Bispecific antibodies for use in lowering the risk of cardiovascular disease events in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations

Abstract

The invention relates to bispecific monoclonal antibodies (bbmAb) or variants thereof for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations.

Description

[0001] Bispecific Antibodies for use in lowering the risk of cardiovascular disease events in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations.

[0002] TECHNICAL FIELD

[0003] The invention relates to bispecific antibodies for the use in lowering the risk of cardiovascular disease events in subjects known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations (CHIP).

[0004] BACKGROUND OF THE DISCLOSURE

[0005] Cardiovascular diseases (CVD) remain the leading cause of disease burden in the world. The estimated global prevalence of CVD doubled from 271 million in 1990 to 523 million in 2019 (Roth GA, Mensah GA, Johnson CO, et al (2020) Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update from the GBD 2019 Study. J Am Coll Cardiol; 76(25):2982-3021). A substantial residual risk for CVD events related to chronic inflammation remains despite standard of care (SoC) management of classic risk factors (diabetes, hypertension, lipids, etc.)).

[0006] Atherosclerotic CVD is a condition commonly characterized by an elevated inflammatory state. Arterial inflammation and endothelial dysfunction play key roles at all stages of the atherothrombotic process. Inflammatory mediators are intimately implicated with the cascade of events leading to atherosclerotic plaque initiation, progression, and rupture. Vascular endothelial cells express a variety of adhesion molecules that recruit monocytes when chronically exposed to noxious stimuli or pathological conditions. Adverse conditions such as hyperlipidemia are associated with enrichment of a pro- inflammatory subset of monocytes. These monocytes apparently enter the intima under the influence of chemotactic stimuli and engulf modified low density lipoprotein (LDL) and cholesterol crystals (Duewell P, Kono H, Rayner KJ, et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature; 464(7293):1357-61). The material internalized by phagocytes induces phagolysosomal damage and subsequent leakage of contents into cytosol to activate inflammasomes and caspase 1 , and consequently the generation of interleukin-1 p (IL-1 ) from pro-interleukin- 1 P.

[0007] Interleukins are key mediators in the chronic vascular inflammatory response in CVD and have been demonstrated in animal models and in humans to be potent modulators of pro-inflammatory processes. The fact that these cytokines and their receptors are highly expressed and are functional in almost all cell types implicated in the pathogenesis of atherosclerosis including smooth muscle cells, certain subset of macrophages and T cells, as well as endothelium, support the role of interleukins in vascular disease. For example, I L-1 p is a potent smooth muscle cell mitogen, an activator of endothelial cells and increases extra cellular matrix and collagen deposition, which plays a role in plaque burden and arterial thickening. Furthermore, lack of I L-1 p or ablation of IL- 1 receptor has been shown to decrease severity of atherosclerosis in apoE deficient mice.

[0008] Clinical evidence from the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) clinical trial demonstrated that I L-1 neutralization with canakinumab can reduce cardiovascular risk by approximately 15% in patients who have had a prior myocardial infarction (Ml) and elevated high-sensitivity C-reactive protein (hsCRP). Patients in the CANTOS trial that had lower on-treatment levels of IL-6 and hsCRP had even greater CVD benefit (approximately 25-35%). I L-1 p signaling promotes the release of IL-6 and hsCRP, and lower on-treatment levels may identify post-MI patients with the greatest potential CVD benefit. In post-hoc subgroup analyses in CANTOS, two populations demonstrated substantially increased residual risk of CVD that was not completely addressed by I L-1 p neutralization. First, patients with increased IL-18 levels at baseline in CANTOS had an increased risk of major adverse cardiovascular event (MACE) (15% increase in risk [95% confidence interval (Cl) 3-29%, p=0.02] for each increase in baseline IL-18), corroborating other preclinical findings implicating IL-18 in CVD pathogenesis (Ridker PM, MacFadyen JG, Thuren T, et al (2020) Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1 p inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J; 41 (23) :2153-63). Second, patients in CANTOS with evidence at baseline of CHIP were found to have higher risk of MACE during the trial follow-up as compared to patients without CHIP (Svensson EC, Madar A, Campbell CD, et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol; 7(5):521-28).

[0009] CHIP refers to the presence of clonal populations of hematopoietic stem cells that occur in absence of diagnostic criteria for hematologic malignancy, in absence of morphological variation in blood cells, and with candidate driver gene mutations at variant allele frequency (VAF) of at least 2% in peripheral blood (Steensma DP, Bejar R, Jaiswal S et al (2015) Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood; 126(1):9-16). CHIP is a disorder of aging with about 15% of people affected by 75 years of age. The risk of coronary heart disease for individuals with CHIP is approximately 2-times greater than in non-carriers matched for CVD factors including age, sex, type 2 diabetes and smoking history (Jaiswal S, Natarajan P, Silver A et al (2017) Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med; 377:111-121). In murine models, there is data suggesting a causative role of CHIP in development of both atherosclerosis and cardiac dysfunction (Fuster J J , Maclauchlan S, Zuriaga MA et al (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science; 355:6327; Sano S, Oshima K, Wang Y et al (2018) CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circulation Research; 123:335-341). CHIP likely contributes to CVD risk through enhanced inflammation, including increased NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) activation. Analysis of the CANTOS data revealed that patients with CHIP, particularly CHIP due to somatic mutations in the TET2 gene, were found to have over 60% higher risk of MACE during the trial follow-up as compared to patients without CHIP (Svensson EC, Madar A, Campbell CD, et al (2022) TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol; 7(5):521-28). Mutations in epigenetic regulators (DNMT3A and TET2) account for approximately 80% of CHIP and are linked to a pro- inflammatory state (Marnell C, Bick A, Natarajan P (2021) Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease. J Mol Cell Cardiol; 161 :98-105).

[0010] CVD is a heterogenous disorder, and the presence of CHIP may mark individuals with a greater inflammatory driven contribution to CVD pathogenesis and potentially greater response to targeted anti-inflammatory therapies. Therapeutic approaches that target additional inflammatory pathways and selecting populations with the potential for greater response to anti-inflammatory therapy (i.e., CHIP) may further attenuate the residual CVD risk seen in CANTOS.

[0011] Inhibition of I L-1 p and IL-18 has the potential to significantly reduce cardiovascular risk in patients.

[0012] SUMMARY OF THE DISCLOSURE

[0013] In a first aspect the disclosure relates to a) a bispecific antibody or functional fragments thereof targeting both IL-1 and IL-18 simultaneously (e.g., bbmAb), for use in reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, and b) a method for reducing the risk of or preventing cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, comprising for a) and b) administering to said subject a therapeutically effective amount of a bispecific antibody, wherein the antibody comprises a first part which is an immunoglobulin with a first variable light chain (VL1) and a first variable heavy chain (VH1), that binds specifically to ILip, and a first constant heavy chain (CH1) with a heterodimerization modification, and a second part which is an immunoglobulin with a second variable light chain (VL2) and a second variable heavy chain (VH2), that binds specifically to IL-18 and a second constant heavy chain (CH2) with a hetero-dimerization modification which is complementary to the hetero-dimerization modification of the first constant heavy chain (e.g., bbmAb).

[0014] In one embodiment of the first aspect of the disclosure, the treated subject has at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2 or more than one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency (VAF) >2%.

[0015] In another embodiment of the disclosure, the treated subject has at least one mutation in one of the CHIP driver genes TET2 or DNMT3A, wherein at least one unique mutation must be present at a variant allele frequency >2%.

[0016] In another embodiment of the first aspect of the disclosure, the treated subject has a coronary heart disease. In another embodiments, the subject had a documented spontaneous myocardial infarction and wherein the bispecific antibody is administered at the earliest 30 days after the myocardial infarction (Ml).

[0017] In an additional embodiment of the first aspect, the cardiovascular event (CVE) or cardiovascular diseases (CVD), which can be a recurrent CVEs or CVDs, is selected from non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization, or non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, or unstable angina requiring unplanned revascularization, or non-fatal myocardial infarction or cardiovascular death, or non-fatal myocardial infarction.

[0018] Therefore, one embodiment of the first aspect of the disclosure, relates to a method to reduce the risk of cardiovascular death in a CHIP patient.

[0019] In another embodiment of the first aspect, the bispecific antibody is administered to a subject subcutaneously.

[0020] In a different embodiment of the first aspect, the dose of the administered bispecific I L-1 p and IL-18 targeting antibody is about 1 mg / kg to about 35 mg / kg. In another different embodiment of the first aspect, the dose of the administered bispecific I L-1 p and IL-18 targeting antibody is about 50 mg to about 900 mg administered subcutaneously. In a specific embodiment the subcutaneously administered dose of the bispecific IL-1 and IL-18 targeting antibody (e.g., bbmAb) is about 600mg.

[0021] In another embodiment of the first aspect, subjects known to be carrier of clonal expansion of hematopoietic cell lines (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, and being at risk of a cardiovascular events (CVE) or cardiovascular diseases (CVD), which can be a recurrent CVEs or CVDs, will receive a subcutaneously administered dose of IL-1 p and IL-18 targeting antibody (e.g., bbmAb) of about 600mg and further administrations of said antibody approximately every month or every second month or every third month or every fourth month or every fifth month or every sixth month after the first administration.

[0022] Additionally, in one embodiment of the first aspect, the subject to be treated has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after Ml and before first administration of bispecific antibody, and wherein bispecific antibody is administered at the earliest 30 days after Ml, and wherein said subject has a reduced hsCRP level of <2 mg / L assessed approximately 3 weeks after first administration of the bispecific antibody.

[0023] Accordingly, one embodiment of the first aspect of the invention relates to uses or methods for reducing circulating levels of inflammatory markers in a subject with known coronary heart disease and clonal expansion of hematopoietic cell lines with somatic mutations (e.g., like the above described subject carrying at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation is present at a variant allele frequency (VAF) >2%.

[0024] In another embodiment of the first aspects of the disclosure, the bispecific antibody targeting both IL-ip and IL-18 is administered in combination with at least one further therapeutic agent. In another embodiment of the first aspect of the disclosure, the said subject is concomitantly receiving standard of care treatment for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs.

[0025] In a different embodiment of the first aspect the disclosure, the uses or methods comprise administering to a subject a therapeutically effective amount of a bispecific antibody targeting both IL-ip and IL-18, wherein the first and second constant heavy chains of the bispecific antibody are human IgA, IgD, IgE, IgG, or IgM, preferably IgD, IgE or IgG, such as human lgG1 , lgG2, lgG3, or lgG4, preferably lgG1. In another embodiment of the herein described methods and uses, the first and second constant heavy chains of the bispecific antibody targeting both I L-1 p and IL-18 are lgG1 , and a. the first constant heavy chain has point mutations generating a knob structure and the second constant heavy has point mutations generating a hole structure, or b. the first constant heavy chain has point mutations generating a hole structure and the second constant heavy has point mutations generating a knob structure, and optionally c. the first and second constant heavy chains have mutations resulting in a disulfide bridge.

[0026] In a specifically preferred embodiment of the herein described methods and uses, the first immunoglobulin VH1 domain of the bispecific antibody targeting both IL-1 and IL-18 comprises: i. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77, and said CDR3 having the amino acid sequence SEQ ID NO:78; or ii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:79, said CDR2 having the amino acid sequence SEQ ID NQ:80, and said CDR3 having the amino acid sequence SEQ ID NO:81 ; and the first immunoglobulin VL1 domain of the bispecific antibody comprises: iii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93, and said CDR3 having the amino acid sequence SEQ ID NO:94 or iv. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:95, said CDR2 having the amino acid sequence SEQ ID NO:96, and said CDR3 having the amino acid sequence SEQ ID NO:97; and the second immunoglobulin VH2 domain of the bispecific antibody comprises: v. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45, and said CDR3 having the amino acid sequence SEQ ID NO:46; or vi. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:47, said CDR2 having the amino acid sequence SEQ ID NO:48, and said CDR3 having the amino acid sequence SEQ ID NO:49; and the second immunoglobulin VL2 domain of the bispecific antibody comprises: vii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61 , and said CDR3 having the amino acid sequence SEQ ID NO:62 or viii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:63, said CDR2 having the amino acid sequence SEQ ID NO:64, and said CDR3 having the amino acid sequence SEQ ID NO:65.

[0027] In another embodiment of the herein described methods and uses, the bispecific antibody targeting both I L-1 p and IL-18 used in the methods / treatments according to any of the preceding aspects comprises: a. the first immunoglobulin VH1 domain of amino acid sequence SEQ ID NO: 85, b. the first immunoglobulin VL1 domain of amino acid sequence SEQ ID NO: 101 , c. the second immunoglobulin VH2 domain of amino acid sequence SEQ ID NO: 53, and d. the second immunoglobulin VL2 domain of amino acid sequence SEQ ID NO: 69.

[0028] In another embodiment of the disclosure, the bispecific antibody targeting both IL- 1 and IL-18 used in the methods / treatments according to preceding aspects comprises: e. the first immunoglobulin heavy chain of amino acid sequence SEQ ID NO: 87, f. the first immunoglobulin light chain of amino acid sequence SEQ ID NO: 103, g. the second immunoglobulin heavy chain of amino acid sequence SEQ ID NO: 55, and h. the second immunoglobulin light chain of amino acid sequence SEQ ID NO: 71.

[0029] In some cases, the subject in need of a treatment for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs, has high serum C- reactive protein (CRP) levels as compared to a control population.

[0030] In one embodiment, the subject in need of a treatment for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs, has a serum C- reactive protein (CRP) level higher than 2 mg / L. In case the subject had a documented myocardial infarction, the CRP level is at least 28 days after Ml and before first administration of bispecific antibody, and wherein bispecific antibody is administered at the earliest 30 days after Ml.

[0031] Therefore, one embodiment of the disclosure, relates to use of a bispecific antibody targeting both I L-1 and IL-18, e.g., bbmAb for the treatment of a CHIP patient to reduce the risk of cardiovascular death in said patient.

[0032] In one embodiment, provided herein is a bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, for use in reducing the serum C-reactive protein (CRP) level in a (CHIP) subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation is present, with variant allele frequency (VAF) >2%.

[0033] In some embodiments, provided herein is the use of a bispecific antibody targeting both I L-1 p and IL-18, e.g., bbmAb, for the manufacture of a medicament for reducing the serum C-reactive protein (CRP) level in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) >2%. In some embodiments, the serum CRP level in the subject decreases, as a consequences of the herein described methods and treatments, by at least 1 mg / l, at least 2 mg / l, at least 3 mg / l, at least 4 mg / l or at least 5 mg / l. In some embodiments, the serum CRP level in a subject known to be a carrier of CHIP cell lines having received the bispecific antibody targeting both I L-1 p and IL-18, e.g., bbmAb, decreases by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% from baseline compared to the patient population not having received the same treatment, e.g., patients having received standard of care (SOC).

[0034] In another aspect the disclosure relates to the use of a bispecific antibody targeting both I L-1 and IL-18, e.g., bbmAb, for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs, in a subject with coronary heart disease known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) >2%.

[0035] In another aspect, the disclosure relates to pharmaceutical composition comprising a bispecific antibody targeting both I L-1 p and IL-18, e.g., bbmAb for use in reducing the risk of or preventing recurrent cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) >2%.

[0036] A cardiovascular event in accordance with one of the above mentioned aspects or embodiments of the disclosure can be recurrent and, hence, one embodiment of the herein disclosed uses or methods relates to reducing the risk of recurrent cardiovascular events in in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation is present with variant allele frequency (VAF) >2%.

[0037] DETAILED DESCRIPTION OF THE DISCLOSURE

[0038] Without wishing to be bound by theory, inflammation is thought to play an important role in CVDs and the occurrence of CVEs, particularly in subjects being carrier of clonal expansion of hematopoietic cell lines / clonal hematopoiesis of indeterminate potential (CHIP) with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2 (CHIP population). The present disclosure is inter alia based on the unexpected finding that certain antibodies that simultaneously neutralize IL- 1 P and IL-18 more potently attenuate pro-inflammatory cytokine production compared to single IL-1 p or IL-18 neutralization alone, which is considered by the inventors to be an efficacious treatment for reducing the risk of or preventing cardiovascular events and recurring cardiovascular events in a CHIP population.

[0039] Clonal hematopoiesis of indeterminate potential (CHIP) is the results of clonally expanded hematopoietic stem cell caused by a mutation. CHIP populations have a twofold higher cardiovascular risk compared to non-CHIP individuals, because CHIP results in a pro-inflammatory state that seems to be linked to CVEs like thromboembolic events, myocardial infarction, and coronary artery disease (Marnell C, Bick A, Natarajan P (2021) Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease. J Mol Cell Cardiol; 161 :98-105. The most prominent mutations resulting in CHIP have been identified in DNA damage repair genes (e.g., PPM1 D, TP53), the tyrosine kinase JAK2, mRNA spliceosome components (e.g., SF3B1 , and SRSF2) and epigenetic regulators (e.g., DNMT3A, TET2, ASXL1).

[0040] As used herein, the umbrella terms cardiovascular disease (CVD) or cardiovascular event (CVE) will be used as they best reflect the underlying etiology of the disease and are used to describe coronary heart diseases, also simply known as heard disease, or known and called as myocardial ischemia, ischemic heart disease or coronary artery disease. All these indications involve a reduction of blood flow to the heart due to e.g., atherosclerotic plaques in the arteries of the heart. Such a cardiovascular event can be recurrent and one embodiment of the herein disclosed uses or methods relates to reducing the risk of recurrent cardiovascular events.

[0041] A cardiovascular event can be a Myocardial Infarction (Ml). Different types of Ml are known, like: i) spontaneous Ml related to ischemia due to a primary coronary event such as plaque erosion and / or rupture, fissuring or dissection, ii) Ml secondary to ischemia due to either increased oxygen demand or decreased supply, e.g., coronary artery spasm, anemia, hypotension, coronary embolism, arrhythmias, hypertension or hypotension, iii) Sudden unexpected cardiac death including cardiac arrest, often with symptoms suggestive of myocardial ischemia, iv) Ml associated with PCI (Percutaneous Coronary Intervention), v) Ml associated with stent thrombosis as documented by autopsy or angiography, vi) Ml associated with CABG (Coronary artery bypass grafting), vii) stable angina and unstable angina. In one embodiment, the CVEs or CVDs treated according to the methods and uses disclosed herein is a recurrent CVE or CVD

[0042] Herein are described methods or uses for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVE or CVD, in a CHIP population by administering to a subject in need thereof an effective amount of a bispecific antibody targeting both I L-1 p and IL-18 simultaneously (e.g., bbmAb) or functional fragments thereof. Accordingly, in one aspect provided is a method for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVE or CVD, in a CHIP population, comprising administering to a subject in need thereof an effective amount of a bispecific antibodies targeting both IL- 1 and IL-18 simultaneously (e.g., bbmAb).

[0043] In one embodiment, the disclosure relates to uses or methods of the bispecific antibody targeting both IL-1 and IL-18, e.g., bbmAb, for reducing the risk of or preventing CVEs or CVDs, wherein said events or diseases are selected from non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization.

[0044] In one embodiment, the disclosure relates to uses or methods of the bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, for reducing the risk of or preventing a cardiovascular event, wherein said event is non-fatal myocardial infarction.

[0045] In one embodiment, the disclosure relates to uses or methods of the bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, for reducing the risk of or preventing a cardiovascular event, wherein said event non-fatal stroke.

[0046] In one embodiment, the disclosure relates to uses or methods of the bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, for reducing the risk of or preventing a cardiovascular event, wherein said event cardiovascular death.

[0047] In one embodiment, the disclosure relates to uses or methods of the bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, for reducing the risk of or preventing a cardiovascular event, wherein said event is unstable angina requiring unplanned revascularization.

[0048] The disclosure relates to bispecific monoclonal antibodies or variants thereof, e.g., bispecific antibodies targeting both IL-i p and IL-18 simultaneously (e.g., bbmAb) for the use in reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVE or CVD, in disease patients having hyper elevated I L-1 p and / or I L-18. The disclosure also relates to methods, treatment regimens, uses, kits and therapies for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVE or CVD, by employing bispecific antibodies targeting both IL-1 p and IL-18 simultaneously, e.g., bbmAb.

[0049] Moreover, the present inventors hypothesize that treatment with an antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb), can allow for a significantly reduced dose frequency, with single administration compared to the more complex investigational combination requiring anti-IL-1 p (every two weeks for e.g., canakinumab or every day for anakinra) potentially with glucocorticoids, cyclosporin and IL-18BP (every two days).

[0050] In one aspect of the invention, the hsCRP levels of >2 mg / L assessed at least 28 days after Ml is reduced by 20% or 21% or 22% or 23% or 24% or 25% or 26% or 27% or 28% or 29% or 30% or more after a single subcutaneous (s.c.) administration of about 600mg bbmAb, measured at 3 weeks after the administration of the bbmAb.

[0051] Another biomarker that is useful in assessing residual inflammatory risk include downstream mediators of IL-1 such as interleukin-6 (IL-6). IL-6 is a known marker of cardiovascular disease associated with obesity, type 2 diabetes, and myocardial infarction. It is known that administration of an IL-1 antibody (e.g., canakinumab) to stabilize post-MI patients resulted in lowering of levels of IL-6, a marker for inflammation. Accordingly, in another embodiment of any use or method according to the invention, IL-6 is used as a biomarker for assessing the response of the stable Ml patient to administration of about 600mg bbmAb administered at the earliest 30 days after Ml.

[0052] In one embodiment the serum level of IL-6 is used as a biomarker for assessing the response of the stable Ml patient to a single subcutaneous (s.c.) administration of about 600mg bbmAb administered at the earliest 30 days after Ml, wherein the IL-6 serum level is measured at 3 weeks after a single subcutaneous (s.c.) dose of bbmAb.

[0053] In one embodiment of the method or use of the invention, the level of IL-6 assessed approximately 3 weeks after first administration of bbmAb is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.

[0054] Accordingly, the present invention is also directed to the use of an antibody that simultaneously neutralizes IL-i p and IL-18 (e.g., bbmAb) in reducing the risk of or preventing a CVE or CVD, which can be a recurrent CVE or CVD, in a CHIP patient that has suffered myocardial infarction (Ml), wherein i) said subject is a CHIP patient with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, and ii) said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after Ml and before first administration of e.g., bbmAb, and iii) about 600 mg of an antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb) is administered to the patient at the earliest 30 days after Ml and, optionally, iv) wherein about 600 mg of an antibody that simultaneously neutralizes IL-1 p and IL- 18 (e.g., bbmAb) is further administered to said patient approximately every month or every second month or every third month or every fourth month or every fifth month or every sixth month after the first administration.

[0055] In another embodiment of the disclosure, the above-described continued administration of the antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb) comprises additional administrations of the antibody to the patients approximately every three months after the first administration.

[0056] Furthermore, the present invention also relates to the use of an antibody that simultaneously neutralizes IL-i p and IL-18 (e.g., bbmAb) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, which can be a recurrent CVEs or CVDs, in a CHIP patient that has suffered myocardial infarction (Ml), wherein i) said subject is a CHIP patient with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, and ii) said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after Ml and before first administration of e.g., bbmAb, and iii) about 600 mg of an antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb) is administered to the patient at the earliest 30 days after Ml and, optionally, iv) wherein about 600 mg of an antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb) is further administered to said patient every month or every second month or every third month or every fourth month or every fifth month or every sixth month after the first administration.

[0057] In another embodiment of the disclosure, the above-described continued administration of the manufactured medicament comprising the antibody that simultaneously neutralizes IL- 1 P and IL-18 (e.g., bbmAb) comprises additional administrations of said medicament to the patients approximately every three months after the first administration.

[0058] In one embodiment of any method or use described herein, said CHIP population patient has high sensitivity C-reactive protein (hsCRP) levels of >3 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >4 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >5 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >6 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >7 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >8 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >9 mg / L assessed at least 28 days after Ml and before first administration of bbmAb. In one embodiment of any method or use described herein, said CHIP patient has high sensitivity C-reactive protein (hsCRP) levels of >10 mg / L assessed at least 28 days after Ml and before first administration of bbmAb.

[0059] In one embodiment of the method or use of the invention, the reduced level of hsCRP in the CHIP patient, assessed approximately 3 weeks after first administration of bbmAb, is <1.9, <1.8, <1.7, <1.6, <1.5, <1.4, <1.3, <1.2, <1.1 , <1.0, <0.9, <0.8, < 0.7, <0.6, or <0.5 mg / L.

[0060] In one embodiment, the reduced level of hsCRP in the CHIP patient, assessed approximately 3 weeks after first administration of bbmAb, is <1.8 mg / L. In another embodiment, the reduced level of hsCRP assessed approximately 3 weeks after first administration of bbmAb is <1.5 mg / L.

[0061] In one embodiment of the method or use of the invention, the level of hsCRP in the CHIP patient, assessed approximately 3 weeks after first administration of bbmAb, is reduced in by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more.

[0062] In another embodiment of any use or method provided herein, the CHIP patient has reduced hsCRP level of <2 mg / L, e.g., 1.9, <1.8, <1.7, <1.6, <1.5, <1.4, <1.3, <1.2, <1.1 , <1.0, <0.9, <0.8, < 0.7, <0.6, or <0.5 mg / L, assessed approximately 3 weeks, approximately 6 weeks, approximately 3 months, approximately 6 months or approximately 9 months after first administration of bbmAb.

[0063] Accordingly, one embodiment provides the use of an antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb) in reducing the risk of or preventing a CVE or CVD, which can be a recurrent CVE or CVD, in a CHIP patient that has suffered myocardial infarction (Ml), i. wherein said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after Ml and before first administration of antibody that simultaneously neutralizes IL-1 and IL-18 (e.g., bbmAb), and ii. wherein about 600 mg of said antibody is administered subcutaneously (s.c.) to the patient at the earliest 30 days after Ml, and iii. wherein the hsCRP level assessed approximately 3 weeks after first administration of said antibody in the patient is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, and optionally, iv) wherein about 600 mg of an antibody that simultaneously neutralizes IL-1 p and IL- 18 (e.g., bbmAb) is further administered to said patient approximately every month or approximately every second month or approximately every third month or approximately every fourth month or approximately every fifth month or approximately every sixth month after the first administration.

[0064] In another embodiment of the disclosure, the above-described continued administration of the antibody that simultaneously neutralizes IL-1p and IL-18 (e.g., bbmAb) comprises additional administrations of the antibody to the patients approximately every three months after the first administration.

[0065] In some embodiments, the reduction in one or more elevated serum inflammatory marker by administration of a bispecific antibody or functional fragments thereof targeting both I L-1 and IL-18 simultaneously can be a reduction of at least about 20%, 30%, 40% or 50% from baseline compared to patients not having received the same treatment, e.g., patients having received standard of care (SOC). In some embodiments, the reduction in one or more elevated serum inflammatory marker by administration of a bispecific antibody or functional fragments thereof targeting both IL-1 p and IL-18 simultaneously can be a reduction of at least about 60%, 70%, 80%, 90% from baseline compared to patients not having received the same treatment, e.g., patients having received standard of care (SOC).

[0066] In some embodiments, the reduction in one or more elevated serum inflammatory marker by administration of a bispecific antibody or functional fragments thereof targeting both IL-1 p and IL-18 simultaneously can be a reduction of at least about 100%, 200%, 300% or more from baseline compared to patients not having received the same treatment, e.g., patients having received standard of care (SOC).

[0067] In another embodiment of any method or use of the invention, said recurrent CV event is hospitalization for unstable angina requiring unplanned revascularization.

[0068] When administered subcutaneously according to any use or method disclosed herein, the antibody that simultaneously neutralizes IL-1 p and IL-18 (e.g., bbmAb) will be administered to the patient in a liquid form, including liquid forms prepared by reconstitution of lyophilized drug formulations, contained in e.g., a prefilled syringe or autoinjector.

[0069] In other embodiments of the method or use of the invention, the patient may concomitantly receive the antibody that simultaneously neutralizes I L-1 p and IL-18 (e.g., bbmAb) and a standard of care treatment for reducing the risk of or preventing CV events, which can be a recurrent CVEs or CVDs. Said standard of care treatment includes, but is not limited to, lipid lowering agents such as a HMG-CoA reductase inhibitor, e.g., a statin such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, pitavastatin, rosuvastatin or mixtures thereof or mixtures with ezetimibe, niacin, amlodipine besylate, inhibitors of proprotein convertase subtilisin / kexin type 9 (PCSK9i) such as alirocumab (Praluent®), evolocumab (Repatha®), bococizumab, inhibitors of cholesterylester transfer protein (CETP) such as anacetrapib, torcetrapib, dalcetrapib, anti-hypertensives such as a calcium channel blocker (e.g., amlodipine, diltiazem, nifedipine, nicardipine, verapamil) or beta-adrenergic blocking drugs such as esmolol, metoprolol, nadolol, penbutolol or anti-hypertensives such as labetalol, metoprolol, hydralazine, nitroglycerin, nicardipine, sodium nitroprusside, clevidipine or a diuretic such as a thiazide diuretic, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone, amiloride hydrochloride, spironolactone, triamterene, or an angiotensin-converting enzyme (ACE) inhibitor such as ramipril, ramiprilat, captopril, lisinopril or an angiotensin II receptor blocker such as losartan, valsartan, olmesartan, irbesartan, candesartan, telmisartan, eprosartan or an angiotensin receptor-neprilysin inhibitor (ARNI) such as sacubitril / valsartan (Entresto®), or an anticoagulant such as acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumacetate, phenprocoumon, warfarin heparin, low molecular weight heparin such as bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin or an inhibitor of platelet aggregation such clopidogrel, elinogrel, prasugrel, cangrelor, ticagrelor, ticlopidine, cilostazol, dipyridamole, picotamide, abciximab, eptifibatide, tirofiban or terutroban or a Prostaglandin analogue (PGI2) such as beraprost, prostacyclin, iloprost or treprostinil, or COX inhibitors such as aspirin, aloxiprin or carbasalate calcium, indobufen or triflusal or cloricromen or ditazole or 1 ,3-indandiones such as clorindione, diphenadione or phenindion, or tioclomarol, or direct thrombin (II) inhibitors such as hirudin, bivalirudin, lepirudin, desirudin (bivalent) or argatroban or dabigatran (monovalent) or oligosaccharides such as fondaparinux, idraparinux, or heparinoids such as danaparoid, sulodexide, dermatan sulfate or direct Xa inhibitors xabans such as apixaban, betrixaban, edoxaban, otamixaban, rivaroxaban or REG1 or defibrotide or ramatroban or antithrombin III or protein C (drotrecogin alfa) or fibrinolytics plasminogen activators: r-tPA such as alteplase, reteplase, tenecteplase or UPA such as urokinase or saruplase or streptokinase or anistreplase or monteplase or other serine endopeptidases or ancrod or fibrinolysin; or brinase or citrate or EDTA or oxalate or digitalis, or digoxin, or nesiritide, or oxygen, or a nitrate such as glyceryl trinitrate (GTN) / nitroglycerin, isosorbide dinitrate, isosorbide mononitrate or an analgesic such as morphine sulfate or a renin inhibitor such as aliskiren or an endothelin A receptor inhibitor or an aldosterone inhibitor.

[0070] In another embodiment the disclosure relates to a pharmaceutical composition comprising an antibody that simultaneously neutralizes IL-1 and IL-18 (e.g., bbmAb) for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1. SRSF2 or JAK2.

[0071] Accordingly, in one embodiment, the disclosure relates to a pharmaceutical composition comprising an antibody that simultaneously neutralizes IL-1 p and IL-18 for use in reducing the risk of or preventing cardiovascular events, which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency >2% and wherein the antibody comprises a. the first immunoglobulin VH1 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 85, b. the first immunoglobulin VL1 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 101 , c. the second immunoglobulin VH2 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 53, and d. the second immunoglobulin VL2 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 69.

[0072] Furthermore, in one embodiment, the disclosure relates to a pharmaceutical composition comprising the antibody that simultaneously neutralizes IL-1 p and IL-18 comprising the VH and VL chain amino acid sequences a. to d. above (e.g., bbmAb) for use in reducing the risk of or preventing cardiovascular events, which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency >2% and wherein the said CHIP patient that has suffered myocardial infarction (Ml), and i. wherein said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after M I and before first administration of the antibody comprising the VH and VL chain amino acid sequences a. to d. above, and ii. wherein about 600 mg of said antibody is administered subcutaneously (s.c.) to the patient at the earliest 30 days after Ml, and optionally, iii. wherein the hsCRP level assessed approximately 3 weeks after first administration of said antibody in the patient is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, and further optionally, iv) wherein about 600 mg of said antibody comprising the VH and VL chain amino acid sequences a. to d. above is further administered to said patient approximately every month or approximately every second month or approximately every third month or approximately every fourth month or approximately every fifth month or approximately every sixth month after the first administration.

[0073] In another embodiment of the disclosure, the continued administration of the pharmaceutical composition comprising the antibody comprising the VH and VL chain amino acid sequences a. to d. in item iv) above comprises additional administration of 600 mg of said antibody to the patient approximately every three months after the first administration.

[0074] In one embodiment, the disclosure relates to a pharmaceutical composition comprising an antibody that simultaneously neutralizes I L-1 p and IL-18 for use in reducing the risk of or preventing cardiovascular events, which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency >2% and wherein the antibody comprises a. the first immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 87, b. the first immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 103, c. the second immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 55, and d. the second immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 71.

[0075] Therefore, in one embodiment, the disclosure relates to a pharmaceutical composition comprising the antibody that simultaneously neutralizes IL-i and IL-18 comprising the heavy and light chain amino acid sequences SEQ ID NO: 87, SEQ ID NO: 103, SEQ ID NO: 55 and SEQ ID NO: 71 (e.g., bbmAb) for use in reducing the risk of or preventing cardiovascular events, which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency >2% and wherein the said CHIP patient that has suffered myocardial infarction (Ml), and i. wherein said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after M I and before first administration of the antibody comprising the heavy and light chain amino acid sequences a. to d. above, and ii. wherein about 600 mg of said antibody is administered subcutaneously (s.c.) to the patient at the earliest 30 days after Ml, and optionally, iii. wherein the hsCRP level assessed approximately 3 weeks after first administration of said antibody in the patient is reduced by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200% or more, and further optionally, iv) wherein about 600 mg of said antibody comprising the heavy and light chain amino acid sequences heavy and light chain amino acid sequences SEQ ID NO: 87, SEQ ID NO: 103, SEQ ID NO: 55 and SEQ ID NO: 71 is further administered to said patient approximately every month or approximately every second month or approximately every third month or approximately every fourth month or approximately every fifth month or approximately every sixth month after the first administration.

[0076] In another embodiment of the disclosure, the continued administration of the pharmaceutical composition comprising the antibody comprising the heavy and light chain amino acid sequences heavy and light chain amino acid sequences SEQ ID NO: 87, SEQ ID NO: 103, SEQ ID NO: 55 and SEQ ID NO: 71 comprises additional administration of 600 mg of said antibody to the patient approximately every three months after the first administration.

[0077] In another embodiment, the disclosure relates to a pharmaceutical composition comprising an antibody that simultaneously neutralizes I L-1 and IL-18 for use in reducing the risk of or preventing cardiovascular events, which can be a recurrent CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency >2%, wherein the antibody comprises a. the first immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 87, b. the first immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 103, c. the second immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 55, and d. the second immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 71 and wherein i) said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after Ml and before first administration of said antibody, and ii) about 600 mg of said antibody is administered to the patient at the earliest 30 days after Ml and, wherein about 600 mg of said antibody is further administered to said patient approximately every third month.

[0078] 1. Definitions

[0079] For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. Additional definitions are set forth throughout the detailed description.

[0080] The term “about” in relation to a numerical value x means, for example, + / -10%. When used in front of a numerical range or list of numbers, the term “about” applies to each number in the series, e.g., the phrase “about 1-5” should be interpreted as “about 1 - about 5”, or, e.g., the phrase “about 1 , 2, 3, 4” should be interpreted as “about 1 , about

[0081] 2, about 3, about 4, etc.”

[0082] The term “approximately” when used in the context of a time period refers to a given time point (e.g. 90 days or 3 month) including a time period before or after that given time point. The term approximately 3 months includes a time period of 90 days + / - 10 days.

[0083] As used herein, the term approximately “6 months” refers to a time period of 180 days that includes + / - 15 days.

[0084] As used herein, the term approximately “9 months” includes a time period of 270 days that includes + / - 20 days.

[0085] The term "IL- 18" is synonym to IL- 18 polypeptide, Interleukin- 18 polypeptide, IFN- gamma inducing factor or Interferon-gamma-inducing-factor or INF-y inducing factor. The term "IL-18" refers to human IL-18, unless another species is indicated. IL-18 is well known to a person skilled in the art, and for example obtainable from MBL® International Corporation under product reference #B001-5. Throughout this specification, the term IL- 18 encompasses both pro-IL-18 (precursor of mature IL-18 prior protease cleavage) and mature IL-18 (post protease cleavage) interchangeably unless it is specified that the pro- or mature form is meant.

[0086] The term “IL-1p” or “IL-1 b” is synonym to IL-1 p polypeptide and lnterleukin-1 polypeptide. The term “IL-1 p” refers to human I L-1 p unless another species is indicated. IL-1 p is well known to a person skilled in the art, and commercially available (e.g., Sino Biological under product reference #10139-HNAE-5). Total IL-18 in serum can be measured by conjugating anti-human IL-18 antibody (e.g., clone 125-2H, MBL International) to Bio-plex Magnetic COOH beads (Bio-Rad, Inc.), detected using biotinylated anti-human IL-18 (clone 159-12B, MBL), and concentrations calculated using the IL-18 contained in the Group II cytokine standard curve (Bio-Rad, Inc.). Free IL-18 can be measured as described in Girard et al. Rheumatology (Oxford). 2016 Dec;55(12):2237- 2247. Serum IL-1 p can be measured using a commercially available ELISA kit (88-7261- 88, eBioscience) used in accordance with manufacturer’s instructions.

[0087] The term "antibody" refers to an intact immunoglobulin or a functional fragment thereof. Naturally occurring antibodies typically comprise a tetramer which is usually composed of at least two heavy (H) chains and at least two light (L) chains. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region, usually comprised of three domains (CH1 , CH2 ad CH3). Heavy chains can be of any isotype, including IgG (lgG1 , lgG2, lgG3 and lgG4 subtypes), IgA (lgA1 and lgA2 subtypes), IgM and I g E. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region (CL). Light chain includes kappa (K) chains and lambda (A) chains. The heavy and light chain variable region is typically responsible for antigen recognition, whilst the heavy and light chain constant region may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity 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 aminoterminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.

[0088] Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a flexible linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc Natl Acad Sc;. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. 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.

[0089] Throughout this specification, complementarity determining regions (“CDR”) are defined according to the Kabat definition unless specified that the CDR are defined according to another definition. The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme) and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) (“IMGT” numbering scheme). For example, for classic formats, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Under Chothia the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL. Under IMGT the CDR amino acid residues in the VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (numbering according to “Kabat”). Under IMGT, the CDR regions of an antibody can be determined using the program IMGT / DomainGap Align.

[0090] By convention, the CDR regions in the heavy chain are typically referred to as H- CDR1 , H-CDR2 and H-CDR3 and in the light chain as L-CDR1 , LCDR2 and L-CDR3. They are numbered sequentially in the direction from the amino terminus to the carboxy terminus.

[0091] As used herein, the term “antagonist” is intended to refer to a binding molecule that inhibits the signalling activity in the presence of activating compound. For example, in the case of IL-18, an IL-18 antagonist would be a binding molecule inhibiting the signalling activity in the presence of IL-18 in a human cell assay such as IL-18 dependent Interferongamma (IFN-y) production assay in human blood cells. Examples of an IL-18 dependent IFN-y production assay in human blood cells are described in more details in the examples below.

[0092] The term bispecific antibody or bispecific antibodies refer to antibodies binding to two different targets, such as IL-18 and IL-1 p. Typically, the bispecific antibody binds each target monovalently.

[0093] The bispecific antibodies are “hetero-dimers”, which means that one part comes from first antibody, specific for a first target, and another part comes from a second antibody, specific for a second target. A “hetero-dimerization modification” is a modification to one or both parts of the antibodies forming the hetero-dimeric bispecific antibody, intended to facilitate such formation. An example of hetero-dimerization modifications of the Fc domains of two I gG 1 parts of antibodies intended to form a bispecific is a “knob” with a bulky amino acid (aa) side chain (S354C, T366W) in the first heavy chain and a “hole” with small aa side chains (Y349C, T366S, L368A, Y407V) were introduced in the second heavy chain as well as an additional disulfide bridge in the CH3 region connecting both heavy chains (Merchant et al., Nat. Biotechnol., 16:677-681 (1998), page 678, table 1).

[0094] As used herein, the term "subject" includes any human subjects receiving the bispecific antibody as presently described. As used herein, the term “patient” and “subject” are used interchangeably. The term subject can additionally or alternatively include any human subject that is known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2. In one aspect a subject is a human being a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2 wherein at least one unique mutation must be present at a variant allele frequency >2%. In another aspect a subject is a human being a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2 or DNMT3A (TET2 or DNMT3A CHIP) wherein at least one unique mutation must be present at a variant allele frequency >2%. In another aspect of the disclosure a subject is a patient with coronary heart disease and TET2 or DNMT3A CHIP, wherein at least one unique mutation must be present at a variant allele frequency >2%.

[0095] As used herein, the terms “C-reactive protein” and “CRP” refers to serum C- reactive protein, which is used as an indicator of the acute phase response to inflammation. In certain embodiments of the uses and methods described herein, hsCRP levels are assessed in a biological sample, e.g., blood, obtained from the patient. A biological sample from the patient is assayed for the level of hsCRP. As used herein, the term “hsCRP” refers to the level of CRP in the blood as measured by high sensitivity CRP testing. The level of CRP or hsCRP in plasma may be given in any concentration, e.g., mg / dl, mg / L, nmol / L. Levels of CRP or hsCRP may be measured by a variety of well-known methods, e.g., radial immunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetric methods, fluorescence polarization immunoassay, and laser nephelometry. Testing for CRP may employ a standard CRP test or a high sensitivity CRP (hsCRP) test (i.e., a high sensitivity test that is capable of measuring low levels of CRP in a sample, e.g., using laser nephelometry). Kits for detecting levels of CRP or hsCRP may be purchased from various companies, e.g., Calbiotech, Inc, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.

[0096] The term “high sensitivity C-reactive protein (hsCRP) level” in the context of a method for reducing the risk of or preventing cardiovascular events in a subject, refers to: • a 60 % increase from normalized levels in treated patients of C-reactive protein (CRP), wherein normalized levels indicate minimal or absent inflammation or disease activity (e.g., CRP < 2 mg / L); or

[0097] • an elevation of CRP of > 2 mg / L.

[0098] As used herein, the term “cardiovascular death” includes sudden cardiac death, death due to acute myocardial infarction (AMI), death due to heart failure, death due to stroke, and death due to other cardiovascular causes.

[0099] As used herein, “sudden cardiac death” is a sudden death that occurs in a previously stable patient who does not have a prior terminal condition, such as malignancy not in remission or end-stage chronic lung disease.

[0100] Death due to acute myocardial infarction (AMI): refers to a death within 30 days after a myocardial infarction (Ml) related to consequences seen immediately after the myocardial infarction, such as progressive congestive heart failure (CHF), inadequate cardiac output, or recalcitrant arrhythmia.

[0101] Death due to heart failure or cardiogenic shock refers to death occurring in the context of clinically worsening symptoms and / or signs of heart without evidence of another cause of death and includes sudden death occurring during an admission for worsening heart failure as well as death from progressive heart failure or cardiogenic shock following implantation of a mechanical assist device. Cardiovascular death due to heart failure is selected from a heart failure with reduced ejection fraction (HFrEF), heart failure with midrange ejection fraction or heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarct, or acute decompensated heart failure.

[0102] Death due to stroke (intracranial hemorrhage or non-hemorrhagic stroke) refers to death occurring up to 30 days after a suspected stroke based on clinical signs and symptoms as well as neuroimaging and / or autopsy, and where there is no conclusive evidence of another cause of death.

[0103] As used herein, “death due to other cardiovascular causes” refers to death due to a cardiovascular cause not included in the above categories (e.g. dysrhythmia, pulmonary embolism, cardiovascular intervention, aortic aneurysm rupture, or peripheral arterial disease). Mortal complications of cardiac surgery or non-surgical revascularization, even if “non-cardiovascular” in nature, should be classified as cardiovascular deaths.

[0104] As used herein, the term “myocardial infarction (Ml)” refers to “acute myocardial infarction”: the term myocardial infarction (Ml) is used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. The term Ml includes an ST-elevated Ml (STEMI) or a non-ST-elevated Ml (NSTEMI). Under these conditions any one of the following criteria meets the diagnosis for Ml: The term “spontaneous Ml” refers to the detection of rise and / or fall of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following: symptoms of ischemia, ECG changes indicative of new ischemia (ST Elevation - New ST elevation at the J-point in two contiguous leads with the cut-off points:> 0.2 mV in men or > 0.15 mV in women in leads V2-V3 and / or > 0.1 mV in other leads, ST depression and T- wave changes - New horizontal or down-sloping ST depression > 0.05 mV in two contiguous leads; and / or T inversion > 0.1 mV in two contiguous leads with prominent R waves or R / S ratio >1., development of pathological Q waves in the ECG (Any Q-wave in leads V2-V3 > 0.02 seconds or QS complex in leads V2 and V3, Q-wave > 0.03 seconds and > 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 an any two leads of a contiguous lead grouping (I, aVL, V6, V4-V6, II, III, aVF), imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

[0105] The term “percutaneous coronary intervention (PCI) related myocardial infarct” refers to PCI in patients with normal baseline troponin values elevations of cardiac biomarkers above the 99th percentile URL within 24 hours of the procedure are indicative of peri-procedural myocardial necrosis. By convention increases of biomarkers greater than 3 x 99th percentile URL are consistent with PCI related myocardial infarction. If the cardiac biomarker is elevated prior to PCI a > 20% increase of the value in that second cardiac biomarker within 24 hours of the PCI and documentation that cardiac biomarkers were decreasing (two samples at least 6 hours apart) prior to the suspected recurrent Ml is also consistent with PCI related Ml. Symptoms of cardiac ischemia are not required.

[0106] Criteria for Prior Myocardial Infarction: Any of the following criteria meets the diagnosis for prior myocardial infarction: development of new pathological Q waves with or without symptoms, imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract in the absence of a non-ischemic cause, pathological findings of a healed or healing myocardial infarction:

[0107] ECG changes associated with prior Myocardial Infarction:

[0108] • Any Q wave in leads V2-V3 > 0.02 seconds or QS complex in leads V2 and V3

[0109] • Q-wave > 0.03 seconds and > 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6, V4-V6, II, III, and aVF)

[0110] • R-wave > 0.04 seconds in V1-V2 and R / S > 1 with a concordant positive T- wave in the absence of a conduction defect

[0111] Criterion for Reinfarction: In patients where recurrent Ml is suspected from clinical signs or symptoms following the initial infarction, an immediate measurement of the employed cardiac biomarker is recommended. A second sample should be obtained 3-6 hours later. Recurrent infarction is diagnosed if there is a > 20% increase of the value in the second sample. This value should exceed the 99th percentile URL. However, if cardiac biomarkers are elevated prior to the suspected new Ml, there must also be documentation of decreasing values (two samples at least 6 hours apart) prior to the suspected new Ml. If the values are falling criteria for reinfarction by further measurement of biomarkers together with features of the ECG or imaging can be applied.

[0112] ECG diagnosis of reinfarction following the initial infarction: may be confounded by the initial evolutionary ECG changes. Reinfarction should be considered when the ST elevation > 0.1 mV reoccurs in an inpatient having a lesser degree of ST elevation or new pathognomonic Q-waves, in at least two contiguous leads, particularly when associated with ischemic symptoms for 10 minutes or longer. The re-evaluation of the ST segment can, however, also be seen in threatening myocardial rupture and should lead to additional diagnostic work-up. ST depression or LBBB on their own should not be considered valid criteria for Myocardial Infarction.

[0113] If biomarkers are increasing or peak is not reached, then there is insufficient data to diagnose recurrent Ml.

[0114] Clinical Classification of different types of Myocardial Infarction:

[0115] • Type 1 - Spontaneous Ml related to ischemia due to a primary coronary event such as plaque erosion and / or rupture, fissuring or dissection.

[0116] • Type 2 - Ml secondary to ischemia due to either increased oxygen demand or decreased supply, e.g., coronary artery spasm, anemia, hypotension, coronary embolism, arrhythmias, hypertension, or hypotension.

[0117] • Type 3 -Sudden unexpected cardiac death including cardiac arrest, often with symptoms suggestive of myocardial ischemia accompanied by presumably new ST elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by angiography and / or at autopsy, but death occurring before blood samples could be obtained or at a time before the appearance of cardiac biomarkers in the blood.

[0118] • Type 4a -Ml associated with PCI (Percutaneous Coronary Intervention).

[0119] • Type 4b -Ml associated with stent thrombosis as documented by autopsy or angiography.

[0120] • Type 5 -Ml associated with CABG (Coronary artery bypass grafting)

[0121] The term “silent Ml”: the following criteria will be used by the central ECG reading vendor to define interval “silent” (no clinical symptoms or signs) Ml between baseline and yearly ECGs (Surawicz B et al, Chou's electrocardiography in clinical practice: adult and pediatric. Philadelphia: Saunders; 2001): Myocardial infarctions are reported only on the basis of pathologic Q waves. Pathologic Q waves are defined as Q wave duration > 40ms and Q / R ratio = 1 / 3.

[0122] Any Q wave in V1 or V2 that is followed by an R wave should be considered abnormal.

[0123] When pathologic Q waves (i.e., myocardial infarction) are present, ST elevation or T wave inversion may be used to classify the infraction as New or Acute. However, ST elevation or T wave inversion in the absence of pathologic Q waves are not sufficient criteria for diagnosis of myocardial infarction.

[0124] • Anterolateral Ml - Pathologic Q waves in leads V3-V6.

[0125] • Anterior Ml - Pathologic Q waves in V3 and V4.

[0126] • Anteroseptal Ml - Pathologic Q waves or QS in leads V1-V4.

[0127] • Extensive Anterior Ml - Pathologic Q waves in leads I, aVL, and V1-V6.

[0128] • High lateral Ml - Pathologic Q waves in leads I and aVL.

[0129] • Inferior Ml - Pathologic Q waves or QS in at least two of the inferior leads: aVF, III, II.

[0130] • Lateral Ml - Pathologic Q waves in leads I, aVL, and V5-V6.

[0131] • Septal Ml - Pathologic Q waves or QS in leads V1-V2, (V3). In the presence of LAHB or LVH a Q or QS in V3 is required.

[0132] • Posterior Ml - Initial R wave duration 40 ms in V1 or V2, and R > S and upright T wave; Inferior or Lateral Ml are usually also present.

[0133] The term “new Ml” as used herein is based on criteria for Ml more stringent than the Expert Consensus Document criteria, requiring Q waves to be > 0.04 sec in duration and an R / S ratio > 1 / 3. These criteria (drawn from the cardiology literature) are designed to minimize the false positive detection of Mis due to very small physiologic Q waves in the inferior and anterolateral leads.

[0134] As used herein, the term “stroke” is defined as the rapid onset of a new persistent neurological deficit attributed to an obstruction in cerebral blood flow and / or cerebral hemorrhage with no apparent non-vascular cause (e.g. tumor, trauma, infection). Available neuroimaging studies will be considered to support the clinical impression and to determine if there is a demonstrable lesion compatible with an acute stroke. Non-fatal strokes will be classified as ischemic, hemorrhagic, or unknown.

[0135] As used herein, the term “unstable angina requiring unplanned revascularization” is defined as no elevation in cardiac biomarkers and clinical presentation (one of the following) with cardiac symptoms lasting >10 minutes and considered to be myocardial ischemia on final diagnosis (rest angina or new onset (<2 months) severe angina (CCS classification severity > III; Grading of Angina Pectoris According to Canadian Cardiovascular Society Classification) or increasing angina (in intensity, duration and / or frequency) and severe recurrent ischemia requiring urgent revascularization: as defined by an episode of angina prompting the performance of coronary revascularization on the index hospitalization or an episode of recurrent angina after discharge that resulted in rehospitalization during which coronary revascularization was performed; and at least one of the following: new or worsening ST or T segment changes on ECG, ST Elevation (new ST elevation at the J point in two anatomically contiguous leads with the cut-off points: > 0.2 mV in men (> 0.25 mV in men < 40 years) or > 0.15 mV in women in leads V2-V3 and / or > 0.1 mV in other leads), ST depression and T-wave Evidence of ischemia on stress testing with cardiac imaging, evidence of ischemia on stress testing without cardiac imaging but with angiographic evidence of > 70% lesion, and / or thrombus in the epicardial coronary artery or initiation / increased dosing of anti-anginal therapy, angiographic evidence of > 70% lesion and / or thrombus in an epicardial coronary artery.

[0136] As used herein, “coronary revascularization" is defined as an invasive procedure, which usually follows coronary angiography, wherein either percutaneous transluminal intervention, followed by Stent Placement, Balloon Angioplasty, or CABG is performed to relieve obstructed coronary arteries. A team of medical professionals lead by either an invasive cardiologist (percutaneous transluminal intervention, followed by stent placement, balloon angioplasty) or a thoracic surgeon (CABG), who performs the described procedures.

[0137] As used herein, the term ”non-coronary revascularization" is defined as vascular surgery or percutaneous intervention. Vascular surgery is defined as the placement of a conduit with or without proximal and / or distal anastamoses. Percutaneous intervention is defined as balloon inflation with or without stenting.

[0138] As used herein, the term “atherosclerosis” occurs when fatty material and a substance called plaque builds up on the walls of the arteries. This causes their lumen to get narrow.

[0139] The term “treat”, “treating”, “treatment”, “prevent”, “preventing” or “prevention” includes therapeutic treatments, prophylactic treatments and applications in which one reduces the risk that a subject will develop a disorder or other risk factor. Treatment does not require the complete curing of a disorder and encompasses the reduction of the symptoms or underlying risk factors.

[0140] The term “treating or preventing” includes the administration of a compound, e.g., the bispecific antibody targeting both IL-ip and IL-18, e.g., bbmAb, optionally in combination with at least one further therapeutic agent, to prevent or delay the onset of the symptoms, complications, or biochemical indicia of a disease, condition, disorder, or syndrome (e.g., for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations. Treatment may be prophylactic (to prevent or delay the onset of the disease, condition, disorder, or syndrome, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease, condition, disorder, or syndrome.

[0141] As used herein, the term “prevent”, “preventing”, or “prevention” in connection to a disease, condition, disorder, or syndrome also refers to prophylactic treatment of a subject who is at risk of developing a condition {e.g., risk of a cardiovascular events in a subject) resulting in a decrease in the probability that the subject will develop the condition.

[0142] Also “treating” may refer to slow the progress of, halt, or reverse disease, condition, disorder, or syndrome progression and improve clinical outcomes.

[0143] As used herein, the term “therapeutically effective amount” of the the bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, described herein refers to an amount of said antibody that will elicit the biological or medical response of a subject, for example, reducing the risk of or preventing cardiovascular events, ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, condition, disorder, or syndrome, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the bispecific antibody targeting both IL-1 p and IL-18, e.g., bbmAb, that, when administered to a subject, is effectively reducing the risk of or preventing cardiovascular events in a CHIP population.

[0144] As used herein, the term “recurrent CV event” is a repeated CV event taking place after the myocardial infarction and comprises non-fatal Ml, non-fatal stroke, cardiovascular (CV) death and hospitalization for unstable angina requiring unplanned revascularization.

[0145] Accordingly, in one embodiment of any method or use of the invention, said recurrent CV event is selected from non-fatal Ml, non-fatal stroke, cardiovascular (CV) death and hospitalization for unstable angina requiring unplanned revascularization.

[0146] In another embodiment of any method or use of the invention, said recurrent CV event is selected from non-fatal Ml, non-fatal stroke and cardiovascular (CV) death.

[0147] In yet another embodiment of any method or use of the invention, said recurrent CV event is non-fatal Ml or cardiovascular (CV) death.

[0148] In another embodiment of any method or use of the invention, said recurrent CV event is non-fatal Ml.

[0149] 2. IL-18 antibody

[0150] Particularly preferred IL-18 antibodies or antigen-binding fragments thereof used in the disclosed methods are human antibodies.

[0151] For ease of reference, the amino acid sequences of the hypervariable regions of a specific IL-18 antibody, called mAb1 , based on the Kabat definition and the Chothia definition, as well as the VL and VH domains and full heavy and light chains are provided in Table 1 , below.

[0152] Table 1. Amino acid sequences of the hypervariable regions (CDRs), variable domains (VH and VL) and full chains of mAb1. The DNA encoding the VL of mAb1 is set forth in SEQ ID NO:18. The DNA encoding the VH of mAb1 is set forth in SEQ ID NO:8.

[0153] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses comprises at least one immunoglobulin heavy chain variable domain (VH) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:1 , said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3. In one embodiment, the IL-18 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (VH) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:4, said CDR2 having the amino acid sequence SEQ ID NO:5, and said CDR3 having the amino acid sequence SEQ ID NO:6.

[0154] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses comprises at least one immunoglobulin light chain variable domain (VL) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:11 , said CDR2 having the amino acid sequence SEQ ID NO:12 and said CDR3 having the amino acid sequence SEQ ID NO:13. In one embodiment, the IL-18 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (VL) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:14, said CDR2 having the amino acid sequence SEQ ID NO:15 and said CDR3 having the amino acid sequence SEQ ID NO:16.

[0155] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses comprises at least one immunoglobulin VHdomain and at least one immunoglobulin VLdomain, wherein: a) the immunoglobulin VHdomain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:1 , said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:4, said CDR2 having the amino acid sequence SEQ ID NO:5, and said CDR3 having the amino acid sequence SEQ ID NO:6; and b) the immunoglobulin VL domain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:11 , said CDR2 having the amino acid sequence SEQ ID NO:12, and said CDR3 having the amino acid sequence SEQ ID NO:13 or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO: 14, said CDR2 having the amino acid sequence SEQ ID NO:15, and said CDR3 having the amino acid sequence SEQ ID NO:16.

[0156] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses comprises: a) an immunoglobulin heavy chain variable domain (VH) comprising the amino acid sequence set forth as SEQ ID NO:7; b) an immunoglobulin light chain variable domain ( L) comprising the amino acid sequence set forth as SEQ ID NO:17; c) an immunoglobulin VH domain comprising the amino acid sequence set forth as SEQ ID NO:7 and an immunoglobulin VL domain comprising the amino acid sequence set forth as SEQ ID NO:17; d) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:1 , SEQ ID NO:2, and SEQ ID NO:3; e) an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:11 , SEQ ID NO:12 and SEQ ID NO:13; f) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; g) an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16; h) an immunoglobulin H domain comprising the hypervariable regions set forth as SEQ ID NO:1 , SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulin VLdomain comprising the hypervariable regions set forth as SEQ ID NO:11 , SEQ ID NO:12 and SEQ ID NO:13; i) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16; j) a light chain comprising SEQ ID NO:19; k) a heavy chain comprising SEQ ID NO:9; or I) a light chain comprising SEQ ID NO:19 and a heavy chain comprising SEQ ID NO:9.

[0157] In some embodiments, the IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses comprises the three CDRs of SEQ ID NO:7 and the three CDRs of SEQ ID NO:17. In other embodiments, the IL-18 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:9 and the three CDRs of SEQ ID NO:19.

[0158] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof (e.g., mAb1) used in the disclosed methods or uses is selected from a human IL-18 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:1 , said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO:11 , said CDR2 having the amino acid sequence SEQ ID NO:12, and said CDR3 having the amino acid sequence SEQ ID NO:13.

[0159] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof (e.g., mAb1) used in the disclosed methods or uses is selected from a human IL-18 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:4, said CDR2 having the amino acid sequence SEQ ID NO:5 and said CDR3 having the amino acid sequence SEQ ID NO:6; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO: 14, said CDR2 having the amino acid sequence SEQ ID NO:15, and said CDR3 having the amino acid sequence SEQ ID NO:16.

[0160] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen-binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:1 , said CDR2 having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; and b) a second domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:11 , said CDR2 having the amino acid sequence SEQ ID NO: 12, and said CDR3 having the amino acid sequence SEQ ID NO: 13; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-terminal extremity of the first domain and to the N-terminal extremity of the second domain.

[0161] In one embodiment, the IL-18 antibody or antigen-binding fragment thereof (e.g., mAb1) used in the disclosed methods or uses is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen-binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:4, said CDR2 having the amino acid sequence SEQ ID NO:5, and said CDR3 having the amino acid sequence SEQ ID NO:6; and b) a second domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:14, said CDR2 having the amino acid sequence SEQ ID NO: 15, and said CDR3 having the amino acid sequence SEQ ID NO: 16; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-terminal extremity of the first domain and to the N-terminal extremity of the second domain.

[0162] The VH or VL domain of an IL-18 antibody or antigen-binding fragment thereof used in the disclosed methods or uses may have VH and / or L domains that are substantially identical to the VH or VL domains set forth in SEQ ID NO:7 and 17. A human IL-18 antibody disclosed herein for use in the disclosed methods or uses may comprise a heavy chain that is substantially identical to that set forth as SEQ ID NO:9 and / or a light chain that is substantially identical to that set forth as SEQ ID NO: 19. A human IL-18 antibody disclosed herein for use in the disclosed methods or uses may comprise a heavy chain that comprises SEQ ID NO:9 and a light chain that comprises SEQ ID NO:19. A human IL-18 antibody disclosed herein may comprise: a) one heavy chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:7 and the constant part of a human heavy chain; and b) one light chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 17 and the constant part of a human light chain.

[0163] Other preferred IL-18 antagonists (e.g., antibodies) for use in the disclosed methods, kits and regimens are those set forth in US Patent No: 9,376,489, which is incorporated by reference herein in its entirety. 3. I L-ip antibody

[0164] Particularly preferred IL-1 p antibodies or antigen-binding fragments thereof used in the disclosed methods are human antibodies.

[0165] For ease of reference, the amino acid sequences of the hypervariable regions of a specific IL-i p antibody, called mAb2, based on the Kabat definition and the Chothia definition, as well as the VL and VH domains and full heavy and light chains are provided in Table 2, below.

[0166] Table 2. Amino acid sequences of the hypervariable regions (CDRs), variable domains (VH and VL) and full chains of mAb2. The DNA encoding the VL of mAb2 is set forth in SEQ ID NO:38. The DNA encoding the VH of mAb2 is set forth in SEQ ID NO:27.

[0167] In one embodiment, the I L-1 p antibody or antigen-binding fragment thereof for use in the disclosed methods or uses comprises at least one immunoglobulin heavy chain variable domain (VH) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:21 , said CDR2 having the amino acid sequence SEQ ID NO:22, and said CDR3 having the amino acid sequence SEQ ID NO:23. In one embodiment, the IL-1 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (VH) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO:25, and said CDR3 having the amino acid sequence SEQ ID NO:26.

[0168] In one embodiment, the I L-1 p antibody or antigen-binding fragment thereof for use in the disclosed methods or uses comprises at least one immunoglobulin light chain variable domain (VL) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:31 , said CDR2 having the amino acid sequence SEQ ID NO:32 and said CDR3 having the amino acid sequence SEQ ID NO:33. In one embodiment, the IL-1 p antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain ( L) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:34, said CDR2 having the amino acid sequence SEQ ID NO:35 and said CDR3 having the amino acid sequence SEQ ID NO:36.

[0169] In one embodiment, the I L-1 p antibody or antigen-binding fragment thereof for use in the disclosed methods or uses comprises at least one immunoglobulin VHdomain and at least one immunoglobulin VLdomain, wherein: a) the immunoglobulin VHdomain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:21 , said CDR2 having the amino acid sequence SEQ ID NO:22, and said CDR3 having the amino acid sequence SEQ ID NO:23; or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO:25, and said CDR3 having the amino acid sequence SEQ ID NO:26; and b) the immunoglobulin VL domain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:31 , said CDR2 having the amino acid sequence SEQ ID NO:32, and said CDR3 having the amino acid sequence SEQ ID NO:33 or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:34, said CDR2 having the amino acid sequence SEQ ID NO:35, and said CDR3 having the amino acid sequence SEQ ID NO:36.

[0170] In one embodiment, the IL-ip antibody or antigen-binding fragment thereof for use in the disclosed methods or uses comprises: a) an immunoglobulin heavy chain variable domain (VH) comprising the amino acid sequence set forth as SEQ ID NO:27; b) an immunoglobulin light chain variable domain (VL) comprising the amino acid sequence set forth as SEQ ID NO:37; c) an immunoglobulin VH domain comprising the amino acid sequence set forth as SEQ ID NO:27 and an immunoglobulin VL domain comprising the amino acid sequence set forth as SEQ ID NO:37; d) an immunoglobulin H domain comprising the hypervariable regions set forth as SEQ ID NO:21 , SEQ ID NO:22, and SEQ ID NO:23; e) an immunoglobulin VLdomain comprising the hypervariable regions set forth as SEQ ID NO:31 , SEQ ID NO:32 and SEQ ID NO:33; f) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26; g) an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36; h) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:21 , SEQ ID NO:22, and SEQ ID NO:23 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:31 , SEQ ID NO:32 and SEQ ID NO:33; i) an immunoglobulin VH domain comprising the hypervariable regions set forth as SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26 and an immunoglobulin VL domain comprising the hypervariable regions set forth as SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36; j) a light chain comprising SEQ ID NO:37; k) a heavy chain comprising SEQ ID NO:29; or I) a light chain comprising SEQ ID NO:39 and a heavy chain comprising SEQ ID NO:29.

[0171] In some embodiments, the I L-1 antibody or antigen-binding fragment thereof (e.g., mAb2) for use in the disclosed methods or uses comprises the three CDRs of SEQ ID NO:37. In other embodiments, the I L-1 antibody or antigen-binding fragment thereof for use in the disclosed methods or uses comprises the three CDRs of SEQ ID NO:27. In other embodiments, the I L-1 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:37 and the three CDRs of SEQ ID NO:27. In some embodiments, the I L-1 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:39. In other embodiments, IL-i antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:29. In other embodiments, the IL-1 p antibody or antigen-binding fragment thereof for use in the disclosed methods or uses comprises the three CDRs of SEQ ID NO:39 and the three CDRs of SEQ ID NO:29.

[0172] In one embodiment, the IL-1 antibody or antigen-binding fragment thereof (e.g., mAb2) for use in the disclosed methods or uses is selected from a human IL-1 p antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:21 , said CDR2 having the amino acid sequence SEQ ID NO:22, and said CDR3 having the amino acid sequence SEQ ID NO:23; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO:31 , said CDR2 having the amino acid sequence SEQ ID NO:32, and said CDR3 having the amino acid sequence SEQ ID NO:33.

[0173] In one embodiment, the IL-1 p antibody or antigen-binding fragment thereof (e.g., mAb2) for use in the disclosed methods or uses is selected from a human IL-1 p antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO:25 and said CDR3 having the amino acid sequence SEQ ID NO:26; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO:34, said CDR2 having the amino acid sequence SEQ ID NO:35, and said CDR3 having the amino acid sequence SEQ ID NO:36.

[0174] In one embodiment, the IL-1 p antibody or antigen-binding fragment thereof for use in the disclosed methods or uses is selected from a single chain antibody or antigenbinding fragment thereof that comprises an antigen-binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:21 , said CDR2 having the amino acid sequence SEQ ID NO:22, and said CDR3 having the amino acid sequence SEQ ID NO:23; and b) a second domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:31 , said CDR2 having the amino acid sequence SEQ ID NO:32, and said CDR3 having the amino acid sequence SEQ ID NO:33; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-terminal extremity of the first domain and to the N-terminal extremity of the second domain.

[0175] In one embodiment, the IL-1 p antibody or antigen-binding fragment thereof (e.g., mAb2) for use in the disclosed methods or uses is selected from a single chain antibody or antigen-binding fragment thereof that comprises an antigen-binding site comprising: a) a first domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:24, said CDR2 having the amino acid sequence SEQ ID NO:25, and said CDR3 having the amino acid sequence SEQ ID NO:26; and b) a second domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:34, said CDR2 having the amino acid sequence SEQ ID NO:35, and said CDR3 having the amino acid sequence SEQ ID NO:36; and c) a peptide linker which is bound either to the N-terminal extremity of the first domain and to the C-terminal extremity of the second domain or to the C-terminal extremity of the first domain and to the N-terminal extremity of the second domain.

[0176] The VHor VLdomain of an IL-i antibody or antigen-binding fragment thereof used in the disclosed methods may have VHand / or VLdomains that are substantially identical to the VHor VLdomains set forth in SEQ ID NO:27 and 37. A human IL-1 antibody disclosed herein for use in the disclosed methods or uses may comprise a heavy chain that is substantially identical to that set forth as SEQ ID NO:29 and / or a light chain that is substantially identical to that set forth as SEQ ID NO:39. A human I L- 1 p antibody disclosed herein for use in the disclosed methods or uses may comprise a heavy chain that comprises SEQ ID NO:29 and a light chain that comprises SEQ ID NO:39. A human IL- 1 P antibody disclosed herein for use in the disclosed methods or uses may comprise: a) one heavy chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:27 and the constant part of a human heavy chain; and b) one light chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:37 and the constant part of a human light chain.

[0177] Other preferred IL-i p antagonists (e.g., antibodies) for use in the disclosed methods, kits and regimens are those set forth in US Patent Nos: 7,446,175 or 7,993,878 or 8,273,350, which are incorporated by reference herein in their entirety.

[0178] 4. Fc modifications

[0179] In addition, or alternative to modifications made within the framework or CDR regions, antibodies used in the methods of the invention may be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigendependent cellular cytotoxicity. Furthermore, an antibody used in the methods of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of residues in the Fc region is that of the Ell numbering scheme of Edelman et al., PNAS, 1969 May, 63(1):78-85.

[0180] In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Patent No. 5,677,425 by Bodmer et al. The number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.

[0181] In another embodiment, the Fc hinge region of an antibody used in the methods of the invention is mutated to decrease the biological half-life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcal protein A (SpA) binding relative to native Fc-hinge domain SpA binding. This approach is described in further detail in U.S. Patent No. 6,165,745 by Ward et al.

[0182] In another embodiment, the antibody used in the methods of the invention is modified to increase its biological half-life. Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Patent No. 6,277,375 to Ward. Alternatively, to increase the biological half life, the antibody used in the methods of the invention can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Patent Nos. 5,869,046 and 6,121 ,022 by Presta et al.

[0183] In yet other embodiments, the Fc region of the antibody used in the methods of the invention is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Patent Nos. 5,624,821 and 5,648,260, both by Winter et al.

[0184] In another embodiment, one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody used in the methods of the invention has altered C1q binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos. 6,194,551 by Idusogie et al.

[0185] In another embodiment, one or more amino acid residues are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94 / 29351 by Bodmer et al.

[0186] In yet another embodiment, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for an Fey receptor by modifying one or more amino acids. This approach is described further in PCT Publication WO 00 / 42072 by Presta. Moreover, the binding sites on human lgG1 for FcyRI, FcyRI I, FcyRI 11 and FcRn have been mapped and variants with improved binding have been described (see Shields, R.L. et al, (2001) J Biol Chem 276:6591-6604).

[0187] In certain embodiments, the Fc domain of lgG1 isotype is used. In some specific embodiments, a mutant variant of lgG1 Fc fragment is used, e.g., a silent lgG1 Fc which reduces or eliminates the ability of the fusion polypeptide to mediate antibody dependent cellular cytotoxicity (ADCC) and / or to bind to an Fey receptor. An example of an lgG1 isotype silent mutant wherein Leucine residue is replaced by Alanine residue at amino acid positions 234 and 235 as described by Hezareh et al, J. Virol (2001); 75(24):12161-8.

[0188] In certain embodiments, the Fc domain of the antibody used in the methods of the invention comprises a mutant preventing glycosylation at position 297 of Fc domain. For example, the Fc domain contains an amino acid substitution of asparagine residue at position 297. Example of such amino acid substitution is the replacement of N297 by a glycine or an alanine.

[0189] Silenced effector functions can be obtained by mutation in the Fc region of the antibodies used in the methods of the invention and have been described in the art: LALA and N297A (Strohl, W., 2009, Curr. Opin. Biotechnol. vol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol. 181 :6664-69; Strohl, W., supra); and DAPA (D265A and P329A) (Shields RL., J Biol Chem. 2001 ;276(9):6591 -604; U.S. Patent Publication US2015 / 0320880). Examples of silent Fc lgG1 antibodies comprise the so-called LALA mutant comprising L234A and L235A mutation in the lgG1 Fc amino acid sequence. Another example of a silent lgG1 antibody comprises the D265A mutation. Another example of a silent lgG1 antibody is the so-called DAPA mutant, comprising D265A and P329A mutations to the lgG1 Fc amino acid sequence. Another silent lgG1 antibody comprises the N297A mutation, which results in aglycosylated / non-glycosylated antibodies. Additional Fc mutations for providing silenced effector function are described in PCT publication no. WO2014 / 145806 (e.g., in Figure 7 of WO2014 / 145806), herein incorporated by reference in its entirety. One example from WO2014 / 145806 of a silent I gG 1 antibody comprises a E233P, L234V, L235A, and S267K mutation, and a deletion of G236 (G236del). Another example from WO2014 / 145806 of a silent lgG1 antibody comprises a E233P, L234V, and L235A mutation, and a deletion of G236 (G236del). Another example from WO2014 / 145806 of a silent lgG1 antibody comprises a S267K mutation.

[0190] In still another embodiment, the glycosylation of an antibody used in the methods of the invention is modified. For example, an aglycosylated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for the antigen. Such carbohydrate modifications can be accomplished by; for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Patent Nos. 5,714,350 and 6,350,861 by Co et al.

[0191] Additionally or alternatively, an antibody to be used in the methods of the invention can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GIcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. For example, EP 1 ,176,195 by Hang et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. Therefore, in one embodiment, the antibodies used in the methods of the invention are produced by recombinant expression in a cell line which exhibit hypofucosylation pattern, for example, a mammalian cell line with deficient expression of the FUT8 gene encoding fucosyltransferase. PCT Publication WO 03 / 035835 by Presta describes a variant CHO cell line, Lecl3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R.L. et al., 2002 J. Biol. Chem. 277:26733-26740). PCT Publication WO 99 / 54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta(1 ,4)-N acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GIcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al., 1999 Nat. Biotech. 17:176-180). Alternatively, the antibodies used in the methods of the invention can be produced in a yeast or a filamentous fungi engineered for mammalian-like glycosylation pattern, and capable of producing antibodies lacking fucose as glycosylation pattern (see for example EP1297172B1).

[0192] Another modification of the antibodies used in the methods of the invention that is contemplated by the invention is one or more modifications to increase formation of a heterodimeric bispecific antibody. A variety of approaches available in the art can be used in for enhancing dimerization of the two heavy chain domains of bispecific antibodies, e.g., bbmAb, as disclosed in, for example, EP 1870459A1 ; U.S. Pat. No. 5,582,996; U.S. Pat. No. 5,731 ,168; U.S. Pat. No. 5,910,573; U.S. Pat. No. 5,932,448; U.S. Pat. No. 6,833,441 ; U.S. Pat. No. 7,183,076; U.S. Patent Application Publication No. 2006204493A1 ; and PCT Publication No. W02009 / 089004A1 , the contents of which are incorporated herein in their entireties.

[0193] Generation of bispecific antibodies using knobs-into-holes is disclosed e.g., in PCT Publication No. W01996 / 027011 , Ridgway et al., (1996), and Merchant et al. (1998).

[0194] In practicing some of the methods of treatment or uses of the present disclosure, a therapeutically effective amount of a bispecific antibodies targeting both IL-1 p and IL-18 simultaneously, e.g., bbmAb, has to be administered to a subject in need thereof.

[0195] Example 1 :

[0196] The generation of bbmAb has been described in detail in the examples 1 to 5 of the patent application WO / 2018 / 229612. The examples 1 of WO / 2018 / 229612, comprising (1) vector construction, (2) Host cell line and transfection, (3) Cell selection and sorting, (4) Cell expansion, (5) Clone stability, (6) Manufacturing, (7) Analytical characterization and purity assessment, (8) Analytical Results are herewith incorporated by reference in their entirety.

[0197] The bbmAb, is a bispecific lgG1 , with LALA silencing mutations, simultaneously binding to two distinct targets, IL-1 p and IL-18. The antibody combines two distinct antigen binding arms (Fab fragments), whereas the Fab directed against IL-1 p is based on mAb2 and contains a kappa light chain (Vk6). The Fab directed against IL-18 is based on mAb1 and is composed of a lambda light chain (VA1). In order to drive hetero-dimerization of the Fc domain during expression a “knob” with a bulky amino acid (aa) side chain (S354C and T366W) in the mAb1 heavy chain and a “hole” with small aa side chains (Y349C, T366S, L368A, Y407V) were introduced in the mAb2 heavy chain. For ease of reference, the amino acid sequences of the hypervariable regions of bbmAb, based on the Kabat definition and the Chothia definition, as well as the VL and VH domains and full heavy and light chains are provided in Table 3, below.

[0198] Table 3. Amino acid sequences of the hypervariable regions (CDRs), variable domains (VH and VL) and full chains of bbmAb. The DNA encoding the first VL of is set forth in SEQ ID NO: 102 and the DNA encoding the second VL is set forth in SEQ ID NO: 70. The DNA encoding the first VH is set forth in SEQ ID NO:86 and the DNA encoding the second VH is set forth in SEQ ID NO: 54.

[0199] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in

[0200] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0201] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0202] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or

[0203] (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin heavy chain variable domain (VHI) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77, and said CDR3 having the amino acid sequence SEQ ID NO:78.

[0204] In one embodiment, the I L-18 / IL-1 bispecific antibody for use in

[0205] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0206] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0207] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin heavy chain variable domain (VHI) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:79, said CDR2 having the amino acid sequence SEQ ID NQ:80, and said CDR3 having the amino acid sequence SEQ ID NO:81.

[0208] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use

[0209] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0210] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin heavy chain variable domain (VHI) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:82, said CDR2 having the amino acid sequence SEQ ID NO:83, and said CDR3 having the amino acid sequence SEQ ID NO:84.

[0211] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in

[0212] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0213] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0214] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin heavy chain variable domain (VH2) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45, and said CDR3 having the amino acid sequence SEQ ID NO:46.

[0215] In one embodiment, the I L-18 / IL-1 bispecific antibody for use in

[0216] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0217] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0218] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin heavy chain variable domain (VH2) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:47, said CDR2 having the amino acid sequence SEQ ID NO:48, and said CDR3 having the amino acid sequence SEQ ID NO:49.

[0219] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in

[0220] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0221] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0222] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin heavy chain variable domain (VH2) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NQ:50, said CDR2 having the amino acid sequence SEQ ID NO:51 , and said CDR3 having the amino acid sequence SEQ ID NO:52.

[0223] In one embodiment, the I L-18 / IL-1 bispecific antibody for use in

[0224] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0225] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0226] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin light chain variable domain (VLI ) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93 and said CDR3 having the amino acid sequence SEQ ID NO:94. In one embodiment, the I L-18 / I L-1 p bispecific antibody for use in

[0227] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0228] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin light chain variable domain (Vi_i ) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:95, said CDR2 having the amino acid sequence SEQ ID NO:96 and said CDR3 having the amino acid sequence SEQ ID NO:97. In one embodiment, the I L-18 / I L-1 p bispecific antibody for use in

[0229] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0230] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0231] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin light chain variable domain (VLi) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:98, said CDR2 having the amino acid sequence SEQ ID NO:99 and said CDR3 having the amino acid sequence SEQ ID NQ:100.

[0232] In one embodiment, the I L-18 / IL-1 bispecific antibody for use in

[0233] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0234] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0235] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin light chain variable domain (VL2) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61 and said CDR3 having the amino acid sequence SEQ ID NO:62.

[0236] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0237] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0238] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin light chain variable domain (VL2) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:63, said CDR2 having the amino acid sequence SEQ ID NO:64 and said CDR3 having the amino acid sequence SEQ ID NO:65. In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in

[0239] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0240] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0241] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin light chain variable domain (VL2) comprising hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:66, said CDR2 having the amino acid sequence SEQ ID NO:67 and said CDR3 having the amino acid sequence SEQ ID NO:68.

[0242] In one embodiment, the I L-18 / I L-1 bispecific antibody for use in

[0243] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0244] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0245] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a first immunoglobulin VHI domain and a first immunoglobulin VLI domain, wherein: a) the first immunoglobulin VHI domain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77, and said CDR3 having the amino acid sequence SEQ ID NO:78; or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:79, said CDR2 having the amino acid sequence SEQ ID NQ:80, and said CDR3 having the amino acid sequence SEQ ID NO:81 ; or iii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:82, said CDR2 having the amino acid sequence SEQ ID NO:83, and said CDR3 having the amino acid sequence SEQ ID NO:84 and b) the first immunoglobulin VLidomain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93, and said CDR3 having the amino acid sequence SEQ ID NO:94 or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:95, said CDR2 having the amino acid sequence SEQ ID NO:96, and said CDR3 having the amino acid sequence SEQ ID NO:97 or iii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:98, said CDR2 having the amino acid sequence SEQ ID NO:99, and said CDR3 having the amino acid sequence SEQ ID NQ:100.

[0246] In one embodiment, the I L-18 / I L-1 p bispecific antibody for use in

[0247] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0248] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0249] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises a second immunoglobulin VH2 domain and a second immunoglobulin VL2 domain, wherein: a) the second immunoglobulin VH2 domain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45, and said CDR3 having the amino acid sequence SEQ ID NO:46; or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:47, said CDR2 having the amino acid sequence SEQ ID NO:48, and said CDR3 having the amino acid sequence SEQ ID NO:49; or iii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:50, said CDR2 having the amino acid sequence SEQ ID NO:51 , and said CDR3 having the amino acid sequence SEQ ID NO:52 and b) the second immunoglobulin VL2 domain comprises (e.g., in sequence): i) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61 , and said CDR3 having the amino acid sequence SEQ ID NO:62 or ii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:63, said CDR2 having the amino acid sequence SEQ ID NO:64, and said CDR3 having the amino acid sequence SEQ ID NO:65 or iii) hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:66, said CDR2 having the amino acid sequence SEQ ID NO:67, and said CDR3 having the amino acid sequence SEQ ID NO:68.

[0250] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in

[0251] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0252] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0253] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises: a) a first immunoglobulin heavy chain variable domain (VH1) comprising the amino acid sequence set forth as SEQ ID NO:85; b) a first immunoglobulin light chain variable domain (Vi_i) comprising the amino acid sequence set forth as SEQ ID NQ:101 ; c) a first immunoglobulin VHI domain comprising the amino acid sequence set forth as SEQ ID NO:85 and a first immunoglobulin VLI domain comprising the amino acid sequence set forth as SEQ ID NO: 101 ; d) a first immunoglobulin VHI domain comprising the hypervariable regions set forth as SEQ ID NO:76, SEQ ID NO:77, and SEQ ID NO:78; e) a first immunoglobulin VLI domain comprising the hypervariable regions set forth as SEQ ID NO:92, SEQ ID NO:93 and SEQ ID NO:94; f) a first immunoglobulin VHI domain comprising the hypervariable regions set forth as SEQ ID NO:79, SEQ ID NQ:80 and SEQ ID NO:81 ; g) a first immunoglobulin VLI domain comprising the hypervariable regions set forth as SEQ ID NO:95, SEQ ID NO:96 and SEQ ID NO:97; h) a first immunoglobulin VHI domain comprising the hypervariable regions set forth as SEQ ID NO:76, SEQ ID NO:77, and SEQ ID NO:78 and a first immunoglobulin VLI domain comprising the hypervariable regions set forth as SEQ ID NO:92, SEQ ID NO:93 and SEQ ID NO:94; i) a first immunoglobulin VHI domain comprising the hypervariable regions set forth as SEQ ID NO:79, SEQ ID NQ:80, and SEQ ID NO:81 and a first immunoglobulin VLI domain comprising the hypervariable regions set forth as SEQ ID NO:95, SEQ ID NO:96 and SEQ ID NO:97; j) a first light chain comprising SEQ ID NQ:103; k) a first heavy chain comprising SEQ ID NO:87; or I) a first light chain comprising SEQ ID NQ:103 and a first heavy chain comprising SEQ ID NO:87.

[0254] In one embodiment, the I L-18 / IL-1 p bispecific antibody for use in

[0255] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0256] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0257] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises: a) a second immunoglobulin heavy chain variable domain (VH2) comprising the amino acid sequence set forth as SEQ ID NO:53; b) a second immunoglobulin light chain variable domain (V1.2) comprising the amino acid sequence set forth as SEQ ID NO:69; c) a second immunoglobulin VH2 domain comprising the amino acid sequence set forth as SEQ ID NO:53 and a second immunoglobulin VL2 domain comprising the amino acid sequence set forth as SEQ ID NO:69; d) a second immunoglobulin VH2 domain comprising the hypervariable regions set forth as SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46; e) a second immunoglobulin VL2 domain comprising the hypervariable regions set forth as SEQ ID NQ:60, SEQ ID NO:61 and SEQ ID NO:62; f) a second immunoglobulin VH2 domain comprising the hypervariable regions set forth as SEQ ID NO:47, SEQ ID NO:48 and SEQ ID NO:49; g) a second immunoglobulin VL2 domain comprising the hypervariable regions set forth as SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65; h) a second immunoglobulin VH2 domain comprising the hypervariable regions set forth as SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46 and a second immunoglobulin VL2 domain comprising the hypervariable regions set forth as SEQ ID NQ:60, SEQ ID NO:61 and SEQ ID NO:62; i) a second immunoglobulin VH2 domain comprising the hypervariable regions set forth as SEQ ID NO:47, SEQ ID NO:48, and SEQ ID NO:49 and a second immunoglobulin VL2 domain comprising the hypervariable regions set forth as SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65; j) a second light chain comprising SEQ ID NO:81 ; k) a second heavy chain comprising SEQ ID NO:55; or I) a second light chain comprising SEQ ID NO:81 and a second heavy chain comprising SEQ ID NO:55.

[0258] In some embodiments, the I L-18 / I L-1 p bispecific antibody for use in

[0259] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0260] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0261] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:69.

[0262] In other embodiments, the I L-18 / I L-1 bispecific antibody for use

[0263] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0264] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0265] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:53 and the three CDRs of SEQ ID NO:69. In some embodiments, the I L-18 / I L-1 p bispecific antibody for use in

[0266] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0267] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0268] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:85.

[0269] In other embodiments, the I L-18 / I L-1 p bispecific antibody for use in (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0270] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0271] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO: 101. In other embodiments, the I L-18 / IL-1 p bispecific antibody for use in

[0272] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0273] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0274] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:85 and the three CDRs of SEQ ID NQ:101.

[0275] In some embodiments, the I L-18 / I L-1 bispecific antibody for use

[0276] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0277] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0278] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:85.

[0279] In other embodiments, the I L-18 / I L-1 p bispecific antibody for use in

[0280] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0281] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO: 101. In other embodiments, the I L-18 / IL-1 p bispecific antibody for use in

[0282] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0283] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0284] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:85 and the three CDRs of SEQ ID NQ:101. In some embodiments, the I L-18 / IL-1 bispecific antibody for use in

[0285] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0286] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0287] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:53. In other embodiments, the I L-18 / IL-1 p bispecific antibody for use in

[0288] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0289] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:69. In other embodiments, the I L-18 / IL-1 p bispecific antibody for use in

[0290] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0291] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0292] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:53 and the three CDRs of SEQ ID NO:69. In an embodiment, the L-18 / IL-1 bispecific antibody for use in (

[0293] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0294] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0295] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, comprises the three CDRs of SEQ ID NO:85, the three CDRs of SEQ ID NQ:101 , the three CDRs of SEQ ID NO:53 and the three CDRs of SEQ ID NO:69.

[0296] In one embodiment, the first part of the IL-18 / IL-1 p bispecific antibody for use in

[0297] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0298] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0299] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, is selected from a human IL-18 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77, and said CDR3 having the amino acid sequence SEQ ID NO:78; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93, and said CDR3 having the amino acid sequence SEQ ID NO:94. Furthermore the second part of the IL-18 / IL-1 p bispecific antibody is selected from a human IL-1 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45, and said CDR3 having the amino acid sequence SEQ ID NO:46; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61 , and said CDR3 having the amino acid sequence SEQ ID NO:62.

[0300] In one embodiment, the first part of the IL-18 / IL-1 p bispecific antibody for use in

[0301] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0302] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0303] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, is selected from a human IL-18 antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77 and said CDR3 having the amino acid sequence SEQ ID NO:78; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93, and said CDR3 having the amino acid sequence SEQ ID NO:94. Furthermore, the second part of the IL- 18 / IL-ip bispecific antibody is selected from a human IL-1 p antibody that comprises at least: a) an immunoglobulin heavy chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2 and CDR3 and the constant part or fragment thereof of a human heavy chain; said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45 and said CDR3 having the amino acid sequence SEQ ID NO:46; and b) an immunoglobulin light chain or fragment thereof which comprises a variable domain comprising, in sequence, the hypervariable regions CDR1 , CDR2, and CDR3 and the constant part or fragment thereof of a human light chain, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61 , and said CDR3 having the amino acid sequence SEQ ID NO:62.

[0304] The first VHior VLidomain of an IL-18 / IL-1 p bispecific antibody used in the disclosed methods may have a first VHI and / or first VLI domains that are substantially identical to the VH or VL domains set forth in SEQ ID NO:85 and 101. An IL-18 / IL-1P bispecific antibody for use in

[0305] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0306] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0307] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, as disclosed herein, may comprise a first heavy chain that is substantially identical to that set forth as SEQ ID NO:87 and / or a first light chain that is substantially identical to that set forth as SEQ ID NO: 103.

[0308] An I L-18 / I L-1 p bispecific antibody for use in

[0309] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0310] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, as disclosed herein, may comprise a first heavy chain that comprises SEQ ID NO:87 and a first light chain that comprises SEQ ID NO: 103. An IL- 18 / 1 L-ip bispecific antibody for use in

[0311] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0312] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0313] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, as disclosed herein, may comprise: a) a first heavy chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:85 and the constant part of a human heavy chain having a hetero-dimerization modification; and b) a first light chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 101 and the constant part of a human light chain. The constant part of the human heavy chain may be lgG1. In one embodiment, the lgG1 is a human lgG1 without effector mutations. In one embodiment, the human heavy chain IgG 1 comprising a silencing mutation N297A, D265A or a combination of L234A and L235A. In one specific embodiment, the human heavy chain I gG 1 comprises the silencing mutation, which is a combination of L234A and L235A, according to SEQ ID NO:87.

[0314] The second VH2 or VL2 domain of an IL-18 / IL-1 p bispecific antibody used in the disclosed methods may have a second VH2 and / or first VL2 domains that are substantially identical to the VH or VL domains set forth in SEQ ID NO:53 and 69. An IL-18 / IL-1 bispecific antibody for use in

[0315] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0316] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, as disclosed herein, may comprise a second heavy chain that is substantially identical to that set forth as SEQ ID NO:55 and / or a second light chain that is substantially identical to that set forth as SEQ ID NO:71. An I L-18 / I L-113 bispecific antibody for use in

[0317] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0318] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0319] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, as disclosed herein, may comprise a second heavy chain that comprises SEQ ID NO:53 and a second light chain that comprises SEQ ID NO:69. An IL- 18 / 1 L-1 p bispecific antibody for use in

[0320] (i) reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0321] (ii) for use in the disclosed methods for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations or

[0322] (iii) for the manufacture of a medicament for reducing the risk of or preventing CVEs or CVDs, in a subject known to be a carrier of clonal expansion of hematopoietic cell lines or (iv) the pharmaceutical composition for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines, as disclosed herein, may comprise: a) a second heavy chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:53 and the constant part of a human heavy chain having a hetero-dimerization modification, which is complementary to the hetero-dimerization of the first heavy chain; and b) a second light chain, comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO:69 and the constant part of a human light chain. The constant part of the human heavy chain may be lgG1. In one embodiment, the lgG1 is a human lgG1 without effector mutations. In one embodiment, the human heavy chain I gG 1 comprising a silencing mutation N297A, D265A or a combination of L234A and L235A. In one specific embodiment, the human heavy chain I gG 1 comprises the silencing mutation, which is a combination of L234A and L235A, according to SEQ ID NO:55.

[0323] Other preferred IL-18 antagonists (e.g., antibodies) for use as the first part of a bispecific antibody in the disclosed methods, kits and regimens are those set forth in US Patent No: 9,376,489, which is incorporated by reference herein in its entirety.

[0324] Other preferred I L- 1 p antagonists (e.g., antibodies) for use as the second part of a bispecific in the disclosed methods are those set forth in US Patent Nos: 7,446,175 or 7,993,878 or 8,273,350, which are incorporated by reference herein in their entirety.

[0325] In vitro activity information of the bbmAb is disclosed in the PCT publications WO2018 / 229612A1 , examples 6 and 7, pages 64-82, which are herein incorporated by reference.

[0326] Example 2: Therapeutic use

[0327] A randomized, placebo-controlled, parallel-group, investigator- and participant-blinded clinical study to investigate efficacy, safety and tolerability of bbmAb in an adult population with coronary heart disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP).

[0328] 2.1 Protocol summary

[0329] Cardiovascular diseases (CVD) remain the leading cause of disease burden in the world. Persistent inflammation is common in populations at increased risk of CVD events and medications that reduce inflammation have been linked to improved CVD outcomes. Inhibition of I L-1 p and IL-18 by direct neutralization with a bispecific monoclonal antibody (bbmAb), may safely and effectively lower the risk of CVD among people with known heart disease and TET2 or DNMT3A CHIP (VAF >2%). This clinical trial will evaluate the effectiveness and safety of a single s.c. dose of bbmAb, to reduce key markers of inflammation related to CVD risk, such as IL-6 and IL-18, in approximately 28 people with known heart disease and TET2 or DNMT3A CHIP (VAF >2%). 2.2 T reatment of interest related Objectives and endpoints

[0330] The treatment of interest is a single s.c. dose of bbmAb (600 mg), or placebo.

[0331] Table 4 Objectives and related endpoints

[0332] Objective(s) Endpoint(s)

[0333] Primary objective(s) Endpoint(s) for primary objective(s)

[0334] • To evaluate the effect of bbmAb versus • Serum level of IL-6 at 3 weeks placebo to reduce circulating levels of after a single s.c. dose of bbmAb inflammatory markers in participants with coronary heart disease and CHIP

[0335] Secondary objective(s) Endpoint(s) for secondary objective(s)

[0336] • To evaluate the safety and tolerability of • Adverse events, and parameters bbmAb in participants with coronary heart from safety assessments, disease and CHIP including vital signs, electrocardiograms, and laboratory assessments (urine and blood)

[0337] • To assess the pharmacokinetics of • Serum concentrations of bbmAb bbmAb in participants with coronary heart after a single s.c. dose of bbmAb disease and CHIP

[0338] 2.2 Primary estimands The primary analysis for bbmAb will assess the effect on the change in IL-6 compared to placebo after 3 weeks of treatment.

[0339] The primary clinical question of interest is: What is the effect of bbmAb in addition to SoC CVD prevention medication in patients with known coronary heart disease and presence of CHIP on the inflammatory markers IL-6 and IL-18. The estimand will capture the effect of the investigational treatments versus placebo under research-like conditions.

[0340] The estimand is defined by the following attributes:

[0341] 1. Population: participants with known coronary heart disease and TET2 or DNMT3A CHIP (VAF >2%) and potential SoC CVD prevention medication

[0342] 2. Endpoints: Serum levels of IL-6 at week 3 after the start of a dosing period for bbmAb.

[0343] 3. Treatment of interest: bbmAb or placebo single dose.

[0344] 2.3 Study design

[0345] This is a multi-center, randomized, placebo-controlled, participant- and investigator-blinded study to evaluate the efficacy, safety, and tolerability a single s.c. dose of bbmAb for inflammatory marker reduction in participants with coronary heart disease and TET2 or DNMT3A CHIP (VAF >2%).

[0346] Participants will be randomized into the trial, of which a minimum of approximately 40% of randomized participants will be CHIP with TET2 somatic mutations. For subgroup allocation, patients with TET2 or DNMT3A CHIP will be determined based on their most common mutation (e.g., patients with mutations in both DNMT3A + TET2 will be allocated to the subgroup based on the mutation with the highest variant allele frequency (VAF).

[0347] Participants meeting all eligibility criteria will be randomized (1 bbmAb+placebo sequence).

[0348] On Day 1, participants will receive the single s.c. dose of either bbmAb or placebo. After initial dosing, assessments will be conducted at site, as specified in Section 1.3, the Schedule of Activities (SoA).

[0349] Table 5 Rationale for study design

[0350] Study Design Aspect Rationale

[0351] Overall In this study, participants will be randomized to a single s.c. dose of bbmAb, and / or placebo. Primary Endpoints For bbmAb, the only primary endpoint is IL-6 levels measured 3 weeks after a single s.c. dose.

[0352] Analysis of primary The IL-6 response to bbmAb will be measured at approximately endpoints 3 week intervals during the approximately 12 week treatment period after only a single dose level. The level of IL-6 obtained 3 weeks after the single dose of 600mg bbmAb s.c. will be used for the primary endpoint, as the peak observed reduction of IL-6 (when measured q3 weeks over the 12 week treatment period) is expected to occur at that point.

[0353] Treatment Sequences Treatment Sequence 1 contributes data for a single dose of active bbmAb.

[0354] Duration of study bbmAb will result in the simultaneous reduction of both IL-1 p and periods IL-18 levels in serum and effective neutralization of I L-1 as well as IL-18 with reductions captured at each 3 week assessment in the 12 week treatment period. The follow-up period up to Day 114 allows for adequate safety monitoring over a period of approximately 5 half-lives.

[0355] Placebo comparator The use of placebo provides a comparison group for an unbiased collection and assessment of safety, tolerability, efficacy, and PD parameters. The study design includes both inter- and intra-individual placebo comparators.

[0356] Rationale for choice of control drugs (comparator / placebo) or combination drugs

[0357] Placebo treatment will be used as a comparator to provide objective control for the evaluation of efficacy, safety, and tolerability during the treatment with bbmAb. For bbmAb, matching placebo in individual 6 mL glass vials each containing 0 mg / 1 mL as a liquid solution will be provided, and will be indistinguishable in appearance.

[0358] 2.4 Study population

[0359] The study population is adults with known coronary heart disease and CHIP with somatic mutations in TET2 or DNMT3A (VAF >2%). Key Inclusion criteria

[0360] • Male and female participants aged between 18 - 80 years (inclusive) at the start of screening will be included.

[0361] • Participants must have a body mass index (BMI) within the range of 18 - 40 kg / m2. BMI = Body weight (kg) / [Height (m)]2 at screening. • Documented spontaneous myocardial infarction (Ml) (diagnosed according to the universal Ml criteria with or without evidence of ST segment elevation) at least 30 days before the start of screening (Thygesen et al 2007).

[0362] • Known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of two genes, TET2 or DNMT3A, with VAF >2%.

[0363] • For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, participants must be on a stable regimen (at least 4 weeks before randomization), with no planned statin dose changes over the course of the trial treatment period. Unplanned statin dose changes during the trial treatment period may occur.

[0364] Key Exclusion criteria

[0365] • Patients receiving concomitant medications that are known to be strong or moderate inducers of cytochrome CYP2C9 enzyme and / or strong inducers of CYP3A, strong inhibitors of CYP2C9 and / or strong or moderate inhibitors of CYP3A and the treatment cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to Day 1 and for the duration of the study.

[0366] • At screening, pre-malignant clonal cytopenias or clonal cytopenia of unknown significance (CCUS).

[0367] • History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the Investigator, at the start of screening.

[0368] • Patients with suspected or proven immunocompromised state at screening.

[0369] • Use of any biologic drugs targeting the immune system within 26 weeks of Day 1.

[0370] • Major non-cardiac surgical or major endoscopic procedures within the past 6 months prior to the start of screening.

[0371] • Multi-vessel coronary artery bypass graft (CABG) surgery within the past 3 years prior to the start of screening.

[0372] • Planned coronary revascularization (percutaneous coronary intervention (PCI) or CABG) or any other major surgical procedure during the study (until End of Study (EOS)).

[0373] • Symptomatic Class IV heart failure (New York Heart Association [NYHA]) at the start of screening.

[0374] • Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for at least 3 months prior to first drug administration (Day 1), during dosing and for 5 months after Day 1 .

[0375] Inclusion criteria

[0376] Participants eligible for inclusion in this study must meet all of the following criteria:

[0377] 1 . Written informed consent must be obtained before any assessment is performed. 2. Male and female participants aged between 18 - 80 years (inclusive) at the start of screening will be included.

[0378] 3. Subjects must have a body mass index (BMI) within the range of 18 - 40 kg / m2. BMI = Body weight (kg) I [Height (m)]2 at screening.

[0379] 4. Documented spontaneous Ml (diagnosed according to the universal Ml criteria with or without evidence of ST segment elevation) at least 30 days before the start of screening (Thygesen K, Alpert JS, White HD et al (2007) Universal Definition of Myocardial Infarction. Circulation; 116:2634-53.).

[0380] Diagnosis of the qualifying Ml should be based on medical history of clinical symptoms consistent with myocardial ischemia associated with elevation of cardiac biomarkers above the 99th percentile of the upper reference limit (preferably troponin) OR development of new pathological Q waves regardless of symptoms (for details, refer to the Universal Definition of Ml (Thygesen et al 2007)).

[0381] Documentation in the medical history to support evidence of prior Ml may include:

[0382] • Evidence of an acute Ml in hospitalization or medical records:

[0383] • requires documentation of a rise and / or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit or above criteria diagnostic for Ml and

[0384] • Evidence of myocardial ischemia as demonstrated by at least one of the following:

[0385] • Symptoms of ischemia

[0386] • ECG changes indicative of new ischemia (new ST-T changes or new Left bundle branch block (LBBB))

[0387] • Development of pathologic Q waves

[0388] • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

[0389] If no documented evidence of an acute Ml in the medical record, then evidence of a prior Ml may include:

[0390] • Development of pathological Q waves with or without symptoms

[0391] • Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract in the absence of a non-ischemic cause

[0392] • Pathologic findings of a healed or healing Ml

[0393] 5. Known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of two genes, TET2 or DNMT3A, with VAF >2%.

[0394] Participants may have a second or additional mutation in a different CHIP driver gene (e.g., DNMT3A + JAK2); however, the most common mutation (highest VAF) must be in either TET2 or DNMT3A. Patients may have more than one different CHIP-driver mutation in the same gene (e.g., two unique known CHIP mutations in TET2) but at least one unique mutation must be present at VAF >2%.

[0395] 6. For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, participants must be on a stable regimen (at least 4 weeks before randomization), with no planned statin dose changes over the course of the trial treatment period. Unplanned statin dose changes during the trial treatment period may occur but must be documented as described in Section 6.2.2.

[0396] 7. Able to communicate well with the investigator, to understand and comply with the requirements of the study.

[0397] Exclusion criteria

[0398] Participants meeting any of the following criteria are not eligible for inclusion in this study.

[0399] 1 . Patients receiving concomitant medications that are known to be:

[0400] • strong or moderate inducers of CYP2C9 enzyme, or

[0401] • strong inducers of CYP3A, or

[0402] • strong inhibitors of CYP2C9, or

[0403] • strong or moderate inhibitors of CYP3A

[0404] • and the treatment cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to Day 1 and for the duration of the study.

[0405] 2. Use of other investigational drugs within 5 half-lives of Day 1 , or until the expected PD effect has returned to baseline, whichever is longer.

[0406] 3. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes.

[0407] 4. History of drug abuse or unhealthy alcohol use within the 12 months prior to the start of screening, per Investigator judgement.

[0408] Unhealthy alcohol use may be considered with a history of, or current, alcohol misuse / abuse or “Five or more drinks on the same occasion on each of 5 or more days in the past 30 days." However unhealthy alcohol use may be considered at lower level per investigator judgement based on participant's history.

[0409] 5. Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder, depression or anxiety, which may jeopardize patient safety or compliance with study procedures, as judged by the Investigator.

[0410] 6. WOCBP, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for at least 3 months prior to first drug administration (Day 1), during dosing and for 5 months after the single s.c. dose administration of bbmAb or placebo dose. Highly effective contraception methods include:

[0411] • Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

[0412] • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

[0413] • Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.

[0414] • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an IUD or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should be stable on the same pill for a minimum of 3 months before taking study treatment.

[0415] Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to Day 1. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

[0416] 7. Pregnant or nursing (lactating) women.

[0417] 8. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 90 days after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.

[0418] 9. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years of the start of screening (except for basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 3 months, or carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed). 10. At screening, pre-malignant clonal cytopenias or clonal cytopenia of unknown significance (CCLIS). Cytopenia in the context of clonal abnormalities is defined as an acquired and persistent anemia (hemoglobin < 12 g / dL in females and < 13 g / dL in males), neutropenia (ANC < 1.8 x 109 / L), and / or thrombocytopenia (platelets < 150 x 109 / L) that is not explained by another known or identifiable condition.

[0419] 11. History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the Investigator, at the start of screening.

[0420] 12. Live vaccinations within 1 month prior to Day 1 or live vaccinations planned during the trial.

[0421] 13. Patients with suspected or proven immunocompromised state at screening, including:

[0422] (a) known clinical diagnosis of Human Immunodeficiency Virus (HIV) infection. Patients on systemic anti-retroviral therapy are also excluded from the trial;

[0423] (b) those with any other medical condition which in the opinion of the Investigator places the patient at unacceptable risk for participation in immunomodulatory therapy or (c) those requiring systemic or local treatment with any immune modulating agent in doses with systemic effects, e.g., high dose oral or i.v. steroids (>20 mg prednisone orally daily for >14 days, >5 mg prednisone orally daily or equivalent dose of i.v. steroid) or high dose methotrexate (>15 mg weekly). Topical, inhaled, local steroid use in doses that are not considered to cause systemic effects are permitted.

[0424] 14. Use of any biologic drugs targeting the immune system (for example, but not limited to: tumour necrosis factor (TNF) blockers, anakinra, rituximab, abatacept, tocilizumab, or canakinumab) within 26 weeks of Day 1. Refer to Section 6.8.2.

[0425] 15. Known diagnosis of a systemic auto-immune disease (e.g., systemic lupus erythematosus, etc.).

[0426] 16. Current use or within 5 half-lives of use of colchicine at start of screening.

[0427] 17. Participants with a Ml resulting from percutaneous coronary interventions (PCI) or coronary artery bypass graft (CABG) procedures.

[0428] 18. Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior to the start of screening.

[0429] 19. Multi-vessel CABG surgery within the past 3 years prior to the start of screening.

[0430] 20. Planned coronary revascularization (PCI or CABG) or any other major surgical procedure during the study (until EOS).

[0431] 21. Symptomatic Class IV heart failure (New York Heart Association [NYHA]) at the start of screening.

[0432] 22. History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as: • Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker

[0433] • History of familial long QT syndrome or known family history of Torsades de Pointe

[0434] 23. Uncontrolled hypertension (defined as systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg) at screening.

[0435] 24. Uncontrolled diabetes, as defined by the investigator, at screening. Clinical and laboratory evidence of uncontrolled diabetes may include but are not limited to: hemoglobin A1C >9%, recurrent fasting glucose >200 mg / dL, frequent urination / thirst not explained by other causes, etc.

[0436] 25. Known nephrotic syndrome diagnosis, or eGFR <30 mL / min calculated using the CKD-EPI formula (https: / / www.kidney.org / professionals / KDOQI / gfr calculator), or >2+ protein on urine dipstick testing at screening.

[0437] 26. History of clinically significant liver disease or liver injury at screening as indicated by abnormal liver enzymes or function tests (as defined below) including but not limited to Alanine Aminotransferase (ALT), Aspartate Transaminase (AST), Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT), alkaline phosphatase (ALP), serum bilirubin, albumin and prothrombin time. The Investigator should be guided by the following criteria:

[0438] • Any single parameter may not exceed 2x upper limit of normal (ULN)

[0439] 27. Uncontrolled asthma at the start of screening, as defined by the Investigator, with high likelihood of requiring systemic corticosteroids during the treatment period.

[0440] 2.5 Study treatment(s)

[0441] The investigational drug bbmAb, or placebo, will be prepared by as indicated in tables 6 and 7 below. bbmAb or placebo will be administered subcutaneously once on Day 1.

[0442] Table 6 Investigational and control drug

[0443] Treatment Title bbmAb bbmAb Placebo

[0444] Treatment 600 mg single injection 0 mg single injection

[0445] Description

[0446] Type Biologic Biologic

[0447] Dose Formulation Solution for injection Solution for injection

[0448] Unit Dose 100 mg / mL 0 mg / mL

[0449] Strength(s)

[0450] Dosage Level(s) 600 mg single dose 0 mg single dose

[0451] Route of Injection Injection

[0452] Administration

[0453] Use Experimental Placebo

[0454] IMP Yes Yes

[0455] Table 7 Dose and treatment schedule Investigational / Control Dose Number of tablets Frequency and / or

[0456] Drug Strength) Regimen bbmAb 100mg / mL 600 mg N / A Once on Day 1 by s.c. injection bbmAb 0 mg / mL 0 mg N / A Once on Day 1 by s.c. injection

[0457] SEQUENCE TABLE

[0458] Useful amino acid and nucleotide sequences for practicing the invention are disclosed in Table 8. Table 8. Sequences according to embodiments of the invention

[0459] Throughout the text of this application, should there be a discrepancy between the text of the specification and the sequence listing, the text of the specification shall prevail.

Claims

WHAT IS CLAIMED IS:1 . A method for reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, comprising administering to said subject a therapeutically effective amount of a bispecific antibody, wherein the antibody comprises a. a first part which is an immunoglobulin with a first variable light chain of (VL1) and a first variable heavy chain (VH1), that binds specifically to a IL1 p, and a first constant heavy chain (CH1) with a hetero-dimerization modification, and b. a second part which is an immunoglobulin with a second variable light chain (VL2) and a second variable heavy chain (VH2), that binds specifically to IL-18 and a second constant heavy chain (CH2) with a hetero-dimerization modification which is complementary to the hetero-dimerization modification of the first constant heavy chain.

2. The method according to claim 1 , wherein the first and second constant heavy chains of the bispecific antibody are lgG1 , and wherein a. the first constant heavy chain has point mutations generating a knob structure and the second constant heavy has point mutations generating a hole structure, or b. the first constant heavy chain has point mutations generating a hole structure and the second constant heavy has point mutations generating a knob structure, and optionally c. the first and second constant heavy chains have mutations resulting in a disulfide bridge.

3. The method according to claims 1-2, wherein: a. the first immunoglobulin VH1 domain of the bispecific antibody comprises i. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77, and said CDR3 having the amino acid sequence SEQ ID NO:78; or ii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:79, said CDR2 having the amino acid sequence SEQ ID NQ:80, and said CDR3 having the amino acid sequence SEQ ID NO:81 ; and d. the first immunoglobulin VL1 domain of the bispecific antibody comprises i. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93, and said CDR3 having the amino acid sequence SEQ ID NO:94 orii. hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:95, said CDR2 having the amino acid sequence SEQ ID NO:96, and said CDR3 having the amino acid sequence SEQ ID NO:97; and e. the second immunoglobulin VH2 domain of the bispecific antibody comprises i. hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45, and said CDR3 having the amino acid sequence SEQ ID NO:46; or ii. hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:47, said CDR2 having the amino acid sequence SEQ ID NO:48, and said CDR3 having the amino acid sequence SEQ ID NO:49; and f. the second immunoglobulin VL2 domain of the bispecific antibody comprises i. hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61, and said CDR3 having the amino acid sequence SEQ ID NO:62 or ii. hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:63, said CDR2 having the amino acid sequence SEQ ID NO:64, and said CDR3 having the amino acid sequence SEQ ID NO:65.

4. The method according to any of the preceding claims, wherein: a. the first immunoglobulin VH1 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 85, b. the first immunoglobulin VL1 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 101, c. the second immunoglobulin VH2 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 53, and d. the second immunoglobulin VL2 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 69.

5. The method according to any of the preceding claims, wherein: a. the first immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 87, b. the first immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 103, c. the second immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 55, and d. the second immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 71.

6. The method according to any one of the preceding claims, wherein the subject has a) at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, and / or b) more than one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at a variant allele frequency >2%.

7. The method according to claim 6, wherein said subject has at least one mutation in the CHIP driver genes TET2 or DNMT3A and a coronary heart disease.

8. The method according to any one of the preceding claims, wherein said subject had a documented myocardial infarction and wherein the bispecific antibody is administered at the earliest 30 days after the myocardial infarction (Ml).

9. The method according to any one of the preceding claims, wherein said cardiovascular event is selected from non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization.

10. The method according to any one of the preceding claims, wherein said cardiovascular event is selected from non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

11. The method according to any one of the preceding claims, wherein said cardiovascular event is non-fatal myocardial infarction or cardiovascular death.

12. The method according to any one of the preceding claims, wherein said cardiovascular event is non-fatal myocardial infarction.

13. The method according to any one of the preceding claims, wherein said CV event is hospitalization for unstable angina requiring unplanned revascularization.

14. The method according to any one of the preceding claims, wherein the bispecific antibody is administered subcutaneously.

15. The method according to any one of claims 1-14, comprising administering about 1 mg / kg to about 35 mg / kg of the bispecific antibody to the subject.

16. The method according to any one of the preceding claims, wherein the dose of the administered bispecific antibody is about 50 mg to about 900 mg administered subcutaneously.

17. The method according to claim 16, wherein the subcutaneously administered dose of the bispecific antibody is about 600mg.

18. The method according to any one of the preceding claims, wherein said subject has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessed at least 28 days after Ml and before first administration of bispecific antibody, and wherein bispecific antibody is administered at the earliest 30 days after Ml, and wherein said subject has a reduced hsCRP level of <2 mg / L assessed approximately 3 months after first administration of the bispecific antibody.

19. The method according to any of the preceding claims, wherein said subject is concomitantly receiving standard of care treatment for reducing the risk of or preventing CV events.

20. A bispecific antibody comprising a. a first part which is an immunoglobulin with a first variable light chain of (VL1) and a first variable heavy chain (VH1), that binds specifically to a IL1 p, and a first constant heavy chain (CH1) with a hetero-dimerization modification, and b. a second part which is an immunoglobulin with a second variable light chain (VL2) and a second variable heavy chain (VH2), that binds specifically to IL-18 and a second constant heavy chain (CH2) with a hetero-dimerization modification which is complementary to the hetero-dimerization modification of the first constant heavy chain, for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1. SRSF2 or JAK2.

21. The bispecific antibody for the use according to claim 20, wherein the first and second constant heavy chains of the bispecific antibody are lgG1 , and wherein a. the first constant heavy chain has point mutations generating a knob structure and the second constant heavy has point mutations generating a hole structure, orb. the first constant heavy chain has point mutations generating a hole structure and the second constant heavy has point mutations generating a knob structure, and optionally c. the first and second constant heavy chains have mutations resulting in a disulfide bridge.

22. The bispecific antibody for the use according to any one of claims 20-21 , wherein: a. the first immunoglobulin VH1 domain of the bispecific antibody comprises i. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:76, said CDR2 having the amino acid sequence SEQ ID NO:77, and said CDR3 having the amino acid sequence SEQ ID NO:78; or ii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:79, said CDR2 having the amino acid sequence SEQ ID NQ:80, and said CDR3 having the amino acid sequence SEQ ID NO:81 ; and b. the first immunoglobulin VL1 domain of the bispecific antibody comprises iii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:92, said CDR2 having the amino acid sequence SEQ ID NO:93, and said CDR3 having the amino acid sequence SEQ ID NO:94 or iv. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:95, said CDR2 having the amino acid sequence SEQ ID NO:96, and said CDR3 having the amino acid sequence SEQ ID NO:97; and c. the second immunoglobulin VH2 domain of the bispecific antibody comprises v. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:44, said CDR2 having the amino acid sequence SEQ ID NO:45, and said CDR3 having the amino acid sequence SEQ ID NO:46; or vi. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:47, said CDR2 having the amino acid sequence SEQ ID NO:48, and said CDR3 having the amino acid sequence SEQ ID NO:49; and d. the second immunoglobulin VL2 domain of the bispecific antibody comprises vii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NQ:60, said CDR2 having the amino acid sequence SEQ ID NO:61 , and said CDR3 having the amino acid sequence SEQ ID NO:62 or viii. hypervariable regions CDR1 , CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:63, said CDR2 having the amino acid sequence SEQ ID NO:64, and said CDR3 having the amino acid sequence SEQ ID NO:65.

23. The bispecific antibody for the use according to any one of claims 20-22, wherein:a. the first immunoglobulin VH1 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 85, b. the first immunoglobulin VL1 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 101 , c. the second immunoglobulin VH2 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 53, and d. the second immunoglobulin VL2 domain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 69.

24. The bispecific antibody for the use according to any one of claims 20-23, wherein: a. the first immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 87, b. the first immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 103, c. the second immunoglobulin heavy chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 55, and d. the second immunoglobulin light chain of the bispecific antibody comprises the amino acid sequence SEQ ID NO: 71.

25. The bispecific antibody for the use according to any one of claims 20-24, wherein the subject has a) at least one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, and / or b) more than one mutation in one of the CHIP driver genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2, wherein at least one unique mutation must be present at said subject has a variant allele frequency >2%.

26. The bispecific antibody for the use according to claim 25, wherein said at least one mutation in the CHIP driver genes TET2 or DNMT3A and a coronary heart disease.

27. The bispecific antibody for the use according to any one of claims 20-26, wherein said subject had a documented spontaneous myocardial infarction and wherein the bispecific antibody is administered at the earliest 30 days after the myocardial infarction (Ml).

28. The bispecific antibody for the use according to any one of claims 20-27, wherein said cardiovascular event is selected from non-fatal myocardial infarction, non-fatal stroke,cardiovascular death, and hospitalization for unstable angina requiring unplanned revascularization.

29. The bispecific antibody for the use according to claim 28, wherein said cardiovascular event is selected from non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

30. The bispecific antibody for the use according to claim 29, wherein said cardiovascular event is selected from non-fatal myocardial infarction or cardiovascular death.

31. The bispecific antibody for the use according to claim 30, wherein said cardiovascular event is selected non-fatal myocardial infarction or cardiovascular death.

32. The bispecific antibody for the use according to claim 31 , wherein said cardiovascular event is non-fatal myocardial infarction.

33. The bispecific antibody for the use according to claim 32, wherein said cardiovascular event is hospitalization for unstable angina requiring unplanned revascularization.

34. The bispecific antibody for the use according to any one of the claims 20-33, wherein the bispecific antibody is administered subcutaneously.

35. The bispecific antibody for the use according to any one of the claims 20-34, comprising administering about 1 mg / kg to about 35 mg / kg of the bispecific antibody to the subject.

36. The bispecific antibody for the use according to any one of the claims 20-35, wherein the dose of the bispecific antibody is about 50 mg to about 900 mg administered subcutaneously.

37. The bispecific antibody for the use according to any one of the claims 20-36, wherein the subcutaneously administered dose of the bispecific antibody is about 600mg.

38. The bispecific antibody for the use according to any one of the claims 20-37, wherein said subject has a high sensitivity C-reactive protein (hsCRP) level of >2 mg / L assessedat least 28 days after Ml and before first administration of bispecific antibody, and wherein bispecific antibody is administered at the earliest 30 days after Ml, and wherein said subject has a reduced hsCRP level of <2 mg / L assessed approximately 3 months after first administration of bispecific antibody.

39. The bispecific antibody for the use according to any one of claims 20 to 38, wherein said subject is concomitantly receiving standard of care treatment for reducing the risk of or preventing CV events.

40. A pharmaceutical composition comprising the antibody for use according to claims 20- 24 for use in reducing the risk of or preventing cardiovascular events in a subject known to be a carrier of clonal expansion of hematopoietic cell lines with somatic mutations in either of the genes TET2, DNMT3A, ASXL1 , PPM1 D, TP53, SF3B1 , SRSF2 or JAK2 wherein at least one unique mutation is present with variant allele frequency (VAF) >2%..

41. The methods according to claims 1-19 or the bispecific antibody for the use according to claims 20 to 39, the pharmaceutical composition according to claim 40, wherein the CV event is a recurrent CV event.

42. The methods according to claims 1-19 or the bispecific antibody for the use according to claims 20 to 39, the pharmaceutical composition according to claim 40, wherein the subject will receive a subcutaneously administered dose of the I L-1 p and IL-18 targeting antibody of about 600mg and further administrations of said antibody approximately every month or approximately every second month or approximately every third month or approximately every fourth month or approximately every fifth month or approximately every sixth month after the first administration.

43. The methods according to claims 1-19 or the bispecific antibody for the use according to claims 20 to 39, the pharmaceutical composition according to claim 40, wherein the further administrations of said antibody will be administered to the subject approximately every third month.

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