450 amino acid residues comprising the sequence of SEQ ID NO: 9, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

6. The antibody for use according to any one of claims 1 to 4, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 449 amino acid residues comprising the sequence of SEQ ID NO: 13, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

7. The antibody for use according to any one of claims 1 to 4, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 449 amino acid residues comprising the sequence of SEQ ID NO: 14, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

8. The antibody for use according to any one of claims 1 to 4, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 448 amino acid residues comprising the sequence of SEQ ID NO: 15, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

9. The antibody for use according to any one of claims 1 to 8, wherein the antibody is NI006 / ALXN2220 or comprises a binding fragment thereof.

10. The antibody for use according to any one of claims 1 to 9, wherein the antibody is a recombinant antibody produced in Chinese Hamster Ovary (CHO) cells, preferably wherein the antibody is produced in CHO-K1 cells.

11. The antibody for use according to any one of claims 1 to 5 and 7 to 10, wherein the heavy chain of the antibody comprises a cyclized N-terminal glutaminyl residue containing pyroglutamic acid (pyro-Q).

12. The antibody for use according to any one of claims 1 to 5 and 9 to 10, wherein the antibody heavy chain further comprises a cleaved C-terminal lysine.

13. The antibody for use according to any one of claims 1 to 12, wherein the antibody is N-glycosylated, preferably wherein the N-linked glycan is located at N300 of the heavy chain of the antibody.

14. The antibody for use according to any one of claims 1 to 13, wherein the subject has symptomatic ATTR-CM and / or NT-proBNP>2000 pg / mL.

15. The antibody for use according to claim 14, wherein the subject has variant ATTR-CM (ATTRv-CM / hATTR-CM) or wild-type ATTR-CM (wATTR-CM).

16. The antibody for use according to claim 14 or claim 15, wherein the subject is an adult subject, preferably a subject 18 years or older but less than 90 years old (≥18 years to ≤90 years old).

17. The antibody for use according to any one of claims 14 to 16, wherein the treatment reduces cardiac amyloid burden and / or the composite endpoint of all-cause mortality (ACM) and total cardiovascular (CV) clinical events over 12 months.

18. The antibody for use according to any one of claims 14 to 17, wherein the treatment reduces the composite endpoint of all-cause mortality (ACM) and heart failure (HF) events.

19. The antibody for use according to any one of claims 14 to 18, wherein the treatment improves at least one of: (a) symptomatic, functional, and health-related quality of life (QoL), as measured by the change from baseline in the Kansas City Cardiomyopathy Questionnaire Global Summary (KCCQ-OS) score; (b) time to cardiovascular (CV)-related death; (c) six-minute walk test (6MWT) scores compared with baseline; (d) rate of cardiovascular (CV) clinical events; (e) Time to all-cause mortality (ACM).

20. The antibody for use according to any one of claims 14 to 19, wherein the treatment has at least one of the following effects: (a) reduce the subject's NT-proBNP level compared to baseline; (b) reduce the rate of heart failure (HF) events; (c) reducing the incidence of intensive oral diuretic therapy, optionally including outpatient intensive oral diuretic therapy; (d) reduce the incidence of disease-modifying therapy changes; (e) reduce the incidence of hospitalization due to atrial fibrillation; (f) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score after 24 months of study treatment; (g) change from baseline in the six-minute walk test (6MWT) after 24 months of study treatment; (h) changes from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia disease stages and NYHA classification; (i) induce changes in GLS relative to baseline; (j) induced changes in stroke volume relative to baseline; (k) elicit changes in echocardiographic parameters of interest relative to baseline; (l) causing changes in hs-cTnT relative to baseline; (m) causing changes relative to baseline in DPD / PYP / HMDP cardiac scintigraphic cardiac uptake and / or cMRI-derived ECV, T1, and T2 maps; (n) caused a change in eGFR relative to baseline; (o) cause a change from baseline in the EQ-5D-5L score and / or cause a change from baseline in the SF-36 score; (p) causing a change relative to baseline in a marker selected from the group consisting of CRP, IL11b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin; preferably, a change relative to baseline in a marker of CRP; (q) causing a change relative to baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6; (r) causing a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4; (s) caused changes from baseline in: (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or (3) sNFL level; (t) Causes a change from baseline in the NIS and / or causes a change in the NC study.

21. The antibody for use according to any one of claims 1 to 20, wherein the anti-TTR antibody is administered intravenously (IV); preferably wherein the anti-TTR antibody is administered every four weeks (q4w) via IV infusion.

22. The antibody for use according to any one of claims 1 to 21, wherein the anti-TTR antibody is administered for at least 24 months, preferably at least 48 months.

23. The antibody for use according to any one of claims 1 to 22, wherein the anti-TTR antibody is administered at a weight-graded fixed dose based on the patient's recorded weight, wherein the recording is performed within 30 days of planned administration, and wherein the dose is administered intravenously (IV) via infusion every four weeks (q4w).

24. The antibody for use according to any one of claims 1 to 23, wherein the anti-TTR antibody triggers elimination of ATTR fibrils from a patient sample in a dose-dependent and time-dependent manner through immune-driven phagocytic clearance.

25. The antibody for use according to claim 24, wherein said elimination of ATTR fibrils by anti-TTR antibody treatment is measured via cardiac tracer uptake scintigraphy or quantification of ECV using cMRI.

26. The antibody for use according to claim 24, wherein treatment of said patient with said anti-TTR antibody results in a dose-dependent and time-dependent reduction of said cardiac amyloid burden of up to about 51% at 12 months, preferably wherein said dose corresponds to 60 mg / kg.

27. The antibody for use according to claim 24, wherein the patient is male or female. (1) ATTR-CM with a wild-type or variant TTR genotype confirmed by a central diagnosis based on evidence of cardiac amyloidosis by echocardiography or cMRI and one of the following: a. Endomyocardial biopsy with confirmatory TTR amyloid typing by immunohistochemistry or mass spectrometry; or b. In the absence of monoclonal gammopathy, 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) shows grade 2 or 3 cardiac uptake; or c. In the presence of monoclonal gammopathy, grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and confirmatory TTR amyloid typing in non-cardiac tissues by immunohistochemistry or mass spectrometry; (2) Willingness to undergo genetic testing for mutations in the TTR gene during screening if genetic testing has not been performed previously or if genetic results are unavailable (3) Echocardiography at screening showed end-diastolic ventricular septal wall thickness ≥11 mm for women or ≥12 mm for men (4) NT-proBNP > 2000 pg / mL measured by the central laboratory at screening (5) treated with loop diuretics for at least 30 days before screening; (6) A history of heart failure documented by one of the following events within 1 year before screening: a. Hospitalization for heart failure b. Urgent heart failure visit c. Episodes of volume overload documented by NT-proBNP > 2000 pg / mL (or equivalent BNP) (7) New York Heart Association (NYHA) class II-IV at screening; and / or (8) Have a life expectancy of at least 6 months based on the judgment of a clinician.

28. The antibody for use according to any one of claims 1 to 27, wherein the anti-TTR antibody is NI006 / ALXN2220 administered in the form of a pharmaceutical formulation at 50 mg / mL in 20 mM histidine buffer, pH 5.8, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80.

29. The antibody for use according to any one of claims 1 to 28, wherein the anti-TTR antibody is NI006 / ALXN2220, which is administered to the patient as an intravenous (IV) infusion, with the initial administration within 2 hours and subsequent administrations within 1 hour.

30. The antibody for use according to any one of claims 1 to 29, wherein the patient has been treated with a disease-modifying agent selected from a TTR silencer and a TTR stabilizer, preferably wherein the disease-modifying agent comprises tafamidis, diflunisal or a TTR silencer.

31. The antibody for use according to any one of claims 1 to 30, wherein the anti-TTR antibody is administered for up to 24 months according to the intervention infusion schedule provided in Table 25.

32. The antibody for use according to claim 31 , wherein after the 24-month treatment period, the anti-TTR antibody is administered as a subsequent treatment according to the intervention infusion schedule of Table 26.

33. The antibody for use according to any one of claims 1 to 32, wherein said treatment results in a reduction in median amyloid when said dose corresponds to a dose of 30 mg / kg to 60 mg / kg in said patient.

34. The antibody for use according to any one of claims 1 to 33, wherein the patients are stratified based on: (1) prior treatment with a disease-modifying agent, wherein the disease-modifying agent is selected from (a) a TTR silencing agent, optionally together with a TTR stabilizer; (b) a TTR stabilizer alone; and (c) no TTR stabilizer or TTR silencing agent treatment; (2) TTR genotype, including ATTR variant (ATTRv) or ATTR wild type (ATTRwt); or (3) Disease severity based on cardiac biomarker levels, including NT-proBNP > 3000 pg / mL and NT-proBNP ≤ 3000 pg / mL, optionally together with pre- and post-treatment high-sensitivity cardiac troponin C (hs-cTnT) levels.

35. The antibody for use according to any one of claims 1 to 34, wherein the efficacy of treatment is measured using endomyocardial biopsy including intraepidermal nerve fiber density (IENFD) and / or sweat gland nerve fiber density (SGNFD).

36. The antibody for use according to any one of claims 1 to 35, wherein serum biomarker levels are monitored before and after treatment with the anti-TTR antibody, wherein the biomarker is selected from: (a) complement factors selected from C3 and C4, and CRP; (b) proinflammatory cytokines selected from IL1b, IL6, IL8, IFNg and TNF-α; (c) anti-inflammatory cytokines selected from IL10, IL1RA; (d) positive acute phase proteins selected from SAA and ferritin; (e) PICP; (f) PIIINP; (g) CITP; (h) PRO-C6; and (i) plasma NNTTR, or a combination thereof.

37. The antibody for use according to any one of claims 1 to 36, wherein the anti-TTR antibody is safe and well tolerated when administered to a human patient.

38. A method of treating ATTR in a human subject in need of such treatment, the method comprising administering to the human subject an anti-transthyretin (TTR) antibody, the anti-transthyretin antibody comprising a heavy chain variable region comprising complementarity determining regions (CDRs), the complementarity determining regions comprising heavy chain CDRs 1-3 and light chain CDRs 1-3, the sequences of the heavy chain CDRs 1-3 being set forth in SEQ ID NOs: 1-3, respectively, and the sequences of the light chain CDRs 1-3 being set forth in SEQ ID NOs: 4-6, wherein the anti-TTR antibody comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NO: 7 and a light chain variable region having at least 80% sequence identity to SEQ ID NO:

8. IDNO:8 having a light chain variable region of an amino acid sequence with at least 80% sequence identity, wherein the antibody is administered at the following doses: (a) 2000 mg to 2500 mg for patients weighing equal to or greater than 40 kg (≥40 kg) to less than 60 kg (<60 kg); (b) 3000 mg to 3500 mg for patients weighing equal to or greater than 60 kg (≥60 kg) to less than 100 kg (<100 kg); or (c) 4000 mg to 5000 mg for patients weighing equal to or greater than 100 kg (≥100 kg).

39. The method of claim 38, wherein the antibody is administered at a dose of: (a) 2400 mg for a patient weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg); (b) 3200 mg for a patient weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg); or (c) 4800 mg for a patient weighing 100 kg or more (≥100 kg).

40. The method of claim 38 or 39, wherein the antibody comprises a human Ig constant region.

41. The method of any one of claims 38 to 40, wherein the antibody comprises human IgG, preferably wherein the antibody comprises human IgGl containing an antibody heavy chain constant region of the human IgGlm3 allotype.

42. The method of any one of claims 38 to 41, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 450 amino acid residues comprising a sequence of SEQ ID NO: 9, and each light chain comprises 214 amino acid residues comprising a sequence of SEQ ID NO:

10.

43. The antibody for use according to any one of claims 38 to 41, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 449 amino acid residues comprising the sequence of SEQ ID NO: 13, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

44. The antibody for use according to any one of claims 38 to 41, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 449 amino acid residues comprising the sequence of SEQ ID NO: 14, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

45. The antibody for use according to any one of claims 38 to 41, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 448 amino acid residues comprising the sequence of SEQ ID NO: 15, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

46. ​​The method of any one of claims 38 to 45, wherein the antibody is NI006 / ALXN222 or comprises a binding fragment thereof.

47. The method according to any one of claims 38 to 46, wherein the antibody is a recombinant antibody produced in Chinese Hamster Ovary (CHO) cells, preferably wherein the antibody is produced in CHO-K1 cells.

48. The method of any one of claims 38 to 47, wherein the heavy chain of the antibody comprises a cyclized N-terminal glutaminyl residue containing pyroglutamic acid (pyro-Q), and optionally wherein the antibody heavy chain further comprises a cleaved C-terminal lysine.

49. The method of any one of claims 38 to 48, wherein the antibody is N-glycosylated, preferably wherein the N-linked glycan is located at N300 of the heavy chain of the antibody.

50. The method of any one of claims 38 to 49, wherein the subject has symptomatic ATTR-CM and / or NT-proBNP>2000 pg / mL.

51. The method of claim 50, wherein the subject has variant ATTR-CM (ATTRv-CM / hATTR-CM) or wild-type ATTR-CM (wATTR-CM).

52. The method of claim 50 or 51, wherein the subject is an adult subject, preferably a subject 18 years or older but less than 90 years old (≥18 years to ≤90 years old).

53. The method of any one of claims 50 to 52, wherein the treatment reduces the composite endpoint of all-cause mortality (ACM) and total cardiovascular (CV) clinical events.

54. The method of any one of claims 50 to 53, wherein the treatment reduces the composite endpoint of all-cause mortality (ACM) and heart failure (HF) events.

55. The method of any one of claims 50 to 54, wherein the treatment improves at least one of: (a) symptomatic, functional, and health-related quality of life (QoL), as measured by the change from baseline in the Kansas City Cardiomyopathy Questionnaire Global Summary (KCCQ-OS) score; (b) time to cardiovascular (CV)-related death; (c) six-minute walk test (6MWT) scores compared with baseline; (d) rate of cardiovascular (CV) clinical events; (e) Time to all-cause mortality (ACM).

56. The method of any one of claims 50 to 55, wherein the treatment has at least one of the following effects: (a) reduce the subject's NT-proBNP level compared to baseline; (b) reduce the rate of heart failure (HF) events; (c) reducing the incidence of intensive oral diuretic therapy, optionally including outpatient intensive oral diuretic therapy; (d) reduce the incidence of disease-modifying therapy changes; (e) reduce the incidence of hospitalization due to atrial fibrillation; (f) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score after 24 months of study treatment; (g) change from baseline in the six-minute walk test (6MWT) after 24 months of study treatment; (h) changes from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia disease stages and NYHA classification; (i) induce changes in GLS relative to baseline; (j) induced changes in stroke volume relative to baseline; (k) elicit changes in echocardiographic parameters of interest relative to baseline; (l) causing changes in hs-cTnT relative to baseline; (m) causing changes relative to baseline in DPD / PYP / HMDP cardiac scintigraphic cardiac uptake and / or cMRI-derived ECV, T1, and T2 maps; (n) Causes change in eGFR relative to baseline (o) cause a change from baseline in the EQ-5D-5L score and / or cause a change from baseline in the SF-36 score; (p) causing a change relative to baseline in a marker selected from the group consisting of CRP, IL11b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin; preferably, a change relative to baseline in a marker of CRP; (q) causing a change relative to baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6; (r) causing a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4; (s) caused changes from baseline in: (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or (3) sNFL level; (t) Causes a change from baseline in the NIS and / or causes a change in the NC study.

57. The method of any one of claims 38 to 56, wherein the anti-TTR antibody is administered intravenously (IV); preferably wherein the anti-TTR antibody is administered every four weeks (q4w) via IV infusion.

58. The method of any one of claims 38 to 57, wherein the anti-TTR antibody is administered for at least 24 months, preferably at least 48 months.

59. The method of any one of claims 38 to 58, wherein the anti-TTR antibody is administered at a weight-graded fixed dose based on the patient's recorded weight, wherein the recording is performed within 30 days of planned administration, wherein the dose is administered intravenously (IV) via infusion every four weeks (q4w).

60. The method of any one of claims 38 to 59, wherein the anti-TTR antibody triggers elimination of ATTR fibrils from the patient sample by immune-driven phagocytic clearance in a dose-dependent and time-dependent manner.

61. The method of claim 60, wherein the elimination of ATTR fibrils by anti-TTR antibody treatment is measured via cardiac tracer uptake scintigraphy or quantification of ECV with cMRI.

62. The method of claim 60, wherein treatment of the patient with the anti-TTR antibody results in a dose-dependent and time-dependent reduction in the cardiac amyloid burden of up to about 51% at 12 months, preferably wherein the dose corresponds to 60 mg / kg at 12 months.

63. The method of claim 60, wherein the patient is male or female. (1) ATTR-CM with a wild-type or variant TTR genotype confirmed by a central diagnosis based on evidence of cardiac amyloidosis by echocardiography or cMRI and one of the following: a. Endomyocardial biopsy with confirmatory TTR amyloid typing by immunohistochemistry or mass spectrometry; or b. In the absence of monoclonal gammopathy, 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) shows grade 2 or 3 cardiac uptake; or c. In the presence of monoclonal gammopathy, grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and confirmatory TTR amyloid typing in non-cardiac tissues by immunohistochemistry or mass spectrometry; (2) Willingness to undergo genetic testing for mutations in the TTR gene during screening if genetic testing has not been performed previously or if genetic results are unavailable (3) Echocardiography at screening showed end-diastolic ventricular septal wall thickness ≥11 mm for women or ≥12 mm for men (4) NT-proBNP > 2000 pg / mL measured by the central laboratory at screening (5) treated with loop diuretics for at least 30 days before screening; (6) A history of heart failure documented by one of the following events within 1 year before screening: a. Hospitalization for heart failure b. Urgent heart failure visit c. Episodes of volume overload documented by NT-proBNP > 2000 pg / mL (or equivalent BNP) (7) New York Heart Association (NYHA) class II-IV at screening; and / or (8) Have a life expectancy of at least 6 months based on the judgment of a clinician.

64. The method of claims 38 to 63, wherein the anti-TTR antibody is NI006 / ALXN2220 administered in a pharmaceutical formulation at 50 mg / mL in 20 mM histidine buffer, pH 5.8, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80.

65. The method of claims 38 to 64, wherein the anti-TTR antibody is NI006 / ALXN2220, which is administered to the patient as an intravenous (IV) infusion, with the initial administration within 2 hours and subsequent administrations within 1 hour.

66. The method of any one of claims 38 to 65, wherein the patient has been treated with a disease-modifying agent selected from a TTR silencing agent and a TTR stabilizer, preferably wherein the disease-modifying agent comprises tafamidis, diflunisal, or a TTR silencing agent.

67. The method of any one of claims 38 to 66, wherein the anti-TTR antibody is administered for up to 24 months according to the intervention infusion schedule provided in Table 25.

68. The method of claim 67, wherein after the 24-month treatment period, the anti-TTR antibody is administered as subsequent treatment according to the intervention infusion schedule of Table 26.

69. The method of any one of claims 38 to 68, wherein the treatment results in a median amyloid reduction when the dose corresponds to a dose of 30 mg / kg to 60 mg / kg in the patient.

70. The method of any one of claims 38 to 69, wherein the patients are stratified based on: (1) prior treatment with a disease-modifying agent, wherein the disease-modifying agent is selected from (a) a TTR silencing agent, optionally together with a TTR stabilizer; (b) a TTR stabilizer alone; and (c) no TTR stabilizer or TTR silencing agent treatment; (2) TTR genotype, including ATTR variant (ATTRv) or ATTR wild type (ATTRwt); or (3) Disease severity based on cardiac biomarker levels, including NT-proBNP > 3000 pg / mL and NT-proBNP ≤ 3000 pg / mL, optionally together with pre- and post-treatment high-sensitivity cardiac troponin C (hs-cTnT) levels.

71. The method of any one of claims 38 to 70, wherein efficacy of treatment is measured using endomyocardial biopsy including intraepidermal nerve fiber density (IENFD) and / or sweat gland nerve fiber density (SGNFD).

72. The method of any one of claims 38 to 71, wherein serum biomarker levels are monitored before and after treatment with the anti-TTR antibody, wherein the biomarker is selected from: (a) complement factors selected from C3 and C4, and CRP; (b) proinflammatory cytokines selected from IL1b, IL6, IL8, IFNg, and TNF-α; (c) anti-inflammatory cytokines selected from IL10, IL1RA; (d) positive acute phase proteins selected from SAA and ferritin; (e) PICP; (f) PIIINP; (g) CITP; (h) PRO-C6; and (i) plasma NNTTR, or a combination thereof.

73. The method of any one of claims 38 to 72, wherein the anti-TTR antibody is safe and well tolerated by a human patient when administered to the human patient.

74. Use of an anti-TTR antibody in the manufacture of a medicament for treating transthyretin-mediated amyloidosis (ATTR) in a subject in need of such treatment, the anti-TTR antibody comprising a heavy chain variable region comprising complementarity determining regions (CDRs), the complementarity determining regions comprising heavy chain CDRs1-3 and light chain CDRs1-3, the sequences of the heavy chain CDRs1-3 being set forth in SEQ ID NOs: 1-3, respectively, and the sequences of the light chain CDRs1-3 being set forth in SEQ ID NOs: 4-6, wherein the anti-TTR antibody comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NO: 7 and a light chain variable region comprising a heavy chain CDR having at least 80% sequence identity to SEQ ID NO:

8. NO:8 has a light chain variable region of an amino acid sequence with at least 80% sequence identity, wherein the treatment comprises administering the antibody at the following doses: (b) 2000 mg to 2500 mg for patients weighing equal to or greater than 40 kg (≥40 kg) to less than 60 kg (<60 kg); (b) 3000 mg to 3500 mg for patients weighing equal to or greater than 60 kg (≥60 kg) to less than 100 kg (<100 kg); or (c) 4000 mg to 5000 mg for patients weighing equal to or greater than 100 kg (≥100 kg).

75. The use of claim 74, wherein the antibody is administered at a dose of: (a) 2400 mg for a patient weighing 40 kg or more (≥40 kg) to less than 60 kg (<60 kg); (b) 3200 mg for a patient weighing 60 kg or more (≥60 kg) to less than 100 kg (<100 kg); or (c) 4800 mg for a patient weighing 100 kg or more (≥100 kg).

76. Use according to claim 74 or 75, wherein the antibody is an antibody according to any one of the preceding claims.

77. The use of any one of claims 74 to 76, wherein the subject is a subject according to any one of the preceding claims.

78. Use according to any one of claims 74 to 77, wherein administration of the antibody is performed according to any one of the preceding claims.

79. Use according to any one of claims 74 to 78, wherein the treatment is performed according to any one of the preceding claims.

80. A therapeutic kit, comprising: (i) one or more containers, wherein the containers comprise a formulation of an anti-TTR antibody in an amount of 2400 mg, 3200 mg, or 4800 mg, or multiple doses of any of these amounts; and (ii) a device for delivering the antibody to a human, wherein the device optionally comprises an infusion bag and / or a syringe, wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs), wherein the complementarity determining regions comprise heavy chain CDR1-3 and light chain CDR1-3, the sequences of which are shown in SEQ ID NOs: 1-3, respectively, and the sequences of which are shown in SEQ ID NOs: 4-6, wherein the anti-TTR antibody comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8, preferably wherein the antibody is according to any one of the preceding claims.

81. A therapeutic kit, comprising: (i) one or more containers, wherein the containers contain a formulation of an anti-TTR antibody in an amount of 2400 mg, 3200 mg, or 4800 mg, or multiple doses of any of these amounts; and (ii) a device for delivering the antibody to a human, wherein the device optionally comprises an infusion bag and / or a syringe, wherein the anti-TTR antibody is antibody NI006 / ALXN2220.

82. An article comprising: The invention provides one or more containers comprising (i) a total amount of 2400 mg, 3200 mg, or 4800 mg of a formulation of an anti-TTR antibody, or multiple doses of any of these amounts; and (ii) instructions for administering the antibody once every four weeks at the following doses: 2400 mg for a subject weighing 40 kg to ≤60 kg; 3200 mg for a subject weighing 360 kg to 100 kg; or 4800 mg for a subject weighing ≤100 kg, wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs1-3 and light chain CDRs1-3, the sequences of which are set forth in SEQ ID NOs: 1-3, respectively, and the sequences of which are set forth in SEQ ID NOs: 4-6, wherein the anti-TTR antibody comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NO: 7 and a light chain variable region comprising a light chain CDR1-3 having at least 80% sequence identity to SEQ ID NO:

8. NO:8 A light chain variable region having an amino acid sequence with at least 80% sequence identity, preferably wherein the antibody is according to any one of the preceding claims.

83. An article comprising: One or more containers comprising (i) a total amount of 2400 mg, 3200 mg, or 4800 mg of a formulation of an anti-TTR antibody, or multiple doses of any of these amounts; and (ii) instructions for administering the antibody once every four weeks at the following doses: 2400 mg for a subject weighing 40 kg to ≤60 kg; 3200 mg for a subject weighing 360 kg to 100 kg; or 4800 mg for a subject weighing ≤100 kg, wherein the anti-TTR antibody is antibody NI006 / ALXN2220.

84. The kit of claim 80 or 81, or the article of manufacture of claim 82 or 83, wherein ALXN2220 / NI006 is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody that specifically recognizes aggregated wild-type and mutant forms of TTR and is expressed in a Chinese hamster ovary cell line, preferably a CHO-K1 cell line.

85. The kit of any one of claims 80, 81 and 84, or the article of manufacture of any one of claims 82 to 84, wherein ALXN2220 / NI006 has a molecular weight of about 150 kDa.

86. The kit of any one of claims 80, 81, 84 and 85, or the article of manufacture of any one of claims 82 to 85, wherein ALXN2220 / NI006 is a concentrate for solution for infusion, which is a sterile, colorless to pale yellow, clear to slightly opalescent liquid, substantially free of visible particles, for intravenous use by infusion after dilution.

87. The kit or article of manufacture of claim 86, wherein each mL of solution contains 50 mg / mL ALXN2220 / NI006 in 20 mM histidine buffer, pH 5.8, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80.

88. The article of manufacture of any one of claims 82 to 87, wherein the recommended dose of ALXN2220 / NI006 on the label is 2400 mg for patients weighing ≥40 kg to <60 kg, 3200 mg for patients weighing ≥60 kg to <100 kg, and 4800 mg for patients weighing ≥100 kg, which dose must be diluted and then administered as an intravenous infusion over about one to two hours once every four weeks.

89. The kit of any one of claims 80, 81, 84, and 85 to 87, or the article of manufacture of any one of claims 82 to 88, wherein ALXN2220 / NI006 is diluted with 5% glucose solution prior to administration.

90. The kit of any one of claims 80, 81, 84, and 85 to 87 and 89, or the article of manufacture of any one of claims 82 to 89, wherein ALXN2220 / NI006 is a clear to opalescent and colorless to pale yellow solution available as a 100 mg / 2 mL (50 mg / mL) solution in a single-dose vial.

91. A method of treating ATTR, the method comprising administering to a human subject a human anti-TTR antibody, wherein the antibody is preferably the antibody according to any one of the preceding claims and is administered at a dose providing about 30 mg / kg or 60 mg / kg to the subject, preferably once every 28 days.

92. A method according to claim 91, wherein the method is carried out according to any one of clauses [112] to [213].

93. An embodiment according to any one of clauses [1] to [249].

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