Agents and methods for treating muscle disorders

Abstract

The present disclosure generally relates to methods and agents for treating cardiomyopathy. More specifically, the present disclosure relates to the use of CD14 antagonist antigen binding molecules to treat cardiomyopathy, including alleviating or inhibiting the occurrence of adverse cardiac remodeling and improving cardiac function, including improving ventricular and atrial function.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 417,313, entitled "Agents and methods for treating myopathies," filed October 18, 2022, and U.S. Provisional Patent Application No. 63 / 464,048, entitled "Agents and methods for treating myopathies," filed May 4, 2023, the entire contents of which are incorporated herein by reference. Field

[0002] The present disclosure generally relates to methods and agents for treating cardiomyopathy. More specifically, the present disclosure relates to the use of CD14 antagonist antigen binding molecules to treat cardiomyopathy, including mitigating or inhibiting the occurrence of adverse cardiac remodeling and improving cardiac function, including improving ventricular and atrial function. [Background technology]

[0003] background Cardiovascular diseases, including hypertension, coronary artery disease, and cardiomyopathies, can lead to heart failure, which is associated with pathological remodeling of the myocardium, heart failure, and sudden death. Epidemiological analyses in Western countries indicate that cardiovascular disease is the leading cause of morbidity and mortality among people over the age of 60. Approximately 600,000 people die from myocardial infarction each year in Europe, and more importantly, heart failure is estimated to affect more than 15 million people worldwide, making it one of the leading causes of death. This number is likely to increase as a result of the aging of the global population. Although traditional pharmacological treatment strategies (e.g., β-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors) have shown efficacy in extending the survival of patients with heart failure, the prognosis for these patients remains poor, necessitating the need for new treatment strategies.

[0004] Cardiomyopathy constitutes a heterogeneous group of myocardial diseases associated with mechanical and / or electrical dysfunction, which leads to cardiac dysfunction accompanied by heart failure, arrhythmias, and sudden death. These diseases usually (but not exclusively) manifest as inappropriate ventricular hypertrophy or enlargement and impaired systolic and / or diastolic function. Compared to the acute phase of myocardial infarction, in which ischemia rapidly causes massive myocardial cell necrosis and an acute inflammatory response results, cardiomyopathy generally does not cause such phenomena and is characterized by chronic inflammation and the gradual progression of structural abnormalities such as cardiac hypertrophy, cardiomyocyte hypertrophy, and myocardial fibrosis.

[0005] Cardiomyopathy is typically classified into two major groups based on the primary organ involvement: primary cardiomyopathies and secondary cardiomyopathies. Primary cardiomyopathies (genetic, non-genetic, acquired) are exclusively or primarily confined to the myocardium and include dilated, hypertrophic, restrictive, arrhythmogenic, and unclassifiable cardiomyopathies. Secondary cardiomyopathies arise from underlying conditions affecting many areas of the body, including nutritional disorders, metabolic disorders (hyperthyroidism, acromegaly), infiltrative processes (neoplasms, amyloidosis), and inflammatory processes (toxins, immune responses, infectious agents).

[0006] Current drug therapies available for the management of cardiomyopathy include vasodilators to lower blood pressure and ease the heart's workload, diuretics to reduce fluid overload, inhibitors and blockers of the body's neurohormonal responses (e.g., ACE inhibitors and β-adrenergic blockers), antiarrhythmic drugs, calcium channel blockers, anticoagulants, anti-inflammatory drugs, such as corticosteroids and other medications. While such drug therapies are effective in the short term, side effects often preclude their use over the long term. Various surgical procedures, such as heart transplantation, have also been proposed for patients with hypertrophic cardiomyopathy who develop refractory heart failure and / or intractable arrhythmias. Alternatively, implantable medical devices, such as ventricular assist devices (VADs), may be implanted in the chest to augment the heart's pumping action, or intra-aortic balloon pumps (IABPs) may be used to maintain cardiac function for short periods of time, typically less than a month. While each of these approaches has proven beneficial to patients, at least to some extent, each has drawbacks that limit their overall effectiveness. For example, drug therapies are often associated with undesirable side effects, and complex therapeutic regimens contribute to low patient compliance. Furthermore, both drug therapies and surgical approaches are very expensive, increasing the medical costs associated with heart failure. Despite ongoing research and development into treatments for cardiomyopathy, there remains a great need for improved and alternative treatments. Summary of the Invention

[0007] overview The present disclosure is based, in part, on the unexpected determination that targeting cluster of differentiation 14 (CD14) by administration of a CD14 antagonist antibody can significantly inhibit the development of ventricular dysfunction, adverse cardiac remodeling, and fibrosis in a mouse model of arrhythmogenic cardiomyopathy (ACM). In particular, administration of a CD14 antagonist antibody to cardiomyopathic animals at the onset of disease was found to restore left ventricular ejection fraction (%LVEF) to levels seen in wild-type animals, as shown in Figure 2, inhibit right ventricular dysfunction by normalizing right ventricular fractional area change (%RVFAC) as shown in Figure 3, reduce ectopic beats by decreasing the frequency of premature ventricular contractions (PVCs) as shown in Figure 4, restore left ventricular mass (LVM) to levels seen in wild-type animals with reduced or minimized hypertrophic remodeling as shown in Figure 5, and reduce myocardial fibrosis as shown in Figure 6. Administration of a CD14 antagonist antibody to cardiomyopathic animals with disease was also found to significantly reduce the further decline in %LVEF as shown in Figures 7 and 8, and myocardial fibrosis as shown in Figure 9. Given that in cardiomyopathy, CD14 is expressed not only on pro-inflammatory M1 macrophages but also on anti-inflammatory M2 macrophages involved in healing and tissue repair, these findings are quite surprising, as targeting M2 macrophages with anti-CD14 antagonist antibodies would be expected to interfere with tissue remodeling and repair, possibly leading to non-treatment or worsening of the disease.

[0008] As shown in Figures 10B and 10C, we also found that the hearts of ACM animals contain proinflammatory CCR2+CD14+ monocytes and macrophages, which may be involved in the development of cardiomyopathy disease, and that such proinflammatory monocytes and macrophages are also generally present in the myocardium of cardiomyopathy subjects, including those with cardiac sarcoidosis, as shown, for example, in Figures 13A and 13B. Notably, as shown in Figures 11 and 12, treatment of ACM animals with an anti-CD14 antagonist antibody at the onset of disease significantly reduced CCR2+CD14+ macrophages in the hearts of treated animals.

[0009] Based on these findings, the inventors generally propose that CD14 antagonists, including CD14 antagonist antigen binding molecules, are useful, for example, as described below, for treating or alleviating at least one symptom of cardiomyopathy, for treating or inhibiting the occurrence of cardiomyopathy, for alleviating or inhibiting the occurrence of adverse cardiac remodeling in cardiomyopathy, for improving cardiac function in cardiomyopathy, for improving ventricular function in cardiomyopathy, for improving atrial function in cardiomyopathy, for reducing the number of premature ventricular contractions (PVCs), for treating or alleviating at least one symptom of atrial fibrillation, and / or for reducing the number of premature atrial contractions (PACs).

[0010] Thus, in one aspect, the present disclosure provides methods for treating or alleviating at least one symptom of cardiomyopathy in a subject. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to a subject. The at least one symptom may be selected from ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolization, fainting, angina, exercise intolerance, orthopnea, heart failure, and sudden cardiac death (SCD). Preferably, administration of the CD14 antagonist antigen binding molecule improves one or more clinical parameters in the subject, illustrative examples of which include reduced left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, adverse cardiac remodeling, right ventricular dysfunction, abnormal cardiac geometry (e.g., increased right ventricular fractional area change), increased end-diastolic volume, frequent premature ventricular contractions, and increased left ventricular muscle mass.

[0011] Disclosed herein in another aspect are methods for alleviating or inhibiting the development of adverse cardiac remodeling in a subject suffering from cardiomyopathy. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

[0012] Another aspect of the present disclosure provides methods for improving cardiac function in a subject suffering from cardiomyopathy. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to the subject. The improvement in cardiac function may include any one or more of the following: improved left ventricular function, improved fractional shortening, improved ejection fraction, reduced end-diastolic volume, reduced left ventricular muscle mass, reduced arrhythmias, reduced frequency of heart murmurs, reduced heart rate, normalized cardiac geometry, or a combination thereof.

[0013] Disclosed herein in yet another aspect are methods for improving ventricular function in a subject suffering from cardiomyopathy. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to a subject. Administration of the CD14 antagonist antigen-binding molecule suitably improves a measurement or metric of the subject's ventricular function, representative examples of which include ventricular strain, systolic function, or diastolic function. In some embodiments, ventricular function may be measured by echocardiography (echo), ambulatory electrocardiogram (Holter) monitoring, cardiac computed tomography (CT), or cardiac magnetic resonance imaging (MRI).

[0014] In a further aspect, methods for improving atrial function in a subject suffering from cardiomyopathy are disclosed herein. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to the subject. Administration of the CD14 antagonist antigen-binding molecule suitably improves a measure or metric of atrial function in the subject, representative examples of which include atrial reservoir function, atrial conduit function, and atrial pump function. In some embodiments, atrial function may be measured by echocardiography, cardiac MRI, ambulatory electrocardiogram (Holter) monitoring, or cardiac CT.

[0015] The cardiomyopathy may be a primary or secondary cardiomyopathy. Representative primary cardiomyopathy includes hereditary cardiomyopathy, mixed (hereditary and non-hereditary) cardiomyopathy, and acquired cardiomyopathy. Non-limiting examples of secondary cardiomyopathy include infiltrative cardiomyopathy, storage cardiomyopathy, toxic cardiomyopathy, granulomatous cardiomyopathy, cardiac cardiomyopathy, neuromuscular cardiomyopathy, nutritional deficiency cardiomyopathy, autoimmune or collagen cardiomyopathy, and electrolyte imbalance cardiomyopathy. In certain embodiments, the cardiomyopathy is ACM, preferably arrhythmogenic right ventricular cardiomyopathy (ARVC). In representative examples of this type, the subject may have one or more mutations in a gene associated with ACM. In some embodiments, the cardiomyopathy is other than ACM ("non-ACM cardiomyopathy").

[0016] In yet another aspect, disclosed herein are methods for reducing the number of premature ventricular contractions (PVCs) in a subject, preferably a subject with cardiomyopathy. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

[0017] Another aspect of the present disclosure provides a method for treating or alleviating at least one symptom of atrial fibrillation in a subject, preferably a subject with cardiomyopathy. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to the subject. The symptom(s) of atrial fibrillation may be tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, heart failure, stroke, or death. In certain embodiments, the subject is suffering from atrial fibrillation.

[0018] Yet another aspect of the present disclosure provides methods for reducing the number of premature atrial contractions in a subject, preferably a subject with cardiomyopathy. These methods generally comprise, consist of, or consist essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

[0019] In any of the aspects and embodiments disclosed herein, the subject may have an implantable cardioverter-defibrillator (ICD). In this illustrative example, administration of the CD14 antagonist antigen-binding molecule suitably reduces the number of electric shocks administered to the subject by the ICD.

[0020] In any of the aspects and embodiments disclosed herein, the antigen-binding molecule may be selected from:

[0021] (i) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSFGNSFMH [SEQ ID NO:7] (3C10 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence RAANLES [SEQ ID NO:8] (3C10 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQSYEDPWT [SEQ ID NO:9] (3C10 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3), an antibody comprising:

[0022] (ii) the following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3), an antibody comprising:

[0023] (iii) the following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2 or H-CDR3, wherein: H-CDR1 comprises, consists of or consists essentially of the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises, consists of or consists essentially of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises, consists of or consists essentially of the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3), an antibody comprising:

[0024] (iv) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2 or H-CDR3, wherein: H-CDR1 comprises, consists of or consists essentially of the sequence NYDIS [SEQ ID NO:22] (18E12 H-CDR1); H-CDR2 comprises, consists of or consists essentially of the sequence VIWTSGGTNYNSAFMS [SEQ ID NO:23] (18E12 H-CDR2); and H-CDR3 comprises, consists of or consists essentially of the sequence GDGNFYLYNFDY [SEQ ID NO:24] (18E12 H-CDR3), an antibody comprising:

[0025] (v) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence QNVGSNVDWY [SEQ ID NO:34] (F1024-1-3 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence KASNRY [SEQ ID NO:35] (F1024-1-3 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence MQSNTNPPW [SEQ ID NO:36] (F1024-1-3 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence DYAMN [SEQ ID NO:37] (F1024-1-3 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence WINTQTGKPTYADDF [SEQ ID NO:38] (F1024-1-3 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence TYFCTRSTFYYSSYIY [SEQ ID NO:39] (F1024-1-3 H-CDR3), an antibody comprising:

[0026] (vi) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2 or H-CDR3, wherein: H-CDR1 comprises, consists of or consists essentially of the sequence DYAMN [SEQ ID NO:37] (F1024 H-CDR1); H-CDR2 comprises, consists of or consists essentially of the sequence WINTQTGKPTYADDFKQ [SEQ ID NO:43] (F1024 H-CDR2); and H-CDR3 comprises, consists of or consists essentially of the sequence STFYYSSYIYGWYFDF [SEQ ID NO:44] (F1024 H-CDR3), an antibody comprising:

[0027] (vii) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSYGNSFMH [SEQ ID NO:45] (r18D11 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence LASNLES [SEQ ID NO:46] (r18D11 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQNNGDPYT [SEQ ID NO:47] (r18D11 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence TYALN [SEQ ID NO:48] (r18D11 H-CDR1); H-CDR2 comprises, consists essentially of, or comprises the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO:49] (r18D11 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence PQSGTSFAY [SEQ ID NO:50] (r18D11 H-CDR3), an antibody comprising:

[0028] (viii) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3), An antibody comprising:

[0029] In certain embodiments, the antigen binding molecule is selected from the following:

[0030] (i) The following: array: A VL domain comprising, consisting of, or consisting essentially of QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIYRAANLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSYEDPWTFGGGTKLGNQ [SEQ ID NO: 1] (3C10 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTTYYPDNVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYYDYHYWGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH), an antibody comprising:

[0031] (ii) the following: array: A VL domain comprising, consisting of, or consisting essentially of QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDPTTFGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); and array: A VH domain comprising, consisting of, or consisting essentially of: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH); an antibody comprising:

[0032] (iii) the following: array: QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQRGDTLPWTFGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVIWTSGGTNYNSAFMSRLSITKDNSESQVFLKMNGLQTDDTGIYYCVRGDGNFYLYNFDYWGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH), an antibody comprising:

[0033] (iv) The following: array: YIVMTQTPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO:57] (F1024-1-3 VL); and array: A VH domain comprising, consisting of, or consisting essentially of EVKLLESGGGLVQPSQTLSISCKASGYTFTDYAMNWVKQAPGDGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 58] (F1024-1-3 VH), an antibody comprising:

[0034] (v) The following: array: A VL domain comprising, consisting of, or consisting essentially of DIVMTQSPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO:59] (F1024 VL); and array: QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMNWVKQAPGNGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 60] (F1024 VH), an antibody comprising:

[0035] (vi) The following: array: A VL domain comprising, consisting of, or consisting essentially of NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDVATYYCQQNNGDPYTFGGGTKLEIIR [SEQ ID NO: 61] (r18D11 VL); and array: A VH domain comprising, consisting of, or consisting essentially of EVQLVESGGGLMQPKGSLKLSCAASGFTFKTYALNWVRQAPGTGLEWVARIRSKSNNYTTYYADSVKDRFTISRDDSQNMLYLQMNNLKTEDTAMYYCVRPQSGTSFAYWGQGTLVTVSA [SEQ ID NO: 62] (r18D11 VH), an antibody comprising:

[0036] (vii) The following: array: A VL domain comprising, consisting of, or consisting essentially of DIVMTQSQKFMSTSVGDRVSVTCKASQYVGTNVAWYQQKPGQSPKALIQSASYRCSGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYNTYVTFGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); and array: QVRLQQPGAELVRPGASVKLSCKASGYTFTTYWMNWVKQRPEDGLEWIGRIDPYDSETHYNQNFKDKAILTVDKSSSTAYMQLSSLTYEDSAVYYCTRKEGRQWGAYFDYWGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH), An antibody comprising:

[0037] The antigen-binding molecule may be humanized or chimeric.

[0038] Representative examples of antigen-binding molecules include a light chain and a heavy chain, wherein: The light chain has the amino acid sequence: the heavy chain comprises, consists of, or consists essentially of the amino acid sequence: METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO:25]; and MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCV RGLRFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 26].

[0039] In a specific embodiment, the antigen binding molecule is the IC14 antibody.

[0040] In any of the aspects and embodiments disclosed herein, the subject is preferably a mammal, representative examples of which include humans, canines, felines, equines, bovines, ovines, and porcines. In a preferred aspect, the subject is a human.

[0041] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen binding molecule may be administered systemically to a subject or locally to the heart (e.g., the left ventricle).

[0042] In any of the aspects and embodiments disclosed herein, the method suitably comprises administering an effective amount of a CD14 antagonist antigen-binding molecule.

[0043] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a daily dose of about 0.1 mg / kg to 50 mg / kg (and all tenths of a mg / kg unit therebetween), about 0.2 mg / kg to 40 mg / kg (and all tenths of a mg / kg unit therebetween), about 0.5 mg / kg to 40 mg / kg (and all tenths of a mg / kg unit therebetween), about 1 mg / kg to 30 mg / kg (and all tenths of a mg / kg unit therebetween), about 2 mg / kg to 20 mg / kg (and all tenths of a mg / kg unit therebetween), about 4 mg / kg to 15 mg / kg (and all tenths of a mg / kg unit therebetween), or about 5 mg / kg to 10 mg / kg (and all tenths of a mg / kg unit therebetween). The daily dose is suitably administered in a single dose or two doses.

[0044] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a weekly dose of about 1 mg / kg to 30 mg / kg (and all integer mg / kg increments therebetween), about 2 mg / kg to 20 mg / kg (and all integer mg / kg increments therebetween), about 4 mg / kg to 15 mg / kg (and all integer mg / kg increments therebetween), or about 5 mg / kg to 10 mg / kg (and all integer mg / kg increments therebetween).

[0045] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen binding molecule is administered to a subject for a period of about 1 day, for a period of about 2 days, for a period of about 3 days, for a period of about 4 days, for a period of about 5 days, for a period of about 6 days, for a period of about 1 week, for a period of about 2 weeks, for a period of about 3 weeks, for a period of about 4 weeks, for a period of about 5 weeks, for a period of about 6 weeks, for a period of about 2 months, for a period of about 3 months, for a period of about 4 months, for a period of about 5 months, for a period of about 6 months, for a period of about 7 months, for a period of about 8 months, for a period of about 9 months, for a period of about 10 months, for a period of about 11 months, for a period of about 1 year, for a period of about 14 months, for a period of about 16 months, for a period of about 18 months, for a period of about 20 months, for a period of about 22 months, or for a period of about 2 years.

[0046] In certain embodiments, the subject has not been diagnosed with autoimmune cardiomyopathy.

[0047] In certain embodiments, the subject has not undergone cardiopulmonary bypass surgery.

[0048] In certain embodiments, the subject is a subject who is not an acute myocardial infarction patient.

[0049] In any of the aspects and embodiments disclosed herein, the method may further include concurrently administering to the subject one or more adjunctive cardiomyopathy therapeutic agents, illustrative examples of which include angiotensin-converting enzyme inhibitors (e.g., Enalipril, Lisinopril), angiotensin receptor blockers (e.g., Losartan, Valsartan), beta-blockers (e.g., Lopressor, Toprol-XL), antiarrhythmic drugs (e.g., amiodarone (Cordarone, Pacerone), flecainide (Tambocor), ibutilide (Corvert), lidocaine (Xylocaine), procainamide (Procan, Procanbid), propranolol (Propylamine ... phenone (Rythmol), quinidine, tocainide (Tonocarid), digoxin, diuretics (e.g., Lasix; or Parkinson's disease medications including, for example, levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, lapinirole, piribedil, cabergoline, apomorphine, lisuride)), statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, antipsychotics (e.g., clozapine), cholinesterase inhibitors, modafinil, thiadiazolidinediones, and nonsteroidal anti-inflammatory drugs. In some of the same and other aspects or embodiments, the method may further include performing a surgical procedure on the subject, wherein the surgical procedure is suitable for treating cardiomyopathy. The surgical procedure may include pacemaker implantation, implantable cardioverter-defibrillator (ICD) implantation, cardiac catheterization, revascularization, coronary artery bypass surgery, and / or heart transplantation. The surgical procedure, optionally together with an adjunctive cardiomyopathy therapeutic agent, may be performed before, simultaneously with, or after administration of the CD14 antagonist antigen-binding molecule.

[0050] Yet another aspect of the present disclosure provides a CD14 antagonist antigen binding molecule for use in treating or alleviating at least one symptom of cardiomyopathy, treating or inhibiting the occurrence of cardiomyopathy, alleviating or inhibiting the occurrence of adverse cardiac remodeling in cardiomyopathy, improving cardiac function in cardiomyopathy, improving ventricular function in cardiomyopathy, improving atrial function in cardiomyopathy, reducing the number of premature ventricular contractions (PVCs), treating or alleviating at least one symptom of atrial fibrillation, or reducing the number of premature atrial contractions (PACs). In some embodiments, the CD14 antagonist antigen binding molecule is used in combination with one or more adjunctive cardiomyopathy therapeutic agents.

[0051] In yet another aspect, there is provided use of a CD14 antagonist antigen binding molecule in the manufacture of a medicament for treating or alleviating at least one symptom of cardiomyopathy, treating or inhibiting the onset of cardiomyopathy, alleviating or inhibiting the onset of adverse cardiac remodeling in cardiomyopathy, improving cardiac function in cardiomyopathy, improving ventricular function in cardiomyopathy, improving atrial function in cardiomyopathy, reducing the number of premature ventricular contractions (PVCs), treating or alleviating at least one symptom of atrial fibrillation, or reducing the number of premature atrial contractions (PACs). In some embodiments, the CD14 antagonist antigen binding molecule is used in combination with one or more adjunctive cardiomyopathy therapeutic agents. [Brief explanation of the drawings]

[0052] [Figure 1] FIG. 1 is a schematic diagram showing the progression of cardiomyopathic disease in the Dsg2mut / mut mouse model.

[0053] [Figure 2] FIG. 2 is a graphical representation showing that early intervention in the form of anti-CD14 treatment of 8-week-old Dsg2mut / mut mice for 8 weeks restores %LVEF to levels seen in wild-type animals.

[0054] [Figure 3] FIG. 3 is a graphical representation showing that early intervention in the form of anti-CD14 treatment of 8-week-old Dsg2mut / mut mice for 8 weeks prevents right ventricular dysfunction by normalizing %RVFAC.

[0055] [Figure 4] FIG. 4 is a graphical representation showing that early intervention in the form of anti-CD14 treatment of 8-week-old Dsg2 mut / mut mice for 8 weeks reduces ectopic heart beats by reducing the frequency of PVCs, as measured by ECG.

[0056] [Figure 5] FIG. 5 is a graphical representation showing that early intervention in the form of anti-CD14 treatment of 8-week-old Dsg2mut / mut mice for 8 weeks restores LVM to levels seen in wild-type animals, thereby minimizing hypertrophic remodeling.

[0057] [Figure 6] FIG. 6 is a graphical representation showing that early intervention in the form of anti-CD14 treatment of 8-week-old Dsg2mut / mut mice for 8 weeks attenuates cardiomyopathy as measured by histological analysis of fibrosis.

[0058] [Figure 7] FIG. 7 is a graphical representation showing that late intervention in the form of anti-CD14 treatment of 16-week-old Dsg2mut / mut mice for 8 weeks significantly improves %LVEF compared to untreated animals.

[0059] [Figure 8] FIG. 8 is a graphical representation showing that late intervention in the form of anti-CD14 treatment of 16-week-old Dsg2mut / mut mice for 8 weeks significantly attenuates further decline in %LVEF compared to untreated animals.

[0060] [Figure 9]FIG. 9 is a graphical representation showing that late intervention in the form of anti-CD14 treatment of 16-week-old Dsg2mut / mut mice for 8 weeks attenuates cardiomyopathy as measured by histological analysis of fibrosis.

[0061] [Figure 10] Figure 10 is a graphical representation showing that the hearts of Dsg2mut / mut mice contain proinflammatory macrophages that co-express CCR2 and CD14. (A) Uniform Manifold Approximation and Projection (UMAP) clustering of the integrated scRNA-seq dataset showing identified cell clusters from Dsg2mut / mut hearts, colored by cell type (i.e., fibroblasts, endothelial cells, B cells, monocytes / macrophages, neutrophils, NK cells, and T cells). (B) Mean expression of CCR2 by cell type. (C) Mean expression of CD14 by cell type.

[0062] [Figure 11] Figure 11 is a photographic representation showing imaging of Ga-DOTA-ECL1i uptake in the hearts of wild-type mice (A and B) and Dsg2mut / mut mice (C and D) treated with an isotype control antibody (IgG2A LALAPG) or anti-CD14 (Big53LALAP mAb) at 5 mg / kg once weekly for 4 weeks. Treatment of Dsg2mut / mut mice began at 8 weeks of age, when clear signs of disease pathology appeared.

[0063] [Figure 12] Figure 12 is a graphical representation showing the percentage injected dose (%ID) of 68Ga-DOTA-ECL1i per gram of cardiac tissue in wild-type (WT) mice and Dsg2mut / mut mice treated with either IgG2A LALAPG isotype control or Big53 LALAPG anti-CD14 mAb for 6 weeks.

[0064] [Figure 13]Figure 13 is a photographic representation showing that human LV tissue obtained from a patient with cardiac sarcoidosis contains CCR2+ monocytes and macrophages. (A) Immunostaining of LV tissue for CCR2 (red) and CD68 (green). (B) Representative positron emission tomography (PET) images showing uptake of 18F-fluorodeoxyglucose (18F-FDG) and 68Ga-DOTA-ECL1i (a gallium-68 radiolabeled CCR2 PET tracer) by the myocardium of a patient with active cardiac sarcoidosis.

[0065] Some drawings and documents contain color representations or are colored. Color illustrations are available from the applicant or the patent office concerned upon request. A fee may be charged if obtained from the patent office. DETAILED DESCRIPTION OF THE INVENTION

[0066] Detailed Description of the Invention 1. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, preferred methods and materials are described. For purposes of this disclosure, the following terms are defined below.

[0067] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0068] The term "about," as used herein, refers to a normal error range for each value that is readily apparent to one of ordinary skill in the art. Reference to "about" in this specification with respect to a value or parameter encompasses (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" refers to a value or parameter (e.g., a quantity, level, concentration, number, frequency, percentage, dimension, size, amount, weight, or length) that differs from the reference value or parameter by about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%.

[0069] As used herein, "and / or" refers to and includes any possible combination of one or more of the associated listed items, and the lack of combination when interpreted as alternatives (or).

[0070] The terms "active agent" and "therapeutic agent" are used interchangeably herein and refer to an agent that prevents, reduces, or ameliorate at least one symptom of a disease or disorder.

[0071] The terms "simultaneous administration," "administering simultaneously," "co-administration," and the like refer to administration of a single composition containing two or more agents, or administration of each agent as a separate composition, and / or administration delivered by separate routes, simultaneously, concurrently, or sequentially, within a sufficient time period that effective results are comparable to those obtained when all such agents are administered as a single composition. "Simultaneous" means that the agents are administered substantially simultaneously, and preferably together in the same formulation. "Concurrently" means that the agents are administered closely in time, e.g., one agent is administered before or after the next, within about one minute to about one day. Any contemporaneity is useful. However, when not administered simultaneously, the agents are often administered within about one minute to about eight hours, suitably within about one hour to about four hours. When administered simultaneously, the agents are suitably administered at the same site on a subject. The term "same site" includes the exact location, but may be within about 0.5 to about 15 centimeters, preferably within about 0.5 to about 5 centimeters. As used herein, the term "separately" means that the agents are administered, for example, at intervals of about one day to several weeks or months. The agents can be administered in any order. As used herein, the term "sequentially" means that the agents are administered consecutively, for example, at intervals of minutes, hours, days, or weeks. Where appropriate, the agents can be administered in regular, repeated cycles.

[0072] The term "adverse cardiac remodeling" refers to a group of molecular, cellular, and tissue space changes that are manifest as changes in cardiac size, shape, and function. These changes have a negative impact on cardiac function and ultimately lead to heart failure. Representative examples of adverse cardiac remodeling include hypertrophy, myocardial thinning, myocardial scarring, myocardial atrophy, reduced cardiac function, decreased myocardial contractility, progression of heart failure, and combinations thereof.

[0073] "Antigen-binding molecule" refers to a molecule having binding affinity for a target antigen. It will be understood that this term extends to immunoglobulins, immunoglobulin fragments, and non-immunoglobulin-derived protein frameworks that exhibit antigen-binding activity. Exemplary antigen-binding molecules useful in practicing the present disclosure include polyclonal and monoclonal antibodies and their fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) antibodies and domain antibodies (including, e.g., shark and camelid antibodies), as well as fusion proteins comprising antibodies and any other modified structures that contain the antigen-binding / recognition portion of an immunoglobulin molecule. Antibodies include antibodies of all classes, e.g., IgG, IgA, or IgM (or subclasses thereof), and antibodies need not be of any particular class. Immunoglobulins can be assigned to different classes depending on the amino acid sequence of the constant region of the antibody's heavy chain. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Antigen-binding molecules also include dimeric antibodies and multivalent forms of antibodies. In certain embodiments, the antigen-binding molecule may be a chimeric antibody, i.e., a portion of the heavy and / or light chain is identical to or homologous to a corresponding sequence in an antibody derived from a particular species or belongs to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to a corresponding sequence in an antibody derived from another species or belongs to a particular antibody class or subclass, as well as a fragment of such an antibody, so long as it exhibits the desired biological activity (see, e.g., US Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-6855).Humanized antibodies are also contemplated and are generally prepared by transferring complementarity-determining regions (CDRs) from the heavy and light chain variable regions of a non-human (e.g., rodent, preferably murine) immunoglobulin into a human variable domain. Thus, typical human antibody residues within the framework regions are replaced with their non-human counterparts. The use of antibody components derived from humanized antibodies eliminates potential problems associated with the immunogenicity of non-human constant regions. General techniques for cloning non-human, particularly murine, immunoglobulin variable domains are described, for example, by Orlandi et al. (1989, Proc. Natl. Acad. Sci. USA 86: 3833). Techniques for producing humanized monoclonal antibodies are described, for example, in Jones et al. (1986, Nature 321:522), Carter et al. (1992, Proc. Natl. Acad. Sci. USA 89: 4285), Sandhu (1992, Crit. Rev. Biotech. 12: 437), Singer et al. (1993, J. Immun. 150: 2844), Sudhir (ed., Antibody Engineering Protocols, Humana Press, Inc. 1995), Kelley (“Engineering Therapeutic Antibodies,” in Protein Engineering: Principles and Practice Cleland et al. (eds.), pages 399-434 (John Wiley & Sons, Inc. 1996), and Queen et al., US Pat. No. 5,693,762. (1997). Humanized antibodies include "primatized" antibodies, in which the antigen-binding region of the antibody is derived from an antibody produced by immunizing macaques with an antigen of interest. Humanized antibodies are also considered antigen-binding molecules.

[0074] The term "antagonist antigen-binding molecule" is used in the broadest sense and includes antigen-binding molecules that inhibit or reduce the biological activity of an antigen (e.g., CD14) to which the antigen-binding molecule binds. For example, an antagonist antigen-binding molecule may partially or completely block the interaction between a receptor (e.g., CD14) and a ligand (e.g., a DAMP or PAMP), or may substantially reduce the interaction by altering or downregulating the tertiary structure of the receptor. Thus, CD14 antagonist antigen binding molecules encompass antigen binding molecules that bind to CD14 and significantly block, inhibit, neutralize, suppress, inhibit, reduce, or decrease (including significantly) CD14 agonist activity, including activation of downstream pathways such as the Toll-like receptor (TLR) signaling pathway (e.g., the TLR4 signaling pathway) and the TIR domain-containing adaptor-inducing IFN-β (TRIF) pathway, or induction of a cellular response to CD14 binding by a CD14 ligand (e.g., a DAMP or PAMP) (e.g., the production of proinflammatory mediators, including proinflammatory cytokines). In some examples, the antibody is monospecific and binds only to CD14. In other examples, the antibody is multispecific (e.g., bispecific) and binds to CD14 and at least one other antigen.

[0075] The term "antibody" is used herein in its broadest sense and specifically encompasses natural antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired immunological interactivity. Naturally occurring "antibodies" include within their scope immunoglobulins comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises specific CH domains (e.g., CH1, CH2, and CH3). Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions are further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antibody constant region may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The antibody may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), subclass, or modified version thereof (e.g., an IgG1 isotype with the L234A and L235A double mutation (IgG1-LA)). The antibody may be of any species, chimeric, humanized, or human. In other embodiments, the antibody is a homomeric heavy chain antibody (e.g., a camelid antibody) that lacks the first constant region domain (CH1) but otherwise retains an intact heavy chain and can bind to an antigen via an antigen-binding domain. The variable regions of the heavy and light chains in an antibody modular recognition domain (MRD) fusion will contain a functional binding domain that interacts with an antigen of interest.

[0076] As used herein, the term "variable domain" (light chain (VL) variable domain, heavy chain (VH) variable domain) refers to each of a pair of light and heavy chain domains that are directly involved in binding an antibody to an antigen. The variable light and heavy chain domains have the same general structure, and each domain contains four FRs with widely conserved sequences connected by three CDRs or "hypervariable regions". The FRs adopt a β-sheet structure, and the CDRs form loops that connect the β-sheet structure. The CDRs of each chain are held in a three-dimensional structure by the FRs and form, together with the CDRs of the other chain, the antigen-binding site.

[0077] The term "antigen-binding portion," as used herein, generally refers to the amino acid residues of an antibody involved in antigen binding, including amino acid residues from the CDRs. Thus, "CDR" or "complementarity-determining region" (also called "hypervariable region") are used interchangeably herein to refer to the amino acid sequences of the light and heavy chains of an antibody that form the three-dimensional loop structure that contributes to the formation of the antigen-binding site. Each of the heavy and light chain variable regions contains three CDRs, designated "CDR1," "CDR2," and "CDR3" for each variable region. The term "CDR set," as used herein, refers to a group of three CDRs present in a single variable region that binds to an antigen. The exact boundaries of these CDRs are defined differently in different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system that can be applied to any variable region of an antibody, but also provides precise residue boundaries that define the three CDRs. These CDRs are referred to as "Kabat CDRs." Chothia and coworkers (Chothia and Lesk, 1987. J. Mol. Biol. 196: 901-917; Chothia et al., 1989. Nature 342: 877-883) have proposed a system for numbering residues that is consistent with Kabat's We discovered that certain subregions within the CDRs adopt nearly identical peptide backbones. Despite significant diversity at the amino acid sequence level, their conformations differ. These regions are designated "L1," "L2," and "L3," or "H1," "H2," and "H3," where "L" and "H" refer to the light and heavy chain regions, respectively. These regions may be referred to as "Chothia CDRs," with boundaries that overlap with the Kabat CDRs.Other boundaries defining CDRs that overlap with the Kabat CDRs are described by Padlan (1995. FASEB J. 9: 133-139) and MacCallum (1996. J. Mol. Biol. 262(5): 732-745). Still other CDR boundary definitions may not strictly adhere to either of these systems, but nevertheless overlap with the Kabat CDRs, although they may be shortened or extended in light of predictions or experimental findings that particular residues or groups of residues, or the entire CDR, do not significantly affect antigen binding.

[0078] As used herein, the term "framework region" or "FR" refers to the remaining sequences of the variable region minus the CDRs. Thus, the light and heavy chain variable domains of an antibody comprise, from N- to C-terminus, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The CDRs and FRs are typically defined according to the standard definition in Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991), and / or those residues from the "hypervariable loops."

[0079] As used herein, the terms "light chain variable region" ("VL") and "heavy chain variable region" (VH) refer to regions or domains in the N-terminal portions of the light and heavy chains, respectively, which have primary amino acid sequences that vary for each antibody. The variable region of an antibody typically consists of the amino-terminal domains of the light and heavy chains, which fold together to form a three-dimensional binding site for antigen. Based on structural similarities, several subtypes of VH and VL have been defined, as described, for example, in the Kabat database.

[0080] The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species and constant region sequences from another species, such as an antibody having murine heavy and light chain variable regions linked to human constant regions.

[0081] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. Most often, humanized antibodies are human immunoglobulins (recipient antibodies) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and capacity. In some cases, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Thus, the FRs and CDRs of the humanized antibody need not exactly correspond to the parental (i.e., donor) sequences, e.g., the donor antibody CDR or consensus framework, by substitution, insertion, and / or deletion of at least one amino acid residue such that the CDR or FR at that site does not correspond to either the donor antibody or the consensus framework. However, such mutations are typically not extensive and generally avoid "key residues" involved in antigen binding. Typically, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region in a consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to a sequence formed from the amino acids (or nucleotides) that occur most frequently in a family of related immunoglobulin sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, 1987)). Thus, a "consensus immunoglobulin sequence" may contain "consensus framework region(s)" and / or "consensus CDR(s)." Within an immunoglobulin family, each position in a consensus sequence is occupied by the amino acid that occurs most frequently at that position in that family. If two amino acids occur equally frequently, both can be included in the consensus sequence.Generally, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. Humanized antibodies also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For details, see Jones et al. (1986, Nature 321:522-525), Riechmann et al. (1988, Nature 332:323-329), and Presta (1992, Curr. Op. Struct. Biol. 2:593-596). The humanized antibody can be selected from any class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. A humanized antibody may comprise sequences from more than one class or isotype, and specific constant domains may be selected to optimize desired effector functions using techniques well known in the art. As used herein, the term "key residues" refers to specific residues in the variable regions that have a greater influence on the binding specificity and / or affinity of an antibody, particularly a humanized antibody. Key residues include, but are not limited to, one or more of the following: residues adjacent to the CDRs, potential glycosylation sites (which may be N- or O-glycosylation sites), rare residues, residues that can interact with antigens, residues that can interact with CDRs, canonical residues, contact residues between the heavy and light chain variable regions, residues in the Vernier zone, and residues in the region of overlap between the Chothia definition of the variable heavy chain CDR1 and the Kabat definition of the original heavy chain framework.

[0082] As used herein, the "Vernier" zone refers to a subset of framework residues that can adjust CDR structure and fine-tune fit to the antigen, as described by Foote and Winter (1992. J. Mol. Biol. 224: 487-499). The Vernier zone residues form a layer below the CDR and may affect the structure of the CDR and the affinity of the antibody.

[0083] As used herein, the term "canonical" residues refers to residues within a CDR or framework that define a particular canonical CDR structure as defined by Chothia et al. (1987. J. Mol. Biol. 196: 901-917; 1992. J. Mol. Biol. 227: 799-817) (both of which are incorporated herein by reference). According to Chothia et al., a significant portion of the CDRs of many antibodies have nearly identical peptide backbone conformations, despite great diversity at the amino acid sequence level. Each canonical structure primarily defines a set of peptide backbone torsion angles for a contiguous segment of amino acid residues that form a loop.

[0084] As used herein, the terms "donor" and "donor antibody" refer to an antibody that provides one or more CDRs to an "acceptor antibody." In some embodiments, the donor antibody is an antibody from a different species than the antibody from which the FRs were obtained or derived. In the context of humanized antibodies, the term "donor antibody" refers to a non-human antibody that provides one or more CDRs.

[0085] As used herein, the terms "acceptor" and "acceptor antibody" refer to an antibody that provides at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequence of one or more FRs. In some embodiments, the term "acceptor" refers to an antibody amino acid sequence that provides a constant region. In other embodiments, the term "acceptor" refers to an antibody amino acid sequence that provides one or more FRs and a constant region. In certain embodiments, the term "acceptor" refers to a human antibody amino acid sequence that provides at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequence of one or more FRs. In accordance with this embodiment, the acceptor may contain at least one, at least two, at least three, at least four, at least five, or at least 10 amino acid residues that are not present in one or more specific positions of a human antibody. The acceptor framework regions and / or acceptor constant regions can be derived or obtained from, for example, germline antibody genes, mature antibody genes, functional antibodies (e.g., antibodies known in the art, antibodies in development, or commercially available antibodies).

[0086] The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies according to the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), such as the CDRs and particularly CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0087] The terms "heavy chain variable region CDR1" and "H-CDR1" are used interchangeably, as are the terms "heavy chain variable region CDR2" and "H-CDR2," "heavy chain variable region CDR3" and "H-CDR3," "light chain variable region CDR1" and "L-CDR1," "light chain variable region CDR2" and "L-CDR2," and "light chain variable region CDR3" and "L-CDR3" antibody fragments. In this specification, complementarity-determining regions ("CDRs") are defined according to the Kabat definition unless otherwise specified. The Kabat definition is a standard for numbering residues in antibodies and is typically used to identify CDR regions (Kabat et al., (1991), 5th edition, NIH publication No. 91-3242).

[0088] Antigen binding can be achieved by "fragments" or "antigen-binding fragments" of intact antibodies. Both terms are used interchangeably herein. Examples of binding fragments encompassed within the term "antibody fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; an F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single antibody arm; and a single-domain antibody (dAb) fragment (Ward et al., 1989. Nature 341:544-546), which consists of a VH domain and isolated complementarity-determining regions (CDRs). In certain embodiments, an antibody of the present disclosure is an antigen-binding fragment lacking all or part of the Fc region.

[0089] A "single-chain variable fragment (scFv)" is a single protein chain in which the VL and VH domains pair to form a monovalent molecule (known as a single-chain Fv (scFv)) (see, e.g., Bird et al., 1988, Science 242:423-426; and Huston et al., 1988, Proc. Natl. Acad. Sci. 85:5879-5883). The two domains, VL and VH, are encoded by separate genes but can be linked using recombinant techniques by an artificial peptide linker that enables them to be produced as a single protein chain. Such single-chain antibodies contain one or more antigen-binding portions. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies.

[0090] The term "monoclonal antibody" and the abbreviations "MAb" and "mAb," as used herein, refer to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each mAb is directed against a single determinant on the antigen. The modifier "monoclonal" should not be construed as requiring production of the antibody by any particular method. Monoclonal antibodies may be produced, for example, by a single clone of antibody-producing cells, including a hybridoma. The term "hybridoma" generally refers to the product of cell fusion between a cultured neoplastic lymphocyte and a primed B or T lymphocyte that expresses the specific immunocompetence of the parent cell.

[0091] An antibody that "binds" to an antigen of interest (e.g., CD14) is one that binds to the antigen with sufficient affinity so that it is useful as a therapeutic agent in targeting cells or tissues expressing the antigen and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody to "non-target" proteins is less than about 10% of the binding of the antibody, oligopeptide, or other organic molecule to its specific target protein, as measured, for example, by fluorescence-activated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, or radioimmunoprecipitation (RIA). Thus, antibodies that antagonize CD14 suitably inhibit or reduce the production of proinflammatory mediators, including proinflammatory cytokines / chemokines. With respect to antibody binding to a target molecule, the terms "specific binding" or "specifically binds" or "specific for" a particular polypeptide or epitope on a particular polypeptide target refer to binding that is measurably different from nonspecific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule, which is a molecule of similar structure that has no binding activity. For example, specific binding can be determined by competition with a control molecule similar to the target, such as an excess of unlabeled target. In this case, specific binding is indicated if the binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled target. The specific region of an antigen to which an antibody binds is typically referred to as an "epitope." The term "epitope" broadly includes a site on an antigen that is specifically recognized by an antibody or T-cell receptor or interacts with a molecule. Generally, an epitope is an active surface group of molecules, such as amino acids or carbohydrate or sugar side chains, and generally can have specific three-dimensional structural characteristics as well as specific charge characteristics. As will be understood by those skilled in the art, anything that can be specifically bound by an antibody can be an epitope.

[0092] As used herein, "arrhythmia" refers to any of a group of conditions in which there is abnormal electrical activity in the heart. This can cause the heart to beat too fast (tachycardia). Arrhythmias can affect the atria and / or ventricles and can occur at any age.

[0093] As used herein, the term "cardiomyopathies" refers to a decline in the function of the myocardium (i.e., the actual heart muscle) for any reason. Subjects suffering from cardiomyopathy are often at risk for arrhythmias, sudden cardiac death, or both. Cardiomyopathy can be acquired or congenital. Common symptoms include dyspnea and peripheral edema, and there is an increased risk of dangerously irregular heart rate and sudden cardiac death. Cardiomyopathy often leads to progressive heart failure, i.e., an inability of the heart pump to maintain a sufficient amount of blood flow to meet the body's basic oxygen demand. Based on the site of the lesion, cardiomyopathy is classified into primary cardiomyopathy, in which the lesion is primarily limited to the heart; and secondary cardiomyopathy, in which the cardiomyopathy is associated with systemic disease. Primary cardiomyopathy is further classified into three types: hereditary, acquired, and hybrid. Examples of inherited cardiomyopathy include hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, glycogen storage disease (PPKA2, Danon disease), conduction abnormalities, mitochondrial cardiomyopathy, and channelopathies (long QT syndrome, Brugada syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Asian SUNDS (sudden nocturnal death syndrome)). Examples of acquired cardiomyopathy include inflammatory cardiomyopathy (myocarditis), stress-induced cardiomyopathy (Tako-Tsubo cardiomyopathy), postpartum cardiomyopathy, tachycardia-induced cardiomyopathy, and cardiomyopathy in infants born to insulin-dependent mothers. Examples of mixed cardiomyopathy include dilated and restrictive cardiomyopathy (left ventricular hypertrophy without dilation).

[0094] Throughout this specification, unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are understood to mean the inclusion of a stated step, element, or group of steps or elements, but not the exclusion of other steps or elements, or group of steps or elements, or group of elements. Thus, use of the term "comprise," etc., indicates that the listed elements are required or mandatory, while other elements are optional and may or may not be present. "Consisting of" means including and limited to what follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements are present. "Consisting essentially of" means including the elements listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activity or behavior specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, while other elements are optional and may or may not be present depending on whether they affect the activity or behavior of the listed elements.

[0095] "An effective amount," in the context of treating a disease or condition, refers to the administration of an amount of a drug or composition to an individual in need of such treatment or prevention, either as a single dose or as part of a series, effective to prevent the onset of symptoms, check for such symptoms, and / or treat existing symptoms of the condition. Effective amounts vary depending on the age, health, and physical condition of the individual to be treated, whether symptoms of the disease are evident, the taxonomic group of the individual to be treated, the formulation of the composition, an evaluation of the medical condition, and other relevant factors. Optimal administration schedules can be calculated from measurements of drug accumulation in the subject's body. Optimal doses may vary depending on the relative efficacy of the drug in individual subjects and can generally be estimated based on EC50 values ​​found to be effective in in vitro and in vivo animal models. One of ordinary skill in the art can readily determine optimal dosages, administration methods, and repetition rates. A relatively wide range of reductions is expected, which can be determined by routine trials.

[0096] As used herein, the term "immune cell" refers to a cell involved in the innate or adaptive (acquired) immune system. Exemplary innate immune cells include phagocytes, such as neutrophils, monocytes, and macrophages; natural killer (NK) cells; polymorphonuclear leukocytes, such as neutrophils, eosinophils, and basophils; and mononuclear cells, such as monocytes, macrophages, and mast cells. Immune cells that play a role in acquired immunity include lymphocytes, such as T cells and B cells.

[0097] As used herein, the terms "inhibit," "inhibits," or "inhibiting" (and grammatical equivalents thereof), in the context of the occurrence of a condition, disease, disorder, or condition, refer to delaying the onset or onset of the condition, disease, disorder, or condition; alleviating the manifestation of the symptoms of the condition, disease, disorder, or condition; minimizing the occurrence of the condition, disease, disorder, or condition; and / or alleviating the symptoms of the condition, disease, disorder, or condition upon onset. The term is not meant to imply complete eradication of the disease and encompasses any type of prophylactic treatment that alleviates the occurrence of the condition or delays the onset or slows the progression of the condition, disease, disorder, or condition.

[0098] "Isolated" means material that is substantially or essentially free from components which normally accompany it in its native state.

[0099] The term "ligand," as used herein, refers to any molecule that can bind to a receptor.

[0100] As the term is used herein, "proinflammatory" refers to a pro-inflammatory effect.

[0101] As used herein, the term "proinflammatory mediator" refers to molecules and cells that have a pro-inflammatory effect and are typically functionally involved in immune system signaling pathways and immune responses. Such agents include cytokines such as chemokines, interleukins, lymphokines, and tumor necrosis factors, as well as growth factors. In certain embodiments, the proinflammatory mediator is a "proinflammatory cytokine." Typically, proinflammatory cytokines include IL-1α, IL-1β, IL-6, and TNF-α, which are primarily involved in the early response. Other proinflammatory mediators include LIF, IFN-γ, IFN-β, IFN-α, OSM, CNTF, TGF-β, GM-CSF, TWEAK, IL-11, IL-12, IL-15, IL-17, IL-18, IL-19, IL-20, IL-8, IL-16, IL-22, IL-23, IL-31, and IL-32 (Tato et al., 2008. Cell 132:900; Cell 132:500, Cell 132:324). Proinflammatory mediators act as endogenous pyrogens (IL-1, IL-6, TNF-α), upregulate the synthesis of secondary mediators and proinflammatory cytokines by macrophages and mesenchymal cells (including fibroblasts, epithelial cells, and endothelial cells), stimulate the production of acute-phase proteins, or attract inflammatory cells. In certain embodiments, the term "proinflammatory cytokine" relates to any one or more of TNF-α, IL-6, IFN-β, IL-1β, and IL-8. In other specific embodiments, the term "proinflammatory cytokine" relates to any one or more of IL-1β, IL-6, TNF-α, IFN-γ, and IFN-β.

[0102] The terms "subject," "patient," and "individual," used interchangeably herein, refer to any subject, particularly a vertebrate subject, and more particularly a mammalian subject (e.g., a human, canine, feline, or equine subject) suffering from cardiomyopathy.

[0103] "Treating" a condition, disease, disorder, or state, or "treatment" thereof, refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, or eliminating the disease; reduction in the extent of the disease; stable (i.e., not worsening) disease state (e.g., maintaining a patient in remission); prevention of the spread of the disease; delay or slowing of disease progression; amelioration or reduction of disease state; reduction in the recurrence of the disease; and causing remission (whether partial or total), i.e., regression of the condition, disorder, or state, or its clinical or subclinical symptoms. "Treating" and "treatment" can also mean prolonging survival compared to expected survival if not receiving treatment, and include either of the following: the benefit to the treated individual is statistically significant or at least perceptible to the patient or physician. In one embodiment, the method of treatment comprises administering to a subject an effective amount of a CD14 antagonist antigen binding molecule, and optionally consists of a single administration or, alternatively, comprises a series of administrations.

[0104] Each embodiment described in this specification applies mutatis mutandis to each embodiment and each embodiment unless otherwise clearly specified. 2. CD14 Antagonist Antigen Binding Molecules for Use in Treating or Inhibiting Cardiomyopathy

[0105] The present disclosure provides methods, uses, and compositions comprising a CD14 antagonist antigen binding molecule for, for example, treating or alleviating at least one symptom of cardiomyopathy, treating or inhibiting the occurrence of cardiomyopathy, alleviating or inhibiting the occurrence of adverse cardiac remodeling in cardiomyopathy, improving cardiac function in cardiomyopathy, improving ventricular function in cardiomyopathy, improving atrial function in cardiomyopathy, reducing the number of premature ventricular contractions (PVCs), treating or alleviating at least one symptom of atrial fibrillation, or reducing the number of premature atrial contractions (PACs).

[0106] The present disclosure contemplates any CD14 antagonist antigen binding molecule that binds to CD14, such as human CD14 (e.g., human mCD14 or sCD14), blocks the binding of a CD14 ligand, preferably a DAMP or PAMP, to CD14, and / or binds to CD14 and inhibits or reduces a CD14 agonist-mediated response, which leads to the production of proinflammatory mediators, including the production of proinflammatory cytokines. Such CD14 antagonist antibodies are well known in the art, and any can be used in the methods and uses of the present disclosure. In some embodiments, the CD14 antagonist antigen binding molecule of the present disclosure inhibits the binding of a CD14 agonist, preferably a DAMP or PAMP, to CD14, thereby inhibiting or reducing the production of proinflammatory cytokines.Illustrative examples of this type of CD14 antagonist antigen-binding molecule include the 3C10 antibody, which binds to an epitope contained in at least a portion of the region from amino acid 7 to amino acid 14 of human CD14 (van Voohris et al., 1983. J. Exp. Med. 158: 126-145; Juan et al., 1995. J. Biol. Chem. 270(29): 17237-17242), the MEM-18 antibody, which binds to an epitope contained in at least a portion of the region from amino acid 57 to amino acid 64 of CD14 (Bazil et al., 1986. Eur. J. Immunol. 16(12):1583-1589; Juan et al., 1995. J. Biol. Chem. 270(10): 5219-5224), and the 4C1 antibody (Adachi et al., 1999. J. Endotoxin Res. 5: 139-146; Tasaka et al., 2003. Am. J. Respir. Cell. Mol. Biol.; 2003. 29(2):252-258), the 28C5 and 23G4 antibodies that inhibit LPS binding and suppress the production of proinflammatory cytokines, the 18E12 antibody that partially inhibits LPS binding and suppresses the production of proinflammatory cytokines (U.S. Patent Nos. 5,820,858, 6,444,206, and 7,326,569 to Leturcq et al.), and the 18E12 antibody that binds to an epitope contained in at least a portion of the region from amino acid 269 to amino acid 315 of human CD14, which inhibits LPS binding and NF-κB activation, and and the F1024-1-3 antibody (U.S. Patent Application Publication No. 2004 / 0091478 to Furusako et al.) and the synthetic F1204 antibody (U.S. Patent Application Publication No. 2008 / 0286290 to Furusako et al.), which inhibit cytokine production, and the r18D11 and rMil2 antibodies (U.S. Patent Application Publication No. 2017 / 0107294 to Espevik et al.), which bind to the LPS-binding and / or signaling domain of human CD14 and inhibit LPS-induced release of proinflammatory cytokines.In some embodiments, the CD14 antagonist antigen-binding molecules of the present disclosure inhibit CD14 binding to TLRs, such as TLR4, thereby blocking CD14 agonist-mediated responses. Examples include the F1024 antibody disclosed in International Publication No. WO 2002 / 42333. Other CD14 antagonist antigen-binding molecules include the single-chain antibody scFv2F9 and the related human-mouse chimeric antibody Hm2F9 (Tang et al. 2007, Immunopharmacol Immunotoxicol. 29, 375-386; and Shen et al., 2014, DNA Cell Biol. 33(9): 599-604). Further examples of CD14 antagonist antigen-binding molecules include anti-human CD14 18D11 IgG1 mAb, 18D11 IgG1 F(ab)'2 fragment, and chimeric r18D11 antibody (IgG2 / 4) (see, e.g., Lau et al., 2013, J Immunol. 191:4769-4777). Each of the above references regarding CD14 antagonist antigen-binding molecules is incorporated herein by reference in its entirety. The CD14 antagonist antigen-binding molecule may be a full-length immunoglobulin antibody or an antigen-binding fragment of an intact antibody, representative examples of which include Fab fragments, F(ab')2 fragments, Fd fragments consisting of the VH and CH1 domains, Fv fragments consisting of the VL and VH domains of a single antibody arm, and single-domain antibody (dAb) fragments consisting of the VH domain (Ward et al., 1989. Nature 341:544-546), which contain isolated CDRs. Preferably, the CD14 antagonist antigen-binding molecule is a chimeric, humanized, or human antibody.

[0107] In some embodiments, the CD14 antagonist antigen binding molecule comprises the VH and VL of the following antibody disclosed in U.S. Pat. No. 5,820,858:

[0108] (1) The following: array: QSPASLAVSLGQRATISC RASESVDSFGNSFMH WYQQKAGQPPKSSIY RAANLES GIPARFSGSGSRTDFTLTINPVEADDVATYFC QQSYEDPWT FGGGTKLGNQ [SEQ ID NO: 1] (3C10 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LVKPGGSLKLSCVASGFTFS SYAMS WVRQTPEKRLEWVA SISSGGTTYYPDNVKG RFTISRDNARNILYLQMSSLRSEDTAMYYCAR GYYDYHY WGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH), an antibody comprising:

[0109] (2) The following: array: QSPASLAVSLGQRATISC RASESVDSYVNSFLH WYQQKPGQPPKLLIY RASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCC QQSNEDPTT FGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LQQSGPGLVKPSQSLSLTCTVTGYSIT SDSAWN WIRQFPGNRLEWMG YISYSGSTSYNPSLKS RISITRDTSKNQFFLQLNSVTTEDTATYYCVR GLRFAY WGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH), an antibody comprising:

[0110] (3) The following: array: QTPSSLSASLGDRVTISC RASQDIKNYLN WYQQPGGTVKVLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQEDFATYFC QRGDTLPWT FGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LESGPGLVAPSQSLSITCTVSGFSLT NYDIS WIRQPPGKGLEWLG VIWTSGGTNYNSAFMS RLSITKDNSESQVFLKMNGLQTDDTGIYYCVR GDGNFYLYNFDY WGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH), An antibody comprising:

[0111] In some embodiments, the CD14 antagonist antigen binding molecule comprises the VH and VL of the following antibody disclosed in U.S. Patent Application Publication No. 2004 / 0091478:

[0112] (1) The following: array: YIVMTQTPTSISISVGERVTMNCKAS QNVGSNVDWY QQKTGQSPKLLIY KASNRY TGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYC MQSNTNPPW TFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); and array: A VH domain comprising, consisting of, or consisting essentially of EVKLLESGGGLVQPSQTLSISCKASGYTFT DYAMN WVKQAPGDGLKWMG WINTQTGKPTYADD FKQRFVFSLETSASTAYLQINNLNIEDTA TYFCTRSTFYYSSYIY GWYFDFWGPGTMVTVSS [SEQ ID NO: 58] (F1024-1-3 VH), An antibody comprising:

[0113] In some embodiments, the CD14 antagonist antigen binding molecule comprises the VH and VL of the following antibody disclosed in US Patent Application Publication No. 2008 / 0286290:

[0114] (1) The following: array: A VL domain comprising, consisting of, or consisting essentially of DIVMTQSPTSISISVGERVTMNC KASQNVGSNVD WYQQKTGQSPKLLIY KASNRYT GVPDRFTGSGSGTDFTFTISNMQAVDLAVYYC MQSNTNPPWT FGGGTKLELKRA [SEQ ID NO:59] (F1024 VL); and array: QIQLVQSGPELKKPGESVKISCKASGYTFT DYAMN WVKQAPGNGLKWMG WINTQTGKPTYADDFKQ RFVFSLETSASTAYLQINNLNIEDTATYFCTR STFYYSSYIYGWYFDF WGPGTMVTVSS [SEQ ID NO: 60] (F1024 VH), An antibody comprising:

[0115] In some embodiments, the CD14 antagonist antigen binding molecule comprises the VH and VL of the following antibodies disclosed in U.S. Patent Application Publication No. 2017 / 0107294:

[0116] (1) The following: array: A VL domain comprising, consisting of, or consisting essentially of NIVLTQSPASLAVSLGQRATISC RASESVDSYGNSFMH WYQQKPGQPPKLLIY LASNLES GVPARFSGSGSRTDFTLTIDPVEADDVATYYC QQNNGDPYT FGGGTKLEIIR [SEQ ID NO: 61] (r18D11 VL); and array: A VH domain comprising, consisting of, or consisting essentially of EVQLVESGGGLMQPKGSLKLSCAASGFTFK TYALN WVRQAPGTGLEWVA RIRSKSNNYTTYYADSVKD RFTISRDDSQNMLYLQMNNLKTEDTAMYYCVR PQSGTSFAY WGQGTLVTVSA [SEQ ID NO: 62] (r18D11 VH), an antibody comprising:

[0117] (2) The following: array: A VL domain comprising, consisting of, or consisting essentially of DIVMTQSQKFMSTSVGDRVSVTC KASQYVGTNVA WYQQKPGQSPKALIQ SASYRCS GVPDRFTGSGSGTDFTLTISNVQSEDLADYFC QQYNTYVT FGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); and array: QVRLQQPGAELVRPGASVKLSCKASGYTFT TYWMN WVKQRPEDGLEWIG RIDPYDSETHYNQNFKD KAILTVDKSSSTAYMQLSSLTYEDSAVYYCTR KEGRQWGAYFDY WGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH), An antibody comprising:

[0118] Antigen binding molecules comprising the VL and VH CDR sequences of the above antibodies and related antibodies are also contemplated, representative embodiments of which include the following: (1) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSFGNSFMH [SEQ ID NO:7] (3C10 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence RAANLES [SEQ ID NO:8] (3C10 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQSYEDPWT [SEQ ID NO:9] (3C10 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3), an antibody comprising: (2) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3), an antibody comprising: (3) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2 or H-CDR3, wherein: H-CDR1 comprises, consists of or consists essentially of the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises, consists of or consists essentially of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises, consists of or consists essentially of the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3), an antibody comprising: (4) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2 or H-CDR3, wherein: H-CDR1 comprises, consists of or consists essentially of the sequence NYDIS [SEQ ID NO:22] (18E12 H-CDR1); H-CDR2 comprises, consists of or consists essentially of the sequence VIWTSGGTNYNSAFMS [SEQ ID NO:23] (18E12 H-CDR2); and H-CDR3 comprises, consists of or consists essentially of the sequence GDGNFYLYNFDY [SEQ ID NO:24] (18E12 H-CDR3), an antibody comprising: (5) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence QNVGSNVDWY [SEQ ID NO:34] (F1024-1-3 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence KASNRY [SEQ ID NO:35] (F1024-1-3 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence MQSNTNPPW [SEQ ID NO:36] (F1024-1-3 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence DYAMN [SEQ ID NO:37] (F1024-1-3 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence WINTQTGKPTYADDF [SEQ ID NO:38] (F1024-1-3 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence TYFCTRSTFYYSSYIY [SEQ ID NO:39] (F1024-1-3 H-CDR3), an antibody comprising: (6) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2 or H-CDR3, wherein: H-CDR1 comprises, consists of or consists essentially of the sequence DYAMN [SEQ ID NO:37] (F1024 H-CDR1); H-CDR2 comprises, consists of or consists essentially of the sequence WINTQTGKPTYADDFKQ [SEQ ID NO:43] (F1024 H-CDR2); and H-CDR3 comprises, consists of or consists essentially of the sequence STFYYSSYIYGWYFDF [SEQ ID NO:44] (F1024 H-CDR3), an antibody comprising: (7) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence RASESVDSYGNSFMH [SEQ ID NO:45] (r18D11 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence LASNLES [SEQ ID NO:46] (r18D11 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQNNGDPYT [SEQ ID NO:47] (r18D11 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence TYALN [SEQ ID NO: 48] (r18D11 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (r18D11 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence PQSGTSFAY [SEQ ID NO: 50] (r18D11 H-CDR3), an antibody comprising: (8) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises, consists of, or consists essentially of the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 comprises, consists of, or consists essentially of the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 comprises, consists of, or consists essentially of the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises, consists of, or consists essentially of the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 comprises, consists of, or consists essentially of the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 comprises, consists of, or consists essentially of the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3), An antibody comprising:

[0119] In some embodiments, the CD14 antagonist antigen-binding molecule is a humanized antibody. In an exemplary embodiment of this type, the humanized CD14 antagonist antibody suitably comprises a donor CDR set corresponding to a CD14 antagonist antibody (e.g., one of the CD14 antagonist antibodies described above) and a human acceptor framework. The human acceptor framework may comprise at least one amino acid substitution relative to the human germline acceptor framework at a key residue selected from the group consisting of residues adjacent to the CDRs; glycosylation site residues; rare residues; canonical residues; contact residues between the heavy chain variable region and the light chain variable region; residues within the Vernier zone; and residues within the overlapping region between the Chia-defined VH CDR1 and the Kabat-defined first heavy chain framework. Techniques for producing humanized mAbs are well known in the art (see, e.g., Jones et al., 1986. Nature 321: 522-525; Riechmann et al., 1988. Nature 332:323-329; Verhoeyen et al., 1988. Science 239: 1534-1536; Carter et al., 1992. Proc. Natl. Acad. Sci. USA 89: 4285-4289; Sandhu, J.S., 1992. Crit. Rev. Biotech. 12: 437-462, and Singer et al., 1993. J. Immunol. 150: 2844-2857). Chimeric or murine monoclonal antibodies can be humanized by transferring murine CDRs from the heavy and light chains of a murine immunoglobulin into the corresponding variable domains of a human antibody. The murine framework regions (FRs) in a chimeric monoclonal antibody are also replaced with human FR sequences. Simply transferring murine CDRs into human FRs often results in a reduction or even loss of antibody affinity, so further modifications may be required to restore the original affinity of the murine antibody. This can be achieved by replacing one or more human residues in the FR regions with their murine counterparts to obtain an antibody with good binding affinity for its epitope.See, e.g., 1991. Biotechnology 9:266-271 and Verhoeyen et al. (1988 supra). Generally, human FR amino acid residues that differ from their murine counterparts and that are located adjacent to or contact one or more CDR amino acid residues are candidates for substitution.

[0120] In some embodiments, the CD14 antagonist antibody is the IC14 antibody (Axtelle et al., 2001. J. Endotoxin Res. 7: 310-314; and U.S. Patent Application Publication No. 2006 / 0121574, which are incorporated herein by reference in their entireties), or an antigen-binding fragment thereof. The IC14 antibody is a chimeric (mouse / human) monoclonal antibody that specifically binds to human CD14. IC14 is derived from the aforementioned mouse 28C5 and contains an IgG4 heavy chain (see U.S. Patent Nos. 5,820,858, 6,444,206, and 7,326,569 to Leturcq et al., and Leturcq et al., 1996. J. Clin. Invest. 98: 1533-1538). Thus, in one embodiment, the CD14 antagonist antibody comprises the IC14 heavy and light chain CDRs, as described above. In another example, the CD14 antagonist antibody comprises a VL domain and a VH domain, wherein: The VL domain has the amino acid sequence: comprising, consisting of, or consisting essentially of QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIK [SEQ ID NO: 25]; and The VH domain has the amino acid sequence: comprising, consisting of, or consisting essentially of LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSS [SEQ ID NO: 26]; or The VL domain has the amino acid sequence: comprising, consisting of, or consisting essentially of DIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIK [SEQ ID NO: 30]; and The VH domain has the amino acid sequence: DVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSS [SEQ ID NO: 31].

[0121] In another embodiment, the CD14 antagonist antibody comprises the light and heavy chains of IC14, wherein:

[0122] The light chain has the amino acid sequence: comprising, consisting of, or consisting essentially of QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 28]; and The heavy chain has the amino acid sequence: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKP comprising, consisting of, or consisting essentially of KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 29]; or The light chain has the amino acid sequence: comprising, consisting of, or consisting essentially of DIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 32]; and The heavy chain has the amino acid sequence: DVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 33].

[0123] Additional CD14 antagonist antigen-binding molecules suitable for use in the methods disclosed herein can be identified by methods well known to those skilled in the art, which generally involve determining whether an antibody can directly antagonize CD14. For example, this method may involve determining whether the antibody can inhibit or reduce the amount or agonistic activity of CD14, where the ability to inhibit or reduce the amount or agonistic activity of CD14 indicates that the antibody is suitable for use in treating cardiomyopathy. In some embodiments, the antibody is contacted with CD14, or a cell expressing CD14 on its surface, or a nucleic acid sequence in which CD14 is expressed, suitably in the presence of a CD14 agonist, such as a DAMP or PAMP, where a decrease in the amount or agonistic activity of CD14 in the presence of the agonist compared to a control indicates that the antibody binds to and directly antagonizes CD14. Reducing or inhibiting CD14 agonist activity includes, for example, inhibiting or reducing activation of downstream pathways such as the TLR signaling pathway (e.g., the TLR4 signaling pathway) and the TRIF pathway, or eliciting a cellular response (e.g., production of proinflammatory mediators, including proinflammatory cytokines).

[0124] These methods can be performed in vivo, ex vivo, or in vitro. In particular, the step of contacting the antibody with CD14 or a cell (e.g., an immune cell) expressing CD14 on its surface can be performed in vivo, ex vivo, or in vitro. The methods can be performed in cell-based or cell-free systems. For example, the method can include contacting a cell expressing CD14 on its surface with the antibody and determining whether contacting the cell with the antibody results in a decrease in the amount or agonist activity of CD14. In such cell-based assays, the CD14 and / or antibody can be endogenous to the host cell, introduced into the host cell or tissue, introduced into the host cell or tissue by causing or allowing expression of an expression construct or vector, or introduced into the host cell by stimulating or activating expression from an endogenous gene in the cell. In such cell-based methods, the amount of CD14 activity can be assessed in the presence or absence of the antibody to determine whether the agent alters the amount of CD14 in the cell, such as through modulation of CD14 expression in the cell, or through destabilization of CD14 protein in the cell, or by altering the CD14 agonist activity of the cell. Lower CD14 agonist activity or the presence of reduced amounts of CD14 on the cell surface in the presence of the antibody indicates that the antibody may be a suitable antagonist of CD14 for use in accordance with the present disclosure.

[0125] In some embodiments, the antibody is further determined to lack substantial or detectable binding to another cellular component, such as a CD14 binding partner, suitably a CD14 binding partner, whether secreted (e.g., MD2) or located on the cell membrane (e.g., TLR4), thereby determining that the antibody is a specific CD14 antagonist. In a non-limiting example of this type, the antibody is contacted with (1) wild-type cells (e.g., immune cells such as macrophages) expressing CD14 on their surface and (2) CD14-negative cells (e.g., immune cells the same as (1) but with a loss of function in the CD14 gene) in the presence of a CD14 agonist such as a DAMP or PAMP. If the antibody inhibits the CD14 agonist activity of the wild-type cells but not the CD14-negative cells, this indicates that the antibody is a CD14-specific antagonist. Cells of this type can be constructed using conventional techniques or animals.

[0126] In other examples, potential CD14 antagonist antigen-binding molecules are evaluated in vivo, for example, in an animal model. In such in vivo models, the effects of antibodies can be evaluated in the circulation (e.g., blood) or heart, or other organs such as the lungs, liver, kidneys, or brain. In certain examples, a cardiomyopathy model is used to evaluate the activity of an antibody.

[0127] Exemplary CD14 antagonist antigen binding molecules preferably cause a decrease in CD14 activity or levels of CD14 activity of at least 5%, at least 10%, at least 25%, at least 50%, at least 60%, at least 75%, or at least 85% or more compared to the absence of the antibody. In some instances, the antibody can cause a decrease in CD14 agonist activity or levels such that agonist activity or levels of CD14 are no longer detectable in the presence of the antibody. Such a decrease can be observed in the sample being tested or, for example, when the method is performed in an animal model.

[0128] Preferably, the antibody is a specific antagonist of CD14, as described above. However, this does not mean that the specific antagonist of CD14 has a complete lack of off-target antagonist activity. In this regard, the specific antagonist of CD14 may have negligible direct binding and effect, such that the antagonist of the activity, signal transduction, or expression of a non-CD14 cellular component has less than 15%, less than 10%, less than 5%, less than 1%, or less than 0.1% of the direct binding and effect of the agent on the activity, signal transduction, or expression of CD14.

[0129] The level or amount of CD14 can be measured by assessing the expression of the CD14 gene. Gene expression can be assessed by examining the production or level of mRNA or the production or level of protein. Expression products, such as mRNA and protein, can be identified or quantified by methods known in the art, including hybridization to specifically identify the mRNA of interest. For example, such methods can include PCR or real-time PCR approaches. Methods for identifying or quantifying a protein of interest can include the use of an antibody that binds to the protein. For example, such methods can include Western blotting. Modulation of CD14 gene expression can be compared in the presence and absence of the antibody. Thus, antibodies that reduce CD14 gene expression compared to levels seen in the absence of the antibody can be identified. Such antibodies can be suitable CD14 antagonists according to the present disclosure.

[0130] Methods for identifying suitable antagonist antigen-binding molecules for use according to the present disclosure can assess CD14 agonist activity. For example, such methods can be performed using peripheral blood mononuclear cells (PBMCs). These cells produce proinflammatory cytokines, such as IL-1α, IL-6, TNF-α, IFN-β, IL-1β, IL-17, and IL-8, in response to stimulation with, for example, LPS. Thus, the method can include combining PBMCs with an antibody or vehicle and adding LPS. The cells can then be incubated for a period of time (e.g., 24 hours) to allow for the production of proinflammatory mediators, such as cytokines. The levels of proinflammatory cytokines, such as IL-1α, IL-6, TNF-α, IFN-β, IL-1β, IL-17, and IL-8, produced by the cells during that period can then be assessed. If the antibody has anti-CD14 properties, production of such cytokines should be reduced compared to vehicle-treated cells. 3. Adjunctive medications and interventions

[0131] The CD14 antagonist antigen-binding molecule may be administered alone or in combination with other active agent(s) (also referred to as "adjunctive therapeutic agents") or other interventions, such as drugs or interventions useful for treating or inhibiting the development of cardiomyopathy. An adjunctive therapeutic agent may be any compound, molecule, or substance that exerts a therapeutic effect on a subject in need thereof, preferably in connection with the treatment of cardiomyopathy.

[0132] Representative adjunctive therapeutic agents suitable for purposes of the present disclosure include, for example, fibrinolytic agents, beta-blockers, high-intensity statins (e.g., atorvastatin or rosuvastatin), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, platelet inhibitors, thiadiazolidinediones, corticosteroids, anticonvulsants, immunosuppressants (e.g., cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolate, methotrexate, basiliximab, daclizumab, rituximab, antithymocyte globulin, thiazolinone ... antilymphocyte globulin, antilymphocyte globulin), antimicrobial agents, calcium channel blockers, digoxin, antiarrhythmic agents, anticoagulants, diuretics (e.g., spironolactone, eplerenone), exon skipping therapeutic methods (e.g., eteplirsen, drisapersen), anti-myostatin antibodies (e.g., PF-06252616), anti-connective tissue growth factor antibodies (e.g., FG-3019), PDE5 inhibitors (e.g., tadalafil, sildenafil), PDE9 inhibitors, NF-κB inhibitors, stop codon read-through agents (e.g., ataluren), utrophin modulators (e.g., SMT C1100, SMT022357), antifibrotic agents (e.g., halofuginone, angiotensin [1-7]), coenzyme Q 10 synthetic analogs of (e.g., idebenone), allogeneic cardiac cell therapy methods (e.g., CAP-1002); Toll-like receptor antagonists (e.g., IMO-8400); mineralocorticoid receptor antagonists; beta-adrenergic receptor antagonists, resveratrol, and SIRT1 activators.

[0133] In some embodiments, the adjunctive agent is a beta-blocker (or beta-adrenergic receptor antagonist). Suitable beta-blockers may be non-selective or beta-1 selective. Non-selective agents bind to both beta-1 and beta-2 receptors, causing antagonistic effects through both receptors. Non-limiting examples of non-selective beta-blockers include propranolol, carvedilol, sotalol, and labetalol. Beta-1 receptor selective blockers bind only to beta-1 receptors, and include, for example, atenolol, bisoprolol, metoprolol, and esmolol.

[0134] In other instances, the adjunct agent is a fibrinolytic agent such as, for example, streptokinase, anistreplase, or tissue plasminogen activator (eg, tenecteplase, reteplase, or alteplase).

[0135] In further examples, the adjunctive agent is a platelet inhibitor such as aspirin, a P2Y12 inhibitor (eg, ticlopidine, clopidogrel, ticagrelor, or prasugrel), or a glycoprotein IIb / IIIa receptor antagonist.

[0136] In another embodiment, the adjunctive agent is an ACE inhibitor. Non-limiting examples of ACE inhibitors include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0137] In some embodiments, the adjunctive agent is a thiadiazolidinedione, representative examples of which include glycogen synthase kinase 3β (GSK3β) inhibitors, which are preferably selective, including reversible and irreversible inhibitors. Thiadiazolidinediones, such as tideglusib or NPE100928, including their derivatives, prevent the electrical, molecular, and structural changes associated with cardiomyopathy, as disclosed, for example, in U.S. Patent Application Publication No. 2022 / 0249448, the contents of which are incorporated herein by reference in their entirety.

[0138] In another example, the adjunctive agent is a corticosteroid, illustrative examples of which include steroids, phenytoin, procainamide; quinine; glucocorticoids (e.g., deflazacort, vamorolone, VBP15, prednisone triamcinolone, systemic methylprednisolone, betamethasone, budesonide, prednisolone, hydrocortisone, dexamethasone, and / or cortisone.

[0139] In some embodiments, the adjunctive agent is an immunosuppressant, representative examples of which include cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, basiliximab, daclizumab, rituximab, antithymocyte globulin, and antilymphocyte globulin.

[0140] In another example, the adjunct is an antimicrobial agent, non-limiting examples of which include: penicillins (e.g., penicillin and amoxicillin); cephalosporins (e.g., cephalexin); macrolides (e.g., erythromycin, clarithromycin, and azithromycin); fluoroquinolones (e.g., levofloxacin and ofloxacin); sulfonamides (e.g., cotrimoxazole and trimethoprim); tetracyclines (e.g., tetracycline and doxycycline); and aminoglycosides (e.g., gentamicin and tobramycin).

[0141] When two or more therapeutic agents are used in combination, the dosage of each therapeutic agent is generally the same as the dosage of each agent when used independently. However, if a therapeutic agent interferes with the metabolism of another, the dosage of each therapeutic agent should be adjusted appropriately. Alternatively, if two or more therapeutic agents exhibit a synergistic effect, one or more dosages may be reduced. Each therapeutic agent may be administered simultaneously or separately at appropriate intervals.

[0142] When combination therapy is desired, the CD14 antagonist antibody is administered separately, simultaneously or sequentially, with one or more additional agents or interventions. In some embodiments, this can be achieved, for example, by administering a single composition or pharmaceutical formulation containing both types of agents, systemically, or by simultaneously administering two separate compositions or formulations, where one composition contains the CD14 antagonist antigen-binding molecule and the other the additional agent. In other embodiments, treatment with the CD14 antagonist antigen-binding molecule can precede or follow treatment with the additional agent by intervals of minutes to hours, or days or weeks.

[0143] When two or more substances are administered to a subject "concurrently," "in combination," or "simultaneously," they may be administered simultaneously in a single composition, or simultaneously in separate compositions, or simultaneously in separate but distinct compositions.

[0144] In another example, administration of the antigen-binding molecule is in conjunction with an intervention (e.g., a surgical procedure) such as percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass including coronary artery bypass grafting (CABG), pacemaker implantation, implantable cardioverter defibrillator (ICD) implantation, cardiac catheterization, revascularization, and heart transplantation.

[0145] In some situations, the antigen-binding molecule and adjunctive agent(s) are administered within about 1 to 12 hours of each other, or within about 2 to 6 hours of each other. In other situations, it is desirable to significantly extend the period for treatment, however, in which case one or more days (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 days) are lost between each administration. In embodiments in which an adjunctive agent is administered separately from the CD14 antagonist antigen-binding molecule, it will be understood that the adjunctive agent may be administered by a method different from that used for the CD14 antagonist antibody. In a further embodiment, when an intervention (e.g., PCI) is performed on the subject, the antigen-binding molecule is administered to the subject within 72 hours of PCI, for example, at or by 12, 24, 36, or 48 hours after the intervention. 4. Pharmaceutical Compositions

[0146] As described herein, CD14 antagonist antigen binding molecules, optionally in combination with at least one adjunctive therapeutic agent, are useful for treating or alleviating at least one symptom of cardiomyopathy, treating or inhibiting the occurrence of cardiomyopathy, alleviating or inhibiting the occurrence of adverse cardiac remodeling in cardiomyopathy, improving cardiac function in cardiomyopathy, improving ventricular function in cardiomyopathy, improving atrial function in cardiomyopathy, reducing the number of premature ventricular contractions (PVCs), treating or alleviating at least one symptom of atrial fibrillation, and / or reducing the number of premature atrial contractions (PACs).

[0147] The CD14 antagonist antigen-binding molecule and optional auxiliary agent(s) are administered either by themselves or preferably in the form of a pharmaceutical composition (optionally containing a pharmaceutically acceptable carrier). Thus, pharmaceutical compositions comprising a CD14 antagonist antigen-binding molecule and, optionally, at least one auxiliary therapeutic agent for use in treating or inhibiting the development of cardiomyopathy are also provided herein.

[0148] The CD14 antagonist antigen-binding molecule and optional adjunctive therapeutic agents can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, stabilizers, or excipients (vehicles) to form pharmaceutical compositions, particularly protein active agents, known in the art. A carrier is "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to its recipient (e.g., a patient). Suitable carriers typically include saline or ethanol polyols, such as glycerol or propylene glycol.

[0149] Antigen-binding molecules can be formulated in neutral or salt forms. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups) and are formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, and maleic acid. Salts formed with free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, and procaine.

[0150] The compositions can be formulated appropriately for systemic administration, including intravenous, intramuscular, subcutaneous, or intraperitoneal administration, and can conveniently comprise a sterile aqueous solution of the antigen-binding molecule that is isotonic with the recipient's blood. Such formulations are typically prepared by dissolving the solid active ingredient in water containing physiologically compatible substances, such as sodium chloride, glycine, etc., to produce an aqueous solution having a buffered pH compatible with physiological conditions, and sterilizing the solution. These can be prepared in unit or multi-dose containers, such as sealed ampoules or vials.

[0151] The composition can incorporate stabilizers such as polyethylene glycol, proteins, sugars (e.g., trehalose), amino acids, inorganic acids, and mixtures thereof. The stabilizers are used in aqueous solutions at appropriate concentrations and pHs. The pH of the aqueous solutions is adjusted to within the range of 5.0 to 9.0, preferably 6 to 8. Anti-adsorption agents may be used when preparing antibodies. Other suitable excipients typically include antioxidants such as ascorbic acid. The composition can be formulated as a controlled-release preparation, which can be achieved by complexing or absorbing the protein with a polymer. Suitable polymers for controlled-release formulations include, for example, polyesters, polyamino acids, polyvinyls, pyrrolidone, ethylene vinyl acetate, and methylcellulose. Another possible method for controlled release is to incorporate the antibody into particles of polymeric materials such as polyesters, polyamino acids, hydrogels, poly(lactic acid), or ethylene vinyl acetate copolymers. Alternatively, instead of incorporating these substances into polymer particles, it is possible to incorporate them into, for example, hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacylate) microcapsules, for example by coacervation techniques or by interfacial polymerization, or into colloidal drug delivery systems, for example liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules, or into macroemulsions.

[0152] The CD14 antagonist antigen-binding molecule and optionally at least one adjuvant can also be administered directly to the airways in the form of an aerosol. For use as an aerosol, the antagonist antigen-binding molecule of the present disclosure in solution or suspension can be packaged in a pressurized aerosol container together with a suitable propellant, for example, a hydrocarbon propellant such as propane, butane, or isobutane, and a conventional adjuvant. The materials disclosed herein can also be administered in a non-pressurized form, such as a nebulizer or atomizer.

[0153] Those skilled in the art will recognize that formulations are routinely designed according to their intended use, ie, route of administration. 5. Treatment method

[0154] The present disclosure also relates to the use of pharmaceutical compositions comprising a CD14 antagonist antigen binding molecule and, optionally, at least one adjunctive therapeutic agent in methods for treating or inhibiting the development of cardiomyopathy. Cardiomyopathy is a measurable decrease in the ability of the myocardium to contract, leading to heart failure. Cardiomyopathy progresses over time with variable onset of arrhythmias and ventricular dysfunction. Electrocardiographic abnormalities can be detected early in the disease and progress with age. The development of cardiomyopathy is characterized by initial diastolic dysfunction followed by eccentric cardiac hypertrophy.

[0155] In some embodiments, the present disclosure provides a method of treating cardiomyopathy, the method comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting the occurrence of cardiomyopathy, the method comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof. In some embodiments, the present disclosure provides a method of slowing cardiomyopathy, the method comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof. In some embodiments, the present disclosure provides a method of slowing the progression of cardiomyopathy, the method comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof. In some embodiments, the present disclosure provides a method of ameliorating cardiomyopathy, the method comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof.

[0156] Cardiomyopathy that can be treated or whose occurrence can be inhibited by the pharmaceutical compositions disclosed herein includes primary and secondary cardiomyopathies. Representative primary cardiomyopathies include: hereditary cardiomyopathies, illustrative examples of which include hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction, conduction disorders, channelopathies (e.g., long QT syndrome), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and idiopathic ventricular fibrillation; mixed (hereditary and non-hereditary) cardiomyopathies, non-limiting examples of which include dilated cardiomyopathy and restrictive cardiomyopathy; and acquired cardiomyopathies, such as myocarditis (e.g., viral myocarditis) and other inflammatory cardiomyopathies (e.g., Kawasaki disease and Chagas disease), stress-induced (Tako-Tsubo) cardiomyopathy, and obstetric cardiomyopathy.Representative secondary cardiomyopathies include: infiltrative cardiomyopathies associated with the accumulation of abnormal substances between muscle cells, non-limiting examples of which include cardiomyopathy resulting from amyloidosis, including primary, familial autosomal dominant, senile, and secondary forms of amyloidosis, Gaucher disease, Hurler disease, and Hunter disease; storage cardiomyopathies, such as hemochromatosis, Fabry disease, glycogen storage disease, and Niemann-Pick disease; toxicity-related cardiomyopathies, such as those resulting from exposure to drugs, heavy metals, and chemical agents, illustrative examples of which include chemotherapy-induced cardiomyopathies (e.g., cardiomyopathies associated with exposure to the following: anthracyclines, such as doxorubicin (adriamycin) and daunorubicin; cyclophosphamide; and radiation) and alcoholic cardiomyopathies; endomyocardial cardiomyopathies, including endocardial fibrosis, idiopathic hypereosinophilic syndrome (Leffler endocarditis); granulomatous cardiomyopathies, endocrine cardiomyopathies, including diabetes, hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma, and acromegaly; cardiac and facial cardiomyopathies, such as Noonan syndrome and multiple lentigines; neuromuscular cardiomyopathies, which may be associated with the accumulation of abnormal substances within muscle cells, non-limiting examples of which include Friedreich's ataxia, Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonic dystrophy, neurofibromatosis, and tuberous sclerosis; nutritional deficiency cardiomyopathies, including cardiomyopathies associated with beriberi (thiamine), pellagra, scurvy, selenium, carnitine, or kwashiorkor; autoimmune or collagen-mediated cardiomyopathies, such as systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, scleroderma, and polyarteritis nodosa; and electrolyte imbalance cardiomyopathies. In certain embodiments, the cardiomyopathy is ACM, which is preferably arrhythmogenic right ventricular cardiomyopathy (ARVC). In other embodiments, the cardiomyopathy is a non-ACM cardiomyopathy.

[0157] In some embodiments, the subject has one or more mutations in a gene associated with cardiomyopathy. The gene associated with cardiomyopathy is, for example, a gene encoding a component of desmosome. Examples of genes encoding a component of desmosome include plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), or plakoglobin (JUP). Other genes associated with cardiomyopathy include, but are not limited to, transmembrane protein 43 (TMEM43), catenin alpha 3 (CTNNA3), desmin (DES), lamin A / C (LMNA), phospholamban (PLN), ryanodine receptor 2 (RYR2), transforming growth factor beta-3 (TGFB3), titin (TTN), filamin C (FLNC), RNA-binding motif protein 20 (RBM20), sodium voltage-gated channel alpha subunit 5 (SCN5A), or BAG co-chaperone 3 (BAG3).

[0158] In some embodiments, the cardiomyopathy is associated with arrhythmia. In representative embodiments of this type, the cardiomyopathy is ACM.

[0159] In some embodiments, the subject has had an implantable cardioverter-defibrillator (ICD) inserted due to a perceived risk of life-threatening arrhythmia, or has previously experienced cardiac arrest, sustained ventricular tachycardia, or a worrisome syncope or presyncope episode.

[0160] In some embodiments, the subject begins to manifest clinical features of the disease, including frequent premature ventricular contractions (PVCs) or non-sustained ventricular tachycardia on ambulatory monitoring, electrocardiogram (ECG) abnormalities such as epsilon waves or precordial T-wave inversion, or evidence of cardiac dysfunction on imaging modalities such as echocardiography and cardiac magnetic resonance imaging. Non-sustained ventricular tachycardia is defined as more than three beats of ventricular origin at a rate of more than 100 beats per minute for a duration of less than 30 seconds. If the rhythm lasts longer than 30 seconds or if hemodynamic instability occurs within 30 seconds, it is considered sustained ventricular tachycardia. In some embodiments, the patient has a deleterious genetic variant that puts them at risk of developing cardiomyopathy and suffering from life-threatening arrhythmias.

[0161] Symptoms and / or complications of cardiomyopathy are well known in the art and include, but are not limited to, ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, embolization, myocardial fibrofatty infiltration, heart failure, or sudden cardiac death (SCD).

[0162] Treatment or inhibition of the development of cardiomyopathic symptoms can be measured by any means known in the art. For example, assessments include echocardiographic assessment, cardiac magnetic resonance imaging (MRI), and cardiac MRI with slow gadolinium enhancement. In particular, LV size, thickness, volume, ejection fraction (EF), and myocardial scar tissue / inflammatory burden and injury can be assessed. Injury, changes in LV dimensions and volume, and scar tissue burden are the main measurements.

[0163] In some embodiments, the present disclosure provides a method of inhibiting the occurrence of adverse cardiac remodeling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of slowing adverse cardiac remodeling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of slowing the progression of adverse cardiac remodeling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of ameliorating adverse cardiac remodeling in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, adverse cardiac remodeling is inhibited, delayed, or ameliorated for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to adverse cardiac remodeling in untreated cardiomyopathic subjects. In some embodiments, adverse cardiac remodeling is inhibited, delayed, or ameliorated by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to adverse cardiac remodeling in untreated cardiomyopathic subjects. In some embodiments, this inhibition, delay, or amelioration of adverse cardiac remodeling is observed at the time points disclosed herein. In some embodiments, adverse cardiac remodeling includes increased myocardial fibrosis. In some embodiments, adverse cardiac remodeling comprises changes in cardiac chamber diameter. In some embodiments, adverse cardiac remodeling comprises changes in myocardial mass (hypertrophy and atrophy). In some embodiments, adverse cardiac remodeling comprises changes in cardiac geometry (heart wall thickness and shape). In some embodiments, adverse cardiac remodeling comprises changes in cardiac inflammatory infiltrate.

[0164] In some embodiments, the present disclosure provides a method for inhibiting the occurrence of cardiac decline in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method for slowing the progression of cardiac decline in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method for ameliorating cardiac decline in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the cardiac decline is inhibited, delayed, or ameliorated for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to cardiac decline in untreated cardiomyopathic subjects. In some embodiments, the cardiac decline is inhibited, delayed, or ameliorated by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to the decline in cardiac function of an untreated cardiomyopathic subject. In some embodiments, this inhibition, delay, or amelioration of cardiac decline is observed at time points disclosed herein. In some embodiments, the cardiac decline is decreased inotropy. In some embodiments, the cardiac decline is decreased myocardial relaxation. In some embodiments, the cardiac decline is thickening of the myocardium. In some embodiments, the cardiac decline is cardiac hypertrophy.

[0165] In some embodiments, administration of a CD14 antagonist antigen binding molecule improves cardiac function in a subject compared to an untreated cardiomyopathic subject. In some embodiments, cardiac function is improved over about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to the cardiac function of an untreated cardiomyopathic subject. In some embodiments, cardiac function is improved by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to the cardiac function of an untreated cardiomyopathic subject. In some embodiments, this improvement in cardiac function is observed at a time point disclosed herein. In some embodiments, the improvement in cardiac function is increased inotropy. In some embodiments, the improvement in cardiac function is increased myocardial relaxation. In some embodiments, the improvement in cardiac function is less thickening of the myocardium. In some embodiments, the improvement in cardiac function is less cardiac hypertrophy. In some embodiments, the improvement in cardiac function is less premature ventricular contractions (PVCs). In some embodiments, the improvement in cardiac function is less premature atrial contractions (PACs).

[0166] In some embodiments, administration of a CD14 antagonist antigen binding molecule improves ventricular function in a subject compared to an untreated cardiomyopathic subject. In some embodiments, ventricular function is improved for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to the ventricular function in an untreated cardiomyopathic subject. In some embodiments, ventricular function is improved by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to the ventricular function in an untreated cardiomyopathic subject. In some embodiments, this improvement in ventricular function is observed at a time point disclosed herein. In some embodiments, the improvement in ventricular function is an improved fractional shortening. In some embodiments, the improvement in ventricular function is an improved ejection fraction. In some embodiments, the improved ventricular performance is a reduced end-diastolic volume. In some embodiments, the improved ventricular performance is a reduced left ventricular muscle mass. In some embodiments, the improved ventricular performance is a reduced ventricular end-diastolic diameter. In some embodiments, the improved ventricular performance is a reduced arrhythmia. In some embodiments, the improved ventricular performance is a reduced heart murmur. In some embodiments, the improved ventricular performance is a reduced heart rate. In some embodiments, the improved ventricular performance is a normalization of cardiac geometry. In some embodiments, the improved ventricular performance is fewer PVCs. PVCs may be measured, for example, by an electrocardiographic device such as a Holter monitor. A reduction in PVCs means a reduction of about ≧1%, about ≧2%, about ≧4%, about ≧5%, about ≧10%, about ≧15%, about ≧20%, about ≧25%, about ≧30%, about ≧35%, about ≧40%, about ≧45%, about ≧50%, or more, compared to the PVC count before treatment (i.e., the subject's baseline PVC rate). The number of PVCs and their reduction can be measured over a period of about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, or more.Alternatively, the number of PVCs and their reduction can be measured over a period of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or more. The number of PVCs and their reduction can be measured over a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or more. The number of PVCs and their reduction can be measured over a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or more.

[0167] In some embodiments, administration of a CD14 antagonist antigen binding molecule improves atrial function in a subject compared to an untreated cardiomyopathic subject. In some embodiments, atrial function is improved for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to an untreated cardiomyopathic subject. In some embodiments, atrial function is improved by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to an untreated cardiomyopathic subject. In some embodiments, this improvement in atrial function is observed at a time point disclosed herein. In some embodiments, the improvement in atrial function is improved atrial reservoir function. In some embodiments, the improvement in atrial function is improved atrial conduit function. In some embodiments, the improved atrial function is improved atrial pumping function. In some embodiments, the improved atrial function is reduced left atrial mass. In some embodiments, the improved atrial function is reduced arrhythmias. In some embodiments, the improved atrial function is fewer PACs. A reduction in PACs means a reduction of about ≧1%, about ≧2%, about ≧4%, about ≧5%, about ≧10%, about ≧15%, about ≧20%, about ≧25%, about ≧30%, about ≧35%, about ≧40%, about ≧45%, about ≧50%, or more, compared to the number of PACs before treatment (i.e., the subject's baseline PAC rate). The number of PACs and their reduction can be measured over a period of about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 120 hours, or more. Alternatively, the number of PACs and their reduction can be measured over a period of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or more. The number of PACs and their reduction can be measured over a period of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or more. The number of PACs and their reduction can be measured over a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or more.

[0168] In some embodiments, the present disclosure provides a method of inhibiting the occurrence of atrial fibrillation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of delaying atrial fibrillation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of delaying the progression of atrial fibrillation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of ameliorating atrial fibrillation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, atrial fibrillation is inhibited, delayed, or ameliorated for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to atrial fibrillation in untreated cardiomyopathic subjects. In some embodiments, atrial fibrillation is inhibited, delayed, or ameliorated by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to atrial fibrillation in untreated cardiomyopathic subjects. In some embodiments, this inhibition, delay, or amelioration of atrial fibrillation is observed at the time points disclosed herein.

[0169] In some embodiments, the present disclosure provides a method of inhibiting the development of fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of delaying the development of fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of delaying the progression of fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the present disclosure provides a method of ameliorating the development of fibrosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, fibrosis is inhibited, delayed, or ameliorated for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared to fibrosis in untreated cardiomyopathic subjects. In some embodiments, fibrosis is inhibited, slowed, or ameliorated by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% compared to fibrosis in untreated cardiomyopathic subjects. In some embodiments, this inhibition, slowing, or amelioration of fibrosis is observed at the time points disclosed herein. In some embodiments, fibrosis is measured using histological techniques (e.g., hematoxylin-eosin (HE) and trichrome staining) on ​​biopsy specimens, where fibrosis is assessed by determining the percentage of collagen present relative to the total tissue area.

[0170] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered chronically. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered for about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, or more. The CD14 antagonist antigen-binding molecules may be administered at any required dosage and / or frequency as disclosed herein.

[0171] In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered until cardiomyopathic symptoms are ameliorated. In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered until cardiomyopathic symptoms are slowed. In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered until cardiomyopathic symptoms are resolved.

[0172] In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered before a patient begins to exhibit one or more symptoms of cardiomyopathy. In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered at the time of onset of a cardiomyopathy symptom. In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered before a patient begins to exhibit cardiomyopathy. In some embodiments, a CD14 antagonist antigen binding molecule disclosed herein is administered after the onset of a cardiomyopathy symptom.

[0173] In some embodiments, the subject is determined to have an abnormal echocardiogram compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have an altered cardiac function compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have a prolonged PR interval compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have elevated U waves compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have wide QRS compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have non-specific ST-T changes compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have sinus arrhythmia compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have deep precordial Q waves and tall R waves compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have an abnormal tonic contraction (TC) compared to non-cardiomyopathic subjects. In some embodiments, tonic contractions result from periods of calcium dysregulation, representing continued ion-driven myocyte contraction, and result in the echocardiographic appearance of left ventricular "filling failure" (Su et al. (2015, Pediatr. Cardiol. Dec. 29). In some embodiments, the subject is determined to have arrhythmias compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have sinus tachycardia compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have systolic dysfunction compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have diastolic dysfunction compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have a low mitral systolic wave velocity compared to non-cardiomyopathic subjects. In some embodiments, the subject is determined to have wall motion abnormalities compared to non-cardiomyopathic subjects. Cardiac function and / or characteristics may be measured using an electrocardiogram.

[0174] In some embodiments, the subject is measured to have enhanced expression of a pro-inflammatory mediator, preferably a pro-inflammatory cytokine, compared to a non-cardiomyopathic subject. In some embodiments, the subject is measured to have enhanced activity of a pro-inflammatory mediator, preferably a pro-inflammatory cytokine, compared to a non-cardiomyopathic subject. In some embodiments, the pro-inflammatory cytokine is any pro-inflammatory cytokine, including, but not limited to, OPN, LTβ4, TNF-α, interleukin-6 (IL-6), and soluble tumor necrosis factor alpha receptor (sTNFαR). The expression or activity of a pro-inflammatory cytokine in a subject can be measured by a cytokine assay.

[0175] In some embodiments, the subject is measured to have reduced neuronal nitric oxide synthase (nNOS) protein expression compared to non-cardiomyopathic subjects. In some embodiments, the subject is measured to have reduced nNOS activity compared to non-cardiomyopathic subjects. In some embodiments, the subject is measured to have altered nNOS protein accumulation compared to non-cardiomyopathic subjects. In some embodiments, the subject is measured to have increased nNOS protein accumulation in the cytosol of skeletal muscle compared to non-cardiomyopathic subjects. In some embodiments, the subject is measured to have decreased nNOS protein accumulation in the sarcolemma of skeletal muscle compared to non-cardiomyopathic subjects. Protein accumulation may be assayed by histological techniques. Protein expression may be assayed by immunoprecipitation. Protein activity may be measured by NO synthase catalytic assay.

[0176] In some embodiments, pharmaceutical compositions comprising a CD14 antagonist antigen-binding molecule and, optionally, at least one adjunctive therapeutic agent ("active agent") disclosed herein are for "systemic delivery," meaning that the active agent(s) are not delivered locally to the site of pathology or action. Instead, the active agent(s) are absorbed into the bloodstream from the injection site, where they act systemically or are transported to the site of action via the circulation. The active agent(s) may be administered by any suitable route, including, for example, oral, intravenous, intramuscular, nasal, subcutaneous, and rectal. In some embodiments, the active agent(s) are for parenteral administration, preferably intravenous administration. In other embodiments, the active agent(s) are for local administration to the pathological site (e.g., myocardial tissue) to be treated. In these embodiments, the active agent(s) may be administered by direct injection, insertion, or implantation into, on, or near the pathological site.

[0177] In some embodiments, the active agent(s) are administered approximately monthly and may be administered topically or intravenously. In some embodiments, the active agent(s) are administered approximately weekly and may be administered topically or intravenously. In some embodiments, the site of administration may not be the site of pathology, e.g., may not be the intended site of action.

[0178] In various embodiments, the plasma concentration of the active agent(s) does not change by more than about 100-fold, about 50-fold, about 10-fold, about 5-fold, or about 3-fold over multiple administrations, such as, for example, at least two, at least about five, or at least about 10 administrations. Administrations are substantially evenly spaced, such as, for example, about every day, or about once a week, or from 1 to about 5 times a month, or about once every two months, or about once every three months. In some embodiments, the active agent(s) is administered to the subject for a period of about 1 day, for a period of about 2 days, for a period of about 3 days, for a period of about 4 days, for a period of about 5 days, for a period of about 6 days, for a period of about 1 week, for a period of about 2 weeks, for a period of about 3 weeks, for a period of about 4 weeks, for a period of about 5 weeks, for a period of about 6 weeks, for a period of about 2 months, for a period of about 3 months, for a period of about 4 months, for a period of about 5 months, for a period of about 6 months, for a period of about 7 months, for a period of about 8 months, for a period of about 9 months, for a period of about 10 months, for a period of about 11 months, for a period of about 1 year, for a period of about 14 months, for a period of about 16 months, for a period of about 18 months, for a period of about 20 months, for a period of about 22 months, or for a period of about 2 years.

[0179] While those skilled in the art can determine the desired dosage for each individual case, a suitable effective amount of a CD14 antagonist antigen-binding molecule to achieve a therapeutic effect may be, for example, within the range of about 0.1 mg to 50 mg (and all intervening integer mg units to one decimal place), about 0.2 mg to 40 mg (and all intervening integer mg units to one decimal place), about 0.5 mg to 40 mg (and all intervening integer mg units to one decimal place), 1 mg to 30 mg (and all intervening integer mg units), 2 mg to 20 mg (and all intervening integer mg units), about 4 mg to 15 mg (and all intervening integer mg units), or about 5 mg to 10 mg (and all intervening integer mg units) per kilogram of body weight per day. In some embodiments, the CD14 antagonist antigen-binding molecule is administered at a low dose. In some embodiments, the CD14 antagonist antigen-binding molecule is administered at a dosage of 1 mg per kilogram of body weight per day to about 9 mg per kilogram of body weight per day. In some embodiments, a suitable effective amount of the CD14 antagonist antigen-binding molecule to achieve a therapeutic effect may be within the range of, for example, 0.1 mg to 50 mg (and all integer mg units to the nearest tenth place), about 0.2 mg to 40 mg (and all integer mg units to the nearest tenth place), about 0.5 mg to 40 mg (and all integer mg units to the nearest tenth place), 1 mg to 30 mg (and all integer mg units to the nearest tenth place), 2 mg to 20 mg (and all integer mg units to the nearest tenth place), about 4 mg to 15 mg (and all integer mg units to the nearest tenth place), or about 5 mg to 10 mg (and all integer mg units to the nearest tenth place) per kilogram of body weight per week. Alternatively, if the condition of the recipient so requires, the dosage may be administered as a continuous infusion.

[0180] In certain embodiments, the subject is a human, but in other embodiments, the subject may be a non-human mammal, such as, for example, a domestic pet (e.g., a dog or cat), a farm or livestock animal (e.g., a horse, cow, sheep, or pig). 6. Representative Embodiments 1. A method for treating or alleviating at least one symptom of cardiomyopathy in a subject, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject. 2. 2. The method of embodiment 1, wherein the at least one symptom is selected from ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolization, fainting, angina, exercise intolerance, orthopnea, heart failure, and sudden cardiac death (SCD). 3. 3. The method of embodiment 1 or embodiment 2, wherein administration of the CD14 antagonist antigen binding molecule improves one or more clinical parameters in the subject. 4. The method of embodiment 3, wherein the one or more clinical parameters are selected from reduced left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, adverse cardiac remodeling, right ventricular dysfunction, abnormal cardiac geometry (e.g., increased right ventricular fractional area change), increased end-diastolic volume, frequent premature ventricular contractions, and increased left ventricular muscle mass. 5. A method for alleviating or inhibiting the occurrence of adverse cardiac remodeling in a subject suffering from cardiomyopathy, the method comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen binding molecule to the subject. 6. A method for improving cardiac function in a subject suffering from cardiomyopathy, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject. 7. 7. The method of embodiment 6, wherein the improvement in cardiac function comprises improvement in left ventricular function, improvement in fractional shortening, improvement in ejection fraction, reduction in end-diastolic volume, reduction in left ventricular muscle mass, reduction in arrhythmia, reduction in frequency of heart murmurs, reduction in heart rate, normalization of cardiac geometry, or a combination thereof. 8. A method for improving ventricular function in a subject suffering from cardiomyopathy, comprising, consisting of, or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule. 9. A method for improving atrial function in a subject suffering from cardiomyopathy, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject. 10. 10. The method of any one of embodiments 1 to 9, wherein the cardiomyopathy is a primary cardiomyopathy or a secondary cardiomyopathy. 11. 11. The method of embodiment 10, wherein the primary cardiomyopathies are selected from hereditary cardiomyopathies (e.g., hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction, conduction disorders, channelopathies (e.g., long QT syndrome), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and idiopathic ventricular fibrillation), mixed (hereditary and non-hereditary) cardiomyopathies (e.g., dilated cardiomyopathy and restrictive cardiomyopathy), and acquired cardiomyopathies (e.g., myocarditis, such as viral myocarditis, and other inflammatory cardiomyopathies, such as Kawasaki disease and Chagas disease, stress-induced (Tako-Tsubo) cardiomyopathy, and obstetric cardiomyopathy). 12. 11. The method of embodiment 10, wherein the secondary cardiomyopathy is selected from inherited cardiomyopathies, illustrative examples of which include hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction, conduction disorders, channelopathies (e.g., long QT syndrome), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and idiopathic ventricular fibrillation; mixed (hereditary and non-hereditary) cardiomyopathies, non-limiting examples of which include dilated cardiomyopathy and restrictive cardiomyopathy; and acquired cardiomyopathies, such as myocarditis (e.g., viral myocarditis) and other inflammatory cardiomyopathies (e.g., Kawasaki disease and Chagas disease), stress-induced (Tako-Tsubo) cardiomyopathy, and obstetric cardiomyopathy.Representative secondary cardiomyopathies include: infiltrative cardiomyopathies associated with the accumulation of abnormal substances between muscle cells, non-limiting examples of which include cardiomyopathy resulting from amyloidosis, including primary, familial autosomal dominant, senile, and secondary amyloidosis, Gaucher disease, Hurler disease, and Hunter disease; storage cardiomyopathies, such as hemochromatosis, Fabry disease, glycogen storage disease, and Niemann-Pick disease; toxicity-related cardiomyopathies, such as those resulting from exposure to drugs, heavy metals, and chemical agents, illustrative examples of which include chemotherapy-induced cardiomyopathies (e.g., cardiomyopathies associated with exposure to the following: anthracyclines, such as doxorubicin (adriamycin) and daunorubicin; cyclophosphamide; and radiation) and alcoholic cardiomyopathies; endomyocardial cardiomyopathies, including endocardial fibrosis and idiopathic hypereosinophilic syndrome (Leffler endocarditis); granulomatous cardiomyopathies, such as endocrine cardiomyopathies, including diabetes mellitus, hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma, and acromegaly; cardiac and facial cardiomyopathies, such as Noonan syndrome and multiple lentigines; and neuromuscular cardiomyopathies, which may be associated with the accumulation of abnormal substances within muscle cells, non-limiting examples of which include Friedreich's ataxia, Duchenne muscular dystrophy, Becker muscular dystrophy, and Emery's muscular dystrophy. -Dreifuss muscular dystrophy, myotonic dystrophy, neurofibromatosis, and tuberous sclerosis; nutritional deficiency cardiomyopathies, including those associated with beriberi (thiamine), pellagra, scurvy, selenium, carnitine, or kwashiorkor; autoimmune or collagen-mediated cardiomyopathies, such as systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, scleroderma, and polyarteritis nodosa; and electrolyte imbalance cardiomyopathies. 13. The method of any one of embodiments 1 to 12, wherein the cardiomyopathy is ACM. 14. A method for treating or alleviating at least one symptom of ACM in a subject, comprising, consisting of, or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule. 15. A method for reducing the number of premature ventricular contractions (PVCs) in a subject, the method comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject. 16. A method for treating or alleviating symptoms of atrial fibrillation in a subject, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen binding molecule to a subject suffering from or at risk of developing atrial fibrillation. 17. A method for reducing the number of premature atrial contractions (PACs) in a subject, the method comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject. 18. The antigen-binding molecule is one of the following: (i) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSFGNSFMH [SEQ ID NO:7] (3C10 L-CDR1); L-CDR2 comprises the sequence RAANLES [SEQ ID NO:8] (3C10 L-CDR2); and L-CDR3 comprises the sequence QQSYEDPWT [SEQ ID NO:9] (3C10 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3), an antibody comprising: (ii) the following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3), an antibody comprising: (iii) the following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3), an antibody comprising: (iv) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence NYDIS [SEQ ID NO:22] (18E12 H-CDR1); H-CDR2 comprises the sequence VIWTSGGTNYNSAFMS [SEQ ID NO:23] (18E12 H-CDR2); and H-CDR3 comprises the sequence GDGNFYLYNFDY [SEQ ID NO:24] (18E12 H-CDR3), an antibody comprising: (v) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence QNVGSNVDWY [SEQ ID NO:34] (F1024-1-3 L-CDR1); L-CDR2 comprises the sequence KASNRY [SEQ ID NO:35] (F1024-1-3 L-CDR2); and L-CDR3 comprises the sequence MQSNTNPPW [SEQ ID NO:36] (F1024-1-3 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence DYAMN [SEQ ID NO:37] (F1024-1-3 H-CDR1); H-CDR2 comprises the sequence WINTQTGKPTYADDF [SEQ ID NO:38] (F1024-1-3 H-CDR2); and H-CDR3 comprises the sequence TYFCTRSTFYYSSYIY [SEQ ID NO:39] (F1024-1-3 H-CDR3), an antibody comprising: (vi) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 comprises the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 comprises the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 comprises the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 comprises the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3), an antibody comprising: (vii) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYGNSFMH [SEQ ID NO:45] (r18D11 L-CDR1); L-CDR2 comprises the sequence LASNLES [SEQ ID NO:46] (r18D11 L-CDR2); and L-CDR3 comprises the sequence QQNNGDPYT [SEQ ID NO:47] (r18D11 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence TYALN [SEQ ID NO: 48] (r18D11 H-CDR1); H-CDR2 comprises the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (r18D11 H-CDR2); and H-CDR3 comprises the sequence PQSGTSFAY [SEQ ID NO: 50] (r18D11 H-CDR3), an antibody comprising: (viii) The following: a) an antibody VL domain or antigen-binding fragment thereof comprising L-CDR1, L-CDR2, or L-CDR3, wherein: L-CDR1 comprises the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 comprises the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 comprises the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3), and b) an antibody VH domain or antigen-binding fragment thereof comprising H-CDR1, H-CDR2, or H-CDR3, wherein: H-CDR1 comprises the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 comprises the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 comprises the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3), an antibody comprising 18. The method of any one of embodiments 1 to 17, wherein the method is selected from: 19. The antigen-binding molecule is one of the following: (i) The following: array: A VL domain comprising, consisting of, or consisting essentially of QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIYRAANLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSYEDPWTFGGGTKLGNQ [SEQ ID NO: 1] (3C10 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTTYYPDNVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYYDYHYWGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH), an antibody comprising: (ii) the following: array: A VL domain comprising, consisting of, or consisting essentially of QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDPTTFGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); and array: A VH domain comprising, consisting of, or consisting essentially of: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH); an antibody comprising: (iii) the following: array: QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQRGDTLPWTFGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); and array: A VH domain comprising, consisting of, or consisting essentially of LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVIWTSGGTNYNSAFMSRLSITKDNSESQVFLKMNGLQTDDTGIYYCVRGDGNFYLYNFDYWGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH), an antibody comprising: (iv) The following: array: YIVMTQTPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO:57] (F1024-1-3 VL); and array: A VH domain comprising, consisting of, or consisting essentially of EVKLLESGGGLVQPSQTLSISCKASGYTFTDYAMNWVKQAPGDGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 58] (F1024-1-3 VH), an antibody comprising: (v) The following: array: A VL domain comprising, consisting of, or consisting essentially of DIVMTQSPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO:59] (F1024 VL); and array: QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMNWVKQAPGNGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 60] (F1024 VH), an antibody comprising: (vi) The following: array: A VL domain comprising, consisting of, or consisting essentially of NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDVATYYCQQNNGDPYTFGGGTKLEIIR [SEQ ID NO: 61] (r18D11 VL); and array: A VH domain comprising, consisting of, or consisting essentially of EVQLVESGGGLMQPKGSLKLSCAASGFTFKTYALNWVRQAPGTGLEWVARIRSKSNNYTTYYADSVKDRFTISRDDSQNMLYLQMNNLKTEDTAMYYCVRPQSGTSFAYWGQGTLVTVSA [SEQ ID NO: 62] (r18D11 VH), an antibody comprising: (vii) The following: array: A VL domain comprising, consisting of, or consisting essentially of DIVMTQSQKFMSTSVGDRVSVTCKASQYVGTNVAWYQQKPGQSPKALIQSASYRCSGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYNTYVTFGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); and array: QVRLQQPGAELVRPGASVKLSCKASGYTFTTYWMNWVKQRPEDGLEWIGRIDPYDSETHYNQNFKDKAILTVDKSSSTAYMQLSSLTYEDSAVYYCTRKEGRQWGAYFDYWGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH), an antibody comprising 19. The method of any one of embodiments 1 to 18, wherein the method is selected from: 20. The method according to any one of embodiments 1 to 19, wherein the antigen-binding molecule is a humanized molecule or a chimeric molecule. twenty one. The antigen-binding molecule comprises a light chain and a heavy chain, wherein: the light chain having the following amino acid sequence: METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 25]; and MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCV RGLRFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR 21. The method of any one of embodiments 1 to 20, comprising VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 26]. twenty two. The method according to any one of embodiments 1 to 21, wherein the antigen-binding molecule is an IC14 antibody. twenty three. 23. The method of any one of embodiments 14 and 18-22, wherein the at least one symptom of ACM is selected from ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolization, fainting, angina, exercise intolerance, orthopnea, heart failure, and sudden cardiac death (SCD). twenty four. The method of any one of embodiments 12 and 16-21, wherein administration of the CD14 antagonist antigen-binding molecule improves one or more clinical parameters in the subject. twenty five. The method of embodiment 22, wherein the subject's one or more clinical parameters are selected from a reduced left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, adverse cardiac remodeling, right ventricular dysfunction, abnormal cardiac geometry (e.g., increased right ventricular fractional area change), increased end-diastolic volume, frequent premature ventricular contractions, and increased left ventricular muscle mass. 26. The method of any one of embodiments 14 and 18-25, wherein the cardiomyopathy is arrhythmogenic right ventricular cardiomyopathy (ARVC). 27. The method of any one of embodiments 16 and 18-22, wherein the symptoms of atrial fibrillation are tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, heart failure, stroke, or death. 28. The method of any one of embodiments 17 and 18-22, wherein the subject suffers from atrial fibrillation (AF). 29. The method of any one of embodiments 1-28, wherein the subject has an implantable cardioverter defibrillator (ICD). 30. 30. The method of embodiment 29, wherein administration of the CD14 antagonist antigen binding molecule reduces the number of electric shocks administered to the subject by an ICD. 31. The method of any one of embodiments 1-7 and 9-30, wherein administration of the CD14 antagonist antigen binding molecule improves a measure of ventricular function in the subject. 32. 32. The method of embodiment 31, wherein the measure of ventricular function is ventricular strain, systolic function, or diastolic function. 33. The method of embodiment 31 or embodiment 32, wherein the ventricular function is measured by echocardiography (echo), ambulatory electrocardiogram (Holter) monitoring, cardiac CT scan, or cardiac magnetic resonance imaging. 34. 34. The method of any one of embodiments 1-33, wherein the subject has one or more mutations in a gene associated with cardiomyopathy. 35. 35. The method of embodiment 34, wherein the gene associated with cardiomyopathy is a gene encoding a component of a desmosome. 36. 36. The method of embodiment 35, wherein the gene encodes plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2), or plakoglobin (JUP). 37. 35. The method of embodiment 34, wherein the gene associated with cardiomyopathy is transmembrane protein 43 (TMEM43), catenin alpha 3 (CTNNA3), desmin (DES), lamin A / C (LMNA), phospholamban (PLN), ryanodine receptor 2 (RYR2), transforming growth factor beta-3 (TGFB3), titin (TTN), filamin C (FLNC), RNA-binding motif protein 20 (RBM20), sodium voltage-gated channel alpha subunit 5 (SCN5A), or BAG co-chaperone 3 (BAG3). 38. The method of any one of embodiments 1-37, wherein said subject is a human, canine, feline, equine, bovine, ovine, or porcine. 39. 39. The method of embodiment 38, wherein the subject is a human. 40. The method of any one of embodiments 1 to 39, wherein the CD14 antagonist antigen-binding molecule is administered systemically. 41. The method of any one of embodiments 1 to 39, wherein the CD14 antagonist antigen-binding molecule is administered locally to the heart (e.g., the left ventricle) of the subject. 42. The method of any one of embodiments 1 to 41, wherein the CD14 antagonist antigen-binding molecule is administered at a daily dose of about 0.1 mg / kg to 50 mg / kg (and all intervening whole mg / kg units), about 0.2 mg / kg to 40 mg / kg (and all intervening whole mg / kg units), about 0.5 mg / kg to 40 mg / kg (and all intervening whole mg / kg units), about 1 mg / kg to 30 mg / kg (and all intervening whole mg / kg units), about 2 mg / kg to 20 mg / kg (and all intervening whole mg / kg units), about 4 mg / kg to 15 mg / kg (and all intervening whole mg / kg units), or about 5 mg / kg to 10 mg / kg (and all intervening whole mg / kg units). 43. The method of embodiment 42, wherein said daily dose is administered in a single dose. 44. The method of embodiment 42, wherein said daily dose is administered in two administrations. 45. The method of any one of embodiments 1 to 42, wherein the CD14 antagonist antigen-binding molecule is administered at a weekly dose of about 1 mg / kg to 30 mg / kg (and all integer mg / kg increments therebetween), about 2 mg / kg to 20 mg / kg (and all integer mg / kg increments therebetween), about 4 mg / kg to 15 mg / kg (and all integer mg / kg increments therebetween), or about 5 mg / kg to 10 mg / kg (and all integer mg / kg increments therebetween). 46. 46. ​​The method of any one of embodiments 1-45, wherein the CD14 antagonist antigen binding molecule is administered to the subject for a period of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 14 months, about 16 months, about 18 months, about 20 months, about 22 months, or about 2 years. 47. The method of any one of embodiments 1-46, wherein the subject has not been diagnosed with autoimmune cardiomyopathy. 48. The method of any one of embodiments 1-47, wherein the subject has not undergone cardiopulmonary bypass surgery. 49. The method of any one of embodiments 1 to 48, wherein the subject is not an acute myocardial infarction patient. 50. The method of any one of embodiments 1-49, comprising co-administering said adjunctive cardiomyopathy therapeutic agent or intervention to the subject. 51. The supplemental cardiomyopathy therapeutic agent may be an angiotensin-converting enzyme inhibitor (e.g., Enalipril, Lisinopril), angiotensin receptor blockers (e.g., Losartan, Valsartan), β-blockers (e.g., Lopressor, Toprol-XL), antiarrhythmic drugs (e.g., amiodarone (Cordarone, Pacerone), flecainide (Tambocor), ibutilide (Corvert), lidocaine (Xylocaine), procainamide (Procan, Procanbid), propafenone (Rythmol), quinidine, tocainide (Tonocarid)), digoxin, diuretics (e.g., La six; or the method of embodiment 50, wherein the anti-inflammatory drug is selected from, for example, levodopa, dopamine agonists (e.g., Parkinson's disease medications including bromocriptine, pergolide, pramipexole, lapinirole, piribedil, cabergoline, apomorphine, lisuride), statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, antipsychotics (e.g., clozapine), cholinesterase inhibitors, modafinil, thiadiazolidinediones, and nonsteroidal anti-inflammatory drugs. 52. 52. The method of any one of embodiments 1-51, further comprising performing a surgical procedure on the subject, wherein the surgical procedure is suitable for treating cardiomyopathy. 53. 53. The method of embodiment 52, wherein the surgical procedure comprises percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass, including coronary artery bypass grafting (CABG), pacemaker implantation, implantable cardioverter defibrillator (ICD) implantation, cardiac catheterization, revascularization, and heart transplantation. 54. The method of embodiment 52 or embodiment 53, wherein the surgical procedure is performed before, simultaneously with, or after administration of a CD14 antagonist antigen-binding molecule, optionally with an adjunctive cardiomyopathy therapeutic agent. 55. A CD14 antagonist antigen binding molecule for use in treating or alleviating at least one symptom of cardiomyopathy. 56. CD14 antagonist antigen-binding molecules for use in attenuating or inhibiting the development of adverse cardiac remodeling in cardiomyopathy 57. A CD14 antagonist antigen-binding molecule for use in improving cardiac function in cardiomyopathy. 58. A CD14 antagonist antigen-binding molecule for use in improving ventricular function in cardiomyopathy. 59. A CD14 antagonist antigen-binding molecule for use in improving atrial function in cardiomyopathy. 60. A CD14 antagonist antigen binding molecule for use in reducing the number of premature ventricular contractions (PVCs). 61. A CD14 antagonist antigen binding molecule for use in treating or alleviating at least one symptom of atrial fibrillation. 62. A CD14 antagonist antigen binding molecule for use in reducing the number of premature atrial contractions (PACs). 63. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for treating or alleviating at least one symptom of cardiomyopathy. 64. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for mitigating or inhibiting the occurrence of adverse cardiac remodeling in cardiomyopathy. 65. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for improving cardiac function in cardiomyopathy. 66. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for improving ventricular function in cardiomyopathy. 67. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for improving atrial function in cardiomyopathy. 68. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for reducing the number of premature ventricular contractions (PVCs). 69. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for treating or alleviating at least one symptom of atrial fibrillation. 70. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for reducing the number of premature atrial contractions (PACs). 71. The use according to any one of embodiments 55 to 70, wherein the CD14 antagonist antigen-binding molecule is used in combination with one or more adjunctive cardiomyopathy therapeutic agents or interventions.

[0181] In order that the present disclosure may be readily understood and put into practical practice, certain preferred embodiments are described by way of the following non-limiting examples. [Example]

[0182] Example 1 Inhibition of the development of arrhythmogenic cardiomyopathy using anti-CD14 antibodies Arrhythmogenic cardiomyopathy (ACM) is the name applied to a spectrum of nonischemic cardiomyopathies with right-dominant (ARVC), left-dominant (ALVC), or biventricular patterns of cardiomyopathy and dysfunction. Most cases are caused by mutations in genes encoding desmosomal proteins. In addition to forming intercellular adherens junctions, several desmosomal proteins are involved in key signaling cascades, including the Wnt and Hippo pathways, whose alterations are implicated in the pathogenesis of ACM. However, exactly how mutations in desmosomal genes lead to the complex clinical picture of arrhythmias and progressive cardiomyopathy remains largely unknown.

[0183] ACM is a leading cause of sudden death in young individuals, particularly athletes. As its name suggests, it is associated with a high incidence of fatal ventricular arrhythmias. In fact, the frequency of appropriate treatment for potentially fatal arrhythmias among all patients fitted with implantable cardioverter-defibrillators is higher for ACM patients than for many other forms of heart disease. Fortunately, sudden deaths in young adults are uncommon, but they clearly cause great disappointment for families whose other members are also at high risk.

[0184] There are no drug therapies for ACM. The only treatment proven to reduce sudden death in ACM is the implantable cardioverter-defibrillator (ICD). While this can save lives, it has significant drawbacks, including significant expense, associated physiological stress, and quality-of-life issues. Perhaps the most significant limitation, however, is that ICDs do not treat or prevent the progression of the underlying myocardial disease. Even if the risk of sudden death could be reduced, chronically progressing cardiomyopathy can progress to severe heart failure for which the only treatment is heart transplantation.

[0185] Compelling evidence now indicates that ACM is a chronic inflammatory disease. Inflammation in ACM has traditionally been considered in the context of inflammatory cell infiltration in the heart, which is common in ACM patients. While these inflammatory cells likely contribute to cardiomyopathy, we also know that in ACM, cardiomyocytes themselves mount a vigorous innate immune response and produce large amounts of potent proinflammatory mediators. Activation of the innate immune response in cardiomyocytes occurs early in ACM and is thought to be a cell-autonomous process driven by upstream signals from ACM disease alleles. It is also a long-lasting, uninterrupted process.

[0186] Based on unpublished data showing that activation of the innate immune response in cardiomyocytes is a major mechanism promoting myocardial injury in ACM, and that disease progression is also mediated by the action of proinflammatory macrophages recruited by signals from cardiomyocytes, we investigated the Dsg2 expression level in ACM to determine whether CD14 blockade would be effective in treating or delaying the development or progression of ACM. mut / mut We proposed testing anti-CD14 antagonist antibodies in a mouse model.

[0187] Dsg2 mut / mut Mice show little to no apparent cardiac structural or functional derangement at 8 weeks of age, but over the next 8 weeks, they develop a robust phenotype that recapitulates the most important clinical features seen in ACM patients: myocardial injury and arrhythmias, as illustrated in Figure 1. This includes a progressive decline in ventricular contractility associated with the development of massive myocardial necrosis, fibrosis, and inflammation. It also includes ECG abnormalities and arrhythmias. These structural and functional changes are associated with a pronounced shift in the distribution of various cardiomyocyte proteins, including desmosomal proteins, connexins, ion channel proteins, proteins involved in the Wnt / β-catenin signaling pathway, and synapse-associated protein 97 (SAP97), a chaperone protein involved in ion channel trafficking to the intercalated disc. As the disease progresses beyond 16 weeks, there is a gradual decline in ejection fraction due to the progression of significant myocardial fibrosis and inflammation. Early intervention using CD14 antagonist antibodies

[0188] Starting at 8 weeks of age, Dsg2 mut / mut Mice and wild-type (WT) control mice were given intraperitoneal (ip) injections of anti-CD14 mAb or isotype control antibody at 14-day intervals for 8 weeks. Results shown in Figures 2-6 show that Dsg2 mice at 16 weeks of age treated with isotype control showed no significant difference. mut / mutWe demonstrate that mice exhibited many features representative of human ACM, including reduced left ventricular ejection fraction (LVEF), increased left ventricular mass (LVM) suggestive of hypertrophic remodeling and reduced right ventricular fractional area change (RVFAC), increased premature ventricular contractions (PVCs), and increased fibrosis as measured by histological analysis.

[0189] In contrast, Dsg2 mut / mut Anti-CD14 treatment of mice was protective against all of these pathological changes, particularly: Anti-CD14 treatment restored %LVEF to levels seen in wild-type animals (Figure 2). Anti-CD14 treatment prevented right ventricular dysfunction by normalizing %RVFAC (Figure 3). Anti-CD14 treatment reduced ectopic heart beats by reducing the frequency of PVCs, as measured by ECG (Figure 4). Anti-CD14 treatment restores LVM to levels seen in wild-type animals, thereby minimizing hypertrophic remodeling (Figure 5). Anti-CD14 treatment reduced cardiomyopathy as measured by histological analysis of fibrosis (Figure 6).

[0190] Therefore, anti-CD14 treatment may be beneficial for Dsg2 in arrhythmogenic cardiomyopathy. mut / mut It inhibited the development of ventricular dysfunction and adverse cardiac remodeling in the model.

[0191] These studies highlight the important role played by CD14 in mediating disease progression in a murine model of ACM, where CD14 blockade preserved ventricular function, reduced PVC frequency, and attenuated or prevented pathologically adverse cardiac remodeling. Given the underlying myocardial disease and ongoing disease progression seen in ACM patients eligible for ICD therapy, CD14 blockade may be beneficial and help alleviate the chronic, progressive cardiomyopathy that ultimately leads to heart failure and heart transplantation. Materials and Methods ACM Mouse Model

[0192] The Jeffrey Saffitz lab at Beth Israel Deaconess Medical Center has a robust mouse model of ACM that expresses a mutation in the gene encoding the desmosomal protein desmoglein-2. mut / mut Mice begin to exhibit key features seen in ACM patients, including myocardial injury (necrosis / fibrotic lesions, myocyte apoptosis), contractile dysfunction, action potential remodeling and ventricular arrhythmias, and inflammation (inflammatory infiltrate, production of inflammatory cytokines) accompanied by activated NFκB in cardiomyocytes. Experimental design

[0193] Starting at 8 weeks of age, Dsg2 mut / mut Mice and WT control mice (n = 7-10 / group) were given intraperitoneal (ip) injections of anti-CD14 mAb (biG53LALA-PG) or isotype control antibody. Mice were injected (100 μL of anti-CD14 or isotype) at a dosage of 5 mg / kg every 14 days. reading

[0194] Mice were echocardiographed at 8 weeks of age, before the start of treatment, and at the end of the study. Electrocardiograms (ECGs) were performed at 16 weeks of age (week 8 of dosing), after which the mice were sacrificed. ECGs were assessed for runs of premature ventricular contractions (PVCs) and ventricular tachycardia; echocardiographic parameters included ejection fraction and ventricular wall / chamber measurements. At sacrifice, hearts were isolated, and one half was fixed in formalin for histological analysis of necrosis and fibrosis, and the other half was frozen for subsequent analysis. Example 2 Treatment of arrhythmogenic cardiomyopathy with anti-CD14 antibody

[0195] The present inventors also investigated Dsg2 mut / mut In a mouse model, we tested whether an anti-CD14 antagonist antibody could treat or slow the progression of ACM, as well as promote the recovery of contractile dysfunction in animals with established disease. Late intervention with CD14 antagonist antibodies

[0196] Starting at 16 weeks of age, Dsg2 mut / mut Mice and WT control mice were given ip injections of anti-CD14 mAb or isotype control antibody at 14-day intervals for 8 weeks. Results shown in Figures 7-9 show that Dsg2 mice at 24 weeks of age treated with isotype control had a significantly higher IFN-γ expression than Dsg2 mice. mut / mut They found that the mice exhibited significantly worse disease symptoms, including a significantly lower %LVEF and significantly higher fibrosis, than before they were administered the isotype control antibody at 16 weeks of age.

[0197] On the other hand, Dsg2 mice treated with anti-CD14 at 16 weeks of age mut / mut Mice significantly prevented or slowed further disease progression, including attenuation of further worsening of % LVEF (FIGS. 7, 8) and myocardial fibrosis (FIG. 9).

[0198] Thus, anti-CD14 treatment of animals with established disease stabilized cardiomyopathy by preventing or significantly slowing further deterioration of ventricular dysfunction and adverse cardiac remodeling. Example 3 Inflammatory macrophages from human and mouse subjects with cardiomyopathy co-express CCR2 and CD14.

[0199] It is known that the mouse heart contains heterogeneous populations of functionally distinct macrophages that have remarkable effects on the pathogenesis of cardiovascular disease. In particular, CCR2- and CCR2+ macrophages are known to have distinct functions in the heart. In this regard, CCR2- macrophages are involved in various forms of tissue remodeling, such as coronary artery development, postnatal coronary artery growth, and cardiac regeneration (Lavine et al., Proc. Natl. Acad. Sci. USA 2014; 111, 16029-16034; Leid et al., Circ. Res. 2016; 118, 1498-1511). For example, following neonatal cardiomyocyte injury, CCR2- macrophages orchestrate cardiac tissue regeneration and functional recovery by promoting coronary vasculature expansion, cardiomyocyte proliferation, and physiological cardiomyocyte hypertrophy. In the absence of CCR2- macrophages, pediatric mouse hearts demonstrate limited regenerative capacity. Within the resting adult heart, CCR2+ macrophages, particularly Ly6C, infiltrate the heart following various forms of tissue injury. high It is an inflammatory population of circulating CCR2+ blood monocytes.

[0200] It is also known that CCR2+ and CCR2- macrophages from human patients with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM), which uniformly express CD14, and CCR2+ macrophages represent an inflammatory population whose abundance is associated with left ventricular (LV) systolic dysfunction and adverse remodeling (Bajpai et al., Nat Med. 2018;24(8):1234-1245).

[0201] Based on this knowledge and the results disclosed in Examples 1 and 2, the inventors determined that Dsg2 mut / mutThey hypothesized that the mouse hearts would also contain a population of proinflammatory macrophages that co-express CCR2 and CD14. To test this hypothesis, they performed a 12-week-Dsg2 study following the method described by Chelko, SP et al. (Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy. bioRxiv Prepr. Serv. Biol. (2023) doi:10.1101 / 2023.07.12.548682). mut / mut Single-cell RNA sequencing (scRNA-seq) analysis of cardiac tissue from mice was performed. This analysis identified seven distinct stromal and immune cell types (Figure 10A), including fibroblasts, endothelial cells, B cells, monocytes / macrophages, neutrophils, NK cells, and T cells. Within the monocyte / macrophage cluster, a significant macrophage subpopulation was identified that co-expressed CCR2 (Figure 10B) and CD14 (Figure 10C). These results support the role of Dsg2 in the immune system. mut / mut Mice were transfected with ACM Dsg2 mut / mut These results show that the model contains pro-inflammatory CCR2+CD14+ monocytes and macrophages, which may be relevant to the development of cardiomyopathy disease.

[0202] Taken together with the finding that proinflammatory CCR2+CD14+ macrophages are also present in other cardiomyopathies, including DCM and ICM, the data presented herein indicate that CCR2+CD14+ cardiac macrophages may be involved in the development of cardiomyopathies in general, and that targeting these macrophages with anti-CD14 antagonists is expected to be beneficial in mitigating or inhibiting the development of any one or more of the following impaired cardiac function, including reduced left ventricular ejection fraction, left ventricular hypertrophy, enhanced myocardial fibrosis, adverse cardiac remodeling, right ventricular dysfunction, abnormal cardiac geometry (e.g., increased right ventricular fractional area change), increased end-diastolic volume, increased frequency of ventricular premature contractions, and increased left ventricular muscle mass, reduced ventricular function, and reduced atrial function, in subjects with cardiomyopathies or at high risk of developing cardiomyopathies. Example 4 Arrhythmogenic cardiomyopathy DSG2 MUT / MUT In mouse models 68 PET imaging of GA-DOTA tetraazacyclododecanetetraacetic acid-ECL1I extracellular loop 1 inversoy imaging

[0203] CC chemokine receptor type 1 (CCR2) is specifically expressed in inflammatory populations of monocytes and macrophages, which contribute to the development and progression of post-traumatic heart failure and cardiac dysfunction. We demonstrated that treatment with big53LALA PG anti-CD14 mAb reduced Dsg2 mut / mut Disclosed herein is the preservation of cardiac function, reduction of fibrosis, and reduction of anterior ventricular contractility in mice. Left untreated, these mice develop pathology consistent with arrhythmogenic cardiomyopathy (ACM) patients by 8 weeks of age. Furthermore, using single-cell RNA-Seq technology, we identified that treatment with anti-CD14 specifically altered the gene expression profile of CCR2+ macrophages in these mice, and we inferred that this mechanism of action is relevant to the therapeutic effects observed in these mice.

[0204] In this study, peptide-based imaging probes 68 Ga-DOTA tetraazacyclododecane tetraacetic acid-ECL1i extracellular loop 1 inverso ( 68 We evaluated the anti-CD14 antibody (Ga-DOTA-ECL1i), which specifically recognizes CCR2+ monocytes and macrophages, known to contribute to fibrosis and adverse remodeling in cardiac and pulmonary injury (Lavine et al., Nat. Cardiovasc Res. https: / / doi.org / 10.1038 / s44161-023-00335-6; Liu et al., Radiology 2017;283(3):758-768). The purpose of the study was to investigate whether treatment with anti-CD14 reduced CCR2+ signatures in control animals. 68We utilized the Ga-DOTA-ECL1i probe to non-invasively detect cardiac inflammation in a mouse model of ACM and further demonstrate the proposed mechanism of action by which CD14 modulates the activity and recruitment of CCR2+ macrophages in the hearts of ACM mice. Materials and Methods Dosage of active ingredients

[0205] Dsg2 mut / mut Mice and wild-type C57 black mice were treated weekly for 4 weeks starting at 8 weeks of age with either big53 LALA PG anti-CD14 mAb (5 mg / kg) or IgG2A LALAPG isotype control (5 mg / kg). Imaging

[0206] Dynamic PET image acquisition (0–60 min) and corresponding computed tomography (CT) images were 68 Immediately after tail vein injection of Ga-DOTA-ECL1i (3.7 MBq per mouse), images were acquired using a cross-calibrated scanner (Inveon microPET / CT [Siemens, Malvern, PA] or Focus 220 PET [Concorde Microsystems, Knoxville, Tenn]). Organ uptake was calculated from PET images as the percentage injected dose (% ID) per gram of tissue within a three-dimensional region of interest using software (Inveon Research Workplace, Siemens) without correction for partial volume effects. Statistical methods:

[0207] Data were analyzed using software (Prism, version 6.07; GraphPad, La Jolla, Calif.). Multiple methods were compared using one-way or two-way analysis of variance with Tukey's test. P < .05 indicated statistical significance. result

[0208] of hearts from wild-type mice treated with either anti-CD14 or isotype control. 68 Ga-DOTA-ECL1i uptake was comparable (Figures 11A and 11B). In comparison, uptake of the PET probe was significantly higher in Dsg2 cells treated with the IgG2A LALAPG isotype control. mut / mut The uptake was much higher in anti-CD14 treated animals (Fig. 11B), and this was reduced in anti-CD14 treated animals to levels comparable to wild-type mice (Fig. 11D). The difference in uptake was demonstrated by calculation of the percentage injected dose per gram of cardiac tissue, and the difference in uptake between untreated and treated Dsg2 mice was significant. mut / mut Statistical significance (p<0.05) was shown between the mice (Fig. 12). conclusion

[0209] 68 Dsg2 injected with Ga-DOTA-ECL1i PET probe mut / mut Imaging of mice confirmed that CCR2+ macrophages, established by previous studies as uniformly expressing CD14, were localized in the hearts of ACM mice at 14 weeks, although it should be noted that disease pathology in these mice was clearly established by 8 weeks of age. Furthermore, treatment of mice with anti-CD14 antibody significantly (p<0.05) reduced the CCR2+ signature in diseased mice. This study noted a significant reduction in CCR2+CD14+ macrophages in the hearts of treated ACM animals, which was accompanied by a restoration of left ventricular ejection fraction (%LVEF) to levels seen in wild-type animals (Figure 2); an inhibition of right ventricular dysfunction by normalizing right ventricular fractional area change (%RVFAC) (Figure 3); a reduction in ectopic beats by reducing the frequency of premature ventricular contractions (PVCs) (Figure 4); a restoration of left ventricular mass (LVM) to levels seen in wild-type animals, associated with a reduction or minimization of hypertrophic remodeling (Figure 5); and a reduction in myocardial fibrosis, which in turn attenuates cardiomyopathy (Figure 6). Example 5 The myocardium of human cardiac sarcoidosis patients contains CCR2+ monocytes and macrophages

[0210] To assess whether the myocardium of human cardiac sarcoidosis patients also contains proinflammatory CCR2+ monocytes and macrophages, immunostaining was performed on LV tissue from patients with cardiac sarcoidosis (CS). Double immunostaining for CD68 (a pan-macrophage marker) and CCR2 (Fig. 13A) revealed that CCR2+ monocytes and macrophages were present within the periphery of granulomas surrounding multinucleated giant cells, and that the abundance of CCR2+ cells correlated with markers of disease activity: in particular, macrophage proliferation and pS6 kinase staining (a reporter of mTOR activation).

[0211] The presence of proinflammatory CCR2+ monocytes and macrophages was further investigated by PET imaging of myocardial tissue obtained from patients with active CS, who exhibited palpitations and advanced atrioventricular (AV) conduction block. 18 F-FDG and 68 Patients underwent serial PET imaging of Ga-DOTA-ECL1i to assess the uptake of these radiotracers by the myocardium. 18 F-FDG is routinely used to assess myocardial viability and to detect infarct areas, including in CS and other inflammatory cardiomyopathies (Khalaf et al., Methodist Debakey Cardiovasc J. 2020;16(2):122-129). 68 Because Ga-DOTA-ECL1i contains a seven amino acid peptide that allosterically binds CCR2, uptake of this radiotracer by myocardial tissue can be used to image CCR2+ monocyte and macrophage infiltration into the heart. 68 Ga-DOTA-ECL1i specifically binds human heart failure specimens with signal intensity related to the abundance of CCR2+ macrophages (Heo et al., J Nucl Med. 2021;62(1):111-114).

[0212] PET imaging results of the CS patient (Figure 13B) revealed that FDG uptake was present in the apical portion of the LV, indicating the presence of infarction, and CCR2 uptake was present in the medial, septal, and basolateral walls of the apical portion of the LV, as well as in the parapeduncular lymph nodes, indicating the development and / or progression of cardiomyopathic disease.

[0213] Having established that proinflammatory cardiac CCR2+ macrophages from patients with cardiomyopathy uniformly express CD14, the inventors propose in the context of the present disclosure that proinflammatory cardiac CCR2+CD14+ macrophages are also present in patients with CS, and that targeting these macrophages with anti-CD14 antagonists is expected to be beneficial in treating or inhibiting the development of CS and associated clinical parameters (e.g., reduced left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, adverse cardiac remodeling, right ventricular dysfunction, abnormal cardiac geometry (e.g., increased right ventricular fractional area change), increased end-diastolic volume, frequent premature ventricular contractions, and increased left ventricular muscle mass).

[0214] The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

[0215] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.

[0216] Throughout this specification, the objective has been to describe preferred embodiments of the present disclosure without limiting the disclosure to any one embodiment or particular collection of features. Accordingly, those skilled in the art will appreciate in light of this disclosure that various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present disclosure. All such modifications and changes are intended to be included within the scope of the appended claims.

Claims

1. A method for treating or alleviating at least one symptom of cardiomyopathy in a subject, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

2. 10. The method of claim 1, wherein the at least one symptom is selected from ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, lightheadedness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolization, fainting, angina, exercise intolerance, orthopnea, heart failure, and sudden cardiac death (SCD).

3. The method of claim 1 or claim 2, wherein administration of the CD14 antagonist antigen binding molecule improves one or more clinical parameters of the subject.

4. 4. The method of claim 3, wherein the one or more clinical parameters are selected from a reduced left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, adverse cardiac remodeling, right ventricular dysfunction, abnormal cardiac geometry (e.g., increased right ventricular fractional area change), increased end-diastolic volume, frequent premature ventricular contractions, and increased left ventricular muscle mass.

5. A method for alleviating or inhibiting the occurrence of adverse cardiac remodeling in a subject suffering from cardiomyopathy, the method comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen binding molecule to the subject.

6. A method for improving cardiac function in a subject suffering from cardiomyopathy, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

7. 7. The method of claim 6, wherein the improvement in cardiac function comprises improvement in left ventricular function, improvement in fractional shortening, improvement in ejection fraction, reduction in end-diastolic volume, reduction in left ventricular muscle mass, reduction in arrhythmia, reduction in frequency of heart murmurs, reduction in heart rate, normalization of cardiac geometry, or a combination thereof.

8. A method for improving ventricular function in a subject suffering from cardiomyopathy, comprising, consisting of, or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.

9. A method for improving atrial function in a subject suffering from cardiomyopathy, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

10. The method according to any one of claims 1 to 9, wherein the cardiomyopathy is a primary cardiomyopathy or a secondary cardiomyopathy.

11. 11. The method of claim 10, wherein the primary cardiomyopathies are selected from hereditary cardiomyopathies (e.g., hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction, conduction disorders, channelopathies (e.g., long QT syndrome), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and idiopathic ventricular fibrillation), mixed (hereditary and non-hereditary) cardiomyopathies (e.g., dilated cardiomyopathy and restrictive cardiomyopathy), and acquired cardiomyopathies (e.g., myocarditis, such as viral myocarditis, and other inflammatory cardiomyopathies, such as Kawasaki disease and Chagas disease, stress-induced (Tako-Tsubo) cardiomyopathy, and obstetric cardiomyopathy).

12. The secondary cardiomyopathies include hereditary cardiomyopathies, illustrative examples of which include hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction, conduction disorders, ion channelopathies (e.g., long QT syndrome), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and idiopathic ventricular fibrillation; mixed (hereditary and non-hereditary) cardiomyopathies, non-limiting examples of which include dilated cardiomyopathy and restrictive cardiomyopathy; and myocarditis (e.g., viral myocarditis) and other inflammatory cardiomyopathies (e.g., Kawasaki disease and Chagas disease), stress-induced (Tako- 11. The method of claim 10, wherein the secondary cardiomyopathies are selected from acquired cardiomyopathies such as idiopathic cardiomyopathies (such as idiopathic cardiomyopathies), idiopathic cardiomyopathies (such as idiopathic cardiomyopathies), and idiopathic cardiomyopathies (such as idiopathic cardiomyopathies), including idiopathic cardiomyopathies (such as idiopathic cardiomyopathies), ... Toxicity-related cardiomyopathies, such as those resulting from exposure to drugs such as steroids, steroid drugs, and steroid drugs, illustrative examples of which include chemotherapy-induced cardiomyopathies (e.g., cardiomyopathies associated with exposure to anthracyclines such as doxorubicin (adriamycin) and daunorubicin; cyclophosphamide; and radiation) and alcoholic cardiomyopathies; endomyocardial cardiomyopathies, including endocardial fibrosis and idiopathic hypereosinophilic syndrome (Leffler's endocarditis); granulomatous cardiomyopathies, such as cardiac sarcoidosis; diabetes mellitus, hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma, and steroid drugs. endocrine cardiomyopathies, including gigantism; cardiac and facial cardiomyopathies, such as Noonan syndrome and multiple lentigines; neuromuscular cardiomyopathies, which may be associated with the accumulation of abnormal substances within muscle cells, non-limiting examples of which include Friedreich's ataxia, Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonic dystrophy, neurofibromatosis, and tuberous sclerosis; nutritional deficiency cardiomyopathies, including cardiomyopathies associated with beriberi (thiamine), pellagra, scurvy, selenium, carnitine, or kwashiorkor;autoimmune or collagen-mediated cardiomyopathies, such as systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, scleroderma, and polyarteritis nodosa; and electrolyte imbalance cardiomyopathies.

13. The method of any one of claims 1 to 12, wherein the cardiomyopathy is ACM.

14. The method according to any one of claims 1 to 12, wherein the cardiomyopathy is non-ACM cardiomyopathy.

15. The method according to any one of claims 1 to 12 and 14, wherein the cardiomyopathy is cardiac sarcoidosis.

16. A method for treating or alleviating at least one symptom of ACM in a subject, comprising, consisting of, or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.

17. A method for reducing the number of premature ventricular contractions (PVCs) in a subject, the method comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

18. A method for treating or alleviating symptoms of atrial fibrillation in a subject, comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen binding molecule to a subject suffering from or at risk of developing atrial fibrillation.

19. A method for reducing the number of premature atrial contractions (PACs) in a subject, the method comprising, consisting of, or consisting essentially of administering a CD14 antagonist antigen-binding molecule to the subject.

20. 20. The method of any one of claims 1 to 19, further comprising co-administering at least one adjunctive therapeutic agent or intervention for treating or inhibiting the development of cardiomyopathy with the CD14 antagonist antigen-binding molecule.

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