Drugs and methods for the treatment of muscle diseases

Abstract

This disclosure relates, in general terms, to methods and agents for treating arrhythmogenic cardiomyopathy (ACM). More specifically, this disclosure relates to the use of CD14 antagonist antigen-binding molecules for treating ACM, including mitigation or inhibition of the development of undesirable cardiac remodeling and improvement of cardiac function, including improvement of ventricular and atrial function, in patients with ACM.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 417,305, entitled “Agents and methods for treating myopathies,” filed on 18 October 2022, and to U.S. Provisional Patent Application No. 63 / 464,052, entitled “Agents and methods for treating myopathies,” filed on 4 May 2023, the contents of which are incorporated herein by reference in their entirety. field

[0002] This disclosure relates, in general terms, to methods and agents for treating arrhythmogenic cardiomyopathy (ACM). More specifically, this disclosure relates to the use of CD14 antagonist antigen-binding molecules for treating ACM, including mitigation or inhibition of the development of undesirable cardiac remodeling and improvement of cardiac function, including improvement of ventricular and atrial function in patients with ACM. [Background technology]

[0003] background Cardiovascular diseases, including hypertension, coronary artery disease, and cardiomyopathy, can lead to heart failure, which is linked to 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 60 years of age. Approximately 600,000 people die from myocardial infarction each year in Europe, and, more importantly, it is estimated that more than 15 million people worldwide suffer from heart failure, making it one of the leading causes of death. This number is trending upward as a result of the aging of the global population. Although conventional pharmacological treatment strategies (e.g., beta-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors) have shown effectiveness in extending the lifespan of heart failure patients, the prognosis for those affected remains poor, and new concepts are still needed.

[0004] Cardiomyopathy constitutes a hybrid group of myocardial diseases associated with mechanical and / or electrical dysfunction, leading to cardiac dysfunction with heart failure, arrhythmias, and sudden death. Typically, these diseases manifest as (though not always) inadequate ventricular hypertrophy or dilation, as well as decreased systolic and / or diastolic function. Compared to the acute phase of myocardial infarction, in which a large number of cardiomyocytes rapidly die due to ischemia and an acute inflammatory response results, cardiomyopathy generally does not produce 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 cardiomyopathy and secondary cardiomyopathy. Primary cardiomyopathy (genetic, non-genetic, and acquired) is limited to the myocardium alone or primarily and includes dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic cardiomyopathy, and unclassifiable cardiomyopathy. Secondary cardiomyopathy arises from underlying conditions affecting multiple areas of the body and includes nutritional deficiencies, metabolic disorders (hyperthyroidism, acromegaly), infiltrative processes (neoplasms, amyloidosis), and inflammatory processes (toxins, immune responses, infectious agents).

[0006] Current drug therapies available for managing cardiomyopathy include vasodilators to lower blood pressure and reduce the workload on the heart, diuretics to reduce fluid overload, inhibitors and blockers of the body's neurohormonal response (e.g., ACE inhibitors and β-adrenergic blockers), antiarrhythmics, calcium channel blockers, anticoagulants, anti-inflammatory drugs such as corticosteroids and other medications. While such drug therapies are effective in the short term, they are often not suitable for long-term use due to side effects. Various surgical procedures, such as heart transplantation, have also been proposed for patients with hypertrophic cardiomyopathy who develop refractory heart failure and / or refractory arrhythmias. Alternatively, implantable medical devices such as ventricular assist devices (VADs) may be implanted in the chest to enhance the heart's pumping action, or intra-aortic balloon pumps (IABPs) may be used to maintain cardiac function for short periods, typically less than a month. While each of these approaches is known to be beneficial to the patient to some extent, each has drawbacks that limit their overall effectiveness. For example, drug therapy often comes with undesirable side effects, and combination therapy regimens contribute to low patient compliance. Furthermore, both drug therapy and surgical approaches are very expensive, increasing healthcare costs associated with heart failure. Despite ongoing research and development regarding treatments for cardiomyopathy, there is still a great need for improved and alternative treatments. [Overview of the project]

[0007] overview This disclosure is partly based on the unexpected finding that targeting differentiation antigen group 14 (CD14) by administration of CD14 antagonist antibodies can significantly inhibit the development of ventricular dysfunction, cardiac remodeling, and fibrosis in a mouse model of ACM. In particular, as shown in Figure 2, administration of CD14 antagonist antibodies to ACM animals at the onset of the disease restored the left ventricular ejection fraction (%LVEF) to levels seen in wild-type animals; as shown in Figure 3, inhibited right ventricular dysfunction by normalizing the percentage change in right ventricular area (%RVFAC); as shown in Figure 4, reduced ectopic heartbeats by reducing the frequency of ventricular premature contractions (PVCs); as shown in Figure 5, restored left ventricular muscle mass (LVM) to levels seen in wild-type animals with a reduction or minimization of hypertrophic remodeling; and as shown in Figure 6, mitigated myocardial fibrosis. As a result, these factors mitigated cardiomyopathy. Administration of CD14 antagonist antibodies to ACM-affected animals resulted in a further decrease in %LVEF, as shown in Figures 7 and 8, and significantly reduced cardiomyopathy, as shown in Figure 9. Assuming that CD14 is expressed not only in pro-inflammatory M1 macrophages but also in anti-inflammatory M2 macrophages involved in healing and tissue repair in cardiomyopathy, these findings are quite surprising, as targeting M2 macrophages with anti-CD14 antagonist antibodies would be expected to interfere with tissue remodeling and repair, which would likely lead to disease non-treatment or exacerbation.

[0008] Based on these findings, we propose that CD14 antagonist antigen-binding molecules are useful, for example, to treat or alleviate at least one symptom of ACM, to treat or inhibit the development of ACM, to alleviate or inhibit the development of undesirable cardiac remodeling in ACM, to improve cardiac function in ACM, to improve ventricular function in ACM, to improve atrial function in ACM, to reduce the number of ventricular premature contractions (PVCs) in ACM, to treat or alleviate at least one symptom of atrial fibrillation in ACM, and / or to reduce the number of atrial premature contractions (PACs) in ACM, as described below.

[0009] Accordingly, in one embodiment, the present disclosure provides methods for treating or alleviating at least one symptom of ACM in a subject. These methods generally involve, consist of, or essentially consist 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, dizziness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibroadipose infiltration, embolus formation, fainting, angina, exercise intolerance, orthopnea, heart failure, and acute cardiac death (SCD). Preferably, administration of a CD14 antagonist antigen-binding molecule improves and helps explain one or more clinical parameters in a patient, including, for example, decreased left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, undesirable cardiac remodeling, right ventricular dysfunction, abnormal cardiac morphology (e.g., increased right ventricular area change), increased end-diastolic volume, frequent ventricular premature contractions, and increased left ventricular muscle mass.

[0010] Methods for mitigating or inhibiting the development of undesirable cardiac remodeling in subjects with ACM are disclosed herein in another embodiment. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to a subject.

[0011] Further aspects of this disclosure provide methods for improving cardiac function in subjects suffering from ACM. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to a subject. Improvement in cardiac function may include one or more of the following: improvement in left ventricular function, improvement in diameter shortening, improvement in ejection fraction, reduction in end-diastolic volume, reduction in left ventricular muscle mass, reduction in arrhythmias, reduction in murmur frequency, reduction in heart rate, normalization of cardiac morphology, or a combination thereof.

[0012] Methods for improving ventricular function in subjects with ACM are disclosed herein in yet another embodiment. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to a subject. Administration of a CD14 antagonist antigen-binding molecule appropriately improves a measure or metric of ventricular function in the subject, typical examples of which include ventricular strain, systolic function, or diastolic function. In some embodiments, ventricular function may be measured by echocardiography, Holter monitoring, computed tomography (CT), or magnetic resonance imaging (MRI).

[0013] In a further embodiment, methods for improving atrial function in subjects suffering from ACM are disclosed herein. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to the subject. Administration of a CD14 antagonist antigen-binding molecule appropriately improves a measured or metric of atrial function in the subject, typical 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, portable electrocardiogram (Holter) monitoring, or cardiac CT.

[0014] Methods for reducing the number of ventricular premature contractions (PVCs) in subjects with ACM are disclosed herein in yet another embodiment. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to the subject.

[0015] Another aspect of this disclosure provides methods for treating or alleviating at least one symptom of atrial fibrillation in a subject suffering from ACM. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to a subject. The (one or more) symptoms of atrial fibrillation may be tachycardia, arrhythmia, chest pain, dizziness, syncope, dyspnea, heart failure, stroke, or death. In certain embodiments, the subject suffers from atrial fibrillation.

[0016] Further aspects of this disclosure provide methods for reducing the frequency of atrial premature contractions in subjects with ACM. These methods generally involve, consist of, or essentially consist of administering a CD14 antagonist antigen-binding molecule to a subject.

[0017] In any of the embodiments and models disclosed herein, the subject may have an implantable cardioverter-defibrillator (ICD). In an example useful for illustrating this type, administration of a CD14 antagonist antigen-binding molecule appropriately reduces the number of electric shocks delivered to the subject by the ICD.

[0018] In any of the embodiments and models disclosed herein, the antigen-binding molecule is selected from the following:

[0019] (i) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3). Antibodies containing;

[0020] (ii) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3), and b) An antibody VH domain or an antigen-binding fragment thereof that contains 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;

[0021] (iii) The following: a) An antibody VL domain or an antigen-binding fragment thereof that contains 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 an antigen-binding fragment thereof that contains 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;

[0022] (iv) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3). Antibodies containing;

[0023] (v) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence QNVGSNVDWY [SEQ ID NO: 34] (F1024-1-3 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence KASNRY [SEQ ID NO: 35] (F1024-1-3 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence MQSNTNPPW [SEQ ID NO: 36] (F1024-1-3 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence DYAMN [SEQ ID NO: 37] (F1024-1-3 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence WINTQTGKPTYADDF [SEQ ID NO: 38] (F1024-1-3 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence TYFCTRSTFYYSSYIY [SEQ ID NO: 39] (F1024-1-3 H-CDR3) Antibodies containing;

[0024] (vi) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3). Antibodies containing;

[0025] (vii) The following: a) an antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSYGNSFMH [SEQ ID NO: 45] (r18D11 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence LASNLES [SEQ ID NO: 46] (r18D11 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQNNGDPYT [SEQ ID NO: 47] (r18D11 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence TYALN [SEQ ID NO: 48] (r18D11 H-CDR1); H-CDR2 contains, essentially consists of, or includes the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (r18D11 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence PQSGTSFAY [SEQ ID NO: 50] (r18D11 H-CDR3). Antibodies containing; and

[0026] (viii) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3). Antibodies containing this substance.

[0027] In certain embodiments, the antigen-binding molecule is selected from the following:

[0028] (i) The following: array: VL domains containing, consisting of, or essentially consisting of QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIYRAANLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSYEDPWTFGGGTKLGNQ [Sequence ID 1] (3C10 VL); and array: VH domains containing, consisting of, or essentially consisting of LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTTYYPDNVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYYDYHYWGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH), Antibodies containing;

[0029] (ii) The following: array: VL domains containing, consisting of, or essentially consisting of QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDPTTFGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); and array: VH domains containing, consisting of, or essentially consisting of LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH), Antibodies containing;

[0030] (iii) The following: array: VL domains containing, consisting of, or essentially consisting of QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQRGDTLPWTFGGGTKLEIK [Sequence ID 5] (18E12 VL); and array: VH domains containing, consisting of, or essentially consisting of LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVIWTSGGTNYNSAFMSRLSITKDNSESQVFLKMNGLQTDDTGIYYCVRGDGNFYLYNFDYWGQGTTLTVSS [Sequence ID 6] (18E12 VH), Antibodies containing;

[0031] (iv) The following: array: VL domains containing, consisting of, or essentially consisting of YIVMTQTPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); and array: VH domains containing, consisting of, or essentially consisting of EVKLLESGGGLVQPSQTLSISCKASGYTFTDYAMNWVKQAPGDGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [Sequence ID 58] (F1024-1-3 VH), Antibodies containing;

[0032] (v) The following: array: VL domains containing, consisting of, or essentially consisting of DIVMTQSPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 59] (F1024 VL); and array: QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMNWVKQAPGNGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [Sequence ID 60] (F1024 VH) contains, consists of, or essentially consists of VH domains, Antibodies containing;

[0033] (vi) The following: array: VL domains containing, consisting of, or essentially consisting of NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDVATYYCQQNNGDPYTFGGGTKLEIIR [SEQ ID NO: 61] (r18D11 VL); and array: VH domains containing, consisting of, or essentially consisting of EVQLVESGGGLMQPKGSLKLSCAASGFTFKTYALNWVRQAPGTGLEWVARIRSKSNNYTTYYADSVKDRFTISRDDSQNMLYLQMNNLKTEDTAMYYCVRPQSGTSFAYWGQGTLVTVSA [SEQ ID NO: 62] (r18D11 VH), Antibodies containing; and

[0034] (vii) The following: array: VL domains containing, consisting of, or essentially consisting of DIVMTQSQKFMSTSVGDRVSVTCKASQYVGTNVAWYQQKPGQSPKALIQSASYRCSGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYNTYVTFGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); and array: QVRLQQPGAELVRPGASVKLSCKASGYTFTTYWMNWVKQRPEDGLEWIGRIDPYDSETHYNQNFKDKAILTVDKSSSTAYMQLSSLTYEDSAVYYCTRKEGRQWGAYFDYWGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH) contains, consists of, or essentially consists of VH domains, Antibodies containing this substance.

[0035] The antigen-binding molecule may be humanized or a chimeric molecule.

[0036] Typical examples of antigen-binding molecules include light chains and heavy chains, where: The light chain has the following amino acid sequence: METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 25] contains, consists of, or essentially consists of; and the heavy chain has the amino acid sequence: MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCV RGLRFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [Sequence ID 26] includes, consists of, or essentially consists of.

[0037] In a specific embodiment, the antigen-binding molecule is an IC14 antibody.

[0038] In any of the embodiments and models disclosed herein, the subject is preferably a mammal, typical examples of which include humans, canids, felines, horses, cattle, sheep, and pigs. In a preferred embodiment, the subject is a human.

[0039] In any of the embodiments and models disclosed herein, the CD14 antagonist antigen-binding molecule may be administered systemically to the subject or topically to the heart (e.g., the left ventricle).

[0040] In any of the embodiments and aspects disclosed herein, the method appropriately includes administering an effective amount of a CD14 antagonist antigen-binding molecule.

[0041] In any of the embodiments and examples disclosed herein, the CD14 antagonist antigen-binding molecule may be administered in daily doses of approximately 0.1 mg / kg to 50 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 0.2 mg / kg to 40 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 0.5 mg / kg to 40 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 1 mg / kg to 30 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 2 mg / kg to 20 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 4 mg / kg to 15 mg / kg (and all integer mg / kg units with one decimal place in between), or approximately 5 mg / kg to 10 mg / kg (and all integer mg / kg units with one decimal place in between). The daily dose is appropriately administered as a single or double dose.

[0042] In any of the embodiments and examples disclosed herein, the CD14 antagonist antigen-binding molecule may be administered in weekly doses of approximately 1 mg / kg to 30 mg / kg (and all integer mg / kg units in between), approximately 2 mg / kg to 20 mg / kg (and all integer mg / kg units in between), approximately 4 mg / kg to 15 mg / kg (and all integer mg / kg units in between), or approximately 5 mg / kg to 10 mg / kg (and all integer mg / kg units in between).

[0043] In any of the embodiments and models disclosed herein, the CD14 antagonist antigen-binding molecule is administered to a subject over a period of approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 1 year, approximately 14 months, approximately 16 months, approximately 18 months, approximately 20 months, approximately 22 months, or approximately 2 years.

[0044] In certain aspects, the subjects are those who have never undergone cardiopulmonary bypass surgery.

[0045] In certain embodiments, the subjects are those who are not patients with acute myocardial infarction.

[0046] In any of the embodiments and models disclosed herein, the method may further include administering one or more adjunct ACM therapeutic agents in parallel, and examples useful for describing such adjunct ACM therapeutic agents 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), propane Examples include phenone (Rythmol), quinidine, tonocarid, digoxin, diuretics (e.g., Lasix; or, for example, levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, rapinirole, piribedil, cabergoline, apomorphine, rislid) including Parkinson's disease medications), 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, thiadiazolidinedione, and nonsteroidal anti-inflammatory drugs. In some of the same and other embodiments, the method may further include performing a surgical procedure on a subject, wherein the surgical procedure is suitable for treating ACM. Surgical procedures may include pacemaker implantation, implantation of an implantable cardioverter-defibrillator (ICD), cardiac catheterization, vascular regeneration, coronary artery bypass surgery, and / or heart transplantation. The surgical procedure may be performed, optionally, in conjunction with an adjunct ACM treatment agent, before, concurrently with, or after the administration of the CD14 antagonist antigen-binding molecule.

[0047] Further aspects of this disclosure provide a CD14 antagonist antigen-binding molecule for use in treating or alleviating at least one symptom of ACM, treating or inhibiting the development of ACM, alleviating or inhibiting the development of undesirable cardiac remodeling in ACM, improving cardiac function in ACM, improving ventricular function in ACM, improving atrial function in ACM, reducing the number of ventricular premature contractions (PVCs) in ACM, treating or alleviating at least one symptom of atrial fibrillation in ACM, or reducing the number of atrial premature contractions (PACs) in ACM. In some embodiments, the CD14 antagonist antigen-binding molecule is used in combination with one or more adjunct ACM therapeutic agents.

[0048] In yet another embodiment, the use of a CD14 antagonist antigen-binding molecule in the manufacture of a drug for treating or alleviating at least one symptom of ACM, treating or inhibiting the onset of ACM, alleviating or inhibiting the onset of undesirable cardiac remodeling in ACM, improving cardiac function in ACM, improving ventricular function in ACM, improving atrial function in ACM, reducing the number of ventricular premature contractions (PVCs) in ACM, treating or alleviating at least one symptom of atrial fibrillation in ACM, or reducing the number of atrial premature contractions (PACs) in ACM is provided. In some embodiments, the CD14 antagonist antigen-binding molecule is used in combination with one or more adjunct ACM therapeutic agents. [Brief explanation of the drawing]

[0049] [Figure 1] Figure 1 is a schematic diagram showing the progression of cardiomyopathy in the Dsg2mut / mut mouse model.

[0050] [Figure 2] Figure 2 is a graph showing that anti-CD14 treatment over 8 weeks in 8-week-old Dsg2mut / mut mice restores %LVEF to levels seen in wild-type animals.

[0051] [Figure 3] Figure 3 is a graph showing that anti-CD14 treatment for 8 weeks in 8-week-old Dsg2mut / mut mice prevents right ventricular dysfunction by normalizing %RVFAC.

[0052] [Figure 4] Figure 4 is a graph showing that anti-CD14 treatment over 8 weeks in 8-week-old Dsg2mut / mut mice reduces ectopic heartbeats by reducing the frequency of PVCs, as measured by ECG.

[0053] [Figure 5] Figure 5 is a graph showing that anti-CD14 treatment for 8 weeks in 8-week-old Dsg2mut / mut mice restored LVM to levels seen in wild-type animals, resulting in minimized hypertrophic remodeling.

[0054] [Figure 6] Figure 6 is a graph showing that anti-CD14 treatment over 8 weeks in 8-week-old Dsg2mut / mut mice reduces cardiomyopathy as measured by histological analysis of fibrosis.

[0055] [Figure 7] Figure 7 is a graph showing that 8 weeks of anti-CD14 treatment in 16-week-old Dsg2mut / mut mice significantly improved %LVEF compared to untreated animals.

[0056] [Figure 8] Figure 8 is a graph showing that 8 weeks of anti-CD14 treatment in 16-week-old Dsg2mut / mut mice significantly reduced the further decline in %LVEF compared to untreated animals.

[0057] [Figure 9]Figure 9 is a graph showing that 8 weeks of anti-CD14 treatment in 16-week-old Dsg2mut / mut mice reduces cardiomyopathy as measured by histological analysis of fibrosis.

[0058] Some drawings and documents include color illustrations or colored versions. Color illustrations are available upon request from the applicant or the relevant patent office. A fee may be charged for obtaining them from the patent office. [Modes for carrying out the invention]

[0059] Detailed description of the present invention 1. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. Any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this disclosure, but preferred methods and materials are described. For the purposes of this disclosure, the following terms are defined below.

[0060] The articles “a” and “an” are used herein to refer to one or more (i.e., at least one) grammatical objects of the articles. For example, “element” means one or more elements.

[0061] Where used herein, the term “about” refers to the normal range of error for each value, which is readily apparent to those skilled in the art. References to “about” in relation to a value or parameter herein include (and describe) embodiments directed toward that value or parameter itself. In certain embodiments, the term “about” refers to a value or parameter (e.g., quantity, level, concentration, number, frequency, percentage, dimension, size, volume, weight, or length) that differs from a reference value or parameter by approximately 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%.

[0062] As used herein, “and / or” means any possible combination of one or more of the related listed items, and the absence of any combination as interpreted alternatively (or).

[0063] The terms “activator” and “therapeutic agent” are used interchangeably herein and refer to agents that prevent, reduce or improve (ameliorate) at least one symptom of a disease or disorder.

[0064] The terms “simultaneous administration,” “administering at the same time,” or “simultaneous administration” refer to the administration of a single composition containing two or more drugs, or the administration of each drug as a separate composition, and / or administration delivered simultaneously, concurrently, or sequentially, by separate routes within a sufficient time to ensure that the effective results are equivalent to those obtained if all such drugs were administered as a single composition. “Simultaneous” means that the drugs are administered substantially at the same time, and preferably together in the same formulation. “Concurrently” means that the drugs are administered in close chronological order, for example, one drug being administered before and after another within about 1 minute to about 1 day. Any contemporaneity is useful. However, if not administered simultaneously, the drugs are often administered within about 1 minute to about 8 hours, preferably within about 1 hour to about 4 hours. When administered simultaneously, the drugs are appropriately administered at the same site of target. 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 drugs are administered at intervals of, for example, about one day to several weeks or several months. The drugs may be administered in any order. As used herein, the term "sequentially" means that the drugs are administered consecutively at intervals of, for example, minutes, hours, days or weeks. Where appropriate, the drugs may be administered in regular repeating cycles.

[0065] The term "undesirable cardiac remodeling" refers to a group of molecular, cellular, and interstitial space changes that are evident in the size, shape, and function of the heart. These changes have a negative impact on cardiac function and ultimately lead to heart failure. Typical examples of undesirable cardiac remodeling include hypertrophy, myocardial thinning, myocardial scarring, myocardial atrophy, reduced cardiac function, decreased myocardial contractility, progression of heart failure, and combinations thereof.

[0066] An "antigen-binding molecule" refers to a molecule that has binding affinity to 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. Representative antigen-binding molecules useful for implementing this disclosure include polyclonal and monoclonal antibodies and their fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) antibodies and domain antibodies (e.g., including antibodies from sharks and camelids), as well as antibody-containing fusion proteins and any other modified structures containing antigen-binding / recognition sites of immunoglobulin molecules. Antibodies include antibodies of all classes, e.g., IgG, IgA, or IgM (or their subclasses), and the antibody does not need to belong to any particular class. Depending on the antibody amino acid sequence in the constant region of the antibody's heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further classified into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional arrangements of different classes of immunoglobulins are well known. Antigen-binding molecules also include dimer antibodies and polyvalent forms of antibodies. In one embodiment, the antigen-binding molecule is a chimeric antibody, i.e., one in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody from a particular species or belongs to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to a corresponding sequence in an antibody from another species or belongs to a particular antibody class or subclass, as well as a fragment of such an antibody (see, e.g., US Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-6855).Similarly, humanized antibodies are also considered, and these are generally constructed by transferring complementarity-determining regions (CDRs) derived from the heavy and light chain variable regions of non-human (e.g., rodent, preferably mouse) immunoglobulins into human variable domains. In this way, typical residues of the human antibody are replaced with non-human counterparts within the framework region. The use of antibody components derived from humanized antibodies eliminates potential problems related to the immunogenicity of non-human constant regions. General techniques for cloning non-human, particularly mouse, immunoglobulin variable domains are described, for example, by Orlandi et al. (1989, Proc. Natl. Acad. Sci. USA 86: 3833). Methods for producing humanized monoclonal antibodies are described, for example, by 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. This is described in (1997). Humanized antibodies include "primatized" antibodies, in which the antigen-binding region of the antibody originates from antibodies produced by immunizing macaque monkeys with the target antigen. Humanized antibodies are also considered as antigen-binding molecules.

[0067] The term "antagonist antigen-binding molecule" is used in its broadest sense to include antigen-binding molecules that inhibit or reduce the biological activity of the 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., DAMP or PAMP), or substantially reduce the interaction through tertiary structural changes or downregulation of the receptor. Therefore, CD14 antagonist antigen-binding molecules include antigen-binding molecules that bind to CD14 and, to some extent, block, inhibit, inactivate, suppress, reduce, or reduce (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 adapter-induced IFN-β (TRIF) pathway, or induction of a cellular response to CD14 binding by a CD14 ligand (e.g., DAMP or PAMP) (e.g., production of pro-inflammatory mediators, including pro-inflammatory cytokines). In some examples, the antibody is monospecific and binds only to CD14. In other examples, the antibody is polyspecific (e.g., bispecific) and binds to CD14 and at least one other antigen.

[0068] The term “antibody” as used herein is used in its broadest sense and specifically includes native antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, insofar as they exhibit the desired immunoreactivity. Naturally occurring “antibodies” within this scope include immunoglobulins comprising at least two heavy chains (H) and two light chains (L) 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 contains specific CH domains (e.g., CH1, CH2, and CH3). Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain CL. The VH and VL regions are further subdivided into hypervariable regions called complementarity-determining regions (CDRs) and 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 carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant region of the antibody can mediate the binding of immunoglobulins to various cells of the immune system (e.g., effector cells) and to host tissues or factors including the first component (C1q) of the classical complement system. Antibodies can be any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), subclass, or modified versions thereof (e.g., IgG1 isotype with L234A and L235A double mutations (IgG1-LA)). Antibodies can be any species, chimeric, humanized, or human. In other embodiments, the antibody is a homomeric heavy-chain antibody (e.g., a camelid antibody) that lacks a 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 the antibody modular recognition domain (MRD) fusion would contain a functional binding domain that interacts with the antigen of interest.

[0069] As used herein, “variable domains” (variable domains of the light chain (VL) and variable domains of the heavy chain (VH)) refer to each pair of light and heavy chain domains directly involved in antibody binding to the antigen. The variable light and heavy chain domains have the same general structure, and each domain contains four FRs with a widely conserved sequence linked by three CDRs or “hypervariable regions.” The FRs take on a β-sheet structure, and the CDRs form loops connecting the β-sheet structures. The CDRs of each chain are held in a three-dimensional structure by the FRs and are formed together with the CDRs of other chains, which are antigen-binding sites.

[0070] The term “antigen-binding region,” as used herein, generally refers to the amino acid residues of an antibody involved in antigen binding, including amino acid residues from the CDR. Therefore, “CDR” or “complementarity-determining region” (also called “hypervariable region”) is used interchangeably herein to refer to the amino acid sequences of the light and heavy chains of an antibody that form a three-dimensional loop structure contributing to the formation of the antigen-binding site. Each of the variable regions of the heavy and light chains has three CDRs, referred to as “CDR1,” “CDR2,” and “CDR3,” respectively. The term “CDR set,” as used herein, refers to a group of three CDRs present within a single variable region that binds to an antigen. The exact boundaries of these CDRs are defined differently by different systems. The system described by Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides a clear residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries that define three CDRs. These CDRs are called "Kabat CDRs". Chothia and collaborators (Chothia and Lesk, 1987. J. Mol. Biol. 196: 901-917; Chothia et al., 1989. Nature 342: 877-883) described Kabat We discovered that certain sub-regions within CDRs employ nearly identical peptide backbones. Despite significant diversity at the amino acid sequence level, their three-dimensional structures differ. These regions are named "L1," "L2," and "L3," or "H1," "H2," and "H3," where "L" and "H" represent the light and heavy chain regions, respectively. These regions can be called "Chothia CDRs," as they have boundaries that overlap with Kabat CDRs.Other boundaries defining CDRs that overlap with the Kabat CDR are described by Padlan (1995. FASEB J. 9: 133-139) and MacCallum (1996. J. Mol. Biol. 262(5): 732-745). Further other CDR boundary definitions may not strictly adhere to any of these systems, but nevertheless, they overlap with the Kabat CDR, although they may be shortened or extended in light of predictions or experimental findings that specific residues or groups of residues, or the entire CDR, do not significantly affect antigen binding.

[0071] As used herein, the term “framework region” or “FR” refers to the remaining sequence of the variable region after subtracting the CDR. Thus, the light and heavy chain variable domains of an antibody contain domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the N-terminus to the C-terminus. CDR and FR are typically defined according to the standard definition in Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991) and / or their residues from the “hypervariable loop”.

[0072] 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, that have altered primary amino acid sequences 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 to the antigen. Based on structural similarities, several subtypes of VH and VL are defined, for example, as described in the Kabat database.

[0073] The term "chimeric antibody" refers to an antibody that contains constant region sequences from another species, such as an antibody with heavy chain and light chain variable region sequences from one species, as well as a mouse heavy chain and light chain variable region linked to a human constant region.

[0074] The "humanized" form of a non-human (e.g., rodent) antibody is a chimeric antibody containing a minimal sequence derived from a non-human immunoglobulin. In most cases, the humanized antibody is a human immunoglobulin (recipient antibody), in which residues from the recipient's hypervariable region are replaced with residues from the hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, that possess the desired specificity, affinity, and capability. In some cases, framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Therefore, the FR and CDR of the humanized antibody do not need to precisely correspond to the parent (i.e., donor) sequence, 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, typically, such mutations are not widespread and generally avoid the "key residues" involved in binding to the antigen. 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 parent 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 most frequently occurring amino acids (or nucleotides) in the family of immunoglobulin sequences in question (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, 1987)). Thus, a “consensus immunoglobulin sequence” may include “(one or more) consensus framework regions” and / or “(one or more) consensus CDRs.” In an immunoglobulin family, each position in the consensus sequence is occupied by the most frequently occurring amino acid at that position in that family. If two amino acids are present with equal frequency, both can be included in the consensus sequence.Generally, humanized antibodies contain at least one and typically two substantially all variable domains, where all or substantially all of the hypervariable loop corresponds to that of a non-human immunoglobulin, and all or substantially all of the FR is a human immunoglobulin sequence. Humanized antibodies also sometimes, generally, contain at least a portion of the immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further 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). Humanized antibodies 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. Humanized antibodies may contain sequences from two or more classes or isotypes, and certain constant domains may be selected to optimize desired effector function using techniques known in the art, and as used herein, the term “key residue” refers to a specific residue within a variable region that has a greater influence on the binding specificity and / or affinity of an antibody, in particular a humanized antibody. Key residues include, but are not limited to, one or more of the following: residues adjacent to the CDR, potential glycosylation sites (which may be N- or O-glycosylation sites), rare residues, residues that can interact with the antigen, residues that can interact with the CDR, canonical residues, contact residues between the heavy chain variable region and the light chain variable region, residues in the vernier zone, and residues in the region overlapping between the Chothia definition of the variable heavy chain CDR1 and the Kabat definition of the first heavy chain backbone.

[0075] As used herein, the “vernier” zone refers to a subset of framework residues that can modify the CDR structure and fine-tune its fit to the antigen, as described in Foote and Winter (1992. J. Mol. Biol. 224: 487-499). Vernier zone residues form a layer beneath the CDR and can affect the structure of the CDR and the affinity of the antibody.

[0076] As used herein, the term “canonical” residues refer 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 incorporated herein by reference). According to Chothia et al., key parts of the CDRs of many antibodies have nearly identical peptide backbone confirmations, despite considerable diversity at the amino acid sequence level. Each canonical structure primarily defines a set of peptide backbone twist angles for a sequence of amino acid residues that form a loop.

[0077] 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 of a different species than the antibody from which the FR was obtained or induced. In the context of humanized antibodies, the term “donor antibody” refers to a non-human antibody that provides one or more CDRs.

[0078] 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. According to this embodiment, the acceptor may include at least one, at least two, at least three, at least four, at least five, or at least ten amino acid residues that are not present at one or more specific positions of the human antibody. The acceptor framework region and / or acceptor constant region are derived from, for example, germline antibody genes, mature antibody genes, or functional antibodies (e.g., antibodies well known in the art, antibodies under development, or commercially available antibodies) or obtained from them.

[0079] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies according to this disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or mutations introduced by somatic mutation in vivo), such as CDRs and, in particular, CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been transplanted onto a human framework sequence.

[0080] The terms “heavy chain variable region CDR1” and “H-CDR1” are used interchangeably with 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, the complementarity-determining region ("CDR") is 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).

[0081] Antigen binding can be performed by an "antigen-binding fragment" of an intact antibody. Both terms are used interchangeably here. Examples of binding fragments encompassed within the antibody term "antibody fragment" include: Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab')2 fragments, bivalent fragments containing two Fab fragments linked by disulfide crosslinking at a hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of the antibody; and single-domain antibody (dAb) fragments (Ward et al., 1989. Nature 341:544-546), which consist of a VH domain and an isolated complementary determination region (CDR). In certain embodiments, the antibodies of this disclosure are antigen-binding fragments lacking all or part of the Fc region.

[0082] A "single-stranded variable fragment (scFv)" is a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-stranded 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 they can be linked by an artificial peptide linker using recombination, which allows them to be made into a single protein chain. Such single-stranded antibodies contain one or more antigen-binding sites. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies.

[0083] When used herein, the terms “monoclonal antibody” and the abbreviations “MAb” and “mAb” refer to antibodies obtained from a substantially homogeneous population of antibodies; that is, individual antibodies within the population are identical except for naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific and directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations, which typically contain different antibodies against different determinants (epitopes), each mAb is directed against a single determinant on an antigen. The modifier “monoclonal” should not be interpreted as requiring antibody production by any particular method. Monoclonal antibodies can be produced, for example, by a single clone of antibody-producing cells, including hybridomas. 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 immune capabilities of the parent cell.

[0084] An antibody that "binds" to a target antigen (e.g., CD14) is an antibody that binds to the antigen with sufficient affinity so as not to cross-react significantly with other proteins, making it useful as a therapeutic agent when targeting cells or tissues expressing the antigen. In such embodiments, the degree 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 particular target protein, as measured, for example, by fluorescence-activated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, or radioimmunoprecipitation (RIA). Thus, an antibody that antagonizes CD14 effectively inhibits or reduces the production of pro-inflammatory mediators, including pro-inflammatory cytokines / chemokines. With respect to the binding of an antibody to a target molecule, the terms "specifically binding," "specifically binding," or "specific" to a particular polypeptide or epitope on a particular polypeptide target mean a binding that is measurably different from a nonspecific interaction. Specific binding can be measured by determining the binding of a molecule by comparing it to the binding of a control molecule, which is a similar molecule with a similar structure that does not possess 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 targets. In this case, specific binding is indicated when the binding of the labeled target to the probe is competitively inhibited by the excess of unlabeled targets. The specific region of an antigen to which an antibody binds is typically called an “epitope.” The term “epitope” broadly includes any site on an antigen that is specifically recognized by an antibody or T cell receptor, or that interacts with a molecule. Generally, an epitope is an active surface group of a molecule, such as an amino acid or a carbohydrate or sugar side chain, and can generally have specific three-dimensional structural properties as well as specific charge properties. As will be understood by those skilled in the art, in practice, anything to which an antibody can specifically bind may be an epitope.

[0085] As used herein, “arrhythmia” refers to any of the group of conditions in which there is abnormal electrical activity in the heart. This can cause the heart to beat too fast (tachycardia). Arrhythmias affect the atria and / or ventricles and can occur at any age.

[0086] Throughout this specification, unless contextually required to require a different interpretation, the terms “comprise,” “comprises,” and “comprising” are understood to mean encompassing the described step, element, or group of steps or elements, but not excluding other steps or elements, or groups of steps or elements, or groups of elements. Thus, the use of terms such as “comprise,” “comprises,” and “comprising” indicates that the listed elements are necessary or essential, while other elements are optional and may or may not be present. “Consists of” means including, and is limited to, what follows the phrase “consists of.” Thus, the phrase “consists of” indicates that the listed elements are necessary or essential, and other elements are absent. “Essentially consists of” means including the elements listed after the phrase, and is limited to other elements that do not interfere with or contribute to the activities or actions specified in the disclosure for the listed elements. Thus, the phrase “essentially consists of” may indicate that the listed elements are necessary or essential, while other elements are optional and may or may not be present depending on whether they affect the activities or actions of the listed elements.

[0087] "Effective dose" means the amount of a drug or composition administered to an individual in need of treatment or prevention, either as a single dose or as part of a series, that is effective in preventing the onset of symptoms, checking for such symptoms, and / or treating existing symptoms of the condition, in the context of treating a disease or condition. The effective dose varies depending on the age, health and physical condition of the individual to be treated, whether the symptoms of the disease are evident, the taxonomic group of the individual to be treated, the composition, the assessment of the medical situation, and other relevant factors. The optimal dosing schedule can be calculated from measurements of drug accumulation in the subject's body. The optimal dose may vary depending on the relative potency of individual subjects and can generally be estimated based on EC50 values ​​that have been found to be effective in in vitro and in vivo animal models. Those skilled in the art can easily determine the optimal dose, method of administration, and repetition rate. A relatively wide range of reductions that can be determined through routine trials is expected.

[0088] As used herein, the term “immune cells” refers to cells involved in the innate or adaptive (acquired) immune system. Examples of innate immune cells include, for example, 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. Examples of immune cells that play a role in acquired immunity include, for example, lymphocytes such as T cells and B cells.

[0089] As used herein, the terms “inhibit,” “inhibits,” or “inhibiting” (and their grammatical equivalents) mean, in relation to the occurrence of a condition, disease, disorder, or state, delaying the onset or development of a condition, disease, disorder, or state; mitigating the manifestation of symptoms of a condition, disease, disorder, or state; minimizing the occurrence of a condition, disease, disorder, or state; and / or mitigating symptoms at the time of the onset of a condition, disease, disorder, or state. The terms do not imply the complete elimination of a disease and encompass all types of preventive measures that reduce the occurrence of a condition or delay or slow the onset of a condition, disease, disorder, or state.

[0090] "Isolated" means a material that, in its original state, substantially or essentially does not contain the components that would normally accompany it.

[0091] As used herein, the term "ligand" refers to any molecule that can bind to a receptor.

[0092] As used herein, the term "pro-inflammatory" refers to an effect that promotes inflammation.

[0093] As used herein, the term “pro-inflammatory mediator” refers to molecules and cells that have a pro-inflammatory effect and are typically functionally involved in the signaling pathways and immune responses of the immune system. Such agents include cytokines such as chemokines, interleukins, lymphokines, and tumor necrosis factor, as well as growth factors. In certain embodiments, pro-inflammatory mediators are “pro-inflammatory cytokines.” Typically, pro-inflammatory cytokines include IL-1α, IL-1β, IL-6, and TNF-α, which are primarily involved in the initial response. Other pro-inflammatory 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). Pro-inflammatory mediators act as endogenous pyrogens (IL-1, IL-6, TNF-α), upregulating the synthesis of secondary mediators and pro-inflammatory cytokines by macrophages and mesenchymal cells (including fibroblasts, epithelial cells, and endothelial cells), stimulating the production of acute-phase proteins, or inducing inflammatory cells. In certain embodiments, the term “pro-inflammatory cytokine” refers to one or more of TNF-α, IL-6, IFN-β, IL-1β, and IL-8. In other specific embodiments, the term “pro-inflammatory cytokine” refers to one or more of IL-1β, IL-6, TNF-α, IFN-γ, and IFN-β.

[0094] The terms “subject,” “patient,” and “individual,” as used interchangeably in this specification, refer to any subject, in particular vertebrate subjects, and more specifically, mammalian subjects suffering from ACM (e.g., human, canid, feline, or equine subjects).

[0095] To “treat” a condition, disease, disorder, or state, or to “treat” them, means an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, the amelioration of one or more symptoms or conditions, whether detectable or undetectable, or whether the disease is eliminated; a reduction in the severity of the disease; a stable (i.e., non-worsening) condition (e.g., maintaining the patient in remission); prevention of disease spread; delay or slowing of disease progression; amelioration or reduction of the condition; a reduction in disease recurrence; and remission (whether partial or complete), i.e., causing regression of the condition, disorder, or state, or its clinical or potential symptoms. “Treating” and “treating” can also mean prolonging survival compared to the survival expected if no treatment is received, and include: the benefit to the treated individual being statistically significant, or at least perceptible to the patient or physician. In one embodiment, the treatment method comprises administering an effective amount of a CD14 antagonist antigen-binding molecule to a target, and optionally consisting of a single administration or, instead, a series of administrations.

[0096] The embodiments described herein shall apply mutatis mutandis to each embodiment unless otherwise explicitly stated. 2. CD14 antagonist antigen binding molecule

[0097] This disclosure provides methods, uses, and compositions comprising a CD14 antagonist antigen-binding molecule for, for example, treating or alleviating at least one symptom of ACM, treating or inhibiting the onset of ACM, alleviating or inhibiting the onset of undesirable cardiac remodeling in ACM, improving cardiac function in ACM, improving ventricular function in ACM, improving atrial function in ACM, reducing the number of ventricular premature contractions (PVCs) in ACM, treating or alleviating at least one symptom of atrial fibrillation in ACM, or reducing the number of atrial premature contractions (PACs) in ACM.

[0098] This disclosure intends any CD14 antagonist antigen-binding molecule that binds to CD14, such as human CD14 (e.g., human mCD14 or sCD14), and blocks the binding of a CD14 ligand, preferably DAMP or PAMP, to CD14, and / or binds to CD14, thereby inhibiting or reducing a CD14 antagonist-mediated response, which results in the production of pro-inflammatory mediators, including the production of pro-inflammatory cytokines. Such CD14 antagonist antibodies are well known in the art and any of them can be used in the methods and uses of this disclosure. In some embodiments, the CD14 antagonist antigen-binding molecules of this disclosure inhibit the binding of a CD14 agonist, preferably DAMP or PAMP, to CD14, and thus inhibit or reduce the production of pro-inflammatory cytokines.In exemplary examples of this type, CD14 antagonist antigen-binding molecules include the 3C10 antibody (van Voohris et al., 1983. J. Exp. Med. 158: 126-145; Juan et al., 1995. J. Biol. Chem. 270(29): 17237-17242) that binds to an epitope contained in at least a portion of the region of human CD14 from amino acids 57 to 64 (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), as well as 28C5 and 23G4 antibodies that inhibit LPS binding and suppress the production of pro-inflammatory cytokines, and 18E12 antibody (US Patent Nos. 5,820,858, 6,444,206 and 7,326,569 against Leturcq et al.) that partially inhibits LPS binding and suppresses the production of pro-inflammatory cytokines, and binds to an epitope contained in at least a portion of the amino acid region 269-315 of human CD14, which inhibits LPS binding and NF-κB activation. The antibodies are selected from the F1024-1-3 antibody (U.S. Patent Application Publication No. 2004 / 0091478 by Furusako et al.) and the synthetic F1204 antibody (U.S. Patent Application Publication No. 2008 / 0286290 by Furusako et al.), which suppress cytokine production, and the r18D11 and rMil2 antibodies (U.S. Patent Application Publication No. 2017 / 0107294 by Espevik et al.), which bind to the LPS-binding and / or signaling domain of human CD14 and inhibit the LPS-induced release of pro-inflammatory cytokines.In some embodiments, the CD14 antagonist antigen-binding molecules of this disclosure inhibit the binding of CD14 to TLRs such as TLR4, thereby blocking the CD14 agonist-mediated response. An example of this is the F1024 antibody disclosed in international publication WO2002 / 42333. Other CD14 antagonist antigen-binding molecules include the single-chain antibody scFv2F9 and the associated 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 concerning CD14 antagonist antigen-binding molecules is incorporated herein by reference in its entirety. CD14 antagonist antigen-binding molecules can be antigen-binding fragments of full-length immunoglobulin antibodies or intact antibodies, typical examples of which include Fab fragments, F(ab')2 fragments, Fd fragments consisting of VH and CH1 domains, Fv fragments consisting of VL and VH domains of a single arm of the antibody, and single-domain antibody (dAb) fragments consisting of a VH domain (Ward et al., 1989. Nature 341:544-546), as well as isolated CDRs. Preferably, the CD14 antagonist antigen-binding molecule is a chimeric, humanized, or human antibody.

[0099] In some embodiments, the CD14 antagonist antigen-binding molecule includes the VH and VL of the following antibodies disclosed in U.S. Patent No. 5,820,858:

[0100] (1) The following: array: VL domains containing, consisting of, or essentially consisting of QSPASLAVSLGQRATISC RASESVDSFGNSFMH WYQQKAGQPPKSSIY RAANLES GIPARFSGSGSRTDFTLTINPVEADDVATYFC QQSYEDPWT FGGGTKLGNQ [SEQ ID NO: 1] (3C10 VL); and array: VH domains containing, consisting of, or essentially consisting of LVKPGGSLKLSCVASGFTFS SYAMS WVRQTPEKRLEWVA SISSGGTTYYPDNVKG RFTISRDNARNILYLQMSSLRSEDTAMYYCAR GYYDYHY WGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH), Antibodies containing;

[0101] (2) The following: array: VL domains containing, consisting of, or essentially consisting of QSPASLAVSLGQRATISC RASESVDSYVNSFLH WYQQKPGQPPKLLIY RASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCC QQSNEDPTT FGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); and array: VH domains containing, consisting of, or essentially consisting of LQQSGPGLVKPSQSLSLTCTVTGYSIT SDSAWN WIRQFPGNRLEWMG YISYSGSTSYNPSLKS RISITRDTSKNQFFLQLNSVTTEDTATYYCVR GLRFAY WGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH), Antibodies containing; and

[0102] (3) The following: array: VL domains containing, consisting of, or essentially consisting of QTPSSLSASLGDRVTISC RASQDIKNYLN WYQQPGGTVKVLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQEDFATYFC QRGDTLPWT FGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); and array: VH domains containing, consisting of, or essentially consisting of LESGPGLVAPSQSLSITCTVSGFSLT NYDIS WIRQPPGKGLEWLG VIWTSGGTNYNSAFMS RLSITKDNSESQVFLKMNGLQTDDTGIYYCVR GDGNFYLYNFDY WGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH), Antibodies containing this substance.

[0103] In some embodiments, the CD14 antagonist antigen-binding molecule includes the VH and VL of the following antibodies disclosed in U.S. Patent Application Publication No. 2004 / 0091478:

[0104] (1) The following: array: VL domains containing, consisting of, or essentially consisting of YIVMTQTPTSISISVGERVTMNCKAS QNVGSNVDWY QQKTGQSPKLLIY KASNRY TGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYC MQSNTNPPW TFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); and array: VH domains containing, consisting of, or essentially consisting of EVKLLESGGGLVQPSQTLSISCKASGYTFT DYAMN WVKQAPGDGLKWMG WINTQTGKPTYADD FKQRFVFSLETSASTAYLQINNLNIEDTA TYFCTRSTFYYSSYIY GWYFDFWGPGTMVTVSS [Sequence ID 58] (F1024-1-3 VH), Antibodies containing this substance.

[0105] 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. 2008 / 0286290:

[0106] (1) The following: array: VL domains containing, consisting of, or essentially consisting 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) contains, consists of, or essentially consists of VH domains, Antibodies containing this substance.

[0107] In some embodiments, the CD14 antagonist antigen-binding molecule includes the VH and VL of the following antibodies disclosed in U.S. Patent Application Publication No. 2017 / 0107294:

[0108] (1) The following: array: VL domains containing, consisting of, or essentially consisting of NIVLTQSPASLAVSLGQRATISC RASESVDSYGNSFMH WYQQKPGQPPKLLIY LASNLES GVPARFSGSGSRTDFTLTIDPVEADDVATYYC QQNNGDPYT FGGGTKLEIIR [SEQ ID NO: 61] (r18D11 VL); and array: VH domains containing, consisting of, or essentially consisting of EVQLVESGGGLMQPKGSLKLSCAASGFTFK TYALN WVRQAPGTGLEWVA RIRSKSNNYTTYYADSVKD RFTISRDDSQNMLYLQMNNLKTEDTAMYYCVR PQSGTSFAY WGQGTLVTVSA [SEQ ID NO: 62] (r18D11 VH), Antibodies containing; and

[0109] (2) The following: array: VL domains containing, consisting of, or essentially consisting 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) contains, consists of, or essentially consists of VH domains, Antibodies containing this substance.

[0110] Antigen-binding molecules containing the above-mentioned antibodies and related antibody VL and VH CDR sequences are also intended, and typical embodiments include the following: (1) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3). Antibodies containing; (2) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3). Antibodies containing; (3) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3). Antibodies containing; (4) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3). Antibodies containing; (5) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence QNVGSNVDWY [SEQ ID NO: 34] (F1024-1-3 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence KASNRY [SEQ ID NO: 35] (F1024-1-3 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence MQSNTNPPW [SEQ ID NO: 36] (F1024-1-3 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence DYAMN [SEQ ID NO: 37] (F1024-1-3 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence WINTQTGKPTYADDF [SEQ ID NO: 38] (F1024-1-3 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence TYFCTRSTFYYSSYIY [SEQ ID NO: 39] (F1024-1-3 H-CDR3) Antibodies containing; (6) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3). Antibodies containing; (7) The following: a) an antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence RASESVDSYGNSFMH [SEQ ID NO: 45] (r18D11 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence LASNLES [SEQ ID NO: 46] (r18D11 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQNNGDPYT [SEQ ID NO: 47] (r18D11 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence TYALN [SEQ ID NO: 48] (r18D11 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (r18D11 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence PQSGTSFAY [SEQ ID NO: 50] (r18D11 H-CDR3). Antibodies containing; and (8) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains, consists of, or essentially consists of the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 contains, consists of, or essentially consists of the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 contains, consists of, or essentially consists of the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains, consists of, or essentially consists of the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 contains, consists of, or essentially consists of the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 contains, consists of, or essentially consists of the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3). Antibodies containing this substance.

[0111] In some embodiments, the CD14 antagonist antigen-binding molecule is a humanized antibody. In this exemplary example, the humanized CD14 antagonist antibody appropriately comprises a donor CDR set corresponding to the CD14 antagonist antibody (e.g., one of the CD14 antagonist antibodies described above) and a human acceptor framework. The human acceptor framework may include at least one amino acid substitution to the human germline acceptor framework in key residues selected from the group consisting of residues adjacent to the CDR; glycosylated site residues; rare residues; standard residues; contact residues between the heavy chain variable region and the light chain variable region; residues in the vernier zone; and residues in the region overlapping between the Chia-defined VH CDR1 and the Kabat-defined first heavy chain framework. Techniques for producing humanized mAbs are well-known in this field (see, for example, 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, JS., 1992. Crit. Rev. Biotech. 12: 437-462, and Singer et al., 1993. J. Immunol. 150: 2844-2857). Chimeric or mouse monoclonal antibodies can be humanized by transferring mouse CDRs derived from the heavy and light chains of mouse immunoglobulins into the corresponding variable domains of human antibodies. The mouse framework region (FR) in the chimeric monoclonal antibody is also replaced with a human FR sequence. Simply transferring mouse CDRs to human FRs often results in a decrease or even loss of antibody affinity; therefore, further modification may be necessary to restore the original affinity of the mouse antibody. This can be achieved by substituting one or more human residues in the FR region with their mouse counterparts to obtain an antibody with good binding affinity to its epitope.See, for example, 1991. Biotechnology 9:266-271) and Verhoeyen et al. (1988, see above). In general, human FR amino acid residues that are different from their mouse counterparts and are located in close proximity to or in contact with one or more CDR amino acid residues are candidates for substitution.

[0112] In some embodiments, the CD14 antagonist antibody is an 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 as a whole) 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 above-mentioned mouse 28C5 and contains an IgG quadruple chain (see U.S. Patents No. 5,820,858, No. 6,444,206, and No. 7,326,569 to Leturcq et al., and Leturcq et al., 1996. J. Clin. Invest. 98: 1533-1538). Therefore, in one embodiment, the CD14 antagonist antibody comprises the IC14 heavy chain and light chain CDR as previously described. In another example, the CD14 antagonist antibody comprises the VL domain and the VH domain, where: The VL domain has the following amino acid sequence: QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIK[SEQ ID NO: 25] contains, consists of, or is essentially made from; and The VH domain has the following amino acid sequence: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSS[Sequence ID 26] contains, consists of, or essentially consists of; or The VL domain has the following amino acid sequence: DIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIK[SEQ ID NO: 30] contains, consists of, or is essentially made from; and The VH domain has the following amino acid sequence: DVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSS[Sequence ID 31] contains, consists of, or essentially consists of.

[0113] In another embodiment, the CD14 antagonist antibody comprises the light and heavy chains of IC14, where:

[0114] The light chain has the following amino acid sequence: QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[SEQ ID NO: 28] contains, consists of, or is essentially made from; and The heavy chain has the following amino acid sequence: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGPS VFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[Sequence ID 29] contains, consists of, or essentially consists of; or The light chain has the following amino acid sequence: DIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[SEQ ID NO: 32] contains, consists of, or is essentially made from; and The heavy chain has the following amino acid sequence: DVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK[Sequence ID 33] contains, consists of, or essentially consists of.

[0115] Further 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, and these methods generally involve determining whether an antibody can directly antagonize CD14. For example, this method may involve determining whether an antibody can inhibit or reduce the amount or agonist activity of CD14, where the ability to inhibit or reduce the amount or agonist activity of CD14 indicates that the antibody is suitable for use in the treatment of ACM. In some embodiments, the antibody is contacted with CD14, or cells expressing CD14 on its surface, or a nucleic acid sequence on which CD14 is expressed, in the presence of a CD14 agonist such as DAMP or PAMP, where a reduction in the amount or agonist activity of CD14 in the presence of the agonist, compared to a control, indicates that the antibody binds to CD14 and directly antagonizes it. Reduced or inhibited CD14 agonist activity includes, for example, inhibition or reduction of activation of downstream pathways such as the TLR signaling pathway (e.g., the TLR4 signaling pathway) and the TRIF pathway, or induction of cellular responses (e.g., production of pro-inflammatory mediators, including pro-inflammatory cytokines).

[0116] These methods can be carried out in vivo, ex vivo, or in vitro. In particular, the step of contacting an antibody with cells expressing CD14 or CD14 on its surface (e.g., immune cells) can be carried out in vivo, ex vivo, or in vitro. The methods can be carried out in a cell-based or cell-free system. For example, this method may include the steps of contacting cells expressing CD14 on their surface with an antibody, and determining whether the contact between the cells and the antibody results in a decrease in the amount of CD14 or agonist activity. In such cell-based assays, CD14 and / or the antibody may be endogenous to the host cell, introduced into the host cell or tissue, introduced into the host cell or tissue by inducing or allowing the expression of an expression construct or vector, or introduced into the host cell by stimulating or activating the expression from an endogenous gene within the cell. Such cell-based methods allow for the evaluation of CD14 activity in or without the presence of an antibody to determine whether the activator alters the amount of CD14 in the cell, such as by regulating intracellular CD14 expression, destabilizing intracellular CD14 proteins, or altering the cell's CD14 agonist activity. Lower CD14 agonist activity or a reduced amount of CD14 on the cell surface in the presence of an antibody indicates that the antibody may be a suitable antagonist of CD14 for use according to this disclosure.

[0117] In some embodiments, it is further determined whether the antibody lacks substantial or detectable binding to another cellular component, such as a CD14 binding partner that is secreted (e.g., MD2) or located on the cell membrane (e.g., TLR4), and thereby it is determined that the antibody is a CD14-specific antagonist. In this non-limiting example, the antibody is brought into contact with (1) wild-type cells expressing CD14 on their surface (e.g., immune cells such as macrophages) and (2) CD14-negative cells (e.g., immune cells the same as in (1) but with loss of function in the CD14 gene) in the presence of a CD14 agonist such as DAMP or PAMP. If the antibody inhibits the CD14 agonist activity of wild-type cells but does not inhibit CD14-negative cells, this indicates that the antibody is a CD14-specific antagonist. This type of cell can be constructed using conventional methods or animals.

[0118] In other examples, potential CD14 antagonist antigen-binding molecules are evaluated in vivo, for example, in animal models. In such in vivo models, the effect of the antibody may be evaluated in circulation (e.g., blood) or the heart, or in other organs such as the lungs, liver, kidneys, or brain. In certain cases, the ACM model is used to evaluate antibody activity.

[0119] Exemplary CD14 antagonist antigen-binding molecules preferably result in a reduction of CD14 activity or CD14 activity by at least 5%, at least 10%, at least 25%, at least 50%, at least 60%, at least 75%, or at least 85% compared to the absence of the antibody. In some examples, the antibody can result in a reduction of CD14 agonist activity or level such that the agonist activity or CD14 level is no longer detectable in the presence of the antibody. Such a reduction is observed in the sample being tested or, for example, when the method is performed in an animal model.

[0120] Preferably, the antibody is a CD14-specific antagonist as described above. However, this does not mean that a CD14-specific antagonist has a complete lack of off-target antagonist activity. In this regard, a CD14-specific antagonist may have a negligible degree of direct binding and effect, such that the antagonist of activity, signaling, or expression of non-CD14 cellular components is less than 15%, less than 10%, less than 5%, less than 1%, or less than 0.1% of the direct binding and effect of its agent on CD14 activity, signaling, or expression.

[0121] The level or amount of CD14 can be measured by evaluating the expression of the CD14 gene. Gene expression can be evaluated 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, such methods can specifically identify the mRNA of interest using hybridization. For example, such methods may include PCR or real-time PCR approaches. Methods for identifying or quantifying the protein of interest may include the use of antibodies that bind to that protein. For example, such methods may include Western blotting. The regulation of CD14 gene expression can be compared in the presence and absence of antibodies. Thus, antibodies that reduce CD14 gene expression compared to the levels observed in the absence of antibodies can be identified. Such antibodies may be suitable antagonists of CD14 according to this disclosure.

[0122] A method for identifying suitable antagonist antigen-binding molecules for use in accordance with this disclosure can be used to evaluate the agonist activity of CD14. For example, such a method can be carried out using peripheral blood mononuclear cells. Such cells produce cytokines such as IL-1α, IL-6, TNF-α, IFN-β, IL-1β, IL-17, and IL-8 in response to stimulation, for example, with LPS. Therefore, the method may include combining peripheral blood mononuclear cells with an antibody or vehicle and adding LPS. The cells can then be incubated for a certain period of time (e.g., 24 hours) to allow for the production of pro-inflammatory mediators such as cytokines. Subsequently, the levels of 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 be evaluated. If the antibody has anti-CD14 properties, the production of such cytokines should be reduced compared to cells treated with the vehicle. 3. Supportive medications and interventions

[0123] CD14 antagonist antigen-binding molecules may be administered alone or in combination with other activators (also called “adjuncts”) or other interventions, such as drugs or interventions useful in treating or inhibiting the development of ACM. Adjunct therapeutic agents may preferably be any compound, molecule, or substance that exerts a therapeutic effect on a target in need in connection with the treatment of ACM.

[0124] Representative adjunctive therapeutic agents suitable for the purposes of this disclosure include, for example, fibrinolytics, beta-blockers, high-strength statins (e.g., atorvastatin or rosuvastatin), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, platelet inhibitors, thiadiazolidinedione, corticosteroids, anticonvulsants, and immunosuppressants (e.g., cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolate, methotrexate, basiliximab, daclizumab, rituximab, antithymocyte globulin). Phosphorin (antilymphocyte globulin), antimicrobial agents, calcium channel blockers, digoxin, antiarrhythmic agents, anticoagulants, diuretics (e.g., spironolactone, eplerenone), exon skipping therapy (e.g., eteplirsen, dorisapersen), 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., atalaren), utrofin modulators (e.g., SMT C1100, SMT022357), antifibrotic agents (e.g., halofdinone, angiotensin [1-7]), coenzyme Q 10 Examples include synthetic analogs (e.g., idebenone), allogeneic cardiac cell therapy methods (e.g., CAP-1002); Toll-like receptor antagonists (e.g., IMO-8400); inorganic corticosteroid receptor antagonists; β-adrenergic receptor antagonists, resveratrol, and SIRT1 activators.

[0125] In some embodiments, the adjuvant is a beta-blocker (or a beta-adrenergic receptor antagonist). Preferred 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-exclusive examples of non-selective beta-blockers include propranolol, carvedilol, sotalol, and labetalol. Beta-1 receptor selective blockers bind only to the beta-1 receptor and include, for example, atenolol, bisoprolol, metoprolol, and esmolol.

[0126] In other examples, the adjuvant is a fibrinolytic agent such as streptokinase, anistreplase, or tissue plasminogen activator (e.g., tenecteplase, leteplase, or alteplase).

[0127] In further examples, adjuvants include platelet inhibitors such as aspirin, P2Y12 inhibitors (e.g., ticlopidine, clopidogrel, ticagrelol, or prasugrel), or glycoprotein IIb / IIIa receptor antagonists.

[0128] Another example, an adjuvant, is an ACE inhibitor. Non-exclusive examples of ACE inhibitors include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0129] In some embodiments, the adjuvant is a thiadiazolidinedione, a typical example of which is a glycogen synthase kinase 3β (GSK3β) inhibitor, which is selective, preferably including reversible and irreversible inhibitors. Thiadiazolidinediones, such as tideglucib or NPE100928, including its derivatives, prevent ACM-related electrical, molecular, and structural changes, 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).

[0130] In another example, the adjunct is a corticosteroid, and examples that are helpful in illustrating this include steroids, phenytoin, procainamide; quinine; glucocorticoids (e.g., deflazacort, vamorolone, VBP15, prednisone triamcinolone, systemic methylprednisolone, betamethasone, budesonide, prednisolone, hydrocortisone, dexamethasone, and / or cortisone).

[0131] In some embodiments, the adjuvant is an immunosuppressant, and typical examples include cyclosporine, tacrolimus, prednisolone, hydrocortisone, sirolimus, everolimus, azathioprine, mycophenolic acid, methotrexate, basiliximab, daclizumab, rituximab, antithymocyte globulin, and antilymphocyte globulin.

[0132] In another example, adjuvants are antimicrobial agents, and non-limiting examples 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 aminoglucosides (e.g., gentamicin and tobramycin).

[0133] When two or more therapeutic agents are used in combination, the dose of each agent is generally the same as the dose of each agent when used independently. However, if one therapeutic agent interferes with the metabolism of another, the dose of each therapeutic agent is appropriately adjusted. Alternatively, if two or more therapeutic agents exhibit a synergistic effect, the dosage of one or more agents may be reduced. Each therapeutic agent may be administered simultaneously or separately at appropriate intervals.

[0134] When combination therapy is desired, the CD14 antagonist antibody is administered separately, concurrently with, or sequentially with one or more adjunct agents or interventions. In some embodiments, this can be achieved, for example, by administering a single composition or pharmacological formulation containing both types of agents systemically, or by administering two separate compositions or formulations simultaneously, where one composition comprises a CD14 antagonist antigen-binding molecule and the other adjunct. In other embodiments, treatment with the CD14 antagonist antigen-binding molecule may precede or follow treatment with the adjunct, at intervals of several minutes to several hours, or several days or weeks.

[0135] When two or more substances are administered to a target "in combination," "in combination," or "simultaneously," they may be administered simultaneously in a single composition, simultaneously in separate compositions, or simultaneously in separate compositions separated from each other.

[0136] In another example, the administration of antigen-binding molecules is used in conjunction with interventions (e.g., surgical procedures) such as percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass grafting (CABG), pacemaker implantation, implantable cardioverter-defibrillator (ICD) implantation, cardiac catheterization, vascular regeneration, and heart transplantation.

[0137] In some situations, the antigen-binding molecule and the adjuvant are administered within approximately 1 to 12 hours of each other, or within approximately 2 to 6 hours of each other. In other situations, it is desirable to significantly extend the duration of treatment, however, in that case, more than one day (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 days) is lost between each administration. In embodiments where the adjuvant is administered separately to the CD14 antagonist antigen-binding molecule, it will be understood that the adjuvant may be administered by a method different from that used for the CD14 antagonist antigen-binding molecule. In further embodiments, if an intervention (e.g., PCI) is performed on the subject, the antigen-binding molecule is administered to the subject within 72 hours of the PCI, for example, at 12, 24, 36, or 48 hours after the intervention or earlier. 4. Pharmaceutical Compositions

[0138] As described herein, the use of a CD14 antagonist antigen-binding molecule in combination with at least one optional adjunct therapeutic agent is useful for treating or alleviating at least one symptom of ACM, treating or inhibiting the development of ACM, alleviating or inhibiting the development of undesirable cardiac remodeling in ACM, improving cardiac function in ACM, improving ventricular function in ACM, improving atrial function in ACM, reducing the number of ventricular premature contractions (PVCs) in ACM, treating or alleviating at least one symptom of atrial fibrillation in ACM, and / or reducing the number of atrial premature contractions (PACs) in ACM.

[0139] CD14 antagonist antigen-binding molecules and optional (one or more) adjuvants are administered either by themselves or, preferably, in the form of a pharmaceutical composition (including an optionally pharmaceutically acceptable carrier). Accordingly, pharmaceutical compositions comprising a CD14 antagonist antigen-binding molecule and optionally at least one adjuvant therapeutic agent for use in treating or inhibiting the development of ACM are also provided herein.

[0140] CD14 antagonist antigen-binding molecules and optional adjunct therapeutic agents can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, stabilizers, or excipients (vehicles) to form pharmaceutical compositions known in the art, particularly protein activators. The carrier is "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to its recipient (e.g., the patient). Suitable carriers typically include saline or ethanol polyols, such as glycerol or propylene glycol.

[0141] Antigen-binding molecules can be formulated in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with a free amino group), which 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 a free carboxyl group can also be derived from inorganic bases such as sodium hydroxide, potassium, ammonium, calcium, or ferric acid, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, and procaine.

[0142] The composition can be appropriately formulated for systemic administration, including intravenous, intramuscular, subcutaneous, or intraperitoneal administration, and may conveniently include a sterile aqueous solution of an antigen-binding molecule that isotonic with the recipient's blood. Such formulations are typically prepared by dissolving a solid active ingredient in water containing a physiologically compatible substance, such as sodium chloride or glycine, to produce an aqueous solution with a physiologically compatible buffered pH, and then sterilizing the solution. These can be prepared in single-dose or multi-dose containers, such as sealed ampoules or vials.

[0143] The composition may 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 pH. The pH of the aqueous solution is adjusted to a range of 5.0 to 9.0, preferably 6 to 8. Antiadsorbents may be used when preparing the antibodies. Other suitable excipients may 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 proteins using polymers. Suitable polymers for controlled-release formulations include, for example, polyesters, polyamino acids, polyvinyl, pyrrolidone, ethylene vinyl acetate, and methylcellulose. Another possible method for controlled release is to incorporate the antibody into particles of polymer material such as polyester, polyamino acids, hydrogels, poly(lactic acid), or ethylene vinyl acetate copolymers. Alternatively, instead of incorporating these substances into polymer particles, they can be incorporated, for example, by coacervation technology or interfacial polymerization, into, for example, hydroxymethylcellulose or gelatin microcapsules and poly(methyl metasylate) microcapsules, or into colloidal drug delivery systems, such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules, or into macroemulsions.

[0144] The CD14 antagonist antigen-binding molecule and at least one adjuvant (optionally) can also be administered directly to the airway in aerosol form. For use as an aerosol, the antagonist antigen-binding molecule of the Disclosure in solution or suspension can be packaged in a pressurized aerosol container with a suitable propellant, such as a hydrocarbon propellant like propane, butane, or isobutane, along with a conventional adjuvant. The materials of the Disclosure can also be administered in a non-pressurized form, such as by a nebulizer or sprayer.

[0145] Those skilled in the art will recognize that formulations are routinely designed according to their intended use, i.e., route of administration. 5. Treatment method

[0146] This disclosure also relates to the use of a pharmaceutical composition comprising a CD14 antagonist antigen-binding molecule and, optionally, at least one adjunct therapeutic agent, in a method for treating or inhibiting the development of ACM. ACM disease progresses over time with a variety of arrhythmias and ventricular dysfunctions. Electrocardiographic abnormalities can be detected early in the disease and progress with age. The development of ACM is characterized by increased myocardial mass, ventricular enlargement, and decreased wall thickness. Changes in ventricular function may be disease-stage dependent in that asymptomatic ACM is associated with diastolic dysfunction, whereas systolic dysfunction is a common finding in symptomatic ACM patients.

[0147] In some embodiments, the Disclosure provides a method for treating ACM, comprising administering the pharmaceutical composition disclosed herein to a subject requiring such treatment. In some embodiments, the Disclosure provides a method for inhibiting the development of ACM, comprising administering the pharmaceutical composition disclosed herein to a subject requiring such treatment. In some embodiments, the Disclosure provides a method for delaying ACM, comprising administering the pharmaceutical composition disclosed herein to a subject requiring such treatment. In some embodiments, the Disclosure provides a method for slowing the progression of ACM, comprising administering the pharmaceutical composition disclosed herein to a subject requiring such treatment. In some embodiments, the Disclosure provides a method for ameliorating ACM, comprising administering the pharmaceutical composition disclosed herein to a subject requiring such treatment.

[0148] In some embodiments, the subject has one or more mutations in a gene associated with ACM. ACM-related genes are, for example, genes encoding components of desmosomes. Examples of genes encoding components of desmosomes include placofilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocolin-2 (DSC2), or placoglobin (JUP). Other genes associated with ACM, but not limited to these, include 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).

[0149] In some embodiments, subjects have either had an implantable cardioverter-defibrillator (ICD) implanted due to a perceived risk of life-threatening arrhythmias, or have previously experienced cardiac arrest, sustained ventricular tachycardia, or a worrying syncope or presyncope episode.

[0150] In some embodiments, subjects are beginning to manifest clinical features of the disease, including frequent ventricular premature contractions (PVCs) or non-sustained ventricular tachycardia on portable monitoring, electrocardiogram (ECG) abnormalities such as epsilon waves or T-wave inversions in the anterior chest, or evidence of cardiac dysfunction on imaging techniques such as echocardiography and magnetic resonance imaging. Non-sustained ventricular tachycardia is defined as more than three ventricular beats at a rate greater than 100 beats / minute with a duration of less than 30 seconds. If the rhythm lasts longer than 30 seconds, or if hemodynamic instability occurs in less than 30 seconds, it is considered sustained ventricular tachycardia. In some embodiments, patients have harmful genetic variants that put them at risk of developing ACM and suffering from life-threatening arrhythmias.

[0151] Symptoms and / or complications of ACM are well known in the art and are not limited to, but include, ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, dizziness, syncope, dyspnea, peripheral edema, abdominal distension, embolus formation, myocardial fibroadipose infiltration, heart failure, or acute cardiac death (SCD).

[0152] The treatment or inhibition of the onset of ACM symptoms can be measured by any means known in the art. For example, evaluations include echocardiography, proximal magnetic resonance imaging (MRI), and cardiac MRI with slow gadolinium sensitization. In particular, LV size, thickness, volume, ejection fraction (EF), and myocardial scar tissue / inflammatory burden, as well as injury, can be evaluated. Injury, changes in LV dimensions and volume, and scar tissue burden are the main measurements.

[0153] In some embodiments, the Disclosure provides a method for inhibiting the occurrence of undesirable cardiac remodeling in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, the Disclosure provides a method for delaying undesirable cardiac remodeling in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, the Disclosure provides a method for delaying the progression of undesirable cardiac remodeling in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, the Disclosure provides a method for ameliorating undesirable cardiac remodeling in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, undesirable cardiac remodeling is inhibited, delayed, or ameliorated over periods of approximately 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 1 year, 2 years, 5 years, and / or 10 years, compared to undesirable cardiac remodeling in untreated ACM subjects. In some embodiments, undesirable cardiac remodeling is inhibited, delayed, or ameliorated by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to undesirable cardiac remodeling in untreated ACM subjects. In some embodiments, this inhibition, delay, or amelioration of undesirable cardiac remodeling is observed at the time disclosed herein. In some embodiments, undesirable cardiac remodeling includes an increase in myocardial fibrosis. In some embodiments, undesirable cardiac remodeling includes changes in the diameter of the heart cavity. In some embodiments, undesirable cardiac remodeling includes changes in myocardial weight (hypertrophy and atrophy). In some embodiments, undesirable cardiac remodeling includes changes in the shape of the heart (cardiac wall thickness and shape). In some embodiments, undesirable cardiac remodeling includes changes in inflammatory infiltration of the heart.

[0154] In some embodiments, the Disclosure provides a method for inhibiting the onset of cardiac function decline in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, the Disclosure provides a method for delaying cardiac function decline in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, the Disclosure provides a method for delaying the progression of cardiac function decline in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, the Disclosure provides a method for ameliorating cardiac function decline in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein to the subject. In some embodiments, cardiac dysfunction is inhibited, delayed, or ameliorated over periods of approximately 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 1 year, 2 years, 5 years, and / or 10 years, compared to cardiac dysfunction in untreated ACM subjects. In some embodiments, cardiac dysfunction is inhibited, delayed, or ameliorated by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to cardiac dysfunction in untreated ACM subjects. In some embodiments, this inhibition, delay, or amelioration of cardiac dysfunction is observed at the time disclosed herein. In some embodiments, cardiac dysfunction is a decrease in inotropy. In some embodiments, cardiac dysfunction is a decrease in myocardial relaxation. In some embodiments, cardiac dysfunction is myocardial thickening. In some embodiments, impaired cardiac function is characterized by cardiac hypertrophy.

[0155] In some embodiments, administration of a CD14 antagonist antigen-binding molecule improves cardiac function in subjects with ACM compared to untreated ACM subjects. In some embodiments, cardiac function improves over approximately 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 1 year, 2 years, 5 years, and / or 10 years compared to the cardiac function of untreated ACM subjects. In some embodiments, cardiac function improves by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the cardiac function of untreated ACM subjects. In some embodiments, this improvement in cardiac function is observed at the time disclosed herein. In some embodiments, the improvement in cardiac function is an increase in inotropy. In some embodiments, the improvement in cardiac function is an increase in myocardial relaxation. In some embodiments, the improvement in cardiac function is less myocardial thickening. In some embodiments, the improvement in cardiac function is less cardiac hypertrophy. In some embodiments, the improvement in cardiac function is less ventricular premature contractions (PVCs). In some embodiments, the improvement in cardiac function is less atrial premature contractions (PACs).

[0156] In some embodiments, administration of a CD14 antagonist antigen-binding molecule improves ventricular function in subjects with ACM compared to untreated ACM subjects. In some embodiments, ventricular function improves over approximately 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 1 year, 2 years, 5 years, and / or 10 years compared to the ventricular function of untreated ACM subjects. In some embodiments, ventricular function improves by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the ventricular function of untreated ACM subjects. In some embodiments, this improvement in ventricular function is observed at the time disclosed herein. In some embodiments, the improvement in ventricular function is an improved diameter shortening rate. In some embodiments, the improvement in ventricular function is an improved ejection fraction rate. In some embodiments, improved ventricular function is a reduced end-diastolic volume. In some embodiments, improved ventricular function is a reduced left ventricular muscle mass. In some embodiments, improved ventricular function is a reduced terminal ventricular flaccid diameter. In some embodiments, improved ventricular function is a reduced arrhythmia. In some embodiments, improved ventricular function is a reduced heart murmur. In some embodiments, improved ventricular function is a reduced heart rate. In some embodiments, improved ventricular function is a normalization of cardiac morphology. In some embodiments, improved ventricular function is fewer PVCs. PVCs may be measured by an electrocardiogram device, such as a Holter monitor. A reduction in PVCs means a reduction of approximately ≥1%, ≥2%, ≥4%, ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, ≥35%, ≥40%, ≥45%, ≥50%, or greater, compared to the number of PVCs before treatment (i.e., the baseline PVC rate of the subject). The number of PVCs and their reduction can be measured over periods of approximately 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, or longer.Alternatively, the number of PVCs and their reduction can be measured over periods of approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer. The number of PVCs and their reduction can be measured over periods of approximately 1 week, 2 weeks, 3 weeks, 4 weeks, or longer. The number of PVCs and their reduction can be measured over periods of approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer.

[0157] In some embodiments, administration of a CD14 antagonist antigen-binding molecule improves atrial function in subjects with ACM compared to untreated ACM subjects. In some embodiments, atrial function improves over approximately 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 1 year, 2 years, 5 years, and / or 10 years compared to the atrial function of untreated ACM subjects. In some embodiments, atrial function improves by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the atrial function of untreated ACM subjects. In some embodiments, this improvement in atrial function is observed at the time 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, improvement in atrial function is improved atrial pump function. In some embodiments, improvement in atrial function is reduced left atrial mass. In some embodiments, improvement in atrial function is reduced arrhythmias. In some embodiments, improvement in atrial function is fewer PACs. PAC reduction means a reduction of approximately ≥1%, ≥2%, ≥4%, ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, ≥35%, ≥40%, ≥45%, ≥50%, or greater, compared to the number of PACs before treatment (i.e., the baseline PAC rate of the subject). The number of PACs and their reduction can be measured over periods of approximately 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, or longer. Alternatively, the number and reduction of PACs can be measured over periods of approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer. The number and reduction of PACs can be measured over periods of approximately 1 week, 2 weeks, 3 weeks, 4 weeks, or longer. The number and reduction of PACs can be measured over periods of approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or longer.

[0158] In some embodiments, the Disclosure provides a method for inhibiting the onset of atrial fibrillation in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, the Disclosure provides a method for delaying atrial fibrillation in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, the Disclosure provides a method for delaying the progression of atrial fibrillation in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, the Disclosure provides a method for ameliorating atrial fibrillation in a subject suffering from ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, atrial fibrillation is inhibited, delayed, or ameliorated over periods of approximately 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 1 year, 2 years, 5 years, and / or 10 years, compared to untreated atrial fibrillation in a patient with ACM. In some embodiments, atrial fibrillation is inhibited, delayed, or ameliorated by approximately 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to untreated atrial fibrillation in a patient with ACM. In some embodiments, this inhibition, delay, or amelioration of atrial fibrillation is observed at the time disclosed herein.

[0159] In some embodiments, the Disclosure provides a method for inhibiting the development of fibrosis in a subject with ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, the Disclosure provides a method for delaying the development of fibrosis in a subject with ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, the Disclosure provides a method for delaying the progression of fibrosis in a subject with ACM, comprising administering a pharmaceutical composition disclosed herein. In some embodiments, the Disclosure provides a method for ameliorating the development of fibrosis in a subject with ACM, comprising administering 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 an untreated ACM subject. In some embodiments, fibrosis 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 fibrosis in untreated ACM subjects. In some embodiments, this inhibition, delay, or amelioration of fibrosis is observed at the time disclosed herein. In some embodiments, fibrosis is measured using histological techniques on biopsy specimens (e.g., hematoxylin-eosin (HE) and triple staining) when the fibrosis is assessed by determining the percentage of collagen present relative to the total tissue area.

[0160] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered over a long period. 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, and about 10 years or more. The CD14 antagonist antigen-binding molecules may be administered in any necessary dosage and / or frequency disclosed herein.

[0161] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until ACM symptoms improve. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until ACM symptoms are ameliorated. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until ACM symptoms are delayed. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until ACM symptoms are resolved.

[0162] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered before the patient begins to exhibit one or more ACM symptoms. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered at the time of onset of ACM symptoms. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered before the patient begins to exhibit ACM symptoms. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered after the onset of ACM symptoms.

[0163] In some embodiments, subjects are measured to have abnormal echocardiograms compared to non-ACM subjects. In some embodiments, subjects are measured to have changes in cardiac function compared to non-ACM subjects. In some embodiments, subjects are measured to have prolonged PR intervals compared to non-ACM subjects. In some embodiments, subjects are measured to have increased U wave amplitudes compared to non-ACM subjects. In some embodiments, subjects are measured to have wider QRS complexes compared to non-ACM subjects. In some embodiments, subjects are measured to have nonspecific ST-T changes compared to non-ACM subjects. In some embodiments, subjects are measured to have sinus arrhythmias compared to non-ACM subjects. In some embodiments, subjects are measured to have deep Q waves and high R waves in the anterior chest compared to non-ACM subjects. In some embodiments, subjects are measured to have abnormal tonic contractions (TCs) compared to non-ACM subjects. In some embodiments, tonic contractions arise from periods of calcium dysregulation representing continuous ion-driven myocyte contractions, resulting in an echocardiographic appearance of left ventricular "filling insufficiency" (Su et al. (2015, Pediatr. Cardiol. Dec. 29)). In some embodiments, subjects are measured to have arrhythmias compared to non-ACM subjects. In some embodiments, subjects are measured to have sinus tachycardia compared to non-ACM subjects. In some embodiments, subjects are measured to have systolic dysfunction compared to non-ACM subjects. In some embodiments, subjects are measured to have diastolic dysfunction compared to non-ACM subjects. In some embodiments, subjects are measured to have lower mitral valve contractile wave velocity compared to non-ACM subjects. In some embodiments, subjects are measured to have wall motion abnormalities compared to non-ACM subjects. Cardiac function and / or characteristics may be measured using electrocardiogram.

[0164] In some embodiments, the subject is measured to have enhanced expression of pro-inflammatory mediators, preferably pro-inflammatory cytokines, compared to non-ACM subjects. In some embodiments, the subject is measured to have enhanced activity of pro-inflammatory mediators, preferably pro-inflammatory cytokines, compared to non-ACM subjects. In some embodiments, the pro-inflammatory cytokines are any pro-inflammatory cytokines, including, but are not limited to, OPN, LTβ4, TNF-α, interleukin-6 (IL-6), and soluble tumor necrosis factor α receptor (sTNFαR). The expression or activity of pro-inflammatory cytokines in the subject can be measured by cytokine assays.

[0165] In some embodiments, the subjects are measured to have reduced expression of neuronal nitric oxide synthase (nNOS) protein compared to non-ACM subjects. In some embodiments, the subjects are measured to have reduced nNOS activity compared to non-ACM subjects. In some embodiments, the subjects are measured to have altered nNOS protein accumulation compared to non-ACM subjects. In some embodiments, the subjects are measured to have increased nNOS protein accumulation in the skeletal muscle cytosol compared to non-ACM subjects. In some embodiments, the subjects are measured to have decreased nNOS protein accumulation in the muscle fiber membrane of skeletal muscle compared to non-ACM 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.

[0166] In some embodiments, the pharmaceutical compositions disclosed herein, comprising a CD14 antagonist antigen-binding molecule and optionally at least one auxiliary therapeutic agent ("activator"), are for "systemic delivery," meaning that the (one or more) activators are not delivered locally to a pathological site or site of action. Instead, the (one or more) activators are absorbed into the bloodstream from the injection site, where they act systemically or are transported to the site of action via circulation. The (one or more) activators may be administered by any preferred route, such as orally, intravenously, intramuscularly, nasally, subcutaneously, and rectally. In some embodiments, the (one or more) activators are for parenteral administration, preferably intravenously. In other embodiments, the (one or more) activators are for local administration to the pathological site to be treated (e.g., myocardial tissue). In these embodiments, the (one or more) activators may be administered by direct injection, insertion, or implantation into, on, or near the pathological site.

[0167] In some embodiments, one or more activators are administered approximately monthly and may be administered topically or intravenously. In some embodiments, one or more activators are administered approximately weekly and may be administered topically or intravenously. In some embodiments, the site of administration may not be a pathological site, for example, not the intended site of action.

[0168] In various embodiments, the plasma concentration of one or more activators does not change by more than approximately 100 times, approximately 50 times, approximately 10 times, approximately 5 times, or approximately 3 times over multiple administrations, such as at least two, at least approximately five, or at least approximately ten administrations. The administrations are spaced substantially evenly, for example, almost daily, or approximately once a week, or 1 to approximately five times a month, or approximately once every two months, or approximately once every three months. In some embodiments, one or more activators are administered to a subject over a period of approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 14 months, 16 months, 18 months, 20 months, 22 months, or 2 years.

[0169] While a person skilled in the art can determine the desired dosage on a case-by-case basis, a suitable effective dose of the CD14 antagonist antigen-binding molecule to achieve a therapeutic effect may be, for example, within the range of approximately 0.1 mg to 50 mg (and all integer mg units to the first decimal place) per kilogram of body weight per day, approximately 0.2 mg to 40 mg (and all integer mg units to the first decimal place) per day, approximately 0.5 mg to 40 mg (and all integer mg units to the first decimal place) per kilogram of body weight per day, 1 mg to 30 mg (and all integer mg units to the first decimal place) per day, 2 mg to 20 mg (and all integer mg units to the first decimal place) per day, approximately 4 mg to 15 mg (and all integer mg units to the first decimal place) per day, or approximately 5 mg to 10 mg (and all integer mg units to the first decimal place) per day. In some embodiments, the CD14 antagonist antigen-binding molecule is administered in low doses. In some embodiments, the CD14 antagonist antigen-binding molecule is administered at a dose 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 dose of the CD14 antagonist antigen-binding molecule to achieve a therapeutic effect may be in the range of, for example, 0.1 mg to 50 mg (and all integer mg units to the first decimal place) per kilogram of body weight per week, about 0.2 mg to 40 mg (and all integer mg units to the first decimal place), about 0.5 mg to 40 mg (and all integer mg units to the first decimal place), 1 mg to 30 mg (and all integer mg units to the first decimal place), 2 mg to 20 mg (and all integer mg units to the first decimal place), about 4 mg to 15 mg (and all integer mg units to the first decimal place), or about 5 mg to 10 mg (and all integer mg units to the first decimal place) per kilogram of body weight per week. Alternatively, if the condition of the recipient individual requires it, the dose may be administered as a continuous intravenous infusion.

[0170] In certain embodiments, the subject is a human, but in other embodiments, it may be a mammal other than a human, such as a domesticated pet (e.g., a dog or cat), or a livestock or farm animal (e.g., a horse, a cow, a sheep, or a pig). 6. Representative Embodiments 1. A method for treating or alleviating at least one symptom of a target arrhythmogenic cardiomyopathy (ACM), comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the target. 2. The method according to Embodiment 1, wherein at least one of the symptoms is selected from ventricular tachycardia, implantable cardioverter-defibrillator (ICD) shock, pulmonary congestion, fluid retention, fatigue, heart murmur, tachycardia, arrhythmia, chest pain, dizziness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolism, fainting, angina, exercise intolerance, orthopnea, heart failure, and acute cardiac death (SCD). 3. The method according to Embodiment 1 or Embodiment 2, wherein administration of the CD14 antagonist antigen-binding molecule improves one or more clinical parameters of the target. 4. The method according to Embodiment 3, wherein one or more of the aforementioned clinical parameters are selected from reduced left ventricular ejection fraction, left ventricular hypertrophy, increased myocardial fibrosis, undesirable cardiac remodeling, right ventricular dysfunction, abnormal cardiac morphology (e.g., increased right ventricular area change), increased end-diastolic volume, frequent ventricular premature contractions, and increased left ventricular muscle mass. 5. A method for mitigating or inhibiting the occurrence of undesirable cardiac remodeling in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject. 6. A method for improving cardiac function in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject. 7. The method according to Embodiment 6, wherein the improvement in cardiac function includes improvement in left ventricular function, improvement in diameter shortening rate, improvement in ejection fraction, reduction in end-diastolic volume, reduction in left ventricular muscle mass, reduction in arrhythmias, reduction in the frequency of heart murmurs, reduction in heart rate, normalization of cardiac shape, or a combination thereof. 8. A method for improving ventricular function in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject. 9. A method for improving atrial function in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject. 10. A method for reducing the number of ventricular premature contractions (PVCs) in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject. 11. A method for treating or alleviating symptoms of atrial fibrillation in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to a subject suffering from or at risk of developing atrial fibrillation. 12. A method for reducing the number of atrial premature contractions in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject. 13. The aforementioned antigen-binding molecule is as follows: (i) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 contains the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 contains the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 contains the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 contains the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3). Antibodies containing; (ii) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 contains the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 contains the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 contains the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 contains the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3). Antibodies containing; (iii) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 contains the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 contains the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 contains the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 contains the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3). Antibodies containing; (iv) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 contains the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 contains the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 contains the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 contains the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3). Antibodies containing; (v) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence QNVGSNVDWY [SEQ ID NO: 34] (F1024-1-3 L-CDR1); L-CDR2 contains the sequence KASNRY [SEQ ID NO: 35] (F1024-1-3 L-CDR2); and L-CDR3 contains the sequence MQSNTNPPW [SEQ ID NO: 36] (F1024-1-3 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence DYAMN [SEQ ID NO: 37] (F1024-1-3 H-CDR1); H-CDR2 contains the sequence WINTQTGKPTYADDF [SEQ ID NO: 38] (F1024-1-3 H-CDR2); and H-CDR3 contains the sequence TYFCTRSTFYYSSYIY [SEQ ID NO: 39] (F1024-1-3 H-CDR3). Antibodies containing; (vi) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 contains the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 contains the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 contains the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 contains the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3). Antibodies containing; (vii) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence RASESVDSYGNSFMH [SEQ ID NO: 45] (r18D11 L-CDR1); L-CDR2 contains the sequence LASNLES [SEQ ID NO: 46] (r18D11 L-CDR2); and L-CDR3 contains the sequence QQNNGDPYT [SEQ ID NO: 47] (r18D11 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence TYALN [SEQ ID NO: 48] (r18D11 H-CDR1); H-CDR2 contains the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (r18D11 H-CDR2); and H-CDR3 contains the sequence PQSGTSFAY [SEQ ID NO: 50] (r18D11 H-CDR3). Antibodies containing; and (viii) The following: a) An antibody VL domain or antigen-binding fragment thereof containing L-CDR1, L-CDR2, or L-CDR3, where: L-CDR1 contains the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 contains the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 contains the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3), and b) An antibody VH domain or antigen-binding fragment thereof containing H-CDR1, H-CDR2, or H-CDR3, where: H-CDR1 contains the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 contains the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 contains the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3). Antibodies containing, The method according to any one of embodiments 1 to 12, selected from the above. 14. The aforementioned antigen-binding molecule is as follows: (i) The following: array: VL domains containing, consisting of, or essentially consisting of QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIYRAANLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSYEDPWTFGGGTKLGNQ [Sequence ID 1] (3C10 VL); and array: VH domains containing, consisting of, or essentially consisting of LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTTYYPDNVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYYDYHYWGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH), Antibodies containing; (ii) The following: array: VL domains containing, consisting of, or essentially consisting of QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDPTTFGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); and array: VH domains containing, consisting of, or essentially consisting of LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH), Antibodies containing; (iii) The following: array: VL domains containing, consisting of, or essentially consisting of QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQRGDTLPWTFGGGTKLEIK [Sequence ID 5] (18E12 VL); and array: VH domains containing, consisting of, or essentially consisting of LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVIWTSGGTNYNSAFMSRLSITKDNSESQVFLKMNGLQTDDTGIYYCVRGDGNFYLYNFDYWGQGTTLTVSS [Sequence ID 6] (18E12 VH), Antibodies containing; (iv) The following: array: VL domains containing, consisting of, or essentially consisting of YIVMTQTPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); and array: VH domains containing, consisting of, or essentially consisting of EVKLLESGGGLVQPSQTLSISCKASGYTFTDYAMNWVKQAPGDGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [Sequence ID 58] (F1024-1-3 VH), Antibodies containing; (v) The following: array: VL domains containing, consisting of, or essentially consisting of DIVMTQSPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 59] (F1024 VL); and array: QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMNWVKQAPGNGLKWMGWINTQTGKPTYADDFKQRFVFSLETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [Sequence ID 60] (F1024 VH) contains, consists of, or essentially consists of VH domains, Antibodies containing; (vi) The following: array: VL domains containing, consisting of, or essentially consisting of NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDVATYYCQQNNGDPYTFGGGTKLEIIR [SEQ ID NO: 61] (r18D11 VL); and array: VH domains containing, consisting of, or essentially consisting of EVQLVESGGGLMQPKGSLKLSCAASGFTFKTYALNWVRQAPGTGLEWVARIRSKSNNYTTYYADSVKDRFTISRDDSQNMLYLQMNNLKTEDTAMYYCVRPQSGTSFAYWGQGTLVTVSA [SEQ ID NO: 62] (r18D11 VH), Antibodies containing; and (vii) The following: array: VL domains containing, consisting of, or essentially consisting of DIVMTQSQKFMSTSVGDRVSVTCKASQYVGTNVAWYQQKPGQSPKALIQSASYRCSGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYNTYVTFGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); and array: QVRLQQPGAELVRPGASVKLSCKASGYTFTTYWMNWVKQRPEDGLEWIGRIDPYDSETHYNQNFKDKAILTVDKSSSTAYMQLSSLTYEDSAVYYCTRKEGRQWGAYFDYWGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH) contains, consists of, or essentially consists of VH domains, Antibodies containing, The method according to any one of embodiments 1 to 13, selected from among them. 15. The method according to any one of Embodiments 1 to 14, wherein the antigen-binding molecule is a humanized molecule or a chimeric molecule. 16. The antigen-binding molecule comprises a light chain and a heavy chain, wherein: The light chain has the following amino acid sequence: The heavy chain comprises METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 25] and the heavy chain has the following amino acid sequence: MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCV RGLRFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR The method according to any one of Embodiments 1 to 15, including VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [Sequence ID 26]. 17. The method according to any one of Embodiments 1 to 16, wherein the antigen-binding molecule is an IC14 antibody. 18. The method according to any one of Embodiments 1 to 17, wherein the ACM is arrhythmogenic right ventricular cardiomyopathy (ARVC). 19. The method according to any one of embodiments 11 and 13-16, wherein the symptoms of atrial fibrillation are tachycardia, arrhythmia, chest pain, dizziness, syncope, shortness of breath, heart failure, stroke, or death. 20. The method according to any one of embodiments 12 to 16, wherein the subject is suffering from atrial fibrillation (AF). twenty one. The method according to any one of Embodiments 1 to 20, wherein the subject has an implantable cardioverter-defibrillator (ICD). twenty two. The method according to Embodiment 21, wherein the administration of the CD14 antagonist antigen-binding molecule reduces the number of electric shocks administered to the subject by the ICD. twenty three. The method according to any one of embodiments 1 to 7 and 9 to 22, wherein administration of the CD14 antagonist antigen-binding molecule improves the measured value of the target ventricular function. twenty four. The method according to Embodiment 23, wherein the measured value of ventricular function is ventricular strain, systolic function, or diastolic function. twenty five. The method according to Embodiment 23 or Embodiment 24, wherein the ventricular function is measured by echocardiography, Holter monitoring, cardiac CT scan, or cardiac magnetic resonance imaging. 26. The method according to any one of Embodiments 1 to 25, wherein the subject has one or more mutations in a gene related to ACM. 27. The method according to Embodiment 26, wherein the gene related to the ACM is a gene encoding a component of the desmosome. 28. The method according to Embodiment 27, wherein the gene encodes placofilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocolin-2 (DSC2), or placoglobin (JUP). 29. The method according to Embodiment 27, wherein the gene related to ACM 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). 30. The method according to any one of Embodiments 1 to 29, wherein the subject is a human, a canid, a feline, or a horse. 31. The method according to Embodiment 30, wherein the subject is a human. 32. The method according to any one of Embodiments 1 to 31, wherein the CD14 antagonist antigen-binding molecule is administered systemically. 33. The method according to any one of Embodiments 1 to 31, wherein the CD14 antagonist antigen-binding molecule is administered locally to the target heart (e.g., the left ventricle). 34. The method according to any one of Embodiments 1 to 33, wherein the CD14 antagonist antigen-binding molecule is administered in a daily dose of approximately 0.1 mg / kg to 50 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 0.2 mg / kg to 40 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 0.5 mg / kg to 40 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 1 mg / kg to 30 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 2 mg / kg to 20 mg / kg (and all integer mg / kg units with one decimal place in between), approximately 4 mg / kg to 15 mg / kg (and all integer mg / kg units with one decimal place in between), or approximately 5 mg / kg to 10 mg / kg (and all integer mg / kg units with one decimal place in between). 35. The method according to Embodiment 34, wherein the aforementioned daily dose is administered in a single dose. 36. The method according to Embodiment 34, wherein the aforementioned daily dose is administered in two doses. 37. The method according to any one of Embodiments 1 to 36, wherein the CD14 antagonist antigen-binding molecule is administered in weekly doses of approximately 1 mg / kg to 30 mg / kg (and all integer mg / kg units in between), approximately 2 mg / kg to 20 mg / kg (and all integer mg / kg units in between), approximately 4 mg / kg to 15 mg / kg (and all integer mg / kg units in between), or approximately 5 mg / kg to 10 mg / kg (and all integer mg / kg units in between). 38. The method according to any one of Embodiments 1 to 37, wherein the CD14 antagonist antigen-binding molecule is administered to the subject over a period of approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 7 months, approximately 8 months, approximately 9 months, approximately 10 months, approximately 11 months, approximately 1 year, approximately 14 months, approximately 16 months, approximately 18 months, approximately 20 months, approximately 22 months, or approximately 2 years. 39. The method according to any one of Embodiments 1 to 38, wherein the subject is a subject who has never undergone cardiopulmonary bypass surgery. 40. The method according to any one of Embodiments 1 to 39, wherein the subject is not a patient with acute myocardial infarction. 41. The method according to any one of Embodiments 1 to 40, comprising simultaneously administering the aforementioned auxiliary ACM treatment agent or intervention to the subject. 42. The aforementioned adjunct ACM treatment agents include angiotensin-converting enzyme inhibitors (e.g., Enalipril, Lisinopril), angiotensin receptor blockers (e.g., Losartan, Valsartan), beta-blockers (e.g., Lopressor, Toprol-XL), antiarrhythmics (e.g., amiodarone (Cordarone, Pacerone), flecainide (Tambocor), ibutilide (Corvert), lidocaine (Xylocaine), procainamide (Procan, Procanbid), propafenone (Rythmol), quinidine, tokainide (Tonocarid)), digoxin, and diuretics (e.g., La six; or the method according to Embodiment 41, for example, selected from levodopa, dopamine agonists (e.g., Parkinson's disease treatments including bromocriptine, pergolide, pramipexole, rapinirole, piribedil, cabergoline, apomorphine, rislid), 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, thiadiazolidinedione, and nonsteroidal anti-inflammatory drugs. 43. The method according to any one of embodiments 1 to 42, further comprising performing a surgical procedure on the subject, wherein the surgical procedure is suitable for treating ACM. 44. The method according to Embodiment 43, wherein the surgical procedure includes percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass including coronary artery bypass grafting (CABG), pacemaker implantation, implantation of an implantable cardioverter-defibrillator (ICD), cardiac catheterization, vascular regeneration, and heart transplantation. 45. The method according to Embodiment 43 or Embodiment 44, wherein the surgical procedure is performed before, simultaneously with, or after the administration of a CD14 antagonist antigen-binding molecule, optionally together with an adjunct ACM therapeutic agent. 46. A CD14 antagonist antigen-binding molecule for use in treating or alleviating at least one symptom of ACM. 47. A CD14 antagonist antigen-binding molecule for use in alleviating or inhibiting the development of adverse cardiac remodeling in ACM 48. A CD14 antagonist antigen-binding molecule for use in improving cardiac function in ACM. 49. A CD14 antagonist antigen-binding molecule for use in improving ventricular function in ACM. <S 50. A CD14 antagonist antigen-binding molecule for use in improving atrial function in ACM. 51. A CD14 antagonist antigen-binding molecule for use in reducing the number of premature ventricular contractions (PVCs) in ACM. 52. A CD14 antagonist antigen-binding molecule for use in treating or alleviating at least one symptom of atrial fibrillation in ACM. 53. A CD14 antagonist antigen-binding molecule for use in reducing the number of premature atrial contractions (PACs) in ACM. 54. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for treating or alleviating at least one symptom of ACM. 55. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for alleviating or inhibiting the development of adverse cardiac remodeling in ACM. 56. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for improving cardiac function in ACM. [[ID=4」]] 57. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for improving ventricular function in ACM. 58. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for improving atrial function in ACM. 59. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for reducing the number of premature ventricular contractions (PVC) in ACM. 60. 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 in ACM. 61. Use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for reducing the number of premature atrial contractions (PAC) in ACM. 62. Use according to any one of embodiments 55 to 61, wherein the CD14 antagonist antigen-binding molecule is used in combination with one or more auxiliary ACM therapeutic agents or interventions.

[0171] To facilitate understanding of the present disclosure and its practical implementation, specific preferred embodiments will be described as the following non-limiting examples.

Example

[0172] Example 1 Inhibition of the development of arrhythmogenic cardiomyopathy using an anti-CD14 antibody Arrhythmogenic cardiomyopathy (ACM) is a name applied to a spectrum of cardiomyopathies and dysfunctions with right-dominant (ARVC), left-dominant (ALVC) or biventricular patterns and non-ischemic cardiomyopathy. Most cases are caused by mutations in genes encoding desmosomal proteins. In addition to forming intercellular adhesion junctions, some desmosomal proteins are involved in important signaling cascades including the Wnt and Hippo pathways where alterations there are related to the pathogenesis of ACM. However, little is known about exactly how mutations in desmosomal genes lead to the complex clinical picture of arrhythmias and progressive cardiomyopathy.

[0173] 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 compared to many other forms of heart disease. Fortunately, sudden death in young adults is rare, but they are clearly a great disappointment to families where other members are also at high risk.

[0174] There are no drug therapies for acute cardiomyopathy (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 high costs, associated physiological stress, and quality of life issues. However, perhaps the most serious limitation is that ICDs do not treat the underlying cardiomyopathy or prevent its progression. Even if the risk of sudden death is reduced, chronically progressing cardiomyopathy can progress to severe heart failure, for which the only treatment is a heart transplant.

[0175] Current, undeniable evidence indicates that ACM is a chronic inflammatory disease. Inflammation in ACM has traditionally been considered in association with inflammatory cell infiltration in the heart, which is common in ACM patients. While these inflammatory cells are likely to contribute to cardiomyopathy, we also know that in ACM, cardiomyocytes themselves possess a vigorous innate immune response, producing large amounts of potent pro-inflammatory signaling molecules. The activation of the innate immune response in cardiomyocytes occurs early in ACM, and it is thought to be a cell-autonomous process driven by upstream signaling from the ACM disease allele. It is also a long-lasting and uninterrupted process.

[0176] Based on unpublished data showing that activation of the innate immune response in cardiomyocytes is the primary mechanism promoting myocardial damage in ACM, and that disease progression is also mediated by the action of pro-inflammatory macrophages mobilized by signals from cardiomyocytes, we have investigated whether CD14 blockade is effective in treating or delaying the onset or progression of ACM. mut / mut We proposed testing anti-CD14 antagonist antibodies in a mouse model.

[0177] Dsg2 mut / mut While mice show little apparent structural or functional disturbance of the heart at 8 weeks of age, over the following 8 weeks they develop a robust phenotype encompassing the most important clinical features seen in ACM patients, namely myocardial damage and arrhythmias, as illustrated in Figure 1. This includes a progressive decline in ventricular contractility associated with the development of extensive myocardial necrosis, fibrosis, and inflammation. It also includes ECG abnormalities and arrhythmias. These structural and functional changes are associated with a clear 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), chaperone proteins involved in ion channel transport to intercalations. If the disease progresses beyond 16 weeks, there is a gradual decrease in ejection fraction due to significant progression of myocardial fibrosis and inflammation.

[0178] Started at 8 weeks of age, Dsg2 mut / mut Mice and wild-type (WT) control mice were administered intraperitoneal (ip) injections of anti-CD14 mAb or isotype control antibody at 14-day intervals over an 8-week period. The results shown in Figures 2-6 are for Dsg2 at 16 weeks of age in mice treated with the isotype control. mut / mutThis study reveals that the mice exhibited many features representative of human ACM, including increased left ventricular muscle mass (LVM) suggesting hypertrophic remodeling and reduced right ventricular area change (RVFAC), increased ventricular premature contractions (PVCs), and increased fibrosis as measured by histological analysis.

[0179] In contrast, Dsg2 mut / mut Anti-CD14 treatment in mice was protective in all of these pathological changes. In particular: Anti-CD14 treatment restored %LVEF to levels seen in wild-type animals (Figure 2). Anti-CD14 therapy prevented right ventricular dysfunction by normalizing %RVFAC (Figure 3). Anti-CD14 therapy reduced ectopic heartbeats by reducing the frequency of PVCs, as measured by ECG (Figure 4). Anti-CD14 therapy restores LVM to levels seen in wild-type animals, thereby minimizing hypertrophic remodeling (Figure 5). Anti-CD14 therapy reduced cardiomyopathy, as measured by histological analysis of fibrosis (Figure 6).

[0180] Therefore, anti-CD14 therapy is used in Dsg2 of arrhythmogenic cardiomyopathy. mut / mut In the model, it inhibited the development of ventricular dysfunction and undesirable cardiac remodeling. Anti-CD14 treatment Dsg2 mut / mut Further investigations are underway to measure changes in inflammatory cytokines and immune cell populations in the heart.

[0181] These studies highlight the important role played by CD14 in mediating disease progression in a murine ACM model in which ventricular function was maintained, PVC frequency was reduced, and pathologic adverse cardiac remodeling was attenuated or prevented by CD14 blockade. Given the underlying myocardial disease and ongoing disease progression seen in ACM patients eligible for ICD therapy, CD14 blockade may be effective and ultimately help mitigate the chronic progressive cardiomyopathy leading to heart failure and heart transplantation. Materials and Methods Mouse Model of ACM

[0182] The laboratory of Jeffrey Saffitz at Beth Israel Deaconess Medical Center has a robust mouse model of ACM that expresses a mutation within the gene for the desmosomal protein desmoglein-2. Beginning at 8 weeks of age, Dsg2 mut / mut mice begin to show important features seen in ACM patients, including myocardial injury (necrosis / fibrotic foci, myocyte apoptosis), systolic dysfunction, action potential remodeling and ventricular arrhythmias, and inflammation (inflammatory infiltrates, production of inflammatory cytokines) with activated NFκB in cardiomyocytes. Experimental Design <0,

[0183] Beginning at 8 weeks of age, Dsg2 mut / mut mice and WT control mice (n = 7 - 10 / group) were given intraperitoneal (i.p.) injections of anti-CD14 mAb (biG53LALA-PG) or isotype control antibody. Mice were injected every 14 days (100 μL of anti-CD14 or isotype) at a dosage of 5 mg / kg. Readouts

[0184] Mice were echocardiographically examined 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 (8th week of dosing), after which the mice were sacrificed. The ECGs were evaluated for ventricular premature contractions (PVCs) and runs of ventricular tachycardia; echocardiographic parameters included ejection fraction and ventricular wall / chamber measurements. At sacrifice, the hearts were isolated, 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

[0185] The inventors also mut / mut Tested in a mouse model whether an anti-CD14 antagonist antibody treats or delays the progression of ACM and whether it promotes recovery of systolic dysfunction in animals with established disease.

[0186] Starting at 16 weeks of age, mut / mut Mice and WT control mice were given i.p. injections of anti-CD14 mAb or isotype control antibody at 14-day intervals over 8 weeks. The results shown in Figures 7-9 revealed that Dsg2 mice at 24 weeks of age treated with isotype control had significantly worse disease symptoms, including significantly lower %LVEF and significantly higher fibrosis compared to before they were administered the isotype control antibody at 16 weeks of age. mut / mut

[0187] On the other hand, Dsg2 mice treated with anti-CD14 at 16 weeks of age significantly impeded or delayed further disease progression, including reduction of further worsening of % LVEF (Figures 7, 8) and myocardial fibrosis (Figure 9). mut / mut

[0188] Thus, anti-CD14 treatment of animals with established disease stabilized cardiomyopathy by preventing or significantly slowing further worsening of ventricular dysfunction and adverse cardiac remodeling.

[0189] All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0190] The references made herein should not be construed as an admission that such references are available as “prior art” to this application.

[0191] Throughout this specification, the objective has been to describe preferred embodiments of the Disclosure without limiting the Disclosure to any one embodiment or particular set of features. Accordingly, those skilled in the art will understand that various modifications and alterations can be made in light of the Disclosure without departing from the scope of the exemplified particular embodiments. All such modifications and alterations are intended to be included in the appended claims.

Claims

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

2. The method according to 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, dizziness, syncope, dyspnea, peripheral edema, abdominal distension, myocardial fibrofatty infiltration, embolism, fainting, angina, exercise intolerance, orthopnea, heart failure, and acute cardiac death (SCD).

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

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

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

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

7. The method according to claim 6, wherein the improvement in cardiac function includes improvement in left ventricular function, improvement in diameter shortening rate, improvement in ejection fraction, reduction in end-diastolic volume, reduction in left ventricular muscle mass, reduction in arrhythmias, reduction in the frequency of heart murmurs, reduction in heart rate, normalization of cardiac shape, or a combination thereof.

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

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

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

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

12. A method for reducing the number of atrial premature contractions in a subject suffering from ACM, comprising, consisting of, or essentially consisting of, administering a CD14 antagonist antigen-binding molecule to the subject.

13. The method according to any one of claims 1 to 12, wherein the ACM is arrhythmogenic right ventricular cardiomyopathy (ARVC).

14. The method according to claim 11 or claim 13, wherein the symptoms of atrial fibrillation are tachycardia, arrhythmia, chest pain, dizziness, syncope, shortness of breath, heart failure, stroke, or death.

15. The method according to any one of claims 12 to 14, wherein the subject is suffering from atrial fibrillation (AF).

16. The method according to any one of claims 1 to 15, wherein the subject has an implantable cardioverter-defibrillator (ICD).

17. The method according to claim 16, wherein administration of the CD14 antagonist antigen-binding molecule reduces the number of electric shocks administered to the subject by an ICD.

18. The method according to any one of claims 1 to 7 and 9 to 17, wherein administration of the CD14 antagonist antigen-binding molecule improves the measured value of the target ventricular function.

19. The method according to claim 18, wherein the measured value of ventricular function is ventricular strain, systolic function, or diastolic function.

20. The method according to claim 18 or 19, wherein the ventricular function is measured by echocardiography, Holter monitoring, cardiac CT scan, or cardiac magnetic resonance imaging.

21. The method according to any one of claims 1 to 20, wherein the subject has one or more mutations in a gene related to ACM.

22. The method according to claim 21, wherein the gene related to the ACM is a gene that codes for a component of the desmosome.

23. The method according to claim 22, wherein the gene encodes placofilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocolin-2 (DSC2), or placoglobin (JUP).

24. The method according to claim 22, wherein the gene related to ACM 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).

25. The method according to any one of claims 1 to 24, wherein the subject is a human.

26. The method according to any one of claims 1 to 25, wherein the CD14 antagonist antigen-binding molecule is administered systemically.

27. The method according to any one of claims 1 to 25, wherein the CD14 antagonist antigen-binding molecule is administered locally to the target heart (e.g., the left ventricle).

28. The method according to any one of claims 1 to 27, further comprising co-administering at least one adjunct therapeutic agent or intervention for treating or inhibiting the development of ACM with a CD14 antagonist antigen-binding molecule.

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