Methods and compositions for treating mmp-9-mediated disorders

Abstract

This disclosure provides methods and compositions for treating non-hereditary heterotopic ossification and hereditary heterotopic ossification such as progressive ossifying fibrous dysplasia (FOP). These methods involve MMP-9 inhibition in therapeutic applications.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 542,679, filed October 5, 2023, and U.S. Provisional Application Serial No. 63 / 699,035, filed September 25, 2024, the entire disclosure of which is incorporated herein by reference for all purposes. Technical Field

[0003] This invention generally relates to the field of treating conditions related to extracellular matrix enzymes and proteases, and the application of therapeutic or preventative compositions to treat such conditions. Background Technology

[0004] Matrix metalloproteinases (MMPs) are enzymes involved in the formation and remodeling of the extracellular matrix. All MMPs possess a conserved catalytic domain containing a zinc atom coordinated to three histidine residues. Types of MMPs include collagenases, gelatinases, matrix lysins, matrix solubilizers, ameliolytics, and membrane MMPs. Structurally, MMP-9 is a gelatinase, thus possessing the signal peptide, propeptide, catalytic domain, zinc-binding domain, and heme-binding-like domain common to MMPs, as well as multiple fibronectin-like domains and an O-glycosylation domain. Specifically, MMP-9 possesses a heme-binding-like domain, a catalytic domain, a signal peptide, a hinge region, and a propeptide region. The catalytic domain of MMP-9 includes a fibronectin type II (FN2) domain, an active site, and a zinc-binding region, and the activity of the MMP-9 enzyme is zinc-dependent. MMPs can degrade a variety of extracellular matrix (ECM) components and influence cell-cell and cell-matrix interactions. MMP-9 is involved in many developmental processes, including ECM degradation, angiogenesis, and endochondral ossification (within the MMP family, it appears to play a unique role in endochondral ossification). Compared to its limited expression in healthy tissues, MMP-9 is found to be highly elevated in many human diseases. Studies in gene knockout mice have revealed the opposing effects of MMP-9 to its closest related MMP, MMP-2 (the only other gelatinase). While MMP-9 deficiency provides protection against disease in a variety of different models, MMP-2 deficiency often lacks this benefit and may even exacerbate the disease. MMP-9 substrates include matrix proteins, growth factors, and cytokines. In addition to extracellular matrix remodeling, MMP-9 can enhance the bioavailability of growth factors (e.g., releasing VEGF from heparan sulfate proteoglycans) or enhance cytokine activity through cleavage. MMP-9 has also been shown to be involved in cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT).

[0005] Numerous studies have demonstrated that MMPs are suitable targets for treating cardiovascular diseases, autoimmune diseases, and cancer. Despite considerable efforts to target MMPs, developing MMP inhibitors for various indications remains challenging, perhaps because different MMPs share conserved catalytic domains. Small-molecule inhibitors targeting catalytic domains not only affect specific MMPs associated with pathogenesis but also other MMPs essential for maintaining normal function. For example, a broad-spectrum MMP inhibitor has been found to have musculoskeletal toxicity. Another broad-spectrum inhibitor, doxycycline, approved for the treatment of periodontal disease, appears to inhibit the synthesis and activity of MMP-2.

[0006] Targeted therapies are under development, such as anddaliximab, a recombinant chimeric humanized antibody against MMP-9, which has been evaluated in multiple clinical trials for its efficacy in various conditions, including chronic obstructive pulmonary disease, gastric adenocarcinoma, Crohn's disease, rheumatoid arthritis, cystic fibrosis, various solid tumors, and ulcerative colitis. Anddaliximab binds to the R162 residue in the catalytic domain of MMP-9 and other residues near the MMP-9 propeptide cleavage site.

[0007] Fibrocystic ossifying dysplasia (FOP) is a rare autosomal dominant genetic disorder characterized by progressively worsening heterotopic ossification of soft connective tissue. It affects approximately one in 1.3 to 2 million people worldwide. FOP patients experience intermittent episodes of soft tissue inflammation, which can be spontaneous or triggered by factors such as trauma, injury, disease, or immunization. These episodes lead to heterotopic ossification of soft tissue, which, over time, results in increasingly limited joint mobility and functional impairment. In some cases, episodes may occur even without subsequent heterotopic ossification.

[0008] MMP-9 plays several key roles in osteogenic osteoporosis (FOP). The pathogenesis of FOP is primarily associated with a highly recurrent autosomal dominant gain-of-function missense mutation, ACVR1 R206H, in the ACVR1 / ALK2 gene, which encodes the BMP receptor. Studies have shown that in the case of ALK2 R206H, activin A has been identified as a key ligand that promotes the differentiation of tissue-resident fibroadipocyte progenitors into chondrocytes. Activin A is not a typical osteogenic BMP ligand, normally initiating pSMAD2 / 3 signaling via its receptor. However, unlike wild-type ALK2, ALK2 R206H responds to activin A, initiating aberrant pSMAD1 / 5 / 8 (BMP-mothers targeting decapentagenic homologs 1 / 5 / 8) signaling, chondrogenesis, and chondrogenesis (HO). The source of activin A appears to be inflammatory cells (e.g., macrophages) recruited to potential HO formation sites, and the availability of activin A is considered a limiting factor in HO development. In vivo studies have shown that chondrocytes continuously require activin A in early FOP lesions. The long-spliced ​​form of activin A, produced by inflammatory macrophages (and possibly chondrocytes), associates with the heparin sulfate chain of dermolysin, which can isolate activin A in the extracellular matrix. Important MMP-9 substrates include extracellular matrix proteins such as heparan sulfate proteoglycans (HSPGs) and fibrin. The intense inflammation associated with FOP flare-ups induces the expression of both activin A and MMP-9, and MMP-9 can biologically activate activin A, thereby driving abnormal chondrogenesis instead of normal tissue repair.

[0009] MMP-9 may play other roles in FOP. BMP signaling is matrix-regulated, which is achieved by tethering BMP ligands (such as BMP2, 4, etc.) to extracellular matrix proteins (such as heparan sulfate proteoglycans (e.g., perfumin) and fibrin, thereby limiting their activity. These proteins are substrates for MMP-9. For example, MMP-9 generates bioavailable VEGF by releasing it from heparan sulfate proteoglycans. MMP-9 can promote BMP signaling through BMP produced by both macrophages and early progenitor cells (which differentiate into chondrocytes), and continuously drive chondrocyte or osteoblast activation by providing bioavailable BMP. Subsequently, it further promotes bone formation through matrix remodeling, angiogenesis (including VEGF), and the recruitment of other progenitor cells. MMP-9 may play a further role in the recruitment and / or activation of progenitor cells.

[0010] There is currently no cure for FOP. Current treatment focuses on reducing inflammation in the early stages of an attack using corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), mast cell inhibitors, leukotriene inhibitors, and bisphosphonates. Prevention of attacks emphasizes avoiding trauma and injury. Non-hereditary HO usually occurs after trauma or surgery. It occurs in up to 40% of hip replacement cases, 30% of fractures or dislocations, high-energy limb trauma, spinal cord injury, trauma, brain injury, burns, fractures, muscle contusions, arthroplasty / replacement, hip surgery / replacement, acetabular surgery / replacement, elbow fractures, long bone fractures of the lower leg, combat-related trauma, amputations, neuromuscular blocks used to manage adult respiratory distress syndrome, non-traumatic myelopathy and other neurological disorders, and more than 90% of severe traumatic amputations. (Meyers C, et al. Heterotopic Ossification: A Comprehensive Review. JBMR Plus. 3(4)(2019):e10172. doi:10.1002 / jbm4.10172). The development of HO is also associated with several predisposing factors, which are often pro-inflammatory, such as axial spondyloarthritis or ankylosing spondylitis and conditions like diffuse idiopathic hypertrophic osteoarthritis (DISH). HO has also been described in patients who experience severe complications following infections such as SarsCoV2 / COVID-19.

[0011] Heterotopic ossification occurs in one or more tissues selected from bone, skin, subcutaneous tissue, skeletal muscle, tendon, ligament, aponeurosis, fibrotic tissue near joints, blood vessel walls, and ligaments.

[0012] As disclosed by Hatsell et al., previous studies have shown that genetic variations in HO, such as progressive ossifying fibrous dysplasia (FOP), are caused by overactivation mutations in the type I bone morphogenetic protein receptor (Tl-BMPR) ACVR1 / ALK2. Therefore, studies evaluating HO therapies have primarily focused on drugs targeting this specific receptor (Hatsell SJ, et al., (2015). Sci Transl Med., 7(303):303ra137). However, trauma-induced HO patients do not carry known T1-BMPR mutations. Although NHHO requires BMP signaling, the presence of a single Tl-BMPR (ACVR1 / ALK2, BMPR1a / ALK3, or BMPR1b / ALK6) alone is insufficient to cause the disease (Agarwal S, et al., (2017). MolTher, 25(8):1974-1987).

[0013] This disclosure provides a method for treating hereditary forms of heterotopic ossification, such as progressive ossifying fibrous dysplasia (FOP), by inhibiting MMP-9, thereby effectively treating or improving clinical outcomes in patients with such conditions without the harmful effects of broad-spectrum MMP inhibitors. For FOP, the first-line therapy can be initiated early in childhood and continued throughout life to reduce or prevent the onset and accumulation of heterotopic ossification, both of which are difficult to predict. Summary of the Invention

[0014] In some embodiments, this document discloses methods for treating non-hereditary heterotopic ossification and hereditary heterotopic ossification (gHO) such as progressive fibrous ossifying dysplasia of bone (FOP) by administering an effective amount of one or more MMP-9 inhibitors. In some embodiments, the MMP-9 inhibitor may be an anti-MMP-9 antibody or its antigen-binding fragment, an inhibitory RNA, an inhibitory peptide, a small molecule inhibitor, or a CRISPR-Cas system.

[0015] In some embodiments, this document discloses a method for treating inflammatory episodes in subjects with progressive ossifying fibrous dysplasia (FOP), comprising administering an MMP-9 inhibitor to the subject. In some embodiments, the inflammatory episode is associated with ectopic ossification in the subject. In some embodiments, the inflammatory episode is not associated with ectopic ossification in the subject. In some embodiments, the episode is spontaneous or caused by an external trigger. In some embodiments, the external trigger is selected from intramuscular injection, biopsy, muscle fatigue, dental procedures, trauma, or infection. In some embodiments, the external trigger is unknown. In some embodiments, the external trigger is ectopic ossification in the subject. In some embodiments, the method reduces the frequency of inflammatory episodes compared to the frequency of inflammatory episodes prior to administration of the MMP-9 inhibitor. In some embodiments, the method reduces the severity of inflammatory episodes compared to the severity of inflammatory episodes prior to administration of the MMP-9 inhibitor.

[0016] In some embodiments, this document discloses a method for treating gHO in a subject in need, comprising administering an MMP-9 inhibitor to the subject.

[0017] In some embodiments, the MMP-9 inhibitor is selected from anti-MMP-9 antibodies or their antigen-binding fragments, inhibitory RNA, inhibitory peptides, small molecule inhibitors, and CRISPR-Cas systems.

[0018] In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment is an anti-MMP-9 antibody or its antigen-binding fragment. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment binds to: (i) a precursor form of MMP-9 and inhibits the activation of said precursor form; and / or (ii) an active form of MMP-9 and inhibits the activity of said active form. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment binds to the precursor form of MMP-9. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment binds to the active form of MMP-9. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7.In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises an amino acid sequence having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises VH and VL, wherein the VH comprises amino acids having at least 99% (e.g., at least 99%, or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises an amino acid sequence having at least 99% (e.g., at least 99%, or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises VH and VL, wherein VH comprises an amino acid having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises adeliximab or its antigen-binding fragment. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with any of the amino acid sequences listed in Table 1.In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater) identity with any of the amino acid sequences listed in Table 1. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater) identity with any of the amino acid sequences listed in Table 1. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or greater) identity with any of the amino acid sequences listed in Table 1. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences having at least 99% (e.g., at least 99% or greater) identity with any of the amino acid sequences listed in Table 1. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences having 100% identity with any of the amino acid sequences listed in Table 1.

[0019] In some embodiments, the repressive RNA comprises an antisense oligonucleotide (ASO), short interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), or shRNA-adapted microRNA (shmiRNA). In some embodiments, the repressive RNA comprises ASO. In some embodiments, the repressive RNA comprises siRNA. In some embodiments, the repressive RNA comprises miRNA. In some embodiments, the repressive RNA comprises shRNA. In some embodiments, the repressive RNA comprises shmiRNA. In some embodiments, the repressive RNA comprises a nucleic acid sequence of any one of SEQ ID NO: 63-80.

[0020] In some embodiments, the repressive RNA or the CRISPR-Cas system is configured in lipid nanoparticles (LNPs).

[0021] In some embodiments, the method further includes administration of an additional active agent or supportive therapy for treating gHO. In some embodiments, the additional active agent or supportive therapy for treating gHO is selected from isotretinoin, etidronate in combination with oral corticosteroids, piperacillin maleate, activin A inhibitors, activin A receptor type 2 (ALK2) inhibitors, ALK2 allele-specific RNA interference, hypoxia-inducible factor-1α (Hif-1α) inhibitors, small molecule inhibitors of the bone morphogenetic protein (BMP) signaling pathway, anti-BMP9 antibody or its antigen-binding fragment, anti-BMP10 antibody or its antigen-binding fragment, anti-TGF-β antibody or its antigen-binding fragment, IL1β inhibitors, IL6 inhibitors, molotinib, cromoglycine, imatinib, adenosine triphosphate bisphosphatase, rapamycin, kinase inhibitors, zicatinib, parovatin, retinoic acid receptor gamma agonists, retinoic acid receptor alpha agonists, bisphosphonates, radiotherapy, anti-inflammatory drugs, physical therapy, and combinations thereof. In some embodiments, the adjunctive active agent comprises a second MMP inhibitor selected from MMP-2 inhibitors, MMP-7 inhibitors, MMP-13 inhibitors, MMP-14 inhibitors, or MMP-16 inhibitors. In some embodiments, the adjunctive active agent or supportive therapy is administered in parallel with the MMP-9 inhibitor. In some embodiments, the adjunctive active agent or supportive therapy is administered sequentially with the MMP-9 inhibitor.

[0022] In some embodiments, the gHO is FOP. In some embodiments, the gHO is characterized by endochondral ossification. In some embodiments, the gHO occurs in one or more tissues selected from bone, skin, subcutaneous tissue, skeletal muscle, tendon, ligament, aponeurosis, periarticular fibrotic tissue, blood vessel walls, and ligaments.

[0023] In some embodiments, the MMP-9 inhibitor is administered at a therapeutically effective dose. In some embodiments, the administration of the MMP-9 inhibitor to the subject reduces the symptoms compared to the symptoms experienced by the subject prior to administration of the MMP-9 inhibitor, the symptoms being selected from: the number of ectopic ossifications, the size of the ectopic ossifications, the growth of ectopic ossifications, or the formation of ectopic ossifications.

[0024] In some embodiments, the subject has been identified as exhibiting gHO formation. In some embodiments, the subject has been identified as exhibiting gHO formation by triple bone scan, computed tomography (CT), or genetic analysis. In some embodiments, genetic analysis identifies the subject as exhibiting gHO formation by detecting gene mutations consistent with gHO.

[0025] In some embodiments, the MMP-9 inhibitor is an anti-MMP-9 antibody and is administered subcutaneously in doses of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 400 mg.

[0026] In some embodiments, the subject is a person. In some embodiments, the subject is less than about thirty years old. In some embodiments, the subject is 12 years old or older. In some embodiments, the antibody is administered weekly or every two weeks. In some embodiments, the subject is 18 years old or older. In some embodiments, the subject is 6-12 years old and the antibody is administered subcutaneously. In some embodiments, the subject is 2-5 years old and the antibody is administered subcutaneously.

[0027] In a preferred embodiment, the subject is older than about 12 years and receives a weekly dose of 150 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is older than about 12 years and receives a weekly dose of 50 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between about 6 and 11 years old and receives a weekly dose of 75 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between about 6 and 11 years old and receives a weekly dose of 25 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between 2 and 5 years old and receives a weekly dose of 45 or 50 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between 2 and 5 years old and receives a weekly dose of 15 mg of an MMP-9 inhibitor.

[0028] In a preferred embodiment, the subject is between about 6 and 11 years old and receives a weekly dose of 75 mg of the MMP-9 inhibitor. In some embodiments, the subject is between about 6 and 11 years old and receives a weekly dose of 25 mg. In some embodiments, the subject is between about 2 and 5 years old and receives a dose of 50 or 45 mg every other week. In some embodiments, the subject is 2-5 years old and receives a dose of 15 mg every other week. In some embodiments, the subject is 6-11 years old and receives a dose of 75 mg every other week. In some embodiments, the subject is 2-5 years old and receives a dose of 45 or 50 mg every other week.

[0029] In some embodiments, the object has a gain-of-function mutation in the ACVR1 / ALK2 gene. In some embodiments, the gain-of-function mutation in the ACVR1 / ALK2 gene is R206H.

[0030] In some embodiments, the MMP-9 inhibitor is administered via systemic delivery. In some embodiments, systemic delivery includes intravenous, intra-arterial, intramuscular, subcutaneous, intraperitoneal, or intrathoracic administration. In some embodiments, the MMP-9 inhibitor is administered via local delivery. In some embodiments, local delivery includes direct injection into the ectopic ossification area, tissue, or organ. In some embodiments, the MMP-9 inhibitor is administered once daily. In some embodiments, the MMP-9 inhibitor is administered to the subject over a period between one month and 90 years. In some embodiments, administration of the MMP-9 inhibitor begins between the ages of 2 and 18 and ends between the ages of 30 and 100.

[0031] In some implementations, the MMP-9 inhibitor has no detectable inhibitory activity against human MMP-2.

[0032] In some embodiments, this document discloses a pharmaceutical composition comprising an inhibitory IgG4 antibody selective for matrix metalloproteinase-9 (MMP-9) but without detectable inhibitory activity against human MMP-2, wherein, when administered once daily intravenously or subcutaneously to human subjects under approximately thirty years of age with an gain-of-function mutation in the ACVR1 / ALK2 gene, the amount of said antibody effectively reduces ectopic bone formation in tissues selected from muscle, tendon, ligament, and fascia in said human subjects. In some embodiments, detectable inhibitory activity is determined by the lack of binding of the anti-MMP-9 antibody to MMP-2. In some embodiments, no detectable binding of the anti-MMP-9 antibody to MMP-2 has been observed in the presence of said anti-MMP-9 antibody at concentrations up to 100 nM.

[0033] In some embodiments, the inhibitory IgG4 antibody comprises adeliximab, and wherein the human subject contains an R206H mutation in the ACVR1 / ALK2 gene.

[0034] In some embodiments, the inhibitory IgG4 antibody comprises adeliximab, and the human subject has at least one symptom of progressive ossifying fibrous dysplasia (FOP).

[0035] In some embodiments, this document discloses a unit dose comprising the pharmaceutical composition as described in the foregoing embodiments, wherein the inhibitory IgG4 antibody comprises adeliximab, which, when administered once daily via intravenous or subcutaneous administration to human subjects aged approximately thirty years of age who have an gain-of-function mutation in the ACVR1 / ALK2 gene, results in an effective reduction of at least about 10% (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more) in ectopic bone formation in tissues selected from muscle, tendons, ligaments, and fascia in the human subject for a period not exceeding about four weeks. In some embodiments, the dose is formulated for subcutaneous administration. Attached Figure Description

[0036] Figure 1 The image shows a plot of heterotopic ossification (HO) in a FOP-induced mouse model with the R206H mutation (Acvrl[R206H]FlEx / +, Gt(ROSA26)SorCreERT2 / +), treated with either a control mediator or AB0046 antibody (a mouse alternative to adeliximab that reproduces MMP-9 inhibitory activity). Disease induction was achieved by intramuscular injection of tamoxifen (75 mg / kg x 7 days, IP) and cardiotoxin (10 μM, 100 μL) into the right gastrocnemius muscle on day 0. Administration was via the IP route at 30 mg / kg (loading dose, used to address initial target-mediated drug treatment) for the first three days prior to injury, followed by 15 mg / kg on days 0 and 3, or 15 mg / kg twice weekly from day 3. HO was quantified ex vivo at the injury site using high-resolution microCT and analyzed using 3D morphometry. The results showed that HO levels were significantly higher in mice treated with IgG control than in mice treated with anti-MMP-9 antibody (left inset), consistent with findings reported by Louenev et al., 2024 (right inset). These results indicate that anti-MMP-9 antibody treatment reduces HO in mice.

[0037] Figure 2 The figure shows the quantification of soft tissue HO (in μCT) in both WT and MMP-9 KO mice, along with example images of soft tissue HO in both WT and KO mice. The figure demonstrates that MMP-9 blockade significantly inhibits NHHO, as primary HO in the soft tissue of MMP-9 KO mice was significantly reduced compared to wild-type littermate controls.

[0038] Figure 3The total amount of ectopic bone measured in both WT and KO MMP-9 mice (in μCT) is shown. HO was measured in soft tissue and osteophytes attached to the calcaneus, and it was shown that HO was significantly reduced in MMP-9 KO mice compared to wild-type littermate controls. Detailed Implementation

[0039] definition

[0040] Unless otherwise defined herein, scientific and technical terms related to this invention shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context otherwise requires, singular terms shall include plural terms, and plural terms shall include singular terms. The nomenclature and terminology used herein in biochemistry, enzymology, molecular and cell biology, microbiology, genetics, protein and nucleic acid chemistry, and hybridization techniques are generally well-known and commonly used in the art.

[0041] The methods and techniques of the present invention are generally carried out in accordance with conventional methods well known in the art, and as described in the various general and more specific references cited and discussed in this specification, unless otherwise stated.

[0042] All publications, patents and other references mentioned in this article are incorporated herein by reference in their entirety.

[0043] Unless otherwise stated, the following terms shall be understood to have the following meanings:

[0044] In this specification and claims, the word “comprising” or variations thereof, such as “including”, should be understood to imply the inclusion of the specified integers or groups of integers, but not to exclude any other integers or groups of integers.

[0045] The term “administration” refers to the administration of one or more compositions (e.g., anti-MMP-9 antibodies) to a subject suffering from the relevant MMP-9 condition.

[0046] The term “MMP-9-mediated disease” generally refers to a disease or condition in which MMP-9 activity or expression is associated with or related to one or more diseases or conditions.

[0047] The term "combination" therapy refers to the administration of one or more therapeutic compositions, such as a JAK inhibitor with an MMP-9 inhibitor or binding protein; or a BTK inhibitor with an MMP-9 inhibitor or binding protein; or a BMP receptor kinase inhibitor with an MMP-9 inhibitor or binding protein; or an MMP-9 inhibitor or binding protein with cicaltinib; or an MMP-9 inhibitor or binding protein with a TNF inhibitor; or an inhibitor of another MMP (including but not limited to MMP-2, 7, 14 and / or 16) with an MMP-9 inhibitor or binding protein; or a BMP signaling pathway inhibitor; or an anti-TNF agent.

[0048] As used in this article, the term “heterotopic ossification” or “HO” refers to the abnormal formation of bone in soft tissue where bone is not normally present.

[0049] As used herein, the term "inflammatory flare" or "flare-up" refers to a symptom of FOP characterized by soft tissue swelling and inflammation. Flares may be spontaneous or triggered by external factors such as intramuscular injections, biopsies, muscle fatigue, dental procedures, trauma, or infection. In some implementations, the external trigger is unknown. In some implementations, the external trigger for a flare is heterotopic ossification within the patient's body. Flares are more common in patients under 8 years of age in the neck, trunk, and upper extremities, while in patients 8 years of age and older, flares are more common in the lower extremities. Flares may be associated with subsequent heterotopic ossification, but may also occur without it. Common symptoms associated with flares include swelling, redness, heat, stiffness, and decreased range of motion.

[0050] The terms "polynucleotide," "nucleic acid molecule," or "nucleotide sequence" refer to a polymer of nucleotides with a length of at least 10 bases. This term includes DNA molecules (e.g., cDNA or genomic or synthetic DNA) and RNA molecules (e.g., mRNA or synthetic RNA), as well as DNA or RNA analogs containing non-natural nucleotide analogs, non-natural mesenchymal glycosidic bonds, or both. Nucleic acids can be in any topological conformation. For example, nucleic acids can be single-stranded, double-stranded, triple-stranded, quadruple-stranded, partially double-stranded, branched, hairpin-shaped, circular, or lock-shaped conformations.

[0051] Unless otherwise stated, for example, for all sequences described herein, such as “nucleic acid containing SEQ ID NO: 1” means that at least a portion of the nucleic acid has either: (i) the sequence of SEQ ID NO: 1, or (ii) a sequence complementary to SEQ ID NO: 1. The choice between the two depends on the specific circumstances. For example, if the nucleic acid is used as a probe, the choice between the two depends on the requirement that the probe is complementary to the desired target.

[0052] As used herein, the term "ectopic ossification" or "HO" refers to the abnormal formation of bone in soft tissues where bone is not normally present. HO can be hereditary (gHO) or non-hereditary (NHHO). This disclosure focuses on the treatment of gHO. gHO is a group of rare autosomal dominant inherited conditions characterized by the formation of new bone in extraskeletal tissues. A non-limiting example of gHO is progressive ossifying fibrous dysplasia (FOP).

[0053] In the context of nucleic acid sequences, the term "sequence identity percentage" or "identity" refers to the number of residues that two sequences share after a maximum alignment. The length of a sequence identity comparison can be at least about 9 nucleotides, typically at least about 20 nucleotides, more commonly at least about 24 nucleotides, typically at least about 28 nucleotides, more commonly at least about 32 nucleotides, and preferably at least about 36 or more nucleotides. Many different algorithms are known for measuring nucleotide sequence identity. For example, FASTA, Gap, or Bestfit can be used to compare polynucleotide sequences; these programs are included in Wisconsin Package Version 10.0 (Genetics Computer Group (GCG), Madison, Wis). FASTA provides the alignment results and sequence identity percentage for the best overlapping region between the query and search sequences. (Pearson, Methods Enzymol. 183:63-98 (1990) (incorporated hereby by reference in its entirety).) For example, the percentage of sequence identity between nucleic acid sequences can be determined using FASTA and its default parameters (word length of 6, NOPAM factor of the scoring matrix) or using Gap and its default parameters (as provided in GCG version 6.1, which is incorporated herein by reference). Alternatively, the computer program BLAST can be used to compare sequences (Altschul et al., J. Mol. Biol. 215:403-410 (1990); Gish and States, Nature Genet. 3:266-272 (1993); Madden et al., Meth. Enzymol. 266:131-141 (1996); Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997); Zhang and Madden, Genome Res. 7:649-656 (1997)), especially blastp or tblastn (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).

[0054] Generally, “rigorous hybridization” is performed at a temperature approximately 25°C lower than the thermal melting point (Tm) of a specific DNA hybrid under a specific set of conditions. “Rigid washing” is performed at a temperature approximately 5°C lower than the Tm of a specific DNA hybrid under a specific set of conditions. Tm is the temperature at which 50% of the target sequence hybridizes with a perfectly matched probe. See Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), p. 9.51, which is incorporated herein by reference. For the purposes of this paper, “rigorous conditions” for solution-phase hybridization are defined as aqueous-phase hybridization (i.e., formamide-free) at 65°C for 8–12 hours in 6xSSC (20xSSC containing 3.0 M NaCl and 0.3 M sodium citrate) and 1% SDS, followed by two washes at 65°C for 20 minutes each in 0.2xSSC and 0.1% SDS. Those skilled in the art will understand that the rate of hybridization at 65°C will vary depending on a number of factors, including the length of the sequences being hybridized and the percentage of identity.

[0055] Nucleic acids (also known as polynucleotides) can include both the sense and antisense strands of RNA, cDNA, and genomic DNA, as well as synthetic forms and mixed polymers described above. They can be chemically or biochemically modified, or may contain non-natural or derived nucleotide bases, as will be readily understood by those skilled in the art. Such modifications include, for example, labeling, methylation, substitution of one or more naturally occurring nucleotides with analogs, internucleotide modifications such as uncharged linkages (e.g., methylphosphonates, triphosphates, phosphoramides, carbamates, etc.), charged linkages (e.g., thiophosphates, dithiophosphates, etc.), side chain portions (e.g., polypeptides), intercalating agents (e.g., acridine, psoralen, etc.), chelating agents, alkylating agents, and modified linkages (e.g., α-terminal nucleic acids, etc.). Furthermore, synthetic molecules are included that can bind to a specified sequence via hydrogen bonds and other chemical interactions to mimic polynucleotides. Such molecules are known in the art and include, for example, molecules in which peptide bonds replace phosphate linkages in the molecular backbone. Other modifications may include, for example, modifications in which the ribose ring contains a bridging portion or other structural analogues, such as those seen in "lock" nucleic acids.

[0056] When applied to nucleic acid sequences, the term "mutation" refers to the insertion, deletion, or alteration of nucleotides in a nucleic acid sequence compared to a reference nucleic acid sequence. A single change (point mutation) can be made at a locus, or multiple nucleotides can be inserted, deleted, or altered at a single locus. Furthermore, any number of loci within a nucleic acid sequence can undergo one or more changes. Nucleic acid sequences can be mutated by any method known in the art, including but not limited to mutagenesis techniques such as "error-prone PCR" (a process of performing PCR under conditions of low DNA polymerase replication fidelity to obtain a high point mutation rate across the entire length of the PCR product; see, for example, Leung et al., Technique, 1:11-15 (1989) and Caldwell and Joyce, PCR Methods Applic. 2:28-33 (1992)); and "oligonucleotide directed mutagenesis" (a process capable of generating site-specific mutations in any cloned DNA segment of interest; see, for example, Reidhaar-Olson and Sauer, Science 241:53-57 (1988)).

[0057] As used herein, the term "attenuation" generally refers to a loss of function, including mutations, partial or complete deletions, insertions, or other variations in the gene sequence or the sequence controlling the transcription of the gene sequence that reduce or inhibit the production of the gene product, or render the gene product nonfunctional. In some cases, loss of function is described as a knockout mutation. Attenuation also includes altering the amino acid sequence by: changing the nucleic acid sequence, placing the gene under the control of a less active promoter, downregulating the expression of interfering RNA, ribozymes, or antisense sequences targeting the gene of interest, or by any other technique known in the art. In one example, a particular enzyme is less sensitive to feedback inhibition or inhibition caused by non-product or reactant components (non-pathway-specific feedback), such that the enzyme activity is not affected by the presence of a compound. In other cases, an enzyme that has been altered and has reduced activity may be referred to as attenuated.

[0058] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of vector is the "plasmid," which typically refers to a circular double-stranded DNA loop into which an additional DNA segment can be linked, but also includes linear double-stranded molecules, such as those produced by polymerase chain reaction (PCR) amplification or by treating circular plasmids with restriction endonucleases. Other vectors include granules, bacterial artificial chromosomes (BACs), and yeast artificial chromosomes (YACs). Another type of vector is the viral vector, in which an additional DNA segment can be linked to a viral genome (discussed in detail below). Some vectors are capable of autonomous replication within the introduced host cell (e.g., vectors with a replication origin that functions within the host cell). Other vectors, upon introduction into the host cell, can integrate into the host cell's genome, thereby replicating along with the host genome. Furthermore, certain preferred vectors are capable of guiding the expression of genes operatively linked to them. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors").

[0059] The term "operable link" or "operable link" refers to an expression control sequence that is adjacent to the gene of interest to control the gene of interest, or acts in a trans or at a certain distance to control the expression of the gene of interest.

[0060] As used herein, the term "expression control sequence" refers to a polynucleotide sequence essential to the expression of a coding sequence that is operationally linked to it. Expression control sequences are sequences that control transcription, post-transcriptional events, and translation of nucleic acid sequences. Expression control sequences include appropriate transcription initiation, termination, promoter, and enhancer sequences; efficient RNA processing signals, such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., ribosome binding sites); sequences that enhance protein stability; and sequences that enhance protein secretion when needed. The nature of such control sequences varies from host organism to host organism; in prokaryotes, such control sequences typically include promoters, ribosome binding sites, and transcription termination sequences. The term "control sequence" is intended to include at least all components essential for expression, and may also include other components with advantages, such as leader sequences and fusion partner sequences.

[0061] As used herein, the term "recombinant host cell" (or simply "host cell") refers to a cell into which a recombinant vector has been introduced. It should be understood that these terms refer not only to a specific target cell but also to its progeny. Subsequent generations may undergo changes due to mutations or environmental influences, and therefore these progeny cells may not be entirely identical to the parent cells, but they are still included within the scope of the term "host cell" as used herein. Recombinant host cells can be cells or cell lines isolated in culture or cells present in living tissues or organisms.

[0062] As used herein, the term "peptide" or "polypeptide" refers to a short sequence of amino acid residues, typically less than about 50 amino acids long and more commonly less than about 30 amino acids long. The terminology used herein encompasses analogs and mimics that imitate structures to mimic biological functions. The term "peptide" or "polypeptide" covers both naturally occurring and non-naturally occurring proteins, as well as their fragments, mutants, derivatives, and analogs. Polypeptides can be monomers or polymers. Furthermore, a polypeptide may contain multiple distinct domains, each possessing one or more distinct activities.

[0063] The terms “isolated protein” or “isolated polypeptide” refer to a protein or polypeptide that, due to its origin or derivation, (1) is not associated with the natural components that accompany it in its natural state, (2) is not found in nature in terms of purity, wherein purity can be determined by the presence of other cellular material (e.g., it does not contain other proteins from the same species), (3) is expressed by cells from a different species, or (4) is not found in nature (e.g., it is a fragment of a polypeptide that is found in nature, or it contains amino acid analogs or derivatives that are not found in nature, or it contains linkages other than standard peptide bonds). Thus, a polypeptide synthesized by chemical methods or synthesized in a cellular system different from the cells of its natural origin will be “isolated” from its natural associated components. Isolation can also render a polypeptide or protein substantially free of its natural associated components using protein purification techniques well known in the art. By this definition, “isolation” does not necessarily require that the described protein, polypeptide, peptide, or oligopeptide has been physically removed from its natural environment.

[0064] As used herein, the term "peptide fragment" refers to a polypeptide that is missing from its full-length counterpart, such as a polypeptide lacking an N-terminal and / or C-terminal group. In a preferred embodiment, the polypeptide fragment is a continuous sequence in which the amino acid sequence of the fragment is identical to the corresponding position in the native sequence. The fragment is typically at least 5, 6, 7, 8, 9, or 10 amino acids long, preferably at least 12, 14, 16, or 18 amino acids long, more preferably at least 20 amino acids long, more preferably at least 25, 30, 35, 40, or 45 amino acids long, even more preferably at least 50 or 60 amino acids long, and even more preferably at least 70 amino acids long.

[0065] "Modified derivatives" refer to polypeptides or fragments thereof that are substantially homologous in their primary structural sequences, but include, for example, in vivo or in vitro chemical and biochemical modifications, or the incorporation of amino acids not present in the native polypeptide. Examples of such modifications include acetylation, carboxylation, phosphorylation, glycosylation, ubiquitination, labeling (e.g., labeling with a radionuclide), and various enzymatic modifications, which should be readily understood by those skilled in the art. Various methods for labeling polypeptides and substituents or labels that can be used for this purpose, including radioisotopes, are known in the art. 125 I, 32 P, 35 S and 3 H, a ligand that binds to a labeled anti-ligand (e.g., an antibody), a fluorophore, a chemiluminescent agent, an enzyme, and an anti-ligand that can specifically bind to a member of the labeled ligand. The choice of label depends on the required sensitivity, ease of primer conjugation, stability requirements, and available instruments. Methods for labeling peptides are well known in the art. For example, see Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992, and supplemental material 2002) (incorporated herein by reference).

[0066] The term "fusion protein" refers to a polypeptide composed of a peptide or fragment coupled with a heterologous amino acid sequence. Fusion proteins are useful because they can be constructed to contain two or more desired functional elements from two or more different proteins. Fusion proteins contain at least 10 consecutive amino acids from the polypeptide of interest, more preferably at least 20 or 30 amino acids, even more preferably at least 40, 50, or 60 amino acids, and even more preferably at least 75, 100, or 125 amino acids. Fusion proteins comprising the entire protein of the present invention have particular use. The heterologous polypeptide contained within the fusion protein of the present invention is at least 6 amino acids in length, typically at least 8 amino acids, and preferably at least 15, 20, and 25 amino acids. Fusion proteins comprising larger polypeptides (such as IgG Fc regions) or even entire proteins (such as proteins containing a green fluorescent protein (“GFP”) chromophore) have particular use. Fusion proteins can be produced recombinantly by constructing a nucleic acid sequence encoding a polypeptide or fragment thereof and then expressing the fusion protein, wherein the nucleic acid sequence is fused in a reading frame with a nucleic acid sequence encoding a different protein or peptide. Alternatively, fusion proteins can be chemically produced by crosslinking a polypeptide or a fragment thereof with another protein.

[0067] The term "non-peptide analog" refers to a compound whose properties are similar to a reference peptide. Non-peptide compounds may also be called "peptide mimics" or "peptide analogs". For example, see Jones, Amino Acid and Peptide Synthesis, Oxford University Press (1992); Jung, Combinatorial Peptide and Nonpeptide Libraries: A Handbook, John Wiley (1997); Bodanszky et al., Peptide Chemistry--A Practical Textbook, Springer Verlag (1993); Synthetic Peptides: A Users Guide (Grant, ed., WH Freeman and Co., 1992); Evans et al., J. Med. Chem. 30:1229 (1987); Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger, Trends Neurosci., 8:392-396 (1985); and the references cited in the above-mentioned works, which are incorporated herein by reference. These compounds are typically developed using computer molecular modeling techniques. Peptide mimics with structures similar to the useful peptides of the present invention can be used to produce equivalent effects, and are therefore envisioned as part of the present invention.

[0068] A "peptide mutant" or "mutant peptide" is a polypeptide whose sequence, compared to the amino acid sequence of a native or wild-type protein, contains one or more amino acid insertions, repeats, deletions, rearrangements, or substitutions. A mutant peptide may have one or more amino acid site substitutions, where a single amino acid at a position is changed to another amino acid; one or more insertions and / or deletions, where one or more amino acids are inserted or deleted from the sequence of the native protein; and / or truncation of the amino acid sequence at the N-terminus and / or C-terminus. A mutant peptide may have the same biological activity as the native protein, but preferably different biological activities. The mutant peptide has at least 85% overall sequence homology with its wild-type counterpart. More ideally, the mutant has at least 90%, 95%, 96%, 97%, 98%, 99%, or higher overall sequence homology with the wild-type protein.

[0069] Sequence homology can be measured using any common sequence analysis algorithm, such as Gap or Bestfit.

[0070] Amino acid substitution may include the following substitutions: (1) reducing sensitivity to protein hydrolysis, (2) reducing sensitivity to oxidation, (3) altering the binding affinity for forming protein complexes, (4) altering binding affinity or enzyme activity, and (5) conferring or altering other physicochemical or functional properties of such analogues.

[0071] As used in this article, the twenty common amino acids and their abbreviations follow their usual usage. See Immunology-ASynthesis (Golub and Gren eds., Sinauer Associates, Sunderland, Mass., 2 nd Ed. 1991, which is incorporated herein by reference. Stereoisomers of twenty common amino acids (e.g., D-amino acids), non-natural amino acids (e.g., α-, α-disubstituted amino acids, N-alkyl amino acids), and other unconventional amino acids may also be suitable components of the polypeptides of this invention. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamic acid, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide designation used herein, the left end corresponds to the amino terminus, and the right end corresponds to the carboxyl terminus, which conforms to standard usage and convention.

[0072] The two proteins are said to be "homological" or "homologous" if the nucleic acid sequence encoding a protein has a similar sequence to that encoding a second protein. Alternatively, the two proteins are said to be homologous if they have "similar" amino acid sequences. (Therefore, the term "homologous protein" is defined as two proteins having similar amino acid sequences.) As used herein, homology between two regions of an amino acid sequence (especially predicted structural similarity) is interpreted as functional similarity.

[0073] When “homologous” is used to refer to proteins or peptides, it should be recognized that the differences in the positions of residues that are not exactly the same are usually due to conserved amino acid substitutions. A “conserved amino acid substitution” is the substitution of an amino acid residue with another amino acid residue having a side chain (R group) that has similar chemical properties (e.g., charge or hydrophobicity). Generally, conserved amino acid substitutions do not substantially alter the functional properties of a protein. If two or more amino acid sequences are different from each other due to conserved substitutions, the percentage of sequence identity or degree of homology can be adjusted upwards to correct the conservation of the substitution. Methods for making such adjustments are well known to those skilled in the art. See, for example, Pearson, 1994, Methods Mol. Biol. 24:307-31 and 25:365-89 (incorporated herein by reference).

[0074] The following six groups contain amino acids that can be conservatively substituted for each other: 1) serine (S), threonine (T); 2) aspartic acid (D), glutamic acid (E); 3) asparagine (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), alanine (A), valine (V); and 6) phenylalanine (F), tyrosine (Y), tryptophan (W).

[0075] Sequence homology (also known as sequence identity percentage) of peptides is typically measured using sequence analysis software. See, for example, the Sequence Analysis Software Package of the Genetics Computer Group (GCG), University of Wisconsin Biotechnology Center, 910 University Avenue, Madison, Wis. 53705. Protein analysis software uses homology measures against various substitutions, deletions, and other modifications, including conserved amino acid substitutions, to match similar sequences. For example, GCG includes programs such as “Gap” and “Bestfit”, which can determine sequence homology or sequence identity between closely related peptides (e.g., homologous peptides from different species) or between wild-type proteins and their mutant peptides using default parameters. See, for example, GCG version 6.1.

[0076] When comparing a specific polypeptide sequence with a database containing a large number of sequences from different organisms, the preferred algorithm is the computer program BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990); Gish and States, Nature Genet. 3:266-272 (1993); Madden et al., Meth. Enzymol. 266:131-141 (1996); Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997); Zhang and Madden, Genome Res. 7:649-656 (1997)), especially blastp or tblastn (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)).

[0077] The preferred parameters for BLASTp are: Expected value: 10 (default); Filter: seg (default); Cost of opening a gap: 11 (default); Cost of expanding a gap: 1 (default); Maximum alignment: 100 (default); Word length: 11 (default); Number of descriptions: 100 (default); Penalty matrix: BLOWSUM62.

[0078] The length of peptide sequences used for homology comparison is typically at least about 16 amino acid residues, typically at least about 20 residues, more commonly at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching databases containing a large number of sequences from different organisms, it is preferable to compare amino acid sequences. Database searches using amino acid sequences can be measured using algorithms other than blastp known in the art. For example, FASTA (the program in GCG version 6.1) can be used to compare peptide sequences. FASTA provides the alignment of the best overlapping regions between the query and search sequences and the percentage of sequence identity. Pearson, Methods Enzymol. 183:63-98 (1990) (incorporated herein by reference). For example, FASTA and its default parameters (word length 2 and PAM250 scoring matrix) can be used to determine the percentage of sequence identity between amino acid sequences, as provided in GCG version 6.1, which is incorporated herein by reference.

[0079] "Specific binding" refers to the ability of two molecules to preferentially bind to each other rather than to other molecules in the environment. Typically, specific binding is at least twice as strong as random binding in a reaction, more often at least 10 times, and frequently at least 100 times stronger. The affinity or cohesion (quantified by the dissociation constant) of a specific binding reaction is usually around 10. -7 M or stronger (e.g., about 10) -8 M, 10 -9 M or even stronger).

[0080] As used herein, the term "region" refers to a physically continuous portion of the primary structure of a biomolecule. For proteins, a region is defined by a continuous portion of the protein's amino acid sequence.

[0081] As used herein, the term "domain" refers to a structure in a biomolecule that contributes to the known or suspected function of the biomolecule. A domain may be the same as a region or a portion thereof; a domain may also include different, discontinuous regions of a biomolecule. Examples of protein domains include, but are not limited to, Ig domains, extracellular domains, transmembrane domains, and cytoplasmic domains.

[0082] As used herein, the term "molecule" refers to any compound, including but not limited to small molecules, peptides, proteins, sugars, nucleotides, nucleic acids, lipids, etc., and such compounds may be natural or synthetic.

[0083] The terms "antibody" and "immunoglobulin" are used interchangeably in the broadest sense to include monoclonal antibodies (e.g., full-length or complete monoclonal antibodies), polyclonal antibodies, monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies, provided they exhibit the desired biological activity), and antibody fragments described herein. A bispecific antibody is a monoclonal antibody and can be a human antibody or a humanized antibody, having binding specificity against at least two different antigens. In the context of this disclosure, these two different binding specificities can target two different MMPs or two different epitopes on a single MMP (e.g., MMP-9).

[0084] The antibodies disclosed herein can also be immunoconjugates. Such immunoconjugates comprise an antibody (e.g., against MMP-9) conjugated to a second molecule (e.g., a reporter molecule). Immunoconjugates may also comprise antibodies conjugated to cytotoxic agents (e.g., chemotherapeutic drugs), toxins (e.g., bacterial, fungal, plant, or animal-derived enzyme-active toxins or fragments thereof), or radioisotopes (i.e., radioconjugates). An antibody that “specifically binds” or “specifically targets” a particular polypeptide or epitope on a particular polypeptide refers to an antibody that binds to that particular polypeptide or epitope without substantially binding to any other polypeptide or polypeptide epitope. In some embodiments, the antibody of this disclosure specifically binds to human MMP-9, having a dissociation constant (Kd) equal to or less than 100 nM, optionally less than 10 nM, optionally less than 1 nM, optionally less than 0.5 nM, optionally less than 0.1 nM, optionally less than 0.01 nM, or optionally less than 0.005 nM as measured at temperatures of about 4°C, 25°C, 37°C, or 42°C; and is present in the form of a monoclonal antibody, scFv, Fab, or other forms of antibody.

[0085] Antibodies can be human, humanized, chimeric, and / or affinity-matured.

[0086] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells, antibodies isolated from a recombinant human antibody library, antibodies isolated from animals (e.g., mice) with transgenic human immunoglobulin genes (see, for example, Taylor, LD, et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, or isolated by any other means involving the splicing of human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are mutagenized in vitro (or, when using animals with transgenic human Ig sequences, in vivo somatic cell mutagenesis), so that the amino acid sequences of the VH and VL regions of the recombinant antibody, while derived from and associated with human germline VH and VL sequences, may not be naturally present in an in vivo human antibody germline library.

[0087] As used herein, "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities (e.g., isolated antibodies that specifically bind to MMP-9 are substantially free of antibodies that specifically bind to antigens other than MMP-9). However, isolated antibodies that specifically bind to MMP-9 may cross-react with other antigens (e.g., MMP-9 molecules from other species). Furthermore, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0088] An "antibody fragment" refers to a portion of a full-length antibody, such as the antigen-binding region or variable region of a full-length antibody. Such antibody fragments may also be referred to as "functional fragments" or "antigen-binding fragments" in this text. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; biantibodies; linear antibodies (Zapata et al. (1995) Protein Eng. 8(10):1057-1062); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of an antibody produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, a name reflecting its tendency to crystallize. Pepsin treatment produces the F(ab')2 fragment, which has two antigen-binding sites and is still capable of cross-linking antigens.

[0089] "Fv" is the smallest antibody fragment containing both complete antigen recognition and antigen binding sites. This region consists of a dimer formed by the tight non-covalent association of a heavy-chain variable domain and a light-chain variable domain. In this configuration, three complementarity-determining regions (CDRs) of each variable domain interact to define the antigen binding site on the surface of the VH-VL dimer. The six CDRs collectively confer antigen-binding specificity to the antibody. However, even a single variable domain (or a separate VH or VL region containing only three of the six antigen-specific CDRs) can recognize and bind antigens, although its affinity is generally lower than that of the entire Fv fragment.

[0090] The “Fab” fragment contains, in addition to the variable regions of the heavy and light chains, a constant region of the light chain and a first constant region (CHI) of the heavy chain. The Fab fragment was initially observed after papain digestion of the antibody. The Fab’ fragment differs from the Fab fragment in that the F(ab’) fragment contains several additional residues at the carboxyl terminus of the CHI domain of the heavy chain, including one or more cysteine ​​residues from the antibody hinge region. The F(ab’)2 fragment contains two Fab fragments linked by disulfide bonds near the hinge region and was initially observed after pepsin digestion of the antibody. In this paper, Fab’-SH is the name for the Fab’ fragment, where the cysteine ​​residues in the constant domain have free thiol groups. Other chemical conjugation methods for antibody fragments are also known.

[0091] Based on the amino acid sequence of their constant domains, the "light chains" of antibodies (immunoglobulins) in any vertebrate species can be classified into two distinct types, called κ and λ. Based on the amino acid sequence of the heavy chain constant domains, immunoglobulins can be divided into five major classes: IgA, IgD, IgE, IgG, and IgM. Several of these classes can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0092] A single-chain Fv, sFv, or scFv antibody fragment contains the VH and VL domains of the antibody, which are contained within a single polypeptide chain. In some embodiments, the Fv polypeptide also includes a polypeptide linker between the VH and VL domains, which allows the sFv to form the desired antigen-binding structure. For a review of sFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113 (Rosenburg and Moore eds.), Springer-Verlag, New York, pp. 269-315 (1994).

[0093] The term "biantibody" refers to a small antibody fragment with two antigen-binding sites, contained within a heavy chain variable domain (VH) linked to a light chain variable domain (VL) on the same polypeptide chain (VH-VL). By using a linker that is too short to allow the two domains on the same chain to pair, these two domains are forced to pair with complementary domains on another chain, thus creating two antigen-binding sites. Biantibodies are also described in EP 404,097, WO 93 / 11161, and Hollinger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448.

[0094] As used herein, the term “MMP-9 activation” refers to the cleavage of the inactive precursor form of MMP-9 to produce the active form of MMP-9.

[0095] As used herein, the term “MMP-9 activity” refers to the enzyme activity of the MMP-9 active form.

[0096] As used herein, the term "MMP-9 inhibitor" refers to an agent that inhibits or reduces the activation, activity, or function of MMP-9. MMP-9 inhibitors include anti-MMP-9 inhibitory antibodies, small molecule inhibitors, RNA interference agents (e.g., siRNA), recombinant expression systems capable of knocking out MMP-9 (e.g., CRISPR-Cas systems), or other agents that inhibit or reduce MMP-9 expression, MMP-9 binding, MMP-9 function, or activity. MMP-9 inhibitors reduce the activation, activity, or function of MMP-9 by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or more). The term "humanized" non-human (e.g., murine) antibody refers to a chimeric antibody containing a minimal sequence derived from a non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (receptor antibodies), in which residues of the receptor hypervariable region are replaced by residues from the hypervariable region of a non-human species (donor antibody), which possess the desired specificity, affinity, and capacity. In some cases, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may contain residues not present in the receptor or donor antibody. These modifications are made to further optimize antibody performance. Typically, humanized antibodies contain the majority of at least one (usually two) variable domains, where all or almost all hypervariable loops correspond to hypervariable loops of non-human immunoglobulins, and all or almost all FRs are FRs of the human immunoglobulin sequence. Humanized antibodies may also optionally contain at least a portion of the immunoglobulin constant region (Fc), typically the Fc of the human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following review articles and references cited in this paper: Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).

[0097] For example, human antibodies can be produced using phage display libraries. Hoogenboom et al. (1991) J. Mol. Biol, 227:381; Marks et al. (1991) J. Mol. Biol. 222:581. Other methods for preparing human monoclonal antibodies are described in Cole et al. (1985) “Monoclonal Antibodies and Cancer Therapy,” Alan R. Liss, p. 77 and Boerner et al. (1991) J. Immunol. 147:86-95.

[0098] Human antibodies can also be produced by introducing human immunoglobulin gene loci into transgenic animals (e.g., mice) whose endogenous immunoglobulin genes have been partially or completely inactivated. Under immune challenges, the production of human antibodies has been observed, which are remarkably similar to those seen in humans in various aspects, including gene rearrangement, assembly, and antibody libraries. For example, this method is described in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016 and in the following scientific publications: Marks et al. (1992) Bio / Technology 10:779-783 (1992); Lonberg et al. (1994) Nature 368:856-859; Morrison (1994) Nature 368:812-813; Fishwald et al. (1996) Nature Biotechnology 14:845-851; Neuberger (1996) Nature Biotechnology 14:826; and Lonberg et al. (1995) Intern. Rev. Immunol. 13:65-93.

[0099] The term "affinity-matured" antibody refers to an antibody in which one or more CDRs undergo one or more alterations, thereby increasing the antibody's affinity for the antigen compared to the parent antibody without these alterations. Preferred affinity-matured antibodies exhibit nanomolar or even picomolar affinity for the target antigen. Affinity-matured antibodies can be produced using procedures known in the art. Marks et al., Bio / Technology 10:779-783 (1992), described affinity maturation through VH and VL domain shuffling. The following describes random mutagenesis of CDR and / or framework residues: Barbas et al. Proc Nat. Acad. Sci, USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0100] As used herein, the term "immunoadhesin" refers to an antibody-like molecule that binds the "binding domain" (adhesin, such as a receptor, ligand, or enzyme) of a heterologous protein to an effector component of the immunoglobulin constant domain. Structurally, an immunoadhesin comprises a fusion protein of an adhesin amino acid sequence (different from the antigen recognition and binding site (antigen binding site) of an antibody, i.e., "heterologous") and an immunoglobulin constant domain sequence with the desired binding specificity. The immunoglobulin constant domain sequence in an immunoadhesin can be derived from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA, IgE, IgD, or IgM.

[0101] As used herein, the term "Fc region" generally refers to a dimeric complex containing the C-terminal polypeptide sequence of an immunoglobulin heavy chain, wherein the C-terminal polypeptide sequence is a sequence obtainable by digesting an intact antibody with papain. The Fc region may contain a native Fc sequence or a variant Fc sequence. Although the boundaries of the Fc sequence of the immunoglobulin heavy chain can vary, the Fc sequence of the human IgG heavy chain is generally defined as a segment from an amino acid residue near Cys226 or Pro230 to the C-terminus of the Fc sequence. The Fc sequence of an immunoglobulin typically contains two constant domains, namely a CH2 domain and a CH3 domain, and optionally includes a CH4 domain. "Fc polypeptide" as used herein refers to one of the polypeptides constituting the Fc region. The Fc polypeptide can be obtained from any suitable immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA, IgE, IgD, or IgM. In some embodiments, the Fc polypeptide contains part or all of the wild-type hinge sequence (typically located at its N-terminus). In some implementations, the Fc peptide does not contain a functional or wild-type hinge sequence.

[0102] As used herein, the term "framework," when referring to the antibody variable region, is intended to refer to all amino acid residues within the variable region other than the CDR region. A variable region frame typically refers to a discontinuous amino acid sequence of approximately 100-120 amino acids, but here it refers only to those amino acids outside the CDR. As used herein, the term "frame region" refers to the individual domains within the frame separated by CDRs.

[0103] The term “pharmaceutical formulation” refers to a formulation of an active ingredient with one or more other pharmaceutical agents, for example, see Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated hereby by reference).

[0104] The term "pharmaceutical acceptable" excipient (mediator, additive) refers to an excipient that can be reasonably administered to a subject to provide an effective dose of the active ingredient.

[0105] The term "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or media suitable for administration to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials involved in the delivery or transport of an investigational drug from one organ or body site to another. Each carrier must be "acceptable," meaning it is compatible with other components in the formulation and will not cause harm to the patient or subject.

[0106] A “stable” formulation is one in which the molecules (e.g., antibody compositions) substantially retain their physical stability, chemical stability, and / or biological activity during storage. Various analytical techniques for measuring protein stability are available in the art and are reviewed, for example, in *Peptide and Protein Drug Delivery*, 247-301, Vincent Lee Ed., MarcelDekker, Inc., New York, NY, Pubs. (1991) and *Jones, A. Adv. Drug Delivery Rev. 10: 29-90* (1993). Stability can be measured at selected temperatures over selected time periods. In some embodiments, the formulation is stable for at least one month at room temperature (about 30°C) or 40°C, and / or for at least one year, or at least two years, at about 2-8°C. Furthermore, the formulation preferably remains stable after freezing (e.g., -70°C) and thawing (hereinafter referred to as “freeze-thaw cycles”).

[0107] As mentioned in this article, if the antibody used in the antibody composition shows virtually no signs of aggregation, precipitation and / or denaturation in the pharmaceutical preparation by visual inspection of color and / or transparency, or by measurement by ultraviolet light scattering or size exclusion chromatography, then the antibody is said to "maintain its physical stability".

[0108] As mentioned in this article, an antibody is said to "remain chemically stable" in a pharmaceutical formulation if its chemical stability at a given time allows it to retain the biological activity defined below. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the antibody. Chemical changes may involve size changes (e.g., shearing), which can be assessed using size exclusion chromatography, SDS-PAGE, and / or matrix-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS). Other types of chemical changes include charge changes (e.g., those occurring due to deamidation), which can be assessed, for example, by ion-exchange chromatography.

[0109] As mentioned herein, if an antibody in a pharmaceutical formulation exhibits biological activity for its intended use, it is said to "retain its biological activity" in the pharmaceutical formulation. For example, if the biological activity of an antibody in a pharmaceutical formulation is within 30%, 20%, or 10% of the biological activity exhibited during the preparation of the pharmaceutical formulation (within the range of assay error), then the biological activity is retained (e.g., determined by an antigen-binding "assay"). "Isotonic" is a term generally accepted in the art. For example, isotonicity may mean that the osmotic pressure of the formulation of interest is substantially the same as that of human blood. The osmotic pressure of isotonic formulations is generally between 250 and 350 mOsm. Isotonicity can be measured, for example, using a vapor pressure osmometer or a cryo-osmometer. An "osmotic agent" is a compound that enables a formulation to be isotonic.

[0110] As used herein, "buffer solution" refers to a buffer solution capable of resisting pH changes caused by its acid-base conjugate components. The pH range of the buffer solutions of this invention is from about 4 to about 8; preferably from about 4.5 to about 7; and most preferably from about 5.0 to about 6.5. Examples of buffer solutions capable of controlling pH within this range include acetate (e.g., sodium acetate), succinate (e.g., sodium succinate), gluconate, histidine, citrate, and other organic acid buffer solutions.

[0111] "Preservatives" are compounds that can be included in formulations to significantly reduce bacterial activity, thereby, for example, aiding in the production of multipurpose formulations. Examples of potential preservatives include octadecyl dimethyl benzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride (a mixture of alkyl benzyl dimethyl ammonium chlorides, wherein the alkyl group is a long-chain compound), and benzalkonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butanol, and benzyl alcohol; alkyl parabens such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol.

[0112] As used herein, the terms “NHHO” or “non-hereditary heterotopic ossification” or “NGHO” or “non-genetic heterotopic ossification” are used interchangeably to refer to non-hereditary conditions involving the gradual formation of ectopic bone in soft tissues, typically occurring after trauma. Spinal cord and traumatic brain injury, war or gunshot wounds, and severe burns can all lead to the formation of extraosseous bone in joints, muscles, or tendons. Non-hereditary heterotopic ossification can occur in almost any musculoskeletal trauma, spinal cord injury, central nervous system injury, head injury, cerebrovascular accident, sickle cell anemia, hemophilia, tetanus, poliomyelitis, multiple sclerosis, toxic epidermal necrolysis, viral infections including COVID-19, and burns. Examples of musculoskeletal trauma include, but are not limited to, hip, knee, shoulder, or elbow replacement surgery; fractures; joint dislocations; or soft tissue trauma to the quadriceps and brachialis muscles. Surgical resection often results in HO recurrence, as is the case with surgical interventions in certain precipitating factors involving chronic inflammation and bone formation, such as axial spondyloarthritis. NHHO can occur in almost any part of the body, but the most common sites include trauma-prone areas such as the elbow, thigh, pelvis, and shoulder. NHHO can cause pain around the ossified site, loss of joint mobility, and consequently, loss of function, as discussed in Myers C, et al., (2019). JBMRPlus, 3(4): e10172. Examples of musculoskeletal trauma include, but are not limited to, hip, knee, shoulder, or elbow replacement surgery; fractures; joint dislocations; or soft tissue injuries to the quadriceps and brachialis muscles. Non-hereditary heterotopic ossification may also be accompanied by fever, swelling, and erythema (e.g., patchy redness of the skin). For example, NHHO is associated with one or more of the following conditions or illnesses: spinal cord injury, trauma, brain injury, burns, fractures, muscle contusions, arthroplasty / replacement, hip surgery / replacement, acetabular surgery / replacement, elbow fractures, long bone fractures of the lower leg, combat-related trauma, amputation, neuromuscular blocks used to treat adult respiratory distress syndrome, and non-traumatic myelopathy.

[0113] As used herein, the terms "triple bone scan" or "three-phase bone scan" are used interchangeably to refer to a diagnostic procedure that includes a series of images that can reveal early bone disease, infection, or fracture. In many cases, these conditions can be imaged via scanning before they are detected by standard X-rays. The scan uses a small amount of radioactive material as a tracer, which is absorbed by the bone and detected by a camera to generate images.

[0114] As used in this article, the term "prevention" refers to treating at-risk patients before the onset of HO (e.g., NHHO or FOP) symptoms to further prevent the condition from progressing.

[0115] As used in this article, the term "tendon transection" refers to a surgical procedure involving the cutting or separation of a tendon.

[0116] As used herein, the term "freedom of choice" means the ability to obtain something at any time or on demand. As a non-limiting example, in this application, the mice used under these experimental conditions were "freely entitled" to food and water, or had free access to and use.

[0117] The term “musculoskeletal disease or condition” or “MSD” refers to injury, condition and / or pain in the bones, joints, ligaments, muscles, nerves, tendons and structures that support the limbs, neck and back.

[0118] As used herein, the term “treatment” refers to the medical management of an object with the aim of improving, alleviating, stabilizing (i.e., preventing deterioration), or curing a disease, pathological condition, or symptom; and in some cases, “treatment” may include prevention of a disease, symptom, or condition. This term includes active treatment (treatment aimed at improving a disease, pathological condition, or symptom), etiological treatment (treatment aimed at treating the cause of the associated disease, pathological condition, or symptom), palliative treatment (treatment aimed at relieving symptoms), preventive treatment (treatment aimed at minimizing or partially or completely suppressing the development or symptoms of an associated disease, pathological condition, or symptom), and supportive treatment (treatment used to complement another therapy). Treatment also includes reducing the severity of a disease or condition; preventing the spread of a disease or condition; delaying or slowing the progression of a disease or condition; improving or alleviating a disease or condition; and remission (whether partial or complete), whether detectable or undetectable. “Alleviating” or “alleviating” a disease or condition means a reduction in the severity and / or adverse clinical manifestations and / or a slowing or prolonging of the progression of the disease, symptom, or condition compared to the severity or time course of the condition without treatment. "Treatment" can also refer to extending life expectancy compared to the expected lifespan without treatment. Groups requiring treatment include those already suffering from the condition or disease, those susceptible to the condition or disease, and those needing prevention measures.

[0119] As used in this article, “parenteral administration” refers to administration methods other than intestinal and local administration, usually by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subdermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intramedullary injections and infusions.

[0120] As used herein, the terms “systemic administration” and “peripheral administration” refer to the (non-direct) administration of a compound, drug, or other substance to the central nervous system, allowing it to enter the patient’s body and undergo metabolism and other similar processes, such as subcutaneous administration.

[0121] As used herein, the term "therapeutic effective dose" or "effective dose" refers to the amount of a therapeutic composition, when administered to a subject alone or in combination with another therapeutic composition, that is effective in preventing or reducing a disease condition or disease progression, such as hereditary heterotopic ossification. The term also includes the preventive effective dose required to achieve the desired preventive effect within the necessary dosage and time intervals. Typically, because the preventive dose is administered to the subject before or at an early stage of the disease, the preventive effective dose will be less than the therapeutic effective dose.

[0122] "Symptom" refers to any condition that can be treated with antibody therapy. This includes both chronic and acute conditions or diseases, including which pathological conditions make a subject susceptible to the disease discussed.

[0123] The actual dosage level of the active ingredient (e.g., antibody, small molecule or peptide inhibitor, inhibitory nucleic acid, and CRISPR-Cas) in the pharmaceutical formulation of the present invention can be adjusted to obtain an amount of active ingredient that effectively achieves the therapeutic response required for a specific patient, composition, and administration method without causing toxicity to the patient.

[0124] The selected dose level will depend on a variety of factors, including the activity of the antibody found in the formulation, route of administration, time of administration, excretion rate of the specific compound used, duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical community.

[0125] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the pharmaceutical composition required by the present invention. For example, a physician or veterinarian can begin administration of the compound of the present invention used in the pharmaceutical formulation of the present invention at a level below that required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

[0126] As used herein, the term “surface plasmon resonance” refers to an optical phenomenon that allows for the analysis of real-time, biospecific interactions by detecting changes in protein concentration in a biosensor matrix, for example, using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). For further description, see Jonsson, U. et al. (1993) Ann. Biol. Clin. 51:19-26; Jonsson, U. et al. (1991) Biotechniques 11:620-627; Johnson, B. et al. (1995) J. Mol. Recognit. 8:125-131; and Johnson, B. et al. (1991) Anal. Biochem. 198:268-277. As used herein, the term “K…” off "K" refers to the dissociation rate constant of an antibody from its antibody / antigen complex. As used herein, the term "K" is... d "" refers to the dissociation constant of a specific antibody-antigen interaction.

[0127] The term "EC" 50 "EC" refers to the concentration of a substance (e.g., a compound or drug) required to activate or enhance a biological process or a component of that process by 50%. For example, EC... 50 It can refer to the agonist concentration that elicits half the response between the baseline response and the maximum response in an appropriate target activity assay.

[0128] The term "IC" 50 "IC" refers to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process or a component of that process by 50%. For example, IC50... 50 It refers to the half-maximum (50%) inhibitory concentration (IC) of a substance, determined in an appropriate assay.

[0129] As used herein, the term "repressive nucleic acid" refers to any nucleic acid that, when administered, interacts with a target gene, resulting in the suppression of the expression or activity of that target gene, such as MMP-9. A repressive nucleic acid molecule can be DNA or a repressive RNA (e.g., siRNA, miRNA, antisense oligonucleotide (ASO), shRNA, lncRNA, pre-miRNA, or miRNA), wherein the RNA is single-stranded, double-stranded, or contains both single-stranded and double-stranded regions. In some embodiments, the repressive nucleic acid is siRNA. In some embodiments, the repressive nucleic acid is an antisense oligonucleotide (ASO). An ASO can be single-stranded or double-stranded DNA, RNA, or a DNA / RNA hybrid. See, for example, *Antisense Oligodeoxynucleotides and Antisense RNA: Novel Pharmacological and Therapeutic Agents*, CRC Press, Boca Raton, Fla., 1997. It should be understood that the compositions disclosed herein possess certain desired functions, such as inhibiting or activating MMP-9 activity, to treat MMP-9-mediated conditions, such as hereditary heterotopic ossification. This document discloses methods and compositions for various therapeutic approaches to achieve the disclosed functions, and it is understood that various structures exist that can perform the same or similar functions associated with these methods and compositions, and these structures are expected to achieve the same or similar results.

[0130] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Exemplary methods and materials are described below, although similar or equivalent methods and materials may also be used in the practice of this disclosure and will be apparent to those skilled in the art. All publications and other references mentioned herein are incorporated herein by reference in their entirety. In the event of any conflict, this specification (including definitions) shall prevail. Materials, methods, and examples are illustrative only and are not intended to be limiting.

[0131] In various aspects of the present invention, methods and compositions for treating a subject by administering one or more MMP-9 inhibitors are provided. In some embodiments, the methods described herein are used to treat hereditary ectopic ossification, such as progressive ossifying fibrous dysplasia (FOP).

[0132] Treatment

[0133] Object selection

[0134] In some embodiments, this document discloses methods for treating a subject identified as having hereditary heterotopic ossification (gHO), including administering to the subject a composition, such as a pharmaceutical composition comprising an MMP-9 inhibitor (e.g., an anti-MMP-9 antibody or an antigen-binding fragment thereof, an inhibitory RNA, a small molecule, an inhibitory peptide, or a recombinant gene knockout or knockdown system, such as a CRISPR-Cas system). In some embodiments, this disclosure provides the use of the MMP-9 inhibitor as described herein for the manufacture of a pharmaceutical remedy. In some embodiments, this disclosure provides the use of the antibody as described herein for the treatment of gHO. In some embodiments, gHO is progressive ossifying fibrous dysplasia (FOP).

[0135] In some embodiments, the subject is a mammal, such as a human. In some embodiments, the subject is less than about thirty years old. In some embodiments, the subject is 12 years old or older. In some embodiments, the subject is 18 years old or older. In some embodiments, the subject is 6-12 years old. In some embodiments, the subject is 2-12 years old. In some embodiments, the subject has a gain-of-function mutation in the ACVR1 / ALK2 gene. In some embodiments, the gain-of-function mutation in the ACVR1 / ALK2 gene is R206H.

[0136] Heteroplasmic ossification refers to the ectopic formation of lamellar bone in soft tissues. (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., Davis, TA, Wang, S., James, AW, and Levi, B., J Bone Joint Surg Am. 2015 Jul 1; 97(13): 1101–1111). Common causes of heterooplasmic ossification include joint replacement surgery, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and thermal injuries. (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., Davis, TA, Wang, S., James, AW, and Levi, B., J Bone Joint Surg Am. 2015 Jul 1; 97(13): 1101–1111). Factors influencing the transformation of progenitor cells into osteogenic precursor cells include oxygen tension, pH, micronutrient availability, and mechanical stimulation. (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., Davis, TA, Wang, S., James, AW, and Levi, B., J BoneJoint Surg Am. 2015 Jul 1; 97(13): 1101–1111). This condition is also known as peripheral osteoarthropathy, myositis ossifying, periarticular new bone formation, periarticular heterotopic ossification, neurogenic osteoma, neurogenic ossifying fibromyalgia, and heterotopic calcification. (Sawyer JR, Myers MA, Rosier RN, Puzas JE. Heterotopicossification: clinical and cellular aspects. Calcif Tissue Int 1991;49:208–15).

[0137] Clinical signs of heterotopic ossification include pain, limited range of motion, swelling or heat in the joint area, increased spasm, and fever. There is currently no effective treatment, and the cause of heterotopic ossification is unknown. (Lisa Harve, BAppSc, GradDipAppSc (exSpSc), MAppSc, PhD, in Management of Spinal Cord Injuries, 2008.)

[0138] Heterotopic ossification can be preventively treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or radiation. (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., Davis, TA, Wang, S., James, AW, and Levi, B., J Bone Joint Surg Am. 2015 Jul 1; 97(13): 1101–1111). Surgery is sometimes recommended for the treatment of heterotopic ossification, but it is not an option when heterotopic ossification occurs in progressive ossifying fibrous dysplasia (a hereditary form of heterotopic ossification). (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., Davis, TA, Wang, S., James, AW, and Levi, B., J Bone Joint Surg Am. 2015 Jul 1; 97(13): 1101–1111). A putative mechanism for heterotopic ossification has been proposed. This mechanism posits that heterotopic ossification occurs as a gradual process, beginning with injury or trauma to skeletal muscle cells, followed by neuronal stimulation, release of substance P, mast cell degranulation and inflammation, recruitment of myeloid and lymphocytes, and release of TGF-β and bone morphogenetic protein (BMP). TGF-β and BMP are thought to act on blood vessels, leading to endothelial-mesenchymal transition (EMT). Following EMT, endothelial-mesenchymal stem cell-like cells (MSCs) and resident MSCs undergo chondrogenesis, followed by endochondral ossification and bone formation.

[0139] MMP-9 induces EMT in human glomerular endothelial cells via Notch activation. While not limited to theory, this paper proposes that MMP-9-mediated conditions such as hereditary heterotopic ossification (e.g., FOP) can be treated by preventing EMT. Therefore, in some embodiments, methods and compositions for treating subjects by administering one or more MMP-9 inhibitors to prevent the progression of EMT and heterotopic ossification are disclosed herein.

[0140] In some aspects of the invention, the methods and compositions of the invention reduce BMP levels and / or BMP signaling in the subject. In other aspects of the invention, the methods and compositions of the invention reduce BMP signaling in soft tissues, joints, muscles, ligaments, bones, and other sites of injury or inflammation against a background of inflammation and heterotopic ossification. In some embodiments of the invention, the method reduces pathological BMP signaling without affecting steady-state BMP signaling.

[0141] According to the Brooker system, heterotopic ossification is classified into four grades, I-IV. Patients with Brooker grade III and IV heterotopic ossification did not show improvement in passive range of motion of the hip joint during postoperative follow-up.

[0142] Therefore, the object of this invention is to improve clinical outcomes in patients with high-grade (Brooker grade III, IV) hereditary heterotopic ossification (e.g., FOP). In some embodiments, one or more therapies of this invention are administered to reduce high-grade hereditary heterotopic ossification. In some embodiments, postoperative passive range of motion is improved in patients. For example, with regard to the hip joint, flexion, internal rotation, external rotation, abduction, and adduction range of motion are all improved.

[0143] FOP is a genetic form of progressive ectopic ossification in soft tissues and muscles. The most common genetic basis of FOP is an autosomal dominant gain-of-function missense mutation in the ACVR1 / ALK2 gene, in which a G-to-A substitution at nucleotide c.617 alters the CGC codon encoding arginine to the CAC codon encoding histidine (R206H). The R260H mutation occurs in the GS domain of ACVR1, leading to overactivation of ACVR1 BMP binding and the SMAD 1 / 5 / 8 signaling pathway. Furthermore, activin A binds to the R260H-mutated ACVR1, causing ACVR1 to phosphorylate SMAD 1 / 5 / 8 instead of SMAD 2 / 3. When SMAD1 and 5 are co-expressed with the R260H-mutated ACVR1, they promote the expression of osteoblast differentiation factors in C2C12 cells and may play a role in ectopic ossification of FOP.

[0144] Standard care for ectopic ossification (FOP) involves treatment with glucocorticoids, NSAIDs, mast cell inhibitors, leukotriene inhibitors, or bisphosphonates. However, these treatments are not highly effective, and the primary method for managing FOP is to avoid injury, which is believed to trigger the progression of heterotopic ossification. Therefore, the purpose of this disclosure is to provide improved treatment for FOP.

[0145] Application route

[0146] The MMP-9 inhibitors suitable for the disclosed methods are formulated for any suitable route of administration, including but not limited to injection (e.g., intravenous injection) in some embodiments. Injection includes, for example, subcutaneous injection, peritoneal injection, intravenous injection, or intramuscular injection. In some embodiments, the antibodies of this disclosure are formulated for subcutaneous administration. In some embodiments, the antibodies of this disclosure are formulated for peritoneal administration. In some embodiments, the antibodies of this disclosure are formulated for intravenous administration (e.g., intravenous injection or infusion). In some embodiments, the antibodies of this disclosure are formulated for intramuscular administration. In some embodiments, administration is performed at one, two, three, four, five, six, seven, or more injection sites. In some embodiments, administration is performed at one injection site. In some embodiments, administration is performed at two injection sites. In some embodiments, administration is performed at three injection sites. In some embodiments, administration is performed at four injection sites. In some embodiments, administration is performed at five injection sites. In some embodiments, administration is performed at six injection sites.

[0147] For in vivo application, contact refers to the administration of the composition (e.g., a composition containing an MMP-9 inhibitor) to the target site by any suitable means. In some embodiments, the MMP-9 inhibitors disclosed herein are administered, for example, systemically or locally, including via parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, or, if local treatment is required, direct injection to the site of heterotopic ossification. Parenteral routes include, for example, intravenous, intraarterial, intraperitoneal, epidural, intramuscular, and intrathecal administration. In some embodiments, such administration is by bolus, continuous infusion, or pulsatile infusion. In some embodiments, the composition is administered by injection, depending on whether the administration is short-term or long-term. Other administration methods are considered, including local administration, particularly percutaneous, transmucosal, rectal, oral, or topical administration, such as via a catheter placed near the desired site.

[0148] Dosage

[0149] MMP-9 inhibitors suitable for the disclosed methods and compositions containing such inhibitors can be administered in a dosage-compatible manner and at a therapeutically effective dose. In some embodiments, the amount to be administered depends on the subject being treated. The precise amount of active ingredient required for administration depends on the clinician's judgment and varies from person to person. However, a suitable regimen for initial administration is generally: an initial administration followed by repeated administration every hour or longer. Alternatively, continuous administration sufficient to maintain blood concentrations is also considered.

[0150] Factors such as the amount of active ingredient in the composition (e.g., an MMP-9 inhibitor), the composition formulation, and the route of administration must be adjusted to provide an amount of active ingredient that effectively achieves the desired therapeutic response in each subject without causing excessive toxicity. The selected dose level will depend on a variety of factors, including the activity of the specific compound used, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition used, the subject's age, sex, weight, condition, general health, diet, and medical history, as well as other similar factors well known in the medical field.

[0151] In some embodiments, the MMP-9 inhibitor suitable for the disclosed methods, or a pharmaceutical composition containing the inhibitor, is administered to the subject at different dosages and different time frames. Furthermore, in some embodiments, the MMP-9 inhibitor is dosed twice weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every twelve weeks, or any combination of such weeks. Dosing cycles are also considered, for example, administering the MMP-9 inhibitor once or twice weekly for four weeks, followed by a two-week break. Other dosing cycles are also considered in this disclosure, including, for example, different combinations of the dosages and weekly cycles described herein.

[0152] In some embodiments, the therapeutically effective dose of the MMP-9 inhibitor or a composition containing such inhibitor varies and is determined based on the severity of the disease, the subject's weight, and the subject's overall condition. In some embodiments, administration is once daily, every other day, weekly, twice monthly, once monthly, or the frequency may be increased or decreased as needed based on the response to the condition or illness and the subject's tolerance to the therapy. In some embodiments, a maintenance dose is required for a longer period (e.g., 4, 5, 6, 7, 8, 10, or 12 weeks or longer) until the expected suppression of symptoms is achieved, with dose adjustments as needed. Progression of the therapy can be easily monitored using routine techniques and assays.

[0153] In some cases, a physician with ordinary technical skills in the art can easily determine and prescribe the required effective dose (ED) of the composition. 50 For example, a physician may start with a dose of the active ingredient used in the composition below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Alternatively, in some embodiments, the dose remains constant.

[0154] MMP-9 inhibitors suitable for the disclosed methods and compositions comprising such inhibitors may be provided in unit dose form for precise administration. The term "unit dose" or "unit dosage form" refers to a physically independent unit suitable for a unit dose in humans and other mammals, each unit containing a predetermined amount of active substance bound to a suitable pharmaceutical excipient, the amount of which is calculated to produce the desired therapeutic effect. In some embodiments, the dosage forms described herein may be administered as unit doses. Typical unit dosage forms include pre-filled, pre-quantitative liquid composition ampoules or syringes, and in the case of solid compositions, pills, tablets, capsules, etc.

[0155] The dosage of an MMP-9 inhibitor or a composition containing such an inhibitor may vary depending on a variety of factors, such as the pharmacodynamic properties of the compound, the route of administration, the recipient's age, health status or weight, the nature and severity of symptoms, the frequency of treatment, the type of concurrent treatment (if any), and the clearance of the therapeutic agent in the animal being treated. Those skilled in the art can determine an appropriate dosage based on these factors. An MMP-9 inhibitor or a composition containing such an inhibitor may be initially administered at an appropriate dosage, which may be adjusted as needed based on clinical response. It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated. Furthermore, it should be understood that for any particular subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the dosage ranges described herein are merely illustrative and not intended to limit the scope or application of the claimed compositions.

[0156] In some embodiments, the antibody is administered intravenously at an initial loading dose, followed by weekly maintenance doses administered subcutaneously. In some embodiments, both the initial loading dose and the maintenance dose are administered subcutaneously.

[0157] Exemplary non-limiting ranges for the therapeutic or preventative effective amounts of the antibodies or antibody portions of the present invention are selected from 10-100 mg, more preferably 20-80 mg, and even more preferably about 40 mg, about 50 mg, or about 150 mg. Other non-limiting ranges, as disclosed in US 8,377,443, include daily administration to a subject of 10 ng / kg up to 100 mg / kg of mammalian body weight or more. Preferably, the dose is selected from 1 µg / kg / day, 100 µg / kg / day, 500 µg / kg / day, 1 mg / kg / day, 10 mg / kg / day, or 20 mg / kg / day. It should be noted that dose values ​​may vary depending on the type and severity of the condition to be alleviated. Furthermore, it should be understood that for any particular subject, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition; and the dosage ranges described herein are merely examples and are not intended to limit the scope or application of the claimed compositions.

[0158] In some embodiments, the antibody is administered intravenously at an initial loading dose, followed by weekly subcutaneous administration at a maintenance dose. In some embodiments, the initial loading dose of the antibody is 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg, administered intravenously. In some embodiments, the maintenance dose is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, administered subcutaneously weekly or every other week.

[0159] In some embodiments, both the initial loading dose and the maintenance dose are administered subcutaneously. In some embodiments, the initial loading dose is 150 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of antibody, administered subcutaneously. In some embodiments, the maintenance dose is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, administered subcutaneously weekly or every other week.

[0160] In some embodiments, the subject is approximately 2 to 5 years old, and the antibody is administered subcutaneously at a dose of 10 mg to 150 mg. Preferably, the antibody is administered subcutaneously at a dose of 15 mg to 50 mg. In some embodiments, the dose is 10 mg. In some embodiments, the dose is 15 mg. In some embodiments, the dose is 20 mg. In some embodiments, the dose is 25 mg. In some embodiments, the dose is 30 mg. In some embodiments, the dose is 35 mg. In some embodiments, the dose is 40 mg. In some embodiments, the dose is 45 mg. In some embodiments, the dose is 50 mg. In some embodiments, the dose is administered weekly or every other week.

[0161] In some embodiments, a maintenance dose, administered weekly or every other week, is given one or more weeks after the loading dose or up to three loading doses, wherein the loading dose is greater than the maintenance dose. In other embodiments, no loading dose is administered. In other embodiments, the loading dose is replaced by the application of another treatment modality.

[0162] In some embodiments, the subject is between about 6 and 11 years old, and the antibody is administered subcutaneously at a dose of 25 mg to 150 mg. Preferably, the antibody is administered subcutaneously at a dose of 25 mg to 75 mg. In some embodiments, the dose is 25 mg. In some embodiments, the dose is 30 mg. In some embodiments, the dose is 35 mg. In some embodiments, the dose is 40 mg. In some embodiments, the dose is 45 mg. In some embodiments, the dose is 50 mg. In some embodiments, the dose is 55 mg. In some embodiments, the dose is 60 mg. In some embodiments, the dose is 65 mg. In some embodiments, the dose is 70 mg. In some embodiments, the dose is 75 mg. In some embodiments, the dose is administered weekly or every other week.

[0163] In a preferred embodiment, the subject is older than about 12 years and receives a weekly dose of 150 mg of an MMP-9 inhibitor (e.g., anddeliximab). In another preferred embodiment, the subject is older than about 12 years and receives a weekly dose of 50 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between about 5 and 11 years old and receives a weekly dose of 75 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between about 6 and 11 years old and receives a weekly dose of 25 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between 2 and 5 years old and receives a weekly dose of 45 or 50 mg of an MMP-9 inhibitor. In another preferred embodiment, the subject is between 2 and 5 years old and receives a weekly dose of 15 mg of an MMP-9 inhibitor.

[0164] In a preferred embodiment, the subject is between about 6 and 11 years old and receives a weekly dose of 75 mg of an MMP-9 inhibitor (e.g., anddeliximab). In some embodiments, the subject is between about 6 and 11 years old and receives a weekly dose of 25 mg. In some embodiments, the subject is between about 2 and 5 years old and receives a weekly dose of 50 or 45 mg of an MMP-9 inhibitor. In some embodiments, the subject is 2-5 years old and receives a dose of 15 mg every other week. In some embodiments, the subject is 6-11 years old and receives a dose of 75 mg every other week. In some embodiments, the subject is 2-5 years old and receives a weekly dose of 45 or 50 mg of an MMP-9 inhibitor.

[0165] In some implementations, two dosing regimens are present. In some implementations, the higher dose provides complete targeted coverage for all age groups. In other implementations, the lower dose provides good coverage and reduces potential side effects related to unclosed epiphyses in children.

[0166] In other implementation schemes, the dosage is adjusted according to age group.

[0167] In some embodiments, the antibody is formulated as a reservoir formulation or a sustained-release formulation, and the dosing interval is reduced by approximately two, three, four, or more than four times. A description of a sustained-release formulation is found, for example, in US 10,000,562. Suitable examples of sustained-release formulations include a semi-permeable matrix of a solid hydrophobic polymer containing the antibody, in the form of a tangible article, such as a film or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or polyvinyl alcohol), polylactic acid (US Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, and degradable lactic-glycolic acid copolymers such as LUPRON DEPOT. TM (Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid. Microencapsulation of recombinant proteins for sustained release has been successfully applied to human growth hormone (rhGH), interferon-(rhIFN-), interleukin-2 and MN rpg 120. Johnson et al., Nat. Med. 2: 795-799 (1996); Yasuda et al., Biomed. Ther. 27: 1221-1223 (1993); Hora et al., Bio / Technology 8: 755-758 (1990); Cleland, “Design and Production of Single Immunization Vaccines Using Polyylactide Polyglycolide Microsphere Systems,” in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds., (Plenum Press: New York, 1995), pp. 439-462; WO 97 / 03692; WO 96 / 40072; WO 96 / 07399; and U.S. Patent No. 5,654,010.

[0168] combination therapy

[0169] In some embodiments, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor, as disclosed herein, includes administering a second therapeutic agent or supportive therapy to the subject. In some embodiments, the second therapeutic agent or supportive therapy is selected from isotretinoin, etidronate in combination with oral glucocorticoids, piperacillin maleate, activin A inhibitors, activin A receptor type 2 (ALK2) inhibitors, ALK2 allele-specific RNA interference, hypoxia-inducible factor-1α (Hif-1α) inhibitors, small molecule inhibitors of the bone morphogenetic protein (BMP) signaling pathway, anti-BMP9 antibody or its antigen-binding fragment, anti-BMP10 antibody or its antigen-binding fragment, anti-TGF-β antibody or its antigen-binding fragment, IL1β inhibitors, IL6 inhibitors, molotinib, cromoglycine, imatinib, adenosine triphosphate bisphosphatase, rapamycin, kinase inhibitors, zicatinib, parovatin, retinoic acid receptor gamma agonists, retinoic acid receptor alpha agonists, bisphosphonates, radiotherapy, anti-inflammatory drugs, physical therapy, and combinations thereof.

[0170] In some embodiments, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor includes combining the MMP-9 inhibitor with a second MMP inhibitor. In some embodiments, the second MMP inhibitor is selected from MMP-2 inhibitors, MMP-7 inhibitors, MMP-13 inhibitors, MMP-14 inhibitors, or MMP-16 inhibitors.

[0171] In some embodiments, an MMP-9 inhibitor or a composition containing the inhibitor is used simultaneously or sequentially with a second therapeutic agent or supportive therapy, depending on the condition to be treated and the subject's weight and age, the severity of the disease, the mode of treatment, etc., which in some cases can be readily determined by a person skilled in the art.

[0172] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with an activin receptor type 2A (ACVR2A) antagonist.

[0173] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with an activin receptor type 2B (ACVR2B) antagonist.

[0174] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with an activin receptor type 1 (ACVR1) antagonist.

[0175] In some embodiments, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor includes administering the MMP-9 inhibitor in combination with an anti-activin receptor type 1 (ACVR1) antibody. In some embodiments, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor includes administering the MMP-9 inhibitor in combination with the anti-activin receptor type 1 (ACVR1) antibody REGN2477.

[0176] In some implementations, treatment of gHO (e.g., FOP) with an MMP-9 inhibitor involves co-administration of the MMP-9 inhibitor with hypoxia-inducible factor-1α (Hif-1α). Without being theoretically limited, treatment with a Hif-1α inhibitor is thought to reduce ectopic ossification by blocking Hif-1α-mediated upregulation of BMP-2 signaling. In the BMP-2 pathway, ligand activation of BMP-2 leads to SMAD 1 / 5 / 8 phosphorylation, which results in gene transcription, cell differentiation, and cell proliferation, thereby increasing osteogenic factors. Therefore, blocking this pathway with a Hif-1α inhibitor can reduce ectopic ossification. Furthermore, Hif-1α leads to increased expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (BFGF), platelet-derived growth factor (PDGF), and angiopoietin-2, all of which are essential for endothelial cell motility, recruitment, and proliferation. (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., David, TA, Wang, S., James, AW, and Levi, B., J Bone Joint Surg Am. 2015 Jul 1; 97(13): 1101–1111). Hif-1a also promotes heterotopic ossification by modulating the sex-determining region Y-box 9, which is an essential cartilaginous progenitor. (Ranganathan, K., Loder, S., Agarwal, S., Wong, VW, Forsberg, J., David, TA, Wang, S., James, AW, and Levi, B., J Bone Joint Surg Am. 2015 Jul 1;97(13): 1101–1111). In some embodiments, treatment of gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with a locally applied Hif-1α inhibitor. In some embodiments, the Hif-1α inhibitor is imatinib, rapamycin, or an inhibitory RNA.

[0177] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with a small molecule inhibitor of bone morphogenetic protein (BMP) signaling.

[0178] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves administering the MMP-9 inhibitor in combination with an antibody against activin B.

[0179] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves administering the MMP-9 inhibitor in combination with an antibody targeting BMP9.

[0180] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves administering the MMP-9 inhibitor in combination with an antibody targeting BMP10.

[0181] In some implementations, the treatment of gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with molotinib.

[0182] In some implementations, treatment of gHO (e.g., FOP) with an MMP-9 inhibitor involves combining the MMP-9 inhibitor with parovatin. Without being bound by theory, the mechanism by which parovatin inhibits heterotopic ossification is thought to be through the RAR-g receptor expressed on chondrocytes and cartilage cells, a transcriptional repressor that inhibits osteogenic processes. (Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, ChandraratnaRA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. NatMed. 2011. April;17(4):454-60. Epub 2011 Apr 3). Administration of parovatin (a RAR-γ receptor agonist) prevents mesenchymal stem cells from differentiating into chondrocytes, thereby inhibiting cartilage formation and endochondral ossification. (Shimono K, TungWE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopicossification by nuclear retinoic acid receptor-γ agonists. Nat Med. 2011.April;17(4):454-60. Epub 2011 Apr 3). Parovatin has shown good efficacy in a mouse model of progressive ossifying fibrous dysplasia and is currently undergoing phase 3 clinical trials.(Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopicossification by nuclear retinoic acid receptor-γ agonists. Nat Med. 2011. April;17(4):454-60. Epub 2011 Apr 3; Ongoing Clinical Trials in FOP, International Fibrodysplasia Ossificans Progressiva Association).

[0183] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves administering the MMP-9 inhibitor in combination with imatinib.

[0184] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor includes the combined administration of the MMP-9 inhibitor and a BMP receptor kinase inhibitor.

[0185] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor involves administering the MMP-9 inhibitor in combination with sarcatnib.

[0186] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor includes the combined administration of the MMP-9 inhibitor and a TNF inhibitor.

[0187] In some implementations, the method of treating gHO (e.g., FOP) with an MMP-9 inhibitor includes the combined administration of an MMP-9 inhibitor and a BTK inhibitor.

[0188] MMP-9 inhibitors

[0189] In some embodiments, this document discloses MMP-9 inhibitors suitable for treating patients with hereditary heterotopic ossification (gHO), such as progressive ossifying fibrous dysplasia (FOP). In some embodiments, the MMP-9 inhibitor suitable for the disclosed methods is an anti-MMP-9 antibody or an antigen-binding fragment thereof (e.g., an inhibitory anti-MMP-9 antibody or an antigen-binding fragment thereof). In some embodiments, the MMP-9 inhibitor suitable for the disclosed methods is a repressive RNA (e.g., an antisense oligonucleotide (ASO), short interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), or shRNA-adapted microRNA (shmiRNA)). In some embodiments, the MMP-9 inhibitor suitable for the disclosed methods is a small molecule inhibitor of MMP-9. In some embodiments, the MMP-9 inhibitor suitable for the disclosed methods is an inhibitory peptide. In some embodiments, the MMP-9 inhibitor suitable for the disclosed methods is a recombinant expression system (e.g., a CRISPR-Cas system) capable of knocking out the MMP-9 gene from the MMP-9 locus of a subject. In some implementations, the MMP-9 inhibitor suitable for the disclosed methods is any combination of the above-described treatment modalities.

[0190] Anti-MMP-9 antibody

[0191] In some embodiments, this document discloses anti-MMP-9 antibodies or antigen-binding fragments thereof, such as inhibitory anti-MMP-9 antibodies or antigen-binding fragments thereof. For example, WO / 2017 / 177179 discloses a variety of anti-MMP-9 antibodies. These antibodies exhibit anti-MMP-9 activity; however, there appear to be no known successful therapies involving the use of such antibodies to treat gHOs such as FOP. Therefore, this document provides a method for treating gHOs by inhibiting MMP-9 through the administration of anti-MMP-9 antibodies or antigen-binding fragments thereof. In some embodiments, the anti-MMP-9 antibody or antigen-binding fragment thereof inhibits MMP-9 activation or enzyme activity.

[0192] In some embodiments, the MMP-9 inhibitor comprises an anti-MMP-9 antibody or an antigen-binding fragment thereof, wherein the anti-MMP-9 antibody or the antigen-binding fragment thereof binds to (i) a precursor form of MMP-9 and inhibits the activation of the precursor form; and / or (ii) an active form of MMP-9 and inhibits the activity of the active form, and is used as a method of treating gHO (e.g., FOP).

[0193] In some implementations, anti-MMP-9 antibodies or their antigen-binding fragments bind to a precursor form of MMP-9 to inhibit MMP-9 activation and are used as a method for treating gHO (e.g., FOP).

[0194] In some implementations, anti-MMP-9 antibodies or their antigen-binding fragments bind to the active form of MMP-9 via allosteric binding to inhibit MMP-9 activity, and are used as a method targeting gHO (e.g., FOP).

[0195] In some embodiments, the therapeutic antibody for administration is characterized by binding to one or more processing sites (e.g., proteolytic cleavage sites) in MMP-9, thereby effectively preventing the proenzyme or precursor enzyme from being processed into an enzyme with catalytic activity, thereby reducing the proteolytic activity of MMP-9.

[0196] In some embodiments, the therapeutic antibody for administration is characterized by its affinity for MMP-9 being at least 2, at least 5, at least 10, at least 25, at least 50, at least 100, at least 500, or 1000 times greater than its affinity for another MMP. Binding affinity can be measured by any method known in the art and can be expressed, for example, as binding rate, dissociation rate, or dissociation constant (K0). d ), equilibrium constant (K) eq (or any term known in the art). Various examples of such affinity maturation antibodies are within the scope of this invention.

[0197] In some embodiments, the therapeutic antibody for administration is characterized as a non-competitive inhibitor of MMP-9 catalytic activity. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment suitable for the methods of this disclosure binds within the catalytic domain of MMP-9. In some embodiments, the anti-MMP-9 antibody or its antigen-binding fragment suitable for the methods of this disclosure binds outside the catalytic domain of MMP-9.

[0198] Other antibodies or antigen-binding fragments thereof that compete with the anti-MMP-9 antibodies or their antigen-binding fragments described herein for binding to MMP-9 are also contemplated within the scope of this invention. For example, an anti-MMP-9 antibody or its functional fragment may compete for binding with antibodies, for example, having a heavy chain polypeptide, a light chain polypeptide, or a combination thereof. In some embodiments, a method for treating gHO (e.g., FOP) includes administering one or more anti-MMP-9 antibodies or antigen-binding fragments comprising one or more amino acid sequences listed in Table 1.

[0199] SDS3 is a Zn that binds to activate MMP-9. 2+ Antibodies targeting active sites and surface epitopes, rather than mimicking endogenous MMP-9 inhibitors or tissue inhibitors of metalloproteinases (TIMPs). In mice, SDS3, at 200 nM K, [the antibody]... D and 1 mM K iBinding and inhibiting MMP-9 provides both preventative and therapeutic effects in a dextran sulfate-induced colitis model. (Sela-Passwell N, Kikkeri R, Dym O, Rozenberg H, Margalit R, Arad-Yellin R, et al. Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential. Nat Med. (2011) 18:143–7. doi:10.1038 / nm.2582). Therefore, in some embodiments, methods for treating gHO (e.g., FOP) include administering a humanized SDS3 antibody. In various other embodiments, the method provides administering a similar antibody or its antigen-binding fragment that binds to Zn, which activates MMP-9. 2+ Active sites and surface epitopes.

[0200] Similar to SDS3, SDS4 is a Zn that binds to activated MMP-9. 2+ Antibodies targeting active sites and surface epitopes, rather than mimicking TIMPs. In mice, SDS3, at 20 nM K, [is effective against these targets]. D and 54 mM K i Binding and inhibition of MMP-9. (Sela-Passwell N, Kikkeri R, Dym O, Rozenberg H, Margalit R, Arad-Yellin R, et al. Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential. Nat Med. (2011) 18:143-7. doi:10.1038 / nm.2582). Therefore, in some embodiments, the method of treating gHO (e.g., FOP) includes administering a humanized SDS4 antibody. In various other embodiments, the method provides administering a similar antibody or its antigen-binding fragment, which binds to Zn to activate MMP-9. 2+ Active sites and surface epitopes.

[0201] Mouse REGA-3G12 binds MMP-9 between Trp116 and Lys214, which is located at the Zn... 2+In the catalytic domain separated by binding sites. (Martens E, Leyssen A, Van Aelst I, Fiten P, Piccard H, Hu J, et al. A monoclonal antibody inhibits gelatinase B / MMP-9 by selectively binding to part of the catalytic domain and not to the fibronectin or zinc binding domains. Biochim Biophys Acta. (2007) 1770:178–86. doi: 10.1016 / j.bbagen.2006.10.012). Mouse REGA-3G12 with 20 nM K DBinding to MMP-9. (Paemen L, Martens E, Masure S, Opdenakker G. Monoclonal antibodies specific for natural human neutrophil gelatinase B used for affinity purification, quantitation by two-site ELISA and inhibition of enzymatic activity. Eur J Biochem. (1995) 234:759–65. doi: 10.1111 / j.1432-1033.1995.759_a.x). In rhesus monkeys, REGA-3G12 prevented the mobilization of interleukin-8 by hematopoietic progenitor cells. (Hu J, Van den Steen PE, Houde M, Ilenchuk TT, Opdenakker G. Inhibitors of gelatinase B / matrix metalloproteinase-9 activity comparison of a peptidomimetic and polyhistidine with single-chain derivatives of a neutralizing monoclonal antibody. Biochem Pharmacol. (2004)67:1001–9. doi: 10.1016 / j.bcp.2003.10.030). Therefore, in some embodiments, the treatment of gHO (e.g., FOP) includes administering a humanized REGA-3G12 antibody or its antigen-binding fragment, which binds MMP-9 between Trp116 and Lys214, or with Zn... 2+ They bind within catalytic domains separated by binding sites.

[0202] WO / 2017 / 177179 discloses anti-MMP-9 antibodies, such as AB0045 (andriximab). Andriximab binds to the catalytic domain of MMP-9, shielding the physiological activation site in the pre-domain through additional contact points, thereby inhibiting pro-MMP-9 activation and suppressing MMP-9 activity in a non-competitive manner. Andriximab has a potency of 2.0–6.6 nMK. D Combined with MMP-9 and at 0.008–0.043 nM K DBinding to pro-MMP-9. Andreximab inhibits human pro-MMP-9 activation to MMP-9 with an IC50 of 8.2 pM. Clinical trials of andreximab have shown the antibody to be safe and well-tolerated. Therefore, in some implementations, methods of treating gHO (e.g., FOP) include administering andreximab or its antigen-binding fragment to the subject. In a surgical orthotopic xenograft model of colorectal cancer, treatment with the AB0046 antibody (a mouse alternative to andreximab) resulted in a reduction in tumor growth and metastasis.

[0203] In some embodiments, the antibodies administered in the treatment of gHO (e.g., FOP) include antibodies disclosed in the following publications: WO / 2017 / 177179, PCT / US2012 / 027160, PCT / US2016 / 067036, PCT / US2016 / 054780, WO / 2016 / 023979A1, WO / 2008 / 102359A1, WO / 2002 / 066057, WO / 2006 / 037513, WO / 2009 / 111508, WO / 2011 / 028883, WO / 2012 / 154654, US / 2010 / 0098659, WO / 2010 / 048455, or WO / 2012 / 048291, all of which are incorporated herein by reference in their entirety.

[0204] In some embodiments, the antibody or its antigen-binding fragment suitable for the methods of this disclosure may be derivatized or linked to other functional molecules. For example, the antibody may be functionally linked (through chemical conjugation, gene fusion, non-covalent association, or other means) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a biantibody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and / or a protein or peptide capable of mediating the association of the antibody with another molecule (such as the streptavidin core region or a multihistidine tag).

[0205] In some embodiments, the antibody or antigen-binding fragment thereof suitable for the disclosed method is used in multiple settings. For example, the antibody or antigen-binding fragment thereof suitable for the disclosed method is administered as a therapeutic agent. In such embodiments, the antibody or antigen-binding fragment thereof can exert its therapeutic effect through multiple mechanisms. For example, the antibody or antigen-binding fragment thereof suitable for the disclosed method may be an antagonist antibody. As another example, the antibody or antigen-binding fragment thereof suitable for the disclosed method may be a blocking antibody. In some embodiments, the antibody or antigen-binding fragment thereof suitable for the disclosed method is a neutralizing antibody.

[0206] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 35, and the light chain comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 36. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 35, and the light chain comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 36. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 35, and the light chain comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 36. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, the heavy chain comprising amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 35, and the light chain comprising amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 36.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 35, and the light chain comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 36. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 35, and the light chain comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 36.

[0207] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 7.

[0208] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain complementarity-determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 8, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 10, and the light chain variable region comprises a light chain complementarity-determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 11, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 13.

[0209] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 1, and the light chain comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 1, and the light chain comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 1, and the light chain comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, the heavy chain comprising amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 1, and the light chain comprising amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 2.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 1, and the light chain comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 1, and the light chain comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 2.

[0210] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0211] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0212] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0213] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0214] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0215] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 3, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0216] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and wherein VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0217] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0218] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0219] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0220] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0221] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 46, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0222] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0223] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0224] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0225] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0226] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0227] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0228] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0229] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0230] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0231] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0232] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0233] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 48, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0234] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0235] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0236] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0237] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0238] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0239] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 54, and VL contains an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0240] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0241] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0242] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0243] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0244] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0245] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 55, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0246] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0247] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0248] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0249] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and wherein VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0250] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0251] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 56, and VL contains an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0252] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0253] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0254] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0255] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0256] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0257] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 4, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0258] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL contains amino acid sequences having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH contains amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL contains amino acid sequences having 100% sequence identity with the amino acid sequence of SEQ ID NO: 47.

[0259] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 57.

[0260] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58, and wherein VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 58.

[0261] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 59.

[0262] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 60.

[0263] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein the VH comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and the VL comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises VH and VL, wherein VH comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 5, and VL comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0264] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 17, and the light chain comprises amino acid sequences having at least 80% (e.g., at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 17, and the light chain comprises amino acid sequences having at least 85% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 17, and the light chain comprises amino acid sequences having at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 17, and the light chain comprises amino acid sequences having at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 18.In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 17, and the light chain comprises an amino acid sequence having at least 99% (e.g., at least 99% or greater) sequence identity with the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises amino acids having 100% sequence identity with the amino acid sequence of SEQ ID NO: 17, and the light chain comprises an amino acid sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO: 18.

[0265] In some embodiments, the anti-MMP-9 antibody suitable for the disclosed method comprises a heavy chain and a light chain, wherein the heavy chain comprises am...

Claims

1. A method for treating a subject suffering from a non-hereditary heterotopic ossification disorder, wherein an effective amount of an MMP-9 inhibitor is administered to the subject.

2. The method according to claim 1, wherein, The MMP-9 inhibitor is selected from anti-MMP-9 antibodies or their antigen-binding fragments, inhibitory RNA, inhibitory peptides, small molecule inhibitors, and CRISPR-Cas systems.

3. The method according to claim 2, wherein, The MMP-9 inhibitor is an anti-MMP-9 antibody or its antigen-binding fragment.

4. The method according to claim 3, wherein, The anti-MMP-9 antibody or its antigen-binding fragment binds to: (i) the precursor form of MMP-9 and inhibits the activation of the precursor form; and / or (ii) the active form of MMP-9 and inhibits the activity of the active form.

5. The method according to claim 4, wherein, The anti-MMP-9 antibody or its antigen-binding fragment binds to the MMP-9 precursor form.

6. The method according to claim 4, wherein, The anti-MMP-9 antibody or its antigen-binding fragment binds to the active form of MMP-9.

7. The method according to any one of claims 3-6, wherein, The anti-MMP-9 antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises amino acids having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprises amino acid sequences having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

7.

8. The method according to claim 7, wherein, The anti-MMP-9 antibody or its antigen-binding fragment includes adeliximab or its antigen-binding fragment.

9. The method according to any one of claims 1-8, wherein, The anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences that have at least 80% sequence identity with any of the amino acid sequences listed in Table 1.

10. The method according to claim 2, wherein, The repressive RNA includes antisense oligonucleotides (ASO), short interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), or shRNA-adapted microRNA (shmiRNA).

11. The method according to claim 2 or 10, wherein, The repressive RNA or the CRISPR-Cas system is configured in lipid nanoparticles (LNPs).

12. A method for treating an inflammatory episode in a subject suffering from progressive ossifying fibrous dysplasia (FOP), comprising administering an MMP-9 inhibitor to the subject.

13. The method according to claim 12, wherein, The inflammatory episodes are associated with heterotopic ossification in the subject.

14. The method according to claim 12, wherein, The inflammatory episodes were not related to heterotopic ossification in the subject.

15. The method according to any one of claims 12-14, wherein, The attacks are either spontaneous or triggered by external factors.

16. The method according to claim 15, wherein, The external triggers are selected from intramuscular injection, biopsy, muscle fatigue, dental procedures, trauma, or infection.

17. The method according to any one of claims 12-16, wherein, The method reduces the frequency of inflammatory attacks compared to the frequency of attacks prior to the administration of the MMP-9 inhibitor.

18. The method according to any one of claims 12-17, wherein, The method reduces the severity of inflammatory attacks compared to the severity of the attacks prior to the administration of the MMP-9 inhibitor.

19. A method for treating hereditary heterotopic ossification (gHO) in a subject of need, comprising administering an MMP-9 inhibitor to the subject.

20. The method according to any one of claims 12-19, wherein, The MMP-9 inhibitor is selected from anti-MMP-9 antibodies or their antigen-binding fragments, inhibitory RNA, inhibitory peptides, small molecule inhibitors, and CRISPR-Cas systems.

21. The method according to claim 20, wherein, The MMP-9 inhibitor is an anti-MMP-9 antibody or its antigen-binding fragment.

22. The method according to claim 21, wherein, The anti-MMP-9 antibody or its antigen-binding fragment binds to: (i) the precursor form of MMP-9 and inhibits the activation of the precursor form; and / or (ii) the active form of MMP-9 and inhibits the activity of the active form.

23. The method according to claim 22, wherein, The anti-MMP-9 antibody or its antigen-binding fragment binds to the MMP-9 precursor form.

24. The method according to claim 22, wherein, The anti-MMP-9 antibody or its antigen-binding fragment binds to the active form of MMP-9.

25. The method according to any one of claims 21-24, wherein, The anti-MMP-9 antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises amino acids having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprises amino acid sequences having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

7.

26. The method of claim 25, wherein, The anti-MMP-9 antibody or its antigen-binding fragment includes adeliximab or its antigen-binding fragment.

27. The method according to any one of claims 12-26, wherein, The anti-MMP-9 antibody or its antigen-binding fragment comprises one or more amino acid sequences that have at least 80% sequence identity with any of the amino acid sequences listed in Table 1.

28. The method according to claim 20, wherein, The repressive RNA includes antisense oligonucleotides (ASO), short interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), or shRNA-adapted microRNA (shmiRNA).

29. The method according to claim 20 or 28, wherein, The repressive RNA or the CRISPR-Cas system is configured in lipid nanoparticles (LNPs).

30. The method according to any one of claims 12-29, wherein, The method also includes the administration of additional active agents or supportive therapies for the treatment of gHO.

31. The method according to claim 30, wherein, The adjunctive active agents or supportive therapies for treating gHO are selected from isotretinoin, etidronate in combination with oral glucocorticoids, pipexicillin maleate, activin A inhibitors, activin A receptor type 2 (ALK2) inhibitors, ALK2 allele-specific RNA interference, hypoxia-inducible factor-1α (Hif-1α) inhibitors, small molecule inhibitors of the bone morphogenetic protein (BMP) signaling pathway, anti-BMP9 antibody or its antigen-binding fragment, anti-BMP10 antibody or its antigen-binding fragment, anti-TGF-β antibody or its antigen-binding fragment, IL1β inhibitors, IL6 inhibitors, molotinib, cromoglycine, imatinib, adenosine triphosphate bisphosphatase, rapamycin, kinase inhibitors, zicatinib, parovatin, retinoic acid receptor gamma agonists, retinoic acid receptor alpha agonists, bisphosphonates, radiotherapy, anti-inflammatory drugs, physical therapy, and combinations thereof.

32. The method according to claim 30 or 31, wherein, The additional active agent comprises a second MMP inhibitor selected from MMP-2 inhibitors, MMP-7 inhibitors, MMP-13 inhibitors, MMP-14 inhibitors, or MMP-16 inhibitors.

33. The method according to any one of claims 30-32, wherein, The additional active pharmaceutical agent or supportive therapy is administered in parallel with the MMP-9 inhibitor.

34. The method according to any one of claims 30-33, wherein, The additional active pharmaceutical agent or supportive therapy is administered sequentially with the MMP-9 inhibitor.

35. The method according to any one of claims 19-34, wherein, The gHO mentioned is FOP.

36. The method according to any one of claims 19-35, wherein, The gHO is characterized by endochondral ossification.

37. The method according to any one of claims 19-36, wherein, The gHO occurs in one or more tissues selected from bone, skin, subcutaneous tissue, skeletal muscle, tendon, ligament, aponeurosis, fibrotic tissue near joints, blood vessel walls, and ligaments.

38. The method according to any one of the preceding claims, wherein, The MMP-9 inhibitor is administered at a therapeutically effective dose.

39. The method according to any one of the preceding claims, wherein, Compared to the symptoms of the subject prior to administration of the MMP-9 inhibitor, administration of the MMP-9 inhibitor to the subject reduced the symptoms selected from: the number of ectopic ossifications, the size of ectopic ossifications, the growth of ectopic ossifications, or the formation of ectopic ossifications.

40. The method according to any one of claims 19-39, wherein, The object has been identified as exhibiting gHO formation.

41. The method according to claim 40, wherein, The subjects have been identified as exhibiting gHO formation by triple bone scan, computed tomography (CT) scan, or genetic analysis.

42. The method according to any one of claims 19-41, wherein, The MMP-9 inhibitor is an anti-MMP-9 antibody and is administered subcutaneously in doses of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 400 mg.

43. The method according to any one of the preceding claims, wherein, The subject is a human being.

44. The method according to claim 43, wherein, The subject is 12 years of age or older, or 18 years of age or older.

45. The method according to claim 43, wherein, The subjects were aged 6-12 years old.

46. ​​The method according to claim 43, wherein, The subject is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or older.

47. The method according to claim 46, wherein, The subjects were aged 2-5 years old.

48. The method according to claim 46, wherein, The subjects were aged 6-11 years old.

49. The method according to claim 43, wherein, The anti-MMP-9 antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises amino acids having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 55, and the light chain variable region comprises amino acid sequences having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

7.

50. The method according to claim 49, wherein, The anti-MMP-9 antibody or its antigen-binding fragment includes adeliximab or its antigen-binding fragment.

51. The method according to any one of claims 43-50, wherein, The subjects were aged 2-5 years, and the antibody or its antigen-binding fragment was administered subcutaneously.

52. The method according to any one of claims 43-50, wherein, The subjects were aged 6-11 years, and the antibody or its antigen-binding fragment was administered subcutaneously.

53. The method according to claim 50, wherein, The subjects were approximately 6 to approximately 11 years old, and the adeliximab or its antigen-binding fragment was administered approximately weekly at a dose of approximately 25 mg to approximately 75 mg.

54. The method according to claim 50, wherein, The subjects were aged approximately 6 to approximately 11 years, and the adeliximab or its antigen-binding fragment was administered at a dose of approximately 25 mg to approximately 75 mg every 8 days to approximately every 16 days.

55. The method according to claim 50, wherein, The subjects were approximately 2 to 5 years old, and the adeliximab or its antigen-binding fragment was administered approximately weekly at a dose of approximately 15 mg to approximately 50 mg.

56. The method of claim 50, wherein, The subjects were approximately 2 to approximately 5 years old, and the adeliximab or its antigen-binding fragment was administered at a dose of approximately 15 mg to approximately 50 mg every 8 days to approximately every 16 days.

57. The method of claim 50, wherein, The subjects were approximately 6 to approximately 11 years old, and the adeliximab or its antigen-binding fragment was administered subcutaneously at a dose of approximately 25 mg, approximately 50 mg, or approximately 75 mg per week.

58. The method according to claim 50, wherein, The subjects were approximately 2 to 5 years old, and the adeliximab or its antigen-binding fragment was administered subcutaneously at a dose of approximately 15 mg, approximately 45 mg, or approximately 50 mg approximately every other week.

59. The method according to claim 50, wherein, The subjects were aged approximately 12 to approximately 50 years, and the adeliximab or its antigen-binding fragment was administered subcutaneously at a dose of approximately 150 mg per week. The method of claim 50, wherein the subject is about 12 to about 50 years old, and wherein the adeliximab or its antigen-binding fragment is administered subcutaneously at a dose of about 50 mg per week.

60. The method of claim 50, wherein, The subjects were aged approximately 12 to approximately 50 years, and the adeliximab or its antigen-binding fragment was administered subcutaneously at a dose of approximately 150 mg every approximately every 8 days to approximately every 16 days.

61. The method according to claim 50, wherein, A single or no more than three loading doses are administered subcutaneously, followed by a maintenance dose of about 15 mg to about 75 mg subcutaneously every seven to about fourteen days, wherein the loading dose is greater than the maintenance dose.

62. The method according to claim 50, wherein, The subjects were aged approximately 2 to approximately 11 years, and the adeliximab or its antigen-binding fragment was administered subcutaneously in a sustained-release formulation.

63. The method according to any one of claims 19-62, wherein, The object has a gain-of-function mutation in the ACVR1 / ALK2 gene.

64. The method according to claim 63, wherein, The gain-of-function mutation in the ACVR1 / ALK2 gene is R206H.

65. The method according to any one of claims 1-41, wherein, The MMP-9 inhibitor is administered via systemic delivery.

66. The method according to claim 5, wherein, The whole-body delivery includes intravenous, intra-arterial, intramuscular, subcutaneous, intraperitoneal, or intrathoracic administration.

67. The method according to any one of claims 1-41, wherein, The MMP-9 inhibitor is administered via local delivery.

68. The method according to claim 7, wherein, The local delivery includes direct injection into the ectopic ossification area, tissue, or organ.

69. The method according to any one of the preceding claims, wherein, The MMP-9 inhibitor was administered to the subject over a period ranging from one month to 90 years.

70. The method according to any one of the preceding claims, wherein, The administration of the MMP-9 inhibitor was initiated between the ages of 2 and 18 and terminated between the ages of 30 and 100.

71. The method according to any one of the preceding claims, wherein, The MMP-9 inhibitor had no detectable inhibitory activity against human MMP-2.

72. A pharmaceutical composition comprising an inhibitory IgG4 antibody selective for matrix metalloproteinase-9 (MMP-9) but without detectable inhibitory activity against human MMP-2, wherein when administered once daily via intravenous or subcutaneous administration to human subjects aged approximately thirty years of age who have an acquired mutation in the ACVR1 / ALK2 gene, the amount of said antibody effectively reduces ectopic bone formation in tissues selected from muscle, tendon, ligament, and fascia in said human subjects.

73. The pharmaceutical composition according to claim 72, wherein, The inhibitory IgG4 antibody comprises adeliximab, and the human subject contains an R206H mutation in the ACVR1 / ALK2 gene.

74. The pharmaceutical composition according to claim 72 or 73, wherein, The inhibitory IgG4 antibody comprises adeliximab, and the human subject has at least one symptom of progressive ossifying fibrous dysplasia (FOP).

75. The pharmaceutical composition according to any one of claims 72-74, wherein, The composition is formulated for subcutaneous application.

76. A unit dose comprising the pharmaceutical composition of claim 72, wherein, The inhibitory IgG4 antibody comprises adeliximab, which, when administered once daily via intravenous or subcutaneous administration to human subjects under approximately thirty years of age who have an acquired mutation in the ACVR1 / ALK2 gene, effectively reduces ectopic bone formation in tissues selected from muscle, tendon, ligament, and fascia in the human subject by at least about 10% over a period of no more than about four weeks.

77. The unit dose according to claim 76, wherein, The dosage is formulated for subcutaneous administration.

Images