Methods for the control and treatment of abdominal aortic aneurysms

Abstract

The present disclosure provides methods of treating abdominal aortic aneurysm (AAA) in a patient diagnosed with AAA, and in particular reducing the diameter of an AAA in the patient. In an embodiment the diameter is reduced by about 40% or about 50%. In an embodiment, the patient being treated is less likely to experience a ruptured AAA. The treatment comprises subcutaneously administering to the patient with AAA a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment thereof. Further provided herein are pharmacologically active agents, compositions, methods and / or dosing schedules for the treatment of cardiovascular disease.

Description

Attorney Docket No. 157570.620200METHODS FOR THE CONTROL AND TREATMENT OF ABDOMINAL AORTIC ANEURYSMSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Patent Application No.63 / 729,746, filed December 9, 2024, and U. S. Provisional Patent Application No.63 / 817,760, filed June 4, 2025, each of which is incorporated by reference herein in its entirety for all purposesTECHNICAL FIELD

[0002] The disclosure relates to therapeutic antibody molecules and treatments for abdominal aortic aneurysms, including controlling the growth and rupture of abdominal aortic aneurysms.BACKGROUND

[0003] Abdominal aortic aneurysm (AAA) is a bulging, weakened area in the wall of the lower segment of the aorta characterized by inflammation and breakdown of the normal medial architecture. Abdominal aortic aneurysm affects over 2.5 million people in the US and 35 million people worldwide (Stuntz, 2016; Song et al., 2023) and accounted formore than an estimated 130,000 deaths globally in 2017 (CDC WONDER, 2020; Song et al., 2023). The majority of AAAs progressively expand over time and require repair either via an endovascular procedure or open surgery repair (Thompson, 2002), to prevent the catastrophic complication of rupture which is almost always fatal (Kent, 2014). Despite numerous efforts to identify novel treatment approaches, no therapy to date has been shown to conclusively slow the growth of AAAs (Golledge et al., 2023a), which remains a critical unmet medical need (Wassef et al., 2001, Kraiss et al., 2013; Lee et al., 2017).

[0004] Various methods have been proposed to address the insufficiencies in the standard of care for AAA Most methodologies employ some sort of invasive device, such as a stent or bypass graft. However, given the mortality rates and life-long follow-up required forAttorney Docket No. 157570.620200such surgical repair of AAAs, the efficacy and cost-effectiveness of such surgeries has been called into question. There are no non-invasive therapies available for preventing the growth and rupture of AAAs and effective pharmacological treatment against the disorder has been elusive. A non-invasive approach through pharmacological options holds promise for patients.

[0005] It has been hypothesized that AAA growth is driven by a complex inflammatory response and that interference with that response may alleviate AAA growth progression. The potential for such an approach is documented in animal models. However, clinical trials assessing the efficacy of pharmacologies such as antihypertensive agents, statins, doxycycline, anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth. (Puertas-Umbert 2023).

[0006] Evidence exists suggesting that interleukin-6 signaling inhibition is relevant to the growth of AAAs and associated mortality rates. See Burgess et al. ATVB (2024)). Human genetic studies have consistently shown a robust association of genetically downregulated IL-6 pathway signaling and a lower risk of AAA (Cai 2018, Georgakis 2020, Harrison 2013, Burgess 2024). Notably, the genetic association is even larger in magnitude than that for coronary artery disease or rheu atologi cal conditions such as rheumatoid arthritis and polymyalgia rheumatica for which IL-6 inhibitors have been approved. Directionally similar results were obtained in a human genetic study exploring AAA growth, though availability of longitudinal imaging data limited the ability to detect differences (Paige 2019). Epidemiological studies have shown that circulating IL-6 levels and concentrations of IL-6 in aortic tissue are higher in patients with AAA compared with controls, including patients with aortic atherosclerosis without dilatation (Thanigaimani 2022). Interleukin (IL)-6 inhibition has been identified as a promising drug target for slowing the growth of AAAs, with human evidence spanning epidemiologic data and genetic analyses (Golledge et al., 2023a). In addition, higher levels of C-reactive protein (CRP), a key downstream biomarker of IL-6 pathway activity, have been associated with higher risk of AAA and larger AAA size, and increases in hs-CRP have been associated with increases in AAA size over time (De Haro 2012, Cersit 2021; Haland et al., 2025). Finally, in experimental models of AAA, pharmacological and genetic inhibition of the IL-6 pathway have been associated with decreased growth rates of AAA (Kokje 2016, Nishihara 2017, Patel 2023), In a mouseAttorney Docket No. 157570.620200model, an IL-6 decoy protein that blocks IL6 proinflammatory trans-signaling appears to reduce the incidence of aortic ruptures but did not result in a change in the aortic diameter between the treated and control mice. (Paige 2019). Another study in a murine elastase model of AAA suggests that IL-6 neutralization in advance of elastase infusion resulted in significant mortality, suggesting a link between IL6 and AAA and a protective effective of IL-6 in the acute phase. This study acknowledges that it is unclear whether and how the experimental findings from an acute murine model would be relevant in protecting against AAA formation in humans. (Kokje 2016). Notably, the study appears to suggest that IL-6 provides protection against AAA rapture and its neutralization may be undesirable.

[0007] Despite numerous efforts to identify novel treatment approaches, no therapy to date has been shown to slow the growth of AAAs (Golledge 2023). For over two decades, discovering new medications that can halt AAA growth has been highlighted as a critical unmet need and a key priority among vascular surgeons and researchers (Wassef 2001, Kraiss 2013, Lee 2017). There remains a need for efficacious pharmacological methods for controlling, slowing or reducing the growth and preventing the rupture of an AAA in human subjects.SUMMARY

[0008] Provided herein is a method of treating a patient who is diagnosed with an abdominal aortic aneurysm. The treatment may result in the prevention of a rupture of an aortic abdominal aneurysm (AAA), controlling the growth of an AAA, and / or a reduction in size of an AAA. The method comprises administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 10.

[0009] In some embodiments, the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least about 98% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least about 98% identity to SEQ ID NO: 7. In one aspect, the anti-IL-6 antibody or antibody fragment comprises a heavy chain polypeptide having the sequence of SEQ ID NO: 1 and a light chain polypeptide having the sequence of SEQ ID NO: 7. In some embodiments, theAttorney Docket No. 157570.620200antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 13 and a light chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 7. In some embodiments, the antibody or antibody fragment comprises a heavy chain polypeptide comprising the sequence of SEQ ID NO: 13 and a light chain polypeptide comprising the sequence of SEQ ID NO: 7.

[0010] In some embodiments, the patient being treated in accordance with methods of the disclosure is diagnosed with an AAA,

[0011] In some embodiments, the patient has a risk factor for developing AAA. For example and without limitation, the risk factor for developing AAA is selected from the group consisting of (a) family history of AAA, (b) smoking (active or prior history), (c) hypertension, (d) hypercholesterolemia, (e) coronary artery disease, (f) peripheral artery' disease (g) diabetes (Type I or Type II); (h) metabolic syndrome; (i) age about 55 or older for men or age about 65 or older for women; (j) dyslipidemia; (k) a family history' of cardiovascular disease; (1) a history of stroke or transient ischemia attack;; (m) homocysteinemia; (n) hyperuricemia; (o) an HDL-C level of < about 40 mg / dL for men or < about 50 mg / dL for women; (p) renal dysfunction (e.g., a creatinine clearance (“CrCL”) of greater than about 30 mL / min and less than about 60 mL / min); (q) retinopathy (e.g., non-proliferative retinopathy, preproliferative retinopathy, proliferative retinopathy, maculopathy, advanced diabetic eye disease, or history of photocoagulation); (r) microalbuminuria (e.g., a positive microal or other strip test, an albumin / creatinine ratio of > about 2.5 mg / mmol, or an albumin excretion rate on timed collection of > about 20 mg / min all on at least two successive occasions); (s) macroalbuminuria (e.g., Albustix or other dip stick evidence of gross proteinuria, an albumin / creatinine ratio of > about 25 mg / mmol, or an albumin excretion rate on timed collection of > about 200 mg / min all on at least two successive occasions); and / or (t) an ankle-brachial index of < about 0.9 without symptoms of intermittent claudication.

[0012] In some embodiments, the patient has recent infection within the past month, past 3 months, past 6 months, or past year. In some embodiments, the patient has recent COVID-19 (SARS-CoV-2) infection within the past month, past 3 months, past 6 months, or past year. In some embodiments, the patient has recent surgery within the past month,Attorney Docket No. 157570.620200past 3 months, past 6 months, or past year. In some embodiments, the patient has periodontal disease.

[0013] In some embodiments, the patient has an absolute neutrophil count of no less than 2.0 x 109per L In some embodiments, the patient has a platelet count of no less than 120 x 109per L. In some embodiments, the patient has a spot urine to creatine ratio of no less than 4.

[0014] In some embodiments, the patient is negative for active tuberculosis, HIV, or hepatitis B or C. In some embodiments, the patient has not received a chronic use of immunosuppressive therapies.

[0015] In some embodiments, the cardiovascular disease is selected from a group consisting of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. In one embodiment, the cardiovascular disease is heart failure.

[0016] In some embodiments, the therapeutically effective dose of the present disclosure is between about 5 mg to about 200 mg. In some embodiments, the therapeutically effective dose is about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 50, about 60, about 70, about 80, about 90, or about 100 mg of the anti-IL-6 antibody or antibody fragment. In some embodiments the therapeutically effective dose is administered indefinitely and may exceed lOOmg for an individual dose or for a cumulative dose.

[0017] In some embodiments, the therapeutically effective dose is about 50 mg every 90 days, e.g., quarterly. In one embodiment, the total therapeutically effective dose (or total cumulative dose) is about 100 mg In some embodiments, the therapeutically effective dose is about 25 mg every 90 days, e.g., quarterly. In one embodiment, the total therapeutically effective dose is about 50 mg. In some embodiments, the therapeutically effective dose is about 15 mg every 30 days, e.g., monthly. In one embodiment, the total therapeutically effective dose is about 90 mg. In some embodiments, the method comprises administering 50 mg of the antibody subcutaneously once every' three months. In some embodiments, the patient is diagnosed with medium-sized AAA. In some embodiments, the patient is male and the AAA has a maximum aneurysm diameter between 40 to 50 mm. In some embodiments, the patient is female and the AAA has a maximum aneurysm diameter between 35 to 45 mm. In some embodiments, the AAA has a volume and / or a diameterAttorney Docket No. 157570.620200and the treatment results in a reduction in the growth rate of the volume and / or diameter. In some embodiments, the reduction in growth rate is a reduction in growth rate over time.

[0018] In one embodiment, the therapeutically effective dose is administered subcutaneously.

[0019] In some embodiments, the dosing schedules for the anti-IL-6 antibody or antibody fragment is every 1 week to every 24 weeks. In one embodiment, the therapeutically effective dose is administered every 4, 8, 12 or 24 weeks. In some embodiments the treatment period over which the therapeutically effective dose is administered is I, 30, 60, 90, 120, 150, or 180 days, for example, every day, every month, every three months, every four months, every 5 months or every 6 months (which may be daily, monthly, quarterly or bi-annually). In some embodiments, the therapeutically effective dose is administered from every 30 days to every 90 days. In one embodiment, the therapeutically effective dose is administered every 30 days (monthly). In one embodiment, the therapeutically effective dose is administered every 90 days (quarterly).

[0020] In some embodiments, the method of the present disclosure comprises: (a) administering a loading dose of the anti-IL-6 antibody or antibody fragment subcutaneously to the patient for at least the first two doses during a loading regimen, and (b) thereafter administering a maintenance dose of the anti-IL-6 antibody or antibody fragment subcutaneously to the patient during a maintenance regimen. In some embodiments, the loading regimen comprises administering the loading dose every 1 week, every' 2 weeks, or every' 4 weeks. In some embodiments, the maintenance regimen comprises administering the maintenance dose every 4 weeks, every 8 weeks, every 12 weeks, or every 24 weeks. In one embodiment, the method of the present disclosure comprises: (a) administering a loading dose of the anti-IL-6 antibody or antibody fragment subcutaneously to the patient every 4 weeks for the first two doses during a loading regimen; and (b) thereafter administering a maintenance dose of the anti -IL-6 antibody or antibody fragment subcutaneously to the patient every' 8 or 12 weeks during a maintenance regimen. In some embodiments, the loading dose is greater than or equal to the maintenance dose. In some embodiments, the loading dose is between 5 mg to 200 mg. In some embodiments, the maintenance dose is between 5 mg to 200 mg.Attorney Docket No. 157570.620200

[0021] In some embodiments, the patient has inflammation. In one embodiment, the patient has IL-6 mediated inflammation In some embodiments, the treatment of the present disclosure is sufficient to reduce the inflammation without causing immune suppression.

[0022] In some embodiments, the immune suppression is measured by absolute neutrophil count (ANC). In some embodiments, the post-treatment ANC is at least 500 cells / pL. In some embodiments, the post-treatment ANC is at least 1000 cehs / pL. In some embodiments, the post-treatment ANC is at least 1500 cells / pL. In some embodiments, the post-treatment ANC is at least 2000 cells / pL. In some embodiments, the ANC is decreased by no more than 2000 cells / pL as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 1500 cells / pL as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 1000 cells / pL as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than 500 cells / pL as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than about 50% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than about 40% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than about 30% as compared to pre¬ treatment levels. In some embodiments, the ANC is decreased by no more than about 20% as compared to pre-treatment levels. In some embodiments, the ANC is decreased by no more than about 10% as compared to pre-treatment levels. In some embodiments, the ANC is not decreased as compared to pre-treatment levels.

[0023] In some embodiments, inflammation is measured by high-sensitivity C-reactive protein (hsCRP) levels. In some embodiments, the patient has an elevated pre-treatment hsCRP level. In some embodiments, the treatment is sufficient to reduce the hsCRP level by more than 70%, 80%, or 90%, e.g., as compared with the expected hsCRP level if not receiving the antibody. In some embodiments, the pre-treatment hsCRP level of the patient is at least 2 mg / L. In some embodiments, the pre-treatment hsCRP level of the patient is at least 4 mg / L. In some embodiments, the pre-treatment hsCRP level of the patient is at least 6 rng / L. In some embodiments, the pre-treatment hsCRP level of the patient is at least 10 mg / L. In some embodiments, the pre-treatment hsCRP level of the patient is 2 mg / L or less. In some embodiments, the pre-treatment hsCRP level of the patient is 1 mg / L or less. In some embodiments, the post-treatment hsCRP level is no more than 2 mg / L. In someAttorney Docket No. 157570.620200embodiments, the post-treatment hsCRP level is no more than 1 mg / L, In some embodiments, the patient has a pre-treatment hsCRP level of greater than or equal to 2 mg / L, In some embodiments, the patient has a pre-treatment hsCRP level of less than 2 mg / L. In some embodiments, the hsCRP level is decreased by at least about 50% as compared to pre-treatment levels. In some embodiments, the hsCRP level is decreased by at least about 60% as compared to pre-treatment levels. In some embodiments, the hsCRP level is decreased by at least about 70% as compared to pre-treatment levels. In some embodiments, the hsCRP level is decreased by at least about 80% as compared to pretreatment levels. In some embodiments, the hsCRP level is decreased by at least about 90% as compared to pre-treatment levels. In some embodiments, the treatment results in hsCRP reduction within about 4, about 8, about 12 or about 24 weeks of treatment. In some embodiments, the treatment results in hsCRP reduction after about 180 days of treatment. In some embodiments, the treatment is sufficient to sustain hsCRP reduction for at least 24, or 48 weeks.

[0024] In some embodiments, hs-CRP is used as a prognostic and predictive biomarker of AAA risk in both primary and secondary settings. Independent of other risk factors, higher levels of hs-CRP may be associated with an increased risk of major adverse events. In some embodiments, the treatment may be administered to high-risk primary prevention patients with the diagnosis of abdominal aortic aneurysm (AAA). The patient may have one or more of the following risk factors: diabetes, tobacco use, hyperlipidemia, or hypertension and having hs-CRP >3 mg / L, excluding patients an estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2, absolute neutrophil count < 2,000 / uL at screening, platelet count < 120,000 / pL at screening, ALT or AST >2.0 * upper limit of normal (ULN) at screening, total bilirubin >1 5 x upper limit of normal at screening in the absence of Gilbert syndrome (in participants with Gilbert syndrome, total bilirubin >2.0 x upper limit of normal is the exclusionary threshold), positive or indeterminate result from interferon gamma release assay (IGRA) at screening, evidence of HIV- 1 or HIV-2 infection by serology at screening, evidence of hepatitis B or C by serology (eg, hepatitis B surface antigen or hepatitis C antibody and RNA positive) at screening.

[0025] In some embodiments, the treatment is sufficient to reduce aneurysm volume and / or diameter by atleast about 10%, about 15%, about 20%, about 25%, about.30%, about 40%Attorney Docket No. 157570.620200about 50% or about 60%. In some embodiments, the treatment is sufficient to reduce aneurysm volume and / or diameter by about 40% or about 50%. In some embodiments, the treatment is sufficient to reduce the growth rate of aneurysm volume and / or diameter by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 40% about 50% or about 60%, e.g., as compared with the expected growth rate if not receiving the antibody. In some embodiments, the reduction in the growth rate of the volume and / or diameter is more than 20%, e.g., as compared with the expected growth rate if not receiving the antibody. In some embodiments, the reduction is measured as the reduction in the annualized change in maximum aneurysm diameter of the AAA. In some embodiments, the treatment results in an increase in time to first AAA rupture, time to first AAA repair, or time to cardiovascular death. In some embodiments, the treatment maintains the size, volume and / or diameter of the aneurysm but avoids the occurrence of a rupture of the AAA. In some embodiments, the incidence of AAA rapture, the incidence of AAA repair, or the incidence of cardiovascular death is reduced by at least 10%, e.g., as compared with the expected incidence if not receiving the antibody. In some embodiments, the incidence of AAA rapture, the incidence of AAA repair, or the incidence of cardiovascular death is reduced by about 20%, e.g., as compared with the expected incidence if not receiving the antibody. In some embodiments the treatment slows the rate of growth of the AAA. The treatment may reduce the risk of AAA -related clinical events, such as AAA-related death, AAA rupture, AAA repair or may reduce the likelihood that the subject will meet the clinical criterial for repair. In some embodiments, the treatment reduced the incidence of rapture or meeting the clinical criterial for repair by at least 10%, 15%, 20%, 25%, 30%, 35% or 40%. In some embodiments, the patient diagnosed with the AAA has an AAA with a maximum transverse diameter of about 40 to 50 mm, inclusive, in men, and 40 to 45 mm, inclusive, in women on CT scan performed at screening. In some embodiments, the maximum transverse diameter is less than 40 to 50 mm, inclusive, in men, and 40 to 45 mm, inclusive, in women on CT scan performed at screening.

[0026] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agent in addition to the anti-IL-6 antibody or antibody fragment as described herein. The therapeutic agentsAttorney Docket No. 157570.620200include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-IGF-1 receptor antibody, anti-VEGF antibody, and / or anti-IL17a antibody), a soluble receptor (e g., soluble IL-1 receptor, soluble TNF-alpha receptor), an anti-inflammatory agent (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or a cardiovascular risk-modifying agent (e.g., anti¬ hypertensive drugs such as adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers; lipid lowering agents such as statins, fibrates, PCSK9 inhibitors, bile acid resins, niacin, selective cholesterol absorption inhibitors, omega-3 fatty acids and fatty acid esters, and adenosine triphosphate-citrate lyase (ACL) inhibitors; anti-diabetic drugs such as metformin; or anti-platelet agents such as aspirin, clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor).

[0027] In some embodiments, the anti-IL-6 antibody or antibody fragment containing said CDRs as described herein is contained in a pharmaceutical composition that comprises said anti-IL6 antibody or antibody fragment and a pharmaceutically acceptable carrier.[002S] In some embodiments, provided are pharmacologically active agents, compositions, methods and / or dosing schedules that have certain advantages compared to the agents, compositions, methods and / or dosing schedules that are currently used and / or known in the art, including the ability to dose less frequently or to administer lower doses to obtain equivalent effects in inhibiting IL-6 mediated signaling.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 presents the schematic for the phase II randomized, double-blind, placebo- controlled trial of pacibekitug in patients diagnosed with AAA.Attorney Docket No. 157570.620200DETAILED DESCRIPTION

[0030] Provided herein are methods of treating abdominal aortic aneurysm (A AA) in a patient diagnosed with AAA comprising subcutaneously administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment, wherein the patient’s AAA volume and / or diameter does not increase and preferably decreases in size and / or the AAA does not rupture.

[0031] Further provided herein are pharmacologically active agents, compositions, methods and / or dosing schedules for the treatment of AAA.ANTIBODIES

[0032] Provided herein are antibodies and antigen-binding fragments thereof that specifically bind IL-6. Antibodies and antigen-binding fragments disclosed herein specifically bind human IL-6. In some embodiments, an antibody may be specific for only human IL-6 and may exhibit no non-human cross-reactivity.

[0033] Throughout the present disclosure, the term “about” may be used in conjunction with numerical values and / or ranges. The term “about” is understood to encompass values near to a recited value and within an acceptable degree of error in the art. For example, “about 40 [units]” may mean within ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1 %, less than ± 1%, or any other value or range of values therein or there below.

[0034] As used herein, the term “antibody” refers to immunoglobulin (Ig) molecules and immunologically active portions or fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen (e.g., IL-6). By “specifically binds” or “immunoreacts with” is meant that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides. In some embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. In some embodiments, an antibody “specifically binds” IL-6 if the antibody binds IL-6 with greater affinity, greater avidity, more readily and / or for greater duration than it binds other polypeptides

[0035] The term “antibody” broadly refers to an immunoglobulin (Ig) molecule, generally, comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, or anyAttorney Docket No. 157570.620200functional fragment, mutant, variant, or derivative thereof, that retains the essential target binding features of an Ig molecule Such mutant, variant, or derivative antibody formats are known in the art.

[0036] In a full-length antibody, each heavy chain comprises a heavy chain variable domain (abbreviated herein as VH domain) and a heavy chain constant region The heavy chain constant region comprises three domains, CHI, CH2 and CH3. Each light chain comprises a light chain variable domain (abbreviated herein as VL domain) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each VH domain and VL domain is composed of three CDRs and four FRs, arranged from amino-terminus to carboxylterminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4

[0037] The term “Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain. The “Fc region” may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The numbering of the residues in the Fc region is according to the EU numbering system. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3. An Fc region can be present in dimer or monomeric form. The Fc region binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0038] Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY) and class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl or IgA2) or subclass. IgG, IgD, and IgE antibodies generally contain two identical heavy chains and two identical light chains and two antigen combining domains, each composed of a VH) and a VL. Generally IgA antibodies are composed of two monomers, each monomer composed of two heavy chains and two light chains (as for IgG, IgD, and IgE antibodies); in this way the IgA molecule has four antigen binding domains, each again composed of a VH and a VL. Certain IgA antibodies are monomeric in that they are composed of two heavy chains and two lightAttorney Docket No. 157570.620200chains. Secreted IgM antibodies are generally composed of five monomers, each monomer composed of two heavy chains and two light chains (as for IgG and IgE antibodies). Thus, the IgM molecule has ten antigen binding domains, each again composed of a VH and a VL. A cell surface form of IgM has a two heavy chain / two light chain structure similar to IgG, IgD and IgE antibodies.

[0039] The term “antigen-binding portion” or “antigen-binding fragment” of an antibody (or “antibody portion” or “antibody fragment”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-6). It has been shown that the antigen-binding function of an antibody can be performed by portions or fragments of a full-length antibody Examples of binding fragments encompassed within the term “antigen binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb (domain antibody) fragment (Ward et al., (1989) Nature 341:544-546; WO 90 / 05144 Al, each herein incorporated by reference in its entirety), which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). The disclosure also encompasses a Fab' fragment. Fab' fragments can be formed by the reduction of F(ab')2 fragments. Fab' is derived from F(ab')2; therefore, it may contain a small portion of Fc. 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 synthetic linker that enables them to be made as a single protein chain in which the VL and VH domains pair to form monovalent molecules (known as single chain Fv (scFv). See e.g., Bird et al (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883. Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. In some embodiments, scFv molecules may be incorporated into a fusion protein. In some embodiments, provided herein is a single chain camelid antibody. In some embodiments, provided herein is a shark heavy chain antibody (V-NAR) See, English et al. (2020) Antibody Therapeutics, 3(1): 1-9. Examples of antigen-binding portions are known in the art (Kontermann and Dubel eds., AntibodyAttorney Docket No. 157570.620200Engineering (2001) Springer-Verlag, New York. 790 pp.). In some embodiments, provided herein is a single domain antibody. In general, the term “antibody” when used herein encompasses an “antibody fragment”. An antibody fragment generally retains the antigen¬ binding properties of a full-length antibody.

[0040] Antibodies and antibody portions provided herein may be in multispecific e.g., bispecific or trispecific) formats. Such multi specific molecules specifically bind to two or more different molecular targets or epitopes. In some embodiments, an antibody or an antigen-binding portion is a bispecific molecule that binds specifically to a first antigen and a second antigen, wherein the first antigen is IL-6 and the second antigen is not IL-6. In some embodiments, an antibody or an antigen-binding portion is a diabody. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). In some embodiments, an antibody or an antigen-binding portion is a triabody, a tetrabody, a bis-scFv or a tandem scFv. In some embodiments, an antibody or an antigen¬ binding portion is a dual affinity re-targeting protein.

[0041] In some embodiments, an anti-IL-6 antigen-binding portion disclosed herein is a Fab, a F(ab')2, a Fab; a Fv, a scFv, a Fd, a single domain antibody, a single chain camelid antibody, a diabody, a triabody, a tetrabody or a bis-scFv.

[0042] As used herein, the terms “immunological binding” and “immunological binding properties” refer to the non-covalent interactions of the type which occur between an immunoglobulin molecule (e.g., antibody or antigen-binding portion thereof) and an antigen for which the immunoglobulin is specific. The strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, wherein a smaller Ka represents a greater affinity. Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen-binding site / antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that equallyAttorney Docket No. 157570.620200influence the rate in both directions. Thus, both the ‘"on rate constant” (Kon) and the “off rate constant” (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. {See, Malmqvist, Nature 361:186-187 (1993)). The ratio of Koff / Konenables the cancellation of all parameters not related to affinity, and is equal to the dissociation constant Kd. (See, Davies et al. (1990) Annual Rev Biochem 59:439-473). An antibody or antigen-binding portion provided herein is said to specifically bind IL-6 when the equilibrium binding constant (Kd) is <10 qM, preferably < 10 nM, more preferably < 10 nM, and most preferably < 100 pM to about 1 pM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art.

[0043] In some embodiments, an anti-IL-6 antibody or antigen-binding portion provided herein is monovalent or bivalent and comprises a single or double chain. Functionally, the binding affinity of an antibody or antigen-binding portion may be within the range of about 10'5M to IO'12M. For example, the binding affinity of an antibody or antigen-binding portion is from about 10’6M to 10"12M, from about 10'' M to 10'12M, from about IO8M to IO'12M, from about IO'9M to IO'12M, from about 10'5Mto 10'11M, from about 10'6M to IO’11M, from about 10'7M to 10'11M, from about 10'8M to I0’11M, from about 10'9M to 10’” M, from about IO'10M to 10'uM, from about 10’3M to IO'10M, from about 10’bM to 10'10M, from about IO'7M to IO'10M, from about 10'8M to 10'i0M, from about 10’9M to IO'10M, from about 10'5M to IO'9M, from about IO'6M to IO'9M, from about IO'7M to 10'9M, from about 10'8M to IO’9M, from about 10'5M to 10'8M, from about 10'6M to 10’8M, from about 10'7M to 10’8M, from about 10’5M to 10'7M, from about IO’6M to 1 O'7M or from about 10‘5M to 10'6M

[0044] A human anti-IL-6 monoclonal antibody (PF-04236921) was described in US8,188,235, which is incorporated herein by reference in its entirety. The human anti-IL-6 monoclonal antibody is a fully human immunoglobulin G2 monoclonal antibody that binds to human IL-6 and has a half-life of 36-51 days In phase I trials in healthy volunteers and patients with rheumatoid arthritis (protocol B0151001, NCT00838565 and NCT01166555), intravenous and subcutaneous (SC) the human anti-IL-6 monoclonal antibody (PF-04236921) was well tolerated and caused sustained suppression of C-reactive protein (CRP), a marker for inflammation that is transcriptionally controlled by IL-6. PF- 04236921 has also been investigated in a phase II trial in patients with systemic lupusAttorney Docket No. 157570.620200erythematosus (SLE, NCT01405196). While the study did not meet the primary end point, improvement was noted in the primary' as well as key secondary'' end points with 10 mg. Overall, the human anti-IL-6 monoclonal antibody demonstrated desirable pharmacokinetic (PK) and pharmacodynamic (PD) properties supporting sustained target inhibition, and low incidence of immunogenicity upon single and multiple dose administration. See Danese, et al., Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II), Gut 2019;68:40-48; Li etal. Pharmacokinetics and C-r eactive protein modelling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease, Br J Clin Pharmacol. 2018 Sep; 84(9): 2059-2074.

[0045] The amino acid and nucleic acid sequences of the human anti -IL-6 antibody (PACIBEKITUG) are provided in Table 1.Table 1. Amino acid and nucleic acid sequences of human anti-I L-6 antibody Antibody name Anti-IL-6 antibody (Pacibekitug)Domain or Region Sequence SEQ ID NOHeavy chain QVQLQQWGAGLLKPSETLSLTCAIYGGSFREYYW 1 (amino acid SWIROPPGKGLEWIGEIFHSGSTNYNPSLKSRVTIS sequence) VDTSKNOFSLKLSSVTAADTAVYYCAREELDDFD IWGQGTMVTVSSASTKGPSVTPLAPCSRSTSESTA ALGCLYTCDYFPEPVTVSWNSGALTSGVHTFPAVL Q S SGL YSL S S WTVPS SNFGTQTYTCN VDHKPSNT KVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDlLMISR’rPEVrCVVVDVSHEDPEVQFNWYVDG VEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWL NGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVTSCSVMHEALHNHYTQKSLSLSPGKHeavy chain QVQLQQWGAGLLKPSETLSLTCAIYGGSFREYYW 13 (amino acid SWIRQPPGKGLEW IGEIFHSGSTNYNPSLKSRVTIS sequence) VDTSKNQFSLKLSSVTAADTAVYYCAREELDDFD IWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL Q S SGL YSL S S VVTVPS SNFGTQTYTCNVDHKP SNT KVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDG VEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYAttorney Docket No. 157570.620200Antibody name Anti-IL-6 antibody (Pacibekitug)TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSC SVMHEALHNHYTQKSLSLSPGHeavy chain CDR1 EYYWS 2 Heavy chain CDR2 EIFHSGSTNYNPSLKS 3 Heavy chain CDR3 EELDDFDI 4 Heavy chain QVQLQQWGAGLLKPSETLSLTCAIYGGSFREYYW 5 variable region SW1RQPPGKGLEWIGEIFHSGSTNYNPSLKSRVTIS (VH) (amino acid VDTSKNQFSLKLSSVTAADTAVYYCAREELDDFD sequence) 1WGQGTMVTVSSHeavy chain caggtgcagctacagcagtggggcgcaggactgttgaagccttcggagacc 6 (nucleic acid ctgtccctcacctgcgctatctatggtgggtccttcagggagtactactggagct sequence) ggatccgccagcccccagggaaggggctggagtggattggggaaatctttca tagtggaagcaccaactacaacccgtccctcaagagtcgagtcaccatatcag tagacacgtccaagaaccagttctccctgaagctgagctctgtgaccgccgcg gacacggctgtgtattactgtgcgagagaggaattagatgattttgatatctggg gccaagggacaatggtcaccgtctcctcagcctccaccaagggcccatcggt cttccccctggcgccctgctccaggagcacctccgagagcacagcggccctg ggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactc aggcgctctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcag gactctactccctcagcagcgtagtgaccgtgccctccagcaacttcggcacc cagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggac aagacagttgagcgcaaatgttgtgtcgagtgcccaccgtgcccagcaccac ctgtggcaggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc atgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacg aagaccccgaggtccagttcaactggtacgtggacggcgtggaggtgcataa tgccaagacaaagccacgggaggagcagttcaacagcacgttccgtgtggtc agcgtcctcaccgtcgtgcaccaggactggctgaacggcaaggagtacaagt gcaaggtctccaacaaaggcctcccagcccccatcgagaaaacc.atctcca aaaccaaagggcagccccgagaaccacaggtgtacaccctgcccccatccc gggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggctt ctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggaga acaactacaagaccacacctcccatgctggactccgacggctccttcttcctct acagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttct catgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctc tccctgtctccgggtaaaLight chain (amino DIOMTOSPSSLSASVGDRVTITCRASQGISSWLAW 7 acid sequence) YOQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTD FTLTISSLOPEDFATYYCQQYKSYPRTFGOGTKVE JKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGECLight chain CDR1 RASQGISSWLA 8Light chain CDR2 AASSLQS 9Attorney Docket No. 157570.620200Antibody name Anti-IL-6 antibody (Pacibekitug)Light chain CDR3 QQYKSYPRT 10 Light chain variable DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAW 11 region (VL) (amino YQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTD acid sequence) FTLTISSLQPEDFATYYCQQYKSYPRTFGQGTKVEIKLight chain (nucleic gacatccagatgacccagtctccatcctcactgtctgcatctgtaggagacaga 12 acid sequence) gtcaccatcacttgtcgggcgagtcagggtattagcagctggttagcctggtat cagcagaaaccagagaaagcccctaagtccctgatctatgctgcatccagttt gcaaagtggggtcccatcaaggttcagcggcagtggatctgggacagatttca ctctcaccatcagtagcctgcagcctgaagattttgcaacttattactgccaaca gtataaaagttaccctcggacgttcggccaagggaccaaggtggaaatcaaa cgaactgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttga aatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggc caaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggag agtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcacc ctga cgctgagcaaagcaga ctacgagaaaca caaagtctacgcctgcgaa gtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgtCDR1, CDR2 and CDR3 (from left to right) sequences are underlined in the heavy chain and light chain, respectively.

[0046] As will be appreciated by the person of ordinary skill in the art, the antibodies of the instant invention may comprise one or more amino acid modifications, substitutions (including conservative substitutions), additions and / or deletions,

[0047] Provided herein is a method of treating AAA in a patient diagnosed with AAA comprising subcutaneously administering to a patient in need thereof a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 10. In some embodiments, said antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98% or about 99% identity to SEQ ID NO: 1 or SEQ ID NO: 13 and a light chain polypeptide comprising a polypeptide having at least about 95%, about 96%, about 97%, about 98% or about 99% identity to SEQ ID NO: 7. In some embodiments, said antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having the sequence of SEQ ID NO: 1 or SEQ ID NO: 13 and a light chain polypeptide comprising a polypeptide having theAttorney Docket No. 157570.620200sequence of SEQ ID NO: 7, In some embodiments, the anti-IL-6 antibody or an antigenbinding portion comprises human IgG2 constant regions.

[0048] As used herein, the term “conservative substitution” refers to replacement of an amino acid with another amino acid which does not significantly deleteriously change the functional activity A preferred example of a “conservative substitution” is the replacement of one amino acid with another amino acid which has a value > 0 in the following BLOSUM 62 substitution matrix (see Henikoff & Henikoff, 1992, PNAS 89: 10915- 10919):A R N D C Q E G H I L K M F P S T W Y VA 4 -1 -2 -2 0 - 1 - 1 0 -2 - 1 - 1 - 1 - 1 -2 - 1 1 0 -3 -2 0R -1 5 0 -2 -3 1 0 -2 0 - 3 -2 2 - 1 -3 -2 -1 - 1 -3 -2 -3N -2 0 6 1 -3 0 0 0 1 - 3 -3 0 - 2 -3 -2 1 0 -4 - 2 -3D -2 -2 1 6 -3 0 2 - 1 - 1 -3 -4 - 1 -3 -3 - 1 0 - 1 - 4 -3 -3C 0 -3 -3 -3 9 - 3 -4 -3 -3 - 1 - 1 -3 - 1 -2 -3 - 1 - 1 -2 -2 -1Q - 1 1 0 0 -3 5 2 -2 0 -3 -2 1 0 - 3 - 1 0 - 1 -2 - 1 - 2E -1 0 0 2 -4 2 5 -2 0 -3 -3 1 -2 -3 - 1 0 - 1 -3 -2 -2G 0 — 2 0 —± ~3 -2 — 2 6 -2 -4 -4 -2 -3 -3 -2 0 -2 -2 -3 -3H -2 0 1 -1 - 3 0 0 - 2 8 - 3 -3 - 1 - 2 -1 -2 - 1 -2 -2 2 -3I - 1 -3 -3 -3 -1 - 3 -3 -4 -3 4 2 -3 1 0 -3 -2 - 1 -3 - 1 3L - 1 -2 -3 -4 - 1 -2 -3 -4 -3 2 4 -2 2 0 -3 -2 - 1 -2 - 1 1K - 1 2 0 -1 -3 1 1 -2 - 1 -3 -2 5 - 1 -3 - 1 0 - 1 -3 -2 -2M - 1 -1 -2 -3 -1 0 -2 -3 -2 1 2 - 1 5 0 -2 - 1 - 1 - 1 - 1 1F -2 -3 -3 -3 -2 - 3 -3 -3 - 1 0 0 -3 0 6 -4 -2 -2 1 3 -1P - 1 -2 -2 - 1 -2 -2 - 3 -3 - 1 -2 -4 7 - 1 - 1 -4 -3 -2s 1 - 1 1 0 - 1 0 0 0 - 1 -2 - 2 0 - 1 -2 - 1 4 1 - 3 - 2 -2T 0 - 1 0 -i - i -2 -2 - 1 - 1 - 1 - 1 -2 - 1 1 5 -2 -2 0W -3 -3 - 4 -4 -2 -3 -2 -2 -3 -2 -3 - 1 11Y „ 2 -2 -2 -3 -2 - 1 -2 -3 2 - 1 - 1 -2 - 1 3 -2 -2 2 7 - 1V 0 -3 -3 -3 -1 - 2 -2 -3 -3 3 1 -2 1 -2 -2 0 -3 - 1 4

[0049] Calculations of sequence homology or identity (the terms are used interchangeably herein) between sequences may be performed as follows.

[0050] To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence forAttomey Docket No 157570.620200optimal alignment and non -homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least about 30%, preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and even more preferably at least about 70%, about 75%, about 80%, about 82%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”) The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, considering the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0051] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman et al. ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package, using either a BLOSUM 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. One set of parameters (and the one that can be used if the practitioner is uncertain about what parameters should be applied to determine if a molecule is within a sequence identity or homology limitation of the invention) is a BLOSUM 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0052] In some embodiments, the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of Meyers et al. ((1989) CABIOS 4:11-Attorney Docket No. 157570.62020017) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0053] In some embodiments, the anti-IL-6 antibody or antigen-binding portion provided herein is monoclonal.

[0054] In some embodiments, the anti-IL-6 antibody is a human antibody. Methodologies exist for making human antibodies. Human antibodies from mice may be produced by using transgenic mice to express human antibody gene sequences. This technology has been used to develop therapeutic antibodies that are believed to be less immunogenic than their rodent-derived equivalents, even those that are humanized. Such mice are made, for example, by introducing large fragments of human heavy- and K-chain loci into the germline of the Ig-inactivated mice. Mice capable of producing human antibodies may produce antibodies with higher affinity and efficacy.

[0055] In some embodiments, the anti-IL-6 antibody or antigen-binding portion provided herein is chimeric. The term “chimeric” is intended to refer to an antibody molecule, or an antigen-binding portion thereof, in which the variable domain sequences are derived from one species and at least one constant region sequence is derived from another species. For example, one or all the variable domains of the light chain(s) and / or one or all the variable domains of the heavy chain(s) of a mouse antibody (e.g., a mouse monoclonal antibody) may each be joined to a human constant region, such as, without limitation an IgGl, IgG2, or an IgG4 human constant region. Examples of chimeric antibodies and suitable techniques for their generation are provided in U. S. 4,816,567; U. S. 4,975,369; and U. S.4,816,397, each of which is incorporated herein by reference in its entirety.

[0056] In some embodiments, the anti-IL-6 antibody or antigen-binding portion provided herein is humanized. The term “humanized” is intended to refer to an antibody, or an antigen-binding portion thereof, that has been engineered to comprise one or more human framework regions in the variable domain together with non-human (e.g., mouse, rat, or hamster) CDRs of the heavy and / or light chain. In some embodiments, a humanized antibody comprises sequences that are entirely human except for the CDRs. In some embodiments, the VH domain, the VL domain, or both the VH domain and the VL domain of an anti-IL-6 antibody or antigen-binding portion provided herein comprise one or more human framework region amino acid sequences. In some embodiments, a humanizedAttorney Docket No. 157570.620200antibody comprises sequences that are entirely human except for the CDRs, which are the CDRs of antibody 32G8H6. Examples of humanized antibodies and suitable techniques for their generation are provided in Hwang et al., Methods 36:35, 2005; Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033, 1989; Jones et al., Nature, 321:522-25, 1986; Riechmann et al., Nature, 332:323-27, 1988; Verhoeyen et al., Science, 239:1534-36, 1988; Orlandi et al., Proc. Natl. Acad. Sci. USA, 86:3833-37, 1989, U. S. 5,225,539, U. S.5,530,101; U. S. 5,585,089; U. S. 5,693,761; U. S. 5,693,762; U. S. 6,180,370; and WO 90 / 07861, each of which is incorporated herein by reference in its entirety,

[0057] In some embodiments, humanization comprises removal of post-translational modification (PTM) sites in the variable domain sequences (e.g., in the CDR or framework sequences) of a non-human antibody. For example, one or more PTM sites in CDR sequences may be removed by substituting certain amino acid residues. In some embodiments, humanization comprises CDR grafting and back mutation.

[0058] In some embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises an immunoglobulin constant region. In some embodiments, the immunoglobulin constant region is IgG, IgE, IgM, IgD, IgA or IgY. In some embodiments, the immunoglobulin constant region is IgGl, IgG2, IgG3, IgG4, IgAl or IgA2. In some embodiments, the immunoglobulin constant region is immunologically inert. In some embodiments, the immunoglobulin constant region comprises one or more mutations to reduce or prevent FcyR binding, antibody-dependent cell-mediated cytotoxicity activity, and / or complement-dependent cytotoxicity activity In some embodiments, the immunoglobulin constant region is a wild-type human IgGl constant region, a wild-type human IgG2 constant region, a wild-type human IgG4 constant region, a human IgGl constant region comprising the amino acid substitutions L234A, L235A and G237A, a human IgGl constant region comprising the amino acid substitutions L234A, L235A, G237A and P331 S or a human IgG4 constant region comprising the amino acid substitution S228P, wherein numbering is according to the EU numbering system. In some embodiments, a position of an amino acid residue in a constant region of an immunoglobulin molecule is numbered according to EU nomenclature (Ward et al., 1995 Therap. Immunol. 2:77-94).22Attorney Docket No. 157570.620200

[0059] In some embodiments, the anti-IL-6 antibody or antigen-binding portion thereof may comprise an immunoglobulin light chain constant region that is a kappa light chain constant region or a lambda light chain constant region.

[0060] In some embodiments, the anti-IL-6 antibody or antigen-binding portion thereof may comprise a human IgG4 constant region comprising the amino acid substitution S228P and a kappa light chain constant region.

[0061] Further provided herein is an immunoconjugate comprising an anti-IL-6 antibody or an antigen-binding portion linked to a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule drug.PHARMACEUTICAL COMPOSITIONS

[0062] The anti-IL-6 antibodies and antigen-binding portions described herein (also referred to herein as “active compounds”) can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise an anti-IL-6 antibody or antigen-binding portion (or an immunoconjugate comprising said antibody or portion), and a pharmaceutically acceptable carrier, diluent or excipient. As used herein, the term “pharmaceutically acceptable” refers to molecular entities and compositions that do not generally produce allergic or other serious adverse reactions when administered using routes well known in the art. Molecular entities and compositions approved by a regulatory agency of the U. S. federal or state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans are considered to be “pharmaceutically acceptable.” As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Some examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as anyAttorney Docket No. 157570.620200conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0063] Provided herein is a pharmaceutical composition comprising (i) an anti-IL-6 antibody or an antigen-binding portion thereof wherein the antibody or antigen-binding portion comprises a VH domain and a VL domain, wherein: (a) the VH domain amino acid sequence comprises HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 3 and HCDR3 of SEQ ID NO: 4; and the VL domain amino acid sequence comprises LCDR1 of SEQ ID NO: 8, LCDR2 of SEQ ID NO: 9 and LCDR3 of SEQ ID NO: 10; and (ii) a pharmaceutically acceptable carrier, diluent or excipient. Provided herein is also the use of a pharmaceutical composition for the treatment of abdominal aortic aneurysm (AAA), which comprises a therapeutically effective dose of an anti -interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 10. Provided herein is also the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of abdominal aortic aneurysm (AAA), which comprises a therapeutically effective dose of an anti -interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 10.

[0064] A pharmaceutical composition disclosed herein may be formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (z.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases,Attorney Docket No. 157570.620200such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0065] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, N. J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin

[0066] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.Attorney Docket No. 157570.620200

[0067] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primojel®, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0068] For administration by inhalation, the compounds may be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0069] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0070] The pharmaceutical agents can also be prepared in the form of suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0071] In some embodiments, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparationAttorney Docket No. 157570.620200of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially. Liposomal suspensions can also be used as pharmaceutically acceptable carriers.

[0072] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0073] Pharmaceutical compositions comprising pacibekitug may include, for example, histidine, sugars (such as sucrose and mannitol), EDTA, polysorbate (such as polysorbate 80), among other excipients.

[0074] In some embodiments, pacibekitug is formulated at a concentration of 85 mg / mL with 20 mM histidine, 63.2 mg / mL sucrose, 16.8 mg / mL mannitol, 0.05 mg / mL EDTA, and 0.2 mg / mL polysorbate 80, pH 5.8. After reconstitution with water for injection, each single use vial contains 106 mg of pacibekitug in 1.25 mL of aqueous solution.

[0075] The pharmaceutical compositions provided herein can be included in a container, pack, or dispenser together with instructions for administration.USES OF ANTIBODIES

[0076] Provided herein are methods and uses of the anti-IL-6 antibodies, anti -IL-6 antigenbinding portions, immunoconjugates and pharmaceutical compositions described herein for providing a therapeutic benefit to a subject diagnosed with AAA. In some embodiments, the AAA may be of a volume and / or diameter that is considered nonfatal. In some embodiments, the AAA may be of a volume and / or diameter that is at high risk for rapture which may lead to death. In some embodiments, the subject diagnosed with the AAA has an AAA with a maximum transverse diameter of about 40 to 50 mm, inclusive, in men, and 40 to 45 mm, inclusive, in women on CT scan performed at screening. InAttorney Docket No. 157570.620200some embodiments, the maximum transverse diameter is less than 40 to 50 mm, inclusive, in men, and 40 to 45 mm, inclusive, in women on CT scan performed at screening. Provided herein is also the use of an anti -interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 1, in the preparation of a medicament for the treatment of abdominal aortic aneurysm (AAA). Provided herein is also the use of an anti -interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 1, in the treatment of treatment of abdominal aortic aneurysm (AAA).

[0077] In some embodiments, the methods described herein further comprise a step of treating a subject with an additional form of therapy. In some embodiments, the additional form of therapy comprises administering one or more therapeutic agent in addition to the said anti-IL-6 antibody or antibody fragment as described herein. The therapeutic agents include, but are not limited to, a second antibody (e.g., an anti-IL-1 antibody, anti-IGF-1 receptor antibody, anti-VEGF antibody, and / or anti-IL17a antibody), a soluble receptor (e.g., soluble IL-1 receptor, soluble TNF-alpha receptor), an anti-inflammatory agent (e.g., paclitaxel, docetaxel, cisplatin, doxorubicin, prednisone, mitomycin, progesterone, tamoxifen, or fluorouracil), or a cardiovascular risk-modifying agent (e.g., antihypertensive drugs such as adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers; lipid lowering agents such as statins, fibrates, PCSK9 inhibitors, bile acid resins, niacin, selective cholesterol absorption inhibitors, omega-3 fatty acids and fatty acid esters, and adenosine triphosphate-citrate lyase (ACL) inhibitors; anti-diabetic drugs such as metformin; or anti-platelet agents such as aspirin, clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor).

[0078] Provided herein is an anti-IL-6 antibody or an anti-IL-6 antigen-binding portion, an immunoconjugate or a pharmaceutical composition described herein, for use as a medicament.

[0079] As used herein, the term “effective amount” or “therapeutically effective amount” refers to the amount of a pharmaceutical agent, e.g., an anti-IL-6 antibody or an antigenbinding portion thereof, which is sufficient to reduce or ameliorate the severity of AAA orAttorney Docket No. 157570.620200may reduce progress! on of AAA, including maintaining the size of the diameter of an AAA or reducing the diameter of an AAA, and / or avoid an AAA rupture. A “therapeutically effective amount” may also be an amount of an anti-IL6 antibody or antigen binding portion thereof that may enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g, prophylactic or therapeutic agent). In some embodiments, the therapeutically effective dose of said anti-IL-6 antibody or antibody fragment is effective to change one or more biomarkers of IL-6 mediated signaling including, but not limited to, total sIL-6R, total IL-6, C -reactive protein (CRP), an / or autoantibody, for unexpectedly prolonged periods of time.

[0080] As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating the effects of an AAA, including reducing the diameter of an AAA or maintaining the diameter of an AAA for a prolonged period of time. In an embodiment, the treatment may reduce the diameter of an AAA by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%. In an embodiment the treatment may reduce the diameter of an AAA by about 40% or about 50%. The treatment may also maintain the diameter of an AAA for a period of time, for example, the treatment may slow or halt the progression of an AAA during the time the treatment is administered. The treatment may also or alternatively reduce the likelihood of an AAA rupture in a patient It will be appreciated that, although not precluded, treating an AAA does not require that the AAA or symptoms associated therewith be completely eliminated.

[0081] As used herein, “pre-treatment” means prior to the first administration of an anti-IL-6 antibody according the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than an anti-IL-6 antibody

[0082] As used herein, “post-treatment” means after the administration of an anti-IL-6 antibody according the methods described herein. Post-treatment includes after any administration of an anti-IL-6 antibody at any dosage described herein. Post-treatment also includes after the treatment phase of an anti-IL-6 antibody.

[0083] The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the AAA being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site ofAttorney Docket No. 157570.620200delivery of the composition, the method of administration, the scheduling of administration and other factors known to medical practitioners Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors and may depend on the severity of the symptoms and / or progression of a disease being treated. Appropriate doses of antibody molecules are well known in the art (Ledermann J. A. et al., 1991, Int. J. Cancer 47: 659-664; Bagshawe K. D. et al., 1991, Antibody, Immunoconjugates and Radiopharmaceuticals 4: 915-922). Specific dosages may be indicated herein or in the Physician’s Desk Reference (2003) as appropriate for the type of medicament being administered may be used. A therapeutically effective amount or suitable dose of an antibody molecule may be determined by comparing its in vitro activity and in vivo activity in an animal model. Methods for extrapolation of effective dosages in mice and other test animals to humans are known. The precise dose will depend upon a number of factors, including whether the antibody is for prevention or for treatment, the size and location of the area to be treated, the precise nature of the antibody (eg., whole antibody, fragment) and the nature of any detectable label or other molecule attached to the antibody.

[0084] A typical antibody dose will be in the range 100 pg to 1 g for systemic applications, and 1 pg to 1 mg for intradermal injection. An initial higher loading dose, followed by one or more lower doses, may be administered. In some embodiments, the antibody is a whole antibody, e.g., the IgGl, IgG2 or IgG4 isotype. This is a dose for a single treatment of an adult subject, which may be proportionally adjusted for children and infants, and also adjusted for other antibody formats in proportion to molecular weight. Treatments may be repeated at daily, twice-weekly, weekly, monthly, quarterly or bi-annually intervals, at the discretion of the physician. The treatment schedule for a subject may be dependent on the pharmacokinetic and pharmacodynamic properties of the antibody composition, the route of administration and the nature of the condition being treated. In some embodiments, the dosing of the present disclosure comprises an amount of at least about 10 mg, or at least about 20 mg, or at least about 30 mg, or at least about 40 mg, or at least about 50 mg of the anti-IL-6 antibody or antibody fragment.

[0085] Treatment may be periodic, and the period between administrations may be about two weeks or more, e.g., about three weeks or more, about four weeks or more, about onceAttorney Docket No. 157570.620200a month or more, about five weeks or more, or about six weeks or more. For example, treatment may be every two to four weeks or every' four to eight weeks. Treatment may be given before, and / or after surgery / , and / or may be administered or applied directly at the anatomical site of surgical treatment or invasive procedure. Suitable formulations and routes of administration are described above. In some embodiments, the dosing schedules for the anti-IL-6 antibody or antibody fragment is once every 4 or 8 weeks up to about 52 total weeks.

[0086] In some embodiments, a subject is a human, a non-human primate, a pig, a horse, a cow, a dog, a cat, a guinea pig, a mouse or a rat. In some embodiments, a subject is an adult human. In some embodiments, a subject is a pediatric human, or may be an elderly human. In some embodiments, the patient has previously received or is concurrently receiving prednisone or the like at the beginning of said treatment. In one aspect, the dosage of prednisone or the like is between 10 mg and 60 mg per day.

[0087] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited herein, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. In the event that one or more of the incorporated documents or portions of documents define a term that contradicts that tenn’s definition in the application, the definition that appears in this application controls. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment, or any form of suggestion, that they constitute valid prior art or form part of the common general knowledge in any country in the world.

[0088] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. It should be understood that the terms “a” and “an” as used herein refer to “one or more” of the enumerated components unless otherwise indicated The use of the alternative (e.g., “or”) should be understood to mean either one,Attorney Docket No. 157570.620200both, or any combination thereof of the alternatives. As used herein, the terms “include’' and “comprise” are used synonymously.

[0089] The disclosure will be further clarified by the following examples, which are intended to be purely exemplary of the disclosure and in no way limiting.Attorney Docket No. 157570.620200EXAMPLESExample 1: Clinical evaluation of human anti-IL6 antibody in patients diagnosed with AAA

[0090] A phase II study is carried out that determines that pacibekitug, a neutralizing fully human monoclonal antibody (mAb) that binds to soluble IL-6, administered subcutaneously (SC) once every 3 months can decrease hs-CRP levels and the growth rate of AAAs. Key outcomes include changes in maximum aneurysm diameter and hs-CRP level, as well as exploration into changes in aneurysm volume. The study will also assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of pacibekitug, along with circulating biomarkers associated with AAA growth, imaging assessments of vascular inflammation / metabolic activity and coronary' plaque burden, and major vascular events. Maximum aneurysm diameter defines the threshold for repair (Isselbacher 2022, Chaikof 2018) because its relationship with rupture risk is well established (Brewater 2003, Brown 2003, Lederle 2002, Lo 2014).

[0091] Given evidence supporting IL-6 inhibition for ASCVD (Sarwar 2012, Swerdlow 2012, Kaptoge 2014, Ridker 2021), measurements of coronary' plaque are also obtained in study participants. Coronary artery disease is highly prevalent in patients with AAA (Hernesniemi 2015), and patients with small AAA are at a high risk of major adverse cardiovascular events (MACE) (Golledge 2023 Apr). Coronary artery endpoints quantified using coronary CT angiography such as total plaque volume and its constituents (noncalcified plaque, calcified plaque, low attenuation plaque, remodeling index, and fat attenuation index have been strongly associated with major adverse cardiovascular outcomes (Nurmohamed 2024 May, Nurmohamed 2024 Sep, Chan 2024).

[0092] A substudy using18F-FDG-PET / CT examines changes in18F-FDG uptake in abdominal aortic aneurysms of subjects.18F-FDG measures vascular metabolic activity and provides a reproducible, non-invasive measure of arterial inflammation, reflecting glucose uptake by macrophages and other plaque cells (Rudd et al., J Am Coll Cardiol 2007; Rudd et al., Circulation 2002).

[0093] Greater aortic inflammation has been reported in abdominal aortic aneurysmal disease than atherosclerosis (Joshi et al., Open Heart 2020), and several studies have shown an association between18F-FDG uptake and rate of growth in AAA (Sakalihasan et al., EurAttorney Docket No. 157570.620200J Vasc Endovasc Surg 2002; Nchimi et al., Circ Cardiovasc Imaging 2014). In one study of 53 patients with aortic aneurysms (47 abdominal), a higher incidence of significant events (defined as aneurysm growth >1 cm per year, dissection rupture, or emergency surgery) were observed over a 30-month follow-up period among patients with increased18F-FDG uptake than in those without (5 of 18 [28%] versus 2 of 35 [6%]; P=0.03) (Nchimi et al., Circ Cardiovasc Imaging 2014). Another study of 17 patients with abdominal aortic aneurysm showed a significant association between1SF-FDG wall-activity ratio and annualized rate of diameter change (R::::0,76, p<0004) (Subramanian, Tawakol, et al, data available on request).Attorney Docket No. 157570.620200

[0094] Objectives and Endpoints:Objective EndpointPrimary Efficacy® Evaluate the effects of pacibekitug compared with ® Annualized change from baseline in maximum placebo on annualized change from baseline in aneurysm diameter through 24 months (720 days) maximum aneurysm diameter of study treatmentSecondary Efficacy* Evaluate the effects of pacibekitug compared with « Proportion of participants with baseline hs-CRP placebo on hs-CRP levels >2 mg / L achieving time-averaged hs-CRP levels <2 mg / L through the Month 24 visit® Proportion of participants with baseline hs-CRP >1 mg / L achieving time-averaged hs-CRP levels <1 mg / L through the Month 24 visit« Time-averaged percent change from baseline in hs-CRP through the Month 24 visit** Evaluate the safety and tolerability of pacibekitug ® Incidence of AEs, SAEs, severe AEs, AEs leading in participants with AAA to discontinuation, and AESIs1* Incidence of abnormal (1) vital signs, (2) physical examinations, (3) electrocardiograms, (4) safety laboratory measurements® Incidence and titer of anti-drug antibodies • Pharmacokinetics• Evaluate the pharmacokinetics of pacibekitug • Serum drug concentrations of pacibekitug over time® Evaluate the effects of pacibekitug compared with ® Time-averaged percent change from baseline in placebo on IL -6 IL-6 levels through the Month 24 visit• Exploratory Efficacy and Pharmacodynamics» Evaluate the effects of pacibekitug compared with ® Change in maximum aneurysm diameter from placebo on change from baseline in maximum baseline to the Month 12 visitaneurysm diameter» Change in maximum aneurysm diameter from the Month 12 visit to the Month 24 visit® Change in maximum aneurysm diameter from baseline to the Month 24 visit» Evaluate the effects of pacibekitug compared with ® Annualized change from baseline in aneurysm placebo on annualized change from baseline in volume through 24 months (720 days) of study aneurysm volume treatment* Evaluate the effects of pacibekitug compared with • Change in aneurysm volume from baseline to the placebo on change from baseline in aneurysm Month 12 visit, from the Month 12 visit to the volume Month 24 visit, and from baseline to the Month 24 visit® Evaluate the effects of pacibekitug on circulating ® Change from baseline in D-dimer and additional biomarkers associated with aneurysm growth exploratory biomarkers at the Month 12 and theMonth 24 visitsAttorney Docket No. 157570.620200Objective Endpoint* Evaluate the effects of pacibekitug compared with ® Change from baseline in coronary noncalcified placebo on change from baseline in coronary plaque volume, total plaque volume, low artery plaque volume and characteristics assessed attenuation plaque volume, remodeling index, and by coronary CTA pericoronaiy adipose tissue attenuation at the Month 12 and the Month 24 visits• Evaluate the effects of pacibekitug compared with • Time to first major vascular event, such as placebo on cardiovascular outcomes adjudicated cardiovascular death, myocardial infarction, by an expert committee ischemic stroke, AAA rupture, / AAA repair, acute limb ischemia or major amputation for vascular cause« T ota 1 num her of m a j or va scul ar events♦ PET / CT Substudy• Primary: Evaluate the effects of pacibekitug • Change from baseline in vascular18F-FDG TBR at compared with placebo on change from baseline in the Month 6 visit in the most diseased segment of vascular inflammation assessed by18F-FDG the index vessel* Exploratory’: Evaluate the effects of pacibekitug « Change from baseline in AAA18F-FDG TBR at compared with placebo on change from baseline in the Month 6 visit in participants with AAA TBRAAA inflammation assessed by18F-FDG >1.6 at the Dav 1 visitAbbreviations: ANC = absolute neutrophil count; AAA = abdominal aortic aneurysm; AE = adverse event, AE Sis ~ adverse events of special interest; CT A = computed tomography angiography;18F-FDG=18F-fluorodeoxyglucose; hs-CRP = high sensitivity C -reactive protein; IL-6 = interleukin 6; PET / CT = positron emission tomography / computed tomography; SAE = serious adverse event; TBR = target-to-background ratio; ULN = upper limit of normal’AESIs include the following: clinically significant infections (infections that meet any SAE criteria, confirmed opportunistic infections, infections requiring prolonged medications [> 14 days], or infections requiring any parenteral treatment), transaminase elevations > 3 x ULN, sustained severe neutropenia (ANC <1000 / pL on 2 consecutive measurements) with evidence of concurrent infection, sustained severe thrombocytopenia (platelet count <50,000 / pL on 2 consecutive measurements) with evidence of concurrent bleeding, and thromboembolic events (thrombotic events and thromboembolism)Attorney Docket No. 157570.620200

[0095] Overall Study Design:

[0096] A randomized, double-blind, placebo-controlled Phase 2 study is conducted to which demonstrates the safety and efficacy, as well as PK and PD, of 50 mg (once every 3 months for a total of 8 doses) of SC administered pacibekitug versus placebo in participants with AAA. The study aims to determine whether this dosing regimen of pacibekitug can decrease the growth rate of medium-sized AAAs (measuring 40-50 mm, inclusive, in men, or 35-45 mm, inclusive, in women) and decrease hs-CRP levels. The study schematic is depicted in Figure 1.

[0097] Participants undergo an optional pre-Screening Period and a Screening Period of up to 60 days to determine eligibility, those who meet all inclusion criteria and no exclusion criteria will be randomized using a centralized Randomization and Trial Supply Management system to pacibekitug 50 mg or placebo (1:1) administered SC once every 3 months.

[0098] Approximately 120 participants (60 pacibekitug: 60 placebo) will be randomized. To mitigate against treatment group imbalances by sex and in the size distribution of the AAAs, the randomization will be stratified by both sex (male or female) and maximum AAA diameter measured on the Screening computed tomography angiography (CT A) scan (<45 mm or >45 mm). Within these strata, participants will be randomized 1: 1 to pacibekitug or placebo.. After the Screening Period, randomized participants will be dosed every 3 months with pacibekitug or placebo for a total of 8 doses over a 2 -year period. All participants will have visits during the Treatment Period at Day 1 and Months 1, 3, and every 3 months thereafter until Month 24. AH participants will undergo a 180-day safety Follow-up Period after the last treatment visit at Month 24

[0099] Study Duration:

[0100] Approximately up to 33 months (an optional Pre-Screening Period within 28 days of Screening, an up to 60-day Screening Period, a 24-month Treatment Period, and a 180- day Follow-up Period).Attorney Docket No. 157570.620200

[0101] Inclusion Criteria;Participants must meet all of the following criteria to participate in the study:1) Age 18 to 85 years, inclusive, at the time of Informed Consent Form (ICF) signature.2) Infrarenal, fusiform AAA with maximum diameter 40 to 50 mm, inclusive, in men, and 35 to 45 mm, inclusive, in women on CTA scan performed at Screening.3) Serum hs-CRP level >2.0 mg / L at Screening and / or at the Pre-screening visit if the Prescreening visit occurs within 28 days of the Screening visit.• Note that hs-CRP testing is not required at the Screening visit if the above criteria for the Pre-screening hs-CRP test are met. However, if hs-CRP testing is performed at the Screening visit, the Screening hs- CRP value must be >2.0 mg / L to meet this inclusion criterion.4) At least one of the following ri sk related factors for rapid AAA growth:i. Rapid growth: Documented increase in maximum aneurysm diameter of at least 2.0 mm / year within 2 years prior to screening; orii. Smoker: Daily cigarette, cigar, or pipe smoking; oriii. Non-diabetic: Absence of diabetes mellitus (Type 1 or Type 2) and screening hemoglobin, Alc (HbAlc) <6.5%.Attorney Docket No. 157570.6202005) Agreement to comply with the following contraception and reproduction restrictions:• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the Screening visit and negative urine pregnancy test at the randomization visit and must agree to use at least 1 acceptable method of contraception during treatment and for 32 weeks after the last dose of study drug. For the purposes of this study, WOCBP are defined as postmenarchal women who are not surgically sterile (presence of ovaries, uterus, and either fallopian tube) AND not definitively postmenopausal, defined as absence of menses for 24 consecutive months before the Screening visit.• Male participants must be surgically sterile or, if sexually active with a female partner of childbearing potential, must agree to use a condom for the duration of the treatment and for 4 months after the last dose of study drug.Participants in the positron emission tomography / computed tomography (PET / CT) mechanistic substudy must also meet the following inclusion criterion:Any target vessel (ascending aorta, abdominal aorta, right carotid artery, or left carotid artery) with mean of the maximum target-to-background ratio ( TBR) >1.6 on the baseline PET / CT scan.

[0102] Exclusion Criteria:Participants are excluded from the study if any of the following criteria apply:AAA and vascular historyAttorney Docket No. 157570.6202001) Probable secondary etiology of AAA, such as connective tissue disease (eg, collagen vascular disorder), heritable or genetic syndrome (eg, Marfan Syndrome, Ehlers-Danlos Syndrome), vasculitis or other rheumatological condition (eg, giant cell arteritis), or infection.2) Prior AAA repair, current indication for repair (eg, symptoms, rapid growth, or embolic complications), or anticipated indication for repair within 2 years after the Day 1 visit.3) History' of aortic dissection, penetrating aortic ulcer, or thoracic aortic aneurysm.4) Evidence of lack of AAA growth, defined as increase in maximum aneurysm diameter <1.0 mm / year, within 2 years prior to screening.5) AAA extension into suprarenal aorta.6) Iliac artery' aneurysm >29 mm in diameter.7) Planned open surgery or endovascular intervention of the abdominal aorta or its branches.Laboratory values8) Estimated glomerular filtration rate <45 mL / min / 1 73 m2. Estimated glomerular filtration rate will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation.9) Absolute neutrophil count (ANC) <2,000 / pL at Screening.10) Platelet count <120,000 / pL at Screening.11) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN) at ScreeningAttorney Docket No. 157570.620200) Total bilirubin >1,5xULN at Screening in the absence of Gilbert syndrome. In participants with Gilbert syndrome, total bilirubin >2.0 * ULN is the exclusionary threshold.) International normalized ratio (INR) outside the therapeutic range (eg, INR 2.0–3.0 for nonvalvular atrial fibrillation) at the Screening visit for participants treated with warfarin.) Hemoglobin values <9.0 g / dL at the Screening visit.) Uncontrolled Type 1 or Type 2 diabetes mellitus (HbAlc >9% at the Screening visit).) Thyroid-stimulating hormone (TSH) < lower limit of normal (LLN) and free T4 or total T3 > ULN at Screening, in the absence of treatment. Patients on treatment may be considered for enrollment after discussion with and approval from the Medical Monitor.) TSH > ULN and free T4 < LLN at Screening, in the absence of treatment.Patients on treatment may be considered for enrollment after discussion with and approval from the Medical Monitor.) Positive or indeterminate result from QuantiFERON®-TB Gold test at Screening without evaluation and completion of a standard course of therapy meeting World Health Organization or local guidelines. For indeterminate test results, retesting may be considered.) Evidence of human immunodeficiency virus (HIV)-l or HIV-2 infection by serology at Screening.Attorney Docket No. 157570.62020020) Evidence of hepatitis B virus or hepatitis C virus infection by serology (eg, hepatitis B surface antigen or hepatitis C antibody and RNA positive) at Screening.Medical conditions related to eligibility for CTA scan21) Inability to complete Screening CTA of the aorta or any condition that would increase the risk associated with CTA or increase likelihood of uninterpretable scan, including:a. Known allergy to iodinated contrast or history of contrast-induced nephropathy (including adverse reaction to contrast at the Screening CTA). b Thyroid cancer in the previous 5 years.c. Planned radioactive iodine treatment.d. Weight >300 lbs (approximately 136 kg) or above manufacturer- recommended limit for the CT scanner and table at the site, whichever is less. e. Inability to hold breath for >10 seconds.f. Contraindication to dosing with beta blocker or nitroglycerin.Other medical conditions22) Clinical evidence or suspicion of active infection at the Screening or Day 1 visit Treated and / or indolent cutaneous infections, such as isolated cutaneous warts or nonsevere tinea pedis, are not exclusionary.23) Serious infection (an infection requiring hospitalization and / or intravenous (IV) antibiotic, IV antifungal, or IV antiviral treatment and / or having a clinical presentation that is viewed by the investigator as consistent with a serious infection) within 6 months before the Day 1 visit.Attorney Docket No. 157570.620200) History (prior or current) of a serious opportunistic infection (ie, not localized thrush due to corticosteroid therapy) within 18 months prior to the Day 1 visit. ) Participants with indwelling urinary or IV catheters at the Screening or Day 1 visit.) History of immunodeficiency (genetic or acquired, such as acquired immunodeficiency syndrome, common variable immunodeficiency, etc).) History of bone marrow or solid organ transplant or anticipated to receive a bone marrow or solid organ transplant during study participation.) History of gastrointestinal (GI) ulceration (with the exception of oral aphthous ulcers), GI perforation, active diverticulitis, active inflammatory bowel disease, or GI abscess within 12 months prior to the Day 1 visit.) History' of GI bleeding (not including hemorrhoidal bleeding) requiring hospitalization and / or transfusion within 3 months prior to the Day 1 visit.) New York Heart Association Class III or IV congestive heart failure and / or hospitalization for heart failure exacerbation within 6 months prior to the Day 1 visit.) Acute coronary syndrome, stroke, transient ischemic attack, or other thrombotic or thromboembolic event, or arterial revascularization procedure within 3 months prior to the Day 1 visit.) Untreated clinically significant arrhythmia within 6 months of the Day 1 visit. ) Uncontrolled hypertension, defined as a systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg based on an average of 2 measurements at Screening.Attorney Docket No. 157570.62020034) Active cancel’ and / or cancer that required treatment within 1 year prior to the Day 1 visit or expected to require treatment during the course of the study. The following are not considered exclusionary: excised basal cell or squamous cell carcinoma of the skin; carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis; low-risk prostate cancer (Gleason score 6 or less and prostate specific antigen <10 mg / mL).35) History of alcohol or other substance abuse within 1 year prior to the Day 1 visit.36) Known allergy to the study drug (pacibekitug or placebo) or any of its ingredients. Prior or current medications37) Metformin use within 4 weeks prior to the Day 1 visit.38)Evolocumab or alirocumab within 4 weeks or inclisiran within 24 weeks prior to the Day 1 visit.39) Chronic systemic glucocorticoid use, defined as >2 weeks of continuous treatment, within 4 weeks of the Day 1 visit, or anticipated need for chronic systemic glucocorticoid use during the course of the study. Note: use of otic, ophthalmic, inhaled, and topical corticosteroids or local corticosteroid injections are not exclusionary.40) Any previous treatment with an immunomodulatory or immunosuppressive agent, including but not limited to systemic corticosteroids, anti -cytokine therapy (eg, other IL-6 inhibitor [siltuximab, tocilizumab, sarilumab, satralizumab], tumor necrosis factor [TNF] inhibitor [adalimumab, etanercept, etc], IL-17 inhibitor [secukinumab, ixekizumab, etc], IL-23 inhibitor [guselkumab, risankizumab, etc],Attorney Docket No. 157570.620200other IL inhibitor), methotrexate, azathioprine, mercaptopurine, mycophenolate mofetil, montelukast, cyclosporin or colchicine, within 5 half-lives of the drug (or 3 months, whichever is longer) prior to the Day 1 visit or anticipated use of such drugs any time during the study.41)Use of systemic antibiotics, antivirals, or antifungals within 14 days prior to the Day 1 visit. Systemic is defined as oral or IV drugs that are absorbed into the circulation.42) Received a live (attenuated) vaccine within 4 weeks prior to the Day 1 visit. 43) Received an investigational drug within 30 days (or 5 half-lives of the investigational drug administered, whichever is longer) prior to the Day 1 visit.44) Expected to receive any of the prohibited concomitant treatments / interventions specified in the protocol during the Treatment Period or safety' Follow-up Period. General exclusions45) Currently breastfeeding at the Screening or Day 1 visit46) Life expectancy anticipated to be <2 years from the Day 1 visit.47) Scheduled, planned, or anticipated surgery', major procedure, or hospitalization that could potentially occur during participation in the study.48) Any condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results, or that w-ould in the opinion of the investigator increase the risk of participating in the study. Participants are excluded from the PET / CT mechanistic substudy if any of the following criteria apply:Attorney Docket No. 157570.62020049) History of Type 1 diabetes mellitus, Type 2 diabetes requiring insulin therapy, or HbAlc >7.5% at the Screening Visit.50) Weight at the Screening visit greater than the weight limit set by the site's PET / CT scanner specifications or BMI >40 kg / m2.51)Blood glucose >170 mg / dL on the pre-FDG measurement.52) Any other factor that, in the opinion of the investigator, would increase participant risk or increase the chance of an uninterpretable PET / CT scan.

[0103] Test Product, Dose, and Mode of Administration:

[0104] The test product dose regimen that is examined in the study is pacibekitug 50 mg administered subcutaneously (SC) every’ 3 months.

[0105] Placebo, Dose, and Mode of Administration:

[0106] Matched placebo injections are administered SC once every 3 months in the placebo group.

[0107] Number of Participants:

[0108] Approximately 120 participants will be enrolled in the study. Participants will be randomized in a 1:1 ratio (60 to receive pacibekitug and 60 to receive placebo). To ensure balance between treatment arras, randomization will be stratified by sex and baseline maximum aneurysm diameter group (<45 mm or >45 mm). The selected sample size is thought to be sufficient to achieve the objectives of this study. No formal statistical inference is planned.

[0109] Analysis of Primary Efficacy Endpoint

[0110] The primary efficacy endpoint is the annualized change from baseline in maximum aneurysm diameter through 24 months (720 days) of study treatment. The analysis of the primary efficacy endpoint will take place when a sufficient number of randomized participants complete Month 12 assessments or discontinue early from the trial and when all randomized participants complete the study.Attorney Docket No. 157570.620200

[0111] Results from a mixed effects model will be used to compare the primary efficacy endpoint at Months 12 and 24. The model will include randomization factors as fixed effects. A Multiple Imputation method will be used to impute missing post-baseline maximum aneurysm diameters. Least-squares estimates of the difference in means and the corresponding 95% confidence intervals will be reported. Details will be specified in the SAP.

[0112] Analysis of Secondary Endpoints

[0113] The secondary efficacy endpoints will include proportion of participants with baseline hs-CRP >2 mg / L achieving time-averaged hs CRP levels <2 mg / L through the Month 24 visit, proportion of parti cipants with baseline hs-CRP >1 mg / L achieving time-averaged hs-CRP levels <1 mg / L through the Month 24 visit, and time-averaged percent change from baseline in hs CRP through the Month 24 visit. An approach similar to that used for the primary efficacy endpoint will be used to analyze continuous secondary efficacy and PD endpoints. Categorical secondary endpoints will be analyzed using a Cochran-Mantel-Haenszel test controlling for stratification factors. Except for the analyses of hs-CRP measurements, no imputation is planned for missing secondary endpoint measurements.

[0114] Statistical Methods:

[0115] Two analyses are planned for this study. The first analysis will be performed when a sufficient number of participants complete Month 12 assessments or discontinue early. A second analysis will be performed when all participants reach the end of study. The Statistical Analysis Plan (SAP) provide further details regarding the definition of analysis populations, analysis variables, and analysis methodology to address all study objectives,

[0116] As a general strategy, continuous efficacy, PD, and safety endpoints will be summarized using the five-number summary (mean, standard deviation, median, minimum, and maximum). Frequency distributions (counts and percentages) will be used to summarize categorical endpoints.

[0117] All summaries will be provided by treatment group. Analyses by treatment group will be presented as follows:Attorney Docket No. 157570.620200* Efficacy and PD analyses: according to the treatment to which participants were randomized.® Safety analyses: according to the treatment participants actually received

[0118] The SAP will be finalized prior to database lock and unblinding. Analyses planned in the SAP will supersede those presented in this protocol.

[0119] Data and Safety Monitoring:

[0120] An Independent Data Monitoring Committee (IDMC) and the internal Safety Management Committee (SMC) will be appointed for this study. Participant safety will be monitored on an ongoing basis, including safety signal detection at any time during the study.

[0121] An IDMC composed of experts external to the study will review unblinded study information during the conduct of the study, assessing safety concerns, efficacy and overall trial conduct, and make recommendations to the sponsor regarding study modification, continuation, or termination. In addition, the sponsor' s blinded internal SMC will meet regularly to monitor the safety of participants including reviews of aggregate data for safety reporting and make recommendations regarding the continuation or changes to the study (including requesting additional unblinded safety analysis from the IDMC or similar qualified party with no direct study responsibilities, or adding new or more frequent safety assessments to the safety monitoring for each study participant).

[0122] Imaging Core Laboratory;

[0123] Computed tomography angiography of the aorta will be performed at the Screening, Month 12, and Month 24 (end-of-treatment [EOT]) visits. Additional CTA of the aorta scans may be performed as clinically indicated as determined by the investigator. Computed tomography angiography of the coronary arteries will be performed at the Day 1, Month 1, and Month 24 (EOT) visits. In the PET / CT substudy,18F-fluorodeoxyglucose(18F-FDG)-PET / CT will be performed at the Day I and Month 6 visits All CTA and PET / CT scans will be sent for central reading by an imaging core laboratory (ICL). All study endpoints will be based on the readings made by the ICL. The tasks and responsibilities of the ICL will be documented in the ICL Charters prior to initiating the study The ICL Charters will include detailed definitions and operatingAttorney Docket No. 157570.620200procedures. At each analysis timepoint, all scans from baseline to that time will be batch read by 2 or 3 core laboratory readers blinded to treatment group and timepoint

[0124] Clinical Event Committee;

[0125] An independent external Clinical Events Committee (CEC) will be established to adjudicate centrally and in a blinded fashion events suspect of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, AAA rupture, AAA repair, clinical criteria for AAA repair, and other relevant events including major adverse limb events (MALE). The CEC will evaluate whether pre-specified criteria for adjudication endpoints are met. The tasks and responsibilities of the CEC will be documented in a CEC Charter prior to initiating the study.

[0126] Risks of Radiation Exposure from CT angiography and18F-FDG-PET / CT:

[0127] For CTA of the aorta, average radiation doses per study range between 5 - 8 mSv. The recommended surveillance imaging is every 12 months for men with AAA diameters 40 - 49 mm and for women with AAA diameters 40 - 44 mm. Patients with larger AAAs are recommended to have surveillance imaging every 6 months. Given these recommendations for clinical care, this study will include CTA of the aorta at Screening, Month 12, and Month 24. Participants will have a total effective dose of 15 - 24 mSv of radiation from these 3 annual scans. All CTAs of the aorta will be analyzed locally for clinical follow-up. Additional CTAs may be performed as clinically indicated as determined by the investigator.

[0128] Patients with AAAs are considered high risk for CAD, with 25 - 50% of deaths in this population due to cardiovascular disease. Observational studies of AAA patients undergoing repair have shown a prevalence of significant CAD of 46 - 65% (Holda et al., 2020; Kioka et al., 2002). In patients undergoing CTA evaluation of the coronary arteries and aorta simultaneously, the prevalence of CAD was higher in those with AAA than those without aortic aneurysms (57.3% vs. 183%) (Kim et al., 2023). Therefore, CTA of the coronary arteries will also be performed on study participants to assess coronary artery plaque volume. CTA of the coronary' arteries is a non-invasive technique that results in non-negligible radiation exposure Over the past 2 decades, there have been a number of exposure-reducing techniques that now allow' for performance of CTA of the coronary arteries with very / low doses of radiation. For most participants in this study,Attorney Docket No. 157570.620200radiation dose associated per CTA of the coronary arteries will be between 3 - 10 mSv radiation, which would result in a total dose from the CTA of coronary' arteries between 9 - 30 mSv for the 3 examinations at the Day 1, Month 12, and Month 24 visits. All CTAs of the coronary arteries will be analyzed locally for clinical follow-up.

[0129] A substudy using18F-FDG-PET / CT will also be performed in participants at participating centers. Each scan yields a radiation dose of approximately 10 mSv. This is necessary to evaluate the mechanistic action of pacibekitug, which is thought to be anti¬ inflammatory, At present,18F-FDG-PET / CT is the most studied method for evaluating arterial inflammation. For this subset of participants,l8F-FDG-PET / CT will be performed at the Day 1 and Month 6 visits, resulting in an estimated cumulative dose of 20 mSv.

[0130] Participants undergoing CTAs of the aorta and the coronary arteries will be exposed to 8 - 18 mSv at the beginning of the first year, 8 - 18 mSv at the beginning of the second year, and 8 - 18 mSv at the beginning of the third year of the study.Participants that are included in the18F-FDG-PET / CT substudy will be exposed to an additional 10 mSv from the first scan, and an additional 10 mSv if they complete the substudy.

[0131] By comparison, the average annual radiation exposure from natural background sources in the US is between 2 and 3.6 mSv. The radiation exposure from this study is less than the maximally allowed annual radiation exposure to radiation workers such as radiology technologists, radiologists, or workers in nuclear plants (50 mSv per year). Scan protocols will follow the guiding principle of As Low As Reasonably Achievable

[0132] Overall, each CTA scan adds a very small theoretical risk of less than 0.05% to the 7% lifetime risk of lung cancer for men and women and to the 12% lifetime risk of breast cancer for women. In contrast, the morbidity risk AAA poses to a participant is significantly higher.

[0133] Table 1 provides a Schedule of Activities (SOA) for the study.TABLE 1Attorney Docket No. 157570.620200OptionalPreScreeningTreatment Follow-up ScreeningiVisit Number -2 -1 1 2 3 4 5 6 7 8 9 10 99 Fl F2Within 28 EOT± EOT+ Visit Day(s) days of -60 to -1 1 30 90 180 270 360 450 540 630 720 / E Earlyrof 90 180 Screening OT Visit Month 0 1 3 6 9 12 15 18 21 24 EOT+ EOT+3 6 Visit Window (days) ±7 ±14 ±14 ±14 ±14 ±14 ±14 ±14 ±14 ±14 ±14 Pre-screening informedXconsent signedInformed consent signed XInclusion / exclusion X XcriteriaRandomization XStudy drugX4X4X X X X X Xadministration3Review of prior AAAXimagingCTA of the aorta3’6X X X XCTA of the coronaryX X X Xarteries3’6PET / CT (substudy)7X XMedical history X XAssessment of cigarette,X X X X X X X X X X X X X Xcigar, or pipe smokingPrior medications andX XproceduresConcomitant medications X X x X X X X X X X X X X X and proceduresVital signs8X X X X X X X X X X X X X X Height XWeight, BMI X X X X X X XPhysical examination9X X X x X X X X X X X XECG10X X X X X X XAE assessment11X X X X X X X X X X X X X X■ ■lis-CRP12X 1 1 X 1 1 X X X X X X X X X XAttorney Docket No. 157570.620200OptionalPreScreeningTreatment Follow-up ScreeningiVisit Number -2 -1 1 2 3 4 5 6 7 8 9 10 99 Fl F2Within 28 EOT± EOT+ Visit Day(s) days of -60 to -1 1 30 90 180 270 360 450 540 630 720 / E EarlyEOT± 90 180 Screening OT Visit Month 0 1 3 6 9 12 15 18 21 24 EOT+ EOT+3 6 Visit Window (days) ±7 ±14 ±14 ±14 ±14 ±14 ±14 ±14 ±14 ±14 ±14 Hemoglobin Ale X XThyroid tests13X X X XHBV, HCV. HIV, TB Xtests14CBC15X X X X X X X X X X X X INR (if on warfarin)16X X X X X X X X X X X X X X Liver tests17X X X X X X X X X X X X X Creatinine and eGFR18X X X X X X X X Lipids / lipoproteins19X X X X X X X Biomarkers of AAA X X X X X X X growth20Exploratory biomarkers21X X X X X X X IL-612X X X X X X X X X X X X X Pacibekitug PK, ADA22X X X X X X X X X X X X X Serum pregnancy testX(WOCBP)23Urine pregnancy' testX X X X X X X X x X X X X (WOCBP)23Abbreviations:18F-FDG-PET / CT =18F -fluorodeoxy glucose positron emission tomograpby / computed tomography; AAA = abdominal aortic aneurysm; ADA = anti-drug antibody; AE adverse event; BMI = body mass index; CBC = complete blood count; CKD-EP1 = Chronic Kidney Disease Epidemiology Collaboration; CT A ~ computed tomography' angiography; ECG ~ electrocardiogram; eGFR “ estimated glomerular filtration rate; EOT = end-of-treatment; F = Follow-up; HbsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV “ hepatitis C virus; HC VAb = hepatitis C virus antibody; HDL “ high-density lipoprotein; HIV = human immunodeficiency virus; hs-CRP = high sensitivity' C -reactive protein; IL-6 = interleukin 6; INR ~ international normalized ratio; LDL = low-density lipoprotein; PK ~ pharmacokinetic; SoA = Schedule of Activities; TB = tuberculosis; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potentialNote: Unscheduled visits / assessments will be performed as needed at the discretion of the investigator. Note: Blinded laboratory results: hs-CRP levels will be provided to sites for the Pre-screening, Screening, and Day 1 visits, but will be blinded after Visit I. IL-6 levels, PK data (pacibekitug levels), and ADA levels will be blinded throughout the study. Potentially unblinding laboratory results will not be shared with blinded study' staff after the Day' 1 visit.Attorney Docket No. 157570.6202001. Pre-screening visit: An optional Pre-screening visit to obtain a blood sample to evaluate hs-CRP level may be considered. This Pre-screening visit should only be performed after i) investigator review of the participant’s charts to preliminarily assess participant eligibility, and ii) participant signing of the prescreening Informed Consent Form. The pre-screening hs-CRP test will be performed by the central laboratory. If the pre-screening hs-CRP value is >2 mg / L and the Pre-screening visit is within 28 da s of the Screening visit, the pre-screening hs-CRP value may be used to support inclusion criterion #3, and hs-CRP testing is not required at the Screening visit.2 Screening Period: Note that fasting is not required for Screening assessments Laboratory tests and blood pressure measurements may be repeated once to assess for eligibility after consultation with and approval from the Medical Monitor The Screening period is up to 60 days prior to Day 1; assessments may occur at any time during the Screening period. Once eligibility is confirmed, it is not necessary to wait the full 60 days to randomize the participant.3. Study drug will be injected after pre -dose vital signs, physical examination, ECG recording, and blood sample collection are performed. After study drug has been administered, participants should remain at the study site for at least 1 hour for AE monitoring.4. Post-dose safety contact: Within 7 days after study drug administration on the Day 1 and Day 90 visits, the site must inquire (through email, text, or phone call) whether the participant has experienced any subacute AEs or hypersensitivity reactions following dosing. The site should make at least 2 attempts to contact the participant within 7 days post dose administration. If there is any such reaction or AE, the site must collect applicable information as needed as an AE, and the investigator must determine whether further monitoring and / or safety intervention is warranted for the safety of the participant5. The Screening CT A of the aorta will be assessed by the CT A core laboratory to determine eligibility. All subsequent CT As of the aorta and the CT As of the coronary arteries will be analyzed locally for clinical follow-up Additional CTA scans may be performed as clinically indicated as determined by the investigator.6. Prior to CTA scans of the aorta or coronary arteries, serum creatinine must be evaluated and eGFR must be calculated and evaluated within 30 days If the eGFR is <45 mL / min / 1.73 m2and the investigator feels that it is safe for the participant to receive iodinated contrast, the CTA may proceed after approval from the Medical Monitor / sponsor. In this circumstance, prophylaxis with intravenous normal saline may be considered at the discretion of the investigator.* If early EOT occurs <180 da s from the prior imaging scan date, imaging will not be performed at the early EOT visit.7 PET / CT: All participants must have fasted for at least 10 hours the previous night after a low-carbohydrate dinner. Participants being imaged in the afternoon may have breakfast from the recommended menu and then fast for at least 4 hours prior to the18F-FDG injection Instructions will be provided regarding the low-carbohydrate dinner and breakfast menu. Thirty’ minutes beforel8F-FDG intravenous injection, glucose will be measured. Participants will be excluded if the blood glucose is >170 mg / dL. Participants with blood glucose levels of 150 to 170 mg / dL may be rescheduled. To prevent the need for rescheduling, the sampling may be repeated within 1 hour to determine if the level drops to below 150 mg / dL. Participants will be imaged after 2 hours of18F-FDG circulation.8 Vital signs include temperature, respiratory rate, heart rate, and blood pressure. Vital signs should be obtained after at least 5 minutes in the sitting position or, when necessary, in a semi-recumbent position Vital signs will be collected prior to blood sample collection, ECG recording, and study drug administration At study drug dosing visits, vital signs will be obtained prior to study drug injection and twice after injection Post-dose vital signs will be obtained 15 minutes (±10 minutes) and 45 minutes (± 15 minutes) after study drug administration9. Physical examinations will include assessments of the skin, oropharynx, lungs, heart, abdomen, and extremities In addition, care should be taken to assess any abnormalities that may be present as indicated by symptoms reported by the participant, the participant’s medical history, AEs, or other findings, with particular attention to signs of infection. Physical examinations will be performed by a medically qualified individual such as a licensed physician, ph sician’s assistant, or a registered nurse practitioner10. Standard 12-lead ECGs will be recorded in the supine position (or with the participant as flat as possible) after vital signs assessments and after the participant has been resting for at least 5 minutes. The ECGs will be locally read by the investigator.Attorney Docket No. 157570.62020011. Only procedure -related AEs will be collected at Pre-screening and Screening visits.12 hs-CRP and IL -6 sampling to be acquired prior to dosing.13. Thyroid tests: TSH with reflex total T3, free T4.14. HBV, HCV, HIV, TB tests: HbsAg, HCVAb, HCVRNA (reflex testing if HCVAb positive), HIV- 1 and HIV-2 antibody, QuantiFERON*-TB Gold test.15 CBC: hematocrit, hemoglobin, red blood cell indices (mean corpuscular hemoglobin, mean corpuscular volume, red blood cell count, red cell distribution width, reticulocyte count), platelet count, white blood cell count, white blood cell differential (basophils, eosinophils, immature forms, lymphocytes, monocytes, neutrophils).16 INR will be evaluated among participants treated with warfarin.17. Liver tests: alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, direct bilirubin, gamma-glutamyl transferase, total bilirubin.18. Creatinine and eGFR: creatinine, eGFR calculated using CKD-EPI equation. Additional creatinine and eGFR testing will be performed before unscheduled CTA scans On CTA scan visits, serum creatinine must be evaluated and eGFR must be calculated and evaluated within 30 days prior to the CTA scan.19 Lipids / Iipoproteins: Lipids (total cholesterol, triglycerides), lipoproteins (HDL cholesterol, LDL cholesterol [direct]), apolipoproteins (apolipoprotein A-l, apolipoprotein B) and lipoprotein (a). Fasting is not required. If nonfasting triglycerides are elevated, a fasting assessment may be made if clinically indicated 20. Biomarkers of AAA growth eg, D-dimer.21. Blood samples for exploratory biomarkers eg, biomarkers related to inflammation and cardiovascular risk.22 Pacibekitug PK, ADA: On dosing visits (Days 1, 30, 90, 180, 270, 360, 450, 540, 630), PK and ADA samples will be collected pre-dose. PK blood samples will also be collected on Study Days 720 / EOT, EOT+90, EOT+180 at approximately the same time as the pre-dose samples were collected on previous dosing visits.23 Pregnancy testing: For participants who are WOCBP, serum p-human chorionic gonadotropin will be performed at the Screening visit and urine pregnancy testing will be performed and confirmed negative prior to study drug administration. Additional testing may be conducted per local requirements For the purposes of this study, WOCBP are defined as postmenarchal women who are not surgically sterile (presence of ovaries, uterus, and either fallopian tube) AND not definitively postmenopausal, defined as absence of menses for 24 consecutive months before the Screening visit.

[0134] Table 2 provides the protocol-required laboratory tests for the study.Table 2Laboratory Tests ParametersHbsAgInfection tests (screening) HCVAb, HCV RNA (reflex testing if HCVAb positive)HIV-1 and HIV-2 antibodyQuantiFERON*-TB Gold testhemoglobin AleAdditional screening blood thyroid tests (TSH with reflex total T3, free T4)testshematocritHem atology hemoglobinred blood cell indices (mean corpuscular hemoglobin, mean corpuscular volume, red blood cell count, red cell distribution width, reticulocyte count)platelet countwhite blood cell countAttorney Docket No. 157570.620200Laboratory Tests Parameterswhite blood cell differential (basophils, eosinophils, immature forms, lymphocytes, monocytes, neutrophils)Coagulation INR (among participants treated with warfarin)Chemistry alanine aminotransferasealbuminalkaline phosphatasea spartate aminotransferasedirect bilirubingamma-glutamyl transferasetotal bilirubin.creatinineeGFRLipids and lipoproteins1total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol [direct] apolipoprotein Al, apolipoprotein Blipoprotein (a)Pharmacodynamic tests hs-CRPIL-6Biomarkers of AAA growth D-dimerexploratory biomarkersPharmacokinetic tests pacibekitug drug concentrationanti-drug antibodiesPregnancy tests serum β-HCGurine β-HCG (local)Abbreviations: β-HCG = beta-human chorionic gonadotropin; eGFR = estimated glomerular filtration rate; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HCVAb = hepatitis C virus antibody; HDL = high-density lipoprotein; HIV = human immunodeficiency virus; hs-CRP = high-sensitivity C-reactive protein; IL -6 = interleukin 6 INR = international normalized ratio; LDL = low-density lipoprotein; TB “ tuberculosis; TSH ~ thyroid-stimulating hormoneI. Fastitig is not required. If nonfasting triglycerides are elevated, a fasting assessment may be made if clinically indicated.Example 2: A phase 2 study of pacibekitug in patients with abdominal aortic aneurysm and elevated high-sensitivity C-reactive protein

[0135] A phase II study is carried out that determines that pacibekitug, a neutralizing fully human monoclonal antibody (mAb) that binds to soluble IL-6, administered subcutaneously (SC) once every 3 months can decrease hs-CRP levels in participants with AAAs. The study will also assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of pacibekitug. Explorations include changes in aneurysm diameter and AAA volume along with circulating biomarkers associated with AAA growth, imaging assessments of vascular inflammation / metabolic activity and coronary plaque burden, and major vascular events.Attorney Docket No. 157570.620200

[0136] Objectives and Endpoints:Objective Endpoint* Evaluate the effects of pacibekitug compared with » Time-averaged percent change from baseline in placebo on hs-CRP hs-CRP through the Month 12 visit® Evaluate the safety and tolerability of pacibekitug • Incidence of AEs. SAEs, severe AEs, AEs leading in participants with AAA to discontinuation, and AESIs1® Incidence of abnormal (1) safety- laboratory-’ measurements. (2) vital signs, (3) electrocardiograms» Incidence and titer of anti-drug antibodies Pharmacokinetics* Evaluate the pharmacokinetics of pacibekitug » Serum drug concentrations of pacibekitug over timeExploratory Efficacy and Pharmacodynamics® Evaluate the effects of pacibekitug compared with ® Change from baseline in hs-CRP through the placebo on hs-CRP levels Month 12 and Month 24 visits• Percentage of participants achieving hs-CRP levels <2 mg / L through the Month 12 and through the Month 24 visits» Percentage of participants achieving hs-CRP levels <1 mg / L through the Month 12 and through the Month 24 visits» Evaluate the effects of pacibekitug on IL -6 « Change from baseline in IL-6 levels through the Month 12 and Month 24 visits• Evaluate the effects of pacibekitug compared with » Annualized change from baseline in maximum placebo on change from baseline in maximum aneurysm diameter through 24 months of study aneurysm diameter treatment® Change in maximum aneurysm diameter from baseline to the Month 12 visit® Change in maximum aneurysm diameter from the Month 12 visit to the Month 24 visit® Change in maximum aneurysm diameter from baseline to the Month 24 visit* Evaluate the effects of pacibekitug compared with • Annualized change from baseline in aneurysm volume through 24 months of study treatment » Change in aneurysm volume from baseline to the Month 12 visit, from the Month 12 visit to the Month 24 visit, and from baseline to the Month 24 visit* Evaluate the effects of pacibekitug on exploratory • Change from baseline in exploratory biomarkers at biomarkers associated with inflammation, the Month 12 and the Month 24 visits cardiovascular risk, and / or AAA growth* Evaluate the effects of pacibekitug compared with • Change from baseline in coronary plaque placebo on change from baseline in coronary characteristics including noncalcified plaque artery plaque volume and characteristics assessed volume, total plaque volume, low attenuation by coronary CTA plaque volume, and remodeling index at theMonth 18 visitAttorney Docket No. 157570.620200Objective Endpoint* Evaluate the effects of pacibekitug compared with ® Time to first major vascular event, such as placebo on cardiovascular outcomes adjudicated cardiovascular death, myocardial infarction, by an expert committee ischemic stroke, AAA rupture, AAA repair, acute limb ischemia or major amputation for vascular cause» Total number of major vascular events♦ PET / CT Substudy* Evaluate the effects of pacibekitug compared with ® Change from baseline in vascular18F-FDG TBR at placebo on change from baseline in vascular the Month 6 visit in the most diseased segment of inflammation assessed by18F-FDG the index vessel» Evaluate the effects of pacibekitug compared with « Change from baseline in AAA18F-FDG TBR at placebo on change from baseline in AAA the Month 6 visit in participants with AAA TBRinflammation assessed by18F-FDG >1.6 at the Day 1 visitAbbreviations: ANC = absolute neutrophil count; AAA = abdominal aortic aneurysm; AE = adverse event; AE Sis = adverse events of special interest; CT A - computed tomography angiography;18F-FDG=18F-fluorodeoxyglucose; hs-CRP = high sensitivity C-reactive protein; IL-6 = interleukin 6; PET / CT = positron emission tomography / computed tomography; SAE = serious adverse event; TBR = target-to-background ratio, ULN = upper limit of normal'AESIs include the following: clinically significant infections (infections that meet any SAE criteria, confirmed opportunistic infections, infections requiring prolonged medications [> 14 days], or infections requiring any parenteral treatment), transaminase elevations > 3 x ULN, sustained severe neutropenia (ANC <1000 / pL on 2 consecutive measurements) with evidence of concurrent infection, confirmed severe thrombocytopenia (platelet count <50,000 / pL on 2 consecutive measurements) with evidence of concurrent bleeding, and thromboembolic events (thrombotic events and thromboembolism)

[0137] Overall Design:

[0138] A randomized, double-blind, placebo-controlled Phase 2 study is conducted to evaluate the safety and efficacy, as well as PK and PD, of 50 mg (once every 3 months for a total of 8 doses) of SC administered pacibekitug versus placebo in participants with AAA and elevated hs-CRP. The study aims to determine whether this dosing regimen of pacibekitug can decrease hs-CRP levels in this population. Exploratory efficacy includes assessment of the effect of this therapy on the growth rate of medium-sized AAAs (measuring 40-50 mm, inclusive, in men, or 35-45 mm, inclusive, in women).

[0139] Participants undergo an optional pre-Screening Period and a Screening Period of up to 60 days to determine eligibility. Those who meet all inclusion criteria and no exclusion criteria will be randomized using a centralized Randomization and Trial Supply Management system to pacibekitug 50 mg or placebo (1:1) administered SC once every 3 months.Attorney Docket No. 157570.620200

[0140] Approximately 120 evaluable participants (60 pacibekitug:60 placebo) will be randomized. To mitigate against treatment group imbalances by factors that could affect the growth rate of AAAs, the randomization will be stratified by screening hs-CRP (<3.0 mg / L or =3.0 mg / L), maximum AAA diameter measured on the Screening computed tomography angiography (CTA) scan (<45 mm or =45 mm), and smoking status (active daily cigarette, cigar or pipe smoking or not). Within these strata, participants will be randomized in a 1: 1 ratio to pacibekitug or placebo.

[0141] After the Screening Period, randomized participants will be dosed every 3 months with pacibekitug or placebo for a total of 8 doses over a 2-year period. All participants will have visits during the Treatment Period at Day 1 and Months 1, 3, and every' 3 months thereafter until Month 24. All participants will undergo a 180-day safety Follow¬ up Period after the last treatment visit at Month 24.

[0142] Study Duration:

[0143] Approximately up to 33 months (an optional Pre-Screening Period within 28 days of Screening, an up to 60-day Screening Period, a 24-month Treatment Period, and a 180-day safety Follow-up Period).

[0144] Inclusion Criteria:Participants must meet all of the following criteria to participate in the study: 1) Age 18 to 85 years, inclusive, at the time of informed consent form (ICF) signature.2) Infrarenal AAA with maximum diameter 40 to 50 mm, inclusive, in men, and 35 to 45 mm, inclusive, in women, on the CTA scan performed at Screening, as assessed locally.3) Serum hs-CRP level =2.0 mg / L at the Screening and / or Pre-screening visit. Note that hs-CRP testing is not required at the Screening visit if the hs-CRP level is =2.0 mg / L. at the Pre-screening visit. However, if hs-CRP testing is performed at the Screening visit, the Screening hs-CRP value must be =2.0 mg / L to meet this inclusion criterion.4) At least one of the following risk factors for AAA growth:a. Absence of diabetes mellitus (Type 1 or Type 2) and screening HbAlc <65%; orb. Active daily cigarette, cigar, or pipe smoking; orAttorney Docket No. 157570.620200c. Documented increase in maximum aneurysm diameter of at least 2.0 mm / year within 2 years prior to Screening. Note: It is not anticipated that many sites will have such data. This documentation provides a way for diabetic AAA patients who are not daily smokers to meet this requirement for an additional risk factor for AAA growth.5) Agreement to comply with contraception and reproduction restrictions of the studya. Women of childbearing potential (WOCBP) and men must use a method of contraception that is highly effective (ie, failure rate <1% per year)ORb. Female participants must be surgically sterile (documented total hysterectomy., bilateral salpingectomy, and / or bilateral oophorectomy) or postmenopausal (no menstrual bleeding for at least 2 years before Screening and either over the age of 60 years or with an elevated plasma follicle-stimulating hormone [FSH] level [ie, >40 mIU / mL] at Screening)ANDc. All WOCBP must have a documented negative serum pregnancy test result at Screening and a negative urine pregnancy test on Day 1. If the serum pregnancy test was performed more than 7 days prior to Day 1, a repeat serum pregnancy test must be performed.

[0145] Exclusion CriteriaParticipants are excluded from the study if any of the following criteria apply:AAA and vascular history1) Documented secondary' etiology of AAA, such as connective tissue disease (eg, collagen vascular disorder), heritable or genetic syndrome (eg, Marfan Syndrome, Ehlers-Danlos Syndrome), vasculitis or other rheumatological condition (eg, giant cell arteritis), or infection.2) Prior AAA repair or current or anticipated indication for AAA repair or other open surgery or endovascular intervention involving the abdominal aorta or its branches within 2 years after the Day 1 visit.3) History of acute aortic syndrome (eg, aortic dissection, penetrating aortic ulcer, or intramural hemorrhage).Attorney Docket No. 157570.6202004) Known iliac artery aneurysm >25 mm in diameter.5) Acute coronary syndrome, stroke, transient ischemic attack, or other thrombotic or thromboembolic event, or arterial revascularization procedure, or NYHA Class IV heart failure or heart failure hospitalization within 6 weeks prior to the Day 1 visit.Attorney Docket No. 157570.620200Laboratory values6) Exclusionary laboratory values at Screening:a. Hemoglobin <9.0 g / dL or absolute neutrophil count (ANC) <2,000 / pL or platelet count <120,000 / p. Lb. Estimated glomerular filtration rate <45 mL / min / 1.73 m2 Estimated glomerular filtration rate will be calculated using the CKD-EPI creatinine equation. c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 upper limit of normal (ULN) or total bilirubin >1.5 × ULN in the absence of Gilbert syndrome. In participants with Gilbert syndrome, total bilirubin >2.0 * ULN is the exclusionary threshold.d. HbAlc >9%.e. Thyroid stimulating hormone (TSH) < lower limit of normal (LLN) and free T4 or total T3 > ULN OR TSH > ULN and free T4 < LLN in the absence of treatment. Patients on treatment may be considered for enrollment after discussion with and approval from the Medical Monitor.f. Poorly controlled international normalized ratio (INR), in the judgment of the investigator, in participants treated with warfarin who are outside the therapeutic range (eg, INR 2.0 to 3.0 for nonvalvular atrial fibrillation) at the Screening visit.Medical conditions related to eligibility for CIA scan of the aorta7) Inability to complete Screening CTA of the aorta or any condition that would increase the risk associated with CTA or increase likelihood of uninterpretable scan, including:a. Known clinically significant allergy to iodinated contrast that cannot be adequately pre-medicated, or any prior anaphylaxis to iodinated contrast.b. Thyroid cancer in the previous 5 years.c. Planned radioactive iodine treatment.d. Weight >450 lbs (approximately 205 kg) or above manufacturer-recommended limit for the CT scanner and table at the site, whichever is less.e. Inability to hold breath for >10 seconds.Other medical conditions8) Infection or risk of infectionAttorney Docket No. 157570.620200a. Clinical evidence or suspicion of active infection at the Screening or Day 1 visit Treated and / or indolent cutaneous infections, such as isolated cutaneous warts or nonsevere tinea pedis, are not exclusionary.b. Positive or indeterminate result from QuantiFERON®-TB Gold test at Screening without evaluation and completion of a standard course of therapy meeting World Health Organization or local guidelines. For indeterminate test results, retesting may be considered.c. Evidence of human immunodeficiency virus (HIV)-l or HIV-2 infection by serology at Screening.d. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection by serology (eg, HBV surface antigen or HCV antibody and RNA positive) at Screening. Participants with a positive HBV surface antibody result that is not consistent with prior vaccination or participants with a positive HCV antibody result will require documentation of negative HBV surface antigen or HCV RNA negative to be eligible.e. Significant infection (an infection requiring hospitalization and / or intravenous (IV) antibiotic, IV antifungal, or IV antiviral treatment and / or having a clinical presentation that is viewed by the investigator as consistent with a significant infection) within 6 months before the Day 1 visit.f. Requiring a chronic indwelling urinary' or IV catheter.g. History of immunodeficiency (genetic or acquired, such as acquired immunodeficiency syndrome, common variable immunodeficiency, etc,) OR bone marrow or solid organ transplant or anticipated to receive a bone marrow or solid organ transplant during study participation.9) History' of gastrointestinal (GI) perforation, active diverticulitis, active inflammatory bowel disease, or GI abscess within 12 months prior to the Day 1 visit OR history of GI bleeding (not including hemorrhoidal bleeding) requiring hospitalization and / or transfusion within 3 months prior to the Day 1 visit.10) Uncontrolled hypertension, defined as a systolic blood pressure >180 mmHg and / or diastolic blood pressure >110 mmHg based on an average of 2 measurements at Screening.Attorney Docket No. 157570.62020011) Active cancer and / or cancer that required treatment within 1 year prior to the Day 1 visit or expected to require treatment during the course of the study. The following are not considered exclusionary: excised basal cell or squamous cell carcinoma of the skin, carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis; low-risk prostate cancer (Gleason score 6 or less and prostate specific antigen <10 mg / mL).Prior or current medications12) Metformin use within 4 weeks prior to the Day 1 visit.13) Chronic systemic glucocorticoid use, defined as >2 weeks of continuous treatment, within 4 weeks of the Day 1 visit, or anticipated need for chronic systemic glucocorticoid use during the course of the study. Note: use of otic, ophthalmic, inhaled, and topical corticosteroids or local corticosteroid injections are not exclusionary.14) Any previous treatment with an immunomodulatory or immunosuppressive agent, including but not limited to systemic corticosteroids, anti-cytokine therapy (eg, other IL-6 inhibitor [siltuximab, tocilizumab, sarilumab, satralizumab], TNF inhibitor [adalimumab, etanercept, etc], IL- 17 inhibitor [secukinumab, ixekizumab, etc], IL-23 inhibitor [guselkumab, risankizumab, etc], other IL inhibitor), methotrexate, azathioprine, mercaptopurine, mycophenolate mofetil, montelukast, cyclosporin or colchicine, within 5 half-lives of the drug (or 3 months, whichever is longer) prior to the Day 1 visit or anticipated use of such drugs any time during the study.15) Received a live (attenuated) vaccine within 4 weeks prior to the Day 1 visit.16) Received an investigational drug within 30 days (or 5 half-lives of the investigational drug administered, whichever is longer) prior to the Day 1 visit.General exclusions17) Currently breastfeeding at the Screening or Day 1 visit.18) Any condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results (eg, life expectancy <2 years, scheduled or planned surgery, history of alcohol or other substance abuse within prior 1 year), or that would in the opinion of the investigator increase the risk of participating in the study (eg, known hypersensitivity to pacibekitug).

[0146] Test Product. Dose, and Mode of Administration:Attorney Docket No. 157570.620200

[0147] The test product dose regimen to be examined in the study is pacibekitug 50 mg administered SC once every' 3 months.

[0148] Placebo, Dose, and Mode of Administration:

[0149] Matched placebo injections will be administered SC once every 3 months in the placebo group.

[0150] Number of Participants:

[0151] Approximately 120 evaluable participants will be enrolled in the study.Participants will be randomized in a 1:1 ratio (60 to receive pacibekitug and 60 to receive placebo). To ensure balance between treatment arms, randomization will be stratified by screening hs-CRP (<3.0 mg / L and =3.0 mg / L), baseline maximum aneurysm diameter (<45 mm or =45 mm), and smoking status (active daily cigarette, cigar or pipe smoking or not). The selected sample size is thought to be sufficient to achieve the objectives of this study. No formal statistical inference is planned.INCORPORATION BY REFERENCE

[0152] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country' in the world.Attorney Docket No. 157570.620200 ReferencesGolledge J, Thanigaimani S, Powell J, and Tsao, PS. Pathogenesis and management of abdominal aortic aneurysm (Review). Eur Heart J. 2023 Jun 30;44(29):2682-2697. doi: 10.1093 / eurheartj / ehad386.Stuntz M. Modeling the Burden of Abdominal Aortic Aneurysm in the USA in 2013 Cardiology. 2016;135(2):127-131. doi: 10.1159 / 000446871.Song P, He Y, Adeloye S et al. The Global and Regional Prevalence of Abdominal Aortic Aneurysms: A Systematic Review and Modeling Analysis Ann Surg. 2023 Jun 1;277(6):912-919. doi: 10.1097 / SLA.0000000000005716.CDC WONDER Underlying Case of Death, 1999-2020 Request https: / / wonder.cdc.gov / controller / datarequest / D76.Thompson RW. Detection and management of small aortic aneurysms. N Eng J Med. 2002 May 9;346(19):1484-1486. doi: 10.1056 / NEJM200205093461910.Kent KC. Clinical practice. Abdominal aortic aneurysms. N Eng J Med 2014 Nov 27;371(22):2101-2108. doi: 10.1056 / NEJMcp1401430.Wassef M, Baxter BT, Chisholm RL, et al. Pathogenesis of abdominal aortic aneurysms: a multidisciplinary research program supported by the National Heart, Lung, and Blood Institute. J Vase Surg. 2001 Oct;34(4):730-738. doi: 10.1067 / mva.2001.116966.Kraiss LW, Conte, MS, Geary RL. et al. Setting high-impact clinical research priorities for the Society for Vascular Surgery. J Vase Surg. 2013 Feb:57(2):493-500. doi: 10.1016 / j.jvs.2012.09.069.Lee R, Jones A, Cassimjee I et al. International opinion on priorities in research for small abdominal aortic aneurysms and the potential path for research to impact clinical management. Int J Cardiol. 2017 Oct 15;245:253-255. doi: 10.1016 / j.ijcard.2017.06.058.Cai T, Zhang Y, Ho Y et al. Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy: A Phenome-Wide Association Study 2018 Sep 1;3(9):849-857. doi: 10.1001 / jamacardio.2018.2287.Georgakis M, Malik R, Gill D et al. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study Circ Genom Precis Med. 2020 Jun;13(3):e002872. doi: 10.1161 / CIRCGEN.119.002872. Epub 2020 May 12.Harrison SC, Smith AJP, Jones GT et al. Interleukin-6 receptor pathways in abdominal aortic aneurysm. Eur Heart J. 2013 Dec;34(48):3707-16. doi: 10.1093 / eurheartj / ehs354.Burgess S, Cronje HT, deGoma E et al. Human genetic evidence to inform clinical development of interleukin-6 signaling inhibition for abdominal aortic aneurysm. ATVB (2024).Paige E, Clement M, Lareyre F et al. Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates Circ Genom Precis Med. 2019 Feb;12(2):e002413. doi: 10.1161 / CIRCGEN.118.002413. Thanigaimani S, Ibrahim M, and Golledge J. Potential of Disease -Modifying Anti-Rheumatic Drugs to Limit Abdominal Aortic. Aneurysm Growth. Biomedicines. 2022 Sep 26;10(10):2409. doi: 10.3390 / biomedicines10102409.70Attorney Docket No. 157570.620200De Haro J, Acin F, Bleda S et al. Prediction of asymptomatic abdominal aortic aneurysm expansion by means of rate of variation of C-reactive protein plasma levels. J Vasc Surg. 2012 Jul;56(1):45-52. doi: 10.1016 / j.jvs.2012.01.003. Epub 2012 May 1.Cersit S, Ocal L, Keskin M et al. Association of C-Reactive Protein-to-Albumin Ratio With the Presence and Progression of Abdominal Aortic Aneurysm. Angiology. 2021 Feb;72(2):153-158. doi: 10.1177 / 0003319720954084. Epub 2020 Sep 10.Kokje VBC, Gabel G, Koole D et al. IL-6: A Janus-like factor in abdominal aortic aneurysm disease Atherosclerosis. 2016 Aug:251:139-146. doi: 10.1016 / j.atherosclerosis.2016.06.021. Epub 2016 Jun 11.Nishihara M, Aoki H, Ohno S et al. The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice. PloS One. 2017 Oct 5;12(10):e0185923. doi: 10.1371 / journal.pone.0185923. eCollection 2017.Patel R, Hall SR, Lanford H et al. Signaling through the IL-6-STAT3 Pathway Promotes Proteolytically-Active Macrophage Accumulation Necessary for Development of Small AAA Vase Endovascular Surg 2023 Jul;57(5):433-444. doi: 10.1177 / 15385744231152961. Epub 2023 Jan 13.Isselbacher EM, Preventza O, Black 3rdJH et al. 2022 ACC / AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association / American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Dec 13;146(24):e334-e482. doi: 10.1161 / CIR.0000000000001106. Epub 2022 Nov 2.Chaikof EL, Dalman RL, Eskandari MK et al The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg. 2018 Jan;67(1):2-77.e2. doi: 10.1016 / j.jvs.2017.10.044.Brewster DC, Cronenwett JL, Hallett Jr JW et al. Guidelines for the treatment of abdominal aort ic aneurysms. Report of a subcommittee of the Joint Council of the American Association for V ascular Surgery and Society for Vascular Surgery. J Vasc Surg. 2003 May;37(5):1106-1117. doi: 10.1067 / mva.2003.363.Brown PM, Zelt DT, and Sobolev B The risk of rupture in untreated aneurysms: the impact of size, gender, and expansion rate. J Vasc Surg. 2003 Feb;37(2):280-284. doi: 10.1067 / mva.2003.119.Lederle FA, Johnson GR, Wilson SE et al Rupture rate of large abdominal aortic aneurysms in patients refusing or unfit for elective repair. JAMA. 2002 Jun 12;287(22):2968-2972. doi: 10.1001 / jama.287.22.2968.Lo RC, Lu Bing, Fokkema MTM et al. Relative importance of aneurysm diameter and body size for predicting abdominal aortic aneurysm rupture in men and women. J Vasc Surg. 2014 May;59(5):1209-1216. doi: 10.1016 / j.jvs.2013.10.104. Epub 2013 Dec 30.Sarwar N for IL6R Genetics Consortium and Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012 Mar 31;379(9822):1205-1213. doi: 10.1016 / S0140-6736(11)61931-4. Epub 2012 Mar 14.Swerdlow DI for The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012 Mar 31;379(9822):1214-1224. doi: 10.1016 / S0140-6736(12)60110-X. Epub 2012 Mar 14.Kaptoge S, Seshasai SRK, Gao Pei et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J. 2014 Mar;35(9):578-589. doi: 10.1093 / eurheartj / eht367. Epub 2013 Sep 10.71Attorney Docket No. 157570.620200Ridker PM and Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circ Res 2021 May 28;128(11): 1728-1746. doi: 10 1161 / CIRCRESAHA.121.319077. Epub 2021 May 17.Hernesniemi JA, Vanni V, and Hakala T. The prevalence of abdominal aortic aneurysm is consistently high among patients with coronary artery disease. J Vasc Surg. 2015 Jul;62(1):232-240.e3. doi: 10.1016 / j.jvs.2015.02.037.Golledge J, Velu R, Quigley F et al. The predictive value of four serum biomarkers for major adverse events in patients with small abdominal aortic aneurysm. J Vasc Surg. 2023 Apr;77(4):1037-1044. doi: 10.1016 / j.jvs.2022.12.001. Epub 2022 Dec 13.Nurmohamed NS, van Rosendael AR, Danad I et al. Atherosclerosis evaluation and cardiovascular risk estimation using coronary computed tomography angiography. Eur Heart J. 2024 May 27;45(20):1783-1800. doi: 10.1093 / eurheartj / ehae190.Nurmohamed NS, Min JK, Anthopolos R et al. Atherosclerosis quantification and cardiovascular risk: the ISCHEMIA trial. Eur Heart J. 2024 Sep 29;45(36):3735-3747. doi: 10.1093 / eurheartj / ehae471.Chan K, Wahome E, Tsiachristas A et al. Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort, study. Lancet. 2024 Jun 15;403(10444):2606-2618. doi: 10.1016 / S0140-6736(24)00596-8. Epub 2024 May 29.Wanhainen A, Mani K, Kullberg J et al. The effect of ticagrelor on growth of small abdominal aortic aneurysms-a randomized controlled trial. Cardiovasc Res. 2020 Feb 1;116(2):450-456. doi: 10.1093 / cvr / cvz133.Prendes CF, Melo RGE, Caldeira D et al. Editor's Choice - Systematic Review and Meta-Analysis of Contemporary Abdominal Aortic Aneurysm Growth Rates. Eur J Vasc Endovasc Surg. 2024 Jan;67(1):132-145. doi: 10.1016 / j.ejvs.2023.09.039. Epub 2023 Sep 28.Olson SL, Wijesinha MA, Panthofer AM et al. Evaluating Growth Patterns of Abdominal Aortic Aneurysm Diameter With Serial Computed Tomography Surveillance. JAMA Surg. 2021 Apr 1;156(4):363-370. doi: 10.1001 / jamasurg.2020.7190.72

Claims

1. Attorney Docket No. 157570.6202002.CLAIMS3.What is claimed is:

1. A method of treating a patient diagnosed with abdominal aortic aneurysm (AAA) comprising administering to the patient a therapeutically effective dose of an anti-interleukin-6 (anti-IL-6) antibody or antibody fragment having the variable heavy (VH) CDRs as defined in SEQ ID NOs 2, 3 and 4, and the variable light (VL) CDRs as defined in SEQ ID NOs 8, 9 and 10.

2. The method of claim 1, wherein the effective dose comprises from about 10 to about 200 mg of the antibody.

3. The method of claim 2, wherein the effective dose comprises 50 mg of the antibody.

4. The method of any one of claims 1-3, wherein the method comprises administering the effective dose monthly, every two months, every' three months, or every six months, preferably every three months.

5. The method of claim 1, wherein the method comprises administering 50 mg of the antibody subcutaneously once every three months6. The method of any one of claims 1-5, wherein the patient is diagnosed with medium¬ sized AAA.10.7 The method of any one of claims 1-6, wherein the patient is male and the AAA has a maximum aneurysm diameter between 40 to 50 mm.

8. The method of any one of claims 1-6, wherein the patient is female and the AAA has a maximum aneurysm diameter between 35 to 45 mm.Attorney Docket No. 157570.6202009. The method of any one of claims 1-8, wherein the AAA has a volume and / or a diameter and the treatment results in a reduction in the growth rate of the volume and / or diameter.

10. The method of claim 9, wherein the reduction in growth rate is a reduction in growth rate over time.

11. The method of any one of claims 1-9, wherein a maximum transverse diameter of the AAA is 40 to 50 mm.

12. The method of any one of claims 1-9, wherein a maximum transverse diameter of the AAA is 35 to 45 mm.

13. The method of claim 9, wherein the reduction in the growth rate of the volume and / or diameter is more than 20%, e.g., as compared with the expected growth rate if not receiving the antibody.

14. The method of claim 12, wherein the reduction in the growth rate of the volume and / or diameter is about 30%, 40%, 50%, or 60%, e.g., as compared with the expected growth rate if not receiving the antibody.

15. The method of any one of claims 9-13, wherein the reduction is measured as the reduction in the annualized change in maximum aneurysm diameter of the AAA.

16. The method of any one of claims 1-14, wherein the treatment results in an increase in time to first AAA rupture, time to first AAA repair, or time to cardiovascular death.

17. The method of any one of claims 1-15, wherein the treatment results in a reduction of the incidence of AAA rupture, the incidence of AAA repair, or the incidence of cardiovascular death.Attorney Docket No. 157570.62020018. The method of claim 16, wherein the incidence of AAA rupture, the incidence of AAA repair, or the incidence of cardiovascular death is reduced by at least 10%, e.g., as compared with the expected incidence if not receiving the antibody.

19. The method of claim 17, wherein the incidence of AAA rupture, the incidence of AAA repair, or the incidence of cardiovascular death is reduced by about 20%, e.g., as compared with the expected incidence if not receiving the antibody.

20. The method of any one of claims 1-18, wherein the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 1 and a light chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 7.

21. The method of any one of claims 1-18, wherein the antibody or antibody fragment comprises a heavy chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 13 and a light chain polypeptide comprising a polypeptide having at least 98% identity to SEQ ID NO: 7.

22. The method of any one of claims 1-18, wherein the antibody or antibody fragment comprises a heavy chain polypeptide having the sequence of SEQ ID NO: 1 and a light chain polypeptide having the sequence of SEQ ID NO: 7.

23. The method of any one of claims 1-18, wherein the antibody or antibody fragment comprises a heavy chain polypeptide comprising the sequence of SEQ ID NO: 13 and a light chain polypeptide comprising the sequence of SEQ ID NO: 7.

24. The method any one of claims 1-22, wherein the patient has inflammation.

25. The method of claim 23, wherein the patient has IL-6 mediated inflammation29.67 Attorney Docket No. 157570.62020026. The method of claim 23 or 24, wherein the treatment is sufficient to reduce the inflammation without causing immune suppression.

27. The method of claim 25, wherein the immune suppression is measured by absolute neutrophil count (ANC).

28. The method of any one of claims 25, wherein the inflammation is measured by high- sensitivity C-reactive protein (hsCRP) levels.

29. The method of claim 27, wherein the treatment is sufficient to reduce the hsCRP level by more than 70%, 80%, or 90%, e.g., as compared with the expected hsCRP level if not receiving the antibody.

30. The method of claim 27, wherein the patient has a pre-treatment hsCRP level of greater than or equal to 2 mg / L.

31. The method of claim 27, wherein the patient has a pre-treatment hsCRP level of less than 2 mg / L.

32. The method of claim 28, wherein the treatment is sufficient to reduce the hsCRP level to 1 mg / L or less, e.g., as compared with the expected hsCRP level if not receiving the antibody.

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