Methods and agents for treating blood flow disorders

Abstract

Disclosed are methods and agents for treating heart failure. More particularly, the present disclosure relates to the use of CD14 antagonist antigen-binding molecules for treating heart failure, including alleviating, reducing or reversing adverse cardiac structural remodeling, improving cardiac contractile function, improving ejection fraction (e.g., left ventricular ejection fraction), left ventricular end-systolic volume, left ventricular end- diastolic volume, left ventricular akinesia, left ventricular dilatation, and / or left ventricular hypertrophy, reducing dyspnea, improving congestion score and / or patient perception of their health status and / or reducing neutrophil / lymphocyte ratio.

Description

METHODS AND AGENTS FOR TREATING BLOOD FLOW DISORDERS1FIELD

[0001] This application claims priority to United States Provisional Application No. 63 / 709896 filed 21 October 2024 entitled "Methods and agents for treating blood flow disorders" and Australian Provisional Application No. 2024903589 filed 4 November 2024 entitled "Methods and agents for treating blood flow disorders", the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates generally to methods and agents for treating heart failure. More particularly, the present disclosure relates to the use of CD14 antagonist antigenbinding molecules for treating heart failure, including alleviating, reducing or reversing adverse cardiac structural remodeling, improving cardiac contractile function, improving ejection fraction (e.g., left ventricular ejection fraction), left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular akinesia, left ventricular dilatation, and / or left ventricular hypertrophy, reducing dyspnea, improving congestion score and / or patient perception of their health status and / or reducing neutrophil I lymphocyte ratio.BACKGROUND

[0003] Heart Failure (HF) is a multi-faceted and life-threatening syndrome caused by structural and functional cardiac abnormalities with an estimated prevalence of more than 65 million people globally. Although heart failure affects people of all ages, the risk of heart failure increases with age and is most common among older people. Accordingly, the number of people living with heart failure is expected to increase significantly as the elderly population grows over the next few decades. Most recent projections for the US suggest that the prevalence of HF will rise from about 6.7 million Americans over the age of 20 in 2024 to 8.7 million in 2030, 10.3 million in 2040, and 11.4 million by 2050, with 1 in 4 persons projected to develop HF in their lifetime (Bozkurt et al., J Card Fail. 2024;Sep 14:S1071-9164).

[0004] HF is characterized by recurrent episodes of decompensation that frequently result in hospitalization or death. The decompensation is associated with structural or functional changes in the heart that lead to its inability to eject and / or accommodate blood within physiological pressure levels, thus causing a functional limitation and requiring immediate therapeutic intervention. These structural or functional changes include decreased cardiac output, decreased cardiac contractility, abnormal diastolic compliance, reduced stroke volume, and pulmonary congestion. The clinical manifestations of heart failure reflect a decrease in the myocardial contractile state and a reduction in cardiac output. Apart from deficiencies in cardiac contractility, the HF disease state may arise from left ventricular failure, right ventricular failure, biventricular failure, systolic dysfunction, diastolic dysfunction, and pulmonary effects. A progressive decrease in the contractile function of cardiac muscle, associated with heart disease, often leads to hypoperfusion of critical organs.

[0005] The causes of HF have been linked to various disorders including coronary artery disease, past myocardial infarction, hypertension, abnormal heart valves, myocarditis, congenital heart disease, severe lung disease, diabetes, severe anemia, hyperthyroidism, arrhythmia or dysrhythmia.

[0006] Current pharmacological approaches for treating HF include drugs that slow progress of the disease, including blockers of the renin-angiotensin aldosterone system (RAAS), beta blockers, and the anti-hypertensive hydralazine, each of which carries risk of serious side effects. HF treatments also include drugs that relieve symptoms of HF, including diuretics, Na+ / K+ ATPase inhibitors, and nitrates, but such drugs have not been shown to improve mortality rates when provided on their own. Despite the advances made by these established therapies, mortality / morbidity remains high and affected patients have a poor quality of life.

[0007] Accordingly, there is a clear unmet need for effective and safe medical therapies for patients with HF.SUMMARY

[0008] The present disclosure is based in part on the unexpected determination that targeting Cluster of Differentiation 14 (CD14) through administration of a CD14 antagonist antibody can significantly slow or reverse progression of HF, including HF with reduced ejection fraction (HFrEF). In particular, it has been found that administration of a CD14 antagonist antibody to animals with established HF, including end-stage / worsening / acute decompensated HF, significantly improves left ventricular (LV) ejection fraction (LVEF), as shown in Figures 2 and 8, reduces LV akinetic area ( / .e., non-contracting heart muscle), as shown in Figure 3, reduces LV end-systolic volume (LVESV), as shown in Figure 4, reduces LV end-diastolic volume (LVEDV), as shown in Figure 5, reduces dyspnea, as shown in Figure 6, improves congestion score, as shown in Figure 7, significantly improves patient perception of their health status as shown in Figure 9, and reduces neutrophil I lymphocyte ratio (NLR), as shown in Figure 10. These findings are remarkable as they indicate that CD14 blockade improves cardiac contractile function, as well as leading to LV reverse remodeling and recovery of cardiac function in subjects with established HF.

[0009] Based on these findings, the present inventors propose that CD14 antagonists generally, including CD14 antagonist antigen-binding molecules, are useful for treating or alleviating at least one sign or symptom of HF, including HFrEF, for reducing progression of HF, for improving, increasing, recovering or restoring cardiac function, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for improving cardiac contractile function in HF, for improving cardiac output in HF, for ameliorating or increasing ejection fraction (e.g., LVEF) in HF, for ameliorating or reducing LVESV in HF, for ameliorating or reducing LVEDV in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, for ameliorating or reducing LV mass in HF, for ameliorating or reducing dyspnea in HF, for ameliorating or reducing congestion score in HF, for ameliorating or improving patient perception of health status in HF, and / or for ameliorating or reducing NLR in HF, as described hereafter.

[0010] Accordingly, in one aspect, the present disclosure provides methods of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject. These methods generally comprise, consist or consist essentially of administering to the subject a CD14 antagonist antigen-binding molecule. The HF may be HF with preserved ejection fraction (HFpEF), HFrEF or HF with mildly reduced ejection fraction (HFmrEF). The HF may be acute HF (AHF), acute decompensated HF (ADHF), or chronic HF (CHF).

[0011] The HF may be Class I HF, Class II HF, Class III HF or Class IV HF according to the New York Heart Association (NYHA) classification scale. The subject may be a patient withstage of progression of HF as classified according to the American College of Cardiology / American Heart Association (ACC / AHA) HF guidelines. For example, the subject may have Stage A progression of HF and is at high risk of heart failure but has no structural heart disease or symptoms of heart failure. In representative examples of this type, the subject is asymptomatic with risk factors such as diabetes or hypertension but no known cardiac changes. Alternatively, the subject may have Stage B progression of HF, having structural heart disease but no symptoms of heart failure. Illustrative examples of this type include subjects with cardiac structural changes or elevated natriuretic peptides, but still in the absence of symptoms. In other embodiments, the subject may have Stage C progression of HF, having structural heart disease and symptoms of heart failure. In other embodiments, the subject may have Stage D progression of HF, having refractory heart failure requiring specialized intervention. In representative examples of this type, the subject has severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).

[0012] The at least one sign may be selected from elevated jugular venous pressure, jugular venous dilatation, third heart sound e.g., gallop rhythm), laterally displaced apical impulse, congested hepatomegaly, hepatojugular reflux, ascites, symptoms of gut congestion, weight gain (e.g., >2 kg / week), anorexia, weight loss (e.g., in advanced heart failure), cachexia, cardiac murmur, high neutrophil / lymphocyte ratio (NLR), peripheral edema (e.g., ankle, sacral, scrotal), pulmonary congestion, pulmonary edema (e.g., acute pulmonary edema), pulmonary rales, pulmonary crepitations, reduced air entry and dullness to, percussion at lung bases (e.g., pleural, effusion), arrhythmias, atrial fibrillation, atrial flutter, tachycardia (e.g., ventricular tachycardia), irregular pulse, tachypnea, Cheyne-Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, nocturia, and narrow pulse pressure.

[0013] The at least one symptom may be selected from breathlessness, orthopnea, paroxysmal nocturnal dyspnea, exertional dyspnea, dyspnea at rest, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling, nocturnal cough, wheezing, bloated feeling, loss of appetite, nausea, confusion (e.g., in the elderly), depression, palpitations, dizziness, syncope, and bendopnea.

[0014] The administration of the CD14 antagonist antigen-binding molecule suitably improves one or more clinical parameters of the subject, representative examples of which include cardiac function, adverse cardiac structural remodeling, cardiac contractile function, cardiac output, ejection fraction (e.g., LVEF), LVESV, LVEDV, LV akinesia, LV dilatation, LV hypertrophy, dyspnea, congestion score, patient perception of health status, and / or NLR. In illustrative examples of this type, the administration of the CD14 antagonist antigen-binding molecule may improve, recover or restore cardiac function, may ameliorate or reverse adverse cardiac structural remodeling, may increase or improve cardiac contractile function, or restore cardiac contractile function to a normal range, may increase or improve cardiac output, or restore cardiac output to a normal range, may increase or improve ejection fraction (e.g., LVEF), or restore ejection fraction (e.g., LVEF) to a normal range, may reduce or improve LVESV, or restore LVESV to a normal range, may reduce or improve LVEDV, or restore LVEDV to a normal range, may ameliorate or reduce LV akinetic area, may ameliorate or reduce LV dilatation, and / or may reduce or improve LV mass, or restore LV mass to a normal range, may ameliorate or reduce dyspnea, may ameliorate or reduce congestionscore, may ameliorate or improve patient perception of health status, and / or may ameliorate or reduce NLR or restore NLRto a normal range.

[0015] In related aspects, methods are disclosed for increasing, improving or recovering cardiac function or restoring cardiac function to a normal range, for ameliorating, reducing or reversing adverse cardiac structural remodeling, for increasing or improving cardiac contractile function or restoring cardiac contractile function to a normal range, for increasing or improving cardiac output or restoring cardiac output to a normal range, for increasing or improving ejection fraction {e.g., LVEF), or restoring ejection fraction {e.g., LVEF) to a normal range, for reducing or improving LVESV, or restoring LVESV to a normal range, for reducing or improving LVEDV, or restoring LVEDV to a normal range, for ameliorating or reducing LV akinetic area, for ameliorating or reducing LV dilatation, for reducing or improving LV mass, or restoring LV mass to a normal range, for ameliorating or reducing dyspnea, for ameliorating or reducing congestion score, for ameliorating or improving patient perception of health status, and / or for ameliorating or reducing NLR or restoring NLR to a normal range, in a subject with HF. These methods generally comprise, consist or consist essentially of administering to the subject a CD14 antagonist antigenbinding molecule. In some embodiments in which cardiac contractile function is improved, the improvement comprises increasing, improving or recovering cardiac function or restoring cardiac function to a normal range, increasing or improving cardiac output or restoring cardiac output to a normal range, increasing or improving LV function or restoring LV function to a normal range, increasing or improving LV fractional shortening or restoring LV fractional shortening to a normal range, increasing or improving ejection fraction or restoring ejection fraction to a normal range, reducing or improving end-diastolic volume or restoring end-diastolic volume to a normal range, decreasing or improving LV mass or restoring LV mass to a normal range, ameliorating or reducing dyspnea, ameliorating or reducing congestion score, ameliorating or improving patient perception of health status, ameliorating or reducing NLR or restoring NLR to a normal range, decreasing arrhythmias, reducing frequency of heart murmurs, reducing heart rate, normalizing of heart geometry, or a combination of any two or more thereof.

[0016] In related aspects, methods are disclosed for treating, inhibiting or reducing progression of HFpEF, or alleviating at least one sign or symptom of HFpEF, or for treating, inhibiting or reducing progression of HFrEF, or alleviating at least one sign or symptom of HFrEF, or for treating, inhibiting or reducing progression of HFmrEF, or alleviating at least one sign or symptom of HFmrEF, or for treating, inhibiting or reducing progression of CHF, or alleviating at least one sign or symptom of CHF, or for treating, inhibiting or reducing progression of CHF, or alleviating at least one sign or symptom of AHF, or for treating, inhibiting or reducing progression of CHF, or alleviating at least one sign or symptom of ADHF, in a subject. These methods generally comprise, consist or consist essentially of administering to the subject a CD14 antagonist antigenbinding molecule.

[0017] Disclosed herein in related aspects are methods for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject with Class I HF, with Class II HF, with Class III HF or with Class IV HF, wherein respective classes are according to the NYHA classification scale. These methods generally comprise, consist or consist essentially of administering to the subject a CD14 antagonist antigen-binding molecule.

[0018] In related aspects, methods are disclosed for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject wherein the subject is a patient with a stage of progression of HF as classified according to the ACC / AHA HF guidelines, wherein the stage of progression is selected from a Stage A patient, a Stage B patient, a Stage C patient and a Stage B patient. These methods generally comprise, consist or consist essentially of administering to the subject a CD14 antagonist antigen-binding molecule.

[0019] In any of the aspects and embodiments disclosed herein, the administration of the CD14 antagonist antigen-binding molecule to the subject results in the subject experiencing one or more of: a shortened duration of hospital stay, an increase in the number of days between hospital stays, a reduced risk of hospitalization, an increase in the time before an initial hospitalization, or a fewer number of hospitalizations relative to a subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule.

[0020] In any of the aspects and embodiments disclosed herein, the antigen-binding molecule may be selected from:(i) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3);(ii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3);(iii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3);(iv) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigenbinding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3);(v) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence QNVGSNVDWY [SEQ ID NO: 34] (F1024-1-3 L-CDR1); L-CDR2 comprises the sequence KASNRY [SEQ ID NO: 35] (F1024-1-3 L-CDR2); and L-CDR3 comprises the sequence MQSNTNPPW [SEQ ID NO: 36] (F1024-1-3 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence DYAMN [SEQ ID NO: 37] (F1024-1-3 H-CDR1); H-CDR2 comprises the sequence WINTQTGKPTYADDF [SEQ ID NO: 38] (F1024-1-3 H-CDR2); and H-CDR3 comprises the sequence TYFCTRSTFYYSSYIY [SEQ ID NO: 39] (F1024-1-3 H-CDR3);(vi) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 comprises the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 comprises the sequence MQSNTNPPWT [SEQ ID NO: 42] (Fl 024 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 comprises the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 comprises the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3);(vii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYGNSFMH [SEQ ID NO: 45] (rl8Dll L-CDR1); L-CDR2 comprises the sequence LASNLES [SEQ ID NO: 46] (rl8Dll L-CDR2); and L-CDR3 comprises the sequence QQNNGDPYT [SEQ ID NO: 47] (rl8Dll L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence TYALN [SEQ ID NO: 48] (rl8Dll H-CDR1); H-CDR2 comprises the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (rl8Dll H-CDR2); and H-CDR3 comprises the sequence PQSGTSFAY [SEQ ID NO: 50] (rl8Dll H-CDR3); and(viii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 comprises the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 comprises the sequence QQYNTYVT [SEQ ID NO: 53] (rM il2 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 comprises the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 comprises the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMi!2 H-CDR3).

[0021] In specific embodiments, the antigen-binding molecule is selected from:(I) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIYRAANLESGIPARFSGSGSRTDFTLT INPVEADDVATYFCQQSYEDPWTFGGGTKLGNQ [SEQ ID NO: 1] (3C10 VL); anda VH domain that comprises, consists or consists essentially of the sequence:LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTTYYPDNVKGRFTISRDNARNILYLQMS SLRSEDTAMYYCARGYYDYHYWGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH);(ii) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDPTTFGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); anda VH domain that comprises, consists or consists essentially of the sequence:LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSK NQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH);(iii) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQ EDFATYFCQRGDTLPWTFGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); anda VH domain that comprises, consists or consists essentially of the sequence:LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVIWTSGGTNYNSAFMSRLSITKDNSESQ VFLKMNGLQTDDTGIYYCVRGDGNFYLYNFDYWGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH);(iv) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:YIVMTQTPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTF TISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); anda VH domain that comprises, consists or consists essentially of the sequence:EVKLLESGGGLVQPSQTLSISCKASGYTFTDYAMNWVKQAPGDGLKWMGWINTQTGKPTYADDFKQRFVFSL ETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 58] (F1024-1- 3 VH);(v) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:DIVMTQSPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFT FTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 59] (F1024 VL); anda VH domain that comprises, consists or consists essentially of the sequence:QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMNWVKQAPGNGLKWMGWINTQTGKPTYADDFKQRFVFSL ETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 60] (F1024 VH).(vi) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRT DFTLTIDPVEADDVATYYCQQNNGDPYTFGGGTKLEIIR [SEQ ID NO: 61] (rl8Dll VL); anda VH domain that comprises, consists or consists essentially of the sequence:EVQLVESGGGLMQPKGSLKLSCAASGFTFKTYALNWVRQAPGTGLEWVARIRSKSNNYTTYYADSVKDRFTIS RDDSQNMLYLQMNNLKTEDTAMYYCVRPQSGTSFAYWGQGTLVTVSA [SEQ ID NO: 62] (rl8Dll VH); and(vii) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:DIVMTQSQKFMSTSVGDRVSVTCKASQYVGTNVAWYQQKPGQSPKALIQSASYRCSGVPDRFTGSGSGTDF TLTISNVQSEDLADYFCQQYNTYVTFGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); anda VH domain that comprises, consists or consists essentially of the sequence:QVRLQQPGAELVRPGASVKLSCKASGYTFTTYWMNWVKQRPEDGLEWIGRIDPYDSETHYNQNFKDKAILTV DKSSSTAYMQLSSLTYEDSAVYYCTRKEGRQWGAYFDYWGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH).

[0022] The antigen-binding molecule may be humanized or chimeric.

[0023] Representative examples of the antigen-binding molecule comprise a light chain and a heavy chain, wherein:the light chain comprises the amino acid sequence:METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPP KLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 25]; andthe heavy chain comprises the amino acid sequence:MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGY ISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 26].

[0024] In a specific embodiment, the antigen-binding molecule is atibuclimab.

[0025] In any of the aspects and embodiments disclosed herein, the subject is suitably a subject with established HF.

[0026] In any of the aspects and embodiments disclosed herein, the subject is suitably a mammal, representative examples of which include humans, canines, felines, equines, bovines, ovines and porcines. In preferred embodiments, the subject is a human.

[0027] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered systemically, or locally to the heart (e.g., left ventricle) of the subject.

[0028] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule is typically administered in an effective amount. The effective amount is suitably one for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, for improving, increasing, recovering or restoring cardiac function, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving LVEF, or restoring LVEF to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV toa normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, for reducing or improving LV mass in HF, for ameliorating or reducing dyspnea in HF, for ameliorating or reducing congestion score in HF, for ameliorating or improving patient perception of health status in HF, and / or for ameliorating or reducing NLR or restoring NLR to a normal range in HF.

[0029] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a daily dose of between about 0.1 mg / kg and 50 mg / kg (and all one tenth integer mg / kg units in between), or between about 0.2 mg / kg and 40 mg / kg (and all one tenth integer mg / kg units in between), or between about 0.5 mg / kg and 40 mg / kg (and all one tenth integer mg / kg units in between), or between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).

[0030] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a weekly dose of between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).

[0031] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a fortnightly dose of between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).

[0032] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a monthly dose of between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).

[0033] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, or at a dosage range between any of the preceding values.

[0034] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered to the subject over a period of about 1 day, or over a period of about 2 days, or over a period of about 3 days, or over a period of about 4 days, or over a period of about 5 days, or over a period of about 6 days, over a period of about 1 week, or over a period of about 2 weeks, or over a period of about 3 weeks, or over a period of about 4 weeks, or over a period of about 5 weeks, or over a period of about 6 weeks, or over a period of about 2 months, or over a period of about 3 months, or over a period of about 4 months, or over a period of about 5 months, or over a period of about 6 months, or over a period of about 7 months, or over a period of about 8 months, or over a period of about 9 months, or over a period of about 10 months, or over a period of about 11 months, or over a period of about 1 year, or over a period of about 14 months, or over a period of about 16 months, or over a period of about 18 months, or over a period of about 20 months, or over a period of about 22 months, or over a period of about 2 years.

[0035] In any of the aspects and embodiments disclosed herein, the subject may be administered a single dose of the CD14 antagonist antigen-binding molecule for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF.

[0036] In any of the aspects and embodiments disclosed herein, the subject may be administered a plurality of doses of the CD14 antagonist antigen-binding molecule for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF. In specific embodiments, the subject is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses of the CD14 antagonist antigen-binding molecule for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF. In representative examples of this type, the subject is administered the plurality of doses over 2 to 26 weeks (and all integer weeks in between), over 2 to 24 weeks (and all integer weeks in between), over 2 to 22 weeks (and all integer weeks in between), over 2 to 20 weeks (and all integer weeks in between), over 2 to 18 weeks, (and all integer weeks in between), over 2 to 16 weeks (and all integer weeks in between), over 2 to 14 weeks (and all integer weeks in between), 2 to 12 weeks, over 2 to 10 weeks (and all integer weeks in between), over 2 to 8 weeks (and all integer weeks in between), over 2 to 6 weeks (and all integer weeks in between), over 2 to 4 weeks (and all integer weeks in between), over 4 to 26 weeks (and all integer weeks in between), over 4 to 24 weeks (and all integer weeks in between), over 4 to 22 weeks (and all integer weeks in between), over 4 to 20 weeks (and all integer weeks in between), over 4 to 18 weeks, (and all integer weeks in between), over 4 to 16 weeks (and all integer weeks in between), over 4 to 14 weeks (and all integer weeks in between), over 4 to 12 weeks (and all integer weeks in between), over 4 to 10 weeks (and all integer weeks in between), over 4 to 8 weeks (and all integer weeks in between), or over 4 to 6 weeks (and all integer weeks in between).

[0037] In any of the aspects and embodiments disclosed herein, a respective dose of the CD14 antagonist antigen-binding molecule is administered to the subject at about daily intervals, about weekly intervals, about fortnightly intervals, about monthly intervals, about bimonthly intervals, about quarterly intervals, about 4-monthly intervals, about half-yearly intervals, or about yearly intervals.

[0038] In any of the aspects and embodiments disclosed herein, the methods may further comprise concurrently administering an ancillary HF therapeutic agent or intervention to thesubject, illustrative examples of which include angiotensin converting enzyme (ACE) inhibitors e.g., enalapril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), neprilysin inhibitors (e.g., sacubitril), angiotensin receptor / neprilysin inhibitors (e.g., sacubitril / valsartan), beta-adrenergic receptor blockers (e.g., acebutolol, atenolol (Tenormin), bisoprolol, metoprolol (LOPRESSOR, TOPROL XL), nadolol (CORGARD), nebivolol (BYSTOLIC), propranolol (INDERAL LA, INNOPRAN XL)), calcium channel inhibitors (e.g., amlodipine (NORVASC), diltiazem (CARDIZEM, TIAZAC), felodipine, isradipine, nicardipine, nifedipine (PROCARDIA), nisoldipine (SULAR), verapamil (VERELAN)), diuretics (e.g., furosemide (LASIX)), antiarrhythmic drugs (e.g., amiodarone (CORDARONE, PACERONE), flecainide (TAMBOCOR), ibutilide (CORVERT) lidocaine (XYLOCAINE), procainamide (PROCAN, PROCANBID), propafenone (RYTHMOL), quinidine, tocainide (TONOCARID)) digoxin); or Parkinson's disease therapies including, for example, levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, Piribedil, cabergoline, apomorphine, lisuride), statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, sodiumglucose cotransporter-2 (SGLT2) inhibitors (e.g., bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), anticholinergics, antipsychotics (e.g., clozapine), alpha-2 receptor agonists (e.g., guanabenz, guanfacine, clonidine, tizanidine, medetomidine, or dexmedetomidine), cholinesterase inhibitors, modafinil, thiazolidinediones and non-steroidal anti-inflammatory drugs, and combinations thereof.

[0039] In any of the aspects and embodiments disclosed herein, the methods may further comprise performing a surgical procedure on the subject, wherein the surgical procedure is suitable for treating HF, illustrative examples of which comprise percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass including coronary artery bypass grafting (CABG), implantation of a pacemaker (e.g., a LV assist device (LVAD)), atrioventricular (AV) node catheter ablation, implantation of an implantable cardioverterdefibrillator (ICD), cardiac catheterization, revascularization and / or heart transplantation. The surgical procedure may be performed before, at the same time as, or after administration of the CD14 antagonist antigen-binding molecule, optionally together with an ancillary HF therapeutic agent.

[0040] Still another aspect of the present disclosure provides a CD14 antagonist antigen-binding molecule for use in treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in increasing, improving or recovering cardiac function or restoring cardiac function to a normal range, in alleviating, reducing or reversing adverse cardiac structural remodeling in HF, in increasing or improving cardiac contractile function, or restoring cardiac contractile function to a normal range, in HF, in increasing or improving cardiac output, or restoring cardiac output to a normal range, in HF, in increasing or improving ejection fraction (e.g., LVEF), or restoring ejection fraction (e.g., LVEF) to a normal range, in HF, in reducing or improving LVESV, or restoring LVESV to a normal range, in HF, in reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, in ameliorating or reducing LV akinetic area in HF, in ameliorating or reducing LV dilatation in HF, in reducing or improving LV mass in HF, in ameliorating or reducing dyspnea, in ameliorating or reducing congestion score, in ameliorating or improving patient perception of health status, and / or in ameliorating or reducing NLR or restoring NLR to a normal range.

[0041] Disclosed in yet another aspect is use of a CD14 antagonist antigen-binding molecule in the manufacture of a medicament for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, for increasing, improving or recovering cardiac function or restoring cardiac function to a normal range, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving ejection fraction {e.g., LVEF), or restoring ejection fraction e.g., LVEF) to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, for reducing or improving LV mass in HF, for ameliorating or reducing dyspnea, for ameliorating or reducing congestion score, for ameliorating or improving patient perception of health status, and / or for ameliorating or reducing NLR or restoring NLR to a normal range.

[0042] The HF may be HFpEF, HFrEF or HFmrEF. The HF may be AHF, ADHF, or CHF. The HF may be Class I HF, Class II HF, Class III HF or Class IV HF according to the NYHA classification scale. The subject may be a patient with a stage of progression of HF as classified according to the ACC / AHA HF guidelines, wherein the stage of progression is selected from a Stage A patient, a Stage B patient, a Stage C patient and a Stage B patient.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a schematic representation depicting anti-CD14 treatment of HF in a mouse model of HF.

[0044] Figure 2 is a graphical representation showing that anti-CD14 treatment of C57 / B6 mice with established HF over an 8-week period significantly increased LVEF (%EF), as compared to control mice administered isotype antibody.

[0045] Figure 3 is a graphical representation showing that anti-CD14 treatment of C57 / B6 mice with established HF over an 8-week period significantly decreased LV akinetic area (infarct size), as compared to control mice administered isotype antibody.

[0046] Figure 4 is a graphical representation showing that anti-CD14 treatment of C57 / B6 mice with established HF over an 8-week period significantly decreased LVESV, as compared to control mice administered isotype antibody.

[0047] Figure 5 is a graphical representation showing that anti-CD14 treatment of C57 / B6 mice with established HF over an 8-week period significantly decreased LVEDV, as compared to control mice administered isotype antibody.

[0048] Figure 6 is a graphical representation showing a statistically significant improvement in dyspnea in patients treated with IC14, which was sustained throughout the course of the study. Mean + / - SEM, N = 6-9 patients. ** P value < 0.01. *** P value <0.001. **** p value <0.0001.

[0049] Figure 7 is a graphical representation showing a statistically significant improvement in the congestion score which was sustained through the day 29 visit in patients treated with IC14. Mean + / - SEM, N= 7-8 patients. * P value <0.05. **P value <0.01.

[0050] Figure 8 is a graphical representation showing a statistically significant improvement in LVEF at day 10 in patients treated with IC14. Mean + / - SEM, N= 8 patients. * P value <0.05.

[0051] Figure 9 is a graphical representation showing a statistically significant improvement in both patient overall summary score and their clinical summary score at day 29 in patients treated with IC14, which was sustained to the end of study at 3 months. Mean + / - SEM, N= 6-7 patients. * P value <0.05. ** P value <0.01.

[0052] Figure 10 is a graphical representation showing a decrease in NLR at 29 days post infusion in patients treated with IC14, which was approaching statistical significance (p=0.05). Mean + / - SEM, N = 8 patients.

[0053] Figure 11 is a graphical representation showing percentage of CD14 receptor occupancy over time from day 8 to day 44 in ADHF patients following administration of IC14.

[0054] Figure 12 is a graphical representation showing correlation between receptor occupancy (% RO) and Presepsin (PSEP) in patients. The baseline PSEP value for all patients was above the 300pg / mL range that indicates an increased risk of mortality in ADHF patients.

[0055] Some figures and text contain color representations or entities. Color illustrations are available from the Applicant upon request or from an appropriate Patent Office. A fee may be imposed if obtained from a Patent Office.DETAILED DESCRIPTION1. Definitions

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are described. For the purposes of the present disclosure, the following terms are defined below.

[0057] The articles "a" and "an" are used herein to refer to one or to more than one ( / .e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0058] The term "about" as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to "about" in connection with a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter perse. In specific embodiments, the term "about" refers to a value or parameter (e.g., quantity, level, concentration, number, frequency, percentage, dimension, size, amount, weight or length) that varies by as much 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference value or parameter.

[0059] As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or). Thus, the term "and / or" as used in a phrase such as "Aand / or B" herein is intended to include "A and B,""A or B,""A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0060] The terms "active agent" and "therapeutic agent" are used interchangeably herein and refer to agents that prevent, reduce or ameliorate at least one symptom of a disease or disorder.

[0061] The terms "administration concurrently" or "administering concurrently" or "coadministering" and the like refer to the administration of a single composition containing two or more agents, or the administration of each agent as separate compositions and / or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such agents are administered as a single composition. By "simultaneously" is meant that the agents are administered at substantially the same time, and desirably together in the same formulation. By "contemporaneously" it is meant that the agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful. However, it will often be the case that when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and suitably within less than about one to about four hours. When administered contemporaneously, the agents are suitably administered at the same site on the subject. The term "same site" includes the exact location but can be within about 0.5 to about 15 centimeters, preferably from within about 0.5 to about 5 centimeters. The term "separately" as used herein means that the agents are administered at an interval, for example at an interval of about a day to several weeks or months. The agents may be administered in either order. The term "sequentially" as used herein means that the agents are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks. If appropriate the agents may be administered in a regular repeating cycle.

[0062] The term "adverse cardiac structural remodeling" refers to a group of molecular, cellular and interstitial changes that manifest as changes in the size, shape and function of the heart. These changes have a negative impact on cardiac function and eventually lead to heart failure. Representative examples of adverse cardiac structural remodeling include cardiac hypertrophy, thinning of the myocardium, scar formation of the myocardium, atrophy of the myocardium, reduced heart function, reduced cardiac contractile function, reduced LV diastolic function, reduced LV systolic function, increased LV dilatation, and combinations thereof. By contrast, "beneficial cardiac structural remodeling" refers to changes that have a positive impact including reducing cardiac hypertrophy, reducing thinning of the myocardium, reducing scar formation of the myocardium, reducing atrophy of the myocardium, increasing cardiac contractile function, increasing cardiac output, increasing LV diastolic function, increasing LV systolic function, reducing or reversing LV dilatation, and combinations thereof. Suitably, the "beneficial cardiac structural remodeling" is "reverse remodeling", including "reverse LV remodeling".

[0063] By "antigen-binding molecule" is meant a molecule that has binding affinity for a target antigen. It will be understood that this term extends to immunoglobulins, immunoglobulin fragments and non-immunoglobulin derived protein frameworks that exhibit antigen-bindingactivity. Representative antigen-binding molecules that are useful in the practice of the present disclosure include polyclonal and monoclonal antibodies as well as their fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) and domain antibodies (including, for example, shark and camelid antibodies), and fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding / recognition site. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called a, 6, e, y, and p, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Antigen-binding molecules also encompass dimeric antibodies, as well as multivalent forms of antibodies. In some embodiments, the antigenbinding molecules are chimeric antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see, for example, US Pat. No. 4,816,567; and Morrison etal., 1984, Proc. Natl. Acad. Sci. USA 81:6851-6855). Also contemplated, are humanized antibodies, which are generally produced by transferring complementarity determining regions (CDRs) from heavy and light variable chains of a non-human (e.g., rodent, preferably mouse) immunoglobulin into a human variable domain. Typical residues of human antibodies are then substituted in the framework regions of the non-human counterparts. The use of antibody components derived from humanized antibodies obviates potential problems associated with the immunogenicity of non-human constant regions. General techniques for cloning non-human, particularly murine, immunoglobulin variable domains are described, for example, by Orland! et al. (1989, Proc. Natl. Acad. Sci. USA 86: 3833). Techniques 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 8i Sons, Inc. 1996), and by Queen et al., U.S. Pat. No. 5,693,762 (1997). Humanized antibodies include "primatized" antibodies in which the antigenbinding region of the antibody is derived from an antibody produced by immunizing macaque monkeys with the antigen of interest. Also contemplated as antigen-binding molecules are humanized antibodies.

[0064] The term "antagonist antigen-binding molecule" is used in the broadest sense and includes an antigen-binding molecule that inhibits or decreases the biological activity of an antigen to which the antigen-binding molecule binds (e.g., CD14). For example, an antagonist antigen-binding molecule may partially or completely block interaction between a receptor (e.g., CD14) and a ligand (e.g., a DAMP or PAMP) or may practically decrease the interaction due to tertiary structure change or down regulation of the receptor. Thus, a CD14 antagonist antigen-binding molecule encompasses antigen-binding molecules that bind to CD14 and that block, inhibit, nullify, antagonize, suppress, decrease or reduce (including significantly), in any meaningful degree, a CD14 agonist activity, including activation of downstream pathways such as Toll-like receptor (TLR) signaling pathways (e.g., TLR4 signaling pathway) and the TIR-domain-containing adapter-inducing IFN-p (TRIF) pathway, or elicitation of a cellular response e.g., production of pro-inflammatory mediators including pro-inflammatory cytokines) to CD14 binding by a CD14 ligand (e.g., a DAMP or PAMP). In some examples, the antibody is monospecific and binds only to CD14. In other examples, the antibody is multispecific (e.g., bispecific) and binds to CD14 and at least one other antigen.

[0065] The term "antibody" herein is used in its broadest sense and specifically covers naturally occurring antibodies, monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), antibody fragments, which exhibit the desired immunointeractivity. A naturally occurring "antibody" includes within its scope an immunoglobulin comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of specific CH domains (e.g., CHI, CH2 and CH3). Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementary determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant regions of the antibodies may mediate the binding of an immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), subclass or modified version thereof (e.g., IgGl isotype, which carries L234A and L235A double mutations (IgGl-LALA)). Antibodies can be of any species, chimeric, humanized or human. In other embodiments, the antibody is a homomeric heavy chain antibody (e.g., camelid antibodies) which lacks the first constant region domain (CHI) but retains an otherwise intact heavy chain and is able to bind antigens through an antigen-binding domain. The variable regions of the heavy and light chains in the antibody-modular recognition domain (MRD) fusions will contain a functional binding domain that interacts with an antigen of interest.

[0066] The "variable domain" (variable domain of a light chain (VL), variable domain of a heavy chain (VH)) as used herein denotes each of the pair of light and heavy chain domains which are involved directly in binding the antibody to the antigen. The variable light and heavy chain domains have the same general structure, and each domain comprises four FRs whose sequences are widely conserved, connected by three CDRs or "hypervariable regions". The FRs adopt a p-sheet conformation and the CDRs may form loops connecting the p-sheet structure. The CDRs in each chain are held in their three-dimensional structure by the FRs and form together with the CDRs from the other chain the antigen binding site.

[0067] The term "antigen-binding portion" when used herein refer to the amino acid residues of an antibody which are responsible for antigen-binding generally, which generallycomprise amino acid residues from the CDRs. Thus, "CDR" or "complementarity determining region" (also referred to as "hypervariable region") are used interchangeably herein to refer to the amino acid sequences of the light and heavy chains of an antibody which form the three-dimensional loop structure that contributes to the formation of an antigen binding site. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated "CDR1", "CDR2", and "CDR3", for each of the variable regions. The term "CDR set" as used herein refers to a group of three CDRs that occur in a single variable region that binds the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as "Kabat CDRs". Chothia and coworkers (Chothia and Lesk, 1987. J. Mol. Biol. 196: 901-917; Chothia et al., 1989. Nature 342: 877-883) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as "LI", "L2", and "L3", or "Hl", "H2", and "H3", where the "L" and the "H" designate the light chain and the heavy chain regions, respectively. These regions may be referred to as "Chothia CDRs", which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995. FASEB J. 9: 133-139) and MacCallum (1996. J. Mol. Biol. 262(5): 732-745). Still other CDR boundary definitions may not strictly follow one of these systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding.

[0068] As used herein, the term "framework region" or "FR" refers to the remaining sequences of a variable region minus the CDRs. Therefore, the light and heavy chain variable domains of an antibody comprise from N- to C-terminus the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDRs and FRs are typically determined according to the standard definition of Kabat, E. A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991) and / or those residues from a "hypervariable loop".

[0069] As used herein, the terms "light chain variable region" ("VL") and "heavy chain variable region" (VH) refer to the regions or domains at the N-terminal portion of the light and heavy chains respectively which have a varied primary amino acid sequence for each antibody. The variable region of an antibody typically consists of the amino terminal domain of the light and heavy chains as they fold together to form a three-dimensional binding site for an antigen. Several subtypes of VH and VL, based on structural similarities, have been defined, for example as set forth in the Kabat database.

[0070] The term "chimeric antibody" refers to antibodies that comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.

[0071] "Humanized" forms of non-human {e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Thus, the FRs and CDRs of a humanized antibody need not correspond precisely to the parental ( / .e., donor) sequences, e.g., a donor antibody CDR or the consensus framework may be mutagenized by substitution, insertion, and / or deletion of at least one amino acid residue so that the CDR or FR at that site does not correspond to either the donor antibody or the consensus framework. Typically, such mutations, however, will not be extensive and will generally avoid "key residues" involved in binding to an antigen. Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region in the consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, 1987)). A "consensus immunoglobulin sequence" may thus comprise a "consensus framework region(s)" and / or a "consensus CDR(s)". In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will generally comprise at least a portion of an 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). A humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including without limitation IgGl, IgG2, IgG3, and IgG4. A humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains may be selected to optimize desired effector functions using techniques well known in the art. As used herein, the term "key residue" refers to certain residues within the variable region that have more impact on the binding specificity and / or affinity of an antibody, in particular a humanized antibody. A key residue includes, but is not limited to, one or more of the following: a residue that is adjacent to a CDR, a potential glycosylation site (can be either N- or O-glycosylation site), a rare residue, a residue capable of interacting with the antigen, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region, a residue within the Vernier zone, and a residue in the region that overlaps between the Chothia definition of a variable heavy chain CDR1 and the Kabat definition of the first heavy chain framework.

[0072] As used herein, "Vernier" zone refers to a subset of framework residues that may adjust CDR structure and fine-tune the fit to antigen as described by Foote and Winter (1992. J. Mol. Biol. 224: 487-499). Vernier zone residues form a layer underlying the CDRs and may impact on the structure of CDRs and the affinity of the antibody.

[0073] As used herein, the term "canonical" residue refers to a residue in a CDR or framework that defines 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 are incorporated herein by reference). According to Chothia et al., critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.

[0074] As used herein, the terms "donor" and "donor antibody" refer to an antibody providing one or more CDRs to an "acceptor antibody". In some embodiments, the donor antibody is an antibody from a species different from the antibody from which the FRs are obtained or derived. In the context of a humanized antibody, the term "donor antibody" refers to a non-human antibody providing one or more CDRs.

[0075] As used herein, the terms "acceptor" and "acceptor antibody" refer to an antibody providing at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the FRs. In some embodiments, the term "acceptor" refers to the antibody amino acid sequence providing the constant region(s). In other embodiments, the term "acceptor" refers to the antibody amino acid sequence providing one or more of the FRs and the constant region(s). In specific 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 sequences of one or more of the FRs. In accordance with this embodiment, an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues that does (do) not occur at one or more specific positions of a human antibody. An acceptor framework region and / or acceptor constant region(s) may be, for example, derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well-known in the art, antibodies in development, or antibodies commercially available).

[0076] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies according to the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or sitespecific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0077] The terms "heavy chain variable region CDR1" and "H-CDR1" are used interchangeably, as are the terms "heavy chain variable region CDR2" and "H-CDR2", the terms "heavy chain variable region CDR3" and "H-CDR3", the terms "light chain variable region CDR1" and "L-CDR1"; the terms "light chain variable region CDR2" and "L-CDR2" and the terms "light chain variable region CDR3" and "L-CDR3" antibody fragment. Throughout the specification,complementarity determining regions ("CDR") are defined according to the Kabat definition unless specified otherwise. The Kabat definition is a standard for numbering the residues in an antibody and it is typically used to identify CDR regions (Kabat etal., (1991), 5th edition, NIH publication No. 91-3242).

[0078] Antigen binding can be performed by "fragments" or "antigen-binding fragments" of an intact antibody. Herein, both terms are used interchangeably. Examples of binding fragments encompassed within the term "antibody fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; an Fd fragment consisting of the VH and CHI domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single domain antibody (dAb) fragment (Ward etal., 1989. Nature 341:544-546), which consists of a VH domain; and an isolated complementary determining region (CDR). In a particular embodiment, the antibody of the present disclosure is an antigen-binding fragment that lacks all or a portion of the Fc region.

[0079] A "single chain variable Fragment (scFv)" is a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1988. Science 242:423-426; and Huston et al., 1988. Proc. Natl. Acad. Sci. 85:5879-5883). Although the two domains VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by an artificial peptide linker that enables them to be made as a single protein chain. Such single chain antibodies include one or more antigen binding moieties. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0080] The term "monoclonal antibody" and abbreviations "MAb" and "mAb", as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each mAb is directed against a single determinant on the antigen. The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. Monoclonal antibodies may be produced, for example, by a single clone of antibodyproducing cells, including hybridomas. The term "hybridoma" generally refers to the product of a cell-fusion between a cultured neoplastic lymphocyte and a primed B- or T-lymphocyte which expresses the specific immune potential of the parent cell.

[0081] An antigen-binding molecule "that binds" an antigen of interest (e.g., CD14) is one that binds the antigen with sufficient affinity such that the antigen-binding molecule is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antigen-binding molecule to a "non-target" protein will be less than about 10% of the binding of the antigenbinding molecule to its particular target protein as determined, for example, by fluorescence activated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation or radioimmunoprecipitation (RIA). Thus, an antigen-binding molecule that antagonizes CD14 suitably inhibits or decreases production of pro-inflammatory mediators,including pro-inflammatory cytokines / chemokines. With regard to the binding of an antigen-binding molecule to a target molecule, the term "specific binding" or "specifically binds to" or is "specific for" a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The specific region of the antigen to which the antigen-binding molecule binds is typically referred to as an "epitope". The term "epitope" broadly includes the site on an antigen which is specifically recognized by an antigen-binding molecule or T-cell receptor or otherwise interacts with a molecule. Generally, epitopes are of active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and generally may have specific three-dimensional structural characteristics, as well as specific charge characteristics. As will be appreciated by one of skill in the art, practically anything to which an antigen-binding molecule can specifically bind could be an epitope.

[0082] The term "cardiac output" refers to a measurement, expressed as a unit of volume e.g., liters) per minute, of the total volume of blood pumped out of the left ventricle per minute.

[0083] As used herein, the term "cardiac function" refers to the function of the heart, including global and regional functions of the heart. The term "global" cardiac function as used herein refers to function of the heart as a whole. Such function can be measured by, for example, stroke volume, ejection fraction, cardiac output, cardiac contractility, etc. The term "regional cardiac function" refers to the function of a portion or region of the heart. Such regional function can be measured, for example, by wall thickening, wall motion, myocardial mass, segmental shortening, ventricular remodeling, new muscle formation, the percentage of cardiac cell proliferation and programmed cell death, angiogenesis and the size of fibrous and infarct tissue.

[0084] Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. Thus, use of the term "comprising" and the like indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0085] As used in the context of the present disclosure, unless otherwise noted, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound orpharmaceutical ingredient which is administered to a patient in an individual administration. The term "dosage regimen" (or "dosing regimen") shall mean a defined sequence of one or more individual administrations.

[0086] The term "ejection fraction" refers to a measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each heart contraction (referred to as systole). Typically, and in some aspects, a normal ejection fraction for an adult over 20 years of age is from about 53% to about 73%.

[0087] By "effective amount", in the context of treating a disease or condition is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring at least one sign or symptom, holding in check at least one sign or symptom, and / or treating at least one existing sign or symptom, of that disease or condition. The effective amount will vary depending upon the age, health and physical condition of the individual to be treated and whether symptoms of disease are apparent, the taxonomic group of individuals to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the subject. Optimum dosages may vary depending on the relative potency in an individual subject and can generally be estimated based on EC50 values found to be effective in in vitro and in vivo animal models. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.

[0088] The term "heart failure" or "HF" refers to a clinical syndrome characterized by typical symptoms (e.g., dyspnea, ankle swelling and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by a structural and / or functional cardiac abnormality, resulting in a reduced cardiac output and / or elevated intracardiac pressures at rest or during stress. In the context of the present disclosure, "heart failure" encompasses both acute and chronic forms of heart failure, and also more specific or related types of disease, such as acute decompensated heart failure, right heart failure, left heart failure, global heart failure, diastolic heart failure and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mid-range ejection fraction (HFmrEF).

[0089] According to the New York Heart Association (NYHA), the clinical condition of heart failure may be classified into four stages depending on the severity thereof, as follows:TABLE 1NYHA Heart Failure ClassificationClass Patient Symptoms / SignsPatients have cardiac disease but without resulting limitation of physical Class I activity. Ordinary physical activity does not cause undue fatigue,palpitations, dyspnea, or anginal pain.Patients have cardiac disease resulting in slight limitation of physical Class II activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.Patients have cardiac disease resulting in marked limitation of physical Class III activity. They are comfortable at rest. Less than ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.Patients have cardiac disease resulting in an inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or Class IVof the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

[0090] According to the AHA / ACC stage classification (American Heart Association / American College of Cardiology), the clinical condition of heart failure is classified into four stages depending on the severity thereof, as follows:TABLE 2AHA / ACC stage classification of heart failure Stage Definition Stage DefinitionA Risk factor is present; however, no cardiac dysfunction is observed.B Cardiac contractile dysfunction of left ventricle with no symptom. C Symptomatic heart failure.D Intractable heart failure.

[0091] As used herein, the term "acute heart failure" denotes sudden onset heart failure, referring to episodes in which a patient with known chronic heart failure or devoid of chronic heart failure abruptly develops worsening symptoms, including worsening symptoms of LV function, and requires hospitalization. Common symptoms of complications due to acute heart failure include, but are not limited to, dyspnea due to pulmonary congestion or cardiogenic shock due to low cardiac output, easy fatigability (exercise intolerance), peripheral edema, anasarca (pronounced generalized edema), nocturia (frequent nighttime urination), bradycardia, heart block, hypotension, dizziness, syncope, diabetes, oliguria or anuria, hypokalemia, bronchospasm, cold sweat, and asthma.

[0092] As used herein, the term "acute decompensated heart failure" or "ADHF" has its general meaning in the art and refers to a state whereby a patient with existing HF, or a patient predisposed to HF, exhibits rapid worsening of heart function over a short period of time, which can be characterized by new HF symptoms and / or signs, worsening of existing HF symptoms and / or signs and / or a rapid increase in the number of additional HF symptoms and / or signs. The particularly relevant symptoms and signs include shortness of breath, swollen legs, dizziness, lightheadedness, and / or fatigue.

[0093] The terms "chronic heart failure" and "CHF" refer to the current clinical classification of CHF based on the presence of signs and symptoms of HF and left ventricular ejection fraction (LVEF), recognizing three categories: "HFrEF," "HFmrEF," and "HFpEF". The terms "heart failure with preserved ejection fraction" and "HFpEF" are used interchangeably herein to refer to a condition where the left ventricle is not able to fill properly with blood during the diastolic ( / .e., filling) phase resulting in a decreased amount of blood pumped out of the heart. HFpEF can be characterized by a peripheral insult, such as commonly associated with comorbidities) that secondarily causes myocardial dysfunction. Left ventricular hypertrophy caused by high blood pressure (hypertension) is a common example. In certain aspects, subjects with HFpEF have an ejection fraction of greater than about 50%. In certain aspects, subjects with HFpEF have an ejection fraction of >50%. In some aspects, subjects with HFpEF have an ejection fraction of greater than about 40%. In some aspects, subjects with HFpEF have an ejection fraction of >40%. The terms "heart failure with mid-range ejection fraction" and "HFmrEF" are used interchangeably herein to refer to subjects with an ejection fraction between about 40% and about 50%. The terms "HFmrEF" and "HFpEF" include two additional criteria, namely increased natriuretic peptides levels (BNP>35 pg / mL and / or NT-proBNP>125 pg / mL) associated with the evidence of structural and / or functional heart disease (left ventricular hypertrophy and / or left atrium enlargement and / or evidence of diastolic dysfunction). The terms "heart failure with reduced ejection fraction" and "HFrEF" are used interchangeably herein to refer to a condition where the left ventricle does not squeeze forcefully enough during the systolic ( / .e., ejecting) phase resulting in a decreased amount of blood pumped out of the heart. HFrEF can be characterized by primary myocardial injury (e.g., myocardial infarction, genetic abnormality, cardiotoxicity). In certain aspects, subjects with HFrEF have an ejection fraction of less than about 50%. In certain aspects, subjects with HFrEF have an ejection fraction of <50%. In some aspects, subjects with HFrEF have an ejection fraction of less than about 40%. In some aspects, subjects with HFrEF have an ejection fraction of <40%. In some aspects, subjects with moderate to severe HFrEF have an ejection fraction of <35%.

[0094] As used herein, a patient is considered as having "established heart failure" or "established HF" if, in addition to evidence of a medical history of HF, the patient presents with at least one clinical parameter selected from the group consisting of: prior well-documented HF hospitalization, elevated B-type natriuretic peptide (BNP) and / or N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, echocardiographic evidence of structural changes consistent with HF (e.g., HFpEF, HFrEF, HFmrEF), and hemodynamic evidence of elevated filling pressures.

[0095] As used herein, a patient with established HF is considered to have an "elevated level of BNP" if the concentration of BNP is >100 pg / mL. In some embodiments, a patient with established HF and sinus rhythm is considered to have an "elevated level of BNP" if the concentration of BNP is >100 pg / mL. In some embodiments, a patient with established HF and atrial fibrillation is considered to have an "elevated level of BNP" if the concentration of BNP is >200 pg / mL.

[0096] As used herein, a patient with established HF is considered to have an "elevated level of NT-proBNP" if the concentration of NT-proBNP is >300 pg / mL. In some embodiments, a patient with established HF and sinus rhythm is considered to have an "elevated level of NT-proBNP" if the concentration of NT-proBNP is >300 pg / mL. In some embodiments, a patient withestablished HF and atrial fibrillation is considered to have an "elevated level of NT-proBNP" if the concentration of NT-proBNP is >600 pg / mL.

[0097] As used herein, a patient is considered as having "established HF" if, in addition to a medical history of HF, echocardiographic evidence of structural changes consistent with HF (e.g., HFpEF, HFrEF, HFmrEF) and / or hemodynamic evidence of elevated filling pressures are present.

[0098] As used herein, a patient with "reduced exercise tolerance" is defined as a patient who displays a mean peak oxygen consumption (VO2) measurement of less than 80% of the age-and sex-adjusted normal (Fletcher et al. Exercise standards. A statement for healthcare professionals from the American Heart Association. Writing Group. Circulation. 1995 Jan. 15;91 (2): 580-615; see Table 2 in Examples section) as measured by cardiopulmonary exercise testing (CPET). To ensure an adequate exercise test, a respiratory exchange ratio (RER)>1.0 must also be achieved. Reduced exercise tolerance or "exercise intolerance" is the primary symptomatic manifestation of HF and is associated with a poor quality of life and increased mortality. Peak VO2 is typically an objective measure of exercise and functional capacity and represents the integrated response of multiple aspects of the cardiovascular, pulmonary, and skeletal muscle systems.

[0099] The term "fractional shortening" refers to a measurement, expressed as a percentage, of change of left ventricle diameter that reflects, for example, left ventricle wall movement during systole and diastole.

[0100] As used herein, the term "immune cell" refers to a cell involved in the innate or adaptive (acquired) immune systems. Exemplary innate immune cells include phagocytic cells such as neutrophils, monocytes and macrophages, Natural Killer (NK) cells, polymorphonuclear leukocytes such as neutrophils eosinophils and basophils and mononuclear cells such as monocytes, macrophages and mast cells. Immune cells with roles in acquired immunity include lymphocytes such as T-cells and B-cells.

[0101] As used herein, the term "inhibit", "inhibits", or "inhibiting" (and grammatical equivalents thereof), in the context of development of a state, disease, disorder or condition, refers to a delay in the appearance or onset of the state, disease, disorder or condition, reducing the manifestation of symptoms of the state, disease, disorder or condition, minimizing development of the state, disease, disorder or condition, and / or the lessening of symptoms upon onset of the state, disease, disorder or condition. The terms are not meant to imply complete abolition of disease and encompasses any type of prophylactic treatment that reduces the incidence of the condition or delays the onset and / or slows progression of the state, disease, disorder or condition.

[0102] The term "parameter" as used herein to refer to measuring heart function and means any heart function that is observable or measurable using suitable measuring techniques available in the art. A non-limiting list of exemplary "parameters" of heart function include heart rate, blood pressure, diastolic relaxation, systolic contraction, ejection fraction e.g., LVEF), diastolic blood pressure, systolic blood pressure, cardiac output, stroke volume, deceleration slope, cardiac index, mitral inflow velocity, and the like. As one having ordinary skill in the art will appreciate, measuring one or more "parameters" of heart function can be used to detect heart failure in a subject and can also be used to determine whether heart function has improved, or if the acute heart failure has been treated following or during treatment.

[0103] As used herein the term "pro-inflammatory" refers to an inflammationpromoting effect.

[0104] As used herein the term "pro-inflammatory mediator" refers to molecules and cells having an inflammation-promoting effect and typically being functionally involved in the signaling pathways and the immune responses of the immune system. Such agents include, but are not limited to, cytokines such as chemokines, interleukins (IL), lymphokines, and tumor necrosis factor (TNF) as well as growth factors. In specific embodiments, the pro-inflammatory mediator is a "pro-inflammatory cytokine". Typically, pro-inflammatory cytokines include IL-la, IL-1(3, IL-6, and TNF-a, which are largely responsible for early responses. Other pro-inflammatory mediators include LIF, IFN-y, IFN-P, IFN-a, OSM, CNTF, TGF-P, 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 etal., 2008. Cell 132:900; Cell 132:500, Cell 132:324). Pro-inflammatory mediators may act as endogenous pyrogens (IL-1, IL-6, TNF-a), up-regulate the synthesis of secondary mediators and pro-inflammatory cytokines by both macrophages and mesenchymal cells (including fibroblasts, epithelial and endothelial cells), stimulate the production of acute phase proteins, or attract inflammatory cells. In specific embodiments, the term "pro-inflammatory cytokine" relates to any one or more of TNF-a, IL-6, IFN-p, IL-ip and IL-8. In other specific embodiments, the term "pro-inflammatory cytokine" relates to any one or more of IL- 1 p, IL-6, TNF-a, IFN-y and IFN-p.

[0105] As used herein, the term "receptor occupancy" refers to the ratio of receptors (e.g., CD14 receptor) occupied by a ligand (e.g., CD14 antagonist antibody) at equilibrium and the total number of receptors available, usually expressed as a percentage of the total number of receptors. The duration of receptor occupancy can be evaluated by measuring and comparing the receptor occupancy at different time points. Measurement of receptor occupancy is known in the art, such as FACS, Positron Emission Computed Tomography (PET), autoradiography, etc. In some embodiments, receptor occupancy may be evaluated by measuring at least one inflammatory biomarker (e.g., Presepsin) that correlates or inversely correlates with the receptor occupancy.

[0106] The terms "reverse remodeling", "reverse adverse cardiac remodeling", and "reverse adverse cardiac structural remodeling" are used interchangeably herein to refer to an improvement in ventricular mechanics and function that revert the heart closer to normal geometry and function, suitably with improved prognosis. Reverse remodeling typically includes restoration of LV systolic function and reduct I on / reversal of LV dilatation.

[0107] As used herein, the term "recovery" and its grammatical equivalents refer to a process in which a heart or part thereof that has at least in part lost the ability, or has impaired or reduced ability, to perform a cardiac function that it previously performed, regains at least in part the ability to perform the function.

[0108] The term "stroke volume" refers to a measurement, expressed as a unit of volume (e.g., liters), of the volume of blood pumped out of the left ventricle at systole or during each systolic cardiac contraction.

[0109] The terms "subject", "patient" and "individual" are used interchangeably herein to refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject with HF. Suitable vertebrate animals that fall within the scope of the present disclosure include, but are not restricted to, any member of the subphylum Chordata including primates (e.g., humans, monkeys and apes, and includes species of monkeys such from the genus Macaca {e.g.,cynomolgus monkeys such as Macaca fascicularis, and / or rhesus monkeys (Macaca mulatta)) and baboon (Papio ursinus), as well as marmosets (species from the genus Callithrix), squirrel monkeys (species from the genus Saimiri) and tamarins (species from the genus Saguinus), as well as species of apes such as chimpanzees (Pan troglodytes)), rodents (e.g., mice rats, guinea pigs), lagomorphs (e.g., rabbits, hares), bovines (e.g., cattle), ovines (e.g., sheep), caprines (e.g., goats), porcines (e.g., pigs), equines (e.g., horses), canines (e.g., dogs), felines (e.g., cats), avians (e.g., chickens, turkeys, ducks, geese, companion birds such as canaries, budgerigars etc.), marine mammals (e.g., dolphins, whales), reptiles (snakes, frogs, lizards etc.), and fish. A preferred subject is a human with HF or at risk of developing HF.

[0110] "Treating" or "treatment" of a state, disease, disorder or condition means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, lessening severity of disease, stabilized (i.e., not worsening) state of disease (e.g., maintaining a patient in remission), preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable, or relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. "Treating" and "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment, includes: the benefit to an individual to be treated is either statistically significant or at least perceptible to the patient or to the physician. In one embodiment, treatment methods comprise administering to a subject an effective amount of a CD14 antagonist antigen-binding molecule and optionally consists of a single administration, or comprises a series of administrations.

[0111] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. CD14 antagonist antigen-binding molecules for use in treating or reducing progression of HF

[0112] The present disclosure provides methods, uses and compositions that include a CD14 antagonist antigen-binding molecule for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, for increasing, improving or recovering cardiac function or restoring cardiac function to a normal range in HF, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving ejection fraction (e.g., LVEF), or restoring ejection fraction (e.g., LVEF) to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, for reducing or improving LV mass in HF, for ameliorating or reducing dyspnea in HF, for ameliorating or reducing congestion score in HF, for ameliorating or improving patient perception of health status in HF, and / or for ameliorating or reducing NLR in HF or restoring NLR to a normal range.

[0113] The present disclosure contemplates 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, suitably a DAMP or PAMP, to CD14 and / or that binds to CD14 and inhibitsor decreases a CD14 agonist-mediated response resulting 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 can be utilized in the methods and uses of the present disclosure. In some embodiments, a CD14 antagonist antigen-binding molecule of the present disclosure inhibits binding of a CD14 agonist, suitably a DAMP or PAMP, to CD14 thus inhibiting or decreasing the production of pro-inflammatory cytokines. In illustrative examples of this type, the CD14 antagonist antigen-binding molecule is selected from the 3C10 antibody that binds to an epitope comprised in at least a portion of the region from amino acid 7 to amino acid 14 of human CD14 (van Voorhis et al., 1983. J. Exp. Med. 158: 126-145; Juan etal., 1995. J. Biol. Chem.270(29): 17237-17242), the MEM-18 antibody that binds an epitope comprised in at least a portion of the region from amino acid 57 to amino acid 64 of CD14 (Bazil et al., 1986. Eur. J. Immunol. 16(12):1583-1589; Juan etal., 1995. J. Biol. Chem. 270(10): 5219-5224), the 4C1 antibody (Adachi et al., 1999. J. Endotoxin Res. 5: 139-146; Tasaka et al., 2003. Am. J. Respir. Cell. Mol. Biol. 2003. 29(2):252-258), the 28C5 and 23G4 antibodies that inhibit binding of LPS and suppress production of pro-inflammatory cytokines, the 18E12 antibody that partly inhibits binding of LPS and suppresses production of pro-inflammatory cytokines (U.S. Patent Nos. 5,820,858, 6,444,206 and 7,326,569 to Leturcq etal.), the F1024-1-3 antibody (U.S. Pat. Appl. Pub. No. 2004 / 0091478 by Furusako et al.) and synthetic F1204 antibody (U.S. Pat. Appl. Pub. No.2008 / 0286290 by Furusako et al.) which bind to an epitope comprised in at least a portion of the region from amino acid 269 to amino acid 315 of human CD14, and which inhibit binding of LPS and NF-KB activation as well as suppressing cytokine production, and the rl8Dll and rMII2 antibodies (U.S. Pat. Appl. Pub. No. 2017 / 0107294 by Espevik et al.), that bind to the LPS-binding and / or signaling domains of human CD14 and inhibit LPS-induced release of pro-inflammatory cytokines. In some embodiments, a CD14 antagonist antigen-binding molecule of the present disclosure inhibits binding of CD14 to a TLR such as TLR4, thereby blocking CD14-agonist mediated response, illustrative examples of which include the F1024 antibody disclosed in International Publication WO2002 / 42333. Other CD14 antagonist antigen-binding molecules include the singlechain antibody scFv2F9 and the related human-mouse chimeric antibody Hm2F9 (Tang et al. 2007, Immunopharmacol Immunotoxicol. 29,375-386; and Shen etal., 2014, DNA Cell Biol. 33(9): 599-604). Further examples of CD14 antagonist antigen-binding molecules include the anti-human CD14 18D11 IgGl mAb, 18D11 IgGl F(ab)'2 fragment and the chimeric rl8Dll antibody (IgG2 / 4) (see e.g., Lau etal., 2013, J Immunol. 191:4769-4777). Each of the above references relating to CD14 antagonist antigen-binding molecules is incorporated herein by reference in its entirety. The CD14 antagonist antigen-binding molecule may be a full-length immunoglobulin antibody or an antigen-binding fragment of an intact antibody, representative examples of which include a Fab fragment, a F(ab')2 fragment, an Fd fragment consisting of the VH and CHI domains, an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, a single domain antibody (dAb) fragment (Ward etal., 1989. Nature 341:544-546), which consists of a VH domain; and an isolated CDR. Suitably, the CD14 antagonist antigen-binding molecule is a chimeric, humanized or human antibody.

[0114] In some embodiments, the CD14 antagonist antigen-binding molecule comprises a VH and VL of an antibody disclosed in U.S. Pat. No. 5,820,858. Representative antigen-binding molecules of this type include:

[0115] (1) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:QSPASLAVSLGQRATISC RASESVDSFGNSFMH WYQQKAGQPPKSSIY RAANLES GIPARFSGSGSRTDFTLTINPVEADDVATYFC QQSYEDPWT FGGGTKLGNQ [SEQ ID NO: 1] (3010 VL); anda VH domain comprising, consisting or consisting essentially of the sequence:LVKPGGSLKLSCVASGFTFS SYAMS WVRQTPEKRLEWVA SISSGGTTYYPDNVKG RFTISRDNARNILYLQMSSLRSEDTAMYYCAR GYYDYHY WGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH);

[0116] (2) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:QSPASLAVSLGQRATISC RASESVDSYVNSFLH WYQQKPGQPPKLLIY RASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCC QQSNEDPTT FGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); anda VH domain comprising, consisting or consisting essentially of the sequence:LQQSGPGLVKPSQSLSLTCTVTGYSIT SDSAWN WIRQFPGNRLEWMG YISYSGSTSYNPSLKS RISITRDTSKNQFFLQLNSVTTEDTATYYCVR GLRFAY WGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH); and

[0117] (3) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:QTPSSLSASLGDRVTISC RASQDIKNYLN WYQQPGGTVKVLIY YTSRLHS GVPSRFSGSGSGTDYSLTISNLEQEDFATYFC QRGDTLPWT FGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); anda VH domain comprising, consisting or consisting essentially of the sequence:LESGPGLVAPSQSLSITCTVSGFSLT NYDIS WIRQPPGKGLEWLG VIWTSGGTNYNSAFMS RLSITKDNSESQVFLKMNGLQTDDTGIYYCVR GDGNFYLYNFDY WGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH);

[0118] In some embodiments, the CD14 antagonist antigen-binding molecule comprises a VH and VL of an antibody disclosed in U.S. Pat. Appl. Pub. No. 2004 / 0091478, a representative example of which includes:

[0119] (1) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:YIVMTQTPTSISISVGERVTMNCKAS QNVGSNVDWY QQKTGQSPKLLIY KASNRY TGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYC MQSNTNPPW TFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); anda VH domain comprising, consisting or consisting essentially of the sequence:EVKLLESGGGLVQPSQTLSISCKASGYTFT DYAMN WVKQAPGDGLKWMG WINTQTGKPTYADD FKQRFVFSLETSASTAYLQINNLNIEDTA TYFCTRSTFYYSSYIY GWYFDFWGPGTMVTVSS [SEQ ID NO: 58] (F1024-1-3 VH).

[0120] In some embodiments, the CD14 antagonist antigen-binding molecule comprises a VH and VL of an antibody disclosed in U.S. Pat. Appl. Pub. No. 2008 / 0286290, a representative example of which includes:

[0121] (1) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:DIVMTQSPTSISISVGERVTMNC KASQNVGSNVD WYQQKTGQSPKLLIY KASNRYTGVPDRFTGSGSGTDFTFTISNMQAVDLAVYYC MQSNTNPPWT FGGGTKLELKRA [SEQ ID NO: 59] (F1024 VL); anda VH domain comprising, consisting or consisting essentially of the sequence:QIQLVQSGPELKKPGESVKISCKASGYTFT DYAMN WVKQAPGNGLKWMG WINTQTGKPTYADDFKQ RFVFSLETSASTAYLQINNLNIEDTATYFCTR STFYYSSYIYGWYFDF WGPGTMVTVSS [SEQ ID NO: 60] (F1024 VH).

[0122] In some embodiments, the CD14 antagonist antigen-binding molecule comprises a VH and VL of an antibody disclosed in U.S. Pat. Appl. Pub. No. 2017 / 0107294, representative examples of which include:

[0123] (1) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:NIVLTQSPASLAVSLGQRATISC RASESVDSYGNSFMH WYQQKPGQPPKLLIY LASNLES GVPARFSGSGSRTDFTLTIDPVEADDVATYYC QQNNGDPYT FGGGTKLEIIR [SEQ ID NO: 61] (rl8Dll VL); anda VH domain comprising, consisting or consisting essentially of the sequence:EVQLVESGGGLMQPKGSLKLSCAASGFTFK TYALN WVRQAPGTGLEWVA RIRSKSNNYTTYYADSVKD RFTISRDDSQNMLYLQMNNLKTEDTAMYYCVR PQSGTSFAY WGQGTLVTVSA [SEQ ID NO: 62] (rl8Dll VH); and

[0124] (2) an antigen-binding molecule comprising:a VL domain comprising, consisting or consisting essentially of the sequence:DIVMTQSQKFMSTSVGDRVSVTC KASQYVGTNVA WYQQKPGQSPKALIQ SASYRCS GVPDRFTGSGSGTDFTLTISNVQSEDLADYFC QQYNTYVT FGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); anda VH domain comprising, consisting or consisting essentially of the sequence:QVRLQQPGAELVRPGASVKLSCKASGYTFT TYWMN WVKQRPEDGLEWIG RIDPYDSETHYNQNFKD KAILTVDKSSSTAYMQLSSLTYEDSAVYYCTR KEGRQWGAYFDY WGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH).

[0125] Also contemplated are antigen-bind molecules that comprise the VL and VH CDR sequences of the above antigen-binding molecules and related antigen-binding molecules, representative embodiments of which include:(1) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3);(2) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises,consists or consists essentially of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3);(3) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3);(4) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3);(5) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence QNVGSNVDWY [SEQ ID NO: 34] (F1024-1-3 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence KASNRY [SEQ ID NO: 35] ( F1024-1-3 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence MQSNTNPPW [SEQ ID NO: 36] (F 1024-1-3 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence DYAMN [SEQ ID NO: 37] (F1024-1-3 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence WINTQTGKPTYADDF [SEQ ID NO: 38] (F1024-1-3 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence TYFCTRSTFYYSSYIY [SEQ ID NO: 39] (F1024-1-3 H-CDR3);(6) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3);(7) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence RASESVDSYGNSFMH [SEQ ID NO: 45] (rl8Dll L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence LASNLES [SEQ ID NO: 46] (rl8Dll L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence QQNNGDPYT [SEQ ID NO: 47] (rl8Dll L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence TYALN [SEQ ID NO: 48] (rl8Dll H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (rl8Dll H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence PQSGTSFAY [SEQ ID NO: 50] (rl8Dll H-CDR3); and(8) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises, consists or consists essentially of the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 comprises, consists or consists essentially of the sequence SASYRCS [SEQ ID NO: 52] (rM il2 L-CDR2); and L-CDR3 comprises, consists or consists essentially of the sequence QQYNTYVT [SEQ ID NO: 53] (rMil2 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises, consists or consists essentially of the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 comprises, consists or consists essentially of the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 comprises, consists or consists essentially of the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3).

[0126] In some embodiments, the CD14 antagonist antigen-binding molecule is a humanized antibody. In illustrative examples of this type, the humanized CD14 antagonist antibody suitably comprises a donor CDR set corresponding to a CD14 antagonist antigen-binding molecule e.g., one of the CD14 antagonist antigen-binding molecules described above), and a human acceptor framework. The human acceptor framework may comprise at least one amino acid substitution relative to a human germline acceptor framework at a key residue selected from the group consisting of: a residue adjacent to a CDR; a glycosylation site residue; a rare residue; a canonical residue; a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and a residue in a region that overlaps between a Chothia-defined VH CDR1 and a Kabat-defined first heavy chain framework. Techniques for producinghumanized mAbs are well known in the art (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). A chimeric or murine monoclonal antibody may be humanized by transferring the mouse CDRs from the heavy and light variable chains of the mouse immunoglobulin into the corresponding variable domains of a human antibody. The mouse framework regions (FR) in the chimeric monoclonal antibody are also replaced with human FR sequences. As simply transferring mouse CDRs into human FRs often results in a reduction or even loss of antibody affinity, additional modification might be required in order to restore the original affinity of the murine antibody. This can be accomplished by the replacement of one or more human residues in the FR regions with their murine counterparts to obtain an antibody that possesses good binding affinity to its epitope. See, for example, Tempest et al. (1991. Biotechnology 9:266-271) and Verhoeyen et al. (1988 supra). Generally, those human FR amino acid residues that differ from their murine counterparts and are located close to or touching one or more CDR amino acid residues would be candidates for substitution.

[0127] In some embodiments, the CD14 antagonist antigen-binding molecule is atibuclimab, also known as the IC14 antibody (Axtelle et al., 2001. J. Endotoxin Res. 7: 310-314; and U.S. Pat. Appl. No. 2006 / 0121574, which are incorporated herein by reference in their entirety) or an antigen-binding fragment thereof. The IC14 antibody is a chimeric (murine / human) monoclonal antibody that specifically binds to human CD14. IC14 was derived from the murine 28C5 noted above and comprises an IgG4 heavy chain (see, Patent Nos. 5,820,858, 6,444,206 and 7,326,569 to Leturcq et al., and Leturcq et al., 1996. J. Clin. Invest. 98: 1533-1538). Thus, in one example, the CD14 antagonist antigen-binding molecule comprises the IC14 heavy chain and light chain CDRs, as described above. In another example, the CD14 antagonist antigen-binding molecule comprises the VL domain and a VH domain, wherein:the VL domain comprises, consists or consists essentially of the amino acid sequence: QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTIN PVEADDVATYYCQQSNEDPYTFGGGTKLEIK [SEQ ID NO: 25]; andthe VH domain comprises, consists or consists essentially of the amino acid sequence: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKN QFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSS [SEQ ID NO: 26];orthe VL domain comprises, consists or consists essentially of the amino acid sequence: DIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDF TLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIK [SEQ ID NO: 30]; andthe VH domain comprises, consists or consists essentially of the amino acid sequence: DVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDT SKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSS [SEQ ID NO: 31].

[0128] In another example, the CD14 antagonist antigen-binding molecule comprises light chain and heavy chain of IC14, wherein:

[0129] the light chain comprises, consists or consists essentially of the amino acid sequence:QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDFTLTIN PVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 28]; andthe heavy chain comprises, consists or consists essentially of the amino acid sequence: LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSKN QFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 29];orthe light chain comprises, consists or consists essentially of the amino acid sequence: DIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTDF TLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 32]; andthe heavy chain comprises, consists or consists essentially of the amino acid sequence: DVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDT SKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPS CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 33].

[0130] Additional CD14 antagonist antigen-binding molecules suitable for use in the methods disclosed herein can be identified by methods well known to those skilled in the art. These methods generally comprise determining whether an antigen-binding molecule is capable of directly antagonizing CD14. For example, the methods may involve determining whether an antigen-binding molecule is capable of inhibiting or decreasing the amount or agonist activity of CD14, wherein the ability to inhibit or decrease the amount or agonist activity of CD14 indicates that the antigen-binding molecule may be suitable for use in treating HF. In some embodiments, the antigen-binding molecule is contacted with CD14, or a cell that expresses CD14 on its surface, or a nucleic acid sequence from which CD14 is expressed, suitably in the presence of a CD14 agonist such as a DAMP or PAMP, wherein a decrease in the amount or agonist activity of CD14 in the presence of the agonist, when compared to a control, indicates that the antigen-binding molecule binds to CD14 and directly antagonizes CD14. A decrease or inhibition of CD14 agonist activity, includes for example inhibiting, or decreasing activation of, downstream pathways such as TLR signaling pathways (e.g., TLR4 signaling pathway) and the TRIF pathway, or elicitation of acellular response (e.g., production of pro-inflammatory mediators including pro-inflammatory cytokines).

[0131] These methods may be carried out in vivo, ex vivo or in vitro. In particular, the step of contacting an antigen-binding molecule with CD14 or with a cell that expresses CD14 on its surface (e.g., immune cells) may be carried out in vivo, ex vivo or in vitro. The methods may be carried out in a cell-based or a cell-free system. For example, the method may comprise a step of contacting a cell expressing CD14 on its surface with an antigen-binding molecule and determining whether the contacting of the cell with the antigen-binding molecule leads to a decrease in the amount or agonist activity of CD14. In such a cell-based assay, the CD14 and / or the antigenbinding molecule may be endogenous to the host cell, may be introduced into a host cell or tissue, may be introduced into the host cell or tissue by causing or allowing the expression of an expression construct or vector or may be introduced into the host cell by stimulating or activating expression from an endogenous gene in the cell. In such a cell-based method, the amount of activity of CD14 may be assessed in the presence or absence of an antigen-binding molecule in order to determine whether the agent is altering the amount of CD14 in the cell, such as through regulation of CD14 expression in the cell or through destabilization of CD14 protein within the cell, or altering the CD14 agonist activity of the cell. The presence of a lower CD14 agonist activity or a decreased amount of CD14 on the cell surface in the presence of the antigen-binding molecule indicates that the antigen-binding molecule may be a suitable antagonist of CD14 for use in accordance with the present disclosure.

[0132] In some examples, it is further determined whether the antigen-binding molecule lacks substantial or detectable binding to another cellular component, suitably a binding partner of CD14, such as a CD14 binding partner that is either secreted e.g., MD2) or located on the cell membrane (e.g., TLR4), to thereby determine that the antigen-binding molecule is a specific antagonist of CD14. In a non-limiting example of this type, the antigen-binding molecule is contacted in the presence of a CD14 agonist such as a DAMP or PAMP (1) with a wild-type cell that expresses CD14 on its surface (e.g., an immune cell such a macrophage), and (2) with a CD14 negative cell (e.g., an immune cell that is the same as in (1) but has a loss of function in the CD14 gene). If the antigen-binding molecule inhibits a CD14 agonist activity of the wild-type cell but not of the CD14 negative cell, this indicates that the antigen-binding molecule is a CD14 specific antagonist. Cells of this type may be constructed using routine procedures or animals.

[0133] In other examples, potential CD14 antagonist antigen-binding molecules are assessed in vivo, such as, for example, in an animal model. In such an in vivo model, the effects of the antigen-binding molecule may be assessed in the circulation (e.g., blood) or heart, or in other organs such as lung, liver, kidney, or brain. In particular examples, models of HF are used to assess the activity of the antigen-binding molecule.

[0134] Exemplary CD14 antagonist antigen-binding molecules suitably result in a decrease in CD14 activity or levels of at least 5%, at least 10%, at least 25%, at least 50%, at least 60%, at least 75%, or at least 85% or more compared to in the absence of the antigenbinding molecule, in some examples, the antigen-binding molecule may result in a decrease in CD14 agonist activity or levels such that the agonist activity or level of CD14 is no longer detectable in the presence of the antigen-binding molecule. Such a decrease may be seen in the sample being tested or, for example, where the method is carried out in an animal model.

[0135] Preferably, the antigen-binding molecule is a specific antagonist of CD14 as described above. However, this does not mean that a specific antagonist of CD14 has a complete absence of off-target antagonistic activity. In this regard, the specific antagonist of CD14 may have negligible or a minor direct binding and effect on other cellular components, such that the antagonism of the activity, signaling or expression of a non-CD14 cellular component, 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 that agent on the activity, signaling or expression of CD14.

[0136] Levels or amounts of CD14 may be measured by assessing expression of the CD14 gene. Gene expression may be assessed by looking at mRNA production or levels or at protein production or levels. Expression products such as mRNA and proteins may be identified or quantified by methods known in the art. Such methods may utilize hybridization to specifically identify the mRNA of interest. For example, such methods may involve PCR or real-time PCR approaches. Methods to identify or quantify a protein of interest may involve the use of antigenbinding molecules that bind that protein. For example, such methods may involve western blotting. Regulation of CD14 gene expression may be compared in the presence and absence of an antigenbinding molecule. Thus, antigen-binding molecules can be identified that decrease CD14 gene expression compared to the level seen in the absence of the antibody. Such antigen-binding molecules may be suitable antagonists of CD14 in accordance with the present disclosure.

[0137] The methods for identifying suitable antagonist antigen-binding molecules for use in accordance with the present disclosure may assess the agonist activity of CD14. For example, such a method may be carried out using peripheral blood mononuclear cells. Such cells will produce pro-inflammatory cytokines such as IL-1 a, IL-6, TNF-a, IFN-[B, IL-ip, IL-17 and IL-8 in response to stimulation with, for example, LPS. Methods may therefore comprise combining peripheral blood mononuclear cells with the antigen-binding molecule or a vehicle and adding LPS. The cells may then be incubated for an amount of time (e.g., 24 hours) to allow the production of pro-inflammatory mediators such as cytokines. The level of pro-inflammatory cytokines such as IL-la, IL-6, TNF-a, IFN-p, IL- 1 P, IL-17 and IL-8 produced by the cells in that time period can then be assessed. If the antigen-binding molecule has anti-CD14 properties, then the production of such cytokines should be reduced compared to the vehicle-treated cells.3. Ancillary agents and interventions

[0138] The CD14 antagonist antigen-binding molecule may be administered alone or in combination with one or more other active agents (also referred to as "ancillary HF therapeutic agents" and the like) or other interventions, such as agents and interventions that are useful for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF. The ancillary HF therapeutic agents may be any compound, molecule, or substance that exerts therapeutic effect to a subject in need thereof, suitably in the context of treating HF.

[0139] Representative ancillary HF therapeutic agents suitable for the purposes of the present disclosure include, for example, antihyperlipoproteinemic agents e.g., HMG-CoA reductase inhibitors such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin, or other agents such as ezetimibe, fibric acid derivatives, niacin, or bile acid sequestrants, such as cholestyramine, colestipol, or colesevelam), antiarteriosclerotic agents, antithrombotic / fibrinolytic agents, blood coagulants (e.g., aprotinin, tranexamic acid, epsilon-aminocaproic acid, or aminomethylbenzoic acid), antiarrhythmic agents (e.g., amiodarone, flecainide, ibutilide, lidocaine,procainamide, propafenone, quinidine, tocainide, or digoxin), antihypertensive agents (e.g., furosemide, bumetanide, amiloridhydralazine, minoxidil, spironolactone, clonidine, or methyldopa), vasopressors e.g., norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine, or dobutamine), diuretics e.g., chlorthalidone, hydrochlorothiazide, metolazone, indapamide, bumetanide, ethacrynic acid, or furosemide), statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin), anti-platelet agents (e.g., aspirin, clopidogrel, ticlopidine, ticagrelor, prasugrel, or cangrelor), SGLT2 inhibitors (e.g., bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), treatment agents for congestive heart failure, antianginal agents (e.g., nitrates such as isosorbide dinitrate, isosorbide mononitrate, or nitro-glycerin; calcium channel inhibitors such as amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, or verapamil); beta-adrenergic receptor blockers such as atenolol, pindolol, propranolol, or metoprolol, or ranolazine), antibacterial agents, renin-angiotensin system (RAS) blockers (e.g., captopril, imidapril, zofenopril, candesartan, delapril, telmisartan, aliskiren, or moexipril), mineralocorticoid receptor antagonists (MRAs) (e.g., spironolactone or eplerenone), ACE inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, or quinapril), angiotensin receptor blockers (e.g., azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan), neprilysin inhibitors (e.g., sacubitril), angiotensin receptor / neprilysin inhibitors (e.g., sacubitril / valsartan), alpha-2 receptor agonists (e.g., guanabenz, guanfacine, clonidine, tizanidine, medetomidine, or dexmedetomidine), cholinesterase inhibitors, modafinil, thiazolidinediones and non-steroidal anti-inflammatory drugs, and combinations thereof.

[0140] When two or more therapeutic agents are used in combination, the dosage of each therapeutic agent is commonly identical to the dosage of the agent when used independently. However, when a therapeutic agent interferes with the metabolism of others, the dosage of each therapeutic agent is properly adjusted. Alternatively, where the two or more therapeutic agents show synergistic effects, the dose of one or more may be reduced. Each therapeutic agent may be administered simultaneously or separately in an appropriate time interval.

[0141] When combination therapy is desired, the CD14 antagonist antigen-binding molecule is administered separately, simultaneously or sequentially with one or more ancillary agents or interventions. In some embodiments, this may be achieved by administering, such as systemically, a single composition or pharmacological formulation that includes both types of agent, or by administering two separate compositions or formulations at the same time, wherein one composition includes the CD14 antagonist antigen-binding molecule and the other the ancillary agent. In other embodiments, the treatment with the CD14 antagonist antigen-binding molecule may precede or follow the treatment with the ancillary agent by intervals ranging from minutes to hours or even days or weeks.

[0142] Where two or more agents are administered to a subject "in conjunction", "in combination" or "concurrently" they may be administered in a single composition at the same time, or in separate compositions at the same time, or in separate compositions separated in time.

[0143] In another example, administration of the antigen-binding molecule is in conjunction with an intervention (e.g., surgical procedure), such as a percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass including coronaryartery bypass grafting (CABG), implantation of a pacemaker, implantation of an implantable cardioverter-defibrillator (ICD), cardiac catheterization, revascularization and heart transplantation.

[0144] In some situations, the antigen-binding molecule and ancillary agent(s) are administered within about 1-12 hours of each other or within about 2-6 hours of each other. In other situations, it may be desirable to extend the time period for treatment significantly, however, where one or more days e.g., 1, 2, 3, 4, 5, 6, 7 or 8 days) lapse between the respective administrations. In embodiments where the ancillary agent is administered separately to the CD14 antagonist antigen-binding molecule, it will be understood that the ancillary agent can be administered by a method which is different to that of the administration method used for the CD14 antagonist antigen-binding molecule. In further embodiments, where 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, such as at the time of or within 12, 24, 36 or 48 hours of the intervention.4. Pharmaceutical compositions

[0145] As described herein, a CD14 antagonist antigen-binding molecule, optionally in combination with at least one ancillary HF therapeutic agent, is useful for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving ejection fraction (e.g., LVEF), or restoring ejection fraction (e.g., LVEF) to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, and / or for reducing or improving LV mass in HF.

[0146] The CD14 antagonist antigen-binding molecule and optionally the ancillary agent(s) can be administered either by themselves suitably in the form of pharmaceutical compositions, which optionally comprise a pharmaceutically acceptable carrier. Thus, also provided herein are pharmaceutical compositions comprising a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, for use in treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in alleviating, reducing or reversing adverse cardiac structural remodeling in HF, in increasing or improving cardiac contractile function in HF, in increasing or improving cardiac output in HF, in increasing or improving ejection fraction (e.g., LVEF), or restoring ejection fraction (e.g., LVEF) to a normal range, in HF, in reducing or improving LVESV, or restoring LVESV to a normal range, in HF, in reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, in ameliorating or reducing LV akinetic area in HF, in ameliorating or reducing LV dilatation in HF, and / or in reducing or improving LV mass in HF.

[0147] The CD14 antagonist antigen-binding molecules and optionally the ancillary HF therapeutic agent(s) may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, stabilizers or excipients (vehicles) to form a pharmaceutical composition as is known in the art, in particular with respect to protein active agents. Carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the composition andnot deleterious to the recipient (e.g. patient) thereof. Suitable carriers typically include physiological saline or ethanol polyols such as glycerol or propylene glycol.

[0148] The antigen-binding molecule may be formulated as neutral or salt forms.Pharmaceutically acceptable salts include the acid addition salts (formed with free amino groups) and which are formed with inorganic acids such as hydrochloric or phosphoric acids, or such organic acids such as acetic, oxalic, tartaric and maleic. Salts formed with the free carboxyl groups may also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxides, and organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine and procaine.

[0149] The compositions may be suitably formulated for systemic administration, including intravenous, intramuscular, subcutaneous, or intraperitoneal administration and conveniently comprise sterile aqueous solutions of the antigen-binding molecule, which are preferably isotonic with the blood of the recipient. Such formulations are typically prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile. These may be prepared in unit or multi-dose containers, for example, sealed ampoules or vials.

[0150] The compositions may incorporate a stabilizer, such as for example polyethylene glycol, proteins, saccharides e.g., trehalose), amino acids, inorganic acids and admixtures thereof. Stabilizers are used in aqueous solutions at the appropriate concentration and pH. The pH of the aqueous solution is adjusted to be within the range of 5.0-9.0, preferably within the range of 6-8. In formulating the antigen-binding molecule, anti-adsorption agent may be used. Other suitable excipients may typically include an antioxidant such as ascorbic acid. The compositions may be formulated as controlled release preparations which may be achieved through the use of polymer to complex or absorb the proteins. Appropriate polymers for controlled release formulations include for example polyester, polyamino acids, polyvinyl, pyrrolidone, ethylenevinylacetate, and methylcellulose. Another possible method for controlled release is to incorporate the antigenbinding molecule into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers. Alternatively, instead of incorporating these agents into polymeric particles, it is possible to entrap these materials in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacylate) microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.

[0151] A CD14 antagonist antigen-binding molecule and optionally at least one ancillary agent may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the antagonist antigen-binding molecules of the present disclosure in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials disclosed herein may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[0152] One of skill in the art will recognize that formulations are routinely designed according to their intended use, i.e. route of administration.5. Methods of treatment

[0153] The present disclosure also relates to the use of a CD14 antagonist antigenbinding molecule, and optionally at least one ancillary HF therapeutic agent, suitably in the form of a pharmaceutical composition, in methods for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving ejection fraction (e.g., LVEF), or restoring ejection fraction (e.g., LVEF) to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, and / or for reducing or improving LV mass in HF, in a subject.

[0154] In some aspects, the present disclosure provides a method of treating HF, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject in need. In some aspects, the present disclosure provides a method of inhibiting HF, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject in need. In some aspects, the present disclosure provides a method of delaying HF, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject in need. In some aspects, the present disclosure provides a method of slowing or reducing progression of HF, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject in need. In some aspects, the present disclosure provides a method of ameliorating HF, comprising administering a a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject in need.

[0155] In some aspects, the present disclosure provides a method of ameliorating adverse cardiac structural remodeling, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of reducing adverse cardiac structural remodeling, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of reversing adverse cardiac structural remodeling, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of slowing the progression of adverse cardiac structural remodeling, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some embodiments, adverse cardiac structural remodeling is inhibited, delayed, or ameliorated for about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 1 year, about 2 years, about 5 years, and / or about 10 years compared with the adverse cardiac structural remodeling in an untreated HF subject. In some embodiments, adverse cardiac structural remodeling is reduced, reversed, delayed and / or ameliorated by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about90% compared with the adverse cardiac structural remodeling in an untreated HF subject. In some embodiments, this reduction, reversal, delay and / or amelioration of adverse cardiac structural remodeling is observed at the time points disclosed herein. In some embodiments, the adverse cardiac structural remodeling comprises an increase in fibrosis of the myocardium. In some embodiments, the adverse cardiac structural remodeling comprises a change in cardiac cavity diameter. In some embodiments, the adverse cardiac structural remodeling comprises a change in cardiac mass (hypertrophy and atrophy). In some embodiments, the adverse cardiac structural remodeling comprises thinning of the myocardium. In some embodiments, the adverse cardiac structural remodeling comprises scar formation of the myocardium (e.g., LV akinetic area). In some embodiments, the adverse cardiac structural remodeling comprises reduced cardiac contractile function. In some embodiments, the adverse cardiac structural remodeling comprises reduced LV diastolic function. In some embodiments, the adverse cardiac structural remodeling comprises reduced LV systolic function. In some embodiments, the adverse cardiac structural remodeling comprises increased LV dilatation. In some embodiments, the adverse cardiac structural remodeling comprises a change in cardiac inflammatory infiltrate.

[0156] In some aspects, the present disclosure provides a method of reducing cardiac deterioration, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of inhibiting cardiac deterioration, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of delaying cardiac deterioration, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of slowing the progression of cardiac deterioration, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some aspects, the present disclosure provides a method of ameliorating cardiac deterioration, comprising administering a CD14 antagonist antigen-binding molecule, and optionally at least one ancillary HF therapeutic agent, to a subject with HF. In some embodiments, cardiac deterioration is reduced, inhibited, delayed, slowed 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 with the cardiac deterioration in an untreated HF subject. In some embodiments, cardiac deterioration is reduced, 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 with cardiac deterioration in an untreated HF subject. In some embodiments, this reduction, inhibition, delay, slowing or amelioration of cardiac deterioration is observed at the time points disclosed herein. In some embodiments, the cardiac deterioration is a decrease in inotropy. In some embodiments, the cardiac deterioration is a decrease in lusitropy. In some embodiments, the cardiac deterioration is a thickening of the heart muscle. In some embodiments, the cardiac deterioration is cardiac hypertrophy.

[0157] In accordance with the present disclosure, the HF may be HFpEF, HFrEF or HFmrEF. The HF may be AHF, ADHF, or CHF. The HF may be a Class I HF, a Class II HF, a Class III HF or a Class IV HF according to the NYHA classification scale. The subject may be a patient with astage of progression of HF as classified according to the ACC / AHA HF guidelines, wherein the stage of progression is selected from a Stage A patient, a Stage B patient, a Stage C patient and a Stage B patient.

[0158] In any of the aspect and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule, and optionally the at least one ancillary HF therapeutic agent, are typically administered to the subject in effective amounts.

[0159] In some aspects, the subject has undergone a surgical procedure prior to administration of the CD14 antagonist antigen-binding molecule, and optionally the at least one ancillary HF therapeutic agent. In other aspects, the subject undergoes a surgical procedure concurrently with the administration of the CD14 antagonist antigen-binding molecule, and optionally the at least one ancillary HF therapeutic agent. The surgical procedure is typically one for treating HF, illustrative examples of which comprise percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass including coronary artery bypass grafting (CABG), implantation of a pacemaker e.g., a LV assist device (LVAD)), atrioventricular (AV) node catheter ablation, implantation of an implantable cardioverter-defibrillator (ICD), cardiac catheterization, revascularization and / or heart transplantation.

[0160] In some aspects, the subject has, or has begun to manifest, clinical signs or symptoms of HF. Clinical signs of HF include, but are not limited to, elevated jugular venous pressure, jugular venous dilatation, third heart sound (e.g., gallop rhythm), laterally displaced apical impulse, congested hepatomegaly, hepatojugular reflux, ascites, symptoms of gut congestion, weight gain (e.g., >2 kg / week), anorexia, weight loss (e.g., in advanced heart failure), cachexia, cardiac murmur, high NLR, peripheral edema (e.g., ankle, sacral, scrotal), pulmonary congestion, pulmonary edema (e.g., acute pulmonary edema), pulmonary rales, pulmonary crepitations, reduced air entry and dullness to, percussion at lung bases (e.g., pleural, effusion), arrhythmias, atrial fibrillation, atrial flutter, tachycardia (e.g., ventricular tachycardia), irregular pulse, tachypnea, Cheyne-Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, nocturia, and narrow pulse pressure. HF symptoms include, but are not limited to, breathlessness, orthopnea, paroxysmal nocturnal dyspnea, exertional dyspnea, dyspnea at rest, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling, nocturnal cough, wheezing, bloated feeling, loss of appetite, nausea, confusion (e.g., in the elderly), depression, palpitations, dizziness, syncope, and bendopnea.

[0161] The treatment or inhibition of signs or symptoms of HF may be measured by any means known in the art. For example, evaluation may include echocardiographic evaluation, cardiac magnetic resonance imagining (MRI), or cardiac MRI with late gadolinium enhancement. In particular, the LV size, thickness, volumes, ejection fraction (EF), and scar / inflammatory burden of the myocardium, as well as strain may be evaluated. Strain, change in LV dimension and volume, and scar burden are key measures.

[0162] Typically, and in certain aspects of the methods described herein, the subject can experience one or more beneficial outcomes after administration of a pharmaceutical composition disclosed herein over a treatment period including, but not limited to, the beneficial outcomes described below.

[0163] In certain aspects, the present disclosure provides methods of decreasing adverse cardiac structural remodeling, increasing beneficial cardiac structural remodeling,increasing ejection fraction {e.g., LVEF), reducing LVESV, reducing LVEDV, reducing LV akinetic area, and / or reducing LV dilatation, as measured for example by magnetic resonance imaging (MRI), ultrasound, echocardiography, and / or computed tomography (CT), in a subject having or at risk of having HF. In some aspects, the subject having HF experiences an increase in beneficial cardiac structural remodeling, an increase in ejection fraction {e.g., LVEF), a decrease in LVESV, a decrease in LVEDV, a decrease in LV akinetic area, and / or a decrease in LV dilatation, as measured for example by MRI, ultrasound, echocardiography, and / or CT, after a period of from about 1 month to about 6 months. In some aspects, the subject experiences a decrease in adverse cardiac structural remodeling, an increase in beneficial cardiac structural remodeling, an increase in ejection fraction {e.g., LVEF), a decrease in LVESV, a decrease in LVEDV, a decrease in LV akinetic area, and / or a decrease in LV dilatation, as measured for example by MRI, ultrasound, echocardiography, and / or CT after a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months, or by an interval between any of the preceding values.

[0164] In some aspects, the subject experiences a change in hemodynamics, as assessed for example by right heart catheterization after a treatment period. In some aspects, the subject experiences a change in one or more parameters after a treatment period including, but not limited to, cardiac contractile function, cardiac output, pulmonary wedge pressure, pulmonary and systemic vascular resistance, and QT interval, as assessed by right heart catheterization. In some aspects, the subject experiences a change in one or more of these parameters after a treatment period of from about 3 hours to about 6 months. In some aspects, the subject experiences a change in one or more of these parameters after a treatment period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, and / or about 6 months, or by an interval between any of the preceding values.

[0165] Subjects with HF can experience pulmonary edema. In some aspects, the subject experiences an improvement in lung function and / or symptoms associated with pulmonary edema. In some aspects, the subject experiences an improvement in lung function and / or symptoms associated with congestive pulmonary edema after a treatment period of from about 3 hours to about 6 months. In some aspects, the subject experiences an improvement in lung function and / or symptoms associated with pulmonary edema after a treatment period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, and / or about 6 months, or by an interval between any of the preceding values.

[0166] In some aspects, the subject experiences one or more of the following parameters after a treatment period: a decrease in N-terminal brain natriuretic peptide (NT proBNP), an increase in 6 minute walking distance; an increase in cardiac output / stroke volume (CO / SV), an increase in ejection fraction {e.g., LVEF), a reduction in LV internal diameter end diastole (LVIDd), an improvement in diastolic function, a reduction in left atrial (LA) volume, a reduction in LV diameter, no change in QT interval, and an improvement in NHYA functional class. In some aspects, the subject experiences a change in one or more of these parameters after atreatment period of from about 3 hours to about 12 months. In some aspects, the subject experiences a change in one or more of these parameters after a treatment period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, and / or about 12 months, or by an interval between any of the preceding values.

[0167] In certain aspects of the methods described herein, the increase or improvement in the subject's cardiac contractile function e.g., in a subject having HFrEF) is measured by ejection fraction, suitably LVEF. In some aspects, the subject's ejection fraction e.g., in a subject having HFrEF) is increased relative to the subject's ejection fraction before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0168] In some aspects of the methods described herein, the subject's ejection fraction is increased by about 2% to about 25% relative to the subject's ejection fraction before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the subject's ejection fraction is increased by about 2% to about 24%. In some aspects, the subject's ejection fraction is increased by about 2% to about 23%. In some aspects, the subject's ejection fraction is increased by about 2% to about 22%. In some aspects, the subject's ejection fraction is increased by about 2% to about 21%. In some aspects, the subject's ejection fraction is increased by about 2% to about 20%. In some aspects, the subject's ejection fraction is increased by about 2% to about 19%. In some aspects, the subject's ejection fraction is increased by about 2% to about 18%. In some aspects, the subject's ejection fraction is increased by about 2% to about 17%. In some aspects, the subject's ejection fraction is increased by about 2% to about 16%. In some aspects, the subject's ejection fraction is increased by about 2% to about 15%. In some aspects, the subject's ejection fraction is increased by about 2% to about 14%. In some aspects, the subject's ejection fraction is increased by about 2% to about 13%. In some aspects, the subject's ejection fraction is increased by about 2% to about 12%. In some aspects, the subject's ejection fraction is increased by about 2% to about 11%. In some aspects, the subject's ejection fraction is increased by about 2% to about 10%. In some aspects, the subject's ejection fraction is increased by about 2% to about 9%. In some aspects, the subject's ejection fraction is increased by about 2% to about 8%. In some aspects, the subject's ejection fraction is increased by about 2% to about 7%. In some aspects, the subject's ejection fraction is increased by about 2% to about 6%. In some aspects, the subject's ejection fraction is increased by about 2% to about 5%. Suitably, the ejection fraction is or comprises LVEF.

[0169] In some aspects of the methods described herein, the subject's ejection fraction is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or about 25%, or by a range between any of the preceding values, relative to the subject's ejection fraction before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0170] In some aspects, the subject experiences beneficial cardiac structural remodeling after a treatment period. In some aspects, the subject experiences beneficial cardiac structural remodeling after a treatment period of about 3 months to about 18 months. In some aspects, the subject experiences beneficial cardiac structural remodeling after a treatment period of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, and / or about 18 months. In specific embodiments of these aspects, the beneficial cardiac structural remodeling is reverse LV remodeling.

[0171] In some aspects of the methods described herein, the subject's beneficial cardiac structural remodeling e.g., as measured by a decrease in akinetic area) is increased by about 2% to about 40% relative to the adverse cardiac structural remodeling e.g., akinetic area) of the subject before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 39%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 38%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 37%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 36%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 35%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 34%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 33%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 32%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 31%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 30%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 29%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 28%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 27%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 26%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 25%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 24%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 23%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 22%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 21%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 20%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 19%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 18%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 17%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 16%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 15%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about2% to about 14%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 13%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 12%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 11%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 10%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 9%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 8%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 7%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 6%. In some aspects, the subject's beneficial cardiac structural remodeling is increased by about 2% to about 5%. Suitably, the beneficial cardiac structural remodeling comprises a decrease in LV akinetic area.

[0172] In some aspects of the methods described herein, the subject's beneficial cardiac structural remodeling is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, or by a range between any of the preceding values, relative to the adverse cardiac structural remodeling e.g., akinetic area) of the subject before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigenbinding molecule.

[0173] In some aspects of the methods described herein, the subject's LVEF is increased by about 2% to about 40% relative to the subject's LVEF before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the subject's LVEF is increased by about 2% to about 39%. In some aspects, the subject's LVEF is increased by about 2% to about 38%. In some aspects, the subject's LVEF is increased by about 2% to about 37%. In some aspects, the subject's LVEF is increased by about 2% to about 36%. In some aspects, the subject's LVEF is increased by about 2% to about 35%. In some aspects, the subject's LVEF is increased by about 2% to about 34%. In some aspects, the subject's LVEF is increased by about 2% to about 33%. In some aspects, the subject's LVEF is increased by about 2% to about 32%. In some aspects, the subject's LVEF is increased by about 2% to about 31%. In some aspects, the subject's LVEF is increased by about 2% to about 30%. In some aspects, the subject's LVEF is increased by about 2% to about 29%. In some aspects, the subject's LVEF is increased by about 2% to about 28%. In some aspects, the subject's LVEF is increased by about 2% to about 27%. In some aspects, the subject's LVEF is increased by about 2% to about 26%. In some aspects, the subject's LVEF is increased by about 2% to about 25%. In some aspects, the subject's LVEF is increased by about 2% to about 24%. In some aspects, the subject's LVEF is increased by about 2% to about 23%. In some aspects, the subject's LVEF is increased by about 2% to about 22%. In some aspects, the subject's LVEF is increased by about 2% to about 21%. In some aspects, the subject's LVEF is increased by about 2% to about 20%. In some aspects, the subject's LVEF is increased by about 2% to about 19%. In some aspects, the subject's LVEF is increased by about 2% to about18%. In some aspects, the subject's LVEF is increased by about 2% to about 17%. In some aspects, the subject's LVEF is increased by about 2% to about 16%. In some aspects, the subject's LVEF is increased by about 2% to about 15%. In some aspects, the subject's LVEF is increased by about 2% to about 14%. In some aspects, the subject's LVEF is increased by about 2% to about 13%. In some aspects, the subject's LVEF is increased by about 2% to about 12%. In some aspects, the subject's LVEF is increased by about 2% to about 11%. In some aspects, the subject's LVEF is increased by about 2% to about 10%. In some aspects, the subject's LVEF is increased by about 2% to about 9%. In some aspects, the subject's LVEF is increased by about 2% to about 8%. In some aspects, the subject's LVEF is increased by about 2% to about 7%. In some aspects, the subject's LVEF is increased by about 2% to about 6%. In some aspects, the subject's LVEF is increased by about 2% to about 5%.

[0174] In some aspects of the methods described herein, the subject's LVEF is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, or by a range between any of the preceding values, relative to the subject's LVEF before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigenbinding molecule.

[0175] In some aspects, the subject experiences a decrease in LV end-systolic volume (LVESV) after a treatment period. In some aspects, the subject experiences LVESV after a treatment period of about 3 months to about 18 months. In some aspects, the subject experiences a decrease in LVESV after a treatment period of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, and / or about 18 months.

[0176] In some aspects of the methods described herein, the subject's LVESV is decreased by about 2% to about 35% relative to the subject's LVESV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the subject's LVESV is decreased by about 2% to about 34%. In some aspects, the subject's LVESV is decreased by about 2% to about 33%. In some aspects, the subject's LVESV is decreased by about 2% to about 32%. In some aspects, the subject's LVESV is decreased by about 2% to about 31%. In some aspects, the subject's LVESV is decreased by about 2% to about 30%. In some aspects, the subject's LVESV is decreased by about 2% to about 29%. In some aspects, the subject's LVESV is decreased by about 2% to about 28%. In some aspects, the subject's LVESV is decreased by about 2% to about 27%. In some aspects, the subject's LVESV is decreased by about 2% to about 26%. In some aspects, the subject's LVESV is decreased by about 2% to about 25%. In some aspects, the subject's LVESV is decreased by about 2% to about 24%. In some aspects, the subject's LVESV is decreased by about 2% to about 23%. In some aspects, the subject's LVESV is decreased by about 2% to about 22%. In some aspects, the subject's LVESV is decreased by about 2% to about 21%. In some aspects, the subject's LVESV is decreased by about 2% to about 20%. In some aspects, thesubject's LVESV is decreased by about 2% to about 19%. In some aspects, the subject's LVESV is decreased by about 2% to about 18%. In some aspects, the subject's LVESV is decreased by about 2% to about 17%. In some aspects, the subject's LVESV is decreased by about 2% to about 16%. In some aspects, the subject's LVESV is decreased by about 2% to about 15%. In some aspects, the subject's LVESV is decreased by about 2% to about 14%. In some aspects, the subject's LVESV is decreased by about 2% to about 13%. In some aspects, the subject's LVESV is decreased by about 2% to about 12%. In some aspects, the subject's LVESV is decreased by about 2% to about 11%. In some aspects, the subject's LVESV is decreased by about 2% to about 10%. In some aspects, the subject's LVESV is decreased by about 2% to about 9%. In some aspects, the subject's LVESV is decreased by about 2% to about 8%. In some aspects, the subject's LVESV is decreased by about 2% to about 7%. In some aspects, the subject's LVESV is decreased by about 2% to about 6%. In some aspects, the subject's LVESV is decreased by about 2% to about 5%.

[0177] In some aspects of the methods described herein, the LVESV is decreased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, or by a range between any of the preceding values, relative to the subject's LVESV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0178] In some aspects, the subject experiences a decrease in LV end-diastolic volume (LVEDV) after a treatment period. In some aspects, the subject experiences LVEDV after a treatment period of about 3 months to about 18 months. In some aspects, the subject experiences a decrease in LVEDV after a treatment period of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, and / or about 18 months, or by an interval between any of the preceding values.

[0179] In some aspects, the subject's LVEDV is decreased by about 2% to about 30% relative to the subject's LVEDV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigenbinding molecule. In some aspects, the subject's LVEDV is decreased by about 2% to about 29%. In some aspects, the subject's LVEDV is decreased by about 2% to about 28%. In some aspects, the subject's LVEDV is decreased by about 2% to about 27%. In some aspects, the subject's LVEDV is decreased by about 2% to about 26%. In some aspects, the subject's LVEDV is decreased by about 2% to about 25%. In some aspects, the subject's LVEDV is decreased by about 2% to about 24%. In some aspects, the subject's LVEDV is decreased by about 2% to about 23%. In some aspects, the subject's LVEDV is decreased by about 2% to about 22%. In some aspects, the subject's LVEDV is decreased by about 2% to about 21%. In some aspects, the subject's LVEDV is decreased by about 2% to about 20%. In some aspects, the subject's LVEDV is decreased by about 2% to about 19%. In some aspects, the subject's LVEDV is decreased by about 2% to about 18%. In some aspects, the subject's LVEDV is decreased by about 2% to about 17%. n some aspects, the subject's LVEDV is decreased by about 2% to about 16%. In some aspects, the subject'sLVEDV is decreased by about 2% to about 15%. In some aspects, the subject's LVEDV is decreased by about 2% to about 14%. In some aspects, the subject's LVEDV is decreased by about 2% to about 13%. In some aspects, the subject's LVEDV is decreased by about 2% to about 12%. In some aspects, the subject's LVEDV is decreased by about 2% to about 11%. In some aspects, the subject's LVEDV is decreased by about 2% to about 10%. In some aspects, the subject's LVEDV is decreased by about 2% to about 9%. In some aspects, the subject's LVEDV is decreased by about 2% to about 8%. In some aspects, the subject's LVEDV is decreased by about 2% to about 7%. In some aspects, the subject's LVEDV is decreased by about 2% to about 6%. In some aspects, the subject's LVEDV is decreased by about 2% to about 5%.

[0180] In some aspects of the methods described herein, the LVEDV is decreased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, or by a range between any of the preceding values, relative to the subject's LVEDV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0181] In certain aspects, the subject having or at risk of having HF e.g., in a subject having HFpEF) experiences a change in LV mass index (LVMI) after a treatment period. In some aspects, the subject experiences a change in LVMI after a treatment period of about 3 months to about 18 months. In some aspects, the subject experiences a change in left ventricular mass index (LVMI) after a treatment period of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, and / or about 18 months. In certain aspects, the left ventricular mass index is measured in g / m 2 and is defined as left ventricular mass divided by body surface as measured by echocardiography or cardiac MRI.

[0182] In certain aspects, the subject having or at risk of having HF experiences one or more parameters selected from a reduction in cardiac fibrosis, a change in diastolic function, a change in systolic function and / or a reduction in left atrial dimension after a treatment period. In some aspects, the subject experiences a change in one or more of these parameters after a treatment period of about 3 months to about 18 months. In some aspects, the subject experiences a change in one or more of these parameters after a after a treatment period of about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, and / or about 18 months, or by an interval between any of the preceding values.

[0183] In some aspects, the subject experiences a shortened duration of hospital stay relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the subject experiences an increase in the number of days between hospital stays relative to a control subject who has not received the CD14 antagonist antigenbinding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the subject experiences a reduced risk ofhospitalization relative to a control subject who has not received the CD14 antagonist antigenbinding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the subject experiences an increase in the time before an initial hospitalization relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the subject experiences a fewer number of hospitalizations relative to a control subject who has not received the CD14 antagonist antigenbinding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the subject experiences a reduced risk of death relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the subject experiences one or more of these parameters after a treatment period of from about 3 hours to about 6 months. In some aspects, the subject experiences one or more of these parameters after a treatment period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, and / or about 6 months, or by an interval between any of the preceding values.

[0184] In certain aspects of the methods described herein, the subject's cardiac contractile function (e.g., in a subject having HFrEF) is increased or improved relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's cardiac contractile function before receiving the CD14 antagonist antigen-binding molecule. In certain aspects, the increase or improvement in the subject's cardiac contractile function (e.g., in a subject having HFrEF) is measured by fractional shortening. In some aspects the subject's fractional shortening (e.g., in a subject having HFrEF) is increased relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's fractional shortening before receiving the CD14 antagonist antigenbinding molecule.

[0185] In some aspects of the methods described herein, the subject's fractional shortening is increased by about 2% to about 25%, by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, relative to the subject's fractional shortening before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0186] In some aspects of the methods described herein, the subject's fractional shortening is increased by about 3% to about 15%, by about 4% to about 14%, by about 5% to about 13%, by about 6% to about 12%, by about 7% to about 11%, or by about 7% to about 10%%, relative to the subject's fractional shortening before administration of the CD14 antagonistantigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0187] In some aspects of the methods described herein, the subject's fractional shortening is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%, or by a range between any of the preceding values%, relative to the subject's fractional shortening before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0188] In certain aspects of the methods described herein, the blood volume in the subject's LV e.g., in a subject having HFrEF) is increased or improved relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's blood volume before receiving the CD14 antagonist antigen-binding molecule. In certain aspects, the increase or improvement in the subject's blood volume e.g., in a subject having HFrEF) is measured by stroke volume in the subject's left ventricle. In some aspects, the stroke volume in the subject's LV (e.g., in a subject having HFrEF) is increased relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's stroke volume before receiving the CD14 antagonist antigen-binding molecule.

[0189] In some aspects of the methods described herein, the stroke volume in the subject's left ventricle is increased by about 1% to about 100% relative to the stroke volume in the subject's left ventricle before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the stroke volume is increased by about 5% to about 95%. In some aspects, the stroke volume is increased by about 10% to about 90%. In some aspects, the stroke volume is increased by about 15% to about 85%. In some aspects, the stroke volume is increased by about 20% to about 80%. In some aspects, the stroke volume is increased by about 25% to about 75%. In some aspects, the stroke volume is increased by about 30% to about 70%. In some aspects, the stroke volume is increased by about 30% to about 65%. In some aspects, the stroke volume is increased by about 35% to about 65%. In some aspects, the stroke volume is increased by about 40% to about 60%.

[0190] In some aspects of the methods described herein, the stroke volume in the subject's left ventricle is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%, or by a range between any of the preceding values, relative to the stroke volume in the subject's left ventricle before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0191] In certain aspects of the methods described herein, the increase or improvement in the subject's blood volume e.g., in a subject having HFrEF) is measured by cardiac output. In some aspects, the subject's cardiac output e.g., in a subject having HFrEF) is increased relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or ascompared to the subject's cardiac output before receiving the CD14 antagonist antigen-binding molecule.

[0192] In some aspects of the methods described herein, the subject's cardiac output is increased by about 2 mL / min to about 20 mL / min relative to the subject's cardiac output before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, suitably wherein the subject's cardiac output is increased by about 2 mL / min to about 19 mL / min, by about 2 mL / min to about 18 mL / min, by about 2 miymin to about 17 mL / min, by about 2 mL / min to about 16 mL / min, by about 2 mL / min to about 15 mL / min, by about 2 mL / min to about 14 mL / min, by about 2 mL / min to about 14 mL / min, by about 2 mL / min to about 13 mL / min, by about 2 mL / min to about 12 mL / min, by about 2 mL / min to about 11 mL / min, by about 2 mL / min to about 10 mL / min, by about 2 mL / min to about 9 mL / min, by about 2 mL / min to about 8 mL / min, by about 2 mL / min to about 7 mL / min, by about 2 mL / min to about 6 mL / min, or by about 2 mL / min to about 5 mL / min.

[0193] In some aspects of the methods described herein, the subject's cardiac output is increased by about 2 mL / min to about 15 mL / min, by about 3 mL / min to about 14 mL / min, by about 4 mL / min to about 13 mL / min, by about 5 mL / min to about 12 mL / min, by about 6 mL / min to about 11 mL / min, or by about 7 mL / min to about 10 mL / min, relative to the subject's cardiac output before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0194] In some aspects of the methods described herein, the subject's cardiac output is increased by at least about 2 mL / min, about 3 mL / min, about 4 mL / min, about 5 mL / min, about 6 mL / min, about 7 mL / min, about 8 mL / min, about 9 mL / min, about 10 mL / min, about 11 mL / min, about 12 mL / min, about 13 mL / min, about 14 mL / min, about 15 mL / min, about 20 mL / min, about 25 mL / min, about 30 mL / min, about 35 mL / min, about 40 mL / min, about 45 mL / min, or about 50 mL / min, or by an interval between any of the preceding values, relative to the subject's cardiac output before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0195] In some aspects of the methods described herein, the cardiac output in the subject's LV is increased by about 1% to about 100% relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the cardiac output in the subject's LV before receiving the CD14 antagonist antigen-binding molecule. In some aspects, the cardiac output in the subject's LV is increased by about 5% to about 95%, by about 10% to about 90%, by about 15% to about 85%, by about 20% to about 80%, by about 25% to about 75%, by about 30% to about 70%, by about 30% to about 65%, by about 35% to about 65%, or by about 40% to about 60% relative to a subject who has not received the CD14 antagonist antigen-binding molecule relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the cardiac output in the subject's LV before receiving the CD14 antagonist antigen-binding molecule.

[0196] In some aspects of the methods described herein, the cardiac output in the subject's LV is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%, or by a range between any of the preceding values, relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's cardiac output before receiving the CD14 antagonist antigen-binding molecule.

[0197] In some aspects of the methods described herein, the level of at least one inflammatory biomarker e.g., Presepsin) in the subject is less than about 80% to less than about 1% of the level of the corresponding at least one inflammatory biomarker in the subject before administration of the CD14 antagonist antigen-binding molecule, or in a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the level of at least one inflammatory biomarker is less than about 70% to less than about 2% of the level of the corresponding at least one inflammatory biomarker. In some aspects, the level of at least one inflammatory biomarker is less than about 60% to less than about 2% of the level of the corresponding at least one inflammatory biomarker. In some aspects, the level of at least one inflammatory biomarker is less than about 50% to less than about 2% of the level of the corresponding at least one inflammatory biomarker. In some aspects, the level of at least one inflammatory biomarker is less than about 40% to less than about 2% of the level of the corresponding at least one inflammatory biomarker.

[0198] In some aspects of the methods described herein, the level of at least one inflammatory biomarker e.g., Presepsin) is about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1%, or by a range between any of the preceding values, relative to the level of the corresponding at least one inflammatory biomarker in the subject before administration of the CD14 antagonist antigen-binding molecule, or in a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0199] In some aspects of the methods described herein, the level of Presepsin in the subject is reduced to about 300 pg / mL to about 1 pg / mL relative to the level of Prespsin in the subject before administration of the CD14 antagonist antigen-binding molecule, or in a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the level of Presepsin in the subject is reduced to about 250 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 200 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 150 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 100 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 90 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 80 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 70 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 60 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 50 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 40 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 30 pg / mL to about 2 pg / mL. In some aspects, the level of Presepsin in the subject is reduced to about 20 pg / mL to about 2 pg / mL.

[0200] In some aspects of the methods described herein, the level of Presepsin is reduced to about 250 pg / mL, about 200 pg / mL, about 150 pg / mL, about 100 pg / mL about 90 pg / mL, about 80 pg / mL, about 90 pg / mL, about 80 pg / mL, about 70 pg / mL, about 60 pg / mL, about 50 pg / mL, about 40 pg / mL, about 30 pg / mL, about 20 pg / mL, about 19 pg / mL, about 18 pg / mL, about 17 pg / mL, about 16 pg / mL, about 15 pg / mL, about 14 pg / mL, about 13 pg / mL, about 12 pg / mL, about 11 pg / mL, about 10 pg / mL, about 9 pg / mL, about 8 pg / mL, about 7 pg / mL, about 6 pg / mL, about 5 pg / mL, about 4 pg / mL, about 3 pg / mL, about 2 pg / mL, or about 1 pg / mL, or by a range between any of the preceding values, relative to the level of Prespsin in the subject before administration of the CD14 antagonist antigen-binding molecule, or in a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0201] In some aspects of the methods described herein, the CD14 antagonist antigenbinding molecule is administered at a dosage that provides or maintains Presepsin at a level less than about 300 pg / mL, less than about 250 pg / mL, less than about 200 pg / mL, less than about 150 pg / mL, less than about 100 pg / mL, less than about 90 pg / mL, less than about 80 pg / mL, less than about 70 pg / mL, less than about 60 pg / mL, less than about 50 pg / mL, less than about 40 pg / mL, less than about 30 pg / mL, less than about 20 pg / mL, less than about 19 pg / mL, less than about 18 pg / mL, less than about 17 pg / mL, a less than bout 16 pg / mL, less than about 15 pg / mL, less than about 14 pg / mL, less than about 13 pg / mL, less than about 12 pg / mL, less than about 11 pg / mL, less than about 10 pg / mL, less than about 9 pg / mL, less than about 8 pg / mL, less than about 7 pg / mL, less than about 6 pg / mL, less than about 5 pg / mL, less than about 4 pg / mL, less than about 3 pg / mL, less than about 2 pg / mL, or less than about 1 pg / mL, or by a range between any of the preceding values.

[0202] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered chronically. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered for about 6 months, for about 7 months, for about 8 months, for about 9 months, for about 10 months, for about 11 months, for about 1 year, for about 2 years, for about 3 years, for about 4 years, for about 5 years, for about 10 years or more. The CD14 antagonist antigen-binding molecules may be administered at any required dose and / or frequency disclosed herein.

[0203] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until HF symptoms improve. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until HF symptoms are ameliorated. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until HF symptoms are delayed. In some embodiments, the CD14 antagonist antigenbinding molecules disclosed herein are administered until HF symptoms are slowed. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered until HF symptoms are cured.

[0204] In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered before the patient begins to exhibit one or more signs or symptoms of HF. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered at the onset of signs or symptoms of HF. In some embodiments, the CD14 antagonist antigen-binding molecules disclosed herein are administered after manifestation of HF symptoms.

[0205] In some embodiments, the subject is determined to have increased activity or expression of a pro-inflammatory mediator, suitably a pro-inflammatory cytokine or a pro-inflammatory immune cell, compared to a non-HF subject. In some embodiments, the pro-inflammatory cytokine is any pro-inflammatory cytokine, including but not limited to, OPN, LT[34, TNF-a, interleukin-6 (IL-6) and soluble tumor necrosis factor-alpha receptor (sTNFaR). The expression or activity of pro-inflammatory cytokines in a subject may be measured through cytokine assays. In some embodiments, the pro-inflammatory immune cell is a pro-inflammatory macrophage such as a CCR2+macrophage. Such pro-inflammatory immune cells may be measured using for example immunocytochemistry and imaging techniques.

[0206] In some aspects of the methods described herein, administration of the CD14 antagonist antigen-binding molecule provides a preventive and / or therapeutic effect that includes one or more of the following clinical and / or biochemical parameters: improved cardiometabolic efficiency, characterized by an increased ratio of [cardiac output / metabolic substrate consumed] and / or characterized by an increased ratio of [cardiac output / oxygen consumed]; increase of the production of ketone bodies in the liver, characterized by increased plasma levels of 3-hydroxybutyric acid and / or the corresponding acylcarnitines (e.g., hydroxybutyrylcarnitine) and increased plasma levels of one or more of the branched-chain amino acids (valine, leucine and isoleucine); improved cardiac function by achieved reduced pre- and / or afterload; improved arterial wall structure function; improved echocardiographic parameters, such as decreased LA (Left atrium dimension measured as right parasternal short-axis), LA / Ao (left atrium to aorta ratio; Ao=Aortic root diameter), IVSd (interventricular septal end diastolic dimension, i.e. the thickness of the interventricular septum), and / or LAD (Left atrium measured as right parasternal long-axis), and improved cardiac biomarkers, such as decreased NT-proBNP and / or decreased cTnl (cardiac Troponin I) and / or increased erythropoietin concentration; as well as improved heart murmur; delayed onset of different phenotypes of cardiac diseases, such as (M)MVD and / or DCM, at least by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more months, or even stopped progression of different phenotypes of cardiac diseases, such as (M)MVD and / or DCM; longer time of survival, at least by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more months, and / or delay of next episode of heart failure, at least by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more months, and / or lower level of cardiac mortality and / or morbidity; improved clinical signs, such as reduced e.g. breathlessness or dyspnea, cough, depression, exercise intolerance, inappetence, syncope, abdominal distention and / or polydipsia; prolongation of time to heart failure, cardiac death, onset of clinical signs, need for additional concomitant medication, and / or increase in dose of concomitant therapy— diuretics); increased longevity; and higher quality of life.

[0207] In some aspects of the methods described herein, administration of the CD14 antagonist antigen-binding molecule reduces dyspnea in the subject to a level that is less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%, of the level of dyspnea in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects of the methods described herein, the dyspnea is reduced to a level thatis at least about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10%, or by a range between any of the preceding values, of the level of dyspnea in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. The level of dyspnea may be assessed by any suitable technique, including subjective self-report scales, representative examples of which include the Modified Borg Scale, Visual Analog Scale (VAS) and a 0-10 Numerical Rating Scale (NRS), which rate symptom intensity. The reduction in the level of dyspnea may be present in the subject after about 24 hours, after about 36 hours, after about 48 hours, after about 60 hours, after about 72 hours, after about 10 days, after about 15 days, after about 20 days, after about 25 days, after about 30 days, after about 2 months, after about 3 months, after about 4 months, after about 5 months, after about 6 months, after about 7 months, after about 8 months, after about 9 months, after about 10 months, after about 11 months, or after about 12 months, post administration of the CD14 antagonist antigenbinding molecule. Suitably, the reduction in the level of dyspnea is maintained in the subject for at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 30 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months, post administration of the CD14 antagonist antigen-binding molecule.

[0208] In some aspects of the methods described herein, administration of the CD14 antagonist antigen-binding molecule reduces congestion (e.g., pulmonary congestion) in the subject to a level that is less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%, of the level of congestion in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects of the methods described herein, the congestion is reduced to a level that is at least about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10%, or by a range between any of the preceding values, of the level of congestion in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. The level of congestion may be assessed by any suitable technique, including a composite congestion score, which counts the presence of congestive findings on physical exam (e.g., peripheral edema, jugular venous distension >10 cm, pulmonary rales, or S3 gallop). The reduction in the level of congestion may be present in the subject after about 24 hours, after about 36 hours, after about 48 hours, after about 60 hours, after about 72 hours, after about 10 days, after about 15 days, after about 20 days, after about 25 days, after about 30 days, after about 2 months, after about 3 months, after about 4 months, after about 5 months, after about 6 months, after about 7 months, after about 8 months, after about 9 months, after about 10 months, after about 11 months, or after about 12 months, postadministration of the CD14 antagonist antigen-binding molecule. Suitably, the reduction in the level of congestion is maintained in the subject for at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 30 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months, post administration of the CD14 antagonist antigen-binding molecule.

[0209] In some aspects of the methods described herein, the subject's clinical score, as evaluated for example by the Kansas City Cardiomyopathy Questionnaire (KCCQ), is increased by about 1% to about 100% relative to the subject's clinical score before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the subject's clinical score is increased by about 5% to about 95%. In some aspects, the subject's clinical score is increased by about 10% to about 90%. In some aspects, the subject's clinical score is increased by about 15% to about 85%. In some aspects, the subject's clinical score is increased by about 20% to about 80%. In some aspects, the subject's clinical score is increased by about 25% to about 75%. In some aspects, the subject's clinical score is increased by about 30% to about 70%. In some aspects, the subject's clinical score is increased by about 30% to about 65%. In some aspects, the subject's clinical score is increased by about 35% to about 65%. In some aspects, the subject's clinical score is increased by about 40% to about 60%.

[0210] In some aspects of the methods described herein, the subject's clinical score is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%, or by a range between any of the preceding values, relative to the subject's clinical score before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0211] In some aspects, the subject's neutrophil I lymphocyte ratio (NLR) is decreased by about 2% to about 40% relative to the subject's NLR before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule. In some aspects, the subject's NLR is decreased by about 2% to about 39%. In some aspects, the subject's NLR is decreased by about 2% to about 38%. In some aspects, the subject's NLR is decreased by about 2% to about 37%. In some aspects, the subject's NLR is decreased by about 2% to about 36%. In some aspects, the subject's NLR is decreased by about 2% to about 35%. In some aspects, the subject's NLR is decreased by about 2% to about 34%. In some aspects, the subject's NLR is decreased by about 2% to about 33%. In some aspects, the subject's NLR is decreased by about 2% to about 32%. In some aspects, the subject's NLR is decreased by about 2% to about 31%. In some aspects, the subject's NLR is decreased by about 2% to about 30%. In some aspects, the subject's NLR is decreased by about 2% to about 29%. In some aspects, the subject's NLR is decreased by about 2% to about 28%. In some aspects, the subject's NLR is decreased by about 2% to about 27%. In some aspects, thesubject's NLR is decreased by about 2% to about 26%. In some aspects, the subject's NLR is decreased by about 2% to about 25%. In some aspects, the subject's NLR is decreased by about 2% to about 24%. In some aspects, the subject's NLR is decreased by about 2% to about 23%. In some aspects, the subject's NLR is decreased by about 2% to about 22%. In some aspects, the subject's NLR is decreased by about 2% to about 21%. In some aspects, the subject's NLR is decreased by about 2% to about 20%. In some aspects, the subject's NLR is decreased by about 2% to about 19%. In some aspects, the subject's NLR is decreased by about 2% to about 18%. In some aspects, the subject's NLR is decreased by about 2% to about 17%. In some aspects, the subject's NLR is decreased by about 2% to about 16%. In some aspects, the subject's NLR is decreased by about 2% to about 15%. In some aspects, the subject's NLR is decreased by about 2% to about 14%. In some aspects, the subject's NLR is decreased by about 2% to about 13%. In some aspects, the subject's NLR is decreased by about 2% to about 12%. In some aspects, the subject's NLR is decreased by about 2% to about 11%. In some aspects, the subject's NLR is decreased by about 2% to about 10%. In some aspects, the subject's NLR is decreased by about 2% to about 9%. In some aspects, the subject's NLR is decreased by about 2% to about 8%. In some aspects, the subject's NLR is decreased by about 2% to about 7%. In some aspects, the subject's NLR is decreased by about 2% to about 6%. In some aspects, the subject's NLR is decreased by about 2% to about 5%.

[0212] In some aspects of the methods described herein, the subject's NLR is decreased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, or by a range between any of the preceding values, relative to the subject's NLR before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

[0213] In some embodiments, pharmaceutical compositions comprising a CD14 antagonist antigen-binding molecule and optionally at least one ancillary HF therapeutic agent ("active agents") disclosed herein are for "systemic delivery", meaning that the active agent(s) is(are) not delivered locally to a pathological site or a site of action. Instead, the active agent(s) is(are) absorbed into the bloodstream from the injection site, where the active agent(s) acts systemically or is transported to a site of action via the circulation. The active agent(s) may be administered by any suitable route, such as for example, orally, intravenously, intramuscularly, nasally, subcutaneously, and intra -rectally. In some embodiments, the active agent(s) is(are) for parenteral administration, preferably intravenous administration. In other embodiments, the active agent(s) is(are) for local administration to a pathological site to be treated e.g., myocardial tissue). In these embodiments, the active agent(s) may be administered by injection, insertion or implantation directly into or onto or adjacent to the pathological site.

[0214] In some embodiments, the active agent(s) is(are) administered about monthly, and may be administered locally or intravenously. In some embodiments, the active agent(s) is(are) administered about weekly, and may be administered locally or intravenously. In some embodiments, the site of administration is not a pathological site, for example, is not the intended site of action.

[0215] In various embodiments, the plasma concentration of the active agent(s) does not change by more than a factor of about 100, or a factor of about 50, or a factor of about 10, or a factor of about 5, or a factor of about 3 over the course of a plurality of administrations, such as at least 2, at least about 5, or at least about 10 administrations of the formulation. The administrations are substantially evenly spaced, such as, for example, about daily, or about once per week, or from one to about five times per month, or about once every two months, or about once every three months. In some embodiments, the active agent(s) is(are) administered to the subject over a period of about 1 day, or over a period of about 2 days, or over a period of about 3 days, or over a period of about 4 days, or over a period of about 5 days, or over a period of about 6 days, over a period of about 1 week, or over a period of about 2 weeks, or over a period of about 3 weeks, or over a period of about 4 weeks, or over a period of about 5 weeks, or over a period of about 6 weeks, or over a period of about 2 months, or over a period of about 3 months, or over a period of about 4 months, or over a period of about 5 months, or over a period of about 6 months, or over a period of about 7 months, or over a period of about 8 months, or over a period of about 9 months, or over a period of about 10 months, or over a period of about 11 months, or over a period of about 1 year, or over a period of about 14 months, or over a period of about 16 months, or over a period of about 18 months, or over a period of about 20 months, or over a period of about 22 months, or over a period of about 2 years.

[0216] While one of skill in the art can determine the desirable dose in each case, a suitable effective dosage of a CD14 antagonist antigen-binding molecule for achieving a therapeutic benefit, may, for example, be in a range of about 0.1 mg and 50 mg (and all one tenth integer mg units in between), or between about 0.2 mg and 40 mg (and all one tenth integer mg units in between), or between about 0.5 mg and 40 mg (and all one tenth integer mg units in between), or between about 1 mg and 30 mg (and all integer mg units in between), or between about 2 mg and 20 mg (and all integer mg units in between), or between about 4 mg and 15 mg (and all integer mg units in between), or between about 5 mg and 10 mg (and all integer mg units in between) per kilogram body weight per day. In some aspects, the CD14 antagonist antigen-binding molecule is administered at a low dose. In certain aspects, the CD14 antagonist antigen-binding molecule is administered at a dose between 1 mg per kilogram per body weight per day to about 9 mg per kilogram per body weight per day. In certain aspects, a suitable effective dosage of the CD14 antagonist antigen-binding molecule for achieving a therapeutic benefit, may, for example, be in a range of 0.1 mg and 50 mg (and all one tenth integer mg units in between), or between about 0.2 mg and 40 mg (and all one tenth integer mg units in between), or between about 0.5 mg and 40 mg (and all one tenth integer mg units in between), or between about 1 mg and 30 mg (and all integer mg units in between), or between about 2 mg and 20 mg (and all integer mg units in between), or between about 4 mg and 15 mg (and all integer mg units in between), or between about 5 mg and 10 mg (and all integer mg units in between) per kilogram body weight per week. The dosage may be administered in a single dose or as two or more doses. Alternatively, if the condition of the recipient so requires, the dosage may be administered as a continuous infusion.

[0217] In certain aspects, the CD14 antagonist antigen-binding molecule may be administered at a weekly dose of between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units inbetween), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).

[0218] In some aspects, the CD14 antagonist antigen-binding molecule may be administered at dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, or by a range between any of the preceding values.

[0219] In certain aspects, the CD14 antagonist antigen-binding molecule may be administered to the subject over a period of about 1 day, or over a period of about 2 days, or over a period of about 3 days, or over a period of about 4 days, or over a period of about 5 days, or over a period of about 6 days, over a period of about 1 week, or over a period of about 2 weeks, or over a period of about 3 weeks, or over a period of about 4 weeks, or over a period of about 5 weeks, or over a period of about 6 weeks, or over a period of about 2 months, or over a period of about 3 months, or over a period of about 4 months, or over a period of about 5 months, or over a period of about 6 months, or over a period of about 7 months, or over a period of about 8 months, or over a period of about 9 months, or over a period of about 10 months, or over a period of about 11 months, or over a period of about 1 year, or over a period of about 14 months, or over a period of about 16 months, or over a period of about 18 months, or over a period of about 20 months, or over a period of about 22 months, or over a period of about 2 years.

[0220] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a dosage that provides and / or maintains at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% CD14 receptor occupancy.

[0221] In any of the aspects and embodiments disclosed herein, the CD14 antagonist antigen-binding molecule may be administered at a dosage and frequency (e.g., a dosage regimen) that provides and / or maintains at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% CD14 receptor occupancy.

[0222] In certain aspects, the subject may be administered a single dose of the CD14 antagonist antigen-binding molecule for treating, inhibiting or reducing progression of HF, oralleviating at least one sign or symptom of HF, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving ejection fraction {e.g., LVEF), or restoring ejection fraction {e.g., LVEF) to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, and / or for reducing or improving LV mass in HF.

[0223] Alternatively, the subject may be administered two or more doses of the CD14 antagonist antigen-binding molecule for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, for alleviating, reducing or reversing adverse cardiac structural remodeling in HF, for increasing or improving cardiac contractile function in HF, for increasing or improving cardiac output in HF, for increasing or improving ejection fraction {e.g., LVEF), or restoring ejection fraction {e.g., LVEF) to a normal range, in HF, for reducing or improving LVESV, or restoring LVESV to a normal range, in HF, for reducing or improving LVEDV, or restoring LVEDV to a normal range, in HF, for ameliorating or reducing LV akinetic area in HF, for ameliorating or reducing LV dilatation in HF, and / or for reducing or improving LV mass in HF. In specific embodiments, the subject is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses of the CD14 antagonist antigen-binding molecule. In representative examples of this type, the subject is administered a plurality of doses of the CD14 antagonist antigen-binding molecule over 2 to 26 weeks (and all integer weeks in between), over 2 to 24 weeks (and all integer weeks in between), over 2 to 22 weeks (and all integer weeks in between), over 2 to 20 weeks (and all integer weeks in between), over 2 to 18 weeks, (and all integer weeks in between), over 2 to 16 weeks (and all integer weeks in between), over 2 to 14 weeks (and all integer weeks in between), 2 to 12 weeks, over 2 to 10 weeks (and all integer weeks in between), over 2 to 8 weeks (and all integer weeks in between), over 2 to 6 weeks (and all integer weeks in between), over 2 to 4 weeks (and all integer weeks in between), over 4 to 26 weeks (and all integer weeks in between), over 4 to 24 weeks (and all integer weeks in between), over 4 to 22 weeks (and all integer weeks in between), over 4 to 20 weeks (and all integer weeks in between), over 4 to 18 weeks, (and all integer weeks in between), over 4 to 16 weeks (and all integer weeks in between), over 4 to 14 weeks (and all integer weeks in between), over 4 to 12 weeks (and all integer weeks in between), over 4 to 10 weeks (and all integer weeks in between), over 4 to 8 weeks (and all integer weeks in between), or over 4 to 6 weeks (and all integer weeks in between).

[0224] In any of the aspects and embodiments disclosed herein, a respective dose of the CD14 antagonist antigen-binding molecule is administered to the subject at about daily intervals, about weekly intervals, about fortnightly intervals, about monthly intervals, about bimonthly intervals, about quarterly intervals, about 4-monthly intervals, about half-yearly intervals, or about yearly intervals.

[0225] In certain aspects, the subject is monitored for responsiveness to treatment or treatment efficacy. For example, responsiveness to treatment or treatment efficacy may be monitored by detecting amelioration or improvement of physical signs or symptoms of HF. This detection may be measured by any means known in the art. For example, responsiveness to treatment or treatment efficacy may be evaluated by echocardiographic evaluation, cardiac magnetic resonance imaging (MRI), or cardiac MRI with late gadolinium enhancement.Representative parameters for detecting amelioration or improvement of physical signs or symptoms of HF include LV size, thickness, volumes, ejection fraction (EF), scar / inflammatory burden of the myocardium, as well as strain. In some aspects, responsiveness to treatment or treatment efficacy is monitored by determining the level of one or more inflammatory mediators, including ones for example disclosed herein, in the subject. In some aspects, responsiveness to treatment or treatment efficacy is monitored by determining the level of at least one inflammatory biomarker in the subject, including, for example, C-reactive protein (CRP), procalcitonin (PCT), vascular endothelial growth factor (VEGF), placental growth factor (PIGF), tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), D-dimer, P-selectin, intercellular adhesion molecule 1 (ICAM-1). vascular cell adhesion protein 1 (VCAM-1), cyclooxygenase-2 (Cox-2), plasminogen activator inhibitor-1 (PAI-1), Presepsin (also known as soluble CD14 subtype; SCD14-ST), growth / differentiation factor 15 (GDF-15), Creatinine, soluble fms-like tyrosine kinase-1 (sFItl), insulin-like growth factor-binding protein-7 (IGFBP7), soluble triggering receptor expressed on myeloid cells-1 (sTREMl), cystatin C and pancreatic stone protein (PSP). In some aspects, responsiveness to treatment or treatment efficacy is monitored by determining the level of at least one HF biomarker in the subject, non-limiting examples of which include, biomarkers of biomechanical stress, including for example natriuretic peptides such as brain natriuretic peptide (BNP), N-terminal brain natriuretic pro-peptide (NT-proBNP), mid-regional atrial natriuretic propeptide (MR-proANP), and C-type NP, biomarkers of cardiac injury and damage such as cardiac troponins including high-sensitivity cardiac troponins (hs-cTn), heart-type fatty acid-binding protein (H-FABP), and glutathione transferase Pl (GSTP1), biomarkers of neurohumoral activation such as aldosterone, adrenomedullin, mid-regional pro-adrenomedullin (MR-proADM), and endothelin-1, biomarkers of renal and skeletal muscle dysfunction including for example neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cancer antigen 125 (CA125), apelin, irisin, myostatin, brain-derived neurotrophic factor (BDNF), IL-15, fibroblast growth factor-21 (FGF-21), and growth differentiation factor-11 (GDF-11), biomarkers of systemic, microvascular adipose tissue inflammation and oxidative stress such as ceruloplasmin, TNFa, myeloperoxidase (MPO), 8-hydroxy-2 '-deoxyguanosine (8-OHdG), thioredoxin 1 (Trxl), high-sensitivity C-reactive protein (hs-CRP), GDF15, adiponectin, fetuin, visfatin, leptin, resistin, and chemerin, as well as biomarkers of extracellular matrix remodeling such as soluble isoform of suppression of tumorigenicity 2 (sST2), galectin-3 (Gal3), procollagen type I carboxyterminal peptide (PICP), procollagen type III amino-terminal peptide (PIIINP), PICP / PIIINP ratio, osteonectin, osteoprotegerin, osteopontin, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of matrix metalloproteinase (TIMP-1).

[0226] In some aspects, treatment of the subject with CD14 antagonist antigen-binding molecule is halted when the subject's signs or symptoms of HF ameliorate or improve and suitably stabilize. In some embodiments of these aspects, the subject is further monitored over a period of about a month, or over a period of about 2 months, or over a period of about 3 months, or over a period of about 4 months, or over a period of about 5 months, or over a period of about 6 months, or over a period of about 7 months, or over a period of about 8 months, or over a period of about 9 months, or over a period of about 10 months, or over a period of about 11 months, or over a period of about 1 year, or over a period of about 14 months, or over a period of about 16 months, or over a period of about 18 months, or over a period of about 20 months, or over a period of about 22 months, or over a period of about 2 years, and is administered one or more doses ofCD14 antagonist antigen-binding molecule, including in a dosage regimen, if the subject's signs or symptoms of HF worsen.

[0227] In certain aspects, the subject is treated with a dosage regimen. For example, a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule may be administered weekly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year. In some aspects, a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule may be administered fortnightly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year. In some aspects, a dosage regimen comprising about 1 mg / kg to about 20 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year. In some aspects, a dosage regimen comprising about 4 mg / kg to about 15 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year. In some aspects, a dosage regimen comprising about 5 mg / kg to about 10 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year or for an interval between any of the preceding values.REPRESENTATIVE EMBODIMENTS1. A method of treating, inhibiting or reducing progression of heart failure (HF), or alleviating at least one sign or symptom of HF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.2. The method of embodiment 1, wherein the HF is selected from HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF).3. The method of embodiment 1, wherein the HF is HFrEF.4. The method of embodiment 1 or embodiment 2, wherein the HF is acute HF (AHF). 5. The method of embodiment 1 or embodiment 2, wherein the HF is acute decompensated HF (ADHF).6. The method of embodiment 1, wherein the HF is chronic HF.7. The method of any one of embodiments 1 to 6, wherein the HF is Class I HF according to the New York Heart Association (NYHA) classification scale.8. The method of any one of embodiments 1 to 6, wherein the HF is Class II HF according to the NYHA classification scale.9. The method of any one of embodiments 1 to 6, wherein the HF is Class III HF according to the NYHA classification scale.10. The method of any one of embodiments 1 to 6, wherein the HF is Class IV HF according to the NYHA classification scale.11. The method of any one of embodiments 1 to 10, wherein the subject has Stage A progression of HF as classified according to the American College of Cardiology / American Heart Association (ACC / AHA) HF guidelines.12. The method of any one of embodiments 1 to 10, wherein the subject has Stage B progression of HF as classified according to the ACC / AHA HF guidelines.13. The method of any one of embodiments 1 to 10, wherein the subject has Stage C progression of HF as classified according to the ACC / AHA HF guidelines.14. The method of any one of embodiments 1 to 10, wherein the subject has Stage D progression of HF as classified according to the ACC / AHA HF guidelines.15. The method of any one of embodiments 1 to 14, wherein the at least one sign is selected from elevated jugular venous pressure, jugular venous dilatation, third heart sound e.g., gallop rhythm), laterally displaced apical impulse, congested hepatomegaly, hepatojugular reflux, ascites, symptoms of gut congestion, weight gain (e.g., >2 kg / week), anorexia, weight loss (e.g., in advanced heart failure), cachexia, cardiac murmur, high NLR, peripheral edema (e.g., ankle, sacral, scrotal), pulmonary congestion, pulmonary edema (e.g., acute pulmonary edema), pulmonary rales, pulmonary crepitations, reduced air entry and dullness to, percussion at lung bases (e.g., pleural, effusion), arrhythmias, atrial fibrillation, atrial flutter, tachycardia (e.g., ventricular tachycardia), irregular pulse, tachypnea, Cheyne-Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, nocturia, and narrow pulse pressure.16. The method of any one of embodiments 1 to 15, wherein the at least one symptom is selected from breathlessness, orthopnea, paroxysmal nocturnal dyspnea, exertional dyspnea, dyspnea at rest, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling, nocturnal cough, wheezing, bloated feeling, loss of appetite, nausea, confusion (e.g., in the elderly), depression, palpitations, dizziness, syncope, and bendopnea.17. The method of any one of embodiments 1 to 16, wherein the administration of the CD14 antagonist antigen-binding molecule improves one or more clinical parameters of the subject.18. The method of embodiment 17, wherein the one or more clinical parameters of the subject are selected from cardiac function, adverse cardiac structural remodeling (e.g. adverse left ventricular (LV) remodeling), cardiac contractile function, cardiac output, ejection fraction (e.g., LV ejection fraction (LVEF)), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV akinesia, LV dilatation, LV hypertrophy, dyspnea, congestion score, patient perception of health status, and NLR.19. The method of any one of embodiments 1 to 18, wherein the administration of the CD14 antagonist antigen-binding molecule increases, improves or recovers cardiac function or restores cardiac function to a normal range.20. The method of any one of embodiments 1 to 19, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or reverses adverse cardiac structural remodeling (e.g. adverse LV remodeling).21. The method of any one of embodiments 1 to 20, wherein the administration of the CD14 antagonist antigen-binding molecule increases or improves cardiac contractile function or restores cardiac contractile function to a normal range.22. The method of any one of embodiments 1 to 21, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates, increases or improves cardiac output or restores cardiac output to a normal range.23. The method of any one of embodiments 1 to 22, wherein the administration of the CD14 antagonist antigen-binding molecule increases or improves ejection fraction (e.g., LVEF) or restores ejection fraction e.g., LVEF) to a normal range.24. The method of any one of embodiments 1 to 23, wherein the administration of the CD14 antagonist antigen-binding molecule reduces or improves LVESV or restores LVESV to a normal range.25. The method of any one of embodiments 1 to 24, wherein the administration of the CD14 antagonist antigen-binding molecule reduces or improves LVEDV or restores LVEDV to a normal range.26. The method of any one of embodiments 1 to 25, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or reduces LV akinetic area.27. The method of any one of embodiments 1 to 26, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or reduces LV dilatation.28. The method of any one of embodiments 1 to 27, wherein the administration of the CD14 antagonist antigen-binding molecule reduces or improves LV mass or restores LV mass to a normal range.29. The method of any one of embodiments 1 to 28, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or reduces dyspnea.30. The method of any one of embodiments 1 to 29, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or reduces congestion score.31. The method of any one of embodiments 1 to 30, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or improves patient perception of health status,32. The method of any one of embodiments 1 to 31, wherein the administration of the CD14 antagonist antigen-binding molecule ameliorates or reduces neutrophil I lymphocyte ratio (NLR) or restores NLR to a normal range.33. A method of increasing, improving or recovering cardiac function or restoring cardiac function to a normal range in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.34. A method of ameliorating, reducing or reversing adverse cardiac structural remodeling in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.35. A method of increasing or improving cardiac contractile function in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.36. The method of embodiment 35, wherein cardiac contractile function comprises increasing or improving cardiac output or restoring cardiac output to a normal range, increasing or improving LV function or restoring LV function to a normal range, increasing or improving LV fractional shortening or restoring LV fractional shortening to a normal range, increasing or improving ejection fraction (e.g., LVEF) or restoring ejection fraction (e.g., LVEF) to a normal range, reducing or improving end-diastolic volume or restoring end-diastolic volume to a normalrange, decreasing or improving LV mass or restoring LV mass to a normal range, decreasing arrhythmias, reducing frequency of heart murmurs, reducing heart rate, normalizing of heart geometry, or a combination thereof.37. A method of increasing or improving ejection fraction (e.g., LVEF), or restoring ejection fraction (e.g., LVEF) to a normal range, in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.38. A method of reducing or improving LVESV, or restoring LVESV to a normal range, in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.39. A method of reducing or improving LVEDV, or restoring LVEDV to a normal range, in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.40. A method of ameliorating or reducing LV akinetic area in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.41. A method of ameliorating or reducing LV dilatation in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.42. A method of reducing or improving LV mass, or restoring LV mass to a normal range, in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.43. A method of ameliorating or reducing dyspnea in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.44. A method of ameliorating or reducing congestion score in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.45. A method of ameliorating or improving patient perception of health status in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.46. A method of ameliorating or reducing NLR or restoring NLR to a normal range in a subject with HF, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.47. The method of any one of embodiments 33 to 46, wherein the HF is HFpEF.48. The method of any one of embodiments 33 to 46, wherein the HF is HFrEF.49. The method of any one of embodiments 33 to 46, wherein the HF is HFmrEF.50. The method of any one of embodiments 33 to 46, wherein the HF is AHF.51. The method of any one of embodiments 33 to 46, wherein the HF is ADHF.52. The method of any one of embodiments 33 to 46, wherein the HF is chronic HF.53. The method of any one of embodiments 33 to 52, wherein the HF is Class I HF according to the NYHA classification scale.54. The method of any one of embodiments 33 to 52, wherein the HF is Class II HF according to the NYHA classification scale.55. The method of any one of embodiments 33 to 52, wherein the HF is Class III HF according to the NYHA classification scale.56. The method of any one of embodiments 33 to 52, wherein the HF is Class IV HF according to the NYHA classification scale.57. The method of any one of embodiments 33 to 56, wherein the subject has Stage A progression of HF as classified according to the ACC / AHA HF guidelines.58. The method of any one of embodiments 33 to 56, wherein the subject has Stage B progression of HF as classified according to the ACC / AHA HF guidelines.59. The method of any one of embodiments 33 to 56, wherein the subject has Stage C progression of HF as classified according to the ACC / AHA HF guidelines.60. The method of any one of embodiments 33 to 56, wherein the subject has Stage D progression of HF as classified according to the ACC / AHA HF guidelines.61. A method of treating, inhibiting or reducing progression of HFpEF, or alleviating at least one sign or symptom of HFpEF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.62. A method of treating, inhibiting or reducing progression of HFrEF, or alleviating at least one sign or symptom of HFrEF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.63. A method of treating, inhibiting or reducing progression of HFmrEF, or alleviating at least one sign or symptom of HFmrEF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.64. A method of treating, inhibiting or reducing progression of AHF, or alleviating at least one sign or symptom of AHF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.65. A method of treating, inhibiting or reducing progression of ADHF, or alleviating at least one sign or symptom of ADHF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.66. A method of treating, inhibiting or reducing progression of CHF, or alleviating at least one sign or symptom of CHF, in a subject, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.67. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the HF is Class I HF according to the NYHA classification scale, the method comprising, consisting, or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.68. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the HF is Class II HF according to the NYHA classification scale, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.69. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the HF is Class III HF according to the NYHA classification scale, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.70. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the HF is Class IV HF according to the NYHAclassification scale, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.71. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the subject has Stage A progression of HF as classified according to the ACC / AHA HF guidelines, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.72. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the subject has Stage B progression of HF as classified according to the ACC / AHA HF guidelines, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.73. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the subject has Stage C progression of HF as classified according to the ACC / AHA HF guidelines, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.74. A method of treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF, in a subject, wherein the subject has Stage D progression of HF as classified according to the ACC / AHA HF guidelines, the method comprising, consisting or consisting essentially of administering to the subject a CD14 antagonist antigen-binding molecule.75. The method of any one of embodiments 1 to 74, wherein the subject experiences one or more of: a shortened duration of hospital stay, an increase in the number of days between hospital stays, a reduced risk of hospitalization, an increase in the time before an initial hospitalization, or a fewer number of hospitalizations relative to a subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's experience before receiving the CD14 antagonist antigen-binding molecule.76. The method of any one of embodiments 1 to 75, wherein the antigen-binding molecule is selected from:(I) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3);(ii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3);(iii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPYT [SEQ ID NO: 27] (IC14 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (IC14 H-CDR3);(iv) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3);(v) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence QNVGSNVDWY [SEQ ID NO: 34] (F1024-1-3 L-CDR1); L-CDR2 comprises the sequence KASNRY [SEQ ID NO: 35] (F1024-1 -3 L-CDR2); and L-CDR3 comprises the sequence MQSNTNPPW [SEQ ID NO: 36] (F1024-1-3 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence DYAMN [SEQ ID NO: 37] (F1024-1-3 H-CDR1); H-CDR2 comprises the sequence WINTQTGKPTYADDF [SEQ ID NO: 38] (F1024-1-3 H-CDR2); and H-CDR3 comprises the sequence TYFCTRSTFYYSSYIY [SEQ ID NO: 39] (F1024-1-3 H-CDR3);(vi) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence KASQNVGSNVD [SEQ ID NO: 40] (F1024 L-CDR1); L-CDR2 comprises the sequence KASNRYT [SEQ ID NO: 41] (F1024 L-CDR2); and L-CDR3 comprises the sequence MQSNTNPPWT [SEQ ID NO: 42] (F1024 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence DYAMN [SEQ ID NO: 37] (F1024 H-CDR1); H-CDR2 comprises the sequence WINTQTGKPTYADDFKQ [SEQ ID NO: 43] (F1024 H-CDR2); and H-CDR3 comprises the sequence STFYYSSYIYGWYFDF [SEQ ID NO: 44] (F1024 H-CDR3);(vii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYGNSFMH [SEQ ID NO: 45] (rl8Dll L-CDR1); L-CDR2 comprises the sequence LASNLES [SEQ ID NO: 46] (rl8Dll L-CDR2); and L-CDR3 comprises the sequence QQNNGDPYT [SEQ ID NO: 47] (rl8Dll L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence TYALN [SEQ ID NO: 48] (rl8Dll H-CDR1); H-CDR2 comprises the sequence RIRSKSNNYTTYYADSVKD [SEQ ID NO: 49] (rl8Dll H-CDR2); and H-CDR3 comprises thesequence PQSGTSFAY [SEQ ID NO: 50] (rl8Dll H-CDR3); and(viii) an antigen-binding molecule that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence KASQYVGTNVA [SEQ ID NO: 51] (rMil2 L-CDR1); L-CDR2 comprises the sequence SASYRCS [SEQ ID NO: 52] (rMil2 L-CDR2); and L-CDR3 comprises the sequence QQYNTYVT [SEQ ID NO: 53] (rM il2 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence TYWMN [SEQ ID NO: 54] (rMil2 H-CDR1); H-CDR2 comprises the sequence RIDPYDSETHYNQNFKD [SEQ ID NO: 55] (rMil2 H-CDR2); and H-CDR3 comprises the sequence KEGRQWGAYFDY [SEQ ID NO: 56] (rMil2 H-CDR3).77. The method of any one of embodiments 1 to 76, wherein the antigen-binding molecule selected from:(i) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIYRAANLESGIPARFSGSGSRTDFTLT INPVEADDVATYFCQQSYEDPWTFGGGTKLGNQ [SEQ ID NO: 1] (3C10 VL); anda VH domain that comprises, consists or consists essentially of the sequence:LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTTYYPDNVKGRFTISRDNARNILYLQMS SLRSEDTAMYYCARGYYDYHYWGQGTTLTVSS [SEQ ID NO: 2] (3C10 VH);(ii) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQS GIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDPTTFGGGTKLEIK [SEQ ID NO: 3] (28C5 VL); anda VH domain that comprises, consists or consists essentially of the sequence:LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSK NQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSA [SEQ ID NO: 4] (28C5 VH);(iii) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQ EDFATYFCQRGDTLPWTFGGGTKLEIK [SEQ ID NO: 5] (18E12 VL); anda VH domain that comprises, consists or consists essentially of the sequence:LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVIWTSGGTNYNSAFMSRLSITKDNSESQ VFLKMNGLQTDDTGIYYCVRGDGNFYLYNFDYWGQGTTLTVSS [SEQ ID NO: 6] (18E12 VH);(iv) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:YIVMTQTPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFTF TISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 57] (F1024-1-3 VL); anda VH domain that comprises, consists or consists essentially of the sequence:EVKLLESGGGLVQPSQTLSISCKASGYTFTDYAMNWVKQAPGDGLKWMGWINTQTGKPTYADDFKQRFVFSL ETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 58] (F1024-1-3 VH);(v) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:DIVMTQSPTSISISVGERVTMNCKASQNVGSNVDWYQQKTGQSPKLLIYKASNRYTGVPDRFTGSGSGTDFT FTISNMQAVDLAVYYCMQSNTNPPWTFGGGTKLELKRA [SEQ ID NO: 59] (F102 VL); anda VH domain that comprises, consists or consists essentially of the sequence:QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMNWVKQAPGNGLKWMGWINTQTGKPTYADDFKQRFVFSL ETSASTAYLQINNLNIEDTATYFCTRSTFYYSSYIYGWYFDFWGPGTMVTVSS [SEQ ID NO: 60] (F1024 VH).(vi) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:NIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRT DFTLTIDPVEADDVATYYCQQNNGDPYTFGGGTKLEIIR [SEQ ID NO: 61] (rl8Dll VL); anda VH domain that comprises, consists or consists essentially of the sequence:EVQLVESGGGLMQPKGSLKLSCAASGFTFKTYALNWVRQAPGTGLEWVARIRSKSNNYTTYYADSVKDRFTIS RDDSQNMLYLQMNNLKTEDTAMYYCVRPQSGTSFAYWGQGTLVTVSA [SEQ ID NO: 62] (rl8Dll VH); and(vii) an antigen-binding molecule comprising:a VL domain that comprises, consists or consists essentially of the sequence:DIVMTQSQKFMSTSVGDRVSVTCKASQYVGTNVAWYQQKPGQSPKALIQSASYRCSGVPDRFTGSGSGTDF TLTISNVQSEDLADYFCQQYNTYVTFGGGTKLELKR [SEQ ID NO: 63] (rMil2 VL); anda VH domain that comprises, consists or consists essentially of the sequence:QVRLQQPGAELVRPGASVKLSCKASGYTFTTYWMNWVKQRPEDGLEWIGRIDPYDSETHYNQNFKDKAILTV DKSSSTAYMQLSSLTYEDSAVYYCTRKEGRQWGAYFDYWGQGTTLTVSS [SEQ ID NO: 64] (rMil2 VH).78. The method according to any one of embodiments 1 to 77, wherein the antigen-binding molecule is humanized or chimeric.79. The method of any one of embodiments 1 to 78, wherein the antigen-binding molecule comprises a light chain and a heavy chain, wherein:the light chain comprises the amino acid sequence:METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPP KLLIYRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 25]; andthe heavy chain comprises the amino acid sequence:MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMGY ISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [SEQ ID NO: 26].80. The method of any one of embodiments 1 to 79, wherein the antigen-binding molecule is atibuclimab.81. The method of any one of embodiments 1 to 80, wherein the subject is a human, a canine, a feline, or an equine.82. The method of embodiment 81, wherein the subject is a human.83. The method of any one of embodiments 1 to 82, wherein the CD14 antagonist antigenbinding molecule is administered systemically.84. The method of any one of embodiments 1 to 83, wherein the CD14 antagonist antigenbinding molecule is administered locally to the heart (e.g., left ventricle) of the subject.85. The method of any one of embodiments 1 to 84, wherein the CD14 antagonist antigenbinding molecule is administered at a daily dose of between about 0.1 mg / kg and 50 mg / kg (and all one tenth integer mg / kg units in between), or between about 0.2 mg / kg and 40 mg / kg (and all one tenth integer mg / kg units in between), or between about 0.5 mg / kg and 40 mg / kg (and all one tenth integer mg / kg units in between), or between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).86. The method of any one of embodiments 1 to 84, wherein the CD14 antagonist antigenbinding molecule is administered at a weekly dose of between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).87. The method of any one of embodiments 1 to 84, wherein the CD14 antagonist antigenbinding molecule is administered at a fortnightly dose of between about 1 mg / kg and 30 mg / kg (and all integer mg / kg units in between), or between about 2 mg / kg and 20 mg / kg (and all integer mg / kg units in between), or between about 4 mg / kg and 15 mg / kg (and all integer mg / kg units in between), or between about 5 mg / kg and 10 mg / kg (and all integer mg / kg units in between).88. The method of any one of embodiments 1 to 84, wherein the CD14 antagonist antigenbinding molecule is administered at dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, or at a dosage range between any of the preceding values.89. The method of any one of embodiments 1 to 88, wherein the CD14 antagonist antigenbinding molecule is administered to the subject over a period of about 1 day, or over a period of about 2 days, or over a period of about 3 days, or over a period of about 4 days, or over a period of about 5 days, or over a period of about 6 days, over a period of about 1 week, or over a period of about 2 weeks, or over a period of about 3 weeks, or over a period of about 4 weeks, or over a period of about 5 weeks, or over a period of about 6 weeks, or over a period of about 2 months, or over a period of about 3 months, or over a period of about 4 months, or over a period of about 5 months, or over a period of about 6 months, or over a period of about 7 months, or over a period of about 8 months, or over a period of about 9 months, or over a period of about 10 months, or over a period of about 11 months, or over a period of about 1 year, or over a period of about 14months, or over a period of about 16 months, or over a period of about 18 months, or over a period of about 20 months, or over a period of about 22 months, or over a period of about 2 years.90. The method of any one of embodiments 1 to 89, wherein the CD14 antagonist antigenbinding molecule is administered at a dosage that provides and / or maintains at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% CD14 receptor occupancy.91. The method of any one of embodiments 1 to 89, wherein the CD14 antagonist antigenbinding molecule is administered at a dosage and frequency e.g., a dosage regimen) that provides and / or maintains at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% CD14 receptor occupancy.92. The method of any one of embodiments 1 to 91, wherein the CD14 antagonist antigenbinding molecule is administered at a dosage that provides or maintains Presepsin at a level less than about 300 pg / mL, less than about 250 pg / mL, less than about 200 pg / mL, less than about 150 pg / mL, less than about 100 pg / mL, less than about 90 pg / mL, less than about 80 pg / mL, less than about 70 pg / mL, less than about 60 pg / mL, less than about 50 pg / mL, less than about 40 pg / mL, less than about 30 pg / mL, less than about 20 pg / mL, less than about 19 pg / mL, less than about 18 pg / mL, less than about 17 pg / mL, a less than bout 16 pg / mL, less than about 15 pg / mL, less than about 14 pg / mL, less than about 13 pg / mL, less than about 12 pg / mL, less than about 11 pg / mL, less than about 10 pg / mL, less than about 9 pg / mL, less than about 8 pg / mL, less than about 7 pg / mL, less than about 6 pg / mL, less than about 5 pg / mL, less than about 4 pg / mL, less than about 3 pg / mL, less than about 2 pg / mL, or less than about 1 pg / mL, or by a range between any of the preceding values.93. The method of any one of embodiments 1 to 92, wherein a single dose of the CD14 antagonist antigen-binding molecule is administered to the subject for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF.94. The method of any one of embodiments 1 to 92, wherein a plurality of doses of the CD14 antagonist antigen-binding molecule is administered to the subject for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF.95. The method of embodiment 94, wherein 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses of the CD14 antagonist antigen-binding molecule is administered to the subject for treating, inhibiting or reducing progression of HF, or alleviating at least one sign or symptom of HF.96. The method of embodiment 94, wherein 2 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.97. The method of embodiment 94, wherein 3 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.98. The method of embodiment 94, wherein 4 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.99. The method of embodiment 94, wherein 5 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.100. The method of embodiment 94, wherein 6 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.101. The method of embodiment 94, wherein 7 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.102. The method of embodiment 94, wherein 8 doses of the CD14 antagonist antigenbinding molecule is administered to the subject for treating or alleviating the at least one sign or symptom of the HF, or for reducing progression of the HF.103. The method of any one of embodiments 93 to 102, wherein a respective dose of the CD14 antagonist antigen-binding molecule is administered to the subject at about daily intervals, about weekly intervals, about fortnightly intervals, about monthly intervals, about bimonthly intervals, about quarterly intervals, about 4-monthly intervals, about half-yearly intervals, or about yearly intervals.104. The method of any one of embodiments 93 to 103, wherein the subject is treated with a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule administered weekly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.105. The method of any one of embodiments 93 to 103, wherein the subject is treated with a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule administered fortnightly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.106. The method of any one of embodiments 93 to 103, wherein the subject is treated with a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.107. The method of any one of embodiments 93 to 103, wherein the subject is treated with a dosage regimen comprising about 2 mg / kg to about 20 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule administered monthly for about a month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.108. The method of any one of embodiments 93 to 103, wherein the subject is treated with a dosage regimen comprising about 4 mg / kg to about 15 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule administered monthly for about a month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.109. The method of any one of embodiments 93 to 103, wherein the subject is treated with a dosage regimen comprising about 5 mg / kg to about 10 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule administered monthly for about a month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year or for an interval between any of the preceding values.110. The method of any one of embodiments 1 to 109, wherein the subject is monitored for responsiveness to treatment or treatment efficacy.111. The method of embodiment 110, wherein the responsiveness to treatment or treatment efficacy is monitored by detecting amelioration or improvement of physical signs or symptoms of HF.112. The method of embodiment 110 or embodiment 111, wherein the responsiveness to treatment or treatment efficacy is monitored by echocardiographic evaluation, cardiac magnetic resonance imaging (MRI), or cardiac MRI with late gadolinium enhancement.113. The method of any one of embodiments 110 to 112, wherein the responsiveness to treatment or treatment efficacy is monitored by determining the level of one or more inflammatory mediators.114. The method of any one of embodiments 110 to 113, wherein the responsiveness to treatment or treatment efficacy is monitored by determining the level of at least one inflammatory biomarker.115. The method of embodiment 114, wherein the at least one inflammatory biomarker comprises Presepsin.116. The method of any one of embodiments 110 to 115, wherein the responsiveness to treatment or treatment efficacy is monitored by determining the level of at least one HF biomarker.117. The method of any one of embodiments 110 to 116, wherein treatment of the subject with the CD14 antagonist antigen-binding molecule is halted when the subject's signs or symptoms of HF ameliorate or improve.118. The method of any one of embodiments 110 to 117, wherein treatment of the subject with the CD14 antagonist antigen-binding molecule is halted when the subject's signs or symptoms of HF stabilize.119. The method of embodiment 117 or embodiment 118, wherein the subject is further monitored over a period of about a month, or over a period of about 2 months, or over a period of about 3 months, or over a period of about 4 months, or over a period of about 5 months, or over a period of about 6 months, or over a period of about 7 months, or over a period of about 8 months, or over a period of about 9 months, or over a period of about 10 months, or over a period of about 11 months, or over a period of about 1 year, or over a period of about 14 months, or over a period of about 16 months, or over a period of about 18 months, or over a period of about 20 months, or over a period of about 22 months, or over a period of about 2 years, and is administered one ormore doses of CD14 antagonist antigen-binding molecule, including in a dosage regimen, if the subject's signs or symptoms of HF worsen.120. The method of any one of embodiments 1 to 119, wherein the subject is treated with a dosage regimen.121. The method of embodiment 120, wherein a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered weekly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.122. The method of embodiment 120, wherein a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered fortnightly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.123. The method of embodiment 120, wherein a dosage regimen comprising about 1 mg / kg to about 30 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.124. The method of embodiment 120, wherein a dosage regimen comprising about 2 mg / kg to about 20 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.125. The method of embodiment 120, wherein a dosage regimen comprising about 4 mg / kg to about 15 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year.126. The method of embodiment 120, wherein a dosage regimen comprising about 5 mg / kg to about 10 mg / kg (and all integer mg / kg units in between) of CD14 antagonist antigen-binding molecule is administered monthly for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about a year or for an interval between any of the preceding values.127. The method of any one of embodiments 1 to 126, further comprising concurrently administering an ancillary HF therapeutic agent or intervention to the subject.128. The method of embodiment 127, wherein the ancillary HF therapeutic agent is selected from angiotensin converting enzyme (ACE) inhibitors (e.g., enalapril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), neprilysin inhibitors (e.g., sacubitril), angiotensin receptor / neprilysin inhibitors (e.g., sacubitril / valsartan), beta-adrenergic receptor blockers (e.g., acebutolol, atenolol (Tenormin), bisoprolol, metoprolol (LOPRESSOR, TOPROL XL), nadolol (CORGARD), nebivolol (BYSTOLIC), propranolol (INDERAL LA, INNOPRAN XL)), calcium channel inhibitors (e.g., amlodipine (NORVASC), diltiazem (CARDIZEM, TIAZAC), felodipine, isradipine,nicardipine, nifedipine (PROCARDIA), nisoldipine (SULAR), verapamil (VERELAN)), diuretics {e.g., furosemide (LASIX)), antiarrhythmic drugs (e.g., amiodarone (CORDARONE, PACERONE), flecainide (TAMBOCOR), ibutilide (CORVERT) lidocaine (XYLOCAINE), procainamide (PROCAN, PROCANBID), propafenone (RYTHMOL), quinidine, tocainide (TONOCARID)) digoxin); or Parkinson's disease therapies including, for example, levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, Piribedil, cabergoline, apomorphine, lisuride), statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), anticholinergics, antipsychotics (e.g., clozapine), alpha-2 receptor agonists (e.g., guanabenz, guanfacine, clonidine, tizanidine, medetomidine, or dexmedetomidine), cholinesterase inhibitors, modafinil, thiazolidinediones and non-steroidal anti-inflammatory drugs, and combinations thereof.129. The method of any one of embodiments 1 to 128, further comprising performing a surgical procedure on the subject, wherein the surgical procedure is suitable for treating HF.130. The method of embodiment 129, wherein the surgical procedure comprises percutaneous coronary intervention (PCI; also known as coronary angioplasty), coronary artery bypass including coronary artery bypass grafting (CABG), implantation of a pacemaker (e.g., a LV assist device (LVAD)), atrioventricular (AV) node catheter ablation, implantation of an implantable cardioverter-defibrillator (ICD), cardiac catheterization, revascularization and / or heart transplantation.131. The method of embodiment 129 or embodiment 130, wherein the surgical procedure is performed before, at the same time as, or after administration of the CD14 antagonist antigenbinding molecule, optionally together with an ancillary HF therapeutic agent.132. The method of any one of embodiments 1 to 131, wherein the subject experiences one or more of the following parameters after administration of the CD14 antagonist antigen-binding molecule or composition: an increase, improvement or recovery of cardiac function or restoration of cardiac function to a normal range, an amelioration, reduction or reversal of adverse cardiac structural remodeling, an increase or improvement cardiac contractile function or restoration of cardiac contractile function to a normal range, an increase, improvement in cardiac output or restoration of cardiac output to a normal range, a decrease in N-terminal brain natriuretic peptide (NT proBNP), an increase in 6 minute walking distance; an increase in cardiac output / stroke volume (CO / SV), an increase in ejection fraction (e.g., LVEF) or restoration of ejection fraction (e.g., LVEF) to anormal range, a reduction or improvement in LVESV, or restoration of LVESV to a normal range, a reduction or improvement in LVEDV, or restoration of LVEDV to a normal range, an amelioration or reduction in LV akinetic area, an amelioration or reduction in LV dilatation, a reduction or improvement of LV mass, or restoration of LV mass to a normal range, a normalization of heart geometry (e.g., a reduction in LV internal diameter end diastole (LVIDd) and / or a reduction in LV diameter), an improvement in diastolic function, a reduction in left atrial (LA) volume, no change in QT interval, an amelioration or reduction of dyspnea, an amelioration or reduction of congestion score, an amelioration or improvement in patient perception of health status, and an amelioration or reduction of NLR or restoration of NLR to a normal range, a decrease in arrhythmias, a reduction in frequency of heart murmurs, a reduction in heart rate, an improvement in NHYA functional class, preferably wherein the subject experiences a change in oneor more of these parameters after a treatment period of from about 3 hours to about 12 months e.g., a treatment period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, and / or about 12 months, or by an interval between any of the preceding values) 133. The method of any one of embodiments 1 to 132, wherein the subject's ejection fraction is increased by about 2% to about 25% relative to the subject's ejection fraction before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's ejection fraction is increased by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, about 2% to about 11%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, preferably wherein the ejection fraction is or comprises LVEF, preferably wherein the subject's ejection fraction is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or about 25%, or by a range between any of the preceding values, relative to the subject's ejection fraction before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.134. The method of any one of embodiments 1 to 133, wherein the subject's beneficial cardiac structural remodeling e.g., as measured by a decrease in akinetic area) is increased by about 2% to about 40% relative to the adverse cardiac structural remodeling e.g., akinetic area) of the subject before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's beneficial cardiac structural remodeling is increased by about 2% to about 39%, by about 2% to about 38%, by about 2% to about 37%, by about 2% to about 36%, by about 2% to about 35%, by about 2% to about 34%, by about 2% to about 33%, by about 2% to about 32%, by about 2% to about 31%, by about 2% to about 30%, by about 2% to about 29%, by about 2% to about 28%, by about 2% to about 27%, by about 2% to about 26%, by about 2% to about 25%, by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, by about 2% to about 11%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, preferably wherein the beneficial cardiac structural remodeling comprises a decrease in LV akinetic area, preferably wherein the subject's beneficial cardiac structural remodeling is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%,about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, or by a range between any of the preceding values, relative to the adverse cardiac structural remodeling e.g., akinetic area) of the subject before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.135. The method of any one of embodiments 1 to 134, wherein the subject's LVEF is increased by about 2% to about 40% relative to the subject's LVEF before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's LVEF is increased by about 2% to about 39%, by about 2% to about 38%, by about 2% to about 37%, by about 2% to about 36%, by about 2% to about 35%, by about 2% to about 34%, by about 2% to about 33%, by about 2% to about 32%, by about 2% to about 31%, by about 2% to about 30%, by about 2% to about 29%, by about 2% to about 28%, by about 2% to about 27%, by about 2% to about 26%, by about 2% to about 25%, by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, by about 2% to about 11%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, preferably wherein the subject's LVEF is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, or by a range between any of the preceding values, relative to the subject's LVEF before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.136. The method of any one of embodiments 1 to 135, wherein the subject's LVESV is decreased by about 2% to about 35% relative to the subject's LVESV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's LVESV is decreased by about by about 2% to about 34%, by about 2% to about 33%, by about 2% to about 32%, by about 2% to about 31%, by about 2% to about 30%, by about 2% to about 29%, by about 2% to about 28%, by about 2% to about 27%, by about 2% to about 26%, by about 2% to about 25%, by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, by about 2% to about 11%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, preferably wherein the LVESV is decreased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%,about 34%, or about 35%, or by a range between any of the preceding values, relative to the subject's LVESV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.137. The method of any one of embodiments 1 to 136, wherein the subject's LVEDV is decreased by about 2% to about 30% relative to the subject's LVEDV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's LVEDV is decreased by about 2% to about 29%, by about 2% to about 28%, by about 2% to about 27%, by about 2% to about 26%, by about 2% to about 25%, by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, by about 2% to about 11%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, preferably wherein the LVEDV is decreased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, or by a range between any of the preceding values, relative to the subject's LVEDV before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.138. The method of any one of embodiments 1 to 137, wherein the subject's fractional shortening is increased by about 2% to about 25%, by about 2% to about 24%, by about 2% to about 23%, by about 2% to about 22%, by about 2% to about 21%, by about 2% to about 20%, by about 2% to about 19%, by about 2% to about 18%, by about 2% to about 17%, by about 2% to about 16%, by about 2% to about 15%, by about 2% to about 14%, by about 2% to about 13%, by about 2% to about 12%, by about 2% to about 10%, by about 2% to about 9%, by about 2% to about 8%, by about 2% to about 7%, by about 2% to about 6%, or by about 2% to about 5%, relative to the subject's fractional shortening before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's fractional shortening is increased by at least about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%, or by a range between any of the preceding values%, relative to the subject's fractional shortening before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.139. The method of any one of embodiments 1 to 138, wherein the stroke volume in the subject's left ventricle is increased by about 1% to about 100% relative to the stroke volume in the subject's left ventricle before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the stroke volume in the subject's left ventricle is increased by about 5% to about 95%, by about 10% to about 90%, by about 15% to about 85%, by about 20% to about 80%, by about 25% to about 75%, by about 30% to about 70%, by about 30% to about 65%, byabout 35% to about 65% or by about 40% to about 60%, preferably wherein the stroke volume in the subject's left ventricle is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%, or by a range between any of the preceding values, relative to the stroke volume in the subject's left ventricle before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.140. The method of any one of embodiments 1 to 139, wherein the subject's cardiac output is increased by about 2 miymin to about 20 mL / min relative to the subject's cardiac output before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's cardiac output is increased by about 2 mL / min to about 19 mL / min, by about 2 mL / min to about 18 mL / min, by about 2 mL / min to about 17 mL / min, by about 2 mL / min to about 16 mL / min, by about 2 mL / min to about 15 mL / min, by about 2 miymin to about 14 mL / min, by about 2 mL / min to about 14 mL / min, by about 2 mL / min to about 13 mL / min, by about 2 mL / min to about 12 mL / min, by about 2 mL / min to about 11 miymin, by about 2 mL / min to about 10 mL / min, by about 2 mL / min to about 9 mL / min, by about 2 mL / min to about 8 mL / min, by about 2 mL / min to about 7 mL / min, by about 2 mL / min to about 6 mL / min, or by about 2 mL / min to about 5 mL / min, preferably wherein the subject's cardiac output is increased by about 2 mL / min to about 15 mL / min, by about 3 mL / min to about 14 mL / min, by about 4 mL / min to about 13 mL / min, by about 5 mL / min to about 12 mL / min, by about 6 mL / min to about 11 mL / min, or by about 7 mL / min to about 10 mL / min, relative to the subject's cardiac output before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the subject's cardiac output is increased by at least about 2 mL / min, about 3 mL / min, about 4 mL / min, about 5 mL / min, about 6 mL / min, about 7 mL / min, about 8 mL / min, about 9 mL / min, about 10 mL / min, about 11 mL / min, about 12 mL / min, about 13 mL / min, about 14 mL / min, about 15 mL / min, about 20 mL / min, about 25 mL / min, about 30 mL / min, about 35 mL / min, about 40 mL / min, about 45 mL / min, or about 50 mL / min, or by an interval between any of the preceding values, relative to the subject's cardiac output before administration of the CD14 antagonist antigen-binding molecule, or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.141. The method of any one of embodiments 1 to 140, wherein the cardiac output in the subject's LV is increased by about 1% to about 100% relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the cardiac output in the subject's LV before receiving the CD14 antagonist antigen-binding molecule, preferably wherein the cardiac output in the subject's LV is increased by about 5% to about 95%, by about 10% to about 90%, by about 15% to about 85%, by about 20% to about 80%, by about 25% to about 75%, by about 30% to about 70%, by about 30% to about 65%, by about 35% to about 65%, or by about 40% to about 60% relative to a subject who has not received the CD14 antagonist antigen-binding molecule relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the cardiac output in the subject's LV before receiving the CD14 antagonist antigen-binding molecule, preferably wherein the cardiac output in the subject's LV isincreased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 100%, or by a range between any of the preceding values, relative to a control subject who has not received the CD14 antagonist antigen-binding molecule or as compared to the subject's cardiac output before receiving the CD14 antagonist antigen-binding molecule.142. The method of any one of embodiments 1 to 141, wherein administration of the CD14 antagonist antigen-binding molecule reduces dyspnea in the subject to a level that is less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%, of the level of dyspnea in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the dyspnea is reduced to a level that is at least about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, or about 10%, or by a range between any of the preceding values, of the level of dyspnea in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule, preferably wherein the reduction in the level of dyspnea is present in the subject after about 24 hours, after about 36 hours, after about 48 hours, after about 60 hours, after about 72 hours, after about 10 days, after about 15 days, after about 20 days, after about 25 days, after about 30 days, after about 2 months, after about 3 months, after about 4 months, after about 5 months, after about 6 months, after about 7 months, after about 8 months, after about 9 months, after about 10 months, after about 11 months, or after about 12 months, post administration of the CD14 antagonist antigen-binding molecule, preferably wherein the reduction in the level of dyspnea is maintained in the subject for at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at leas...

Claims

WHAT IS CLAIMED IS:

1. A method of recovering cardiac function in a subject with established heart failure (HF), the method comprising, consisting or consisting essentially of administering to the subject an effective amount of a CD14 antagonist antigen-binding molecule.

2. The method of claim 1, wherein the HF is selected from HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF).

3. The method of claim 1, wherein the HF is HFrEF.

4. The method of claim 1 or claim 2, wherein the HF is acute HF (AHF).

5. The method of claim 1 or claim 2, wherein the HF is acute decompensated HF (ADHF).

6. The method of claim 1, wherein the HF is chronic HF.

7. The method of any one of claims 1 to 6, wherein the HF is Class I HF according to the New York Heart Association (NYHA) classification scale.

8. The method of any one of claims 1 to 6, wherein the HF is Class II HF according to the NYHA classification scale.

9. The method of any one of claims 1 to 6, wherein the HF is Class III HF according to the NYHA classification scale.

10. The method of any one of claims 1 to 6, wherein the HF is Class IV HF according to the NYHA classification scale.

11. The method of any one of claims 1 to 10, wherein the subject has Stage A progression of HF as classified according to the American College of Cardiology / American Heart Association (ACC / AHA) HF guidelines.

12. The method of any one of claims 1 to 10, wherein the subject has Stage B progression of HF as classified according to the ACC / AHA HF guidelines.

13. The method of any one of claims 1 to 10, wherein the subject has Stage C progression of HF as classified according to the ACC / AHA HF guidelines.

14. The method of any one of claims 1 to 10, wherein the subject has Stage D progression of HF as classified according to the ACC / AHA HF guidelines.

15. The method of any one of claims 1 to 14, wherein administration of the CD14 antagonist antigen-binding molecule ameliorates or improves at least one sign of HF selected from elevated jugular venous pressure, jugular venous dilatation, third heart sound e.g., gallop rhythm), laterally displaced apical impulse, congested hepatomegaly, hepatojugular reflux, ascites, symptoms of gut congestion, weight gain (e.g., >2 kg / week), anorexia, weight loss (e.g., in advanced heart failure), cachexia, cardiac murmur, high NLR, peripheral edema (e.g., ankle, sacral, scrotal), pulmonary congestion, pulmonary edema (e.g., acute pulmonary edema), pulmonary rales, pulmonary crepitations, reduced air entry and dullness to, percussion at lung bases (e.g., pleural, effusion), arrhythmias, atrial fibrillation, atrial flutter, tachycardia (e.g., ventricular tachycardia), irregular pulse, tachypnea, Cheyne-Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, nocturia, and narrow pulse pressure.

16. The method of any one of claims 1 to 15, wherein administration of the CD14 antagonist antigen-binding molecule ameliorates or improves at least one symptom of HFselected from breathlessness, orthopnea, paroxysmal nocturnal dyspnea, exertional dyspnea, dyspnea at rest, reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, ankle swelling, nocturnal cough, wheezing, bloated feeling, loss of appetite, nausea, confusion e.g., in the elderly), depression, palpitations, dizziness, syncope, and bendopnea.

17. The method of any one of claims 1 to 16, wherein the administration of the CD14 antagonist antigen-binding molecule improves one or more clinical parameters of the subject selected from adverse cardiac structural remodeling e.g. adverse LV remodeling), cardiac contractile function, cardiac output, ejection fraction e.g., LV ejection fraction (LVEF)), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV akinesia, LV dilatation, and LV hypertrophy, dyspnea, congestion score, patient perception of health status, and neutrophil I lymphocyte ratio (NLR).

18. The method of any one of claims 1 to 17, wherein the administration of the CD14 antagonist antigen-binding molecule reduces dyspnea in the subject to a level that is less than about 95% of the level of dyspnea in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

19. The method of any one of claims 1 to 18, wherein the administration of the CD14 antagonist antigen-binding molecule reduces congestion in the subject to a level that is less than about 95% of the level of congestion in the subject before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

20. The method of any one of claims 1 to 19, wherein the administration of the CD14 antagonist antigen-binding molecule increases the subject's clinical score, as evaluated for example by the Kansas City Cardiomyopathy Questionnaire (KCCQ), by at least about 5% relative to the subject's clinical score before administration of the CD14 antagonist antigenbinding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

21. The method of any one of claims 1 to 20, wherein the administration of the CD14 antagonist antigen-binding molecule decreases the subject's neutrophil I lymphocyte ratio (NLR) by about 2% to about 40% relative to the subject's NLR before administration of the CD14 antagonist antigen-binding molecule or relative to a control subject who has not received the CD14 antagonist antigen-binding molecule.

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