Methods for treating or preventing transthyretin-mediated amyloidosis

Abstract

Provided herein are anti-TTR antibody dosing regimens useful for treating transthyretin amyloid cardiomyopathy (ATTR-CM) in adult human patients. In embodiments, patients are treated with anti-TTR antibodies, including NI006 / ALXN2220.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 383,807 and European Patent Application No. 22 207 651.5, both filed November 15, 2022, and European Patent Application No. 23 020 175.8, filed April 6, 2023. The entire contents of the above patent applications are incorporated herein by reference.

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

[0003] Systemic amyloidosis is an invasive disease caused by the progressive deposition of amyloid fibrils in organs such as the heart, liver, and pancreas. In the case of cardiac amyloidosis, the most common forms include immunoglobulin light chain and transthyretin amyloidosis. Currently approved drugs stabilize or block the production of amyloidogenic precursors, preventing further amyloid deposition. This approach reduces cellular damage and disease progression without removing existing amyloid deposits, resulting in functional recovery of affected organs and thus improving quality of life and survival. Therapeutic strategies based on monoclonal antibodies that can selectively bind to and induce the removal of amyloid deposits could be an important treatment for systemic amyloidosis, including cardiac amyloidosis.

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

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

[0006] Under certain conditions that are not well understood and may include acidic pH, oxidative stress, and local factors, the TTR protein can adopt misfolded, misassembled, and / or aggregated TTR conformations and become toxic, resulting in transthyretin-mediated amyloidosis (ATTR).

[0007] Antibodies (e.g., human antibodies) that target misfolded, misassembled, and / or aggregated TTR have been developed. Improved methods (e.g., antibody dosing regimens) suitable for treating or preventing ATTR in subjects are needed, with acceptable benefit / risk profiles and, preferably, dosing / administration that is as convenient for the subject and physician as possible.

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

[0009] Provided herein are methods and associated dosing regimens for treating or preventing wild-type or hereditary transthyretin-mediated amyloidosis (ATTR), including, inter alia, ATTR-CM, an ATTR amyloidosis resulting in cardiomyopathy (CM). More specifically, the present invention provides anti-transthyretin (TTR) antibodies for use in methods of treating ATTR in a subject in need of such treatment, the methods comprising administering the antibody to: (a) a patient weighing 40 kg or more (≧40 kg) but less than 60 kg (<60 kg) at a dose of 2000 mg to 2500 mg; (b) a patient weighing 60 kg or more (≧60 kg) but less than 100 kg (<100 kg) at a dose of 3000 mg to 3500 mg; or (c) a patient weighing 100 kg or more (≧100 kg) at a dose of 4000 mg to 5000 mg.

[0010] As shown in Example 1, anti-TTR antibodies as used in accordance with the present invention, exemplified by ALXN2220 (also known as NI006), have been shown to be safe and well-tolerated in human patients and to deplete amyloid transthyretin deposits from cardiac tissue in a dose- and time-dependent manner by antibody-dependent cellular phagocytosis (ADCP), with the most pronounced effects observed at doses greater than 10 mg / kg when administered once every four weeks. Furthermore, the antibodies were applied at a maximum dose of 60 mg per kilogram of 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 showed 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, and 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 over time in untreated patients with ATTR-CM and are strongly correlated with patient mortality, the data point to the utility of the anti-TTR antibodies of the present disclosure in treating and / or preventing ATTR-CM in human patients.

[0011] Although immunotherapy of ATTR may prove possible using anti-TTR antibodies, the dosing regimens used in clinical trials with weight-adjusted doses have proven inconvenient in clinical practice because weight-adjusted dose administration is complex and error-prone, for example, in measuring body weight, calculating the appropriate dose to administer, and extracting the corresponding drug volume from the vial. Furthermore, this approach results in substantial drug waste, corresponding 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, i.e., a body weight-lumped flat dose, was developed to overcome the above-mentioned drawbacks.

[0013] In this regard, a PK / PD model was established, and a flat dose in the range of 2000 mg to 5000 mg was calculated to be safe and effective. See Example 5. In this regard, single- and multiple-dose PK studies in rats confirmed the pharmacokinetic (PK) profile of the IgG1 molecule. Taking all of this into consideration, a body weight-adjusted flat dose was calculated, and a dose in the range of 2000 mg to 2500 mg for patients weighing 40 kg or more (≧40 kg) but less than 60 kg (<60 kg), a dose in the range of 3000 mg to 3500 mg for patients weighing 60 kg or more (≧60 kg) but less than 100 kg (<100 kg), and a dose in the range of 4000 mg to 5000 mg for patients weighing 100 kg or more (≧100 kg) were 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, the method comprising administering the antibody to: (a) a patient weighing 40 kg or more (≧40 kg) but less than 60 kg (<60 kg) at a dose of 2000 mg to 2500 mg; (b) a patient weighing 60 kg or more (≧60 kg) but less than 100 kg (<100 kg) at a dose of 3000 mg to 3500 mg; or (c) a patient weighing 100 kg or more (≧100 kg) at a dose of 4000 mg to 5000 mg.

[0014] More specifically, in one initial embodiment, the following doses are proposed: 5000 mg for patients weighing ≥ 100 kg; 3500 mg for patients weighing 60 kg < 100 kg; and 2500 mg for patients weighing < 60 kg, administered IV every 28 days (q4w). 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 expected efficacy, these weight-branched flat doses were further optimized, resulting in: 2400 mg for patients weighing ≥ 40 kg but < 60 kg; 3200 mg for patients weighing ≥ 60 kg but < 100 kg; or 4800 mg for patients weighing ≥ 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 but less than 60 kg, at a dose of 3200 mg to patients weighing ≥60 kg but less than 100 kg, or at a dose of 4800 mg to patients weighing ≥100 kg. These flat doses are used in a Phase 3 Clinical Trial Protocol (CTP), as outlined in Example 8. As indicated in the CTP, one concept for monitoring during administration of study drug and the post-infusion observation period includes heart rate, blood pressure, and oxygen saturation, as well as ECG assessments at screening, and both pre- and post-infusion monitoring at weeks 1, 3, and 12, and approximately every 12 weeks thereafter.

[0015] As mentioned above, the antibody ALXN2220 / NI006 was used as the drug substance in the clinical trial referred to in Example 1. The parent antibody of NI006 was first described in WO 2015 / 092077 (designated antibody NI-301.37F1) and Michalon et al., Nat. Commun. 12 (2021), 3142 (designated antibody NI301A). As disclosed in WO 2015 / 092077, NI006 (NI-301.37F1) is characterized, inter alia, by binding to aggregated human wild-type transthyretin (wtATTR), as shown in Figures 2-4 and 7, and described in Examples 3-6, and further described in the last paragraph of page 46. Furthermore, WO 2015 / 092077 discloses that NI006 (NI-301.37F1) does not bind to the monomer or dimer of human native transthyretin (TTR), as shown in Example 5 and Figure 4. This binding profile is advantageous because the antibody selectively binds to aggregated wtTTR and can therefore be trivially considered for the treatment of not only hereditary transthyretin amyloidosis (hATTR), a polyneuropathy caused by mutations in the gene encoding TTR (formerly known as familial amyloid polyneuropathy, FAP), but also wild-type transthyretin amyloidosis (wtATTR), also known as senile systemic amyloidosis (SSA). Furthermore, the antibody does not risk interfering with the assembly of native monomers into physiological tetramers. The antibody comprises, in its variable region or binding domain, a complementarity determining region (CDR) and a variable heavy chain (VH) having the amino acid sequences shown in Figures 1C and 1M, respectively, of WO 2015 / 092077. H ) and variable light chain (V L ) U.S. Patent No. 10,344,080 is incorporated by reference in its relevant portions (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, preferably human aggregated TTR, but does not bind to physiological TTR species can be used in accordance with the present invention. Preferably, the anti-TTR antibody used in accordance with the present invention is NI006 / ALXN2220, or an equivalent antibody, preferably of human origin, that has substantially the TTR binding profile of NI006. For example, WO 2015 / 092077 discloses two additional human antibodies, namely, antibody NI-301.59F1 and antibody NI-301.35G11, that exhibit the aforementioned binding profile, 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 characterized in WO 2015 / 092077 and Michalon et al., Nat Commun. 12 (2021), 3142; see also above.

[0017] Thus, in one embodiment, an antibody or antigen-binding fragment used in accordance with the present invention comprises a heavy chain variable region comprising complementarity-determining regions (CDRs) comprising heavy chain CDRs 1 to 3, the sequences of which are set forth in SEQ ID NOS: 1 to 3, and light chain CDRs 1 to 3, the sequences of which are set forth in SEQ ID NOS: 4 to 6, respectively, wherein the anti-TTR antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising at least 80% sequence identity to SEQ ID NOS: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NOS: 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 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: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 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: 12.

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

[0021] To avoid the generation of "anti-drug antibodies" (ADA) by subjects administered the antibodies described herein, the antibodies are preferably human or humanized, typically human IgG, most preferably human IgG1. In a preferred embodiment, the antibodies are 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 a human constant heavy chain (HC) amino acid sequence as exemplified in SEQ ID NO: 9 and a corresponding human constant light chain (LC), here a kappa light chain, as exemplified in SEQ ID NO: 10. As further explained below, IgG antibodies are organized as a tetramer consisting of an HC and two light LC chains linked by disulfide bridges. The theoretical molecular weight of antibody NI006 / ALXN2220 is 144.2 kDa, and the masses determined by mass spectrometry (MS) are 144.2 kDa (deglycosylated) and 147.0 kDa to 147.6 kDa (intact IgG1), respectively.

[0023] The antibody NI006 / ALXN2220 has been produced in Chinese hamster ovary (CHO)-K1 cells. CHO cells are the most widely used mammalian cells for the production of recombinant monoclonal antibodies due to their ability to perform post-translational modifications (PTMs) on antibody molecules, which typically also occur in humans. Genetic engineering by mutagenesis has led to the establishment of different CHO daughter cell lines with improved quality. Among these variants are CHO-K1, CHO-S, CHO-DXB11, and CHO-DG44. Thus, in one embodiment, antibodies for use according to the present invention are produced in CHO cells, preferably 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 HC of the N-terminal glutamine to pyroglutamic acid, loss of the C-terminal lysine, and N-glycosylation. In this regard, an N-glycosylation site was identified at position 300 (HC N300, SEQ ID NO: 9). Accordingly, in one embodiment, an antibody for use according to the present invention lacks a C-terminal lysine, i.e., the antibody has undergone C-terminal lysine clipping. In particular, the C-terminal lysine shown in SEQ ID NO: 9 is trimmed from the heavy chain of the antibody, preferably from each heavy chain of the antibody. Alternatively, the N-terminal glutamine has been modified as pyroglutamic acid, i.e., the heavy chain of the antibody shown in SEQ ID NO: 9 has undergone N-terminal glutaminyl cyclization. The sequence, i.e., the sequence of the heavy chain containing cyclic pyroglutamic acid and no N-terminal glutamate, is shown in SEQ ID NO: 14.

[0025] Alternatively, the heavy chain of an antibody for use according to the invention is missing the C-terminal lysine and the N-terminal glutamine is modified as pyroglutamic acid. The sequence, i.e., the sequence of a heavy chain with the C-terminal lysine truncated, 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, in particular N-glycosylated. More particularly, the heavy chain of the antibody is glycosylated, even more particularly N300 of the heavy chain.

[0027] In a preferred embodiment, an anti-TTR antibody for use according to the invention lacks a C-terminal cysteine, has a modified glutamine at the N-terminus as pyroglutamic acid, and contains at least one N-glycosylation site.

[0028] Thus, 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, in which the N-terminal glutamine in the heavy chains is modified to pyroglutamic acid, the C-terminal lysine is missing, and the heavy chains are 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, in which the heavy chains are N-glycosylated.

[0029] As described above, anti-TTR antibodies, when used in accordance with the present invention, depleted amyloid transthyretin from cardiac tissue in a dose- and time-dependent manner. Thus, in some embodiments, ATTR amyloidosis leads to cardiomyopathy (CM), and thus, in preferred embodiments, subjects treated in accordance with the present invention have ATTR amyloidosis with CM (ATTR-CM). In preferred embodiments, the treated subjects have either mutant ATTR (ATTRv / hATTR) or wild-type ATTR-CM (wATTR). Even more preferably, the treated subjects have either mutant ATTR-CM (ATTRv-CM / hATTR-CM) or wild-type ATTR-CM (wATTR-CM).

[0030] 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 ligament 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 pre-eclampsia.

[0031] In some embodiments, the subject has been diagnosed with inherited ATTR-CM for 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 the TTR protein that forms deposits in the heart) and a negative genetic test for a TTR mutation.

[0033] Preferably, the diagnosis is based on either the presence of symptomatic ATTR, preferably ATTR-CM, or an NT-proBNP level of >2000 pg / mL. The use of NT-proBNP as a biomarker for ATTR is recognized in the art, and a staging system 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 estimated glomerular filtration rate (eGFR) (Gillmore et al., European Heart Journal 39 (2018), 2799-2806)) with an NT-proBNP cutoff of 3000 pg / mL. See also Perfetto et al., Internal and Emergency Medicine 17 (2022), 957-969. Therefore, depending on the levels of cTnT and eGFR, and considering only the level of NT-proBNP, subjects have cardiac ATTR grades I, II and III. Thus, the subjects to be treated are preferably either symptomatic for ATTR, preferably ATTR-CM, and / or have NT-proBNP levels >2000 pg / mL.

[0034] Additionally or alternatively, the subject is an adult subject, particularly an adult subject, preferably a subject aged 18 to 90 (≧18 to ≦90).

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

[0036] Treatment of a human subject with an antibody used in accordance with the invention, in one embodiment, results in lower cardiac amyloid burden and / or a composite 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 method(s) results in a dose- and time-dependent reduction in the patient's TTR activity after a designated treatment period (e.g., 4, 6, 8, 10, 12, 15, 18, 21, or 24 months or longer, e.g., 48 months) 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%).

[0037] Preferably, treatment, i.e., administration of the dosing regimen of the present invention, improves at least one of the following: (a) symptoms, functionality, and health-related quality of life (QoL) measured by change from baseline in the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score; (b) time to cardiovascular (CV)-related death; (c) 6-minute walk test (6MWT) score compared with baseline; (d) Rate of cardiovascular (CV) clinical events; and (e) Time to all-cause mortality (ACM).

[0038] In one embodiment, the treatment comprises: (a) reducing NT-proBNP levels in a subject compared to baseline; (b) reduce the rate of heart failure (HF) events; (c) reducing the incidence of augmentation of oral diuretic therapy, possibly including outpatient augmentation of oral diuretic therapy; (d) reducing the incidence of changes in disease-modifying therapy; (e) reducing the incidence of hospitalization for atrial fibrillation; (f) induce change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score over 24 months of study treatment; (g) induce a change from baseline in the 6-minute walk test (6MWT) beyond 24 months of study treatment; (h) derive change from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia stages and NYHA classification; (i) induce change from baseline in GLS; (j) induce change from baseline in stroke volume; (k) induce changes from baseline in echocardiographic parameters of interest; (l) induce change from baseline in hs-cTnT; (m) induce changes from baseline in DPD / PYP / HMDP cardiac scintigraphy cardiac uptake and / or cMRI-derived ECV, T1, and T2 mapping; (n) induce change from baseline in eGFR; (o) induce a change from baseline in EQ-5D-5L score and / or induce a change from baseline in SF-36 score; (p) inducing a change from baseline in a marker selected from CRP, IL IL1b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A and ferritin, preferably CRP; (q) induce a change from baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6; (r) induce a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4; (s) Induce change from baseline in (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or sNFL level; and / or (t) Induce change from baseline in NIS and / or induce change in NC test.

[0039] In some embodiments, antibodies for use according to the invention are administered to a subject once every four weeks (q4w).

[0040] In some embodiments, the antibodies for use according to the invention are administered to the subject intravenously (IV), preferably by IV infusion, i.e. the method of treating as defined herein above comprises administering the antibody to the subject intravenously (IV), preferably by IV infusion.

[0041] In some embodiments, antibodies for use according to the invention are administered for at least 24 months, preferably at least 48 months, i.e., the method of treatment comprises administering the antibody for at least 24 months, preferably at least 48 months.

[0042] In some embodiments, the antibody for use in accordance with the invention is administered in a weight-based flat dose based on the patient's recorded weight, preferably a flat dose as defined herein above, which weight is recorded within 30 days of the scheduled administration, and the dose is administered intravenously (IV) by infusion every four weeks (q4w), i.e., the method comprises administering the antibody in a weight-based flat dose based on the patient's recorded weight, preferably a flat dose as defined herein above, which weight is recorded within 30 days of the scheduled administration, and the dose is administered intravenously (IV) by infusion every four weeks (q4w).

[0043] In pharmacological studies (Michalon, 2021), NI006 / ALXN2220 was shown to activate immune cells through binding to Fc gamma receptors. Using different in vitro and in vivo models, it has been demonstrated that NI006 / ALXN2220 causes the clearance of ATTR fibrils from patient samples via immune-driven phagocytic clearance in a dose- and time-dependent manner. Thus, NI006 / ALXN2220 induces antibody-mediated phagocytosis of ATTR fibrils by phagocytic immune cells, such as macrophages, resulting in the removal of ATTR deposits from tissues.

[0044] Thus, in some embodiments, antibodies for use according to the invention cause clearance of ATTR fibrils from patient samples in a dose- and time-dependent manner via immune-driven phagocytic clearance.

[0045] In the Phase 1 study NI006-101, 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 pharmacokinetic profile was found to be dose-proportional, provide sustained antibody levels, and be compatible with monthly dosing. In this study, cardiac ATTR deposit burden was estimated using two different methods: quantification of cardiac tracer uptake in the heart by scintigraphy or quantification of ECV by cMRI. These two PD measures are surrogates of cardiac amyloid burden and help estimate baseline amyloid burden and change over time during the clinical trial. NI006 / ALXN2220 demonstrated a dose- and time-dependent reduction in cardiac amyloid burden by up to approximately 51% at 60 mg / kg at 12 months. Thus, preferably, clearance of ATTR fibrils by anti-TTR antibody treatment is measured by quantification of ECV by cardiac tracer uptake scintigraphy or cMRI. See Phase 1 Study NI006-101. More preferably, treatment of a patient with an anti-TTR antibody results in a dose- and time-dependent reduction in cardiac amyloid burden by up to about 51% at 12 months, preferably corresponding to a dose of about 60 mg / kg administered to the patient. Thus, in some embodiments, treatment with an anti-TTR antibody according to the method(s) results in a dose- and time-dependent reduction in myocardial amyloid burden in a patient by 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 designated treatment period (e.g., 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 21 months, or 24 months, e.g., 48 months).

[0046] In some embodiments, a patient treated with an antibody according to the invention: (1) Evidence of cardiac amyloidosis by echocardiography or cMRI and the following: a. Endomyocardial biopsy with confirmatory TTR amyloid typing by either 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 monoclonal gammopathy; or c. Confirmation of TTR amyloid typing by either immunohistochemistry or mass spectrometry in noncardiac tissues in the presence of grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and monoclonal hypergammaglobulinemia. have a centrally confirmed diagnosis of ATTR-CM with either a wild-type TTR genotype or a mutant TTR genotype based on one of the following: (2) willingness to be genetically tested for mutations in the TTR gene during screening if genetic testing has not been previously performed or if genetic results are not available; (3) End-diastolic ventricular septal wall thickness of 11 mm or more in women and 12 mm or more in men measured by echocardiography at screening. (4) have NT-proBNP >2000 pg / mL as measured by a central laboratory at screening; (5) treatment with loop diuretics for at least 30 days before screening; (6) The following events occurred within one year prior to screening: a. Heart failure hospitalization b. Emergency heart failure visit c. Episodes of volume overload documented by NT-proBNP > 2000 pg / mL (or equivalent BNP) have a history of heart failure as evidenced by one of the following: (7) New York Heart Association (NYHA) classification II to IV at screening, and / or (8) have a life expectancy of at least 6 months according to a clinician's judgment; It is intended for men or women.

[0047] As outlined in European Patent Application No. 22 207 645.7 and U.S. Provisional Applications Nos. 63 / 383,803 and 63 / 503,286, and the International Application entitled "Pharmaceutical compositions for treating or preventing transthyretin-mediated amyloidosis" (Attorney Docket No. NE30A100 / P-WO), filed November 15, 2023, the contents of which are incorporated herein by reference in their entirety, a formulation comprising 50 mg / mL of antibody, i.e., ALXN2220 / NI006, at pH 5.8, in 20 mM histidine buffer, 80 mg / mL or 65 mg / mL sucrose, and 0.3 mg / mL polysorbate 80 has been found to be particularly suitable for ensuring long-term stability of the formulation. Thus, a formulation containing 50 mg / mL of antibody, i.e., 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.

[0048] Thus, in some embodiments, antibodies for use according to the invention are administered in a pharmaceutical formulation of 50 mg / mL in 20 mM histidine buffer (e.g., L-histidine and L-histidine monohydrochloride), pH 5.8, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80. Alternatively, antibodies for use according to the invention are administered in a pharmaceutical formulation of 50 mg / mL in 20 mM histidine buffer (e.g., L-histidine and L-histidine monohydrochloride), pH 5.8, 65 mg / mL sucrose, 0.3 mg / mL polysorbate 80.

[0049] Preferably, antibodies for use according to the invention are administered to a patient as an intravenous (IV) infusion over 2 hours for the first dose and over 1 hour for each subsequent dose, i.e. the method comprises administering the antibody to a patient as an intravenous (IV) infusion over 2 hours for the first dose and over 1 hour for each subsequent dose.

[0050] In some embodiments, the subject has previously been treated with a disease-modifying agent selected from a TTR silencer and a TTR stabilizer, and / or is concurrently receiving a disease-modifying agent selected from a TTR silencer and a TTR stabilizer. For example, the TTR tetramer stabilizer can be diflunisal, tafamidis (VYNDAQEL® or VYNDAMAX®), or acoramidis (AG10). Currently, tafamidis, an effective oral disease-modifying treatment, is the only approved pharmacological treatment that specifically targets both wild-type and inherited ATTR-CM. According to the present invention, ALXN2220 activity has been shown to be maintained in the presence of tafamidis.

[0051] In some embodiments, antibodies used in accordance with the invention are administered for up to 24 months according to the intervention infusion schedule provided in Table 25. Preferably, as a follow-up after the 24-month treatment period, antibodies used in accordance with the invention are administered according to the intervention infusion schedule in 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, preferably according to the intervention infusion schedule in Table 26, as a follow-up after the 24-month treatment period.

[0052] As shown in the Examples, treatment with an anti-TTR antibody results in median amyloid reduction when the antibody is administered in patients at doses of 30 mg / kg and 60 mg / kg, and based on PK modeling, the same amyloid reduction is expected to occur at a flat dose. Thus, in some embodiments, treatment with an anti-TTR antibody, when used in accordance with the present invention, results in median amyloid reduction when the antibody is administered in patients at doses corresponding to doses of 30 mg / kg to 60 mg / kg. Preferably, therapeutic efficacy is measured using endomyocardial biopsies, including intraepidermal nerve fiber density (IENFD) and / or sweat gland nerve fiber density (SGNFD).

[0053] In some embodiments, the patient (1) prior treatment with a disease-modifying agent, wherein the disease-modifying agent is selected from: (a) a TTR silencer, optionally together with a TTR stabilizer; (b) a TTR stabilizer alone; and (c) no TTR stabilizer or TTR silencer treatment; (2) TTR genotype, including ATTR mutant (ATTRv) or ATTR wild-type (ATTRwt); or (3) Disease severity based on cardiac biomarker levels, including NT-proBNP >3000 pg / mL vs. NT-proBNP ≤3000 pg / mL, optionally along with pre- and post-treatment high-sensitivity cardiac troponin C (hs-cTnT) levels. The study is stratified based on:

[0054] Additionally, serum biomarker levels can be monitored before and after treatment with an antibody used in accordance with the present invention to monitor therapeutic efficacy. In particular, in some embodiments, the biomarkers are selected from (a) complement factors selected from C3 and C4, and CRP; (b) pro-inflammatory cytokines selected from IL1b, IL6, IL8, IFNg, and TNF-α; (c) anti-inflammatory cytokines selected from IL10 and 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.

[0055] definition To avoid any doubt, it is emphasized that expressions such as "in some embodiments," "in certain embodiments," "in some cases," "in some aspects," "in further embodiments," "in one embodiment," "in a further aspect," "in a first aspect," "in a second aspect," and the like are used and meant to indicate that any of the embodiments described therein should be read in conjunction with each of the features of those embodiments, and that the present disclosure is intended to treat any combination of features of those embodiments and aspects as if recited in one embodiment. The same applies to any combination of embodiments and features set forth in the appended claims and examples, which are also intended to be combined with features from the corresponding embodiment disclosed in the description. For consistency and brevity only, the embodiments are characterized by dependency, but in fact, each embodiment and combination of features that may be interpreted as dependency(s) must be considered literally disclosed and not as a selection among different alternatives. In this regard, those 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 having substantially the same properties and equivalents.

[0056] As used herein, the term "about" as used herein refers to a value that is ±10%; preferably ±5% of the recited value.

[0057] In the context of the present invention, the term "and / or" is understood to mean that all members of the group connected by the term "and / or" are mutually alternately and in each case mutually cumulatively disclosed in any combination. The expression "A, B and / or C" 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).

[0058] As used herein, the term "antibody" includes its corresponding binding fragments, and the dosages referred to herein refer to the molecular weight of NI006, which is approximately 147 kDa for an intact IgG1 antibody. Therefore, for use with antibodies whose MW differs significantly, the dosage can be adjusted accordingly. Similarly, if an antibody with a lower or longer serum half-life is used, for example, due to modifications such as altered glycosylation and / or PEGylation, the dosage and administration interval can be recalculated, respectively.

[0059] 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. The pharmaceutical compositions are formulated for administration to a subject, such as a mammal, e.g., a human, to prevent, treat, or control a particular disease or condition that affects or may affect the subject (e.g., 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 ligament amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and pre-eclampsia, etc.).

[0060] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject, such as a mammal (e.g., a human), without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0061] As used herein, the terms "capable of binding" and "binds" refer to the ability of an antibody to bind to, for example, aggregated TTR under experimental conditions, for example, in an ELISA assay.

[0062] As used herein, the term "between" includes endpoints.

[0063] "Percent (%) sequence identity" with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to those in the reference polynucleotide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment to determine percent nucleic acid or amino acid sequence identity can be accomplished in a variety of ways within the capabilities of those skilled in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. For example, percent sequence identity values ​​can be generated using the sequence comparison computer program BLAST. By way of illustration, the percent sequence identity of a given nucleic acid or amino acid sequence A to, with, or relative to a given nucleic acid or amino acid sequence B is calculated as follows (alternatively, one can say that a given nucleic acid or amino acid sequence, A, has a certain percent sequence identity to, with, or relative to a given nucleic acid or amino acid sequence B): Multiply 100 by (fraction X / Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in a programmatic alignment of A and B, and where Y is the total number of nucleic acids in B. It will be understood that if the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, then the percent sequence identity of A to B will not equal the percent sequence identity of B to A.

[0064] As used herein, the term "treat" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, where the goal is to prevent or slow (alleviate) an undesirable physiological change or disorder, such as the onset of heart failure. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "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 years or more, e.g., over the subject's lifetime) compared to expected survival in the absence of treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in whom the onset of the condition or disorder is to be prevented.

[0065] When used in this specification, the term ``loading volume'' means the target's blood (for example, serum or blood) concentration at the desired therapeutic level (for example, ≧1μg / mL, ≧1μg / mL, ≧2.5μg / mL, ≧5μg / mL, ≧10μg / mL, ≧20μg / mL 16 0μg / 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, ≧4 10μg / mL, ≧420μg / mL, ≧430μg / mL, ≧440μg / mL, ≧450μg / mL, ≧460μg / mL, ≧470μg / 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, ≧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, ≧890μg / mL, ≧900μg / mL,This refers to a dose of antibody of about 600 mg to 4000 mg (e.g., 2400 mg, 2500 mg, 3000 mg, 3200 mg, or 3500 mg) increasing to ≥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 greater). 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), biweekly (e.g., every other week or every 14 days), monthly (e.g., every 28±7 days), or bimonthly (e.g., every other month, e.g., every 56±7 days) before a maintenance dose (e.g., the initial maintenance dose or any subsequent maintenance doses) is administered to the subject.

[0066] As used herein, the term "maintenance dose" refers to a dose of antibody 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 to 60 mg / kg (e.g., 10 mg / kg, 30 mg / kg, or 60 mg / kg) that maintains a desired minimum blood (e.g., serum or plasma) concentration of the antibody. For example, a concentration 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, ≥ 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, ≥ 350 μg / mL, ≥ 360 μg / mL, ≥ 370 μg / mL, ≥ 380 μg / mL, ≥ 390 μg / mL, ≥ 400 μg / mL, ≥ 410 μg / mL, ≥ 420 μg / mL, ≥ 430 μg / μg / mL, ≧160μg / mL, ≧170μg / mL, ≧180μg / mL, ≧190μg / mL, ≧200μg / mL, ≧210μg / mL, ≧220μg / mL, ≧230μg / mL, ≧240μg / mL, ≧250μ g / 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 mL, ≧460μg / mL, ≧470μg / mL, ≧480μg / mL, ≧490μg / mL, ≧500μg / mL, ≧510μg / mL, ≧520μg / mL, ≧530μg / mL, ≧540μg / mL, ≧550μg / m L, ≧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, ≧730μg / mL, ≧740μg / mL, ≧750μg / mL,It is desirable to maintain a minimum concentration of ≥ 760 μg / mL, ≥ 770 μg / mL, ≥ 780 μg / mL, ≥ 790 μg / mL, ≥ 800 μg / mL, ≥ 810 μg / mL, ≥ 820 μg / mL, ≥ 830 μg / mL, ≥ 840 μg / mL, ≥ 850 μg / mL, ≥ 860 μg / mL, ≥ 870 μg / mL, ≥ 880 μg / mL, ≥ 890 μg / mL, ≥ 900 μg / 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 greater). The maintenance dose may be administered to a subject at a concentration (e.g., 10-60 mg / kg, e.g., 10 mg / kg, 30 mg / kg, or 60 mg / kg) or a flat dose (e.g., about 600 mg-4000 mg, e.g., 2400 mg, 2500 mg, 3000 mg, or 3200 mg), preferably a dose lower than a loading dose previously administered to the same subject or a subject of the same weight class. [Brief explanation of the drawings]

[0067] [Figure 1] 1 is a schematic diagram showing exemplary dosing regimens. The red boxes indicate the single ascending dose (SAD) phase for each of Cohorts 1-6, as further described in Example 1. The blue boxes indicate the multiple ascending dose (MAD) phase for each of Cohorts 1-6, as further described in Example 1. The solid green cells in the table labeled DEC are exemplary time periods, such as data evaluation committees, for examining subjects for safety and / or therapeutic efficacy before and after the indicated dose. [Figure 2] FIG. 1 is a schematic diagram showing exemplary dosing regimens for the open-label expansion OLE phase for each of Cohorts 1-6, as further described in Example 1. The solid green cells in the table labeled DEC are exemplary time periods, such as data evaluation committees, for examining subjects for safety and / or therapeutic efficacy before and after the indicated dose. [Figure 3]1 is a schematic diagram showing exemplary dosing regimens. The red box indicates the single ascending dose (SAD) phase of Cohort 7, as further described in Example 1. The blue box indicates the multiple ascending dose (MAD) phase of Cohort 7, as further described in Example 1. The green open box indicates the open-label expansion OLE phase of Cohort 7, as further described in Example 1. The solid green cells in the table labeled DEC are exemplary time periods, such as data evaluation committees, for examining subjects for safety and / or therapeutic efficacy before and after the indicated dose. [Figure 4] Scintigraphy (A) and serial intraventricular ECV maps (B) are shown visualizing amyloid transthyretin depletion in ATTR-CM by NI006 / ALXN2220. Figure 4(A) shows serial bone scintigraphy from one patient randomized to NI006 / ALXN2220 and one patient randomized to placebo at baseline, 4 months (after completion of double-blind SAD / MAD), and 12 months (after completion of OLE). Quantification of cardiac tracer uptake is indicated by the heart / whole body ratio (H / WB ratio (%)). Individual cumulative administered NI006 / ALXN2220 doses (g) and NI006 / ALXN2220 exposure (*AUC in mg / mL) are provided for each post-baseline imaging time point. Figure 4(B) shows serial intraventricular ECV maps for one patient randomized to NI006 / ALXN2220 and one patient randomized to placebo at baseline, 4 months, and 12 months, with quantification of cardiac amyloid deposition shown by ECV measurements (in %). Individual cumulative administered NI006 / ALXN2220 dose (g) and NI006 / ALXN2220 exposure (days*mg / mL) are provided for post-baseline imaging time points. [Figure 5]Figure 5 shows graphs visualizing changes in cardiac amyloid burden, specifically the relative change from baseline (RCFB) of cardiac amyloid derived from quantification of serial bone scintigraphy (triangles) and MRI (dots). Figure 5(A) shows RCFB per assigned NI006 / ALXN2220 dose cohort and placebo at 4 and 12 months. Figure 5(B) shows RCFB in patients assigned to NI006 / ALXN2220 against individual cumulative NI006 / ALXN2220 exposure at 4 and 12 months. [Figure 6] Figure 6 shows graphs visualizing the change in cardiac amyloid in placebo switchers at 12 months, specifically the relative change from baseline (RCFB), derived from quantification of serial bone scintigraphy (triangles) and MRI (dots) in cardiac amyloid from patients randomized to placebo. Figure 6(A) shows RCFB at 4 months and after switching to NI006 / ALXN2220 during the open-label expansion phase at 12 months. Figure 6(B) shows RCFB at 12 months in patients randomized to placebo but who switched to NI006 / ALXN2220, compared with their individual cumulative NI006 / ALXN2220 exposure at 12 months. [Figure 7] Figure 7 shows graphs visualizing changes in cardiac biomarkers and echocardiographic parameters, particularly the relative change from baseline in cardiac biomarkers and echocardiographic parameters after 12 months of treatment with NI006 / ALXN2220. Figure 7(A) shows the relative change from baseline (RCFB) in NT-proBNP and troponin T per assigned NI006 / ALXN2220 dose cohort (top), and the relative change for each patient's individual cumulative NI006 / ALXN2220 exposure at 12 months (bottom). Figure 7(B) shows the absolute change from baseline (ACFB) in echocardiographic indices of cardiac structure (end-diastolic volume, ED-IVS), systolic function (left ventricular ejection fraction, LVEF, left systolic and diastolic volumes, LVESV and LVEDV), and diastolic function (left atrial volume, LAV, and E / e' ratio). [Figure 8]8(A) and 8(B) show graphs visualizing predicted serum NI006 / ALXN2220 95th percentile Cmax (FIG. 8(A)) and median AUC 28 days (FIG. 8(B)) after a single dose simulation by 1000 doses and body weights. Observed individual Cmax and simulated individual AUC 28 days. [Figure 9] 9A-9B show graphs visualizing predicted serum NI006 / ALXN2220 95th percentile Cmax (FIG. 9(A)) and median AUC28d (FIG. 9(B)) at steady state (9 q4w doses). Simulations by 1000 doses and body weights. Observed individual Cmax and simulated individual AUC28d. [Figure 10] A study schematic is shown for a Phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of amyloid-deficient ALXN2220 in adult participants with transthyretin amyloid cardiomyopathy (ATTR-CM). a Participants will be receiving standard of care as determined by the treating and study physicians (which may include conventional heart failure treatments and approved disease-modifying agents for ATTR amyloidosis). b Randomization will be stratified by three factors: current treatment with disease-modifying agents (TTR silencers ± TTR stabilizers vs. TTR stabilizers alone vs. none), TTR genotype (mutated 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 visits will occur up to 120 days after the last dose of study intervention. DETAILED DESCRIPTION OF THE INVENTION

[0068] 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 human anti-transthyretin (TTR) antibody that is capable of binding to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof, and does not substantially recognize physiological TTR species, and is effective in treating or preventing diseases associated with transthyretin-mediated amyloidosis (ATTR), such as ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC), and senile systemic amyloidosis (SSA). The present invention is for use in methods of treating or preventing a subject having or at risk of having TTR-related ocular amyloidosis, 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 ligament amyloidosis (including carpal tunnel syndrome), rotator cuff tear and lumbar spinal stenosis, and preeclampsia, wherein the method comprises administering an anti-TTR antibody or pharmaceutical composition thereof in the dosing regimen described herein. The method provides for a reduction in cardiac amyloid deposits in the heart. The dosing regimens described herein may, for example, allow for dosing of anti-TTR antibodies at about monthly dosing frequencies (e.g., once every 28±7 days and once every 4 weeks, respectively), and may result in favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties that reduce the level of cardiac amyloid (e.g., misfolded TTR protein) deposits in the heart. Thus, the treatment regimens described herein can provide surprisingly beneficial therapeutic and prophylactic effects to subjects with or at risk of having an ATTR-associated disease (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-associated ocular amyloidosis, TTR-associated renal amyloidosis, TTR-associated hyperthyroxinemia, TTR-associated ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and pre-eclampsia).

[0069] In particular, in one embodiment, this method comprises administering an antibody in a dosing regimen that results in a sustained (e.g., maintained for 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 days, 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 or greater (e.g., from about 1 μg / mL to about 1000 μg / mL).

[0070] In some embodiments, the antibody is administered to a subject at a concentration 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 200μg / mL, about 210μg / mL, about 220μg / mL, about 230μg / mL, about 240μg / mL, about 250μg / mL, about 260μg / mL, about 270μg / mL, about 280μg / mL, about 290μg / mL, about 300μg / mL, about 310μg / mL, about 320 μg / mL, approximately 330 μg / mL, approximately 340 μg / mL, approximately 350 μg / mL, approximately 360 μg / mL, approximately 370 μg / mL, approximately 380 μg / mL, approximately 390 μg / mL, approximately 400 μg / mL, approximately 410 μg / mL, approximately 420 μg / mL, approximately 430 μg / mL, approximately 440 μg / mL , about 450μg / mL, about 460μg / mL, about 470μg / mL, about 480μg / mL, about 490μg / mL, about 500μg / mL, about 510μg / mL, about 520μg / mL, about 530μg / mL, about 540μg / mL, about 550μg / mL, about 560μg / mL, about 570 μg / mL, approximately 580 μg / mL, approximately 590 μg / mL, approximately 600 μg / mL, approximately 610 μg / mL, approximately 620 μg / mL, approximately 630 μg / mL, approximately 640 μg / mL, approximately 650 μg / mL, approximately 660 μg / mL, approximately 670 μg / mL, approximately 680 μg / mL, approximately 690 μg / mL , about 700μg / mL, about 710μg / mL, about 720μg / mL, about 730μg / mL, about 740μg / mL, about 750μg / mL, about 760μg / mL, about 770μg / mL, about 780μg / mL, about 790μg / mL, about 800μg / mL, about 810μg / mL, about 820 μg / mL, approximately 830 μg / mL, approximately 840 μg / mL, approximately 850 μg / mL, approximately 860 μg / mL, approximately 870 μg / mL, approximately 880 μg / mL, approximately 890 μg / mL, approximately 900 μg / mL, approximately 910 μg / mL, approximately 920 μg / mL, approximately 930 μg / mL, approximately 940 μg / mL,In some embodiments, the antibody is for administration in a dosing regimen that results in a sustained plasma concentration of the antibody of between 10 μg / mL and about 75 μg / mL (e.g., between about 10 μg / mL and about 50 μg / mL, between about 20 μg / mL and about 60 μg / mL, or between about 50 μg / mL and about 75 μg / mL). Alternatively, the antibody is for administration in a dosing regimen that results in a sustained plasma concentration of the antibody 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). Alternatively, the antibody is for administration in a dosing regimen that results in a sustained plasma 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 a subject weighing about 40 to 140 kg receiving about 10 mg / kg of antibody once a month is about 20 to 100 μg / mL. In another embodiment, the trough concentration of the antibody in a subject weighing about 40 to 140 kg receiving about 60 mg / kg of antibody once a month is about 140 to 700 μg / mL.

[0071] The present invention further provides a human anti-transthyretin (TTR) antibody capable of binding to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof, and which does not substantially recognize physiological TTR species, comprising a human anti-transthyretin (TTR) antibody administered to a subject having or at risk of having transthyretin-mediated amyloidosis (ATTR) in a dose of about 2,000 μg of TTR. * day / mL ~ approx. 100,000μg * day / mL, e.g., at least 30,000 μg *The present invention relates to a human anti-TTR antibody for use in treating or preventing transthyretin-mediated amyloidosis (ATTR) in a subject by administering the antibody in a dosing regimen that results in a sustained plasma concentration of the antibody in terms of area under the curve (AUC) in days / mL (e.g., area under the plasma drug concentration-time curve in the subject after 17 to 50 weeks of treatment / administration).

[0072] In some embodiments, the anti-TTR antibody is administered at a dose of about 2,000 μg. * day / mL ~ approx. 50,000μg * day / mL (e.g., approximately 2,000 μg in a subject) * day / mL, approximately 2,500 μg * day / mL, approximately 3,000μg * day / mL, approximately 3,500μg * day / mL, approximately 4,000μg * day / mL, approximately 5,000μg * day / mL, approximately 6,000μg * day / mL, approximately 7,000μg * day / mL, approximately 8,000μg * day / mL, approximately 9,000μg * day / mL, approximately 10,000μg * day / mL, approximately 15,000μg * day / mL, approximately 20,000μg * day / mL, approximately 30,000μg * day / mL, approximately 40,000μg * day / mL, or approximately 50,000 μg * The antibody is for administration at a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., area under the plasma drug concentration-time curve in a subject after 17 weeks of treatment / dosing) of 0.01 mg / mL (days / mL).

[0073] Alternatively, the anti-TTR antibody is administered to the subject at a dose of about 2,500 μg * day / mL ~ approx. 100,000μg * day / mL, approximately 5,000μg * day / mL ~ approx. 100,000μg * day / mL, or approximately 10,000 μg* day / mL ~ approx. 100,000μg * day / mL (e.g., approximately 2,500 μg * day / mL, approximately 3,000μg * day / mL, approximately 3,500μg * day / mL, approximately 4,000μg * day / mL, approximately 5,000μg * day / mL, approximately 6,000μg * day / mL, approximately 7,000μg * day / mL, approximately 8,000μg * day / mL, approximately 9,000μg * day / mL, approximately 10,000μg * day / mL, approximately 15,000μg * day / mL, approximately 20,000μg * day / mL, approximately 30,000μg * day / mL, approximately 40,000μg * day / mL, approximately 50,000μg * day / mL, approximately 60,000μg * day / mL, approximately 70,000μg * day / mL, approximately 80,000μg * day / mL, approximately 90,000μg * day / mL, or approximately 100,000 μg * The antibody is for administration at a dosing regimen that results in a maintenance plasma concentration of the antibody of AUC (e.g., area under the plasma drug concentration-time curve in a subject after 50 weeks of treatment / dosing) in mL / days.

[0074] In some embodiments, administration of anti-TTR antibodies according to the invention is useful for long-term treatment and / or follow-up treatment (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) after initial further dosing and amyloid clearance.

[0075] In a preferred embodiment, an anti-TTR antibody for use in accordance with the present 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).

[0076] Alternatively, anti-TTR antibodies for use in accordance with the present 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).

[0077] In some embodiments, the anti-TTR antibody is administered at a dose of about 0.3 mg / kg.

[0078] In some embodiments, the anti-TTR antibody is administered at a dose of about 1 mg / kg.

[0079] In some embodiments, the anti-TTR antibody is administered at a dose of about 3 mg / kg.

[0080] In some embodiments, the anti-TTR antibody is administered at a dose of about 10 mg / kg.

[0081] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0082] 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).

[0083] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0084] In some embodiments, the anti-TTR antibody is administered at a dose of about 40 mg / kg.

[0085] In some embodiments, the anti-TTR antibody is administered at a dose of about 50 mg / kg.

[0086] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0087] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg, resulting in a sustained plasma concentration of the antibody in the subject of about 50 μg / mL.

[0088] In some embodiments, the anti-TTR antibody is administered at a dose of about 10 mg / kg, resulting in a sustained plasma concentration of the antibody in the subject of about 20 μg / mL to about 100 μg / mL.

[0089] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg, resulting in a sustained plasma concentration of the antibody in the subject of about 65 μg / mL to about 350 μg / mL.

[0090] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg, resulting in a sustained plasma concentration of the antibody in the subject of about 140 μg / mL to about 700 μg / mL.

[0091] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0092] In some embodiments, the anti-TTR agent is initially 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).

[0093] 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 present invention, an anti-TTR antibody is initially 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), followed by 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).

[0094] As described above, the anti-TTR antibodies used in accordance with the present invention deplete amyloid transthyretin from cardiac tissue in a dose- and time-dependent manner, with the most pronounced effect observed at doses greater than 10 mg / kg when administered once every four weeks. Thus, in a preferred embodiment, the anti-TTR antibodies are administered at doses greater than 10 mg / kg, e.g., 10 mg / kg to 100 mg / kg, preferably 10 mg / kg to 60 mg / kg, more preferably 30 mg / kg or 60 mg / kg, and preferably, the antibodies are administered once every four weeks (q4w). Furthermore, data from bone scintigraphy and MRI showed that the 30 mg / kg and 60 mg / kg doses reduced cardiac amyloid deposition by a median of 12.8% and 25.6% compared to baseline at 4 months, and 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.

[0095] Thus, in a more preferred embodiment of the invention, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0096] In another preferred embodiment of the invention, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0097] Thus, methods of treatment or prevention according to the present invention preferably involve administering the antibody at a dose of more than 10 mg / kg, for example 10 mg / kg to 100 mg / kg, preferably 10 mg / kg to 60 mg / kg, more preferably 30 mg / kg or 60 mg / kg, and preferably the antibody is administered once every four weeks (q4w).

[0098] Based on the mg / kg dose results in safety and efficacy studies, modeling was performed to calculate a flat dose that is more convenient for administration and is therefore a preferred embodiment of the present invention. In particular, a PK / PD model was established and a flat dose in the range of 600 mg to 7500 mg was calculated to be safe and effective, see Examples 5 and 6.

[0099] Thus, in one embodiment of the present invention, the anti-TTR antibody is administered in a dose 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, 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, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 730 00mg, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg , 3800mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000 mg, 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, 6350m The maintenance dose is administered at a dose of 6000 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. In a preferred embodiment, the maintenance dose is about 2500 mg, e.g., 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, e.g., preferably 3200 mg.

[0100] In some embodiments, the anti-TTR antibody is further administered in an amount 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, , 2600mg, 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 g, 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6050mg, 6100mg, 61 50mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 6350mg , 6400mg, 6450mg, 6500mg, 6550mg, 6600mg, 6650mg, 6700mg, 6750mg, 6800mg, 6850mg, 6900mg, 6950mg, 7000mg, 7050mg, 7100mg, 7150mg, 7200mg, 7250mg, 7300mg, 7350mg, 7400mg, 7450mg, or 7500mg).

[0101] Preferably, the anti-TTR antibody is administered at 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).

[0102] In a preferred embodiment, the loading dose is about 2500 mg, for example, 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, for example, preferably 2400 mg.

[0103] Preferably, anti-TTR antibodies according to the present invention are administered at the maintenance dose of about 600 mg to about 7500 mg, which is preceded by a loading dose of about 600 mg to about 7500 mg, preferably about 600 mg to about 4000 mg, of the anti-TTR antibody. In an optional embodiment, the loading dose is administered once every two weeks for up to two months prior to the maintenance dose.

[0104] In a more preferred embodiment, 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.

[0105] In a more preferred embodiment, the maintenance and loading dose of the anti-TTR antibody is about 3000 mg, more preferably about 3500 mg, and most preferably about 3200 mg.

[0106] In some embodiments of the invention, the anti-TTR antibody is administered at a dose 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, , 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 38 00mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg , 5100mg, 5200mg, 5300mg, 5400mg, 5500mg, 5600mg, 5700mg, 5800mg, 5900mg, 6000mg, 6050mg, 6100mg, 61 50mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 6350m In a preferred embodiment, the dose is about 2500 mg, 3000 mg, 3500 mg, or 5000 mg, i.e., preferably the dose is 2200 mg, 3200 mg, or 4800 mg.

[0107] Using the PK / PD model described above, it was further found that a flat dose was most beneficial for achieving the safest and most effective treatment, depending on the patient's weight, see Figures 8, 9 and Example 5.

[0108] Thus, in one embodiment of the present invention, an 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 or less. In one embodiment, an 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 or less. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 2500 mg to a patient weighing about 40 kg to about 60 kg or less. In one embodiment of the present invention, an 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, an 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, an 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 present invention, an anti-TTR antibody is administered at a dose of 4000 mg to 5000 mg to a patient weighing approximately 100 kg or less. In one embodiment, an anti-TTR antibody is administered at a dose of 4000 mg, 4500 mg, or 5000 mg to a patient weighing approximately 100 kg or less. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 4000 mg or 5000 mg to a patient weighing approximately 100 kg or less, and most preferably, an anti-TTR antibody is administered at a dose of 5000 mg to a patient weighing approximately 100 kg or less.

[0109] As described in Example 6, based on data from the Phase I clinical trial, the above-described PK / PD model was further refined to ensure administration of the full amount of drug present in each vial while maintaining the same desired efficacy level, eliminating residual volume and corresponding drug waste. Notably, slightly lower flat doses were developed using the PK / PD model, which also improves patient convenience since a smaller amount of drug is administered and infused, respectively. These flat doses are used in the Phase III clinical trial, as outlined in Example 8.

[0110] Thus, in a preferred embodiment of the present invention, an anti-TTR antibody is administered to a patient weighing between about 40 kg and less than 60 kg at a dose within the range of 2200 mg and 2700 mg (including the endpoint). In a preferred embodiment, an anti-TTR antibody is administered to a patient weighing between about 40 kg and less than 60 kg at a dose of 2400 mg. In one embodiment of the present invention, an anti-TTR antibody is administered to a patient weighing between about 60 kg and less than 100 kg at a dose of 3000 mg to 3500 mg. In a preferred embodiment, an anti-TTR antibody is administered to a patient weighing between about 60 kg and less than 100 kg at a dose of 3200 mg. In one embodiment of the present invention, an anti-TTR antibody is administered to a patient weighing between about 100 kg and less than 100 kg at a dose of 4400 mg to 5200 mg. In a preferred embodiment, an anti-TTR antibody is administered to a patient weighing between about 100 kg and less than 100 kg at a dose of 4800 mg.

[0111] In some embodiments, the anti-TTR antibody is administered to a 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 weekly by subcutaneous infusion or continuous infusion via pump.

[0112] 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).

[0113] In some embodiments, the anti-TTR antibody is administered to the subject once every 28 days.

[0114] In some embodiments, the anti-TTR antibody is administered to a subject once every 35 days. In preferred embodiments, the anti-TTR antibody is administered to a subject once every 28 days. Preferably, the anti-TTR antibody is administered once every four weeks (q4w).

[0115] Thus, in one embodiment, the anti-TTR antibody is administered at a dose of 30 mg / kg once every 28 days.

[0116] In one embodiment, the anti-TTR antibody is administered at a dose of 30 mg / kg once every 35 days.

[0117] In one embodiment, the anti-TTR antibody is administered at a dose of 30 mg / kg once every four weeks (q4w).

[0118] In one embodiment, the anti-TTR antibody is administered at a dose of 60 mg / kg once every 28 days.

[0119] In one embodiment, the anti-TTR antibody is administered at a dose of 60 mg / kg once every 35 days.

[0120] In one embodiment, the anti-TTR antibody is administered at a dose of 60 mg / kg once every four weeks (q4w).

[0121] 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 or less.

[0122] 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 or less.

[0123] In one embodiment, the anti-TTR antibody is administered at a dose of 2500 mg once every four weeks (q4w) to a patient weighing 40 kg to 60 kg or less.

[0124] 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 or less.

[0125] 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 or less.

[0126] In one embodiment, the anti-TTR antibody is administered at a dose of 2400 mg once every four weeks (q4w) to a patient weighing 40 kg to 60 kg or less.

[0127] In one embodiment, the anti-TTR antibody is administered at a dose of 3500 mg once every 28 days to a patient weighing ≥ 60 kg to 100 kg.

[0128] In one embodiment, the anti-TTR antibody is administered at a dose of 3500 mg once every 35 days to a patient weighing ≥ 60 kg to 100 kg.

[0129] In one embodiment, the anti-TTR antibody is administered at a dose of 3500 mg once every 28 days to a patient weighing ≥ 60 kg to 100 kg.

[0130] In one embodiment, the anti-TTR antibody is administered at a dose of 3200 mg once every 28 days to a patient weighing ≥ 60 kg to 100 kg.

[0131] In one embodiment, the anti-TTR antibody is administered at a dose of 3200 mg once every 35 days to a patient weighing ≥ 60 kg to 100 kg.

[0132] In one embodiment, the anti-TTR antibody is administered at a dose of 3200 mg once every four weeks (q4w) to patients weighing ≥ 60 kg to 100 kg.

[0133] In one embodiment, the anti-TTR antibody is administered at a dose of 5000 mg once every 28 days to a patient weighing ≧100 kg.

[0134] In one embodiment, the anti-TTR antibody is administered at a dose of 5000 mg once every 35 days to a patient weighing ≧100 kg.

[0135] In one embodiment, the anti-TTR antibody is administered at a dose of 5000 mg once every four weeks (q4w) to a patient weighing ≧100 kg.

[0136] In one embodiment, the anti-TTR antibody is administered at a dose of 4800 mg once every 28 days to a patient weighing ≧100 kg.

[0137] In one embodiment, the anti-TTR antibody is administered at a dose of 4800 mg once every 35 days to a patient weighing ≧100 kg.

[0138] In one embodiment, the anti-TTR antibody is administered at a dose of 4800 mg once every four weeks (q4w) to a patient weighing ≧100 kg.

[0139] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months to 30 months (e.g., 4 to 12 months, 8 to 16 months, 12 to 20 months, 16 to 24 months, or 20 to 30 months).

[0140] In some embodiments, the anti-TTR antibody is administered to the subject for about 12 to 18 months (e.g., 12 to 15 months, 13 to 16 months, 14 to 17 months, or 15 to 18 months).

[0141] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months.

[0142] In some embodiments, the anti-TTR antibody is administered to the subject for about 11 months.

[0143] In some embodiments, the anti-TTR antibody is administered to the subject for about 24 months to about 48 months, but for at least 24 months.

[0144] In some embodiments, the anti-TTR antibody is administered to the subject at a dose of about 30 mg / kg or 60 mg / kg for about 12 to 18 months (e.g., 12, 13, 14, 15, 16, 17, or 18 months).

[0145] 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 to 18 months (e.g., for about 12, 13, 14, 15, 16, 17, or 18 months).

[0146] In some embodiments, the loading dose is administered once every two weeks for up to two months before the maintenance dose is administered. In some embodiments, the maintenance dose is lower than the loading dose.

[0147] 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-TTR antibody) schedule provided in Table 25. In further embodiments, the anti-TTR antibody is administered as a follow-up after the 24-month treatment period according to the intervention infusion schedule in Table 26.

[0148] In some embodiments, the plasma concentration of the anti-TTR antibody is 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). 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, 210μg / mL, approximately 220μg / mL, approximately 230μg / mL, approximately 240μg / mL, approximately 250μg / mL, approximately 260μg / mL, approximately 270μg / mL, approximately 280μg / mL, approximately 290μg / mL, approximately 300μg / mL, approximately 310μg / mL, approximately 320μg / mL, approximately 330μ g / mL, approximately 340 μg / mL, approximately 350 μg / mL, approximately 360 μg / mL, approximately 370 μg / mL, approximately 380 μg / mL, approximately 390 μg / mL, approximately 400 μg / mL, approximately 410 μg / mL, approximately 420 μg / mL, approximately 430 μg / mL, approximately 440 μg / mL, approximately 450 μg / mL, Approximately 460μg / mL, approximately 470μg / mL, approximately 480μg / mL, approximately 490μg / mL, approximately 500μg / mL, approximately 510μg / mL, approximately 520μg / mL, approximately 530μg / mL, approximately 540μg / mL, approximately 550μg / mL, approximately 560μg / mL, approximately 570μg / mL, approximately 580μ g / mL, approximately 590μg / mL, approximately 600μg / mL, approximately 610μg / mL, approximately 620μg / mL, approximately 630μg / mL, approximately 640μg / mL, approximately 650μg / mL, approximately 660μg / mL, approximately 670μg / mL, approximately 680μg / mL, approximately 690μg / mL, approximately 700μg / mL,Approximately 710μg / mL, approximately 720μg / mL, approximately 730μg / mL, approximately 740μg / mL, approximately 750μg / mL, approximately 760μg / mL, approximately 770μg / mL, approximately 780μg / mL, approximately 790μg / mL, approximately 800μg / mL, approximately 8 10μg / mL, approximately 820μg / mL, approximately 830μg / mL, approximately 840μg / mL, approximately 850μg / mL, approximately 860μg / mL, approximately 870μg / mL, approximately 880μg / mL, approximately 890μg / mL, approximately 900μg / mL, approximately 910μ 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), and maintained for about 1 day to about 30 days (e.g., about 1, 2, 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, or 30 days).

[0149] In some embodiments, the plasma concentration is from about 1 μg / mL to about 1000 μg / mL (e.g., from about 1 μg / mL to about 100 μg / mL, from about 2.5 μg / mL to about 125 μg / mL, from about 5 μg / mL to about 150 μg / mL, from about 10 μg / mL to about 200 μg / mL, from about 65 μg / mL to about 350 μg / mL, from about 20 μg / mL to about 200 μg / mL, from about 20 μg / mL to about 100 μg / mL, from about 50 μg / mL to about 150 μg / mL, or from about 75 μg / mL to about 175 μg / mL, from about 100 μg / mL to about 800 μg / mL, from about 140 μg / mL to about 700 μg / mL, from 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, Approximately 180μg / mL, approximately 190μg / mL, approximately 200μg / mL, approximately 210μg / mL, approximately 220μg / mL, approximately 230μg / mL, approximately 240μg / mL, approximately 250μg / mL, approximately 260μg / m L, approximately 270μg / mL, approximately 280μg / mL, approximately 290μg / mL, approximately 300μg / mL, approximately 310μg / mL, approximately 320μg / mL, approximately 330μg / mL, approximately 340μg / mL, approximately 350μg / mL, approximately 360μg / mL, approximately 370μg / mL, approximately 380μg / mL, approximately 390μg / mL, approximately 400μg / mL, approximately 410μg / mL, approximately 420μg / mL, approximately 430μg / mL, approximately 440μ g / mL, approximately 450μg / mL, approximately 460μg / mL, approximately 470μg / mL, approximately 480μg / mL, approximately 490μg / mL, approximately 500μg / mL, approximately 510μg / mL, approximately 520μg / mL, approximately 53 0μg / mL, approximately 540μg / mL, approximately 550μg / mL, approximately 560μg / mL, approximately 570μg / mL, approximately 580μg / mL, approximately 590μg / mL, approximately 600μg / mL, approximately 610μg / mL, approximately 620μg / mL, approximately 630μg / mL, approximately 640μg / mL, approximately 650μg / mL, approximately 660μg / mL, approximately 670μg / mL, approximately 680μg / mL, approximately 690μg / mL, approximately 700μg / mL,Approximately 710μg / mL, approximately 720μg / mL, approximately 730μg / mL, approximately 740μg / mL, approximately 750μg / mL, approximately 760μg / mL, approximately 770μg / mL, approximately 780μg / mL , about 790μg / mL, about 800μg / mL, about 810μg / mL, about 820μg / mL, about 830μg / mL, about 840μg / mL, about 850μg / mL, about 860μg / 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) and maintained for about 1 day to about 1 week.

[0150] In some embodiments, administration of an anti-TTR antibody or antigen-binding fragment thereof is monitored by determining 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 determining 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 progress in ATTR therapy; see, e.g., Perfetto et al., Internal and Emergency Medicine 17 (2022), 957-969 (incorporated herein by reference).

[0151] Thus, in one embodiment, a decrease in the level of the biomarker indicates therapeutic efficacy.

[0152] 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.

[0153] 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 preferred embodiments, the subject has an N-terminal pro-b-type natriuretic peptide (NT-proBNP) level greater than 2000 pg / mL.

[0154] In one embodiment of the present invention, administration of an anti-TTR antibody according to the present invention is further coupled with determining C-reactive protein (CRP) levels, where a dose-dependent, transient increase in CRP levels (e.g., for about 1 to about 14 days, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days) indicates on-target immune activation and therapeutic efficacy. Thus, CRP can be used as a biomarker, where a dose-dependent, transient increase in CRP levels indicates on-target immune activation and therapeutic efficacy.

[0155] 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).

[0156] In some embodiments, administration of the anti-TTR antibody results in a decrease in myocardial mass as measured, for example, by echocardiography or cardiac MRI.

[0157] 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), as assessed, for example, by echocardiography. For example, echocardiography can be used to measure the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E / e' ratio) to assess cardiovascular function.

[0158] Analysis of clinical trials conducted within the scope of the present invention surprisingly revealed that cardiac amyloid deposition was reduced (see Example 1) and CRP levels transiently increased in a dose-dependent manner after administration of 30 mg / kg or 60 mg / kg of anti-TTR antibody to patients. This is the first time that therapeutic intervention has even been shown to result in substantial and sustained amyloid depletion, supporting preclinical data demonstrating the ability of NI006 / ALXN2220 to induce degradation of transthyretin amyloid. Without being bound by a particular mechanism or theory, this TTR amyloid-degrading effect of NI006 / ALXN2220 may be mediated through the recruitment of phagocytes via their Fc effector function.

[0159] Therefore, because of this observation, CRP may serve as a biomarker for monitoring the success of amyloidosis treatment, specifically, by phagocytosis-mediated TTR depletion. This effect was particularly pronounced after the first administration of the antibody. The transient CRP response observed with anti-TTR antibodies was mostly asymptomatic. CRP is a cyclic pentameric protein found in plasma, and its circulating concentration increases, for example, in response to inflammation. The amino acid sequence of CRP is known; see, for example, UniProt Reference: P02741 CRP_HUMAN. Early CRP kinetics has been described as a possible actionable intra-treatment biomarker for predicting response to first-line immune checkpoint blockade (IO) combination therapy in metastatic renal cell carcinoma (mRCC); see Klumper et al., Clinical & Translational Immunology 10 (2021), e1358. However, the observation that CRP kinetics accompanies phagocytic amyloid clearance in a transient and dose-dependent manner has not been previously reported or suggested.

[0160] Thus, in a further aspect, the present invention relates to CRP as a biomarker for on-target immune activation and / or for monitoring the effectiveness of a treatment of amyloidosis, preferably systemic amyloidosis, preferably ATTR, most preferably ATTR-CM. In a further preferred embodiment, CRP as a biomarker is used to monitor the treatment of amyloidosis, preferably systemic amyloidosis, preferably ATTR, most preferably ATTR-CM, wherein the treatment is carried out by depleting TTR through phagocytosis-mediated TTR depletion. More specifically, the present invention relates to the use of CRP as a biomarker for on-target immune activation and / or for monitoring the effectiveness of a treatment of the above-mentioned amyloidosis, e.g., ATTR, preferably ATTR-CM, with an amyloid-depleting device, e.g., a therapeutic agent capable of depleting amyloid deposits, preferably through phagocytosis, preferably cardiac amyloid deposits. In a preferred embodiment, the therapeutic agent / amyloid-depleting agent is an anti-TTR antibody as defined herein.

[0161] In this aspect, the present invention further relates to a method for monitoring the effectiveness of on-target immune activation and / or treatment of amyloidosis, preferably systemic amyloidosis, more preferably ATTR, most preferably ATTR-CM, with a therapeutic agent capable of depleting amyloid deposits, preferably cardiac amyloid deposits, with amyloid defects, for example, via phagocytosis, the method comprising determining the level of CRP in a sample from a subject receiving treatment, preferably wherein the level of CRP is determined at a first time point, e.g., a first time point before administration of the amyloid defects, and at least one second time point, e.g., one second time point, after administration of the amyloid defects, wherein an increase in the level of CRP in the sample at the second time point compared to the sample at the first time point indicates therapeutic effectiveness. In a preferred embodiment, the second time point is after the first administration of an amyloid-depleting drug. In a preferred embodiment, the amyloid-depleting drug is an anti-TTR, preferably an anti-TTR as defined herein, most preferably formulated as described herein and provided at 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.

[0162] The present invention further relates to kits containing reagents for detecting and measuring the level of CRP in patient samples, which are particularly useful for monitoring the therapeutic efficacy of therapeutic / amyloid-depleting drugs as described above. In preferred embodiments, the kits contain non-immunological and / or immunological reagents for detecting CRP, such as anti-CRP antibodies, nucleic acid probes, or phosphorylcholine (PC) conjugates containing multiple copies of a covalently attached PC moiety. The kits may further include reagents and / or instructions for use. Preferably, the amyloid-depleting / therapeutic agent whose efficacy is monitored is an anti-TTR antibody as described herein, administered at the indicated dose. Means and methods for detecting CRP are known to those skilled in the art.

[0163] The present invention further relates to articles of manufacture (e.g., kits, preferably therapeutic kits) that include an effective dose (preferably a 30 mg / kg dose or a 60 mg / kg dose) of an anti-TTR antibody as described herein, and optionally reagents for delivering said dose, e.g., in the form of a formulation, to provide flat doses of 2500 mg, 3500 mg, and 5000 mg, respectively. Most preferably, therapeutic kits of the present invention provide flat doses of 2400 mg, 3200 mg, and / or 4800 mg. Thus, the kit preferably comprises one or more containers containing a formulation of an anti-TTR antibody as defined herein above, preferably a formulation of antibody NI006 / ALXN2022, preferably defined by its CDR regions, VH region, and VL region, and by its heavy and light chains as defined herein above, where the container contains 2400 mg, 3200 mg, or 4800 mg of antibody, or multiple doses of antibody, e.g., 4800 mg, 6400 mg, 9600 mg, or 7200 mg, 9600 mg, or 14400 mg, etc. The kit preferably further comprises means for delivering the antibody to a subject, which means comprises an infusion bag and / or a syringe.

[0164] Thus, a kit may include an anti-TTR antibody, e.g., provided in a container such as a vial, optionally an infusion bag to which the antibody is added, and optionally an infusion solution and / or diluent (e.g., a pharmaceutical, more preferably glucose). The kit may further include means for detecting biomarkers for monitoring the effectiveness of the treatment, preferably cardiac troponin T (TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and / or C-reactive protein (CRP). Alternatively, a kit of the present invention may further include means for detecting at least N-terminal pro-B-type natriuretic peptide (NT-proBNP). In one embodiment, an article of manufacture may include the above-described kit for detecting an anti-TTR antibody and CRP.

[0165] The invention also relates to an article of manufacture comprising, in one or more containers as defined for the kit above, a label specifying that the antibody is indicated for the treatment of cardiomyopathy in wild-type or hereditary transthyretin-mediated amyloidosis in adults. Alternatively, the label indicates a dosing regimen, preferably a flat-dose regimen, according to the invention.

[0166] 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), which may be diluted prior to administration. In some embodiments, the anti-TTR antibody has 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, e.g., 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 21 mg / mL, or about 22 mg / mL).

[0049] The compound is administered to a subject in an aqueous formulation at a dilution concentration of 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.

[0167] In some embodiments, the subject has been previously treated with and / or is concurrently receiving a TTR tetramer stabilizer, e.g., the TTR tetramer stabilizer is selected from the group consisting of diflunisal, tafamidis, and acoramidis (AG10).

[0168] In some embodiments, the anti-TTR antibody is administered to a subject by intravenous infusion in an aqueous formulation having a pH of about 5.0-6.5 and comprising a histidine buffer, a sugar such as sucrose, and a surfactant such as polysorbate 80 (PS80), wherein the anti-TTR antibody is present in the aqueous formulation at a concentration of about 25-125 mg / mL.

[0169] In some embodiments, the aqueous formulation has a pH of about 5.8 and contains 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 the antibody is present in the aqueous formulation at a concentration of about 50 mg / mL or about 100 mg / mL.

[0170] In some embodiments, the aqueous formulation has a pH of about 5.8 and contains 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 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.

[0171] In some embodiments, the anti-TTR antibody is administered to the subject in a diluted form that includes a diluent.

[0172] 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) may be used as a diluent at a concentration of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / v.

[0173] In some embodiments, the infusion line is flushed with a diluent before and after intravenous infusion.

[0174] In some embodiments, intravenous infusion is performed using an infusion syringe or a syringe pump equipped with an infusion pump. In one embodiment, a total antibody dose of up to 100 mg is administered by infusion, e.g., a syringe pump equipped with an infusion syringe. In one embodiment, a total antibody dose of more than 100 mg is administered by infusion pump. In one embodiment, the anti-TTR antibody is diluted in an infusion bag prefilled with diluent.

[0175] In some embodiments, the injection syringe contains a minimum dose of 10 mL of the aqueous formulation.

[0176] In some embodiments, the total volume of the diluted form administered to a subject, including the wash volume, 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). For example, in some embodiments, the total volume of a single dose does not exceed 200 mL.

[0177] In some embodiments, for at least the initial infusion, the aqueous formulation is administered over a period of about 2 hours (±10 minutes).

[0178] In some embodiments, the aqueous formulation is administered over a period of about 1 hour (±10 minutes).

[0179] In some embodiments, ATTR amyloidosis leads to cardiomyopathy (CM), and thus, in preferred embodiments, a subject treated according to the present invention has ATTR amyloidosis with CM (ATTR-CM). In some embodiments, a subject has ATTR polyneuropathy (ATTR-PN). In some embodiments, a subject has familial amyloid polyneuropathy (FAP). In some embodiments, a subject has familial amyloid cardiomyopathy (FAC). In some embodiments, a subject has senile systemic amyloidosis (SSA). In some embodiments, a subject has systemic familial amyloidosis. In some embodiments, a subject has leptomeningeal / central nervous system (CNS) amyloidosis. In some embodiments, a subject has Alzheimer's disease. In some embodiments, a subject has TTR-related ocular amyloidosis. In some embodiments, a subject has TTR-related renal amyloidosis. In some embodiments, a subject has TTR-related hyperthyroxinemia. In some embodiments, the subject has TTR-related ligament 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 pre-eclampsia.

[0180] In some embodiments, the subject has been diagnosed with inherited ATTR-CM for a known pathogenic TTR mutation.

[0181] In some embodiments, the subject has sporadic wild-type ATTR-CM (WT-ATTR-CM) (e.g., a wild-type ATTR gene that encodes the TTR protein that forms deposits in the heart) and a negative genetic test for a TTR mutation.

[0182] 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 either 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 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 by either immunohistochemistry or mass spectrometry in non-cardiac tissue in the presence of monoclonal gammopathy.

[0183] Additionally or alternatively, the subject's left ventricular ejection fraction (LVEF) prior to receiving a treatment method described herein is 20% or greater (e.g., about 20% to about 60%, e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%), as measured, e.g., by echocardiography. In one embodiment, the subject has an LVEF of 50% to 70% (e.g., 50%, 55%, 60%, 65%, or 70%) after receiving a treatment method described herein (e.g., the subject exhibits an increase in LVEF after treatment compared to the LVEF before treatment).

[0184] Additionally or alternatively, the subject has a left ventricular wall thickness (LVWT) of 12 mm or greater (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), as measured, for example, by echocardiography, prior to undergoing a therapeutic method described herein. In one embodiment, the subject has an LVWT of less than 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 a therapeutic method described herein.

[0185] Additionally or alternatively, a subject, particularly a woman, may have a cerebral aneurysm (e.g., a cerebral aneurysm) 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, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, 41 mm, 42 mm, 43 mm, 44 mm, 45 mm, 46 mm, 47 mm, 48 mm, 49 mm, 50 mm, 51 mm, 52 mm, 53 mm, 54 mm, 55 mm, 56 mm, 57 mm, 58 mm, 59 mm, 60 mm, 61 mm, 62 mm, 63 mm, 64 mm, 65 mm, 66 mm, 67 mm, 68 mm, 69 mm, 70 mm, 71 mm, 72 mm, 73 mm, 74 mm, 75 mm, 76 mm, 77 mm, 78 mm, 79 mm, 80 mm, 81 mm, 82 mm, 83 mm, 84 mm, 85 mm, 86 mm, 87 mm, 88 mm, 89 mm, 90 mm, 91 mm, 92 mm, 93 mm, 94 mm, 95 mm, 96 mm, 97 mm, 98 mm 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).

[0186] Additionally or alternatively, a subject (e.g., a female) has an end-diastolic ventricular 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 a treatment method described herein. Or a subject (e.g., a male) has an end-diastolic ventricular septal wall thickness of less than 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 a treatment method described herein.

[0187] Additionally or alternatively, the subject has an NT-proBNP level of about 300 pg / mL to about 20,000 pg / mL before undergoing the treatment methods described herein, and preferably, the subject has an NT-proBNP level of >2000 pg / mL before undergoing the treatment methods described herein. The use of NT-proBNP as a biomarker in ATTR is recognized in the art, and staging systems have been developed based on the level of this biomarker (in combination with the level of cardiac troponin T (cTnT) (Grogan et al., J Am Coll Cardiol 68 (2016), 1014-1020) or in combination with estimated glomerular filtration rate (eGFR) (Gillmore et al., European Heart Journal 39 (2018), 2799-2806)) with an NT-proBNP cutoff of 3000 pg / mL. See also Perfetto et al., Internal and Emergency Medicine 17 (2022), 957-969. Thus, depending on the levels of cTnT and eGFR, and considering only the level of NT-proBNP, subjects have grades I, II and III cardiac ATTR.

[0188] Additionally or alternatively, the subject has a history of heart failure as evidenced by one of the following events within about one year prior to receiving the treatment methods described herein: (i) heart failure hospitalization, (ii) emergency heart failure visit, and (iii) an episode of volume overload as evidenced by NT-proBNP>2000 pg / mL (or equivalent BNP).

[0189] Preferably, the subject is an adult subject.

[0190] Thus, the treatment regimens of the present invention can be used to treat subjects with any one or all of the aforementioned indications / characteristics. In one embodiment of the present invention, the heavy chain variable region of an anti-TTR antibody or antigen-binding fragment thereof used in accordance with the present 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 an 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] As mentioned above, the parent antibody NI006 is also described in WO 2015 / 092077 (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 TTR 41-45 (SEQ ID NO: 51 in WO 2015 / 092077). Characterization of the antibody's binding properties revealed that it exhibits high binding affinity for misfolded TTR in the subnanomolar range and is highly selective for the amyloid conformation of TTR, i.e., it selectively binds with high affinity to disease-associated ATTR aggregates and exerts similar binding affinity to wild-type TTR and mutant TTR, which are associated with sporadic or genetic disorders, respectively, and do not bind to physiological TTR monomers. Furthermore, anti-TTR antibodies bind to ATTR deposits in cardiac tissue obtained at autopsy from ATTR-CM patients. Thus, in one embodiment, an antibody used in accordance with the present invention is an antibody equivalent to the above-characterized antibody having heavy and light chain variable regions comprising the amino acids of SEQ ID NO:7 and SEQ ID NO:8, meaning that the equivalent antibody has substantially the same binding properties as the above-characterized antibody having heavy and light chain variable regions comprising the amino acids of SEQ ID NO:7 and SEQ ID NO:8. In particular, the equivalent antibody is (i) binds to a human TTR epitope containing or consisting of the amino acid sequence TTR41 to TTR45; (ii) exhibit high binding affinity for misfolded TTR in the subnanomolar range; (iii) are highly selective for the amyloid conformation of TTR, i.e., bind selectively with high affinity to disease-associated ATTR aggregates; (iv) It exerts similar binding to wild-type and mutant TTR. It is associated with sporadic or genetic disorders. (v) does not bind to physiological TTR monomers, and / or (vi) binds to ATTR deposits in cardiac tissue obtained at autopsy from patients with ATTR-CM.

[0195] In one embodiment, an equivalent antibody exhibits one of binding characteristics (i) through (vi). In one embodiment, an equivalent antibody exhibits at least two of the enumerated binding characteristics. In one embodiment, an equivalent antibody exhibits at least three of the enumerated binding characteristics. In one embodiment, an equivalent antibody exhibits at least four of the enumerated binding characteristics. In one embodiment, an equivalent antibody exhibits at least five of the enumerated binding characteristics. In a preferred embodiment, an equivalent antibody exhibits all of binding characteristics (i) through (vi).

[0196] The antibody NI006 / ALXN2220 is a fully human IgG1m3 allotype antibody and therefore 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), here a kappa light chain, as exemplified in SEQ ID NO: 10.

[0197] As shown in Example 7 and discussed in detail above, the major PTMs identified in antibody NI006 / ALXN2220 are an HC modification of glutamine to pyroglutamic acid at the N-terminus, loss of the C-terminal lysine, and N-glycosylation. Thus, in a preferred embodiment, the heavy chain of an anti-TTR antibody for use in accordance with the present invention lacks a C-terminal cysteine, has a modified glutamine at the N-terminus as pyroglutamic acid, and contains at least one N-glycosylation site.

[0198] Another class of anti-TTR antibodies that can be used in accordance with the present invention is described in an international application by 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 by Prothena Biosciences) in the treatment of human subjects in need of treatment as provided herein. NN-6019 (PRX004) is described in Higaki et al., Amyloid 23 (2016) 86-97, and corresponds to and is a humanized version of the antibody 14G8 disclosed in WO 2016 / 120810 and WO 2018 / 007922, more specifically WO 2019 / 108689, 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 the TTR amyloid protein found in ATTR. Thus, antibody PRX004 has the same epitope as PRX004, i.e., the amino acid sequence TTR. 89-97 or the amino acid TTR 101-109 and are humanized versions of the originally cloned murine monoclonal antibodies 14G8, 9D5, 5A1, 6C1 disclosed in WO 2016 / 120810, WO 2018 / 007924, WO 2018 / 007924, and WO 2018 / 007923 (the disclosures in these references, including the antibody sequences associated with these antibody clones and / or their deposits, e.g., their full length and / or CDRs, are incorporated herein by reference).

[0199] Thus, in one embodiment, the antibody for use in accordance with the invention is a monoclonal antibody comprising a mature heavy chain variable region comprising the three CDRs of SEQ ID NO: 61 in WO 2019 / 108689, and a mature light chain variable region comprising the three CDRs of SEQ ID NO: 70 in WO 2019 / 108689, except that positions H52 and L26 according to Kabat numbering may 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 in WO 2019 / 108689, and a mature light chain variable region comprising the three CDRs of SEQ ID NO: 16 in WO 2019 / 108689. In one embodiment, the antibody is characterized by comprising a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 65 set forth in WO 2019 / 108689, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO: 76 set forth in WO 2019 / 108689. More preferably, the antibody is characterized as set forth in claims 26 to 35 of WO 2019 / 108689, the contents of which are incorporated herein by reference.

[0200] In a further aspect, the present invention relates to a TTR tetramer stabilizer for use in a method of treating or prophylaxis in a subject with ATTR 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 ligament amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and preeclampsia), wherein the subject has previously been treated and / or is concurrently treated with an anti-TTR antibody according to the present invention.

[0201] In some embodiments, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, tafamidis, and acoramidis (AG10).

[0202] In a further aspect, the invention relates to a method of treating ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloidotic 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 ligament amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and preeclampsia) by administering a human anti-TTR antibody to a human subject at a dosage of about 0.3 mg / kg to about 100 mg / kg given once every 3 to 42 days. The antibody is preferably as defined herein 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 therefore comprises a human constant heavy chain (HC) amino acid sequence exemplified by SEQ ID NO:9 and a corresponding human constant light chain (LC) exemplified by SEQ ID NO:10, preferably with the post-translational modifications described above. The antibody is formulated into the pharmaceutical composition at a concentration of about 10 mg / mL to about 100 mg / mL.

[0203] 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 to It is administered at doses of 60mg / kg, 40mg / kg to 50mg / kg, 40mg / kg to 60mg / kg, 40mg / kg to 70mg / kg, 40mg / kg to 80mg / kg, 50mg / kg to 60mg / kg, 50mg / kg to 70mg / kg, 50mg / kg to 80mg / kg, 60mg / kg to 70mg / kg, 60mg / kg to 80mg / kg, or 70mg / kg to 80mg / kg).

[0204] 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).

[0205] In some embodiments, the anti-TTR antibody is administered at a dose of about 0.3 mg / kg.

[0206] In some embodiments, the anti-TTR antibody is administered at a dose of about 1 mg / kg.

[0207] In some embodiments, the anti-TTR antibody is administered at a dose of about 3 mg / kg.

[0208] In some embodiments, the anti-TTR antibody is administered at a dose of about 10 mg / kg.

[0209] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg.

[0210] 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).

[0211] In some embodiments, the anti-TTR antibody is administered at a dose of about 30 mg / kg, resulting in a sustained plasma concentration of the antibody in the subject of about 50 μg / mL.

[0212] In some embodiments, the anti-TTR antibody is administered at a dose of about 60 mg / kg.

[0213] In some embodiments, the anti-TTR antibody is initially 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).

[0214] 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).

[0215] In a preferred embodiment of the present invention, an anti-TTR antibody is initially 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), followed by 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).

[0216] In a further preferred embodiment, the anti-TTR antibody is administered at a dose greater than 10 mg / kg, e.g., 10 mg / kg to 100 mg / kg, preferably 10 mg / kg to 60 mg / kg, and preferably the antibody is administered once every four weeks.

[0217] In a more preferred embodiment, the anti-TTR antibody is administered at a dose of about 30 mg / kg, and preferably the antibody is administered once every four weeks.

[0218] In another preferred embodiment, the anti-TTR antibody is administered at a dose of about 60 mg / kg, preferably, the antibody is administered once every four weeks.

[0219] In some embodiments, the anti-TTR antibody is administered in a dose 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, 2600mg, 2700mg, 2800mg, 2900mg, 3000mg, 3100mg, 3200mg, 3300mg, 3400mg, 3500mg, 3600mg, 3700mg, 380 0mg, 3900mg, 4000mg, 4100mg, 4200mg, 4300mg, 4400mg, 4500mg, 4600mg, 4700mg, 4800mg, 4900mg, 5000mg, 5100mg, 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, Maintenance doses of 6400mg, 6450mg, 6500mg, 6550mg, 6600mg, 6650mg, 6700mg, 6750mg, 6800mg, 6850mg, 6900mg, 6950mg, 7000mg, 7050mg, 7100mg, 7150mg, 7200mg, 7250mg, 7300mg, 7350mg, 7400mg, 7450mg, or 7500mg are administered.

[0220] 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.

[0221] In one embodiment of the present invention, the anti-TTR antibody is further administered at 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).

[0222] In preferred embodiments, the loading dose is about 2500 mg, e.g., 2400 mg, about 3000 mg, or about 3500 mg, e.g., 3200 mg.

[0223] Preferably, the anti-TTR antibody is administered at the aforementioned maintenance dose of about 600 mg to about 7500 mg, followed by the aforementioned loading dose of about 600 mg to about 4000 mg of the anti-TTR antibody. In an optional embodiment, the loading dose is administered once every two weeks for up to two months prior to the administration of the maintenance dose.

[0224] In one embodiment of the present invention, the maintenance or loading dose of the anti-TTR antibody is about 3000 mg.

[0225] In one embodiment of the present invention, an anti-TTR antibody is administered at a dose of 2000 mg to 2500 mg to a patient weighing between about 40 kg and less than about 60 kg. In one embodiment, an anti-TTR antibody is administered at a dose of 2000 mg or 2500 mg to a patient weighing between about 40 kg and about 60 kg or less. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 2500 mg to a patient weighing between about 40 kg and about 60 kg or less. In one embodiment of the present invention, an anti-TTR antibody is administered at a dose of 3000 mg to 3500 mg to a patient weighing between about 60 kg and about 100 kg. In one embodiment, an anti-TTR antibody is administered at a dose of 3000 mg or 3500 mg to a patient weighing between about 60 kg and about 100 kg. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 3500 mg to a patient weighing between about 60 kg and about 100 kg. In one embodiment of the present invention, an anti-TTR antibody is administered at a dose of 4000 mg to 5000 mg to a patient weighing about 100 kg or less. In one embodiment, an anti-TTR antibody is administered at a dose of 4000 mg, 4500 mg, or 5000 mg to a patient weighing about 100 kg or less. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 4000 mg or 5000 mg to a patient weighing about 100 kg or less, and most preferably, an anti-TTR antibody is administered at a dose of 5000 mg to a patient weighing about 100 kg or less.

[0226] In a preferred embodiment of the present invention, an anti-TTR antibody is administered at a dose within the range of 2200 mg and 2700 mg (including the endpoint) to a subject weighing between about 40 kg and less than 60 kg. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 2400 mg to a patient weighing between about 40 kg and less than 60 kg. In one embodiment of the present invention, an anti-TTR antibody is administered at a dose within the range of 3000 mg and 3500 mg (including the endpoint) to a patient weighing between about 60 kg and less than 100 kg. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 3200 mg to a patient weighing between about 60 kg and less than 100 kg. In one embodiment of the present invention, an anti-TTR antibody is administered at a dose within the range of 4400 mg to 5200 mg (including the endpoint) to a patient weighing between about 100 kg and less. In a preferred embodiment, an anti-TTR antibody is administered at a dose of 4800 mg to a patient weighing between about 100 kg and less.

[0227] In some embodiments, the anti-TTR antibody is administered to a 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).

[0228] 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).

[0229] In some embodiments, the anti-TTR antibody is administered to the subject once every 28 days.

[0230] In some embodiments, the anti-TTR antibody is administered to the subject once every 35 days.

[0231] In some embodiments, the anti-TTR antibody is administered to the subject once every four weeks (q4w).

[0232] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months to 30 months (e.g., 4 to 12 months, 8 to 16 months, 12 to 20 months, 16 to 24 months, or 20 to 30 months).

[0233] In some embodiments, the anti-TTR antibody is administered to the subject for about 12 to 18 months (e.g., 12 to 15 months, 13 to 16 months, 14 to 17 months, or 15 to 18 months).

[0234] In some embodiments, the anti-TTR antibody is administered to the subject for about 4 months.

[0235] In some embodiments, the anti-TTR antibody is administered to the subject for about 11 months.

[0236] In some embodiments, the anti-TTR antibody is administered to the subject at a dose of about 30 mg / kg for about 12 to 18 months (e.g., 12, 13, 14, 15, 16, 17, or 18 months).

[0237] In some embodiments, the loading dose is administered once every other week for up to two months before the administration of the maintenance dose.

[0238] In some embodiments, administration of an 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, or about 50 μg / mL to about 1000 μg / mL).

[0239] In some embodiments, the plasma concentration is from about 1 μg / mL to about 1000 μg / mL (e.g., from about 1 μg / mL to about 100 μg / mL, from about 2.5 μg / mL to about 125 μg / mL, from about 5 μg / mL to about 150 μg / mL, from about 10 μg / mL to about 200 μg / mL, from about 65 μg / mL to about 350 μg / mL, from about 20 μg / mL to about 200 μg / mL, from about 20 μg / mL to about 100 μg / mL, from about 50 μg / mL to about 150 μg / mL, from about 75 μg / mL to about 175 μg / mL, from about 100 μg / mL to about 800 μg / mL, from about 140 μg / mL to about 700 μg / mL, 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, Approximately 220μg / mL, approximately 230μg / mL, approximately 240μg / mL, approximately 250μg / mL, approximately 260μg / mL, approximately 270μg / mL, approximately 280μg / mL, approximately 290μg / mL, approximately 300μg / mL, approximately 310μg / mL, approximately 320μg / mL, approximately 330μg / mL, approximately 340μ g / mL, approximately 350 μg / mL, approximately 360 μg / mL, approximately 370 μg / mL, approximately 380 μg / mL, approximately 390 μg / mL, approximately 400 μg / mL, approximately 410 μg / mL, approximately 420 μg / mL, approximately 430 μg / mL, approximately 440 μg / mL, approximately 450 μg / mL, approximately 460 μg / mL, Approximately 470μg / mL, approximately 480μg / mL, approximately 490μg / mL, approximately 500μg / mL, approximately 510μg / mL, approximately 520μg / mL, approximately 530μg / mL, approximately 540μg / mL, approximately 550μg / mL, approximately 560μg / mL, approximately 570μg / mL, approximately 580μg / mL, approximately 590μ g / mL, approximately 600 μg / mL, approximately 610 μg / mL, approximately 620 μg / mL, approximately 630 μg / mL, approximately 640 μg / mL, approximately 650 μg / mL, approximately 660 μg / mL, approximately 670 μg / mL, approximately 680 μg / mL, approximately 690 μg / mL, approximately 700 μg / mL, approximately 710 μg / mL,Approximately 720μg / mL, approximately 730μg / mL, approximately 740μg / mL, approximately 750μg / mL, approximately 760μg / mL, approximately 770μg / mL, approximately 780μg / mL, approximately 790μg / mL, approximately 800μg / mL, approximately 810μg / mL, Approximately 820μg / mL, approximately 830μg / mL, approximately 840μg / mL, approximately 850μg / mL, approximately 860μg / mL, approximately 870μg / mL, approximately 880μg / mL, approximately 890μg / mL, approximately 900μg / mL, approximately 910μg / mL, The concentration is maintained at 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, 2, 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, or 30 days).

[0240] In some embodiments, the plasma concentration is from about 1 μg / mL to about 1000 μg / mL (e.g., from about 1 μg / mL to about 100 μg / mL, from about 2.5 μg / mL to about 125 μg / mL, from about 5 μg / mL to about 150 μg / mL, from about 10 μg / mL to about 200 μg / mL, from about 65 μg / mL to about 350 μg / mL, from about 20 μg / mL to about 200 μg / mL, from about 20 μg / mL to about 100 μg / mL, from about 50 μg / mL to about 150 μg / mL, from about 75 μg / mL to about 175 μg / mL, from about 100 μg / mL to about 800 μg / mL, from about 140 μg / mL to about 700 μg / mL, 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, Approximately 220μg / mL, approximately 230μg / mL, approximately 240μg / mL, approximately 250μg / mL, approximately 260μg / mL, approximately 270μg / mL, approximately 280μg / mL, approximately 290μg / mL, approximately 300μg / mL, approximately 310μg / mL, approximately 320μg / mL, approximately 330μg / mL, approximately 340μ g / mL, approximately 350 μg / mL, approximately 360 μg / mL, approximately 370 μg / mL, approximately 380 μg / mL, approximately 390 μg / mL, approximately 400 μg / mL, approximately 410 μg / mL, approximately 420 μg / mL, approximately 430 μg / mL, approximately 440 μg / mL, approximately 450 μg / mL, approximately 460 μg / mL, Approximately 470μg / mL, approximately 480μg / mL, approximately 490μg / mL, approximately 500μg / mL, approximately 510μg / mL, approximately 520μg / mL, approximately 530μg / mL, approximately 540μg / mL, approximately 550μg / mL, approximately 560μg / mL, approximately 570μg / mL, approximately 580μg / mL, approximately 590μ g / mL, approximately 600 μg / mL, approximately 610 μg / mL, approximately 620 μg / mL, approximately 630 μg / mL, approximately 640 μg / mL, approximately 650 μg / mL, approximately 660 μg / mL, approximately 670 μg / mL, approximately 680 μg / mL, approximately 690 μg / mL, approximately 700 μg / mL, approximately 710 μg / mL,Approximately 720μg / mL, approximately 730μg / mL, approximately 740μg / mL, approximately 750μg / mL, approximately 760μg / mL, approximately 770μg / mL, approximately 780μg / mL, approximately 790μg / mL, approximately 800μg / mL, approximately 810μg / mL, approximately 820μg / mL, approximately 830μg / mL, approximately 840μg / mL, approximately 850μg / mL, approximately 860μg / mL, approximately 870 The concentration is maintained at about 1 day to about 1 week at 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.

[0241] In some embodiments, administration of the anti-TTR antibody is monitored by determining the level of one or more biomarkers.

[0242] In some embodiments, the marker is a protein marker obtained from the serum or plasma of a subject, e.g., an ATTR-CM patient.

[0243] In some embodiments, the biomarkers include cardiac troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and a decrease in the level of the biomarkers indicates the effectiveness of the treatment. In a preferred embodiment, the biomarker is at least NT-proBNP. Additionally, or alternatively, the biomarker includes C-reactive protein (CRP), where an increase in CRP levels, preferably in a dose-dependent manner, and a transient increase in CRP levels (e.g., for about 1 to about 14 days, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days) indicates on-target immune activation and the effectiveness of the treatment.

[0244] In some embodiments, administration of an anti-TTR antibody or antigen-binding fragment thereof results in a reduction in cardiac amyloid burden and / or a composite of all-cause mortality (ACM) and total cardiovascular (CV) clinical events and / or heart failure (HF) events.

[0245] In some embodiments, administration of the anti-TTR antibody results in a reduction in myocardial mass as measured by cardiac magnetic resonance imaging (MRI).

[0246] In some embodiments, treatment with an anti-TTR antibody according to the method(s) results in a dose- and time-dependent reduction in a patient after a designated treatment period (e.g., 4, 6, 8, 10, 12, 15, 18, 21, or 24 months or more, e.g., 48 months) 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%).

[0247] Preferably, treatment, i.e., administration of the dosing regimen of the present invention, improves at least one of the following: (a) symptoms, functionality, and health-related quality of life (QoL) measured by change from baseline in the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score; (b) time to cardiovascular (CV)-related death; (c) 6-minute walk test (6MWT) score compared with baseline; (d) Rate of cardiovascular (CV) clinical events; and (e) Time to all-cause mortality (ACM).

[0248] In one embodiment, the treatment comprises: (a) reducing NT-proBNP levels in a subject compared to baseline; (b) reduce the rate of heart failure (HF) events; (c) reducing the incidence of augmentation of oral diuretic therapy, possibly including outpatient augmentation of oral diuretic therapy; (d) reducing the incidence of changes in disease-modifying therapy; (e) reducing the incidence of hospitalization for atrial fibrillation; (f) induce change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score over 24 months of study treatment; (g) induce a change from baseline in the 6-minute walk test (6MWT) beyond 24 months of study treatment; (h) derive change from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia stages and NYHA classification; (i) induce change from baseline in GLS; (j) induce change from baseline in stroke volume; (k) induce changes from baseline in echocardiographic parameters of interest; (l) induce change from baseline in hs-cTnT; (m) induce changes from baseline in DPD / PYP / HMDP cardiac scintigraphy cardiac uptake and / or cMRI-derived ECV, T1, and T2 mapping; (n) induce change from baseline in eGFR; (o) induce a change from baseline in EQ-5D-5L score and / or induce a change from baseline in SF-36 score; (p) inducing a change from baseline in a marker selected from CRP, IL IL1b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A and ferritin, preferably CRP; (q) induce a change from baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6; (r) induce a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4; (s) Induce change from baseline in (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or sNFL level; and / or (t) Induce change from baseline in NIS and / or induce change in NC test.

[0249] 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), as assessed, for example, by echocardiography. For example, echocardiography can be used to measure the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E / e' ratio) to assess cardiovascular function.

[0250] In some embodiments, the anti-TTR antibody is provided in an aqueous formulation at a concentration of about 25-125 mg / mL, which is diluted prior to administration. In some embodiments, the anti-TTR antibody has 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, e.g., 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 21 mg / mL, or about 22 mg / mL).

[0049] The compound is administered to a subject in an aqueous formulation at a dilution concentration of 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.

[0251] In some embodiments, the subject has been previously treated with a TTR tetramer stabilizer and / or is concurrently receiving a TTR tetramer stabilizer.

[0252] In some embodiments, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, tafamidis, and acoramidis (AG10).

[0253] In some embodiments, the antibody is administered to a subject by intravenous infusion in an aqueous formulation having a pH of about 5.0 to 6.5 and comprising a histidine buffer, a sugar such as sucrose, and a surfactant such as polysorbate 80 (PS80), wherein the antibody is present in the aqueous formulation at a concentration of about 25 to 125 mg / mL.

[0254] In some embodiments, the aqueous formulation has a pH of about 5.8 and contains 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.

[0255] In some embodiments, the aqueous formulation has a pH of about 5.8 and contains 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.

[0256] In some embodiments, the antibody is administered to the subject in a diluted form that includes a diluent.

[0257] 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) may be used as a diluent at a concentration of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / v.

[0258] In some embodiments, the infusion line is flushed with a diluent before and after intravenous infusion.

[0259] In some embodiments, intravenous infusion is performed using an infusion syringe or a syringe pump equipped with an infusion pump. In one embodiment, a total antibody dose of up to 100 mg is administered by infusion, e.g., a syringe pump equipped with an infusion syringe. In one embodiment, a total antibody dose of more than 100 mg is administered by infusion pump. In one embodiment, the anti-TTR antibody is diluted in an infusion bag prefilled with diluent.

[0260] In some embodiments, the injection syringe contains a minimum dose of 10 mL of the aqueous formulation.

[0261] In some embodiments, the total volume of the diluted form administered to a subject does not exceed 200 mL (including flushing volume).

[0262] In some embodiments, for at least the initial infusion, the aqueous formulation is administered over a period of about 2 hours (±10 minutes).

[0263] In some embodiments, the aqueous formulation is administered over a period of about 1 hour (±10 minutes).

[0264] In some embodiments, ATTR amyloidosis leads to cardiomyopathy (CM).

[0265] In some embodiments, the subject 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 ligament amyloidosis, including carpal tunnel syndrome. In some embodiments, the subject has a rotator cuff tear and lumbar spinal stenosis, hi some embodiments, the subject has pre-eclampsia.

[0266] In some embodiments, the subject has been diagnosed with inherited ATTR-CM for a known pathogenic TTR mutation.

[0267] In some embodiments, the subject has sporadic WT-ATTR-CM and a negative genetic test for a TTR mutation.

[0268] 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 either 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 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 by either immunohistochemistry or mass spectrometry in non-cardiac tissue in the presence of monoclonal gammopathy.

[0269] In some embodiments, the subject has a left ventricular ejection fraction (LVEF) of 20% or greater (e.g., about 20% to about 60%, e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%), as measured, e.g., by echocardiography, prior to undergoing a treatment method described herein. In one embodiment, the subject has an LVEF of 50% to 70% (e.g., 50%, 55%, 60%, 65%, or 70%) after undergoing a treatment method described herein (e.g., the subject exhibits an increase in LVEF after treatment compared to the LVEF before treatment).

[0270] In some embodiments, the subject has a left ventricular wall thickness (LVWT) of 12 mm or greater (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) as measured, for example, by echocardiography, prior to undergoing a therapeutic method described herein. In one embodiment, the subject has an LVWT of less than 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 a therapeutic method described herein.

[0271] In some embodiments, prior to undergoing the methods of treatment described herein, a subject, particularly a woman, has a cerebral aneurysm (e.g., a cerebral aneurysm) 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, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, 40 mm, 41 mm, 42 mm, 43 mm, 44 mm, 45 mm 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).

[0272] In some embodiments, a subject (e.g., a female) has an end-diastolic ventricular 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 a treatment method described herein, or a subject (e.g., a male) has an end-diastolic ventricular septal wall thickness of less than 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 a treatment method described herein.

[0273] 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 therapeutic 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 therapeutic methods described herein, and preferably, the subject has an NT-proBNP level of >2000 pg / mL before undergoing the therapeutic methods described herein.

[0274] 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, and 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.

[0275] In some embodiments, the subject has a history of heart failure as evidenced by one of the following events within about one year prior to receiving the treatment methods described herein: (i) heart failure hospitalization, (ii) emergency heart failure visit, and (iii) an episode of volume overload evidenced by NT-proBNP (or equivalent BNP) greater than 2000 pg / mL.

[0276] In some embodiments, the heavy chain variable region of an anti-TTR antibody used in accordance with the 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 therefore comprises a human constant heavy chain (HC) amino acid sequence exemplified in SEQ ID NO:9 and a corresponding human constant light chain (LC) exemplified in SEQ ID NO:10, preferably with the post-translational modifications identified above, e.g., the HC amino acid sequence preferably present in SEQ ID NO:15.

[0277] In some embodiments, the method further comprises administering a TTR tetramer stabilizer, hi some embodiments, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, tafamidis, and acoramidis (AG10), preferably tafamidis is administered as specified above.

[0278] In a further aspect, the present invention provides the use of a human anti-TTR antibody capable of binding to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof, and which does not substantially recognize physiological TTR species, in subjects with or at risk of having ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC)). The present invention relates to the use of an anti-TTR antibody in the manufacture of a medicament for treating or preventing the following conditions: myopathy (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 ligament amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and preeclampsia. As outlined in more detail above, in one embodiment, the anti-TTR antibody is capable of binding to wild-type TTR aggregates and mutant TTR aggregates. Additionally or alternatively, the anti-TTR antibody does not bind to physiological TTR tetramers, 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 herein above.

[0279] The use is carried out by administering to a subject a concentration 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 150 μg / mL, about 15 ... 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, Approximately 230μg / mL, approximately 240μg / mL, approximately 250μg / mL, approximately 260μg / mL, approximately 270μg / mL, approximately 280μg / mL, approximately 290μg / mL, approximately 300μg / mL, approximately 310μg / mL, approximately 320μg / mL, approximately 330μg / mL, approximately 340μg / mL, approximately 350μ g / mL, approximately 360 μg / mL, approximately 370 μg / mL, approximately 380 μg / mL, approximately 390 μg / mL, approximately 400 μg / mL, approximately 410 μg / mL, approximately 420 μg / mL, approximately 430 μg / mL, approximately 440 μg / mL, approximately 450 μg / mL, approximately 460 μg / mL, approximately 470 μg / mL, Approximately 480μg / mL, approximately 490μg / mL, approximately 500μg / mL, approximately 510μg / mL, approximately 520μg / mL, approximately 530μg / mL, approximately 540μg / mL, approximately 550μg / mL, approximately 560μg / mL, approximately 570μg / mL, approximately 580μg / mL, approximately 590μg / mL, approximately 600μ g / mL, approximately 610 μg / mL, approximately 620 μg / mL, approximately 630 μg / mL, approximately 640 μg / mL, approximately 650 μg / mL, approximately 660 μg / mL, approximately 670 μg / mL, approximately 680 μg / mL, approximately 690 μg / mL, approximately 700 μg / mL, approximately 710 μg / mL, approximately 720 μg / mL,Approximately 730μg / mL, approximately 740μg / mL, approximately 750μg / mL, approximately 760μg / mL, approximately 770μg / mL, approximately 780μg / mL, approximately 790μg / mL, approximately 800μg / mL , about 810μg / mL, about 820μg / mL, about 830μg / mL, about 840μg / mL, about 850μg / mL, about 860μg / mL, about 870μg / mL, about 880μg / mL The method includes administering the pharmaceutical agent in a dosing regimen that results in a sustained plasma concentration of the antibody of 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.

[0280] Furthermore, the present invention relates to the use of human anti-TTR antibodies capable of binding to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof, and that do not substantially recognize physiological TTR species, in subjects with or at risk of having ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy, etc.). The present invention relates to the use of an anti-TTR antibody in the manufacture of a medicament for treating or preventing the following conditions: familial amyloidosis (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 ligament amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and preeclampsia. As outlined in more detail above, in one embodiment, the anti-TTR antibody is capable of binding to wild-type TTR aggregates and mutant TTR aggregates. Additionally or alternatively, the anti-TTR antibody does not bind to physiological TTR tetramers, 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 herein above.

[0281] Use approximately 2,000 μg in subjects * day / mL ~ approx. 100,000μg * day / mL, approximately 2,500μg * day / mL ~ approx. 100,000μg * day / mL, approximately 5,000μg * day / mL ~ approx. 100,000μg * day / mL, or approximately 10,000 μg * day / mL ~ approx. 100,000μg * day / mL (e.g., approximately 2,000 μg * day / mL, approximately 2,500 μg * day / mL, approximately 3,000μg * day / mL, approximately 3,500μg * day / mL, approximately 4,000μg * day / mL, approximately 5,000μg * day / mL, approximately 6,000μg * day / mL, approximately 7,000μg * day / mL, approximately 8,000μg * day / mL, approximately 9,000μg * day / mL, approximately 10,000μg * day / mL, approximately 15,000 μg * day / mL, approximately 20,000μg * day / mL, approximately 30,000μg * day / mL, approximately 40,000μg * day / mL, approximately 50,000μg * day / mL, approximately 60,000μg * day / mL, approximately 70,000μg * day / mL, approximately 80,000μg * day / mL, approximately 90,000μg * day / mL, or approximately 100,000 μg * day / mL), preferably at least 30,000 μg * This involves administering the pharmaceutical agent in a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., area under the plasma drug concentration-time curve in the subject after 17-50 weeks of treatment / administration) in days / mL.

[0282] In some embodiments, the anti-TTR antibody is administered at a dose of about 2,000 μg. *day / mL ~ approx. 50,000μg * day / mL (e.g., approximately 2,000 μg in a subject) * day / mL, approximately 2,500 μg * day / mL, approximately 3,000μg * day / mL, approximately 3,500μg * day / mL, approximately 4,000μg * day / mL, approximately 5,000μg * day / mL, approximately 6,000μg * day / mL, approximately 7,000μg * day / mL, approximately 8,000μg * day / mL, approximately 9,000μg * day / mL, approximately 10,000μg * day / mL, approximately 15,000μg * day / mL, approximately 20,000μg * day / mL, approximately 30,000μg * day / mL, approximately 40,000μg * day / mL, or approximately 50,000 μg * The antibody is for administration at a dosing regimen that results in a sustained plasma concentration of the antibody with an AUC (e.g., area under the plasma drug concentration-time curve in a subject after 17 weeks of treatment / dosing) of 0.01 mg / mL (days / mL).

[0283] In some embodiments, the anti-TTR antibody is administered to a subject at a concentration of about 2,500 μg * day / mL ~ approx. 100,000μg * day / mL, approximately 5,000μg * day / mL ~ approx. 100,000μg * day / mL, or approximately 10,000 μg * day / mL ~ approx. 100,000μg * day / mL (e.g., approximately 2,500 μg * day / mL, approximately 3,000μg * day / mL, approximately 3,500μg * day / mL, approximately 4,000μg * day / mL, approximately 5,000μg * day / mL, approximately 6,000μg * day / mL, approximately 7,000μg * day / mL, approximately 8,000μg * day / mL, approximately 9,000μg* day / mL, approximately 10,000μg * day / mL, approximately 15,000μg * day / mL, approximately 20,000μg * day / mL, approximately 30,000μg * day / mL, approximately 40,000μg * day / mL, approximately 50,000μg * day / mL, approximately 60,000μg * day / mL, approximately 70,000μg * day / mL, approximately 80,000μg * day / mL, approximately 90,000μg * day / mL, or approximately 100,000 μg * The antibody is intended for administration at a dosing regimen that results in a sustained plasma concentration of the antibody in AUC (e.g., area under the plasma drug concentration-time curve in a subject after 50 weeks of treatment / dosing) in days / mL.

[0284] In some embodiments, administration of anti-TTR antibodies is useful for long-term treatment and / or follow-up treatment (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) after initial further dosing and amyloid clearance.

[0285] The invention further relates to the use of a human anti-TTR antibody in the manufacture of a medicament for treating ATTR (e.g., ATTR-CM, ATTR polyneuropathy (ATTR-PN), familial amyloidotic 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 ligament amyloidosis (including carpal tunnel syndrome, rotator cuff tear, and lumbar spinal stenosis), and pre-eclampsia), (a) The use includes administering a dose of about 0.3 to about 100 mg / kg of the pharmaceutical agent to the subject once every 3 to 56 days (e.g., once every 3 to about 35 days, e.g., once 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); or the use includes administering a dose of about 600 mg to about 7500 mg, preferably about 2500 mg, depending on the patient's weight, respectively. g, 3500 mg, or 5000 mg, or about 2400 mg, 3200 mg, or 4800 mg, once every 3 to 56 days (e.g., once every 3 to about 35 days, e.g., once 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), preferably once every four weeks (q4w); (b) The antibody or antigen-binding fragment thereof comprises a heavy chain variable region having at least 80% (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 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% (e.g., 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO:8, or the antibody is an equivalent antibody having substantially the same binding characteristics as defined herein. See also 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 a human constant heavy chain (HC) amino acid sequence exemplified by SEQ ID NO: 9 and a corresponding human constant light chain (LC) exemplified by SEQ ID NO: 10, preferably with the post-translational modifications described above. The antibody or antigen-binding fragment thereof is present in the pharmaceutical preparation at a concentration of about 10 mg / mL to about 125 mg / mL. In some embodiments, the antibody is diluted from a concentrated stock prior to administration. The concentration of the pharmaceutical preparation can be diluted, for example, in a dilution bag, prior to administration to a subject.

[0286] Treatment methods Described herein are methods of 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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and pre-eclampsia) by administering an anti-TTR antibody.

[0287] 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) as well as a reduction in cardiac amyloid deposits (e.g., misfolded TTR protein) in the subject's heart (e.g., a 5% or greater, 10% or greater, 15% or greater, 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, 50% or greater, 55%, 60% or greater, 65% or greater, 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 100% reduction) within 4 to 30 months (e.g., within 5 to 25 months, within 10 to 20 months, or within 12 to 18 months) after treatment with the methods described herein.

[0288] The methods described herein include the administration of a recombinant anti-TTR antibody that can bind 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 or provide prophylaxis in subjects with or at risk of having an ATTR-associated disease (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-associated ocular amyloidosis, TTR-associated renal amyloidosis, TTR-associated hyperthyroxinemia, TTR-associated ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and preeclampsia). The antibody may be administered in a dosing regimen that results in a sustained (e.g., maintained over a period of time) blood (e.g., serum or plasma) concentration in a subject over a period of time as described herein (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). Maintenance 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, 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 410μg / mL, at least 420μg / mL, at least 430μg / mL, at least 440μg / mL, at least 450μg / mL, at least 460μg / mL, at least 470μg / mL, at least 480μg / mL, at least 490μg / mL, at least 500μg / mL, at least 510μg / mL, at least 520μg / mL, at least 530μg / mL, at least 540μg / mL, at least 550μg / mL, at least 560μg / mL, at least 570μg / mL, at least 58 0 μg / mL, at least 590 μg / mL, at least 600 μg / mL, at least 610 μg / mL, at least 620 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 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, 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,The concentration may be 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 990 μg / mL, or 1000 μg / mL, and may be maintained for at least 3 days to about 42 days (e.g., about 3 to about 35 days, about 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).

[0289] The antibody may also be administered to a subject at a dose of about 2,000 μg * day / mL ~ approx. 100,000μg * day / mL, approximately 2,500μg * day / mL ~ approx. 100,000μg * day / mL, approximately 3,000μg * day / mL ~ approx. 100,000μg * day / mL, approximately 5,000μg * day / mL ~ approx. 100,000μg * day / mL, or approximately 10,000 μg * day / mL ~ approx. 100,000μg * day / mL, or approximately 2,000 μg * day / mL ~ approx. 50,000μg * day / mL, approximately 5,000μg * day / mL ~ approx. 50,000μg * day / mL, or approximately 10,000 μg * day / mL ~ approx. 50,000μg * day / mL (e.g., approximately 2,000 μg * day / mL, approximately 2,500 μg * day / mL, approximately 3,000μg * day / mL, approximately 3,500μg * day / mL, approximately 4,000μg * day / mL, approximately 5,000μg * day / mL, approximately 6,000μg * day / mL, approximately 7,000μg * day / mL, approximately 8,000μg * day / mL, approximately 9,000μg *day / mL, approximately 10,000μg * day / mL, approximately 15,000μg * day / mL, approximately 20,000μg * day / mL, approximately 30,000μg * day / mL, approximately 40,000μg * day / mL, approximately 50,000μg * day / mL, approximately 60,000μg * day / mL, approximately 70,000μg * day / mL, approximately 80,000μg * day / mL, approximately 90,000μg * day / mL, or approximately 100,000 μg * The antibody may be administered at a dosage level that results in a sustained plasma concentration of the antibody with an AUC (e.g., area under the plasma drug concentration-time curve in a subject after treatment / administration) of 1000 μg / mL. The sustained plasma concentration of the antibody as determined by the AUC may vary depending on the duration of treatment. For example, after 17 weeks of treatment, the AUC may be approximately 2,000 μg / mL. * day / mL ~ approx. 50,000μg * day / mL, and after 50 weeks of treatment, the AUC was approximately 2,500 μg * day / mL ~ approx. 100,000μg * day / mL.

[0290] The dosing regimen can include administering an antibody or antigen-binding fragment thereof at 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). For example, the antibody may be administered at a dosage 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 specifically, the dosing regimen may 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, 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, preferably about 10 mg / kg to about 60 mg / kg, and most preferably about 30 mg / kg or 60 mg / kg.

[0291] In one embodiment, only a maintenance dose is administered.

[0292] Dosing regimens can also include administering an antibody at 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, or 9000 mg to 10,000 mg). For example, the antibody can be administered at a dose of about 3000 mg or 3500 mg of an anti-TTR antibody. More specifically, 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, preferably about 600 mg to about 7,500 mg. The dosing regimen may further include administering a loading dose of about 300 mg to 6,000 mg, about 600 mg to 5,000 mg, preferably about 600 mg to 4,000 mg, preferably administered every other week for up to two months before the maintenance dose.

[0293] The dosing regimen may include administering a flat dose based on the subject's body weight. Thus, the dosing regimen may include, for example, administering 2500 mg of an anti-TTR antibody to a subject weighing about 40 kg to about 60 kg or less, or 3500 mg of an anti-TTR antibody to a subject weighing about 60 kg to about 100 kg or more, or 5000 mg to a subject weighing about 100 kg or less.

[0294] Preferably, the dosing regimen may include, for example, administering 2400 mg of anti-TTR antibody to a subject weighing between about 40 kg and about 60 kg or less, or, for example, administering 3200 mg of anti-TTR antibody to a subject weighing between about 60 kg and about 100 kg, or, for example, administering 4800 mg to a subject weighing about 100 kg or less.

[0295] The anti-TTR antibody may be administered to a subject once every 3 to 42 days (e.g., about once 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), 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 may be administered via subcutaneous infusion or continuous infusion via a pump, for example, once weekly.

[0296] The anti-TTR antibody may be administered to the subject at a dose of about 30 mg / kg for at least 12 months (e.g., about 12-18 months, e.g., about 12 months).

[0297] Further 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 the efficacy of treatment is monitored and evaluated are described herein.

[0298] antibody Anti-TTR antibodies can be administered to a subject (e.g., a human) to treat or prevent (e.g., prophylactically) a disease or disorder (e.g., ATTR or ATTR-CM) as described herein. Methods 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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, and preeclampsia) described herein utilize anti-TTR antibodies, e.g., human anti-TTR antibodies. The anti-TTR antibodies herein can bind to mutated, misfolded, misassembled, and / or aggregated TTR species and / or fragments thereof (e.g., with a dissociation constant (KD )) and may not substantially recognize physiological TTR species.

[0299] Preferably, the antibody can be any antibody that exhibits high binding affinity for misfolded TTR in the subnanomolar range, is highly selective for the amyloid conformation of TTR, i.e., binds selectively with high affinity to disease-associated ATTR aggregates, exerts similar binding to wild-type TTR and mutant TTR associated with sporadic or genetic disease, does not bind to physiological TTR monomers, and / or binds to ATTR deposits in cardiac tissue obtained at autopsy from ATTR CM patients. Binding characteristics can be determined by 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.

[0300] For example, the anti-TTR antibodies described herein have different K D , e.g., a K of >300 nM for wild-type native TTR D and / or a K of 15 nM or less D , e.g., a KD of 5 nM or less, e.g., a KD of 2 nM or less for denatured TTR, and / or a KD of 35 nM or less D For example, a KD of 20 nM or less for native TTR-V30M, a KD of 5 nM or less for native TTR-V122I, and / or a KD of 150 nM or less. D For example, it may have a KD of 2 nM or less for native TTR-L55P.

[0301] 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 were defined according to 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).

[0302] 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).

[0303] [Table 1-1]

[0304] [Table 1-2] CDR = complementarity determining region; VH = heavy chain variable region; VL = light chain variable region, HC = heavy chain; LC = light chain. ** N-terminal glutamate is modified to pyroglutamic acid

[0305] An 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. Additionally, an anti-TTR antibody or antigen-binding fragment thereof may comprise one or more CDR sequences having an amino acid sequence with one, two, or three mismatches 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 certain examples, 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.

[0306] An anti-TTR antibody or antigen-binding fragment thereof may have a VH region comprising an amino acid sequence having at least 70% sequence identity, at least 75% sequence identity, at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 91% sequence identity, at least 92% sequence identity, at least 93% sequence identity, at least 94% sequence identity, at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In a particular example, an 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.

[0307] The anti-TTR antibody or antigen-binding fragment thereof may have a VL region comprising an amino acid sequence having at least 70% sequence identity, at least 75% sequence identity, at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 91% sequence identity, at least 92% sequence identity, at least 93% sequence identity, at least 94% sequence identity, at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In a particular 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.

[0308] An anti-TTR antibody or antigen-binding fragment thereof may 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 particular example, an 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.

[0309] An anti-TTR antibody or antigen-binding fragment thereof may 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 particular example, an 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.

[0310] In some embodiments, the anti-TTR antibody is an anti-TTR antibody described in U.S. Patent No. 10,344,080 or 11,180,545, each of which is incorporated by reference in its entirety. The anti-TTR antibody may be an anti-TTR antibody described in U.S. Patent Application Publication No. 20220144928, which is incorporated by reference in its entirety.

[0311] 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 do not substantially affect the biological properties (e.g., binding activity) of the anti-TTR antibodies. See also below. For example, an antibody may have amino acid substitutions in the framework regions (FR) to improve antigen binding. In another example, multiple 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 which is incorporated herein by reference.

[0312] The variant antibodies or antigen-binding fragments thereof are functionally active and may have less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% of the amino acids by number of residues substituted or deleted while retaining essentially the same immunological properties, including, but not limited to, binding to TTR as described herein (i.e., an equivalent antibody having substantially the same binding properties to TTR as an exemplary antibody characterized in U.S. Pat. Nos. 10,344,080 and 11,180,545, 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). The antibody described above (corresponding to WO 2015 / 092077, where the antibody is designated NI-301.37F1) and Michalon et al., Nat. Commun. 12 (2021), 3142 (referred to as antibody NI301A) (i) selectively binds with high affinity to disease-associated ATTR aggregates, and (ii) binds to misfolded / aggregated wild-type and mutant TTR associated with sporadic and genetic diseases, respectively, as well as to ATTR deposits in cardiac tissue obtained at autopsy from ATTR-CM patients, but does not substantially bind to native TTR monomers, and importantly, is capable of clearing ATTR fibrils by macrophage-mediated phagocytosis. This latter property can be readily tested as described in WO 2020 / 094883. See also Michalon et al. (2021) supra.

[0313] 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 the exemplified antibodies, that exhibit biological activity, e.g., binding of an antigen such as TTR. Antibodies may contain one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids that occur only naturally in unrelated biological systems, modified amino acids from mammalian systems, etc.), antibodies with substituted linkages, and other modifications known in the art.

[0314] The anti-TTR antibody fragment may be selected from the group consisting of a bis-Fab fragment, a Fab fragment, a Fab'-SH fragment, an Fv fragment, an scFv fragment, and a (Fab')2 fragment.

[0315] 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.

[0316] 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 may have a VH region consisting of an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO:7 and a VL region consisting of an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO:8.

[0317] In this regard, those skilled in the art recognize that effector function and potency may depend, inter alia, on the IgG class or isotype, and that IgG2 and IgG4 have only weakened effector functions 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, e.g., IgG1. Of course, in addition to using native IgG immunoglobulins, corresponding effector functions can be engineered. See, e.g., Saunders KO (2019) Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life.Front.Immunol.10:1296.doi:10.3389 / fimmu.2019.01296.

[0318] The five major classes of immunoglobulins are IgG, IgM, IgA, IgD, and IgE. They are distinguished by the type of heavy chain found in the molecule. IgG molecules have heavy chains known as gamma chains; IgM have mu chains; IgA have alpha chains; IgE have epsilon chains; and IgD have delta chains; for a review, see, e.g., Schroeder et al., J. Allergy Clin. Immunol. 125 (2010), S41-S52. Furthermore, different subclasses exist: IgA is further divided into subclasses IgA1 and IgA2, and IgG is further divided into subclasses IgG1, IgG2, IgG3, and IgG4. Furthermore, there are two types of light chains: kappa (κ) and lambda (λ).

[0319] In principle, antibodies used according to the present invention can be of any type of class and subclass and can contain any type of light chain, as long as the antibody binds to misfolded and preferably aggregated TTR, and as long as the binding specificity for TTR, as preferably shown in the examples of WO 2015 / 092077 for antibody NI-301.37F1, remains essentially unaffected and no adverse effects occur when the antibody is administered to patients, which adverse effects can be determined as described in Example 1. However, preferably, complete IgG antibodies are used, in which the antibody contains constant domains. Thus, in one embodiment, the immunoglobulin heavy and / or light chain constant domains present in the antibody used according to the present invention are of the IgG, IgM, IgA, IgD, or IgE type, preferably 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 the IgG1, IgG2, IgG3, or IgG4 subclass, most preferably the IgG1 subclass.

[0320] As described above, NI006 / ALXN2220 induces antibody-mediated phagocytosis of ATTR fibrils by phagocytic immune cells, such as macrophages, resulting in the clearance of ATTR deposits from tissues. Thus, in one embodiment, the antibody contains a region equivalent to the human IgG constant region, such as an IgA subclass or an engineered Fc region, as described in Liu et al., Antibodies 9 (2020), 64, capable of mediating phagocytosis.

[0321] Recombinant expression of fully human IgG1 antibodies with human or mouse constant domains can be performed substantially as described in the Examples of WO 2015 / 092077. Preferably, the antibodies are monoclonal or derived from monoclonal antibodies.

[0322] Not only do IgGs have the four subclasses described above, but human heavy and light chain genes also exhibit extensive structural polymorphism and are inherited as closely related haplotypes. Allotypic variants can be immunogenic and elicit antibody responses as a result of alloimmunization. Therefore, allotype switching may be particularly interesting for providing non-immunogenic antibody therapeutics. Although a wide range of allotypes (polymorphisms) is known, research has focused on serologically defined allotypes. IgG protein allotypes are defined by the expression of unique epitopes recognized by unique serum reagents. Allotypes expressed on the constant region of the IgG heavy chain are referred to as Gm (genetic markers) along 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 Figure 1A of Jefferis and Lefrance, mAbs 1 (2009), 1-7 and Irani et al., Molecular Immunology 67 (2015), 171-182, the contents of which are incorporated herein by reference. Thus, in one embodiment, the antibody used in accordance with the present invention is of any one of the following allotypes, but is not limited to: 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, preferably G1m2, G1m3 or G1m17, most preferably G1m3.

[0323] As explained above, antibody NI006 / ALXN2220 is a fully human IgG1m3 allotype antibody, composed of two identical heavy chains of the IgG1 subclass and the IgG1m3 allotype. Additionally, as mentioned above, the original human antibody NI-301.37F1 is a kappa type, and therefore, NI006 / ALXN2220 is composed of two identical light chains of the kappa 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, such as the IgG1m3 isotype, has a unique amino acid sequence of the constant region of its heavy chain. 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, each heavy chain (HC) comprising the amino acid sequence set forth in SEQ ID NO: 9, and two light chains (LC), each light chain (LC) comprising the amino acid sequence set forth 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 intra- and inter-chain disulfide bonds, and the locations of the disulfide bridges identified by Lys-C and trypsin digestion and subsequent LC-MS (see Example 7) are as follows: LC:C23-LC:C88 LC:C134-LC:C194 LC:C214-HC:C223 HC:C22-HC:C97 HC:C147-HC:C203 HC1:229-HC2:229 and HC1:232-HC2:232 HC:C264-HC:C324 HC:C370-HC:C428. (Amino acid numbering corresponds to the heavy chain sequence shown in SEQ ID NO: 9)

[0324] Thus, the antibodies used according to the invention may be characterized by containing preferably at least eight disulfide bridges at the above positions.

[0325] Furthermore, each heavy chain of antibody NI006 / ALXN2220 contains a single N-linked glycosylation site at Asn300. The N-linked glycosylation structures are predominantly fucosylated complex biantennary glycans with either zero galactose residues (GOF) (approximately 49%) or one galactose residue (GIF) (approximately 25%). A detailed glycosylation profile is shown in Example 7. Glycosylation plays an important 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 regarding the safety and efficacy of biotherapeutics.

[0326] Thus, in a preferred embodiment, the antibody used in accordance with the present invention is an IgG antibody, has an N-glycosylated heavy chain, and preferably, when expressed, for example, in CHO cells, the N-linked glycosylation site is Asn300, and the antibody comprises N-linked glycosylation structures that are predominantly glycans with 0 galactose residues (GOF) (about 49%) or 1 galactose residue (GIF) (about 25%). Most preferably, the antibody has a glycosylation profile as shown in Example 7.

[0327] Additionally, one or several amino acids at the amino or carboxy termini of the light and / or heavy chains, such as the C-terminal lysine of the heavy chain (if present), may be partially or completely deleted or derivatized in the molecule.

[0328] Thus, in one embodiment, the antibody present in the pharmaceutical composition of the 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 missing. The sequence of such a heavy chain is set forth in SEQ ID NO: 13.

[0329] 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 set forth in SEQ ID NO: 14 or SEQ ID NO: 15.

[0330] Most preferably, the antibody has a heavy chain that does not contain a C-terminal lysine, i.e., the C-terminal lysine has been C-terminally lysine clipped, the N-terminal glutamine has been replaced with pyroglutamic acid, i.e., N-terminal glutaminyl cyclized (see SEQ ID NO: 15), and is N-glycosylated.

[0331] The amino acid sequences of the heavy and light chains are shown below:

[0332] [Table 2] (SEQ ID NO: 9, NI006 / ALXN2220, heavy chain amino acid sequence, where constant region amino acids are underlined, and where the C-terminal lysine (K) is optional and / or the N-terminal glutamine (Q) undergoes intramolecular cyclization resulting in the formation of pyroglutamic acid)

[0333] [Table 3] (SEQ ID NO: 10, NI006 / ALXN2220, light chain amino acid sequence, where constant region amino acids are underlined).

[0334] 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 comprised in the pharmaceutical composition of the present invention has a molecular weight of about 150 kDa, preferably about 147 kDa.

[0335] antibody preparations Any of the anti-TTR antibodies or antigen-binding fragments thereof described herein and used in accordance with the present invention (e.g., an anti-TTR antibody having 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 having 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 having substantially the same binding characteristics, and an anti-TTR antibody having a heavy chain having the amino acid sequence of SEQ ID NO:9, preferably an anti-TTR antibody comprising, for example, a PTM as mentioned hereinabove, an anti-TTR antibody having an amino acid sequence of SEQ ID NO:13, 14 or 15, preferably the amino acid sequence of SEQ ID NO:15, a heavy chain which is preferably N-terminally cyclized and N-glycosylated at the HC, and a light chain having the amino acid sequence of SEQ ID NO:10) may have a concentration of about 1 mg / mL to about 500 mg / mL (e.g., 25 mg / mL). The anti-TTR antibody may be formulated at a concentration of about 10 mg / mL to about 125 mg / mL, e.g., about 10 mg / mL to about 90 mg / mL, e.g., about 20 mg / mL to about 80 mg / mL, e.g., about 25 mg / mL to about 75 mg / mL, e.g., about 25 mg / mL to about 125 mg / mL, e.g., about 10 mg / mL to about 90 mg / mL, e.g., about 25 mg / mL to about 125 ... It may be provided in the form of an aqueous formulation (e.g., a pharmaceutical composition) at a concentration of 5 mg / mL. Exemplary antibodies with the same binding specificity, specifically, antibodies that have strong binding to misfolded / aggregated TTR but no binding to physiological TTR monomers, are provided, for example, in WO 2015 / 092077, including antibodies NI-301.59F1 and NI-301.35G11, the contents of which are incorporated herein by reference.

[0336] For example, anti-TTR antibodies may be administered at concentrations of 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, about The anti-TTR antibodies described herein are formulated into aqueous solutions (e.g., pharmaceutical compositions) of 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, or about 125 mg / mL.

[0337] In one example, the anti-TTR antibody is provided as an aqueous solution in a vial (e.g., a glass vial) at a concentration of 50 mg / mL (±12%) or 100 mg / mL (±12%). The total volume of the aqueous solution in the vial is 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 mL to about 1.5 mL, about 1 mL to about 2 ... .5mL to about 1.25mL, about 1.5mL to about 2mL, about 1.9mL to about 1.2mL, about 2.1mL to about 2.25mL) or about 1mL to about 100mL (for example, about 1mL to about 1.8mL) mL, about 1.9mL, about 2mL, about 2.1mL, about 2.2mL about 2.25mL, about 2.3mL, about 2.4mL, about 2.5mL about 3mL, about 4mL, about 5mL, about 6mL, about 7mL, The volume can be 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. In another example, the total volume of the aqueous solution in the vial is 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 sufficient amount of the vial to provide the desired total dose.

[0338] subject 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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, preeclampsia, or a known pathogenic TTR mutation (e.g., one that causes amyloidosis). The subject can have a negative genetic test for sporadic WT-ATTR-CM and a TTR mutation. Genetic testing can be performed by standard laboratory techniques, such as DNA or RNA sequencing or protein sequencing using mass spectrometry.

[0339] In some instances, the subject to be treated has previously been treated with a TTR tetramer stabilizer (e.g., diflunisal, tafamidis (and acoramidis (AG10)). Alternatively, the subject may be receiving treatment with an anti-TTR antibody as described herein while simultaneously receiving treatment with a TTR tetramer stabilizer (e.g., diflunisal, tafamidis, and acoramidis (AG10)).

[0340] Administration of an anti-TTR antibody (e.g., at a particular dosage, frequency, and / or duration of treatment described below) can provide a therapeutic or prophylactic benefit to a subject. Treatment of such a prophylactic benefit of the antibody is achieved by providing a TTR antibody level 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, ≥ 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, ≥ 350 μg / mL, ≥ 360 μg / mL, ≥ 370 μg / mL, ≥ 380 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, ≧360μ g / mL, ≧370μg / mL, ≧380μg / mL, ≧390μg / mL, ≧400μg / mL, ≧410μg / mL, ≧420 μg / mL, ≧430μg / mL, ≧440μg / mL, ≧450μg / mL, ≧460μg / mL, ≧470μg / mL, ≧4 80μg / mL, ≧490μg / mL, ≧500μg / mL, ≧510μg / mL, ≧520μg / mL, ≧530μg / mL, ≧540μg / mL, ≧550μg / mL, ≧560μg / mL, ≧570μg / mL, ≧580μg / mL, ≧590μg / m L, ≧600μg / mL, ≧610μg / mL, ≧620μg / mL, ≧630μg / mL, ≧640μg / mL, ≧650μg / mL, ≧660μg / mL, ≧670μg / mL, ≧680μg / mL, ≧690μg / mL, ≧700μg / mL, ≧710μ g / mL, ≧720μg / mL, ≧730μg / mL, ≧740μg / mL, ≧750μg / mL, ≧760μg / mL, ≧77 0μg / mL, ≧780μg / mL, ≧790μg / mL, ≧800μg / mL, ≧810μg / mL, ≧820μg / mL, ≧ 830μg / mL, ≧840μg / mL, ≧850μg / mL, ≧860μg / mL, ≧870μg / mL, ≧880μg / mL,≧890 μg / mL, ≧900 μg / 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 more). Furthermore, such plasma concentrations can be maintained for any period of time (e.g., 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 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days). For example, the plasma concentration can be maintained at ≥1 μg / mL for 21 to 35 days. For example, the plasma concentration can be maintained at ≥2.5 μg / mL for 21 to 35 days. For example, the plasma concentration can be maintained at ≥5 μg / mL for 21 to 35 days. For example, the plasma concentration can be maintained at ≥10 μg / mL for 21 to 35 days. Preferably, the indicated plasma concentrations can be maintained for 21 to 35 days, preferably 28 to 35 days, and most preferably 28 or 35 days.

[0341] Alternatively, the therapeutic or prophylactic effect of the antibody may be measured at 2,000 μg * day / mL (e.g., ≥ 2,000 μg * day / mL, ≧4,000μg * day / mL, ≧6,000μg * day / mL, ≧8,000μg * day / mL, ≧10,000μg * day / mL, ≧12,000μg * day / mL, ≧14,000μg * day / mL, ≧16,000μg * day / mL, ≧18,000μg * day / mL, ≧20,000μg * day / mL, ≧22,000μg * day / mL, ≧24,000μg * day / mL, ≧26,000μg *Daily / mL, ≥28,000 μg * Daily / mL, ≥30,000 μg * Daily / mL, ≥32,000 μg * Daily / mL, ≥34,000 μg * Daily / mL, ≥36,000 μg * Daily / mL, ≥38,000 μg * Daily / mL, ≥40,000 μg * Daily / mL, ≥42,000 μg * Daily / mL, ≥44,000 μg * Daily / mL, ≥46,000 μg * Daily / mL, ≥48,000 μg * Daily / mL, ≥50,000 μg * Daily / mL, ≥52,000 μg * Daily / mL, ≥54,000 μg * Daily / mL, ≥56,000 μg * Daily / mL, ≥58,000 μg * Daily / mL, ≥60,000 μg * Daily / mL, ≥62,000 μg * Daily / mL, ≥64,000 μg * Daily / mL, ≥66,000 μg * Daily / mL, ≥68,000 μg * Daily / mL, ≥70,000 μg * Daily / mL, ≥72,000 μg * Daily / mL, ≥74,000 μg * Daily / mL, ≥76,000 μg * Daily / mL, ≥78,000 μg * Daily / mL, ≥80,000 μg * Daily / mL, ≥82,000 μg * Daily / mL, ≥84,000 μg * Daily / mL, ≥86,000 μg * Daily / mL, ≥88,000 μg * Daily / mL, ≥90,000 μg * Daily / mL, ≥92,000 μg * Daily / mL, ≥94,000 μg * Daily / mL, ≥96,000 μg * Daily / mL, ≥98,000 μg * Daily / mL, ≥100,000 μg *This may result in a sustained plasma concentration of antibody with an area under the curve (AUC) in days / mL.

[0342] Treatment Monitoring and Evaluation A skilled artisan (e.g., a clinician) can monitor and evaluate the effectiveness of treatment. Methods for monitoring and evaluating the effectiveness of treatment are described below.

[0343] For any of the methods described herein, the effectiveness of treatment can be assessed or monitored according to standard techniques known in the art. For example, administration of an anti-TTR antibody or pharmaceutical composition thereof can be monitored by determining the level (e.g., mRNA or protein level) of one or more biomarkers (e.g., ATTR biomarkers). 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 suppressor of tumorigenicity 2 (sST2), carboxy-terminal propeptide of procollagen type 1 (PICP), and propeptide of procollagen type III (PIIINP). In some embodiments, administration of an anti-TTR antibody is monitored by determining the levels 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 pharmaceutical composition thereof may be monitored by determining the level (e.g., mRNA or protein level) of N-terminal pro-B-type natriuretic peptide (NT-proBNP).

[0344] In one embodiment, a decrease in the level of the biomarker indicates efficacy of the treatment.

[0345] For example, a subject may have an NT-proBNP level of about 300 pg / mL to about 20,000 pg / mL before undergoing the therapeutic methods described herein, and may have a level of about 0 pg / mL to about 300 pg / mL after undergoing the therapeutic methods described herein. Preferably, a subject may have an NT-proBNP level of >2000 pg / mL before undergoing the therapeutic methods described herein.

[0346] In another example, a subject may have a TnT level of about 10 pg / mL to about 200 pg / mL before undergoing a treatment method described herein, and a level of 0 pg / mL to about 10 pg / mL after undergoing a treatment method described herein.

[0347] Any decrease (e.g., a 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease) in the levels of TnT or NT-proBNP (e.g., more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, or more than 12 months, or relative to an untreated ATTR subject) indicates treatment 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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or pre-eclampsia may have elevated levels (e.g., about 300 pg / mL to about 20,000 pg / mL) of NT-proBNP, which may decrease over time in the blood (e.g., plasma or serum) of a subject being treated with the methods described herein.

[0348] An increase in CRP levels, particularly a dose-dependent, transient (e.g., about 1 to about 14 days, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days) increase in CRP levels (e.g., over time or relative to untreated ATTR subjects) also indicates on-target immune activation and therapeutic efficacy.

[0349] Any suitable laboratory technique for determining the protein level of a biomarker (e.g., TnT, NT-proBNP, and CRP) in a sample (e.g., blood, e.g., 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 blotting, high-performance liquid chromatography (HPLC), surface plasmon resonance, optical spectroscopy, and immunohistochemistry (IHC). Any suitable laboratory technique for determining the mRNA expression level of a biomarker (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, MASSARRAY® technology, SAGE, and RNA sequencing.

[0350] To detect and measure the level of CRP, the above-mentioned kit containing a reagent for detecting and measuring the level of CRP in a patient sample can also be used. As mentioned, means and methods for detecting CRP are known to those skilled in the art; see, for example, U.S. Patent Application Publication No. 2006 / 0246522 and the references cited in sections

[0010] to

[0017] of U.S. Patent Application Publication No. 2006 / 0246522. In general, detection of CRP can be achieved by any suitable method. Exemplary detection methods include immunodetection (e.g., by using antibodies that specifically bind to CRP), optical methods (e.g., both confocal and non-confocal microscopy, detection of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, and birefringence or refractive index (e.g., surface plasmon resonance, ellipsometry, resonant mirror methods, grating coupler waveguide methods, or interferometry)), electrochemical methods (voltammetry and amperometry techniques), atomic force microscopy, and radio frequency methods such as multipolar resonance spectroscopy. In this regard, standard immunoassays can be used for the detection of CRP, which can be performed in a variety of different formats and generally involve detection of 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 the patient. Immunoassays can be performed in any of a variety of formats, and generally, the assay measures the reactivity between the anti-biomarker antibody and a patient sample. For example, commercially available kits for the detection of CRP-like ELISA kits are available to the skilled artisan, such as the CRP / C-Reactive Protein ELISA Kit from LifeSpan BioSciences, Seattle, Washington, USA.

[0351] Further methods for monitoring or assessing therapeutic efficacy can include monitoring or assessing the level of cardiac amyloid burden and cardiac mass in a subject. Subjects with an ATTR-associated disease (e.g., ATTR, ATTR-CM, ATTR-PN, FAP, FAC, SSA, systemic familial amyloidosis, CNS, Alzheimer's disease, TTR-associated ocular amyloidosis, TTR-associated renal amyloidosis, TTR-associated hyperthyroxinemia, TTR-associated ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia) have a cardiac amyloid burden of ≥ 20% (e.g., about 20% to about 60%, e.g., 20%, 25%, 30%, 35%) or more prior to receiving a therapeutic method described herein. , 40%, 45%, 50%, 55%, or 60%) and / or may have 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) as measured by, for example, echocardiography prior to receiving the therapeutic methods described herein. A reduction in the level of cardiac amyloid burden or myocardial mass (e.g., a 5% to 100% reduction compared to a control) indicates therapeutic efficacy in the subject in response to the treatment described herein. For example, a reduction in left ventricular myocardial mass of about 5% to about 25% over a treatment period of about 17 weeks to about 50 weeks indicates therapeutic efficacy in 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. Cardiac mass reduction and cardiac amyloid burden can be measured by cardiac magnetic resonance imaging (MRI).

[0352] A further example for monitoring or assessing the effectiveness of a treatment may include monitoring and assessing cardiac function, which may be assessed by echocardiography. For example, an echocardiogram may be used to measure systolic function (strain), thickness and filling pressure, as well as LVEF, left ventricular end-diastolic / end-systolic 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).

[0353] Other readouts for assessing 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. Subjects walk around a set circuit for a total of 6 minutes. The test score is the distance the subject walks on a flat, hard surface during the 6-minute period (measured in meters and rounded up to the nearest decimal point). The KCCQ is a 23-item self-administered questionnaire developed to independently measure subjects' perceptions of their health status, including heart failure symptoms, their impact on physical and social function, and how their heart failure affects their quality of life within 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 heart-retention (HR) / whole-body-retention (WBR) and heart-retention (HR) / skull-retention (SR) ratios.

[0354] Dosing regimen Any of the anti-TTR antibodies or pharmaceutical compositions thereof as used in accordance with the present invention may 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 ligament 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.

[0355] Dosage For any of the methods described herein, the anti-TTR antibody or pharmaceutical composition thereof may 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) 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, anti-TTR antibodies as used in accordance with the present invention may be administered in doses of 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 , 16mg / 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, 45mg / 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, 60m g / 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 / kg, 75 The compound may be administered at a dose (e.g., maintenance dose and / or loading dose) of 76 mg / kg, 77 mg / kg, 78 mg / kg, 79 mg / kg, 80 mg / kg, 81 mg / kg, 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, or 100 mg / kg.

[0356] More specifically, anti-TTR antibodies used in accordance with the present invention may be administered to a subject at a starting dose of about 0.3 mg / kg to 10 mg / kg, e.g., 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. Furthermore, the anti-TTR antibodies used in accordance with the present invention preferably have a dose of about 10 mg / kg to about 60 mg / kg, e.g., 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, or 32 mg / 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, 45mg / 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, or 60mg / kg may be administered to the subject at a maintenance dose of

[0357] For example, preferably, an anti-TTR antibody or a pharmaceutical composition thereof may be administered at a dose of 30 mg / kg to 60 mg / kg, such as 30 mg / kg or 60 mg / kg. The anti-TTR antibody may be administered at a dose of 30 mg / kg. The anti-TTR antibody may be administered at a dose of 60 mg / kg.

[0358] For any of the methods described herein, the anti-TTR antibody or pharmaceutical composition thereof may be administered (e.g., in a dosing regimen) at a dose (e.g., a maintenance dose and / or a 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 may be administered in an amount of 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, or 2000 mg. , 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750m g, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg, 3350mg, 3400mg, 3450mg, 3500 mg, 3550mg, 3600mg, 3650mg, 3700mg, 3750mg, 3800mg, 3850mg, 3900mg, 3950mg, 4000mg, 4050mg, 4100mg, 4150mg, 4200mg, 425 0mg, 4300mg, 4350mg, 4400mg, 4450mg, 4500mg, 4550mg, 4600mg, 4650mg, 4700mg, 4750mg, 4800mg, 4850mg, 4900mg, 4950mg, 50 00mg, 5050mg, 5100mg, 5150mg, 5200mg, 5250mg, 5300mg, 5350mg, 5400mg, 5450mg, 5500mg, 5550mg, 5600mg, 5650mg, 5700mg, 5 750mg, 5800mg, 5850mg, 5900mg, 5950mg, 6000mg, 6050mg, 6100mg, 6150mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 6250mg,It may be administered at doses (e.g., maintenance doses and / or loading doses) of 6260 mg, 6270 mg, 6280 mg, 6290 mg, 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.

[0359] More specifically, the anti-TTR antibodies used in accordance with the present invention preferably have a total concentration of 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, It may be administered at a loading dose of about 600 mg to about 4000 mg (loading dose), such as 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, or 4000 mg. In one embodiment, preferably after administration of a loading dose, an anti-TTR antibody as used in accordance with the invention preferably has a vasopressin concentration of 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, 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, 6000 mg, 6100 mg, 00mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700 mg, 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, 4050mg, 4100 mg, 4150mg, 4200mg, 4250mg, 4300mg, 4350mg, 4400mg, 4450mg, 4500mg, 4550mg, 4600mg, 4650mg, 47 00mg, 4750mg, 4800mg, 4850mg, 4900mg, 4950mg, 5000mg, 5050mg, 5100mg, 5150mg, 5200mg, 5250mg, 5300mg, 5350mg, 5400mg, 5450mg, 5500mg, 5550mg, 5600mg, 5650mg, 5700mg, 5750mg, 5800mg, 5850m g, 5900mg, 5950mg, 6000mg, 6050mg, 6100mg, 6150mg, 6200mg, 6210mg, 6220mg, 6230mg, 6240mg, 625 0mg, 6260mg, 6270mg, 6280mg, 6290mg, 6300mg, 6350mg, 6400mg, 6450mg, 6500mg, 6550mg, 6600mg, 6 It may be administered at a maintenance dose of about 600 mg to about 7500 mg (e.g., a maintenance dose) of 650 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.

[0360] For example, an anti-TTR antibody or a pharmaceutical composition thereof can be administered at a dose of 2000 mg to 5000 mg, for example, 2400 mg, 2500 mg, 3000 mg, 3200 mg, or 3500 mg, preferably 3500 mg or 3200 mg, and most preferably 3200 mg.

[0361] Anti-TTR antibodies are 2000mg, 2010mg, 2020mg, 2030mg, 2040mg, 2050mg, 2060mg, 2070mg, 2080mg, 2090mg, 2100mg, 2110mg, 2120mg, 2130mg, 2140mg, 2150mg, 2160mg, 2170mg, 2180mg, 2190mg, 2200mg, 2210mg, 2220mg, 2230mg, 2240mg, 2250mg, 2260mg, 2270mg, 2280mg, 2290mg, 2300mg, 2310mg, 2320mg, 2330mg, 23 40mg、2350mg、2360mg、2370mg、2380mg、2390mg、2400mg、2410mg、2420mg、2430mg、2440mg、2450mg、2460mg、2470mg、2480mg、2490mg、2500mg、2510mg、 2520mg、2530mg、2540mg、2550mg、2560mg、2570mg、2580mg、2590mg、2600mg、2610mg、2620mg、2630mg、2640mg、2650mg、2660mg、2670mg、2680mg、2690mg 、2700mg、2710mg、2720mg、2730mg、2740mg、2750mg、2760mg、2770mg、2780mg、2790mg、2800mg、2810mg、2820mg、2830mg、2840mg、2850mg、2860mg、2870 mg、2880mg、2890mg、2900mg、2910mg、2920mg、2930mg、2940mg、2950mg、2960mg、2970mg、2980mg、2990mg、3000mg、3010mg、3020mg、3030mg、3040mg、305 0mg、3060mg、3070mg、3080mg、3090mg、3100mg、3110mg、3120mg、3130mg、3140mg、3150mg、3160mg、3170mg、3180mg、3190mg、3200mg、3210mg、3220mg、3 230mg、3240mg、3250mg、3260mg、3270mg、3280mg、3290mg、3300mg、3310mg、3320mg、3330mg、3340mg、3350mg、3360mg、3370mg、3380mg、3390mg、3400mg、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、It may be administered in doses (e.g., maintenance and / or loading doses) 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.

[0362] Most preferably, the flat dose is administered according to the body weight of the subject being treated, as further explained above.

[0363] Any of the dosages described herein can be administered to a subject as a maintenance dose and / or a loading dose. For example, a method 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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia) can include 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 a further example, the method may further comprise administering an 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).

[0364] The methods described herein contemplate administering an anti-TTR antibody to a subject multiple times, 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 may be administered. Further contemplated herein is escalation (e.g., increase) of the administered dose. For example, administration of two or more doses can include one, two, three, four, five, or six escalations (e.g., increases) of the dose (e.g., if the subject is unresponsive or inadequately responsive to a previous dose administered). For example, escalation can include increases 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. Escalation can occur at any time during a subject's treatment. Escalation can also be performed if blood (e.g., serum or plasma) levels of antibody are determined to be below a desired threshold (e.g., less than 10 μg / mL).

[0365] In a preferred embodiment, the anti-TTR antibody is administered in a weight-based flat dosing regimen comprising: (a) 2400 mg for patients weighing ≥40 kg but less than 60 kg; (b) 3200 mg for patients weighing ≥60 kg but less than 100 kg; or (c) 4800 mg for patients weighing ≥100 kg. Preferably, the weight-based dosing regimen is administered intravenously (IV) to adult patients.

[0366] Frequency and duration of treatment For any of the methods described herein, the anti-TTR antibody or pharmaceutical composition thereof may 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, the anti-TTR antibody may 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, most preferably 2400 mg, 3200 mg, or 5000 mg). mg or 4800 mg) may be administered about once 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.

[0367] Additionally, treatment with an anti-TTR antibody can be administered to a subject for any period of time, e.g., at least 6 months, 12 months, or 18 months (e.g., from 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 to 30 months or 12 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, the anti-TTR antibody can be administered to the subject at the frequencies described above (e.g., about once every 28 days to about once every 35 days) for the subject's lifetime.

[0368] 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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or pre-eclampsia may utilize any combination of the dosages, frequencies, and / or durations of treatment described above.

[0369] In a preferred embodiment, the anti-TTR antibody (e.g., ALXN2220) is administered every four weeks (q4w).

[0370] Route of administration Administration of anti-TTR antibodies to a subject can be, for example, subcutaneous or intravenous (e.g., by intravenous infusion). For example, anti-TTR antibodies can be administered intravenously using a syringe pump or an administration syringe in an infusion bag. If an infusion line is utilized for administration, the infusion line can be flushed before and / or after infusion of the anti-TTR antibody. Infusion syringes can be used for administration of total antibody doses up to 100 mg, while infusion pumps are used for administration of total antibody doses greater 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%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / v. A diluted form (e.g., an aqueous solution) of the anti-TTR antibody can be administered to a subject using an injection 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). Administration of the anti-TTR antibody in aqueous solution may occur over a period of 1 to 5 hours, e.g., 1, 2, 3, 4, or 5 hours, e.g., 2 hours ± 10 minutes. The first administration of the anti-TTR antibody may occur over, e.g., 2 hours ± 10 minutes, while subsequent administrations may occur over, e.g., approximately 1 hour ± 10 minutes.

[0371] Preferably, the anti-TTR antibody (e.g., ALXN2220) is administered to the patient intravenously (IV) in the form of an infusion solution, e.g., a pharmaceutical formulation at 50 mg / mL, using a syringe.

[0372] Pharmaceutical Composition Methods for treating or preventing ATTR-associated diseases described herein (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 ligament amyloidosis, carpal tunnel syndrome, rotator cuff tear, lumbar spinal stenosis, or preeclampsia) may utilize any anti-TTR antibody as described herein formulated into a pharmaceutical composition. For example, a pharmaceutical composition containing an anti-TTR antibody may be formulated with sucrose, polysorbate 80, and / or a polar excipient, such as a buffer (e.g., histidine). Furthermore, a pharmaceutical composition containing an anti-TTR antibody may be formulated at a desired pH (e.g., pH 5.8) as described herein. Pharmaceutical compositions containing anti-TTR antibodies may further comprise a pharmaceutically acceptable excipient or diluent as described herein.

[0373] The pharmaceutical composition may also contain sucrose in an amount, for example, about 6% to about 9%, about 6% to about 7%, or about 7.5% to about 8.5% weight / volume (w / v) (e.g., about 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, or 9% weight / volume (w / v) sucrose).

[0374] The pharmaceutical composition may also include polysorbate 80 (PS80) in an amount of, for example, about 0.001% to about 0.1% w / v (e.g., about 0.001%, 0.005%, 0.01%, 0.05%, or 0.1% w / v of PS80).

[0375] The pharmaceutical composition may also include a polar excipient. The polar excipient may be or include, for example, a sugar, a polyol, or an amino acid. The sugar may be, for example, sucrose, trehalose, fructose, lactose, dextrose, or mannitol. The polyol may be, for example, polyethylene glycol or sorbitol. The amino acid may 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 (e.g., 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.

[0376] The pharmaceutical composition can include a polar excipient (e.g., histidine) in an amount of 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).

[0377] 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).

[0378] Pharmaceutical compositions may contain pharmaceutically acceptable excipients (e.g., buffers, carriers, stabilizers, or preservatives) or diluents (e.g., saline and aqueous buffer solutions).

[0379] The pharmaceutical composition may be administered 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, about 2.25 mL, The aqueous solution may be provided (e.g., in a vial or other container, as described herein) in a volume of 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).

[0380] The pharmaceutical composition may be any pharmaceutical composition described in the patent application entitled "Pharmaceutical Compositions for Treating or Preventing Transthyretin-Mediated Amyloidosis," filed on November 15, 2022, having application number EP 22 207 645.7 and attorney docket number NE30A100 / P-EP (incorporated herein by reference).

[0381] 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 contains 6.5% or 8% weight per unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and a pH of 5.8.

[0382] In one example, a pharmaceutical composition containing an antibody is formulated for intravenous or infusion injection and contains the antibody at a concentration of approximately 50 mg / mL. The pharmaceutical composition contains 6.5% weight per 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 pH 5.8. The composition can be present in a container in a volume of 2 mL.

[0383] 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 contains 6.5% weight per unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and pH 5.8. The composition can be present in a container with a volume of 20 mL.

[0384] 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 contains 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 pH 5.8. The composition can be present in a container in a volume of 2 mL.

[0385] 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 pH 5.8. The composition can be present in a container with a volume of 20 mL.

[0386] 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 contains 6.5% weight per unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and pH 5.8. The composition can be present in a container in a volume of 2 mL.

[0387] 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 contains 6.5% weight per unit volume (w / v) sucrose, 0.03% w / v polysorbate 80, 20 mM histidine, and pH 5.8. The composition can be present in a container with a volume of 20 mL.

[0388] 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 pH 5.8. The composition can be present in a container in a volume of 2 mL.

[0389] 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 pH 5.8. The composition can be present in a container with a volume of 20 mL. [Example]

[0390] Example 1. A Phase 1, Open-Label, Double-Blind, Placebo-Controlled, Multicenter, Single and Multiple Ascending Dose Study of NI006 in Patients with Amyloid Transthyretin Cardiomyopathy Followed by an Open-Label Expansion Overall design This example describes a randomized, placebo-controlled, double-blind study combining single ascending dose (SAD) and multiple ascending dose (MAD) phases followed by an open-label extension OLE phase in subjects with amyloid transthyretin (ATTR)-cardiomyopathy (CM). The study is designed as a human pre-emptive study of the safety, tolerability, and exploratory efficacy profile of single and multiple doses of antibody NI006, an anti-TTR antibody having a heavy chain variable (VH) region with the amino acid sequence of SEQ ID NO:7 and a light chain variable (VL) region with the amino acid sequence of SEQ ID NO:8, from 0.3 mg / kg 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 of healthy elderly human subjects, as described, for example, in WO 2015 / 092077 (U.S. Pat. Nos. 10,344,080; and 11,180,545), where the antibody is designated NI-301.37F1.

[0391] The objectives and endpoints of this study are shown in Table 2. Subjects will be administered NI006 or a placebo (e.g., control) during each phase. Subjects who complete the SAD phase will be enrolled in the MAD phase. Subjects who complete the MAD phase will have the opportunity to continue into the OLE phase with dose escalation. A second, open-label extension (OLE2) phase is optional to allow for long-term treatment at a maximum dose of 30 mg / kg or less. There are several exemplary cohorts of subjects described herein (e.g., Cohorts 1-7), each receiving various doses 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). Exemplary trial schemas are provided in Figure 1 (e.g., SAD / MAD cohorts 1-6), Figure 2 (OLE cohorts 1-6), and Figure 3 (SAD / MAD and OLE cohort 7).

[0392] Subjects in cohorts 1-5 have the potential to enter a second OLE phase (OLE2) at a maximum dose of 30 mg / kg for up to 10 months of treatment.

[0393] The detailed study design implemented in this final dose study is described below.

[0394] The first two patients in each dose cohort (sentinel) were randomized 1:1 to receive NI006 or placebo. The four subsequent patients in each cohort were randomized 3:1 to receive NI006 or placebo if no sentinel-related safety signals occurred. After satisfactory review of sufficient SAD safety data, the next higher dose cohort was initiated. Patients received a total of four q4w doses of NI006 or placebo during the SAD / MAD combination phase. Cardiac imaging was performed at baseline and 4 months to assess changes in NI006 and placebo during the SAD / MAD phase. Replacement patients were recruited if patients discontinued during the SAD / MAD phase for reasons other than suspected drug toxicity. Patients who entered the OLE phase remained blinded at that time, regardless of their treatment assignment during the SAD / MAD phase, but were eligible to receive eight q4w doses of NI006. As new safety information became available from the SAD / MAD phase of the higher-dose cohort, patients who started at lower dose levels were titrated to the maximum safe dose level at each dose. Cardiac imaging was performed at the end of the OLE phase at 12 months.

[0395] NI006 was administered as an IV infusion over approximately 2 hours (±10 minutes; with a maximum of 3 hours at 60 mg / kg). Subsequent infusions were administered over approximately 50-70 minutes. Patients were hospitalized for 4 nights after the SAD and first OLE dose (i.e., first NI006 dose in patients randomized to placebo) and for 1-2 nights after each of the three MAD doses. All further doses during the OLE phase were administered as outpatient visits.

[0396] [Table 4]

[0397] Patient population Forty patients with wild-type or hereditary ATTR-CM (median age 72 years, 97.5% male), chronic heart failure, and baseline NT-proBNP levels of 766-5892 pg / mL were enrolled in this study. More specifically, the study population consisted of patients with a confirmed diagnosis of ATTR-CM, regardless of underlying genotype (ATTRv or ATTRwt), with left ventricular wall thickness ≥ 14 mm, left ventricular ejection fraction (LVEF) ≥ 40%, NYHA stage I-III, NT-proBNP levels between 600 pg / mL and 6000 pg / mL, and eGFR > 30 mL / min / 1.73 m2, according to current guidelines (Garcia-Pavia et al., Eur Heart J. 42 (2021), 1554-68; Kittleson et al., Circulation 142 (2020), e7-e22). Concomitant treatment with tafamidis was accepted if the dose had been 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). Patient demographic and clinical characteristics are shown in Table 3.

[0398] [Table 5] * The French study site did not allow collection of ethnic background information. Plus-minus values ​​are mean ± standard deviation. NT-proBNP indicates N-terminal pro-B-type natriuretic peptide, GFR indicates glomerular filtration rate, and NYHA indicates New York Heart Association.

[0399] SAD phase in cohorts 1-6 The treatment regimen described herein begins on the first day an anti-TTR antibody is administered to a subject, which will be considered day 1 of the treatment regimen. Days 1 through 29 of the treatment regimen will be considered the SAD phase for Cohorts 1 through 6 (see, e.g., Figure 1, red boxes). Subjects from Cohorts 1 through 6 will receive treatment with an anti-TTR antibody or placebo on day 1 of the SAD phase. Cohort 1 will receive 0.3 mg / kg of an anti-TTR antibody or placebo on day 1 of the SAD phase. Cohort 2 will receive 1 mg / kg of an anti-TTR antibody or placebo on day 1 of the SAD phase. Cohort 3 will receive 3 mg / kg of an anti-TTR antibody or placebo on day 1 of the SAD phase. Cohort 4 will receive 10 mg / kg of an 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.

[0400] MAD phase of cohorts 1-6 Days 30 through 148 of the treatment regimen are considered the MAD phase (see, e.g., Figure 1, blue box). Subjects in cohorts 1 through 6 who complete the SAD phase will continue in the MAD phase of the study, which will include three additional doses of anti-TTR antibody or placebo beginning 35 days after the subject's initial treatment with the anti-TTR antibody.

[0401] For example, an anti-TTR antibody or placebo will be administered at the subject's assigned dose (e.g., based on their cohort) on day 36 of the treatment regimen, followed by a 28±2 day inter-treatment regimen. For example, cohort 1 will receive 0.3 mg / kg of anti-TTR antibody or placebo on day 36, any one of days 62-66 (e.g., day 64), and any one of days 90-94 (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 one of days 62-66 (e.g., day 64), and any one of days 90-94 (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 one of days 62-66 (e.g., day 64), and any one of days 90-94 (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 one of days 62-66 (e.g., day 64), and any one of days 90-94 (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 one of days 62-66 (e.g., day 64), and any one of days 90-94 (e.g., day 92) of the treatment regimen. Cohort 6 will receive 60 mg / kg of anti-TTR antibody or placebo on day 36, any one of days 62-66 (e.g., day 64), and any one of days 90-94 (e.g., day 92) of the treatment regimen.

[0402] In another example, an anti-TTR antibody or placebo will be administered at the subjects' assigned dose (e.g., based on their cohort) on day 36 of the treatment regimen, followed by a 28±7 day inter-treatment regimen. For example, Cohort 1 will receive a 0.3 mg / kg anti-TTR antibody or placebo treatment regimen on day 36, any one of days 57-71 (e.g., day 64), and any one of days 85-99 (e.g., day 92). Cohort 2 will receive a 1 mg / kg anti-TTR antibody or placebo treatment regimen on day 36, any one of days 57-71 (e.g., day 64), and any one of days 85-99 (e.g., day 92). Cohort 3 will receive a treatment regimen of 3 mg / kg anti-TTR antibody or placebo on day 36, any one of days 57-71 (e.g., day 64), and any one of days 85-99 (e.g., day 92). Cohort 4 will receive a treatment regimen of 10 mg / kg anti-TTR antibody or placebo on day 36, any one of days 57-71 (e.g., day 64), and any one of days 85-99 (e.g., day 92). Cohort 5 will receive a treatment regimen of 30 mg / kg anti-TTR antibody or placebo on day 36, any one of days 57-71 (e.g., day 64), and any one of days 85-99 (e.g., day 92). Cohort 6 will receive a treatment regimen of 60 mg / kg anti-TTR antibody or placebo on day 36, any one of days 57-71 (e.g., day 64), and any one of days 85-99 (e.g., day 92).

[0403] SAD / MAD phase of Cohort 7 The treatment regimen described herein (see, e.g., Figure 3) begins on the first day that an anti-TTR antibody is administered to a subject, which will be considered day 1 of the treatment regimen. Days 1 through 28 of the treatment regimen will be considered the SAD phase for Cohort 7. Subjects from Cohort 7 will receive treatment with an anti-TTR antibody or placebo on day 1 of the SAD phase. For example, Cohort 7 may receive 30 mg / kg of an anti-TTR antibody or placebo on day 1 of the SAD phase.

[0404] Days 29 through 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 study, which will include three additional doses of anti-TTR antibody or placebo beginning 28 days after the subject's initial treatment with the anti-TTR antibody.

[0405] For example, an anti-TTR antibody or placebo may be administered to subjects at 30 mg / kg on day 29 of the treatment regimen, followed by a 28±2 day inter-treatment regimen. For example, Cohort 7 may receive 30 mg / kg of an anti-TTR antibody or placebo on day 29, any one of days 55-59 (e.g., day 57), and any one of days 83-87 (e.g., day 85) of the treatment regimen.

[0406] In another example, an anti-TTR antibody or placebo will be administered to subjects at 30 mg / kg on day 29 of the treatment regimen, followed by a 28±7 day inter-treatment regimen. For example, Cohort 7 may receive 30 mg / kg of an anti-TTR antibody or placebo on day 29, any one of days 50-64 (e.g., day 57), and any one of days 78-92 (e.g., day 85) of the treatment regimen.

[0407] OLE phase for cohorts 1-6 Days 120 through 351 of the treatment regimen are considered the OLE phase (see, e.g., Figure 2). Subjects in Cohorts 1-6 who completed the SAD phase continue into the OLE phase of the study. Subjects who received placebo during the SAD and MAD phases may now receive anti-TTR antibody during the OLE phase.

[0408] The starting dose of anti-TTR antibody for a subject who received placebo in the SAD and MAD phases will either be the same dose level as that subject's SAD and MAD phases (e.g., if the subject received 1 mg / kg in the SAD and MAD phases, then the subject would receive 1 mg / kg of anti-TTR antibody as a starting dose in the OLE phase), or will be the highest dose of anti-TTR antibody deemed safe and well-tolerated at the time of that 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).

[0409] The OLE phase involves eight additional doses of anti-TTR antibody or placebo beginning 119 days after the subject's initial treatment with the anti-TTR antibody. Subjects 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 or placebo on day 120 of the treatment regimen, followed by a 28±2 day or 28±7 day intertreatment regimen.

[0410] For example, Cohort 7 would receive a treatment regimen of 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 one of days 146-150 (e.g., day 148), any one of days 174-178 (e.g., day 176), any one of days 202-206 (e.g., day 204), any one of days 230-234 (e.g., day 232), any one of days 258-262 (e.g., day 260), any one of days 286-290 (e.g., day 288), and any one of days 314-318 (e.g., day 316).

[0411] 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 one of days 141-155 (e.g., day 148), any one of days 169-183 (e.g., day 176), any one of days 197-211 (e.g., day 204), any one of days 225-239 (e.g., day 232), any one of days 253-267 (e.g., day 260), any one of days 281-295 (e.g., day 288), and any one of days 309-323 (e.g., day 316) of the treatment regimen.

[0412] During the OLE phase for cohorts 1-6, the dose of anti-TTR antibody may be escalated one or more times. The antibody titration may occur between one or more treatments: on any one of days 141-155 (e.g., any one of days 146-150, e.g., day 148), any one of days 169-183 (e.g., any one of days 174-178, e.g., day 176), any one of days 197-211 (e.g., any one of days 202-206, e.g., day 204), any one of days 225-239 (e.g., any one of days 230-234, e.g., day 232), any one of days 253-267 (e.g., any one of days 258-262, e.g., day 260), any one of days 281-295 (e.g., any one of days 286-290, e.g., day 288), and / or any one of days 309-323 (e.g., any one of days 314-318, e.g., day 316).

[0413] Escalation can include increases of 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 intermediate treatment. For example, escalation can occur between each treatment. In another example, escalation can occur at least once, twice, three times, four times, five times, or six times.

[0414] OLE phase for cohort 7 Days 120 through 232 of the treatment regimen are considered the OLE phase for Cohort 7 (e.g., Figure 3). Subjects from Cohort 7 who complete the MAD phase will continue in the OLE phase of the study, including four additional doses of anti-TTR antibody or placebo beginning 119 days after the subject's initial treatment with the anti-TTR antibody. For example, the anti-TTR antibody or placebo will be administered to the subject at 30 mg / kg on day 120 of the treatment regimen, followed by an inter-treatment regimen 28±2 days later or 28±2 days later.

[0415] For example, Cohort 7 would receive a treatment regimen of 30 mg / kg anti-TTR antibody or placebo on day 120, any one of days 146-150 (e.g., day 148), any one of days 174-178 (e.g., day 176), and any one of days 202-206 (e.g., day 204).

[0416] In another example, Cohort 7 would receive 30 mg / kg of anti-TTR antibody or placebo on the treatment regimen on day 120, any one of days 141-155 (e.g., day 148), any one of days 169-183 (e.g., day 176), and any one of days 197-211 (e.g., day 204).

[0417] Expanded OLE (OLE+) phase of cohorts 1-2 If a subject from Cohort 1 or Cohort 2 received one to seven doses in the OLE phase and therefore did not complete the OLE phase, the subject would enter the extended OLE (OLE+) phase. The OLE+ phase involves one or two additional doses of anti-TTR antibody beginning 28±2 days after the last treatment with the anti-TTR antibody. For example, the anti-TTR antibody would be administered to the subject at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg 28±2 days after the last treatment with the anti-TTR antibody, followed by one additional treatment 28±2 days or 28±7 days later. Titration of the anti-TTR antibody is possible, for example, from 0.3 mg / kg to 1 mg / kg, from 1 mg / kg to 3 mg / kg, from 3 mg / kg to 10 mg / kg, from 10 mg / kg to 30 mg / kg, or from 30 mg / kg to 60 mg / kg. For example, titration can occur during the first administration of the OLE+ phase, the second administration of the OLE+ phase, or both.

[0418] OLE Phase 2 in cohorts 1-5 Subjects from any one of cohorts 1-5 who receive at least one dose (e.g., 1-7) in the OLE or OLE+ phase will enter the OLE2 phase, which includes up to eight additional doses of anti-TTR antibody. Subjects will be treated at a maximum dose of 30 mg / kg during OLE2. Subjects treated at doses less than 30 mg / kg prior to initiating OLE2 should begin OLE2 at the last dose level at which they were treated in the OLE or OLE+ phase and may be titrated from one dose level to another on a monthly (e.g., 28±2 days or 28±7 days) basis (e.g., if a subject's previous dose was 3 mg / kg, they should begin OLE2 at that dose, which may then be titrated to 10 mg / kg for the second OLE2 treatment and then to 30 mg / kg for the third OLE2 treatment). Titration may include increases 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 interim treatment. For example, if a subject has no break between OLE and OLE2 and is already at a dose of 10 mg / kg or higher at the end of OLE, the subject can be titrated / administered directly to 30 mg / kg. Titration can occur between each treatment. In other examples, escalation can occur at least once, twice, three times, four times, five times, six times, or seven times.

[0419] Administration Anti-TTR antibodies will be administered intravenously using a syringe pump or a dosing syringe in an infusion bag. Aqueous formulations of anti-TTR antibodies should be brought to room temperature before use. Immediate use after opening a single-use vial containing anti-TTR antibodies is recommended. Anti-TTR antibodies should be clear or slightly opalescent, colorless or slightly yellow. Aqueous anti-TTR antibody formulations that are cloudy or contain sediment should not be used.

[0420] A subject's initial dose (e.g., on day 1 of the treatment regimen) will be delivered over approximately 2 hours (±10 minutes). The initial dose for subjects in Cohort 6 will be delivered for a maximum maintenance time of 3 hours. If the first infusion is tolerated without hypersensitivity-related adverse events, subsequent infusions will be delivered over approximately 1 hour (±10 minutes) for Cohorts 1-5, or 60-70 minutes for Cohorts 6 and 7.

[0421] A subject's first OLE dose (e.g., on day 120 of the treatment regimen) is delivered over approximately 2 hours (±10 minutes). A subject's first OLE dose in Cohort 6 may be delivered for up to a 3-hour maintenance period.

[0422] The initial dose of subjects in the OLE2 phase will be delivered over approximately 2 hours (±10 minutes). All subsequent infusions can be delivered over approximately 1 hour (±10 minutes).

[0423] In the event of a report of an infusion site reaction or similar adverse event, the infusion maintenance time for any infusion may be increased to a maximum of 3 hours.

[0424] End of infusion (EOI) is defined as completing the entire anti-TTR infusion and flushing the entire infusion line.

[0425] An adverse event is defined as any untoward medical occurrence in a subject administered a medicinal product (e.g., an anti-TTR antibody) that does not necessarily have a causal relationship to this treatment. Thus, an adverse event can be any untoward or unintended sign (including abnormal laboratory findings), symptom, or disease (whether medicinal product-related or not) that is associated over time with the use of a medicinal product (e.g., an anti-TTR antibody). An adverse event can be any of the following: ●-New diseases; • worsening of signs or symptoms or underlying disease or comorbidities during treatment; • Unrelated to participation in a clinical trial or the effect of a drug (e.g., anti-TTR antibody) or comparator drug; A combination of one or more of the above factors

[0426] Dose-limiting toxicity The dose-limiting toxicity (DLT) period for safety evaluation is defined as 28 calendar days after the subject's first infusion with the anti-TTR antibody.

[0427] A DLT was defined as an adverse reaction (based on the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (e.g., Table 4)) captured within 28 days of the subject's first dose and meeting any of the criteria defined below.

[0428] DLT includes: 1. Hypersensitivity reactions, including cytokine release syndrome grade 3 or greater; 2. Injection site reaction grade 3 or greater; or 3. New / acute onset of the following symptoms most likely due to cardiac inflammation due to exposure to anti-TTR antibodies: Any of the following: Sinus tachycardia grade 3 or higher ■ Arrhythmia (atrial fibrillation, supraventricular tachycardia) Grade 3 or higher ■Mobitz II Signs and symptoms of myocarditis / cardiac inflammation Grade 3 or higher New onset of acute heart failure Fainting Cardiogenic shock ●Difficulty breathing ■ Significant ECG abnormalities (ST elevation, complete atrioventricular (AV) block, ventricular tachycardia); and Any of the following: a) A sudden decrease in LVEF of more than 10 points from baseline with an absolute value of <40%; and / or b) Increased troponin (100% increase from previous value in the absence of acute renal failure).

[0429] Cardiotoxicity should be assessed in great detail, with particular attention to unexpected and unpredictable findings and / or their severity in the context of the subject's medical history and concomitant medications.

[0430] Any other procedures deemed necessary by the treating physician may be performed to reveal the presence of DLT.

[0431] [Table 6] ADL = activities of daily living; * Instrumental ADLs include preparing meals, shopping for groceries or clothes, using the telephone, and managing money. ** Self-care ADLs refer to bathing, dressing and undressing, self-feeding, using the toilet, taking medication, and not being bedridden.

[0432] Management of infusion-related reactions Below are guidelines for the treatment of infusion-related reactions. Mild reactions (flushing, mild headache, nausea, mild discomfort, mild weakness) ○ Slowly infuse at half the previous speed (maximum infusion time cannot exceed 3 hours) ○ Assess vital signs (blood pressure, pulse rate, oxygen saturation [SpO2]) every 15 minutes ○30-minute observation If the response is dissipating, begin increasing the rate every 15 minutes until the original target rate is reached. If the reaction reoccurs, reduce the injection to the maximum rate previously allowed. If reaction persists or worsens, see moderate reaction below. Moderate reactions (fever, severe headache, wheezing, hives, SpO2 <95%, vomiting) Stop the injection ○ Withdraw 3 mL of blood from the cannula (discard the blood) Connect a new 0.9% NaCl infusion bag to the cannula with new tubing and begin the infusion at a maintenance rate per subject weight according to local guidelines. ○Assess vital signs every 5 minutes (blood pressure, pulse rate, SpO2) If SpO2 < 95%, initiate O2 supplementation (mask or nasal according to patient age and local guidelines) Give diphenhydramine 1 mg / kg body weight IV (or other antihistamine according to hospital practice and recommended doses) Give acetaminophen 500 mg orally for fever or headache (or give other nonsteroidal anti-inflammatory drugs [NSAIDs] according to hospital practice and recommended dosages) Additional medications recommended to be used if necessary (or equivalent / similar medications according to hospital practice and recommended dosages): Hydrocortisone 2mg / kg body weight IV Ondansetron 4mg IV for nausea and vomiting Albuterol 5mg inhalation for wheezing If the reaction dissipates: Wait 30 minutes after giving the IV dose, then resume the infusion at half the rate at which the infusion reaction occurred (maximum total infusion time cannot exceed 3 hours) Increase the rate every 15 minutes (as tolerated) until you reach the original target rate. If the reaction occurs again, repeat the reaction procedure, increasing only to the highest rate previously tolerated. If the reaction persists: Consider the additional medications listed above If the reaction worsens: See "Severe Reactions" section below. Severe reactions (anaphylaxis) Anaphylaxis is a life-threatening medical emergency and should always be managed in accordance with local guidelines and procedures to ensure the quickest, safest, and most efficient resolution of the reaction. The following are general recommendations: Stop the injection ○ Withdraw 3 mL of blood from the cannula (discard the blood) Connect a new 0.9% NaCl infusion bag to the cannula with new tubing and begin the infusion at a maintenance rate per subject weight according to local guidelines. ○Assess vital signs every 5 minutes (blood pressure, pulse rate, SpO2) If SpO2 < 95%, initiate O2 supplementation (mask or nasal according to patient age and local guidelines) Administer epinephrine 0.01 mg / kg body weight (1:1000 dilution or 1 mg / mL, use a maximum of 0.5 mL) intramuscularly. Give diphenhydramine 1 mg / kg body weight IV (or other antihistamine according to hospital practice and recommended doses) Additional medications recommended to be used if necessary (or equivalent / similar medications according to hospital practice and recommended dosages): Hydrocortisone 2mg / kg body weight IV Ondansetron 4 mg IV for nausea and vomiting Albuterol 5mg inhalation for wheezing Acetaminophen 500 mg PO (or other NSAID per hospital practice and recommended dose) for fever or headache Dissipation of the reaction: Do not restart the injection Monitor as medically indicated Reaction persists or worsens: Repeat above medications as needed according to label / hospital practice Continue treatment until reaction resolves, then monitor as medically indicated.

[0433] Pre-injection medication If a subject experiences any type of infusion-related reaction during the study, premedication with an antihistamine (e.g., diphenhydramine) and / or antipyretic (e.g., acetaminophen) and / or corticosteroid (e.g., hydrocortisone 2-4 mg / kg body weight, or equivalent) 30-60 minutes prior to the infusion is recommended. Because the specific medications used may vary by country and institution, this is left to the discretion of the medical professional. As an example, in any subject who previously had even a mild infusion reaction, it is recommended that diphenhydramine and acetaminophen be given prior to the infusion.

[0434] Efficacy evaluation The following efficacy assessments may be performed on this study as exploratory readouts.

[0435] 6-minute walk test The 6-minute walk test (6-MWT) is a submaximal exercise test used to assess walking endurance and aerobic capacity. Subjects walk around a set circuit for a total of 6 minutes. The test score is the distance the subject walks on a flat, hard surface during the 6-minute period (measured in meters, which may be rounded up to the nearest decimal point).

[0436] Kansas City Cardiomyopathy Questionnaire The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire developed to independently measure subjects' perceptions of their health status, including heart failure symptoms, their impact on physical and social functioning, and how heart failure affects their quality of life within a 2-week recall period.

[0437] The KCCQ tool quantifies six different domains and two summary scores: The KCCQ symptom domain quantifies the frequency and burden of clinical symptoms of heart failure, including fatigue, shortness of breath, paroxysmal nocturnal dyspnea, and subjective edema / swelling. A global symptom score is generally used in the analysis. Subscale scores for both frequency and severity are also available. The KCCQ physical function domain measures limitations experienced by subjects due to heart failure symptoms when performing daily activities. Activities are generic, gender-neutral, and generalizable across cultures while also capturing diverse activity requirements. • The KCCQ quality of life domain is designed to reflect the subject's assessment of their quality of life, taking into account their current state of heart failure. • The KCCQ Social Limitations domain quantifies the extent to which HF symptoms impair a subject's ability to interact in a number of gender-neutral social activities. The KCCQ self-efficacy domain quantifies subjects' perceptions of how to prevent heart failure exacerbations and manage complications as they occur. This measure is not included in the summary score. The KCCQ symptom stability domain measures recent changes in a subject's symptoms; whether they be shortness of breath, fatigue, or swelling. It compares the subject's frequency of heart failure symptoms at the time of KCCQ completion to their frequency two weeks prior. As a measure of change, it is best interpreted as a baseline assessment of the subject's symptom stability at study entry and immediately thereafter, and as a measure of acute response to treatment. This domain is not included in the summary score. ●Clinical summary scores include total symptoms and physical function scores to correspond to NYHA classification. • The overall summary score includes scores for total symptoms, physical functioning, social limitations, and quality of life.

[0438] Echocardiography A complete echocardiogram can be performed to record systolic function (strain), thickness and filling pressures, and LVEF. · Left ventricular end-diastolic / end-systolic diameter and systolic function (LVEF according to Simpson), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV); · Left ventricular diastolic function – mitral flow E / A ratio, E / e', maximum left atrial volume or left atrial volume index; Right ventricular function - TAPSE and transtricuspid regurgitation systolic gradient Overall longitudinal distortion; and / or · End-diastolic-interventricular septum (ED-IVS) and end-diastolic-posterior wall (ED-PW).

[0439] Magnetic resonance imaging, bone scintigraphy One of the following assessments can be performed for each subject: Magnetic resonance imaging (MRI) in a subset of subjects, including: o Morphological (e.g., LV mass) and functional assessments (e.g., LV ejection fraction, global longitudinal strain); Native T1 mapping, assessment of extracellular volume after gadolinium administration; and ○T2 (inflammation). Bone scintigraphy using DPD or HMDP in a subset of subjects, including: Cardiac reserve (HR) / whole body reserve (WBR) ratio Heart rate (HR) / skull rate (SR) ratio

[0440] The data from these imaging modalities is sent to a central reading provider for central reading.

[0441] Biomarkers Biomarkers may be assessed pre- and post-infusion at specific time points during the course of the study. Serum samples (approximately 12 mL of blood per sample) may be collected during the study and may be used for analysis of novel biomarkers to identify effects on amyloidosis or other medically relevant conditions, as well as clinical and biological responses to anti-TTR antibodies.

[0442] Biomarkers during the SAD, MAD and OLE stages may include, but are not limited to: Indicators of cardiac function and stress: ○Plasma NT-proBNP Troponin T Acute phase proteins, complement activation and inflammatory markers: C3, C4 and C-reactive protein (CRP) ○IL1b, IL6, IL8, IFNg, TNF-α (pro-inflammatory cytokines) ○IL10, IL1RA (anti-inflammatory cytokines) Serum amyloid A (SAA), ferritin (positive acute phase protein)

[0443] Biomarkers in OLE2 may include, but are not limited to: ATTR circulation level Indicates cardiac function and cardiac stress Plasma NT-proBNP, troponin T or galectin 3 (Gal-3), soluble tumor suppressor 2 (sST2) Cardiac fibrosis biomarkers: Carboxy-terminal propeptide of procollagen type 1 (PICP) Procollagen type III propeptide (PIIINP) Acute phase proteins, complement activation and inflammatory markers: C3, C4 and C-reactive protein (CRP) ○IL1b, IL6, IL8, IFNg, TNF-α (pro-inflammatory cytokines) ○IL10, IL1RA (anti-inflammatory cytokines) Serum amyloid A (SAA), ferritin (positive acute phase protein)

[0444] Immunohistochemistry of tissue samples Immunohistochemistry (IHC) of heart, adipose, or salivary gland biopsies may be performed in a subset of subjects. In OLE2, in the case of salivary gland biopsies, a saliva sample is collected at the time of biopsy.

[0445] Test results The safety and efficacy of the antibody NI006 were evaluated after completing the Phase 1 trial. Primary results were generated after all patients in the highest dose cohort completed the placebo-controlled SAD / MAD phase. Unless otherwise indicated, results are presented for the safety population, i.e., the population including all patients who received at least one dose of study drug (NI006 or placebo). All available data from the OLE phase at the time of analysis data cut were included in the analysis. No formal statistical hypotheses were tested, and imputation was not performed for missing data. For descriptive statistics, patients randomized to NI006 were grouped according to their nominal dose cohort at enrollment, while placebo patients were pooled from all dose cohorts. OLE data were aggregated using the same nominal group allocation, regardless of potential titration. Absolute (ACFB) or relative change from baseline (RCFB) was calculated. For patients who received placebo during the SAD / MAD phase before switching to NI006 treatment during the OLE, the pre-OLE baseline was used to calculate change during the OLE. Kruskal-Wallis tests were used to compare ACFB / RCFB between either the six dose cohorts and placebo, or between the high-dose cohort (10-60 mg / kg), the low-dose cohort (0.3-3 mg / kg), and placebo. Data analysis was performed at a contract testing facility using Statistical Analysis System® (SAS®) version 9.4 (or higher), and plots were generated using the GGplot2 package for R.

[0446] The following results were obtained:

[0447] As described above, 40 patients with wild-type or hereditary ATTR-CM (median age 72 years, 97.5% male), chronic heart failure, and baseline NT-proBNP levels ranging from 766 to 5892 pg / mL were randomized 4:2 to receive intravenous infusions of NI006 or placebo every 4 weeks in six ascending dose cohorts (0.3 to 60 mg / kg). After four double-blind infusions, participants in the open-label expansion phase received eight additional doses of NI006 with stepwise dose escalation.

[0448] 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 of an IgG antibody, and no anti-NI006 antibodies were identified. Data from bone scintigraphy and MRI showed that the 30 mg / kg and 60 mg / kg doses 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, and echocardiographic parameters showed improvement in systolic and diastolic function. Thus, this study is the first to demonstrate that the anti-TTR antibody NI006 can substantially deplete cardiac transthyretin amyloid, accompanied by a reduction in NT-proBNP and signs of improved cardiac function.

[0449] In more detail Patient characteristics In total, 40 participants (median age 72 years, range 28-87 years, 97.5% male), including four replacement participants, were enrolled sequentially at dose levels ranging from 0.3 mg / kg to 60 mg / kg. 27 were randomized to NI006 and 13 to placebo (Table 3). The majority of patients presented with ATTRwt-CM (33 / 40, 82.5%) and were receiving concomitant therapy with tafamidis (36 / 40, 90%). Some degree of polyneuropathy was documented in 15 of the 40 patients (37.5%). According to established markers of ATTR-CM disease severity (NYHA, NAC, and MAYO stages), patients with mild to advanced disease status were enrolled, with a trend toward a greater number of progressive patients randomized to NI006 than to placebo (Table 3). Otherwise, baseline parameters were well balanced between the different NI006 dose cohorts and placebo, including echocardiographic parameters and baseline amyloid burden estimates on scintigraphy and cMRI.Study adherence was high: 85% of patients (34 / 40, including replacement patients) received all four planned placebo-controlled doses in the SAD / MAD phase, and 97% (34 / 35) of eligible patients enrolled in the OLE phase after completing SAD / MAD.

[0450] Safety and tolerability of NI006 The primary objective of the study 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 investigating both clinically relevant treatment-emergent adverse events (AEs) reported by investigators and by assessing changes in safety markers, including orthogonal echocardiograms, close ECG monitoring during dosing and hospitalization, and laboratory safety parameters measured locally at the study site. Blinded safety data were continuously monitored by both the investigator and sponsor and reviewed by a Data Evaluation Committee (DEC).

[0451] Results indicated that NI006 was generally safe and well tolerated up to the highest dose level tested. Patients did not experience dose-limiting toxicities, and no serious AEs (SAEs) considered related to NI006 occurred (i.e., no serious adverse reactions). Most patients experienced one or more AEs (38 / 40, 95%) during the SAD / MAD phase, the majority of which were mild to moderate in intensity (CTCAE Grade 1 and 2, 64.9% and 31.4%, respectively), and there was no dose-dependence in the overall incidence of non-serious AEs or SAEs (see Tables 5 and 6). Two patients (one in one placebo, 3 mg / kg cohort) were reported to have died during the OLE phase, both due to progression of amyloidosis (see Table 7).

[0452] As expected in this patient population, cardiac disorders, particularly heart failure and arrhythmia events, were numerically the most frequently observed system organ class (SOC) for AEs.

[0453] The frequency and type of these AEs were similar across dose cohorts, with no trend toward a dose-dependent increase in event severity (see Tables 6 and 8). A non-serious AE of cytokine release syndrome, accompanied by an associated increase in cardiac biomarkers, was reported in three patients in the 10 mg / kg and 30 mg / kg cohorts during the SAD / MAD phase. All three patients continued dosing throughout the SAD / MAD and OLE phases without recurrence of the AE. A trend toward a dose-dependent increase in the incidence of musculoskeletal events, consisting primarily of arthralgia and arthritis events, was observed with dose escalation in the SAD / MAD phase and in patients switching from placebo in the OLE phase (see Table 7). The majority of these events were grade 1 to grade 2 in intensity and did not result in a discontinuation. Two subjects experienced a transient, asymptomatic decrease in platelet count, one of whom discontinued treatment due to a non-serious grade 3 event of thrombocytopenia. No infusion reactions (IRs) or other clinically significant or changes from baseline in safety laboratory parameters, vital signs, or ECG parameters were observed.

[0454] [Table 7] Numbers represent n of patients (% in group) and [n of events]. * Subjects will be counted only once at the highest CTCAE grade.

[0455] [Table 8]

[0456] [Table 9] Numbers represent n of patients (% in group) and [n of events]. * Subjects will be counted only once at the highest CTCAE grade.

[0457] [Table 10]

[0458] PK and immunogenicity profile Serum NI006 concentrations were measured continuously throughout the study in all patients using a validated assay. Individual total serum NI006 exposure was calculated as the area under the curve (AUC) from simulated PK profiles using individual parameter estimates. Monitoring for the development of anti-drug antibodies was performed throughout the study. For immunogenicity analysis, the presence of potential anti-drug antibodies was assessed using biotinylated and sulfo-tagged NI006 as the detection reagent in an electrochemiluminescence immunoassay validated by QPS (The Netherlands). For PK analysis, serum NI006 concentrations were measured using a validated sandwich ELISA assay constructed based on two anti-idiotypic Fab fragments that selectively bind to NI006. The lower limit of assay quantitation (LLOQ) was 0.17 μg / mL. Noncompartmental analysis (NCA) was performed by Nuventra (Durham, NC, USA) on serum NI006 concentration versus time data for calculation of standard PK parameters. A validated installation of Phoenix WinNonlin version 8.2.2 utilized an intravenous (IV) infusion model using actual blood sampling times and dose levels. Population PK modeling was performed by LYO-X (Switzerland) using a two-compartment model with linear antibody clearance from the central compartment and antibody binding to its target ATTR and elimination of the NI006:ATTR complex in the peripheral compartment. Population PK parameters were estimated using a stochastic approximation of expectation maximization (SAEM) algorithm implemented in Monolix. At 4 and 12 months, patients' individual total serum NI006 exposure was calculated from the simulated PK profiles using individual parameter estimates and the linear trapezoidal rule.

[0459] The pharmacokinetic profile of NI006 was shown to be typical of human IgG with low to moderate intersubject variability: after a single IV dose, serum NI006 concentrations declined biphasically, with an elimination half-life ranging from 15.5 to 19.2 days. Exposure, as measured by Cmax and AUC, increased dose-proportionally with increasing dose. There was gradual dose-dependent drug accumulation that reached a stable level after repeated doses q4w. No patients developed anti-drug antibodies (ADAs) throughout the study, including OLE.

[0460] Amyloid depletion Amyloid depletion was measured by scintigraphy and cardiac magnetic resonance imaging (MRI). Specifically, for cardiac amyloid imaging, all enrolled patients underwent either serial scintigraphy or cardiac MRI. The choice of imaging modality was independently selected by the investigator for each patient, allowing for adjustments at the study site for both individual patient characteristics (e.g., claustrophobia may interfere with MRI) and regional standards. For both imaging modalities, acquisition was performed according to harmonized protocols across study sites, and analysis was performed at a central imaging core laboratory by two independent blinded readers. For planar scintigraphy, the effect of NI006 on cardiac amyloid burden was estimated using the change in cardiac tracer retention relative to whole-body retention (cardiac / whole-body retention ratio, H / WBR ratio). Correspondingly, contrast-enhanced cardiac MRI was used to estimate the treatment effect of NI006 by changes in the amount of extracellular volume (ECV) in the left ventricle. Relative changes at 4 and 12 months were calculated separately for scintigraphy and MRI imaging, and across results from both imaging modalities.

[0461] Cardiac MRI was recorded using a local scanner at the study site. The acquisition protocol was based on the most recent guidelines [1-3] and was standardized at all sites during the trial preparation phase, and adherence to the laboratory manual was continuously monitored. MRI scans were interpreted by two independent readers (expert radiologists or cardiologists) at the imaging core laboratory using Medis software (Medis, Leiden, The Netherlands). All MRIs were analyzed independently. The central reader was blinded not only to treatment assignment, but also to patient identifiers, dose cohorts, and acquisition time points. MRI acquisition and analysis procedures were similar to those described by Martinez-Naharro et al. (PMID 28728692): T1 and ECV measurements were performed before and after contrast administration, defining the entire left ventricular myocardium at the basal and midventricular levels as the region of interest. T1 measurements of both the ventricular myocardium and blood were performed in the short-axis view. Information on hematocrit was available. ECV was calculated according to the following formula:

[0462]

number

[0463] A consensus reading was performed when the discrepancy between both readers exceeded a predetermined range of ±10% of the critical parameter.

[0464] as tracers according to the harmonized acquisition protocol established in the laboratory manual during the test setup. 99m Tc-hydroxyl-methylene-diphosphonate (HMDP) or 99mBone scintigraphy was acquired at the test site using Tc-3,3-diphosphono-1,2-propanedicarboxylic acid (DPD). Adherence to the laboratory manual and image quality were continuously monitored. Planar whole-body images were acquired 3 hours after tracer injection. The acquired images were read centrally at the imaging core lab by two independent nuclear physicians using Syngovia software (Siemens). To calculate the heart / whole-body retention ratio (H / WB ratio), areas with potentially high tracer retention (e.g., bladder, kidneys, injection site) were considered as rejection zones using the following formula:

[0465]

number

[0466] Treatment with NI006 was shown to substantially reduce cardiac ATTR amyloid deposition in patients with ATTR-CM, as measured by both scintigraphy and cMRI, compared with baseline as early as 4 months (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 an increase in cardiac amyloid deposition after 4 months and a decrease in amyloid burden after switching to NI006 for 8 months of OLE treatment. Pooled data from both imaging techniques showed 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% compared with baseline at 4 months. After 8 months of further treatment with OLE, including several dose escalations from 10 mg / kg to 30 mg / kg and 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. Relative changes from baseline were significantly different between the low-dose cohort (0.3-3 mg / kg), the high-dose cohort (10-60 mg / kg), and placebo for both scintigraphy (p=0.011) and MRI (p=0.016) at 4 months. Higher total NI006 exposure, simulated from individual PK profiles to account for unplanned treatment interruptions (e.g., pandemic-related) and individual titration schedules during OLE, correlated with higher cardiac amyloid reductions at 4 months (r = -0.673) and 12 months (r = -0.651) across both imaging modalities (Figure 5B). Data from the placebo switch were consistent with and confirmed these observations (Figure 6).

[0467] Effects on cardiac biomarkers and echocardiographic parameters Echocardiograms were used to assess changes in cardiac structure and function using the plasma biomarkers NT-proBNP and troponin-T. Furthermore, even though the study was unpowered, global functional capacity and quality of life were assessed 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 acquired at three time points throughout the study: complete echocardiograms for efficacy analysis were recorded at baseline before the first treatment, after completion of the MAD (4 months), and after completion of the OLE (12 months). A uniform acquisition protocol was applied at all sites, and analyses were performed centrally by experienced cardiologists at an imaging core laboratory (Biotrial, Rennes, France), demonstrating low intra-reader variability and blinded to pseudonymized patient IDs, treatment assignment, dose cohort, and acquisition time point. Measurements were performed in triplicate (sinus rhythm) or quintuplet (atrial fibrillation) using EchoPAC CE Medical software (GE Healthcare, Milwaukee, MI, USA), and the mean of the triplicate / quintuplet values ​​was used for further analysis. If the recording did not allow for measurement of individual parameters (e.g., low echogenicity, insufficient number of recorded loops, suboptimal sections), the measurement was reported as missing.

[0468] In addition, before each of the first five treatment doses and before discharge, a nonstandardized orientation echocardiogram was performed by the investigator or co-investigator according to local practice to rule out a sudden deterioration in systolic left ventricular function or the occurrence of a pericardial effusion.

[0469] Plasma biomarkers of cardiac stress and function, NT-proBNP and troponin-T, were shown to decrease compared with baseline in most patients at 12 months (Figure 7A). NI006 reduced NT-proBNP in a dose- and time-dependent manner. The greatest reduction in cardiac amyloid burden was observed in the 30 mg / kg and 60 mg / kg cohorts, with median relative reductions from baseline in NT-proBNP 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, below the inclusion threshold for this study. Similarly, troponin-T showed a greater decrease from baseline with higher total NI006 exposure.

[0470] Patients in the two dose cohorts with the highest amyloid clearance, 30 mg / kg and 60 mg / kg, also showed signs of treatment benefit at 12 months in echocardiographic parameters of cardiac structure, systolic function, and diastolic function (Figure 7B): decreases in left ventricular wall thickness (median 1 mm decrease in ED-IVS in both dose cohorts), increases in LVEF (median absolute increases of 12% and 6%, respectively), which appeared to be driven primarily by decreases in end-systolic volume (LVESV), decreases in left atrial volume (median decreases of 9 and 28 mL), and decreases in the E / e' ratio (median absolute changes of -7.6 and -4.7).

[0471] Overview and Discussion NI006 is useful for treating transthyretin amyloidosis with cardiomyopathy, regardless of underlying genotype. In patients with a confirmed ATTR-CM diagnosis, this first-in-human study demonstrated that intravenous administration of NI006 every 4 weeks for 12 months was generally safe and well-tolerated up to the highest dose tested. As determined by two different proxies of cardiac amyloid burden, bone scintigraphy and cardiac MRI, NI006 depleted amyloid transthyretin from cardiac tissue in a dose- and time-dependent manner, with the most pronounced effect at doses above 10 mg / kg q4w. Echocardiographic and laboratory parameters indicative of disease status in ATTR-CM patients showed signs of improvement in the highest-dose cohort.

[0472] The good tolerability of NI006 and the absence of infusion reactions and dose-limiting toxicities may be due to the human origin of its amino acid sequence and its exceptional selectivity for misfolded amyloid transthyretin protein without binding to physiological TTR tetramers. Some adverse events, including transient cytokine release and reported cases of joint pain after the initial dose, may be related to NI006's activation of phagocytic immune cells when it binds to its target.

[0473] Disease-stabilizing therapies, including TTR tetramer stabilization with tafamidis or acoramidis, or silencing of TTR gene expression, are expected to slow the accumulation of new ATTR amyloid deposits but, conceptually, do not work to clear existing ATTR amyloid deposits. Published data from clinical trials and real-world settings indicate that disease-stabilizing therapies can improve amyloid burden on imaging proxies compared with untreated populations (Chamling et al., Clin Res Cardiol. 112 (2023), 353-62; Fontana et al., JACC Cardiovasc Imaging. 14 (2021), 189-99), but substantial improvement compared with baseline is rare (Wu et al., ESC Heart Fail. 9 (2022), 4335-4339). In this study, tafamidis-treated patients achieved a median overall H / WB ratio of 5.0% and a median ECV of 1.0%. Patients presented with advanced cardiac amyloid deposition at 59.8%, a cutoff associated with increased mortality, and further progression of amyloid deposition (median RCFB +6.1% across both imaging modalities) after 4 months of placebo treatment, demonstrating the urgent need for the development of novel therapies capable of reversing this disease pathology (Figure 5). In this patient population, treatment with NI006-deficient cardiac ATTR amyloid deposits was dose- and time-dependent. For the first time, therapeutic intervention resulted in substantial and sustained amyloid depletion, as evidenced by complementary imaging techniques. In some patients, near-complete clearance of cardiac amyloid was achieved during the treatment period and as early as 4 months. The H / WB ratio of scintigraphic tracer uptake could be reduced to values ​​approaching 2.0% after 12 months of treatment, a threshold observed in heart failure (HF) patients without amyloidosis (Galat et al., J Nucl Cardiol. 22 (2015) 853-857) or ECV of approximately 40% after 12 months (this may also indicate near-complete clearance of cardiac ATTR amyloid, a threshold associated with improved prognosis (Schelbert et al., JACC Cardiovasc Imaging. 12 (2019), 2305-2318)).These findings demonstrate the ability of NI006 to induce degradation of transthyretin amyloid by recruitment of phagocytes via Fc effector function and further support preclinical data that are mechanistically similar to the antibodies aducanumab, lecanemab, and donanemab for amyloid beta depletion in Alzheimer's disease.

[0474] In ATTR-CM, NT-pro-BNP is associated with mortality in patients with cardiac amyloidosis when assessed at diagnosis or serially as a change from baseline (see, for example, Kristen et al., PLoS One. 12 (2017), e0173086). Treatment with NI006 reduces NT-proBNP compared to baseline in a dose- and time-dependent manner, whereas treatment with tafamidis predicts an increase (Nativi-Nicolau et al., ESC Heart Fail. 8 (2021), 3875-3884; Rapezzi et al., JACC Heart Fail. 9 (2021), 115-123). Patients treated with 30 mg / kg or 60 mg / kg over 12 months had a median relative reduction in NT-proBNP of over 72% compared to baseline, with a median NT-proBNP reduction of 420 ng / L, and echocardiographic changes suggestive of improved systolic and diastolic function over several months. These findings indicate possible downstream clinical benefit of amyloid clearance in patients with ATTR-CM treated with NI006.

[0475] In conclusion, this study is the first to demonstrate that substantial depletion of cardiac transthyretin amyloid, the primary disease...

Claims

1. 1. An anti-transthyretin (TTR) antibody for use in a method of treating transthyretin-mediated amyloidosis (ATTR) in a subject in need thereof, the method comprising administering the antibody to: (a) a patient weighing 40 kg or more (≧40 kg) but less than 60 kg (<60 kg) at a dose of 2000 mg to 2500 mg; (b) a patient weighing 60 kg or more (≧60 kg) but less than 100 kg (<100 kg) at a dose of 3000 mg to 3500 mg; or (c) a patient weighing 100 kg or more (≧100 kg) at a dose of 4000 mg to 5000 mg; 1. An anti-transthyretin (TTR) antibody for use in a method of treating transthyretin-mediated amyloidosis (ATTR) in a subject in need of treatment, wherein the antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 1-3, and light chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 4-6, respectively; and the anti-TTR antibody comprises a heavy chain variable region comprising at least 80% sequence identity with SEQ ID NOS: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with SEQ ID NOS:

8.

2. 2. The antibody for use according to claim 1, wherein the antibody is administered at a dose of 2400 mg to a patient weighing ≥ 40 kg but less than 60 kg; (b) at a dose of 3200 mg to a patient weighing ≥ 60 kg but less than 100 kg; or (c) at a dose of 4800 mg to a patient weighing ≥ 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, comprising a human IgG constant region, preferably comprising a human IgG1 constant region comprising an antibody heavy chain constant region of the human IgG1m3 allotype.

5. 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, each heavy chain comprising 450 amino acid residues comprising the sequence of SEQ ID NO: 9, and each light chain comprising 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

6. 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, each heavy chain comprising 449 amino acid residues comprising the sequence of SEQ ID NO: 13, and each light chain comprising 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

7. 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, each heavy chain comprising 449 amino acid residues comprising the sequence of SEQ ID NO: 14, and each light chain comprising 214 amino acid residues comprising the sequence of SEQ ID NO:

10.

8. 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, each heavy chain comprising 448 amino acid residues comprising the sequence of SEQ ID NO: 15, and each light chain comprising 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 said antibody is a recombinant antibody produced in Chinese Hamster Ovary (CHO) cells, preferably said 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 comprising pyroglutamic acid (pyroQ).

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 clipped C-terminal lysine.

13. The antibody for use according to any one of claims 1 to 12, wherein the antibody is N-glycosylated, preferably the N-linked glycan is on 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 above 2000 pg / mL.

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

16. 16. The antibody for use according to claim 14 or 15, wherein the subject is an adult human subject, preferably a subject aged 18 to 90 years (18 to 90 years).

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

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

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

20. The treatment comprises: (a) reducing NT-proBNP levels in said subject compared to baseline; (b) reducing the rate of heart failure (HF) events; (c) reducing the incidence of augmentation of oral diuretic therapy, possibly including outpatient augmentation of oral diuretic therapy; (d) reducing the incidence of changes in disease-modifying therapy; (e) reducing the incidence of hospitalization for atrial fibrillation; (f) induce change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score over 24 months of study treatment; (g) induce a change from baseline in the 6-minute walk test (6MWT) over 24 months of study treatment; (h) derive change from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia stages and NYHA classification; (i) induce change from baseline in GLS; (j) induce change from baseline in stroke volume; (k) deriving the change from baseline in the echocardiographic parameter of interest; (l) induce change from baseline in hs-cTnT; (m) induce changes from baseline in DPD / PYP / HMDP cardiac scintigraphy cardiac uptake and / or cMRI-derived ECV, T1 and T2 mapping; (n) Induce change from baseline in eGFR (o) induce a change from baseline in EQ-5D-5L scores and / or induce a change from baseline in SF-36 scores; (p) inducing a change from baseline in a marker selected from CRP, IL IL1b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin, preferably CRP; (q) inducing a change from baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6; (r) induce a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4; (s) Induce change from baseline in (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or (3) sNFL level; (t) Induce a change from baseline in the NIS and / or induce a change in the NC test; The antibody for use according to any one of claims 14 to 19, having at least one of the following effects:

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

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

23. 23. The antibody for use of any one of claims 1-22, wherein the anti-FAP antibody is administered in a flat dose, weight-blended, based on the patient's recorded weight, said recording being made within 30 days of a scheduled dose, and the dose is administered intravenously (IV) by infusion every four weeks (q4w).

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

25. 25. The antibody for use of claim 24, wherein the clearance of ATTR fibrils by the anti-ATTR antibody treatment is measured by quantification of ECV by cardiac tracer uptake scintigraphy or cMRI.

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

27. The patient: (1) Evidence of cardiac amyloidosis by echocardiography or cMRI and the following: a. Endomyocardial biopsy with confirmatory TTR amyloid typing by either 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 monoclonal gammopathy; or c. Confirmatory TTR amyloid typing by either immunohistochemistry or mass spectrometry in non-cardiac tissues in the presence of grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and monoclonal hypergammaglobulinemia. have a centrally confirmed diagnosis of ATTR-CM with either a wild-type TTR genotype or a mutant TTR genotype based on one of the following: (2) willingness to be genetically tested for mutations in the TTR gene during screening if genetic testing has not been previously performed or genetic results are not available; (3) End-diastolic ventricular septal wall thickness of 11 mm or more in women and 12 mm or more in men measured by echocardiography at screening. (4) have NT-proBNP >2000 pg / mL as measured by a central laboratory at screening; (5) receiving treatment with loop diuretics for at least 30 days prior to screening; (6) The following events within one year prior to screening: a. Heart failure hospitalization b. Emergency heart failure visit c. Episodes of volume overload documented by NT-proBNP >2000 pg / mL (or equivalent BNP) have a history of heart failure as evidenced by one of the following: (7) New York Heart Association (NYHA) classification class II to IV at screening, and / or (8) have a life expectancy of at least 6 months according to a clinician's judgment; 25. The antibody for use according to claim 24, which is male or female.

28. 28. The antibody for use of any one of claims 1 to 27, wherein the anti-FTP antibody is NI006 / ALXN2220 administered in a pharmaceutical formulation of 50 mg / mL in 20 mM histidine buffer, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80, pH 5.

8.

29. 29. The antibody for use of any one of claims 1 to 28, wherein the anti-FTP antibody is NI006 / ALXN2220 and is administered in the patient as an intravenous (IV) infusion over 2 hours for the first dose and over 1 hour for each subsequent dose.

30. 30. The antibody for use according to any one of claims 1 to 29, wherein the patient is being 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. 31. The antibody for use of any one of claims 1 to 30, wherein the anti-FAT antibody is administered according to the intervention infusion schedule provided in Table 25 for up to 24 months.

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

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

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

35. 35. The antibody for use according to any one of claims 1 to 34, wherein the therapeutic efficacy is measured using endomyocardial biopsies including intra-epidermal nerve fibre density (IENFD) and / or sweat gland nerve fibre density (SGNFD).

36. Serum biomarker levels are monitored before and after treatment with the anti-FTR antibody, and the biomarkers are selected from (a) complement factors selected from C3 and C4 together with CRP; (b) pro-inflammatory cytokines selected from IL1b, IL6, IL8, IFNg, and TNF-α; (c) anti-inflammatory cytokines selected from IL10 and 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. The antibody for use according to any one of claims 1 to 35, selected from:

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

38. A method of treating ATTR in a human subject in need thereof, comprising administering to the human subject an anti-transthyretin (TTR) antibody comprising a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs 1-3 whose sequences are set forth in SEQ ID NOS: 1-3 and light chain CDRs 1-3 whose sequences are set forth in SEQ ID NOS: 4-6, respectively, wherein the anti-TTR antibody comprises a heavy chain variable region having at least 80% sequence identity to SEQ ID NOS: 7 and a light chain variable region having at least 80% sequence identity to SEQ ID NOS:

8. and a light chain variable region comprising the amino acid sequence, wherein the antibody is administered to (a) a patient weighing 40 kg or more (≧40 kg) but less than 60 kg (<60 kg) at a dose of 2000 mg to 2500 mg; (b) a patient weighing 60 kg or more (≧60 kg) but less than 100 kg (<100 kg) at a dose of 3000 mg to 3500 mg; or (c) a patient weighing 100 kg or more (≧100 kg) at a dose of 4000 mg to 5000 mg.

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

40. 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 a human IgG, preferably wherein the antibody comprises a human IgG1 comprising an antibody heavy chain constant region of the human IgG1m3 allotype.

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

10.

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

10.

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

10.

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

10.

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

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

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

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

52. 52. The method of claim 50 or 51, wherein the subject is an adult human subject, preferably a subject aged 18 years or older and less than 90 years ((18 years or older and less than 90 years)).

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

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

55. The treatment comprises: (a) symptoms, functionality, and health-related quality of life (QoL) measured by change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score; (b) time to cardiovascular (CV)-related death; (c) 6-minute walk test (6MWT) score compared with baseline; (d) rate of cardiovascular (CV) clinical events; (e) Time to all-cause mortality (ACM) The method according to any one of claims 50 to 54, wherein at least one of the following is improved:

56. The treatment has the following effects: (a) reducing NT-proBNP levels in said subject compared to baseline; (b) reducing the rate of heart failure (HF) events; (c) reducing the incidence of augmentation of oral diuretic therapy, possibly including outpatient augmentation of oral diuretic therapy; (d) reducing the incidence of changes in disease-modifying therapy; (e) reducing the incidence of hospitalization for atrial fibrillation; (f) induce change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score over 24 months of study treatment; (g) induce a change from baseline in the 6-minute walk test (6MWT) over 24 months of study treatment; (h) derive change from baseline in ATTR-CM disease severity based on Mayo, NAC, and Columbia stages and NYHA classification; (i) induce change from baseline in GLS; (j) induce change from baseline in stroke volume; (k) deriving the change from baseline in the echocardiographic parameter of interest; (l) induce change from baseline in hs-cTnT; (m) induce changes from baseline in DPD / PYP / HMDP cardiac scintigraphy cardiac uptake and / or cMRI-derived ECV, T1 and T2 mapping; (n) Induce change from baseline in eGFR (o) induce a change from baseline in EQ-5D-5L scores and / or induce a change from baseline in SF-36 scores; (p) inducing a change from baseline in a marker selected from CRP, IL IL1b, IL6, IL8, IFNg, TNF-α, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin, preferably CRP; (q) inducing a change from baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6; (r) induce a change from baseline in a marker selected from TTR (prealbumin), TSH, RBP, and fT4; (s) Induce change from baseline in (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and / or (3) sNFL level; (t) Induce a change from baseline in the NIS and / or induce a change in the NC test; The method according to any one of claims 50 to 55, comprising at least one of:

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

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

59. 59. The method of any one of claims 38-58, wherein the anti-FAP antibody is administered in a flat dose, weight-blended, based on the patient's recorded weight, said recording occurring within 30 days of a scheduled dose, and wherein the dose is administered intravenously (IV) by infusion every four weeks (q4w).

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

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

62. 61. The method of claim 60, wherein treatment of the patient with the anti-FTR antibody results in a dose- and time-dependent reduction in 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 patient: (1) Evidence of cardiac amyloidosis by echocardiography or cMRI and the following: a. Endomyocardial biopsy with confirmatory TTR amyloid typing by either 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 monoclonal gammopathy; or c. Confirmatory TTR amyloid typing by either immunohistochemistry or mass spectrometry in non-cardiac tissues in the presence of grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) and monoclonal hypergammaglobulinemia. have a centrally confirmed diagnosis of ATTR-CM with either a wild-type TTR genotype or a mutant TTR genotype based on one of the following: (2) willingness to be genetically tested for mutations in the TTR gene during screening if genetic testing has not been previously performed or genetic results are not available; (3) End-diastolic ventricular septal wall thickness of 11 mm or more in women and 12 mm or more in men measured by echocardiography at screening. (4) have NT-proBNP >2000 pg / mL as measured by a central laboratory at screening; (5) receiving treatment with loop diuretics for at least 30 days prior to screening; (6) The following events within one year prior to screening: a. Heart failure hospitalization b. Emergency heart failure visit c. Episodes of volume overload documented by NT-proBNP >2000 pg / mL (or equivalent BNP) have a history of heart failure as evidenced by one of the following: (7) New York Heart Association (NYHA) classification class II to IV at screening, and / or (8) have a life expectancy of at least 6 months according to a clinician's judgment; 61. The method of claim 60, wherein the subject is male or female.

64. 64. The method of claims 38-63, wherein the anti-FTP antibody is NI006 / ALXN2220 administered in a pharmaceutical formulation of 50 mg / mL in 20 mM histidine buffer, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80, pH 5.

8.

65. 65. The method of claims 38-64, wherein the anti-FATTR antibody is NI006 / ALXN2220, which is administered in the patient as an intravenous (IV) infusion over two hours for the first dose and over one hour for each subsequent dose.

66. 66. The method of any one of claims 38 to 65, wherein the patient is being 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.

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

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

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

70. The patient: (1) Prior treatment with a disease-modifying agent, wherein the disease-modifying agent is: (a) a TTR silencer, optionally together with a TTR stabilizer; (b) a TTR stabilizer alone; and (c) no TTR stabilizer or TTR silencer treatment; (2) prior treatment with a disease-modifying agent selected from the group consisting of ATTR genotypes including ATTR mutant (ATTRv) and ATTR wild-type (ATTRwt); or (3) disease severity based on cardiac biomarker levels, including NT-proBNP >3000 pg / mL vs. NT-proBNP <=3000 pg / mL, optionally along with pre- and post-treatment high-sensitivity cardiac troponin C (hs-cTnT) levels; The method of any one of claims 38 to 69, wherein the method is stratified based on:

71. 71. The method of any one of claims 38 to 70, wherein the therapeutic efficacy is measured using endomyocardial biopsies including intra-epidermal nerve fiber density (IENFD) and / or sweat gland nerve fiber density (SGNFD).

72. Serum biomarker levels are monitored before and after treatment with the anti-FTR antibody, and the biomarkers are selected from (a) complement factors selected from C3 and C4 and CRP; (b) pro-inflammatory cytokines selected from IL1b, IL6, IL8, IFNg, and TNF-α; (c) anti-inflammatory cytokines selected from IL10 and 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.

72. The method of any one of claims 38 to 71, wherein the method is selected from:

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

74. 1. An anti-FTR antibody comprising a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 1-3, respectively, and light chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 4-6, in the manufacture of a medicament for treating transthyretin-mediated amyloidosis (ATTR) in a subject in need of such treatment, wherein the anti-FTR antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 1-3, respectively, and light chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 4-6, and a light chain variable region comprising an amino acid sequence having sequence identity to:

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

76. The use according to claim 74 or 75, wherein the antibody is an antibody according to any one of claims 1 to 75.

77. 77. The use according to any one of claims 74 to 76, wherein the subject is a subject according to any one of claims 1 to 76.

78. 78. The use according to any one of claims 74 to 77, wherein the administration of the antibody is carried out as defined in any one of claims 74 to 77.

79. The use according to any one of claims 74 to 78, wherein the treatment is carried out by a method according to any one of claims 1 to 78.

80. 80. A therapeutic kit comprising: (i) one or more containers containing a formulation of an anti-FTP antibody in an amount of 2400 mg, 3200 mg or 4800 mg, or multiple doses of any one of them; and (ii) means for delivery of said antibody to a human, optionally comprising an infusion bag and / or a syringe, wherein said antibody comprises a heavy chain variable region comprising complementarity determining regions (CDRs) comprising heavy chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 1-3, and light chain CDRs 1-3, the sequences of which are set forth in SEQ ID NOS: 4-6, respectively; said anti-FTP antibody comprising a heavy chain variable region comprising at least 80% sequence identity with SEQ ID NOS: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with SEQ ID NOS: 8; and preferably wherein said antibody is as defined in any one of claims 1-79.

81. 1. A therapeutic kit comprising: (i) one or more containers containing a formulation of an anti-FTP antibody in an amount of 2400 mg, 3200 mg, or 4800 mg, or multiple doses of any one of them; and (ii) a means for delivering the antibody to a human, the means optionally comprising an infusion bag and / or a syringe, and the anti-FTP antibody is antibody NI006 / ALXN2220.

82. 1. An article of manufacture comprising one or more containers containing (i) a formulation of an anti-FATTR antibody in a total amount of 2400 mg, 3200 mg, or 4800 mg, or multiple doses of any one thereof; and (ii) a leaflet specifying that the antibody is to be administered once every four weeks at a dose of 2400 mg to a subject weighing 40 kg to 60 kg or less, at a dose of 3200 mg to a subject weighing 360 kg to 100 kg, or at a dose of 4800 mg to a subject weighing 100 kg or less, wherein the antibody is 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, and wherein the antibody is according to any one of claims 1 to 81.

83. 1. An article of manufacture comprising one or more containers containing (i) a formulation of an anti-FTR antibody in a total amount of 2400 mg, 3200 mg, or 4800 mg, or multiple doses of any one thereof; and (ii) a leaflet providing that the antibody is to be administered once every four weeks at a dose of 2400 mg to a subject weighing 40 kg to 60 kg or less, at a dose of 3200 mg to a subject weighing 360 kg to 100 kg, or at a dose of 4800 mg to a subject weighing ≦100 kg, wherein the anti-FTR antibody is antibody NI006 / ALXN2220.

84. 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-derived immunoglobulin gamma 1 (IgG1) monoclonal antibody that specifically recognizes aggregated wild-type and mutant forms of FTP, and is expressed in a Chinese hamster ovary cell line, preferably a CHO-K1 cell line.

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

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

87. 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 at pH 5.8, 80 mg / mL sucrose, 0.3 mg / mL polysorbate 80.

88. 88. The article of manufacture of any one of claims 82-87, wherein the recommended dose of ALXN2220 / NI006 on the label is 2400 mg for patients weighing 40 kg or greater but less than 60 kg, 3200 mg for patients weighing 60 kg or greater but less than 100 kg, and 4800 mg for patients weighing 100 kg or greater, which must be diluted and then administered as an intravenous infusion over about 1 to 2 hours once every four weeks.

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

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

91. 1. A method of treating ATTR, comprising administering to a human subject a human anti-FAT antibody, preferably as defined in any one of claims 1 to 90, at a dose providing about 30 mg / kg or 60 mg / kg to the subject, preferably once every 28 days.

92. 92. The method of claim 91, wherein the method is performed according to any one of items [112] to [213].

93. The embodiment according to any one of items [1] to [249].

Images