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WO2024240562A1 - Nouvelle immunothérapie pour troubles et états musculo-squelettiques - Google Patents

Nouvelle immunothérapie pour troubles et états musculo-squelettiques Download PDF

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WO2024240562A1
WO2024240562A1 PCT/EP2024/063351 EP2024063351W WO2024240562A1 WO 2024240562 A1 WO2024240562 A1 WO 2024240562A1 EP 2024063351 W EP2024063351 W EP 2024063351W WO 2024240562 A1 WO2024240562 A1 WO 2024240562A1
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antibody
seq
amino acid
ttr
positions
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PCT/EP2024/063351
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Peter Kahr
Aubin MICHALON
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Neurimmune Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the present invention generally relates to a novel immunotherapy for a musculoskeletal disorder or condition in a subject.
  • Musculoskeletal conditions are the leading contributor to disability worldwide with approximately 1.71 billion people suffering from these conditions worldwide. Musculoskeletal impairments comprise more than 150 different diseases/conditions that affect the system and are characterized by impairments in the muscles, bones, joints and adjacent connective tissues leading to temporary or lifelong limitations in functioning and participation. Musculoskeletal conditions are typically characterized by pain (often persistent) and limitations in mobility and dexterity, reducing people’s ability to work and participate in society; see publication of the World Health Organization, "Musculoskeletal health" of July 14, 2022. Forms of arthritis make up the majority of musculoskeletal disorders, with injuries, systemic autoimmune diseases, unspecified chronic widespread pain disorders and lower back and neck pain making up the rest.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs disease-modifying antirheumatic drugs
  • the present invention is based on the surprising finding that administration of an anti-TTR antibody to patients having amyloid transthyretin cardiomyopathy (ATTR-CM) led to clearance of deposits present in the joints of the treated patients.
  • ARR-CM amyloid transthyretin cardiomyopathy
  • the present invention generally relates to anti-TTR antibodies for use in the treatment and prevention of a musculoskeletal condition or disorder, wherein the disorder or conditions is preferably a disorder or condition that affects the joints and more preferably, a disorder or condition associated with pathological deposits in the joints.
  • the anti-TTR antibody is preferably administered at a dose of at least 30 mg/kg once very 28 days and preferably at a dose of about 30 mg/kg or 60 mg/kg once every 28 days.
  • the anti-TTR antibody specifically recognizes misfolded mutated and wild-type TTR and targets with high affinity the disease-associated amyloid conformation but not physiological forms of TTR, /. ⁇ ., not the wild type TTR tetramer.
  • the antibody does also not bind wild type TTR monomers and dimers.
  • Anti-TTR antibodies have been described for example in WO 2015/092077 Al and shown to be useful in the treatment of transthyretin amyloidosis (ATTR) and in particular in the treatment of amyloid transthyretin cardiomyopathy (ATTR-CM); see EP 22 207 651.5 and EP 23 020 175.8.
  • ATTR includes two sub-types - wild-type ATTR (wtATTR) and variant ATTR (vATTR) - that vary regarding their pathogenesis.
  • wtATTR wild-type ATTR
  • vATTR variant ATTR
  • TTR common precursor protein transthyretin
  • TTR physiologically functions as a transport protein for thyroxin and retinol-binding protein.
  • TTR is predominantly synthesized in the liver and occurs as a tetramer in its natural form (Alshehri etal., J. Neuroendocrinol. 27 (2015), 303-3239).
  • vATTR formerly known as hereditary/mutant ATTR, is an autosomal-dominant disorder.
  • wtTTR wild-type TTR
  • vTTR mutant/variant TTR
  • the pathogenic mechanism of ATTR is triggered by a partial unfolding of the TTR protein and subsequent aggregation into beta-pleated sheets forming amyloid fibrils (Eisele et al., Nat. Rev. Drug Discov. 14 (2015), 759-780).
  • Example 1 The clinical trials as described in Example 1 were set up to further confirm the therapeutic applicability of antibody NI006/ALXN2220 for the treatment of ATTR-CM and to identify the optimal dosing regimen. Indeed, a reduction of cardiac amyloid has been observed during the studies and the antibody was found to be effective in the treatment of ATTR-CM. However, surprisingly, it was also shown that there is a strong tracer signal in the joint, for example the shoulder and elbow joints of some patients enrolled in the study, i.e., patients having been diagnosed with ATTR-CM, wherein the signal decreased during treatment with the anti-TTR antibody. Thus, treatment with an anti-TTR antibody did not only improve cardiac function in the patients but presumably led to the reduction of joint deposits.
  • Pathological deposits can be found in many musculoskeletal diseases and conditions, like carpal tunnel syndrome, arthritis, e.g., osteoarthritis, lumbar spine stenosis, amyloid arthropathy, brachial biceps tendon rupture, trigger finger, rotator cuff disease, and joint pain. Removal of these deposits usually results in improvements of symptoms and pathological reversion of musculoskeletal disease, potentially also resolving / reducing local inflammation following removal of the deposits and reductions of mechanical stress on adjacent nerves and filaments, to improve symptoms, which can be further evaluated for example by self-assessments and physical assessments like common tests to diagnose a disease (see for example Reiman and Manske J Man Manip Ther. 19 (2011), 91- 99), or via the 6-minutes walking distance assay as described in Example 1.
  • arthritis e.g., osteoarthritis, lumbar spine stenosis, amyloid arthropathy, brachial biceps tendon rupture, trigger finger,
  • NI006/ALXN2220 can improve joint functions and on the long run improve joint inflammation in the treatment of musculoskeletal conditions and diseases which are associated with such deposits, and which are associated with ATTR such as ATTR-CM, respectively, by triggering clearance of the deposits.
  • ATTR ATTR-CM
  • arthralgias have been observed in some patients as adverse events during therapy with anti-TTR antibody NI006/ALXN2220.
  • said anti-TTR antibody mediates ATTR fibril clearance by antibody effector functions, in particular antibodydependent cellular phagocytosis (ADCP); see Example 3 and Figure 3 of WO 2023/099788 Al.
  • the anti-TTR antibody for use in accordance with the method of the present invention has an active Fc domain and is capable of inducing ADCP, which may be tested by using the PDAX mouse model disclosed in WO 2020/094883 Al and the potency assay as disclosed in WO 2023/099788 Al.
  • amyloid deposits have been observed in glenohumeral joint arthritis (Birnbrich et al., JSES Reviews, Reports, and Techniques 2 (2022), 201-204), various amyloid deposits, including deposits derived from TTR have been shown to be present in knee osteoarthritis (OA), it has been shown that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human OA, and that TTR deposition promotes progression of OA (Yanagisawa et al., The Journal of Protein Folding Disorders 23 (2016), 26-32; Akasaki et al., Arthritis Rheumatol.
  • TTR amyloidosis of TTR has been identified as one amyloidosis responsible for osteoarticular manifestations and in particular for carpal tunnel syndrome (M'Bappe and Grateau, Best Practice & Research Clinical Rheumatology 26 (2012), 459-475), and severe hand pain has been identified as an extracardiac manifestation of TTR amyloidosis (Patel et al., BMJ Case Rep 12 (2019), e229677).
  • ATTR orthopedic manifestations of ATTR are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff (Perfetto et al., Biomedicines 10 (2022), 3226).
  • hip (THA) and knee (TKA) arthroplasties have been observed in patients with ATTR-CM (Rubin etal., Amyloid 24 (2017), 226-230.
  • the present disclosure is based, in part, on the effect of anti-TTR antibodies such as NI006/ALXN2220 on joint deposits in patients which have been diagnosed with ATTR-CM.
  • anti-TTR antibodies such as NI006/ALXN2220
  • the present disclosure provides a method of treating a subject, e.g., human patient, in need for treatment of musculoskeletal conditions and diseases that are associated with amyloid deposits, with an anti-TTR antibody such as NI006/ALXN2220.
  • an anti-TTR antibody such as NI006/ALXN2220.
  • the musculoskeletal conditions and diseases are associated with amyloidogenic TTR deposits.
  • Representative examples include, but are not limited to, e.g., arthritis, in particular osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, carpal tunnel syndrome, joint pain, amyloid arthropathy, lumbar spine stenosis, as well as ligament and tendon disorders, in particular brachial biceps tendon rupture, trigger finger, and rotator cuff disease.
  • arthritis in particular osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, carpal tunnel syndrome, joint pain, amyloid arthropathy, lumbar spine stenosis, as well as ligament and tendon disorders, in particular brachial biceps tendon rupture, trigger finger, and rotator cuff disease.
  • the present invention further relates to a pharmaceutical composition, kit of parts or article of manufacture comprising an anti-TTR antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis and a disease-modifying anti-rheumatic drug and/or an anti-inflammatory agent.
  • TTR transthyretin
  • Fig. 1 Representative images for changes in scintigraphy tracer uptake after treatment with NI006/ALXN2220 (A-C). Shown are serial bisphosphonate scintigraphs of two patients randomized to NI006/ALXN2220 (A and C) and one patient (B) randomized to placebo, at baseline, at 4 months (after placebo-controlled SAD/MAD completion) and at 12 months (after OLE completion). Quantification of cardiac tracer uptake is indicated by heart/whole body ratio (H/WB ratio in %). Individual cumulative administered NI006/ALXN2220 dose (in g) as well as NI006/ALXN2220 exposure (AUC in day*mg/mL) are provided for the post-baseline imaging timepoints.
  • Fig. 2 Changes from Baseline in the Kansas City Cardiomyopathy Questionnaire - Overall Summary and 6-Minute Walk Distance in Patients Randomized to NI006/ALXN2220 at 12 months. Absolute changes from baseline the in Kansas City Cardiomyopathy Questionnaire - Overall Symptom Score and 6-minute walk distance after 12 months of treatment with NI006/ALXN2220 versus individual cumulative NI006/ALXN2220 exposure. Linear regression lines with unadjusted 95% confidence intervals are presented for patients randomized to NI006/ALXN2220. Confidence intervals should not be used to reject or not reject a treatment effect.
  • ACFB denotes absolute change from baseline, KCCQ-OS Kansas City Cardiomyopathy Questionnaire - Overall Symptom Score and 6-MWD 6-minute walk distance.
  • the scores from a KCCQ questionnaire range from 0 to 100 with 0 to 24 indicating very poor to poor, 25 to 49 indicating poor to fair, 50 to 74 indicating fair to good, and 75 to 100 indicating good to excellent quality of life.
  • the present invention generally relates to the immunotherapy of musculoskeletal conditions and disorders caused by and/or associated with transthyretin (TTR) amyloidosis (ATTR). More specifically, the present invention relates to the embodiments as characterized in the claims, disclosed in the description and illustrated in the Examples and Figures further below.
  • TTR transthyretin
  • ARR amyloidosis
  • the term “and/or” is understood to mean that all members of a group which are connected by the term “and/or” are disclosed cumulatively in any combination, both alternatively to each other and in each case to each other.
  • TRR When using the term “ATTR”, usually vATTR as well as wtATTR is meant if not indicated otherwise. Similarly, if not indicated otherwise, “TTR” also refers to wtTTR and vTTR.
  • antibody as referred to herein includes whole antibodies and any antigen binding fragment (i.e., "antigen-binding portion") or single chain versions thereof.
  • An “antibody” refers, in one embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region (CH) is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and various complement proteins.
  • CDRs can be defined differently according to different methods.
  • the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by Kabat et al., NIH Publication 91 (1991), 3242.
  • the CDRs can be referred to as "Kabat CDRs” (e.g., "Kabat LCDR2" or "Kabat HCDR1").
  • the positions of the CDRs of a light or heavy chain variable region can be as defined by Chothia et al., Nature 342 (1989), 877- 883).
  • these regions can be referred to as “Chothia CDRs” (e.g, “Chothia LCDR2" or “Chothia HCDR3”).
  • the positions of the CDRs of the light and heavy chain variable regions can be as defined by a Kabat-Chothia combined definition.
  • these regions can be referred to as “combined Kabat-Chothia CDRs”. Thomas et al., Mol Immunol 33 (1996), 1389-1401 exemplifies the identification of CDR boundaries according to Kabat and Chothia definitions.
  • the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by the International Immunogenetics database (IMGT) standard. Marie-Paule Lefranc et al., Developmental & Comparative Immunology 27 (2003), 55-77 exemplify the identification of and CDR boundaries according to IMGT standard. Accordingly, these regions can be referred to as "IMGT CDRs" (e.g., "IMGT-LCDR2" or "IMGT-HCDR3").
  • antigen or "antigen target,” as used herein, refer to a molecule or a portion of a molecule that is capable of being bound to by an antibody, one or more Ig binding domain, or other immunological binding moiety, including, for example, the engineered polypeptides or fusion proteins disclosed herein.
  • An antigen is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen.
  • An antigen may have one or more epitopes.
  • antibody fragment refers to one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen.
  • fragments are, for example between about 8 and about 1500 amino acids in length, suitably between about 8 and about 745 amino acids in length, suitably about 8 to about 300, for example about 8 to about 200 amino acids, or about 10 to about 50 or 100 amino acids in length. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term "antigen-binding fragment" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CHI domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) an dAb fragment (Ward et al., Nature 341 (1989), 544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker, for example, antibody fragments comprising variable heavy chain (VH) CDRs and/or variable light chain (VL) CDR
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., Science 242 (1988), 423-426; and Huston et al. Proc. Natl. Acad. Sci. USA 85 (1988), 5879-5883.
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.
  • binding domain refers to the portion of a protein or antibody which comprises the amino acid residues that interact with an antigen. Binding domains include, but are not limited to, antibodies (e.g., full length antibodies), as well as antigen-binding portions thereof, e.g., containing VHCDR1-3 and VLCDR1-3, as provided above. The binding domain confers on the binding agent its specificity and affinity for the antigen. The term also covers any protein having a binding domain which is homologous or largely homologous to an immunoglobulin-binding domain.
  • anti-TTR antibody usually refers to an antibody that binds misfolded/aggregated TTR and not the physiological TTR tetramer.
  • misfolded/aggregated TTR and not the physiological TTR tetramer.
  • terapéuticaally effective amount or “clinically active concentration” of a substance, it is meant that a given substance is administered to a subject suffering from a condition, in an amount sufficient to ensure, alleviate or partially arrest the condition or one or more of its symptoms. Such therapeutic treatment may result in a decrease in severity of disease symptoms, or an increase in frequency or duration of symptom-free periods. Effective amounts for a given purpose and a given agent will depend on the severity of the disease or injury as well as the weight and general state of the subject. As used herein, the term “subject” includes any mammal, preferably a human.
  • Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., EDso (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • EDso the dose therapeutically effective in 50% of the population
  • LD50 the dose lethal to 50% of the population.
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • the present invention relates to anti-TTR antibodies which are capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species, i.e., the amyloidogenic form of TTR, for use in a method of treating or preventing a musculoskeletal disorder or condition in a subject.
  • TTR transthyretin
  • the anti-TTR antibodies are capable of binding mutated and misfolded TTR species.
  • the anti-TTR antibodies are capable of binding mutated and misassembled TTR species.
  • the anti-TTR antibodies are capable of binding mutated and aggregated TTR species.
  • the anti-TTR antibodies are capable of binding misfolded and misassembled TTR species.
  • the anti-TTR antibodies are capable of binding misfolded and aggregated TTR species. In one embodiment, the anti-TTR antibodies are capable of binding misassembled and aggregated TTR species. In one embodiment, the anti-TTR antibodies are capable of binding mutated, misfolded and misassembled TTR species. In one embodiment, the anti-TTR antibodies are capable of binding mutated, misfolded and aggregated TTR species. In one embodiment, the anti-TTR antibodies are capable of binding misfolded, misassembled and aggregated TTR species. In one embodiment, the anti-TTR antibodies are capable of binding misfolded, aggregated, and mutated TTR species.
  • the disease or condition to be treated with the anti-TTR antibody is a musculoskeletal disorder or condition associated with amyloidogenic TTR, preferably at the joint.
  • the anti-TTR antibody is used in the treatment of musculoskeletal conditions and diseases in human subjects in accordance with the present invention, in one embodiment the anti-TTR antibody is humanized, preferably human-derived and non-immunogenic in human.
  • the present invention has been exemplified with anti-TTR antibody NI006/ALXN2220, wherein the parent antibody NI-301.37F1 has been first described in WO 2015/092077 Al.
  • Said antibody is capable of binding a human TTR epitope which comprises or consists of the amino acid sequence TTR41-45 (SEQ ID NO: 51 of WO 2015/092077 Al and present SEQ ID NO: 15) and comprises in its variable region or binding domain the complementary determining regions (CDRs) and variable heavy (VH) and variable light (VL) chain having the amino acid sequences depicted in Fig.
  • the theoretical molecular weight of antibody NI006/ALXN2220 is 144.2 kDa, and the weight determined by mass spectrometry (MS) is 144.2 kDa (deglycosylated) and between 147.0 and 147.6 kDa (intact IgGl), respectively.
  • This antibody and cognate antibodies have been derived from memory B cell repertoire of healthy aged human donors; see description of the Examples in WO 2015/092077 Al. Characterization of the binding properties of the antibody demonstrated that it presents high binding affinity to misfolded TTR in the sub-nanomolar range, is highly selective for the amyloid conformation of TTR, and exerts similar binding to wtTTR and vTTR. Since this human-derived antibody is selective for misfolded TTR and as illustrated in the Examples can trigger removal of joint deposits, it represents the most favorable therapeutic candidate for use the treatment of musculoskeletal diseases.
  • Antibody NI006/ALXN2220 is produced in Chinese hamster ovary (CHO)-Kl 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 the antibody molecules, which typically take place in the human body as well.
  • PTMs post-translational modifications
  • CHO-K1 CHO-S
  • CHO-DXB 11 CHO-DG44.
  • the antibody for use in accordance with the present invention is produced in CHO cells, preferably in a CHO-K1 cell line and is purified from the cell culture medium for further use.
  • the major PTMs that have been identified in antibody NI006/ALXN2220 are the modification in the HC of glutamine at the N-terminus to pyroglutamic acid, the loss of C-terminal lysine, and N-glycosylation.
  • the N- glycosylation site was identified at position 300 (HC N300, SEQ ID NO: 18).
  • the antibody for use in accordance with the present invention has lost the C-terminal lysine, /. ⁇ ., the antibody has undergone C-terminal lysine clipping.
  • the C-terminal lysine as shown in SEQ ID NO: 18 is chopped of the heavy chain of the antibody, preferably of each heavy chain of the antibody. Said sequence, i.e., the sequence of the heavy chain with a clipped off C-terminal lysine is set forth in SEQ ID NO: 20.
  • the glutamine at the N-terminal is modified as pyro-glutamic acid, i.e., the heavy chain of the antibody as shown in SEQ ID NO: 18 has undergone N-terminal glutaminyl cyclization.
  • Said sequence, i.e., the sequence of the heavy chain which comprises cyclic pyroglutamic acid and no N-terminal glutamine is set forth in SEQ ID NO: 21.
  • the heavy chain of the anti-TTR antibody present in the pharmaceutical composition of the present invention has lost the C-terminal lysine and the glutamine at the N-terminal is modified as pyro-glutamic acid.
  • Said sequence, i.e., the sequence of the heavy chain with a clipped off C-terminal lysine and which comprises cyclic pyroglutamic acid and no N-terminal glutamine is set forth in SEQ ID NO: 22.
  • the antibody is glycosylated, in particular N-glycosylated. More particularly, the heavy chain of the antibody is glycosylated and even more particularly N300 of the heavy chain.
  • the anti-TTR antibody for use in accordance with the present invention lacks the C-terminal cysteine, has a modified glutamine at the N-terminal as pyroglutamic acid and comprises at least one N-glycosylation site.
  • WO 2015/092077 Al discloses further human-derived antibodies that could be shown to bind to the same human TTR epitope as NI-301.37F1, i.e. antibody NI-301.28B3 and NI-301.12D3 which VH and VL chain amino acid sequences including indication of the CDRs are depicted for NI-301.28B3 in Fig. IE (present SEQ ID NOs: 8 and 10) and forNI-301.12D3 in Fig. IL of WO 2015/092077 Al (present SEQ ID NOs: 12 and 14).
  • the anti- TTR antibody for use in accordance with the present invention may be generally characterized by binding a human TTR epitope which comprises or consists of the amino acid sequence TTR41-45 (SEQ ID NO: 51 of WO 2015/092077 Al and present SEQ ID NO: 15).
  • a human TTR epitope which comprises or consists of the amino acid sequence TTR41-45 (SEQ ID NO: 51 of WO 2015/092077 Al and present SEQ ID NO: 15).
  • anti-TTR antibodies presumably suitable for use in the treatment of musculoskeletal disorders or conditions in accordance with the present invention is described in international applications by Prothena Biosciences Limited (Prothena).
  • embodiments of the disclosure relate to the use of anti-TTR antibody NN-6019 of Novo Nordisk (formerly known as PRX004 from Prothena Biosciences) in the treatment of human patients in need of such treatment, as provided herein.
  • NN-6019 corresponds to and is the humanized version of antibody 14G8 described in Higaki et al., Amyloid 23 (2016) 86-97 and which is disclosed in WO 2016/120810 Al and WO 2018/007922A2 and more specifically in WO 2019/108689 Al, the disclosure in these documents being incorporated by reference.
  • NN- 6019 is an investigational monoclonal antibody designed to specifically target and clear the misfolded (toxic) forms of the TTR amyloid protein found in ATTR. Accordingly, antibody PRX004 would be another preferred anti-TTR antibody for use in the treatment of musculoskeletal disease in accordance with the present invention among others which recognize the same epitope as PRX004, i.e.
  • amino acids TTR89-97 or an epitope comprising amino acids TTR101-109 are humanized versions of the originally cloned mouse monoclonal antibodies 14G8, 9D5, 5A1, 6C1 disclosed in WO 2016/120810 Al, WO 2018/007924 A2, WO 2018/007924 A2 and WO 2018/007923 Al, the disclosure in these references, including, the antibody sequences, e.g., full-length and/or CDRs thereof, relating to these antibody clones and/or deposits thereof are incorporated herein by reference.
  • a further presumably suitable antibody is a humanized version of antibody 18C5 or an isolated monoclonal antibody that competes for binding to human TTR with monoclonal antibody 18C5, preferably that binds to the same epitope on human TTR as a monoclonal antibody 18C5, wherein 18C5 is a mouse antibody characterized by a mature heavy chain variable region having an amino acid sequence comprising SEQ ID NO: 81 and a mature light chain variable region having an amino acid sequence comprising SEQ ID NO: 87 as disclosed in WO 2019/071205 Al, the disclosure in these references, including, the antibody sequences, e.g., full-length and/or CDRs thereof, relating to these antibody clones and/or deposits thereof are incorporated herein by reference.
  • Still another class of humanized anti-TTR antibodies presumably suitable for use in the treatment of musculoskeletal conditions in accordance with the present invention is described in international applications by The Chemo-Sero-Therapeutic Research Institute and KM Biologies Co., Ltd., respectively, recognizing an epitope comprising amino acids TTR78-89 or TR118-122 as disclosed for antibodies 371M and 313M in WO 2015/115332 and for the antibody described in WO 2015/115331 Al (which is designated herein as XY for ease of reference), the disclosure in these references, including, the antibody sequences, e.g., full-length and/or CDRs thereof, relating to these antibody clones and/or deposits thereof are incorporated herein by reference.
  • ATTR There are two forms of ATTR, namely wtATTR and vATTR which are caused by pathological aggregation of wtTTR and vTTR, respectively, wherein especially wtATTR is found in many musculoskeletal diseases, like carpal tunnel syndrome and osteoarthritis; see Perfetto et al., Biomedicines 10 (2022), 3226.
  • the antibody binds amyloidogenic wtTTR as well as amyloidogenic vTTR.
  • NI006/ALXN2220 which is a fully human IgGlm3 allotype, also known as NI- 301.37F1 which is disclosed in WO 2015/092077 Al and binds to a TTR epitope comprising the amino acid sequence TTR41-45 as set forth in SEQ ID NO: 51 of WO 2015/092077 Al (present SEQ ID NO: 15).
  • antibodies binding an epitope comprising said amino acid sequence are also a suitable for use in the treatment in accordance with the present invention, e.g., antibodies NI-301.28B3 and NI-301.12D3 as also disclosed in WO 2015/092077 Al, the disclosure in these references, including, the antibody sequences, e.g., full-length and/or CDRs thereof, relating to these antibody clones and/or deposits thereof are incorporated herein by reference.
  • the anti-TTR antibody is derived from human antibody NI-301.37F1, NI-301.28B3 or NI-301.12D3 and characterized by comprising in its variable region, i.e. binding domain the complementarity determining regions (CDRs) of the variable heavy (VH) and variable light (VL) chain having the amino acid sequences depicted in Fig.
  • CDRs complementarity determining regions
  • the anti-TTR antibody is characterized by the CDRs of the VH and VL chain and by the entire VH and VL chain, respectively depicted in Fig. 1C and IM of WO 2015/092077 AL
  • the antibody preferably comprises
  • VH variable heavy chain comprising the following VH complementary determining regions (CDRs) 1, 2, and 3, and/or a variable light (VL) chain comprising the following VL CDRs 1, 2, and 3:
  • VH-CDR1 positions 31-35 of SEQ ID NO: 10 ofWO 2015/092077 Al (present SEQ ID NO: 2) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VH-CDR2 positions 52-67 of SEQ ID NO: 10 of WO 2015/092077 Al (present SEQ ID NO: 2) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VH-CDR3 positions 100-109 of SEQ ID NO: 10 of WO 2015/092077 Al (present SEQ ID NO: 2) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VL-CDR1 positions 24-34 of SEQ ID NO: 12 of WO 2015/092077 Al (present SEQ ID NO: 4) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VL-CDR2 positions 50-56 of SEQ ID NO: 12 of WO 2015/092077 Al (present SEQ ID NO: 4) or a variant thereof, wherein the variant comprises one or two amino acid substitutions, and
  • VL-CDR3 positions 89-97 of SEQ ID NO: 12 of WO 2015/092077 Al (present SEQ ID NO: 4) or a variant thereof, wherein the variant comprises one or two amino acid substitutions; and/or (ii) a VH chain and/or a VL chain, wherein
  • the VH chain comprises the amino acid sequence depicted in SEQ ID NO: 10 of WO 2015/092077 Al (present SEQ ID NO: 2) or SEQ ID NO: 53 of WO 2015/092077 Al (present SEQ ID NO: 6), or a variant thereof, wherein the variant comprises one or more amino acid substitutions;
  • the VL chain comprises the amino acid sequence depicted in SEQ ID NO: 12 of WO 2015/092077 Al (present SEQ ID NO: 4), or a variant thereof, wherein the variant comprises one or more amino acid substitutions; preferably wherein the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NOs: 10 or 53 and 12 of WO 2015/092077 Al, respectively (present SEQ ID NOs: 2 or 6 and 4, respectively).
  • the antibody comprises a shortened VH chain, z.e., the antibody comprises a VH and/or VL chain, wherein
  • the VL chain comprises the amino acid sequence depicted in present SEQ ID NO: 4, or a variant thereof, wherein the variant comprises one or more amino acid substitutions; preferably wherein the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NOs: 16 and 4, respectively.
  • the antibody comprises a shortened VH and VL chain, z.e., the antibody comprises a VH chain and/or a VL chain, wherein
  • the VH chain comprises the amino acid sequence depicted in present SEQ ID NO: 16, or a variant thereof, wherein the variant comprises one or more amino acid substitutions;
  • the VL chain comprises the amino acid sequence depicted in present SEQ ID NO: 17, or a variant thereof, wherein the variant comprises one or more amino acid substitutions; preferably wherein the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NOs: 16 and 17, respectively.
  • the anti-TTR antibody is characterized by the CDRs of the VH and/or VL chain and by the entire VH and VL chain, respectively depicted in Fig. IE of WO 2015/092077 Al.
  • the antibody preferably comprises
  • VH variable heavy chain comprising the following VH complementary determining regions (CDRs) 1, 2, and 3, and/or a variable light (VL) chain comprising the following VL CDRs 1, 2, and 3:
  • VH-CDR1 positions 31-37 of SEQ ID NO: 18 ofWO 2015/092077 Al (present SEQ ID NO: 8) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VH-CDR2 positions 52-67 of SEQ ID NO: 18 of WO 2015/092077 Al (present SEQ ID NO: 8) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VH-CDR3 positions 100-116 of SEQ ID NO: 18 of WO 2015/092077 Al (present SEQ ID NO: 8) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VL-CDR1 positions 24-34 of SEQ ID NO: 20 of WO 2015/092077 Al (present SEQ ID NO: 10) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VL-CDR2 positions 50-56 of SEQ ID NO: 20 of WO 2015/092077 Al (present SEQ ID NO: 10) or a variant thereof, wherein the variant comprises one or two amino acid substitutions, and
  • VL-CDR3 positions 89-98 of SEQ ID NO: 20 of WO 2015/092077 Al (present SEQ ID NO: 10) or a variant thereof, wherein the variant comprises one or two amino acid substitutions; and/or
  • the VH chain comprises the amino acid sequence depicted in SEQ ID NO: 18 of WO 2015/092077 Al (present SEQ ID NO: 8), or a variant thereof, wherein the variant comprises one or more amino acid substitutions;
  • the VL chain comprises the amino acid sequence depicted in SEQ ID NO: 20 of WO 2015/092077 Al (present SEQ ID NO: 10), or a variant thereof, wherein the variant comprises one or more amino acid substitutions; preferably wherein the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NO: 18 and 20 of WO 2015/092077 Al, respectively (present SEQ ID NO: 8 and 10, respectively).
  • the anti-TTR antibody is characterized by the CDRs of the VH and/or VL chain and by the entire VH and VL chain, respectively depicted in Fig. IE of WO 2015/092077 Al.
  • the antibody preferably comprises
  • VH variable heavy chain comprising the following VH complementary determining regions (CDRs) 1, 2, and 3, and/or a variable light (VL) chain comprising the following VL CDRs 1, 2, and 3:
  • VH-CDR1 positions 31-35 of SEQ ID NO: 46 ofWO 2015/092077 Al (present SEQ ID NO: 12) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VH-CDR2 positions 50-66 of SEQ ID NO: 46 of WO 2015/092077 Al (present SEQ ID NO: 12) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VH-CDR3 positions 99-108 of SEQ ID NO: 46 of WO 2015/092077 Al (present SEQ ID NO: 12) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VL-CDR1 positions 23-36 of SEQ ID NO: 48 of WO 2015/092077 Al (present SEQ ID NO: 14) or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
  • VL-CDR2 positions 52-58 of SEQ ID NO: 48 of WO 2015/092077 Al (present SEQ ID NO: 14) or a variant thereof, wherein the variant comprises one or two amino acid substitutions, and
  • VL-CDR3 positions 91-100 of SEQ ID NO: 48 of WO 2015/092077 Al (present SEQ ID NO: 14) or a variant thereof, wherein the variant comprises one or two amino acid substitutions; and/or
  • the VH chain comprises the amino acid sequence depicted in SEQ ID NO: 46 of WO 2015/092077 Al (present SEQ ID NO: 12), or a variant thereof, wherein the variant comprises one or more amino acid substitutions;
  • the VL chain comprises the amino acid sequence depicted in SEQ ID NO: 48 of WO 2015/092077 Al (present SEQ ID NO: 14), or a variant thereof, wherein the variant comprises one or more amino acid substitutions; preferably wherein the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NO: 46 and 48 of WO 2015/092077 Al, respectively (present SEQ ID NO: 12 and 14, respectively).
  • the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NO: 46 and 48 of WO 2015/092077 Al, respectively (present SEQ ID NO: 12 and 14, respectively).
  • antibody NI-301.37F1/NI006/ALXN2220 is used in the method in accordance with the present invention.
  • immunoglobulins The five primary classes of immunoglobulins are IgG, IgM, IgA, IgD and IgE. These are distinguished by the type of heavy chain found in the molecule. IgG molecules have heavy chains known as gamma-chains; IgMs have mu-chains; IgAs have alpha-chains; IgEs have epsilon-chains; and IgDs have delta-chains; see for review, e.g., Schroeder et al., J. Allergy Clin. Immunol. 125 (2010), S41-S52.
  • IgAs are further divided into subclasses IgAl and IgA2
  • IgGs are further divided into subclasses IgGl, IgG2, IgG3, and IgG4.
  • two types of light chain, kappa (K) and lambda (X) exist.
  • the antibody as used in accordance with the present invention may be of any kind of class and subclass, respectively, and may comprise any kind of light chain, as long as the antibody binds to misfolded and preferably aggregated forms of TTR, and preferably as long as binding specificity towards TTR as indicated in the Examples of WO 2015/092077 Al for antibody NI-301.37F1 remains unaffected in kind and as long as no adverse effects occur when administering said antibody to a patient, wherein the adverse effects can be determined as described in Example 1.
  • preferably complete IgG antibodies are used, wherein the antibody comprises a constant domain.
  • the immunoglobulin heavy and/or light chain constant domain present in the antibody as used in accordance with the present invention is of the IgG type, the IgM type, the IgA type, the IgD type or the IgE type, preferably of the IgG type.
  • the immunoglobulin heavy and/or light chain constant domain present in the antibody as used in accordance with the present invention is of the IgAl, IgAl, IgGl, IgG2, IgG3, or IgG4 subclass, preferably of the IgGl, IgG2, IgG3, or IgG4 subclass and most preferably of the IgGl subclass.
  • the antibody is a monoclonal antibody or derived from a monoclonal antibody.
  • Gm Generic marker
  • Glm Generic marker
  • allotype number or letter
  • Glml Glm(a)
  • G3m5 G3m(bl)
  • Human immunoglobulin allotypes are listed in Table 1 of Jefferis and Lefrance, mAbs 1 (2009), 1-7 and in Fig. 1A of Irani et al., Molecular Immunology 67 (2015), 171-182, which content is herein incorporated by reference.
  • the antibody as used in accordance with the present invention is of any one of the following allotypes, but not limited thereto: Glml, Glm2, Glm3, Glml7, G2m23, G3m21, G3m28, G3ml l, G3m5, G3ml3, G3ml4, G3ml0, G3ml5, G3ml6, G3m6, G3m24, G3m26, G3m27, A2ml, A2m2, A2m3, Eml, Kml, Km2, and Km3, but preferably of Glm2, Glm3, or Glm 17, and most preferably of Glm3.
  • antibody NI006/ALXN2220 is a fully human IgGlm3 allotype antibody and composed of two identical heavy chains of the IgGl subclass and the IgGlm3 allotype.
  • original human antibody NI-301.37F1 is of the kappa type and thus, NI006/ALXN2220 is composed of two identical light chains of the kappa subclass.
  • variable heavy (VH) and variable light (VL) chains of NI006/ALXN2220 are set forth in SEQ ID NOs: 2 and 6 and 16, respectively, and each isotype like the IgGlm3 isotype has a unique amino acid sequence of the constant regions of their heavy chains; see Jefferis and Lefrance (2009), supra.
  • the antibody as used in accordance with the present invention is characterized by two heavy chains, wherein each heavy chain (HC) comprises a amino acid sequence set forth in SEQ ID NO: 18, and by two light chains, wherein each light chain (LC) comprises a amino acid sequence set forth in SEQ ID NO: 19.
  • Each heavy chain is comprised of 450 amino-acid residues, and each light chain consists of 214 amino acid residues.
  • the four chains are stabilized by intra-chain and inter-chain disulfide bonds, wherein the positions of the disulfide bridges, which have been identified per Lys-C and trypsin digestion and subsequent LC-MS (see Example 2) are the following:
  • amino acid numbering corresponds to the heavy and light chain sequence set forth in SEQ ID NOs: 18 and 19
  • the antibody for use in accordance with the present invention comprises at least 8 disulfide bridges, preferably at the above-identified positions.
  • each heavy chain of antibody NI006/ALXN2220 contains a single N-linked glycosylation site at Asn300.
  • the N-linked glycosylation structure is predominantly a fucosylated, complex biantennary glycan with 0 galactose residues (GOF) (about 49 %) or with 1 galactose residue (GIF) (about 25 %).
  • Glycosylation plays a vital 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 the glycoprotein, and provides insightful information on the safety and efficacy of bio-therapeutics.
  • the antibody for use in accordance with the present invention has a heavy chain which is N-glycosylated, preferably wherein the N-linked glycosylation site is Asn300, preferably wherein the antibody comprises a N-linked glycosylation structure which is predominantly a glycan with 0 galactose residues (GOF) (about 49 %) or with 1 galactose residue (GIF) (about 25 %).
  • the antibody has the glycosylation profile as shown in Example 2.
  • one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain may be missing or derivatized in a proportion or all of the molecules.
  • the antibody for use in accordance with the present invention has a heavy chain that does not comprise a C-terminal lysine.
  • the C-terminal lysine included in SEQ ID NO: 18 is missing.
  • the sequence of such a heavy chain is set forth in SEQ ID NO: 20.
  • the antibody for use in accordance with the present invention has a heavy chain, in which the glutamine at the N-terminal is derivatized, preferably substituted with pyroglutamate.
  • This pyroglutamate formation is also referred to as N-terminal cyclization.
  • the sequence of such a heavy chain is set forth in SEQ ID NO: 21 or SEQ ID NO: 22, in which the N-terminal glutamine is absent.
  • the antibody for use in accordance with the present invention has a heavy chain that does not comprise a C-terminal lysine, /. ⁇ ., which C-terminal lysine has undergone C-terminal lysine clipping, in which the glutamine at the N-terminal is substituted with pyroglutamate, i.e., which has undergone N-terminal glutaminyl cyclization (see SEQ ID NO: 22), and which is N-glycosylated.
  • amino acid sequences of the heavy and light chains are shown below:
  • PTMs post-translational modifications
  • the antibody as used in accordance with the present invention may show methionine (M) oxidation, preferably at HC position 255; asparagine (N) deamidation, preferably at HC position 318 and/or at HC position 387; asparagine (N) succinimide formation, preferably at HC position 318; and/or amidation of the C-terminal proline (P) after the loss of the C-terminal lysine and glycine.
  • M methionine
  • N asparagine
  • N asparagine
  • N asparagine
  • succinimide formation preferably at HC position 318
  • P C-terminal proline
  • the anti-TTR antibody with the above-mentioned heavy and light chain variable regions is also described in WO 2015/092077 Al (designated as antibody NI-301.37F1) and in Michalon et al., Nat Commun. 12 (2021), 3142 (designated as antibody NI301A) and is capable of binding a human TTR epitope which comprises or consists of the amino acid sequence TTR41-45 (SEQ ID NO: 51 of WO 2015/092077 Al and present SEQ ID NO: 15).
  • the antibody as used in accordance with the present invention is an antibody, which is equivalent to the above-characterized antibody having a heavy chain and a light chain variable region including the amino acid sequence of SEQ ID NOs: 10 or 53 and 12 of WO 2015/092077 Al, respectively (present SEQ ID NOs: 2 or 6 and 4, respectively) meaning that the equivalent antibody has substantially the same binding characteristics than the above-characterized antibody having a heavy chain and a light chain variable region including the amino acid sequence of SEQ ID NOs: 10 or 53 and 12 of WO 2015/092077 Al, respectively (present SEQ ID NOs: 2 or 6 and 4, respectively).
  • the equivalent antibody is equivalent to the above-characterized antibody having a heavy chain and a light chain variable region including the amino acid sequence of SEQ ID NOs: 10 or 53 and 12 of WO 2015/092077 Al, respectively (present SEQ ID NOs: 2 or 6 and 4, respectively).
  • the equivalent antibody is equivalent to the above-characterized antibody having a heavy chain and a light chain variable region including the amino acid sequence of SEQ ID NO
  • TTR41-45 presents high binding affinity to misfolded TTR in the sub-nanomolar range
  • (iii) is highly selective for the amyloid conformation of TTR, i.e., binds selectively with high affinity to the disease associated ATTR aggregates
  • the equivalent antibody shows one of the binding characteristics (i) to (vi). In one embodiment, the equivalent antibody shows at least two of the listed binding characteristics. In one embodiment, the equivalent antibody shows at least three of the listed binding characteristics. In one embodiment, the equivalent antibody shows at least four of the listed binding characteristics. In one embodiment, the equivalent antibody shows at least five of the listed binding characteristics. In a preferred embodiment, the equivalent antibody shows all of the binding characteristics (i) to (vi).
  • the antibody as used in accordance with the present invention has an active Fc domain.
  • the antibody as used in accordance with the present invention preferably comprises a constant domain, preferably a human constant domain with an active Fc domain and has an IgG format, i.e., being a full IgG antibody, preferably an IgGl antibody or isotype. Recombinant expression of complete human IgGl antibodies with a human constant domain can be performed substantially as described in, e.g.
  • the antibody as used in accordance with the present invention is in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising a physiologically acceptable diluent or carrier, and optionally excipients or auxiliaries.
  • the antibody can be formulated according to methods well known in the art; see for example Remington: The Science and Practice of Pharmacy (2000) by the University of Sciences in Philadelphia, ISBN 0-683-306472.
  • suitable pharmaceutical carriers and diluents are well known in the art and include buffer solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc.
  • Compositions comprising such carriers can be formulated by well-known conventional methods. Administration of the suitable compositions may be effected by different ways known in the art.
  • Exemplarily routes of administration include topical, intravenous, oral, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, intranasal or intramuscular.
  • the anti-TTR antibody is formulated in a liquid formulation and is designed to be administered intravenously (i.v.), in particular by intravenous infusion as performed in the clinical trials outlined in the Examples.
  • the antibody can be injected directly into a particular tissue where deposits have accumulated, for example into the joints.
  • the antibody and the formulation, respectively, can be administered to the subject at a suitable dose, i.e., in a therapeutically effective amount to reduce the risk, lessen the severity, or delay the onset of at least one sign or symptom of the musculoskeletal disease in subjects susceptible to or otherwise at risk of the disease (prophylactic approach), or to ameliorate or at least inhibit further deterioration of at least one sign or symptom of the disease in a subject suffering from the musculoskeletal disease (therapeutic approach).
  • a regime is for example considered therapeutically or prophylactically effective if an individual treated subject achieves an outcome more favorable than the mean outcome in a control population of comparable subjects not treated by methods disclosed herein.
  • the regime is therapeutically effective if the deposits observed in the patients are reduced during treatment.
  • dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. In general, subjects can be administered according to any other schedule determined by empirical analysis.
  • the antibody as used in accordance with the present invention is administered at a dose of about 10 mg/ko about 100 mg/kg, preferably at least 10 mg/kg, 30 mg/kg, 60 mg/kg, or 100 mg/kg i.e., the method of treating or preventing a musculoskeletal disorder or condition comprises administering the antibody at a dose of about at least 10 mg/kg, 30 mg/kg, 60 mg/kg, or 100 mg/kg.
  • the antibody as used in accordance with the present invention is administered once every 28 days, z.e., the method of treating or preventing a musculoskeletal disorder or condition comprises administering the antibody once every 28 days. In one embodiment, the antibody as used in accordance with the present invention is administered for at least 4 to 12 months, /. ⁇ ., the method of treating or preventing a musculoskeletal disorder or condition comprises administering the antibody for at least 4 to 12 months. Preferably, the antibody as used in accordance with the present invention is administered at a dose of about at least 10 mg/kg, 30 mg/kg or 60 mg/kg once every 28 days for at least 4 to 12 months.
  • the dose of the antibody in the method of treatment in accordance with the present invention is such that the treatment results in a median amyloid reduction when the dose corresponds to a dose between 30 and 60 mg/kg in the patient.
  • dosing regimen may be applied in accordance with the present invention which result in amyloid removal to substantially the same extent as the 30 mg/kg and 60 mg/kg treatment arm in the Clinical Trials.
  • fixed doses, lower/higher doses with smaller or larger intervals of administration can generally be chosen and considered equivalent to the preferred dosages of 30 mg/kg every 28 days and 60 mg/kg every 28 days.
  • the doses refer to a molecular weight of antibody NI006/ALXN2220 with approximately 147 kDa for the intact IgGl antibody, for the use of antibodies or binding fragments which significantly differ in their MW the dose may be adjusted accordingly.
  • an antibody is used with a lower or longer serum half-life, for example because of altered glycosylation and/or modification such as PEGylation, the dose and dosing interval, respectively, may be recalculated.
  • exposure Cmax and AUC
  • the progress of the musculoskeletal disorder or condition or progress of the treatment can be monitored by determining the relative change in scintigraphy tracer uptake at the joints or bones.
  • Increased tracer uptake means that more deposits are detected, wherein deposits are associated with the musculoskeletal disorder or condition.
  • an increase of tracer uptake into the joints or bones indicates a progression of the disorder or condition, and a reduction of tracer uptake suggests efficacy of the treatment.
  • any tracer can be used which is able to detect deposits and amyloid deposits, respectively in a subject.
  • the tracer comprises bisphosphonate, preferably " m Tc-hydroxyl-methylene- diphosphonate (HMDP) or " m Tc-3, 3 -diphosphono- 1,2-propanodicarboxylic acid (DPD).
  • HMDP m Tc-hydroxyl-methylene- diphosphonate
  • DPD 3 -diphosphono- 1,2-propanodicarboxylic acid
  • the subject to be treated in accordance with the present invention can be screened for the presence of a musculoskeletal disorder or condition, which is preferably associated with deposits in the joints/bones, by determining scintigraphy tracer uptake at the joints and/or bones, wherein an increased uptake compared to a healthy control indicates the onset or presence of the disorder or condition.
  • the antibody as used in accordance with the present invention is administered in combination with a disease-modifying anti-rheumatic drug or an anti-inflammatory agent.
  • such agents are corticosteroids (disease-modifying anti-rheumatic drug) and/or non-steroidal anti-inflammatory drugs (NSAID).
  • NSAID non-steroidal anti-inflammatory drugs
  • the disease-modifying anti-rheumatic drug and the antiinflammatory agent are administered in combination with the anti-TTR antibody.
  • Administration of the disease-modifying anti-rheumatic drug and/or anti-inflammatory agent is preferably performed after administration of the anti-TTR antibody and after occurrence of the arthralgias and arthritis as performed in the clinical studies as outlined in the Examples.
  • TTR tetramer stabilizers, silencers, and gene-editing therapies have been designed to prevent ATTR accumulation, but these drugs do not directly target amyloid that has already been deposited, for example in the heart.
  • therapies that stabilize or silence TTR might have a lower amyloid load, on the basis of surrogate markers on scintigraphy and cardiac MRI than untreated patients, but substantial reductions are rare.
  • those alternative strategies may perform better in combination with anti-TTR antibody for use in methods of treating for example joint and bone disorder associated with ATTR.
  • the present invention further relates to practicing the therapeutic methods described herein with a combination therapy comprising an-ATTR antibody as provided in the foregoing paragraphs and drugs that act as TTR tetramer stabilizers, silencers, as well as geneediting therapies, for example.
  • a combination therapy is used with a TTR stabilizer as disclosed in WO 2021/228987 Al, wherein combined treatment with an anti-TTR antibody, exemplary shown based on antibody NI006/ALXN2220, also designed as NI-301.37F1, and a TTR tetramer stabilizer such as tafamidis, diflunisal and AGIO have been shown to result in a significant clearance rate of TTR fibrils in mice; see, e.g., Example 2 of WO 2021/228987 Al.
  • Diflunisal is an anti-amyloidogenic agent and acts as TTR tetramer stabilizer, which has been launched by Merck Sharp & Dohme for the treatment of rheumatoid arthritis (RA) and has been commercialized (Dolobid) for the treatment of rheumatic pain and osteoarthritis.
  • RA rheumatoid arthritis
  • Dolobid rheumatic pain and osteoarthritis.
  • particular embodiments of the present disclosure provide for combined use of an anti-TTR antibody with a TTR tetramer stabilizer, in particular diflunisal, for the treatment of a musculoskeletal diseases in human patients needing such treatment, such as, e.g., human patients with arthritis, rheumatic conditions, and osteoarthritis.
  • the anti-TTR antibody as used in accordance with the present invention is administered in combination with another agent effective in the treatment or prophylaxis of musculoskeletal diseases or conditions, preferably of arthritis, rheumatic conditions, and osteoarthritis.
  • agent can include a TTR tetramer stabilizer, for example diflunisal or tafamidis.
  • TTR tetramer stabilizer for example diflunisal or tafamidis.
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising
  • an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis, and
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising (i) an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis, and
  • TTR transthyretin
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising
  • an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis, and
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising
  • an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis, and
  • TTR tetramer stabilizer e.g., diflunisal.
  • the pharmaceutical composition, kit of parts, or article of manufacture further comprises a pharmaceutically acceptable carrier.
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising
  • an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis,
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising
  • an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis, (ii) an anti-inflammatory agent, and
  • TTR tetramer stabilizer e.g., diflunisal.
  • the present invention further relates to a pharmaceutical composition, kit of parts, or article of manufacture comprising
  • an antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and is capable of removing ATTR by inducing phagocytosis,
  • TTR tetramer stabilizer e.g., diflunisal.
  • the pharmaceutical composition, kit of parts, or article of manufacture further comprises a pharmaceutically acceptable carrier.
  • the antibody comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention is a human-derived anti-TTR antibody.
  • the antibody comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention has a constant region which is of an IgG isotype, preferably the IgGl isotype. Most preferably, the antibody is of the IgGlm3 allotype.
  • the antibody comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention is characterized by the VH and VL regions, and the CDRs, respectively as recited in detail above.
  • the antibody comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention is characterized by the two heavy chains and two light chains as recited in detail above.
  • the antibody comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention is characterized by having the abovelisted PTMs.
  • the antibody is the antibody or antigen-binding fragment thereof as used in accordance with the present invention and as characterized hereinbefore, respectively.
  • the disease-modifying anti-rheumatic drug comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention is a corticosteroid.
  • the anti-inflammatory agent comprised in the pharmaceutical composition, kit of parts, or article of manufacture of the present invention is a NSAID.
  • the present invention further relates to a method of treating a musculoskeletal condition or disorder as defined herein, wherein the treatment comprises at least administering of an anti- TTR antibody as defined herein, and optionally one or more agents supporting said treatment like anti-inflammatory agents, disease-modifying anti-rheumatic drug, and/or TTR tetramer stabilizer as defined herein to a subject in need thereof.
  • the treatment comprises at least administering of an anti- TTR antibody as defined herein, and optionally one or more agents supporting said treatment like anti-inflammatory agents, disease-modifying anti-rheumatic drug, and/or TTR tetramer stabilizer as defined herein to a subject in need thereof.
  • the therapeutic benefit of the therapy according to the invention can be assessed for example by self-assessments and physical assessments like common tests to diagnose a disease (see for example Reiman and Manske J Man Manip Ther. 19 (2011), 91-99), or by the 6-minutes walking distance assay as described in Example 1. Furthermore, the therapeutic benefit of the therapy according to the invention may be assessed by means of reduction in local inflammation with a concomitant reduction in pain and improvement in functional capacity and quality of life, for example by EULAR or ACR response criteria (see Van Gestel et al., Arthritis Rheum 39 (1996), 34 - 40 and Felson et al., Arthritis Rheum 38 (1995), 727-35).
  • the anti-TTR antibody as defined hereinbefore i.e., an anti-TTR antibody which is capable of binding mutated, misfolded, misassembled and/or aggregated transthyretin (TTR) species and which comprises in a preferred embodiment the indicated sequences and which is most preferably antibody NI006/ALXN2220 characterized by its CDRs and its VH and VL region, respectively, and most preferably by its two heavy chains and two light chains, can be used in a method of diagnosing a musculoskeletal disorder or condition in a subject, e.g., a human patient which is in particular associated with amyloidogenic TTR deposits in the joints/bones.
  • the musculoskeletal disorder is a muscular disorder as defined hereinbefore. An increased antibody binding in/at the joints and/or bones of the patient and the respective tissue, respectively, in comparison to a control is indicative for the disease.
  • the present invention further relates to kit for treating or preventing a musculoskeletal disorder or condition as defined hereinbefore in a human patient, the kit comprising a dose of an antitransthyretin (TTR) antibody which is capable of binding mutated, misfolded, misassembled or aggregated transthyretin (TTR) species, preferably wherein the antibody is the antibody or antigen-binding fragment thereof as defined hereinbefore and most preferably antibodyNI006/ALXN2220 as characterized by its CDRs and its VH and VL region, respectively, and most preferably by its two heavy chains and two light chains; and instruction for using the anti-TTR antibody in the method of treatment as defined hereinbefore.
  • TTR transthyretin
  • Example 1 A phase 1 (la/lb) first-in-human, double-blind, placebo-controlled, international, multicenter, single- and multiple-ascending dose randomized clinical trial in patients with ATTR-CM and chronic heart failure followed by an open label extension phase
  • NI006 is a recombinant human anti-ATTR monoclonal IgGl antibody that was generated based on a comprehensive immune repertoire analysis of memory B-cell complements of healthy elderly human subjects as described for example in WO 2015/092077 Al, where the antibody is named NI-301.37F1.
  • Amyloid transthyretin cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin.
  • NI006/ALXN2220 is a recombinant human anti-ATTR antibody developed to remove ATTR amyloid by phagocytic immune cells.
  • the present study was a phase 1 (la/lb) double-blind, placebo-controlled, international, multicenter, single-ascending dose (SAD) and multiple-ascending dose (MAD) randomized clinical trial in patients with ATTR-CM and chronic heart failure followed by an open label extension (OLE) phase.
  • Patients were randomized 4:2 to NI006/ALXN2220 or placebo.
  • Patients randomized to NI006/ALXN2220 were sequentially enrolled in 6 ascending dose cohorts from 0.3 mg/kg to 60 mg/kg.
  • the study comprised a 4-month placebo-controlled single- and multiple-ascending dose phase followed by an 8-month open-label extension phase where all patients (placebo and NI006/ALXN2220-treated) received NI006/ALXN2220.
  • the first 2 patients in each dose cohort were randomized 1 :1 to receive NI006/ALXN2220 or placebo.
  • the 4 subsequent patients in each cohort were randomized in a 3 : 1 ratio to NI006/ALXN2220 or placebo if no relevant safety signals occurred in the sentinels.
  • the next higher dose cohort was opened.
  • NI006/ALXN2220 was administered as IV infusion over approximately 2 hours ( ⁇ 10 minutes; except for up to 3 hours at 60 mg/kg) at first infusion without premedication. Subsequent infusions were administered over approximately 50 - 70 minutes without premedication. Patients were hospitalized for 4 nights after the initial single-ascending dose administration and after the first open label extension administration (i.e. first NI006/ALXN2220 administration in patients randomized to placebo), and for 1 to 2 nights after each of the three MAD administrations. All further administrations in the open label extension phase were performed as outpatient visits.
  • the study population was comprised of patients with a confirmed diagnosis of ATTR-CM, with a left ventricular wall thickness of at least 14 mm, a left ventricular ejection fraction of at least 40%, NYHA classes I to III, eGFR of greater than 30 mL/min/1 ,73m 2 , and an NT-proBNP level between 600 and 6000 pg/mL at the time of screening; see Table 1 below.
  • Concomitant treatment with tafamidis was allowed, but treatment with other ATTR-specific drugs was not permitted.
  • Patients were recruited at 6 specialized amyloidosis centers in 4 European countries between February 2020 and April 2022.
  • the primary objective was to determine the safety and tolerability profile of NI006/ALXN2220. Dose escalation was guided by assessing clinically relevant treatment-emergent adverse events (AEs) and safety markers that included laboratory tests, echocardiography, and ECGs. Blinded safety data were monitored continuously by both the investigators and sponsor and reviewed by the Data Evaluation Committee. Pharmacokinetic profile and immunogenicity assessments
  • Serial serum NI006/ALXN2220 concentrations were measured throughout the study in all patients using a validated assay. Individual total serum NI006/ALXN2220 exposures were calculated as the area under the curve from the simulated pharmacokinetic profiles. In more detail, serum NI006/ALXN2220 concentrations were measured using a validated sandwich ELISA assay built on two anti-idiotypic Fab fragments binding selectively to NI006/ALXN2220. The assay lower limit of quantification (LLOQ) was 0.17 ug/mL.
  • NCA noncompartmental analysis
  • Bisphosphonate scintigraphys were acquired at trial sites using " m Tc-hydroxyl-methylene- diphosphonate (HMDP) or " m Tc-3,3-diphosphono-l,2-propanodicarboxylic acid (DPD) as tracers according to a harmonized acquisition protocol established in a laboratory manual during trial set-up. Adherence to the laboratory manual and image quality was monitored continuously. Planar whole-body images were acquired 3h after tracer infusion. Reading of acquired images was performed centrally at the imaging core lab by two independent nuclear physicians using Syngovia software (Siemens) blinded to the pseudonymized patient ID, treatment allocation, dose cohort and acquisition timepoint. To calculate the heart-to- whole body retention ratio (H/WB ratio), potential areas of high tracer retention (e.g. bladder, kidneys, injection site) were considered as rejection areas in the following formula:
  • Consensus readings were performed in case of disagreement between both readers beyond a pre-defined range of ⁇ 10% for the key parameters.
  • MRIs Cardiac MRIs were recorded using local scanners at the study sites. The acquisition protocol was based on latest guidelines and standardized across all sites during the trial set-up phase and adherence to the laboratory manual was continuously monitored. MRI scans were interpreted by two independent readers (specialized radiologists or cardiologists) at the imaging core lab using Medis software (Medis, Leiden, The Netherlands). All MRIs were analyzed individually; central readers blinded to the pseudonymized patient ID, treatment allocation, dose cohort and acquisition timepoint. The MRI acquisition and analysis procedure was similar to the method described by Martinez-Naharro et al., Am Coll Cardiol 70 (2017), 466-477.
  • KCCQ- OS Kansas City Cardiomyopathy Questionnaire - Overall Summary
  • 6-MWD 6-minute walk distance
  • echocardiography The scores from a KCCQ-OS questionnaire range from 0 to 100 with 0 to 24 indicating very poor to poor, 25 to 49 indicating poor to fair, 50 to 74 indicating fair to good, and 75 to 100 indicating good to excellent quality of life.
  • Standardized echocardiograms were acquired at 3 timepoints throughout the trial: Full echocardiograms for efficacy analyses were recorded at baseline prior to the first treatment, after MAD completion (4 months) and after open label extension completion (12 months). Harmonized acquisition protocols were applied across all sites and analysis was performed centrally at the imaging core lab (Biotrial, Rennes, France) by an experienced cardiologist with demonstrated low intra-reader variability blinded to the pseudonymized patient ID, treatment allocation, dose cohort and acquisition timepoint. Measurements were performed in triplicate (sinus rhythm) or quintuplet (atrial fibrillation) using EchoP AC CE Medical software (GE Healthcare, Milwaukee, MI, USA) and the mean value of the triplicates/quintuplets was used for further analysis. If recording did not allow measurement of individual parameters (e.g., poor echogenicity, insufficient number of loops recorded, suboptimal section), measurements were reported as missing.
  • results presented here were generated after all patients in the highest dose cohort had completed the placebo-controlled single- and multiple-ascending dose phases. Results are presented for all patients that received at least one dose of NI006/ALXN2220 or placebo (safety population). All available data from the open label extension phase were included (data cut-off November 03, 2022). There were no formal statistical hypotheses tested and no imputations were performed for missing data. Patients randomized to NI006/ALXN2220 were grouped according to their nominal dose cohort at enrollment, while patients who were assigned to placebo were pooled from all dose cohorts. Open label extension data were aggregated using the same, nominal group allocation.
  • Prespecified grouping of patients receiving higher (at least 10 mg/kg) or lower (up to 3 mg/kg) doses was done to explore the effects of NI006/ALXN2220. Absolute or relative change from baseline at 4 and 12 months were calculated. A pre-open label extension baseline evaluation was used for the calculation of change during the open label extension for patients randomized to placebo. Data handling and analysis was performed using Statistical Analysis System® (SAS®) version 9.4, and GGplot2 package for R was used for data visualization.
  • SAS® Statistical Analysis System®
  • NT-proBNP N-terminal pro-B-type natriuretic peptide
  • GFR glomerular filtration rate which was estimated using the Chronic Kidney Disease-Epidemiology Collaboration equation, NAC National Amyloidosis Center, and NYHA: New York Heart Association.
  • Table 3 Additional baseline characteristics
  • the scores from a KCCQ questionnaire range from 0 to 100 with 0 to 24 indicating very poor to poor, 25 to 49 indicating poor to fair, 50 to 74 indicating fair to good, and 75 to 100 indicating good to excellent quality of life.
  • 6MWD denotes 6-minute walk distance
  • ACE Angiotensin-converting enzyme
  • ARB Angiotensin Receptor Blocker
  • ECV extracellular volume
  • ED-IVS end-diastolic interventricular septum H/WB ratio of heart to whole body
  • LAV left atrial volume LVEF left ventricular ejection fraction
  • LVESV/LVEDV left ventricular end-systolic/diastolic volume LAV left atrial volume
  • NAC National Amyloidosis Center KCCQ-OS Kansas City Cardiomyopathy Questionnaire-Overall Summary score
  • SGLT2 Sodiumglucose Cotransporter-2.
  • NI006/ALXN2220 appeared to have a favorable safety profile up to the highest dose level; no patient experienced a dose-limiting toxicity and no serious adverse event (SAE) occurred that was considered related to NI006/ALXN2220 (Table 4).
  • SAE serious adverse event
  • AE adverse event
  • AEs heart failure and arrhythmias, which is expected in this patient population.
  • the frequency and type of AEs appeared similar across NI006/ALXN2220 dose cohorts.
  • Three patients who were assigned to the 10 mg/kg or the 30 mg/kg cohorts experienced cytokine release syndrome with an associated increase in cardiac biomarkers, a non-serious grade 1 or 2 AE, during the single- and multiple-ascending dose phase. All 3 patients completed dosing throughout the study and the open label extension phase without recurrence; see narratives below.
  • a numerical increase in musculoskeletal events was observed with ascending doses in the single- and multipleascending dose phase and in placebo patients when switched to NI006/ALXN2220 in the open label extension phase.
  • the majority of these events were of mild intensity, managed with nonsteroidal anti-inflammatory drugs or low dose corticosteroids that were tapered off during continued treatment but did lead to one patient in the 10 mg/kg dose group discontinuing the trial and one patient from the 30 mg/kg dose group withdrawing consent to participate in the open label extension phase.
  • the first patient (with ATTRv, 68-years old, NYHA stage II, NAC stage II, MAYO stage II, who had a baseline NT-proBNP level of 4088 pg/mL) was initially assigned to placebo and received only 4 administrations of NI006/ALXN2220 during the open label extension phase (10 mg/kg dose at each administration). He was hospitalized for heart failure once during the single-ascending dose/multiple-ascending dose phase while on placebo, once at the end of the open label extension phase, and once more during the follow-up period after the open label extension phase. He died 99 days after the last administration of NI006/ALXN2220. The patient’s cause of death was disease progression.
  • the second patient was 85-years old with ATTRwt and NAC stage III at baseline (NYHA stage II, MAYO stage III, with a baseline NT-proBNP level of 3776 pg/mL).
  • This patient experienced progressive deterioration with multiple heart failure hospitalizations during the open label extension phase.
  • This patient received a total of 8 infusions (6 infusions of the 3mg/kg dose and 2 infusions of the 10 mg/kg dose), when patient’s condition no longer permitted participation in the trial.
  • the patient died at home 77 days after the last administration of NI006/ALXN2220.
  • Case 1 (Cohort 4; lOmg/kg dose group) is a 74-y ear-old male with NYHA Class I heart failure who experienced cytokine release syndrome of moderate intensity as evidenced by transient elevation of body temperature (38 °C) and heart rate (95 bpm) with a concomitant decrease in blood pressure to 93/51 mmHg and oxygen saturation (88% on room air) approximately 30 hours after completion of the first administration of NI006/ALXN2220.
  • Treatment for cytokine release syndrome included IV corticosteroids, IV fluids, oxygen via nasal cannula, and antipyretics. No infectious etiology for the vital sign changes were identified.
  • a Grade 1 treatment emergent adverse event of ventricular arrhythmia (12 beat run of non-sustained ventricular tachycardia) was reported on Day 4; the participant was otherwise asymptomatic throughout the hospitalization and was discharged per protocol on Day 5 and did not experience additional events of cytokine release syndrome or myocarditis during continued participation, including after up-titration to 30 mg/kg.
  • Case 2 (Cohort 5; 30mg/kg dose group), a 69-y ear-old male with NYHA Class II heart failure and bilateral carpal tunnel syndrome, experienced cytokine release syndrome of mild intensity as evidenced by progressive swelling, warmth, and pain in both wrists, myalgia of both thighs, and elevations of C-reactive protein (23 mg/1; reference range ⁇ 5 mg/1) and interleukin-6 (108 pg/ml) approximately 9 hours after completion of the second administration of NI006/ALXN2220, for which he received treatment with cool packs and antipyretics. There were no concurrent clinically meaningful changes in blood pressure, heart rate, body temperature, or oxygen saturation.
  • the participant was discharged per protocol on day 3 after the infusion.
  • the participant continued treatment as planned, with recurring pain in different small joints in both the upper and lower limbs, including a moderate relapse of reactive arthritis of the wrists with minimal C-reactive protein elevation (11.4 mg/1) occurring days after the third dose, for which he received treatment with glucocorticoids.
  • the patient also had two cardiac-related events reported: myocarditis (day 53) associated with a peak troponin 45.3 pg/ml (pre-dose level: 31.8 pg/ml) without any other cardiac abnormalities (no cMRI was performed) and without associated symptoms following the second dose of study drug .
  • the troponin subsequently returned to baseline by day 65 and an additional event of increased troponin (day 99 through day 120, peak level: 45 pg/ml) occurred following the third dose of study drug.
  • Case 3 (Cohort 5; 30mg/kg dose group), a 60-year old male with NYHA Class II heart failure, experienced cytokine release syndrome of mild intensity evidenced by flushing of face and arms, headache, and elevated body temperature (39.2°C) approximately 30 minutes after completion of the first administration of NI006/ALXN2220, for which he received treatment with glucocorticoids and antipyretics. Lab results demonstrated a moderate increase of interleukin-6 (45.3 pg/ml; baseline ⁇ 12.9 pg/mL) on Day 3 and of C-reactive protein (65.7 mg/1) on Day 4.
  • Adverse event (AE) severity was classified according to the Common Terminology Criteria for Adverse Events (CTCAE) grading scale where Grade 0 is no symptoms and Grade 5 is death related to an adverse event. Data are presented as n of patients (percentage in cohort) and [number of events] .
  • Numbers represent n of patients (% within group) and [n of events] .
  • CCAE Common Terminology Criteria for Adverse Events
  • Table 6A AE Summary for Combined Single- and Multiple-Ascending Dose Phase and Open Label Extension Phase (0.3 mg/kg - 10 mg/kg)
  • Table 6B AE Summary for Combined Single- and Multiple-Ascending Dose Phase
  • Numbers represent n of patients (% within group) and [n of events] .
  • CCAE Common Terminology Criteria for Adverse Events
  • the NI006/ALXN2220 pharmacokinetic profile was consistent with human IgG characteristics with low-to-moderate inter-subject variability: following a single intravenous dose, serum NI006/ALXN2220 concentrations declined in a biphasic manner with an elimination half-life ranging from 15.5 to 19.2 days. Exposure to NI006/ALXN2220, which was as measured as the maximal concentration and the area under the curve, increased with higher doses in a doseproportional manner. None of the patients developed anti-drug antibodies throughout the study, including during the open label extension phase.
  • NT -proBNP and Troponin-T appeared to be associated with exposure to higher doses of NI006/ALXN2220.
  • Table 9B Baseline and Changes in Cardiac Biomarkers at 4 and 12 Months (30 mg/kg, 60 mg/kg, NI006/ALXN2220 low dose, NI006/ALXN2220 high dose)
  • KCCQ-OS Kansas City Cardiomyopathy Questionnaire - Overall Summary questionnaire
  • the scores from a KCCQ-OS questionnaire range from 0 to 100 with 0 to 24 indicating very poor to poor, 25 to 49 indicating poor to fair, 50 to 74 indicating fair to good, and 75 to 100 indicating good to excellent quality of life.
  • Table 11 Baseline and Changes in Echocardiographic Parameters at 12 Months Numbers represent mean ⁇ SD and median (interquartile range).
  • ED-IVS denotes end-diastolic interventricular septum, LVEF left ventricular ejection fraction, LVESV left ventricular end-systolic volume, LVEDV left-ventricular end-diastolic volume, LAV left atrial volume, and E/e’ the ratio between the early mitral inflow velocity and mitral annular early diastolic velocity.
  • Dose response relationship for investigator-reported signs of musculoskeletal immune activation To identify signs of musculoskeletal immune activation, clinically reported (adverse) events that were coded in the System Organ Class (SOC) musculoskeletal and connective tissue disorders were used. As shown in Table 12, in high dose cohorts (> 10 mg/kg) (cohorts 4-7 of the NI006/ALXN2220 arm), signs of musculoskeletal immune activation are most frequent immediately after treatment initiation (SAD/MAD Phase). Over time, signs are reported less frequently.
  • SOC System Organ Class
  • Table 12 Dose response relationship for investigator-reported signs of musculoskeletal immune activation associated with the NI006/ALXN2220 treatment, "n" is total number of patients per cohort / phase. The number of affected patients is in [brackets] and the number with no brackets is the number of adverse events.
  • NI006/ALXN2220 appeared favorable up to the highest dose tested. There was no apparent dose-limiting toxicity and no drug-related serious adverse reactions occurred. The pharmacokinetic profile was consistent with an IgG antibody, and no anti-drug antibodies were detected. At doses of at least 10 mg/kg, scintigraphy tracer uptake and extracellular volume assessed by cardiac MRI, both imaging surrogates for amyloid deposition, appeared to be reduced. In addition, concomitantly scintigraphy tracer uptake in the shoulders and elbows appeared to be reduced. Median NT -proBNP and Troponin-T levels also seemed to be decreased over 12 months.
  • NI006/ALXN2220 The favorable safety profile of NI006/ALXN2220 and the absence of anti-drug antibodies and dose-limiting toxi cities may be related to the human source of NI006/ALXN2220’s amino acid sequence and its selectivity for misfolded ATTR with absent binding to physiological TTR; see Mi chai on etal., Nat Commun 21 (2021), 3142. In fact, there were no variations of TTR plasma levels observed across dose cohorts (Table 13).
  • arthralgias might be more common with NI006/ALXN2220 and possibly related to NI006/ALXN2220's activation of phagocytic immune cells aimed at musculoskeletal ATTR deposits; see Basdavanos et al., Am J Cardiol 190 (2023), 67-74; Rubin et al., Amyloid 24 (2017), 226-230, which could explain the concomitant reduction in tracer uptake in the shoulder and elbow joints observed during the present study.
  • Bisphosphonate scintigraphy uptake has also been associated with histological cardiac amyloid load and outcomes in ATTR-CM patients; see Morioka et al., J Am Heart Assoc 11 (2022), e024717; Castano et al., JAMA Cardiol 1 (2016), 880-889; Rapezzi et al., JACC Cardiovasc Imaging 4 (2011), 659-70; Hutt et al., Eur Heart J Cardiovasc Imaging 18 (2017), 1344-1350.
  • TTR tetramer stabilizers, silencers and TTR gene-editing therapy have been designed to prevent ATTR accumulation, but do not target amyloid that has already been deposited in the heart directly; see loannou et al., Circulation 146 (2022), 1657-1670; Lopez-Sainz et al., Rev Esp Cardiol (Engl Ed) 74 (2021), 149-158; Gillmore et al., N Engl J Med 385 (2021), 493-502.
  • NI006/ALXN2220 at doses of at least 10 mg/kg, seemed to reduce heart-to- whole body ratio on scintigraphy and cMRI extracellular volume values after 4 and 12 months of treatment.
  • NT-pro-BNP and Troponin levels are frequently elevated and associated with a worse prognosis; see Grogan et al., J Am Coll Cardiol 68 (2016), 1014-20; Gillmore et al., Eur Heart J 39 (2016), 2799-2806; Law et al., ESC Heart Fail 7 (2020), 3942-3949.
  • Echocardiographic assessments as well as functional and quality-of-life measures, such as 6- minutes walking distance and the KCCQ-OS score, respectively, are also frequently used to measure disease progression; see Garcia-Pavia et al., Eur J Heart Fail 23 (2021), 895-905.
  • NT -proBNP 500 pg/mL from baseline to 12 months
  • Biomarkers, including NT -proBNP and Troponin T, echocardiographic assessments and clinical assessments are suggestive of a clinical improvement.
  • Antibody NI006/ALXN2220 was produced in the CHO-K1 cell line (ATCC No. CCL 61) and obtained from the cell culture after culturing in a large-scale production bioreactor.
  • the amino acid sequence of NI006/ALXN2220’s mature heavy chain (HC) and light chain (LC) is set forth in SEQ ID NOs: 18 and 19, with the below-mentioned modifications.
  • the total number of amino acids, number of amino acids of the heavy chain, and number of amino acids of the light chain are 1328, 450, and 214, respectively.
  • characterization of antibody NI006/ALXN2022 was mainly performed by standard procedures, for example by mass spectroscopy analysis.
  • mass spectroscopy analysis For example, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of fragments of NI006/ALXN2220 obtained from Lys-C and trypsin sequential digestion as well as free sulfhydryl analysis was used to identify post-translational modifications of NI006/ALXN2220.
  • LC-MS/MS liquid chromatography with tandem mass spectrometry
  • the characterization of antibody-based therapeutics via LC-MS analysis is a standard procedure and can be performed by a skilled artisan; see for example Robotham and Kelly, Approaches to the Purification, Analysis and Characterization of Antibody-Based Therapeutics (2020), 1-33.
  • N-glycan profiling was performed by releasing the N-glycans by using PNGase F and subsequent labelling with 2-AB, followed by HILIC (Hydrophilic Interaction Chromatography) separation and fluorescence detection (FLD) with a UPLC system. Individual N-glycans and unknown peaks were quantified by their peak area percentages relative to the total peak area.
  • HILIC Hydrophilic Interaction Chromatography
  • the molecular weight of antibody NI006/ALXN2220 as determined by standard mass spectroscopy is approximately 147.1 kDa for the intact IgGl and 144.2 kDa for the deglycosylated variant.
  • the monoclonal antibody NI006/ALXN2220 is an IgGl subclass antibody, which is composed of two heavy chains of the IgGl subclass and two light chains of the kappa subclass. The four chains are stabilized by multiple disulfide bonds. In particular, as determined by standard procedures, i.e., per Lys-C and trypsin digestion and subsequent LC-MS, at least the following disulfide bridges are present in NI006/ALXN2220:
  • NI006/ALXN2220 is a glycoprotein and the constant region of each heavy chain contains one N-linked glycan site at residue N300.
  • the major N-glycan types are GOF (-49.0%) and GIF (-25.4%).
  • the following glycosylation profile (the types of sugar, the location of glycosylation site(s), etc.) has been determined for NI006/ALXN2220:
  • the nomenclature of the glycans follows the order of HexNac-Hexose-Fucose-NeuAc-NeuGc. For example, 23000 is HexNac(2)-Hexose(3)-Fucose(0)-NeuAc(0)-NeuGc(0).
  • GIFa and GIFb are isomers and are grouped into GIF.
  • GIF is calculated as the sum of GIFa and GIFb using the original unrounded numbers.
  • HC refers to heavy chain and LC refers to light chain.
  • pE(Q) refers to the N-terminal glutamine modified as pyro-glutamic acid.
  • -K refers to loss of the C-terminal lysine.
  • -K -G Amidation(P) refers to the amidation of the C-terminal proline after the loss of the C-terminal lysine and glycine.
  • N-linked glycosylation of the heavy chain N-terminal pyro-glutamic acid modified from N-terminal glutamine, and C-terminal lysine clipping of the heavy chain are the major post-translational modifications of NI006/ALXN2220

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Abstract

L'invention concerne une immunothérapie de maladies et de troubles musculo-squelettiques qui sont associés à l'amylose liée à la transthyrétine.
PCT/EP2024/063351 2023-05-19 2024-05-15 Nouvelle immunothérapie pour troubles et états musculo-squelettiques WO2024240562A1 (fr)

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WO2012080518A1 (fr) 2010-12-17 2012-06-21 Neurimmune Holding Ag Anticorps humains anti-sod1
WO2014124334A2 (fr) * 2013-02-08 2014-08-14 Misfolding Diagnostics, Inc. Anticorps anti-transthyrétine et leurs utilisations
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