WO2023038619A1

WO2023038619A1 - USE OF IL-1β BINDING ANTIBODIES

Info

Publication number: WO2023038619A1
Application number: PCT/US2021/049412
Authority: WO
Inventors: Jianjun Zhang; John Heymach; Seyed MOGHADDAM
Original assignee: Board Of Regents, The University Of Texas System
Priority date: 2021-09-08
Filing date: 2021-09-08
Publication date: 2023-03-16
Also published as: WO2023038667A1

Abstract

The present invention relates to the use of an IL-1β inhibitor, particularly an IL-1β binding antibody or a functional fragment thereof, for the treatment of indeterminate pulmonary nodules (IPNs), and/or for the prevention of lung cancers, especially lung cancers likely arising from typically earlier diagnosed indeterminate pulmonary nodules (IPNs), especially IPNs having at least a partial inflammatory basis.

Description

USE OF IL-iβ BINDING ANTIBODIES

TECHNICAL FIELD

The present invention relates to the use of an IL-iβ inhibitor, particularly an IL-iβ binding antibody or a functional fragment thereof, for the treatment of indeterminate pulmonary nodules (IPNs), and/or for the prevention of lung cancers, especially lung cancers likely arising from typically earlier diagnosed indeterminate pulmonary nodules (IPNs), especially IPNs having at least a partial inflammatory basis.

BACKGROUND OF THE DISCLOSURE

Growing implementation of low-dose helical CT screening (LDCT) and the advent of high resolution CT for diagnostic imaging have resulted in a dramatic increase in the number of indeterminate pulmonary nodules identified, most of which present as ground glass opacities (GGOs). As reported in the initial LDCT screening study, nearly 30% of subjects were found to have pulmonary nodules, the majority of which were IPNs. While many of these lesions may be resected with minimal morbidity, the cost and relevance of surgical resection have been called into question. In addition, multifocality is a relatively common occurrence, with up to 25% of the patients harboring multiple IPNs, which makes surgical resection more challenging. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have produced only disappointing results to date. This may be due to the constellation of many factors, including the lack of reliable molecular biomarkers to identify high-risk patients, the lack of appropriate molecular targets, and the lack of appropriate drugs based on our rudimentary knowledge on early carcinogenesis of lung cancers.

Thus, there remains a need to effectively treat IPNs, especially for the benefit of preventing IPNs from progressing into lung cancers.

SUMMARY OF THE DISCLOSURE

The present invention relates to the use of an IL-iβ inhibitor, particularly an IL-iβ binding antibody or a functional fragment thereof, particularly canakinumab or a functional fragment thereof, or gevokizumab or a functional fragment thereof, for the treatment of indeterminate pulmonary nodules (IPNs), and/or for the prevention of lung cancers, especially lung cancers likely arising from typically earlier diagnosed indeterminate pulmonary nodules (IPNs), especially IPNs having at least a partial inflammatory basis.

In one aspect, the present invention relates to a method of treating indeterminate pulmonary nodules comprising the step of administering an effective amount of an IL-iβ inhibitor, particularly an IL-iβ binding antibody or a functional fragment thereof, particularly canakinumab or a functional fragment thereof, or gevokiz or a functional fragment thereof, into a subject in need thereof.

In one aspect, the present invention relates to a method of prevention of of lung cancer, comprising the step of administering an effective amount of an IL-iβ inhibitor, particularly an IL-iβ binding antibody or a functional fragment thereof, particularly canakinumab or a functional fragment thereof, or gevokiz or a functional fragment thereof, into a subject in need thereof, wherein the subject has indeterminate pulmonary nodules (IPNs).

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on September 7, 2021, is named PAT059146 SL .txt and is 15,839 bytes in size.

DETAILED DESCRIPTION OF THE DISCLOSURE

Historically, ground glass opacities (GGOs) have been the most common type of IPNs that were thought to correlate with the fairly imprecise category of bronchioloalveolar carcinomas (BAC) if they persisted or grew. In early 2011, the IASLC/ATS/ERS jointly proposed a reclassification of BAC to highlight the spectrum of invasiveness that may be delineated within this group of lesions. It has been postulated that atypical adenomatous hyperplasia (AAH) represents a preneoplastic lung lesion that can progress to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), and further to frankly invasive adenocarcinoma(Weichert W, et al Curr Opin Pulm Med 20:309-16, 2014; Hitoshi Dejima et al, Nat Commun. 2021; 12: 2722). With the intent to identify the pivotal molecular events driving the formation and progression of lung preneoplasia, an international collaboration with clinical researchers in Japan and China, where pulmonary nodules are often treated with surgical resection, was initiated. Preliminary analysis of multiregion whole exome sequencing (WES) data from AAH (N=22), AIS (N=27), MIA (N=54) and synchronous invasive ADC (N=13) revealed genomic evolution from AAH to AIS, MIA and ADC with a progressive increase in mutation burden and genomic heterogeneity. Interestingly, aneuploidy was a common phenomenon in AIS, MIA and ADC, but not in AAH, while allelic imbalance (Al) only became prevalent in MIA and ADC. These data indicate progressive genomic evolution at the single nucleotide level during carcinogenesis of lung ADC with macroevolution at the transition from AAH to AIS and AIS to MIA, possibly driven by ploidy change and Al, respectively. Meanwhile, considerable overlap was observed between AAH, AIS, MIA and ADC, suggesting profound heterogeneity of these lesions and limitation of histologic classification. Top cancer genes frequently altered in this cohort include EGFR, KRAS, STK11/LKB1, RBM10, TP53, etc.. Phylogenetic analysis revealed varying evolutionary processes in different lesions again highlighting the substantial heterogeneity even at the preneoplastic states. Further analysis indicated that some cancer gene mutations may be early events (e.g., KRAS mutations: similar incidence between different stages; subclonal in some AAH, but always clonal in AIS, MIA or ADC), while others may be later events (e.g., EGFR mutations and STK11/LKB1 losses: significantly more common in AIS, MIA and ADC than AAH; subclonal in some AIS and MIA specimens). The actual data is reported in Hu X, et al, Nat Commun. 2019 Jul 5;10(l):2978., the disclosure of which is hereby incorporated by reference.

Immune surveillance is an important host protection process inhibiting carcinogenesis. However, our understanding of immune surveillance during early lung carcinogenesis is limited, primarily because of the scarcity of preneoplasia specimens. Our recent study and preliminary analyses of a cohort of AAH (N=22), AIS (N=27), MIA (N=54) and synchronous invasive ADC (N=13) have suggested that immunosuppression may begin in preneoplasia and evolve gradually with disease progression. The data is reported in Dejima H, et al. J.Nat Commun. 2021 May 11;12(1):2722, the disclosure of which is hereby incorporated by reference.

Many cancers may arise on the background of chronic inflammation, which could play a major role in tumor invasion, progression, and metastases. This is particularly relevant for carcinogenesis of lung cancer, as lung tissue is continuously exposed to the external environment, and infection, smoking and other external inhaled toxins may lead to a persistent inflammatory response. For example, several recent epidemiological studies have shown increased risk of lung cancer in smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, when compared to those without the disease (de-Torres JP, et al . Am J Respir Crit Care Med, 191:285-91, 2015. Importantly, among smokers with COPD, despite smoking cessation, inflammation persists and lung function continues to deteriorate while the risk of lung cancer remains elevated (Rutgers SR, et al. Thorax 55:12-8, 2000). These studies further support a link between lung cancer promotion and chronic airway inflammation. We have shown essential roles for NF-KB mediated production of IL-6 and TNF in promotion of lung cancer by COPD-related inflammation through induction of an immunosuppressive lung microenvironment (Caetano MS, et al. Cancer Res, 2016). Interleukin ip (IL- 1 P) is a potent activator of NF-KB pathway which gets initiated by activation of the IL- 1 receptor-associated kinase (IRAK). Inflammatory activation in the lung is partly mediated through pathways involved in production of active IL-iβ that leads to activation of NF-KB pathway and release of inflammatory cytokines like IL-6 and TNF as described above. It is known that IL-1 is abundant at tumor sites, where it may affect the process of carcinogenesis, tumor growth and invasiveness and also the patterns of tumor-host interactions. High levels of IL-iβ were found in serum of lung cancer patients and correlated with poor prognosis. High levels of IL-1 P have been found in lung of mouse with lung tumors in the absence or presence of COPD (Moghaddam SJ, et a. Am J Respir Cell Mol Biol 40:443-53, 2009). In mice, activation of pro-interleukin- ip processing was reported to accelerate tumor growth, invasiveness, and metastasis. Canakinumab is a human monoclonal antibody targeting interleukin ip. In a recent randomized, double-blind, placebo-controlled trial, Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), canakinumab was found to significantly decrease the risk of invasive lung cancer (hazard ratio: 0.61 (95%CI 0.39-0.97) and 0.33 (0.18-0.59) for the 150 mg and 300 mg groups, respectively, compared to placebo (Ridker PM, et al. Lancet 390:1833-1842, 2017).

Taken together, the above findings provide the basis for the primary hypothesis that chronic inflammation contributes to malignant transformation of preneoplasia into invasive lung cancers and that modulation of immune/inflammation microenvironment of lung preneoplasia prevent the development of invasive lung cancers. Thus, in one asepct, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in a subject in the treatment of indeterminate pulmonary nodules (IPNs).

Alternatively the present invention provides a method of treating indeterminate pulmonary nodules comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof.

A pulmonary nodule is defined as a focal opacity measuring typically less than 3 cm in diameter. Pulmonary nodules are a frequent incidental finding on routine chest computed tomography (CT). Pulmonary nodules smaller than 8 mm in diameter are considered small nodules, while nodules ranging between 3 and 5 mm in diameter are classified as very small nodules, representing approximately 50% of all pulmonary nodules detected on CT. Micronodule is a term that should be reserved only for nodules smaller than 3 mm. In patients without malignancy, these micronodules should be considered benign until proven otherwise.

Indeterminate pulmonary nodules (IPNs) refer to either one or more pulmonary nodules without histologic diagnosis confirming malignancy. IPNs can be categorized merely by size as above. In some embodiments, very small nodules (3 mm to 5 mm), small nodules (5 mm to 8 mm) and nodules larger than 8 mm are considered to be treated by the present invention. In other embodiments, nodules greater than 3 mm, greater than 5 mm, greater than 8 mm are considered to be treated by the present invention.

Alternatively, IPNs can be categorized by morphology, including, but not limited to, ground glass opacity (GGO), solid or partial solid form, all of which can be considered to be treated by the present invention.

Alternatively, IPN can be categorized by the combination of size and morphology. For example an IPN of a size smaller than 3 mm, e.g., 1.5 mm, but with partial solid morphology or with solid morphology, can be considered to be treated by the present invention. Typical clinically meaningful IPNs are nodules (ground glass opacity-GGO, solid or partial solid) over 6 mm. Typically the nodules grow or change, for example from GGO to partial solid, or from partial solid to solid. Such growth or change can be normally detected during periodic CT scanning, normally 3 months to 6 months apart. IPN that has grown or has undergone morphological change within a period of one year, typically 6 months, or typically 3 months, are considered to be treated by the present invention. In another aspect, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in a subject in the prevention of lung cancer, wherein the subject has indeterminate pulmonary nodules (IPNs), especially lung cancer likely arising from typically earlier diagnosed indeterminate pulmonary nodules (IPNs).

Alternatively the present invention provides a method of preventing lung cancer comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof, wherein the subject has IPNs, especially lung cancer likely arising from typically earlier diagnosed indeterminate pulmonary nodules (IPNs).

In another aspect, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in a subject in delaying the onset of lung cancer, wherein the subject has IPNs, especially lung cancer likely arising from typically earlier diagnosed indeterminate pulmonary nodules (IPNs).

Alternatively, the present invention provides a method of delaying the onset of lung cancer comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof, wherein the subject has IPNs, especially lung cancer likely arising from typically earlier diagnosed IPNs.

The term “prevent,” “preventing” or “prevention” as used herein means the prevention or delay of the occurrence of cancer, particularly lung cancer, in a subject who is otherwise at high risk of developing cancer.

In one embodiment, the risk of developing cancer, e.g., lung cancer, in patients receiving the prevention treatment according to the present invention is reduced by at least about 20%, at least about 30%, at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably compared to a patient not receiving Treatment of the Invention in the prevention settings. Typically the risk reduction can be shown in a clinical trial setting.

The term “delaying the onset of lung cancer” as used herein is to be understood as the onset of lung cancer being delayed in a subject receiving treatment as described herein as compared to a subject not receiving treatment, or typically, such difference can shown in a clinical setting by comparing a group that received the treatment of the invention vs. placebo control group, or by collecting real world evidence. For example, the onset of lung cancer is delayed by at least about 6 months, by at least about 12 months, by about 12 months, by about 24 months, by about 36 months in the group receiving the Treatment of the Invention compared to the group not receiving the Treatment of the Invention, wherein the two groups are randomly built.

In one embodiment, the subject is 18 years or older.

In one embodiment, the IPN is high risk IPN.

The term “high risk IPN” as used herein, refers to IPN which is determined to have the risk of progressing to lung cancer by a treating physician, e.g., the physician who has identified IPNs, or the physician, likely an oncologist, to whom the subject is referred after a diagnosis of having IPN, after he/she has considered all available facts, which include, but are not limited to, the size of the nodule, the morphology of the nodule, the subject’s disease history, e.g., cancer history, family disease history, the subject’s age, obesity, smoking habits, and history of exposure to environmenal hazards. Typically, IPN has the risk of progressing into NSCLC.

In one embodiment, “high risk” refers to the risk or probability of IPN developing into lung cancer, typically, NSCLC, in the subject having IPN, such as a risk or probability equal to or greater than 5%, equal to or greater than 10%, equal to or greater than 15%, equal to or greater than 20%, equal to or greater than 25%, equal to or greater than 30%, equal to or greater than 35%, or equal to or greater than 40%, calculated according to the Brock University cancer prediction equation.

Typically, the Brock University cancer prediction equation is expressed as:

Log odds = (0.0287 * (Age - 62)) + Sex (female= +0.6011; male = 0) + Family History of Lung Cancer (yes= + 0.2961; no=0) + Emphysema - (5.3854* (Nodule size/10)'^{0 5} - 1.58113883)) + Nodule type + Nodule Upper Lung - (0.0824 * (Nodule count - 4)) + Spiculation - 6.7892.

The Brock University equation has taken into account the relativity of various factors in their impact on lung cancer development. A skilled person would understand that, along with the progress in understanding lung cancer development, this equation could be subject to modifications, for example, by adding or deleting certain factors, or by modifying the constants in the formula to reflect more closely the impact of each respective factors.

In one embodiment, the subject is selected from any one of the following categories: a. A subject with no history of lung cancer with 10-30% cancer probability by Brock University cancer prediction equation. Typically the subject has persistent IPNs. b. A subj ect with no history of lung cancer with > 30% cancer probability by Brock University cancer prediction equation, but biopsy showed no clear evidence of malignancy. Typically the subject has persistent IPNs. c. A subj ect with history of Stage I-III NSCLC, who has completed treatment with curative intent with 5-30% cancer probability by Brock University cancer prediction equation. Typically the subject has persistent IPNs. d. A patient with history of Stage I-III NSCLC, who has completed treatment with curative intent, with > 30% cancer probability by Brock University cancer prediction equation, but biopsy showed no clear evidence of malignancy. Typically the subject has persistent IPNs.

In one embodiment, the subject has multiple indeterminate pulmonary nodules (IPNs).

In one embodiment, the IPN is detected by CT screening. In one embodiment, the IPN is detected by low-dose helical CT screening (LDCT).

In one embodiment, the subject has persistent IPNs. The term “persistent IPN” as used here, is understood as IPN detected on two CT scans, typically at least 3 months apart, with no evidence of shrinkage or regression. Typically, the IPN in the subject is detected by LDCT- guided lung cancer screening or imaging studies for other reasons (incidentalomas).

In one embodiment, the IPN in the subject is at the stage of GGO.

In one embodiment, the IPN in the subject is at the stage of bronchioloalveolar carcinomas (BAC).

In one embodiment, the IPN in the subject is at the stage of atypical adenomatous hyperplasia (AAH).

In one embodiment, the IPN in the subject is at the stage of adenocarcinoma in situ (AIS).

In one embodiment, the IPN in the subject is at the stage of minimally invasive adenocarcinoma (MIA).

In one embodiment, the subj ect has no history of cancer. In one embodiment, the subject has no history of lung cancer. In one embodiment, the subject has a history of cancer. In one embodiment, the cancer is a solid cancer. In one embodiment, the subject has a history of lung cancer.

In one embodiment, the subject has PD-L1 expression. Typically, high PD-L1 expression is defined as Tumor Proportion Score (TPS) equal or greater than about 50%, as determined by an FDA-approved test.

In one embodiment, the subject has EGFR genomic tumor aberrations.

In one embodiment, the subject has ALK genomic tumor aberrations.

In one embodiment, the IPNs have at least a partial inflammatory basis.

The phrases “IPNs have at least a partial inflammatory basis” or “IPNs having at least a partial inflammatory basis” refers to IPNs in which IL-iβ mediated inflammatory responses contribute to the formation of the IPNs and/or in which IL-iβ mediated inflammatory responses increase the risk of IPNs further developing into lung cancer. The phrases also include IPNs that will benefit from the treatment of an IL-iβ inhibitor, such as an IL-iβ binding antibody or a functional fragment thereof. Such IPNs generally have concomitant inflammation activated or mediated in part through activation of the Nod-like receptor protein 3 (NLRP3) inflammasome with consequent local production of interleukin- 1 p. In a patient with such IPNs, the expression, or even the overexpression, of IL-iβ can be generally detected, commonly at the site of the nodules, especially in the surrounding tissue of the nodules, in comparison to normal tissue. The expression of IL-iβ can be detected by routine methods known in the art, such as immunostaining, ELISA based assays, in-situ hybridization, RNA sequencing or RT- PCR in the nodules as well as in serum/plasma. The expression of, or increased expression of, IL-iβ can be concluded, for example, against negative control, usually normal tissue at the same site, or higher than normal level of IL-iβ in serum/plasma. Simultaneously or alternatively, a patient with such IPNs has generally chronic inflammation, which is manifested, typically, by higher than normal level of CRP or hsCRP, IL-6 or TNFa.

As inflammation in general contributes to nodule growth at already an early stage, administration of an IL-iβ inhibitor, such as IL-iβ binding antibody or a functional fragment thereof (e.g., canakinumab or gevokizumab), could potentially inhibit nodule growth effectively at the early stage and prevent or delay the nodules from progression to cancer effectively at the early stage, even if the inflammation status, such as expression or overexpression IL-iβ, or the elevated level of CRP or hsCRP, IL-6 or TNFa, is still not apparent or measurable. However, a subject having IPNs can still benefit from the treatment, which can be shown in clinical trials. The clinical benefits can be measured by parameters such as including, but not limited to, disappearance of the nodules, shrinkage of the nodules, stablization of the nodules, regression rate of the nodules and lung cancer free survivial. The regression of pulmonary nodules is based on the modified RECIST criteria (Table 7). If a subj ect treated with the DRUG of the invention (IL- 1 P inhibitor, such as IL- 1 P binding antibody or a functional fragment thereof, e.g., canakinumab or gevokizumab) has shown any improvement in one or more of the above parameters, the subject is considered to have benefited from the treatment according to the present invention (Treatment of the Invention).

Inhibition of IL-iβ resulted in reduced inflammation status, including but not limited to reduced hsCRP or IL-6 level. Thus the effect of the present invention in cancer patients can be measured by reduced inflammation status, including but not limited to reduced hsCRP or IL-6 level.

Available techniques known to the skilled person in the art allow detection and quantification of IL-iβ in tissue as well as in serum/plasma, particularly when the IL-iβ is expressed at a higher than normal level. For example, using the R&D Systems high sensitivity IL-iβ ELISA kit, IL-iβ cannot be detected in the majority of healthy donor serum samples, as shown in the following Table 1.

Table 1

Thus, in a healthy person the IL-iβ level is barely detectable or just above the detection limit according to this test with the high sensitivity R&D® IL-iβ ELISA kit. It is expected that a patient with cancer having at least partial inflammatory basis in general has higher than normal levels of IL-iβ and that the levels of IL-iβ can be detected by the same kit. Taking the IL-iβ expression level in a healthy person as the normal level (reference level), the term “higher than normal level of IL-iβ” means an IL-iβ level that is higher than the reference level. Normally, at least about 2 fold, at least about 5 fold, at least about 10 fold, at least about 15 fold, or at least about 20 fold of the reference level is considered as higher than normal level. Alternatively, taking the IL-iβ expression level in a healthy person as the normal level (reference level), the term “higher than normal level of IL-iβ” means an IL-iβ level that is higher than the reference level, normally higher than 0.8 pg/ml, higher than 1 pg/ml, higher than 1.3 pg/ml, higher than 1.5 pg/ml, higher than 2 pg/ml, higher than 3 pg/ml, as determined preferably by the R&D kit mentioned above. Blocking the IL-iβ pathway normally triggers the compensating mechanism leading to more production of IL-iβ. Thus the term “higher than normal level of IL-iβ” also means and includes the level of IL-iβ either post, or more preferably, prior to the administration of an IL-iβ binding antibody or a fragment thereof. Treatment of cancer with agents other than IL-iβ inhibitors, such as some chemotherapeutic agents, can result in production of IL-iβ in the tumor microenvironment. Thus the term “higher than normal level of IL-iβ” also refers to the level of IL-iβ either prior to or post the administration of such an agent.

When using staining, such as immunostaining, to detect IL-iβ expression in a tissue preparation, the term “higher than normal level of IL-iβ” means that the staining signal generated by a specific IL-iβ protein or IL-iβ RNA detecting molecule is distinguishably stronger than the staining signal of the surrounding tissue not expressing IL-iβ.

Available techniques known to the skilled person in the art allow detection and quantification of IL-6 in tissue as well as in serum/plasma, particularly when the IL-6 is expressed to a higher than normal level. For example, using the R&D Systems (RnDsystems.com) “high quantikine HS ELISA, human IL-6 Immnunoassay,” IL-6 can be detected in majority of healthy donor serum samples, as shown in the following Table 2.

Table 2

It is expected that in a patient with cancer having at least partial inflammatory basis in general has higher than normal level of IL-6 and can be detected by the same kit. Taking the IL-6 expression level in a healthy person as the normal level (reference level), the term “higher than normal level of IL-6” means an IL-6 level that is higher than the reference level, normally higher than 1.9 pg/ml, higher than 2 pg/ml, higher than 2.2 pg/ml, higher than 2.5 pg/ml, higher than2.7 pg/ml, higher than 3 pg/ml, higher than 3.5 pg/ml, or higher than 4 pg/ml, as determined preferably by the R&D kit mentioned above. Blocking the IL-iβ pathway normally triggers the compensating mechanism leading to more production of IL-1 p. Thus, the term “higher than normal level of IL-6” also means and includes the level of IL-6 either post, or more preferably, prior to the administration of an IL-iβ binding antibody or a fragment thereof. Treatment of cancer with agents other than IL-iβ inhibitors, such as some chemotherapeutic agents, can result in production of IL- 1 P in the tumor microenvironment. Thus the term “higher than normal level of IL-6” also refers to the level of IL-6 either prior to or post the administration of such an agent.

When using staining, such as immunostaining, to detect IL-6 expression in a tissue preparation, the term “higher than normal level of IL-6” means that the staining signal generated by specific IL-6 protein or IL-6 RNA detecting molecule is distinguishably stronger than staining signal of the surrounding tissue not expressing IL-6.

As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of a disorder, e.g., an indeterminate pulmonary nodule, or the amelioration of one or more symptoms, suitably of one or more discernible symptoms, of the disorder resulting from the administration of one or more therapies. In specific embodiments, the terms “treat,” “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms “treat,” “treatment” and “treating” refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.

IL- IP inhibitors, especially IL- IP binding antibody or a fragment thereof

As used herein, IL-iβ inhibitors include but are not limited to, canakinumab or a functional fragment thereof, gevokizumab or a functional fragment thereof, Anakinra, diacerein, Rilonacept, nidanilimab, IL-1 Affibody (SOBI 006, Z-FC (Swedish Orphan Biovitrum/Affibody)) and Lutikizumab (ABT-981, Abbott), CDP-484 (Celltech), LY-2189102 (Lilly).

In one embodiment, for any use or method of the invention, said IL-iβ binding antibody is canakinumab.

In other embodiments of any use or method of the invention, said IL-iβ binding antibody is gevokizumab.

In one embodiment, said IL-iβ binding antibody is LY-2189102, which is ahumanised IL-iβ monoclonal antibody.

In one embodiment, said IL-iβ binding antibody or a functional fragment thereof is CDP-484 (Celltech), which is an antibody fragment blocking IL-iβ.

In one embodiment, said IL-iβ binding antibody or a functional fragment thereof is IL- 1 Affibody (SOBI 006, Z-FC (Swedish Orphan Biovitrum/Affibody)).

By “IL-iβ binding antibody” is meant any antibody capable of binding to IL-iβ and specifically and consequently inhibiting or modulating the binding of IL-iβ to its receptor and further consequently inhibiting IL-iβ function. Preferably, an IL-iβ binding antibody does not bind to IL- la.

Preferably an IL-iβ binding antibody includes:

(1) An antibody comprising three VL CDRs having the amino acid sequences RASQSIGSSLH (SEQ ID NO: 1), ASQSFS (SEQ ID NO: 2), and HQSSSLP (SEQ ID NO: 3), and three VH CDRs having the amino acid sequences VYGMN (SEQ ID NO: 4), IIWYDGDNQYYADSVKG (SEQ ID NO: 5), and DLRTGP (SEQ ID NO: 6);

(2) An antibody comprising three VL CDRs having the amino acid sequences RASQDISNYLS (SEQ ID NO: 7), YTSKLHS (SEQ ID NO: 8), and LQGKMLPWT (SEQ ID NO: 9), and three VH CDRs having the amino acid sequences TSGMGVG (SEQ ID NO: 10), HIWWDGDESYNPSLK (SEQ ID NO: 11), and NRYDPPWFVD (SEQ ID NO: 12); and

(3) An antibody comprising the six CDRs as described in either (1) or (2), wherein one or more of the CDR sequences, preferably at most two of the CDRs, preferably only one of the CDRs, differ by one amino acid from the corresponding sequences described in either (1) or (2), respectively.

Preferably an IL-iβ binding antibody includes: (1) An antibody comprising three VL CDRs having the amino acid sequences RASQSIGSSLH (SEQ ID NO: 1), ASQSFS (SEQ ID NO: 2), and HQSSSLP (SEQ ID NO: 3) and comprising the VH having the amino acid sequence specified in SEQ ID NO: 8;

(2) An antibody comprising the VL having the amino acid sequence specified in SEQ ID NO: 23 and comprising three VH CDRs having the amino acid sequences VYGMN (SEQ ID NO: 4), IIWYDGDNQYYADSVKG (SEQ ID NO: 5), and DLRTGP (SEQ ID NO: 6);

(3) An antibody comprising three VL CDRs having the amino acid sequences RASQDISNYLS (SEQ ID NO: 7), YTSKLHS (SEQ ID NO: 8), and LQGKMLPWT (SEQ ID NO: 9), and comprising the VH having the amino acid sequences specified in SEQ ID NO: 26;

(4) An antibody comprising the VL having the amino acid specified in SEQ ID NO: 25, and comprising three VH CDRs having the amino acid sequences TSGMGVG (SEQ ID NO: 10), HIWWDGDESYNPSLK (SEQ ID NO: 11), and NRYDPPWFVD (SEQ ID NO: 12);

(5) An antibody comprising three VL CDRs and the VH sequence as described in either (1) or (3), wherein one or more of the VL CDR sequences, preferably at most two of the CDRs, preferably only one of the CDRs, differ by one amino acid from the corresponding sequences described in (1) or (3), respectively, and wherein the VH sequence is at least 90% identical to the corresponding sequence described in (1) or (3), respectively; and

(6) An antibody comprising the VL sequence and three VH CDRs as described in either (2) or (4), wherein the VL sequence is at least 90% identical to the corresponding sequence described in (2) or (4), respectively, and wherein one or more of the VH CDR sequences, preferably at most two of the CDRs, preferably only one of the CDRs, differ by one amino acid from the corresponding sequences described in (2) or (4), respectively.

Preferably an IL-iβ binding antibody includes:

(1) An antibody comprising the VL having the amino acid sequence specified in SEQ ID NO: 23 and comprising the VH having the amino acid sequence specified in SEQ ID NO: 24;

(2) An antibody comprising the VL having the amino acid specified in SEQ ID NO: 25, and comprising the VH having the amino acid sequences specified in SEQ ID NO: 26; and

(3) An antibody described in either (1) or (2), wherein the constant region of the heavy chain, the constant region of the light chain or both has been changed to a different isotype as compared to canakinumab or gevokizumab. Preferably an IL-iβ binding antibody includes:

(1) Canakinumab (SEQ ID NO:27 and 28); and

(2) Gevokizumab (SEQ ID NO:29 and 30).

An IL-1 β binding antibody as defined above has substantially identical or identical CDR sequences as those of canakinumab or gevokizumab. It thus binds to the same epitope on IL-1 P and has similar binding affinity as canakinumab or gevokizumab. The clinically relevant doses and dosing regimens that have been established for canakinumab or gevokizumab as therapeutically efficacious in the treatment of cancer, especially cancer having at least partial inflammatory basis, would be applicable to other IL-iβ binding antibodies.

Additionally or alternatively, an IL-iβ antibody refers to an antibody that is capable of binding to IL-1 p specifically with affinity in the similar range as canakinumab or gevokizumab. The Kd for canakinumab in W02007/050607 is referenced with 30.5 pM, whereas the Kd for gevokizumab is 0.3 pM. Thus affinity in the similar range refers to between about 0.05 pM to 300 pM, preferably 0.1 pM to 100 pM. Although both binding to IL-iβ, canakinumab directly inhibits the binding to IL-1 receptor, whereas gevokizumab is an allosteric inhibitor. It does not prevent IL-iβ from binding to the receptor but prevents receptor activation. Preferably an IL-1 P antibody has a binding affinity in a range similar to canakinumab, preferably in the range of 1 pM to 300 pM, preferably in the range of 10 pM to 100 pM, wherein preferably said antibody directly inhibits binding. Preferably an IL-iβ antibody has the binding affinity in the similar range as gevokizumab, preferably in the range of 0.05 pM to 3 pM, preferably in the range of 0.1 pM to 1 pM, wherein preferably said antibody is an allosteric inhibitor.

As used herein, the term “functional fragment” of an antibody as used herein, refers to portions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-iβ). Examples of binding fragments encompassed within the term “functional fragment” of an antibody include single chain Fv (scFv), a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHI domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989), which consists of a VH domain; and an isolated complementarity determining region (CDR); and one or more CDRs arranged on peptide scaffolds that can be smaller, larger, or fold differently to a typical antibody.

The term “functional fragment” also refer to one of the following: • bispecific single chain Fv dimers

• “diabodies” or “triabodies,” multivalent or multispecific fragments constructed by gene fusion

• scFv genetically fused to the same or a different antibody

• scFv, diabody or domain antibody fused to an Fc region

• scFv fused to the same or a different antibody

• Fv, scFv or diabody molecules may be stabilized by the incorporation of disulphide bridges linking the VH and VL domains.

• Minibodies comprising a scFv joined to a CH3 domain may also be made.

• Other examples of binding fragments are Fab’, which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CHI domain, including one or more cysteines from the antibody hinge region, and Fab’-SH, which is a Fab’ fragment in which the cysteine residue(s) of the constant domains bear a free thiol group.

Typically and preferably, an functional fragment of an IL-iβ binding antibody is a portion or a fragment of an “IL-iβ binding antibody” as defined above.

Dosing regimens

An therapeutically effective amount of IL-iβ inhibitor, such as an IL-iβ antibody or a functional fragment thereof, can be administered to a subject with IPNs to treat IPN, to prevent lung cancer arisen from IPNs, or to delay the onset of lung cancer arisen from IPNs.

In one embodiment, the IL-iβ inhibitor, particularly an IL-iβ binding antibody or a functional fragment thereof, is administered at a dose of about 30 mg to about 400 mg, per treatment, , preferably subcutaneously or intravenously.

The IL-iβ binding antibody or a functional fragment thereof is administered in the frequency range from about every 2 weeks to about every 3 months, typically about every 3 weeks, about every 4 weeks (one month), about every 6 weeks, about every 8 weeks (2 months) or about every 3 months.

In one embodiment, canakinumab is administered at a dose of about 100 mg to about 400 mg per treatment. In one further embodiment canakinumab is administered at a dose of about 200 mg per treatment. In another further embodiment canakinumab is administered at a dose of about 400 mg per treatment. Canakinumab is administered about every 3 weeks, every 4 weeks (one month), every 6 weeks, every 8 weeks (2 months) or every 3 months. In a preferred embodiment canakinumab or a functional fragment thereof is administered about every 6 weeks, every 8 weeks (2 months) or every 3 months.

In one embodiment, about 200 mg of canakinumab is administered every 3 weeks.

In one embodiment, about 200 mg of canakinumab is administered every 6 weeks.

In one embodiment, about 200 mg of canakinumab is administered every 8 weeks (2 months).

In one embodiment, about 400 mg of canakinumab is administered every 8 weeks (2 months).

In one embodiment, about 400 mg of canakinumab is administered every 12 weeks (3 months).

In one embodiment, canakinumab or or a functional fragment thereof is administered subcutaneously.

Suitably, the above dose and dosing apply to the use of a functional fragment of canakinumab according to the present invention.

In one embodiment, gevokizumab is administered at a dose of about 30 mg to about 300 mg per treatment.

In one embodiment, gevokizumab is administered at a dose of about 30 mg to 240 mg per treatment, particularly at about 60 mg, 90 mg, 120 mg per treatment, typically about 120 mg per treatment.

In one embodiment, gevokizumab is administered about every 4 weeks (one month), every 8 weeks (two months) or every 12 weeks (three months).

In one embodiment, gevokizumab is administered about every 8 weeks (2 months) or every 12 weeks (3 months).

Gevokizumab is administered subcutaneously or intravenously, preferably intravenously.

Suitably, the above dose and dosing apply to the use of a functional fragment of gevokizumab according to the present invention.

The term “per treatment,” as used in this application and particularly in this context, should be understood as the total amount of drug received per hospital visit or per self administration or per administration helped by a health care giver. Normally and preferably the total amount of drug received per treatment is administered to a patient within about 2 hours, preferably within about one hour, or within about one-half hour (e.g., 30 minutes). In one preferred embodiment the term “per treatment” is understood as the drug is administered with one injection, preferably in one dosage.

In practice sometimes the dosing interval cannot be strictly kept due to the limitation of the availability of doctor, patient or the drug/facility. Thus the dosing interval can slightly vary, normally between about ±5 days, about ±4 days, about ±3 days, about ±2 days or preferably about ±1 day.

The dosing regimens disclosed herein are applicable in each and every canakinumab or gevokizumab related embodiment disclosed in this application, including but not limited to monotherapy or in combination with one or more anti-cancer therapeutic agents.

When canakinumab or gevokizumab is used in combination with one or more anticancer therapeutic agents, e.g., a checkpoint inhibitor, especially when the one or more therapeutic agents is the standard of care (SoC) of the cancer indication, the dosing interval of canakinumab or gevokizumab can be adjusted to be aligned with the combination partner for the sake of patient convenience. Normally, there is no need to change the canakinumab or gevokizumab dose per treatment. For example, canakinumab about 200 mg is administered about every 3 weeks in combination with pembrolizumab.

Biomarkers

In one aspect, the present invention provides the use of an IL-iβ inhibitor, such as IL- ip binding antibody or a functional fragment thereof, suitably canakinumab or gevokizumab, in the treatment of IPNs or in the prevention of lung cancer, in a subject having IPN, who has a higher than normal level of C-reactive protein (hsCRP).

As used herein, “C-reactive protein” and “CRP” refer to serum or plasma C-reactive protein, which is typically used as an indicator of the acute phase response to inflammation. Nonetheless, CRP levels may become elevated in chronic illnesses such as IPNs. The level of CRP in serum or plasma may be given in any concentration, e.g., mg/dl, mg/L, or nmol/L. Levels of CRP may be measured by a variety of well-known methods, e.g., radial immunodiffusion, electroimmunoassay, immunoturbidimetry (e.g., particle (e.g., latex)- enhanced turbidimetric immunoassay), ELISA, turbidimetric methods, fluorescence polarization immunoassay, and laser nephelometry. Testing for CRP may employ a standard CRP test or a high sensitivity CRP (hsCRP) test (i.e. , a high sensitivity test that is capable of measuring lower levels of CRP in a sample, e.g., using immunoassay or laser nephelometry). Kits for detecting levels of CRP may be purchased from various companies, e.g., Calbiotech, Inc, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, Abbott Laboratories etc.

As used herein, the term “hsCRP” refers to the level of CRP in the blood (serum or plasma) as measured by high sensitivity CRP testing. For example, Tina-quant C-reactive protein (latex) high sensitivity assay (Roche Diagnostics Corporation) may be used for quantification of the hsCRP level of a subject. Such latex-enhanced turbidimetric immunoassay may be analysed on the Cobas® platform (Roche Diagnostics Corporation) or Roche/Hitachi (e.g., Modular P) analyzer. In the CANTOS trial, the hsCRP level was measured by Tina-quant C-reactive protein (latex) high sensitivity assay (Roche Diagnostics Corporation) on the Roche/Hitachi Modular P analyzer, which can be used typically and preferably as the method in measuring hsCRP level. Alternatively the hsCRP level can be measured by another method, for example by another approved companion diagnostic kit, the value of which can be calibrated against the value measured by the Tina-quant method.

Each local laboratory employs a cut-off value for abnormal (high) CRP or hsCRP based on that laboratory’s rule for calculating normal maximum CRP, i.e., based on that laboratory’s reference standard. A physician generally orders a CRP test from a local laboratory, and the local laboratory determines CRP or hsCRP value and reports normal or abnormal (low or high) CRP using the rule that particular laboratory employs to calculate normal CRP, namely based on its reference standard. Thus, whether a patient has a higher than normal level of C-reactive protein (hsCRP) can be determined by the local laboratory where the test is conducted.

It is plausible that an IL-iβ inhibitor, such as an IL-iβ antibody or a fragment thereof, such as canakinumab or gevokizumab, is effective in treating IPNs, especially when said subject has higher than normal level of hsCRP.

In one aspect, the present invention provides high sensitivity C-reactive protein (hsCRP) or CRP for use as a biomarker in the treatment of IPNs, with an IL-iβ inhibitor, e.g., IL-iβ binding antibody or a functional fragment thereof. The level of hsCRP is possibly relevant in determining whether a subject with IPNs is at risk of developing lung cancer and/or whether the subject should be treated with an IL-iβ binding antibody or a functional fragment thereof. In one embodiment, a subject is eligible for the treatment and/or prevention if the level of hsCRP is equal to or higher than about 2 mg/L, or equal to or higher than about 2.5 mg/L, or equal to or higher than about 4.5 mg/L, or equal to or higher than about 7.5 mg/L, as assessed prior to the administration of the IL-iβ binding antibody or a functional fragment thereof.

In one aspect, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in the treatment of IPNs in a subject, wherein the efficacy of the treatment correlates with the reduction of hsCRP in said subject, comparing to prior treatment. In one embodiment, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in the treatment of IPNs, wherein the hsCRP level in the subject has reduced to below about 5.2 mg/L, preferably to below about 3.2 mg/L, preferably to below about 2.0 mg/L, about 6 months, or preferably about 3 months from the first administration of said IL-iβ binding antibody or a functional fragment thereof at a proper dose, preferably according to the dosing regimen of the present invention.

In one aspect, the present invention provides an IL-iβ binding antibody or a functional fragment thereof (e.g., canakinumab or gevokizumab) for use in the treatment of IPNs in a subject, wherein the hsCRP level of the subject has reduced by at least about 20%, by about 20- 34% (e.g., about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, or about 34%), by about 35%, or by at least about 50%, or by at least about 60%, about 6 months, or preferably about 3 month from the first administration of said IL-iβ binding antibody or a functional fragment thereof at a proper dose, preferably according to the dosing regimen of the present invention, as compared to the hsCRP level just prior to the first administration of the IL-iβ binding antibody or a functional fragment thereof, canakinumab or gevokizumab). Further preferably, the hsCRP level of said patient has reduced by least about 35% or at least about 50% or at least about 60% after the first administration of the drug of the invention according to the dose regimen of the present invention.

In one aspect, the present invention provides IL-6 use as a biomarker in the treatment of IPNs, with an IL-iβ inhibitor, e.g., IL-iβ binding antibody or a functional fragment thereof. The level of IL-6 is possibly relevant in determining whether a patient with diagnosed or undiagnosed cancer or is at risk of developing cancer should be treated with an IL-iβ binding antibody or a functional fragment thereof. In one embodiment, patient is eligible for the treatment and/or prevention if the level of IL-6 is equal to or higher than about 1.9 pg/ml, higher than about 2 pg/ml, higher than about 2.2 pg/ml, higher than 2.5 pg/ml, higher than about 2.7 pg/ml, higher than about 3 pg/ml, higher than about 3.5 pg/ml, as assessed prior to the administration of the IL-iβ binding antibody or a functional fragment thereof. Preferably the patient has an IL-6 level equal to or higher than about 2.5 mg/L

In one aspect, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in the treatment of IPNs in a subject, wherein the efficacy of the treatment correlates with the reduction of IL-6 in said subject, comparing to prior treatment. In one embodiment, the present invention provides an IL-iβ binding antibody or a functional fragment thereof for use in the treatment of cancer, e.g., cancer having at least a partial inflammatory basis, wherein IL-6 level, of said patient has reduced to below about 2.2 pg/ml, preferably to below about 2 pg/ml, preferably to below about 1.9 pg/ml, about 6 months, or preferably about 3 months from the first administration of said IL-iβ binding antibody or a functional fragment thereof at a proper dose, preferably according to the dosing regimen of the present invention.

In one aspect, the present invention provides an IL-iβ binding antibody or a functional fragment thereof (e.g., canakinumab or gevokizumab) for use in the treatment of IPNs in a subject, wherein the IL-6 level of said subject has reduced by at least about 20%, by about 20- 34%, by about 35% or at least by about 50% or at least by about 60%, about 6 months, or preferably about 3 months from the first administration of said IL-iβ binding antibody or a functional fragment thereof (e.g., canakinumab or gevokizumab) at a proper dose, preferably according to the dosing regimen of the present invention, as compared to the IL-6 level just prior to the first administration. Further preferably, the IL-6 level of said patient has reduced by least about 35%, or at least about 50%, or at least about 60% after the first administration of the DRUG of the invention according to the dose regimen of the present invention.

The reduction of the level of hsCRP and the reduction of the level of IL-6 can be used separately or in combination to indicate the efficacy of the treatment or as prognostic markers.

In one embodiment, the present invention provides an IL-iβ inhibitor, such as an IL- ip binding antibody or functional fragment thereof, for use in the treatment of IPNs, wherein the high sensitivity C-reactive protein (hsCRP) level of the subject has reduced by at least about 20%, preferably by at least 40%, preferably by at least 50%, compared to baseline assessed after the first administration but before the second administration of the IL-iβ inhibitor, such as the IL-iβ binding antibody or functional fragment thereof. In one embodiment, the present invention provides an IL-iβ inhibitor, such as an IL- ip binding antibody or functional fragment thereof, for use in the treatment of IPNs, wherein the interleukin-6 (IL-6) level of the subject has reduced by at least about 20%, preferably by at least 40%, preferably by at least 50%, compared to baseline assessed after the first administration but before the second administration of the IL-iβ inhibitor, such as the IL-iβ binding antibody or functional fragment thereof. IL-iβ induces numerous downstream mediators implicated in the inflammatory process including, chemokines, cytokines (including IL- 1 P, IL-6 and tumor necrosis factor-alpha (TNF - a)), cyclooxygenase 2, leukocyte adhesion molecules, acute phase proteins, neutrophilic response, thrombocytosis, as well as extracellular matrix components fibronectin, and collagen types I, III and IV. Similar to hsCRP or IL-6, the present invention envisages any one or any combination of the above mentioned molecules as biomarkers to select subject or to indicate the efficacy of the Treatment of the Invention.

Naive patient and first line treatment

In one embodiment, the present invention provides an IL-iβ inhibitor, such as an IL-iβ antibody or a functional fragment thereof, suitably canakinumab or gevokizumab, for use as the first line treatment of IPNs. The term “first line treatment” means the subject having IPNs is a naive patient, who has not received any prior treatment against IPNs, thus Drug of the Invention is the first treatment given to the subject. Furthermore the term “first line treatment” also can refer to that situation, in which the subject is given the IL-iβ antibody or a functional fragment thereof before the subject develops resistance to the initial treatment with one or more other therapeutic agents.

Combination

In one aspect, the present invention provides an IL-iβ inhibitor, particularly an IL-iβ binding antibody or a functional fragment thereof, suitably canakinumab or gevokizumab, for use in a patient in need thereof in the treatment of IPNs or in the prevention of lung cancers arisen from IPNs, in combination with one or more therapeutic agents, including, but not limited to, a checkpoint inhibitor, a steroid, such as inhaled or oral low dose steroids, anon-steroid antiinflammatory drug (NS AID), including, but not limited to aspirin, colchicine, ibuprofen and celecoxib. Checkpoint inhibitor suitable for the combination use of the present inventoin includes but not limited to nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, tislelizumab and spartalizumab.

Checkpoint inhibitors de-suppress the immune system through a mechanism different from IL-iβ inhibitors. Thus the addition of IL-iβ inhibitors, particularly IL-iβ binding antibodies or a functional fragment thereof, to the standard checkpoint inhibitor will further activate the immune response, particularly in the tumor microenvironment.

In one embodiment, the one or more checkpoint inhibitors is nivolumab.

In one embodiment, the one or more checkpoint inhibitors is pembrolizumab.

In one embodiment, the one or more checkpoint inhibitors is tislelizumab.

In one embodiment, the one or more checkpoint inhibitors is atezolizumab.

Immunotherapies that target immune checkpoints, also known as checkpoint inhibitors, are currently emerging as key agents in cancer therapy. The immune checkpoint inhibitor can be an inhibitor of the receptor or an inhibitor of the ligand. Examples of the inhibiting targets include, but are not limited to, a co-inhibitory molecule [e.g., a PD-1 inhibitor (e.g., an anti- PD-1 antibody molecule), a PD-Ll inhibitor (e.g., an anti-PD-Ll antibody molecule), a PD-L2 inhibitor (e.g., an anti-PD-L2 antibody molecule), a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody molecule), a TIM-3 inhibitor (e.g, an anti-TIM-3 antibody molecule), an activator of a co-stimulatory molecule (e.g., a GITR agonist (e.g., an anti-GITR antibody molecule)], a cytokine [e.g, IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra)], an inhibitor of cytotoxic T-lymphocyte-associated protein 4 (e.g., an anti-CTLA-4 antibody molecule) or any combination thereof.

PD-1 Inhibitors

In one aspect of the invention, the IL-iβ inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof is administered together with a PD-1 inhibitor.

In some embodiments, the PD-1 inhibitor is chosen from spartalizumab, Nivolumab, Pembrolizumab, MEDI0680, REGN2810/cemiplimab, TSR-042, PF-06801591, tislelizumab/BGB-A317, BGB-108 (Beigene), INCSHR1210, or AMP-224.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of PF-06801591.

Further known anti-PD-1 antibodies include those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorporated by reference in their entireties.

In one embodiment, the anti-PD-1 antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-1 as, one of the anti-PD-1 antibodies described herein.

In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, e.g., as described in US 8,907,053, incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).

PD-L1 Inhibitors

In one aspect of the invention, the IL- ip inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof is administered together with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is chosen from FAZ053 (Novartis), Atezolizumab (Genentech/Roche), Avelumab (Merck Serono and Pfizer), Durvalumab (Medlmmune/AstraZeneca), or BMS- 936559 (Bristol-Myers Squibb).

In one embodiment, the PD-L1 inhibitor is an anti-PD-Ll antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-Ll antibody molecule as disclosed in US 2016/0108123, published on April 21, 2016, entitled “Antibody Molecules to PD-L1 and Uses Thereof,” incorporated by reference in its entirety.

In one embodiment, the anti-PD-Ll antibody molecule is Atezolizumab.

In one embodiment, the anti-PD-Ll antibody molecule is Avelumab.

In one embodiment, the anti-PD-Ll antibody molecule is Durvalumab (Medlmmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-Ll antibodies are disclosed in US 8,779,108, incorporated by reference in its entirety.

In one embodiment, the anti-PD-Ll antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-Ll antibodies are disclosed in US 7,943,743 and WO 2015/081158, incorporated by reference in their entireties.

Further known anti-PD-Ll antibodies include those described, e.g., in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/079174, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082, incorporated by reference in their entireties.

LAG-3 Inhibitors

In one aspect of the invention, the IL-iβ inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof is administered together with a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is chosen from LAG525 (Novartis), BMS-986016 (Bristol- Myers Squibb), TSR-033 (Tesaro), IMP731 or GSK2831781 and IMP761 (Prima BioMed).

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as disclosed in US 2015/0259420, published on September 17, 2015, entitled “Antibody Molecules to LAG-3 and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the LAG-3 inhibitor is LAG525 (leramilimab).

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839, incorporated by reference in their entireties.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9,244,059, incorporated by reference in their entirety.

Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, incorporated by reference in their entireties.

In one embodiment, the anti-LAG-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on LAG-3 as, one of the anti-LAG-3 antibodies described herein. In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (Prima BioMed), e.g, as disclosed in WO 2009/044273, incorporated by reference in its entirety.

TIM-3 Inhibitors

In one aspect of the invention, the IL- ip inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof, is administered together with a TIM-3 inhibitor.

In one embodiment, the anti-TIM-3 antibody molecule is disclosed in US 2015/0218274, published on August 6, 2015, entitled “Antibody Molecules to TIM-3 and Uses Thereof,” incorporated by reference in its entirety.

In another embodiment, the anti-TIM3 antibody molecule is MBG453. Without wishing to be bound by theory, it is typically believed that MBG453 is a high-affinity, ligandblocking, humanized anti-TIM-3 IgG4 antibody which can block the binding of TIM-3 to phosphatidyserine (PtdSer). Historically MBG453 (sabatolimab) is often misspelled as MGB453.

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro).

APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO 2016/161270, incorporated by reference in its entirety.

In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2.

In one embodiment, the anti-TIM-3 antibody molecule is LY3321367.

In one embodiment, the anti-TIM-3 antibody molecule is Sym023 (Symphogen).

In one embodiment, the anti-TIM-3 antibody molecule is BGB-A425 (Beigene).

In one embodiment, the anti-TIM-3 antibody molecule is INCAGN-2390 (Agenus/Incyte).

In one embodiment, the anti-TIM-3 antibody molecule is MBS-986258 (BMS/Five Prime).

In one embodiment, the anti-TIM-3 antibody molecule is RO-7121661 (Roche).

In one embodiment, the anti-TIM-3 antibody molecule is LY-3415244 (Eh Lilly).

Further known anti-TIM-3 antibodies include those described, e.g., in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087, incorporated by reference in their entireties. In one embodiment, the anti-TIM-3 antibody is an antibody that competes for binding with, and/or binds to the same epitope on TIM-3 as, one of the anti-TIM-3 antibodies described herein.

GITR Agonists

In one aspect of the invention, the IL- ip inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof, is administered together with a GITR agonist. In some embodiments, the GITR agonist is GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen) or INBRX-110 (Inhibrx).

In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846, published on April 14, 2016, entitled “Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy,” incorporated by reference in its entirety.

In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 14.

Table 3: Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecule

In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156 and other anti-GITR antibodies are disclosed, e.g., in US 9,228,016 and WO 2016/196792, incorporated by reference in their entireties. In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed, e.g, in US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al. Cancer Res. 2017; 77(5): 1108-1118, incorporated by reference in their entireties.

In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed, e.g., in US 7,812,135, US 8,388,967, US 9,028,823, WO 2006/105021, and Ponte J et al. (2010) Clinical Immunology, 135:S96, incorporated by reference in their entireties.

In one embodiment, the anti-GITR antibody molecule is INC AGNI 876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are disclosed, e.g., in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entireties.

In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, e.g., in US 9,464,139 and WO 2015/031667, incorporated by reference in their entireties.

In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, e.g, in US 2017/0022284 and WO 2017/015623, incorporated by reference in their entireties.

In one embodiment, the GITR agonist (e.g, a fusion protein) is MEDI 1873 (Medlmmune), also known as MEDI 1873. MEDI 1873 and other GITR agonists are disclosed, e.g, in US 2017/0073386, WO 2017/025610, and Ross et al. Cancer Res 2016; 76(14 Suppl): Abstract Abstract No. 561, incorporated by reference in their entireties. In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain, a functional multimerization domain, and a receptor binding domain of a glucocorticoid-induced TNF receptor ligand (GITRL) of MEDI 1873.

Further known GITR agonists (e.g. , anti-GITR antibodies) include those described, e.g. , in WO 2016/054638, incorporated by reference in its entirety.

In one embodiment, the anti-GITR antibody is an antibody that competes for binding with, and/or binds to the same epitope on GITR as, one of the anti-GITR antibodies described herein.

In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding fragment (e.g., an immunoadhesin binding fragment comprising an extracellular or GITR binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).

Table 4: Amino acid sequence of exemplary anti-GITR antibody molecules

IL 15/IL- 15Ra complexes

In one aspect of the invention, the IL- ip inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof, is administered together with an IL-15/IL-15Ra complex. In some embodiments, the IL-15/IL-15Ra complex is chosen fromNIZ985 (Novartis), ATL-803 (Aitor) or CYP0150 (Cytune).

In one embodiment, the IL-15/IL-15Ra complex comprises human IL- 15 complexed with a soluble form of human IL-15Ra. The complex may comprise IL- 15 covalently or noncovalently bound to a soluble form of IL-15Ra. In a particular embodiment, the human IL- 15 is noncovalently bonded to a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 of the composition comprises an amino acid sequence of SEQ ID NO: 17 in Table 9 and the soluble form of human IL-15Ra comprises an amino acid sequence of SEQ ID NO: 18 in Table 5, as described in WO 2014/066527, incorporated by reference in its entirety. The molecules described herein can be made by vectors, host cells, and methods described in WO 2007/084342, incorporated by reference in its entirety.

Table 5. Amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes

In one embodiment, the IL-15/IL-15Ra complex is ALT-803, an IL-15/IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu/Fc soluble complex). ALT-803 is disclosed in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra Fc fusion protein comprises the sequences as disclosed in Table 6

In one embodiment, the IL-15/IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Cytune). The sushi domain of IL-15Ra refers to a domain beginning at the first cysteine residue after the signal peptide of IL-15Ra, and ending at the fourth cysteine residue after said signal peptide. The complex of IL-15 fused to the sushi domain of IL-15Ra is disclosed in WO 2007/04606 and WO 2012/175222, incorporated by reference in their entireties. In one embodiment, the IL-15/IL-15Ra sushi domain fusion comprises the sequences as disclosed in Table 6.

Table 6. Amino acid sequences of other exemplary IL-15/IL-15Ra complexes

CTLA-4 Inhibitors

In one aspect of the invention, the IL- ip inhibitor, e.g., an IL-iβ antibody or a functional fragment thereof, is administered together with an inhibitor of CTLA-4. In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody or fragment thereof. Exemplary anti-CTLA- 4 antibodies include Tremelimumab (formerly ticilimumab, CP-675,206); and Ipilimumab (MDX-010, Yervoy®).

The term “in combination with” is understood as the two or more drugs are administered subsequently or simultaneously. Alternatively, the term “in combination with” is understood that two or more drugs are administered in the manner that the effective therapeutic concentrations of the drugs are expected to be overlapping for a majority of the period of time within the subject’s body. The drug of the invention and one or more combination partner (e.g., another drug, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect. The terms “co-administration” or “combined administration” or “used in combination” or “administered in combination” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The drug administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the subject and the treatment regimen will provide combined beneficial effects of the drug combination in treating the conditions or disorders described herein. Formulations and devices IL-iβ antibody, such as canakinumab or gevokizumab, or a functional fragments thereof, can be provided in the form of lyophilized form for reconstitution. In one embodiment, canakinumab is provided in the form of lyophilized form for reconstitution containing at least about 200 mg drug per vial, preferably not more than about 250 mg, preferably not more than about 225 mg in one vial. IL-iβ antibody, such as canakinumab or gevokizumab, or a functional fragments thereof, can be provided in the form of liquid formulation, ready to use. In one embodiment, the liquid formulation is filled in a prefilled syringe or by an auto-injector. Preferably the prefilled syringe or the auto-injector contains the full amount of therapeutically effective amount of the drug. Preferably the prefilled syringe or the auto-injector contains about 200 mg of canakinumab or about 120 mg of gevokizumab.

Efficacy and safety

Due to its good safety profile, IL-iβ antibody, such as canakinumab or gevokizumab, or fragments thereof, can be administered to a patient for a long period of time, providing and maintaining the benefit of suppressing IL-iβ mediated inflammation.

In one embodiment, the subject is administered with IL-iβ binding antibody or a functional fragment thereof, for a period of at least 3 months, or typically for a period of at least 6 months, or for a period of at least 12 months, particularly for a period of 12 to 24 months. Typically the subject is administered with IL-iβ binding antibody or a functional fragment thereof, for a period of about 24 months.

In one embodiment, the subject is administered with IL-iβ binding antibody or a functional fragment thereof for at least a period of 3 months, or typically for at least a period of 6 months, and if the subject has regression of IPNs, then the treatment will continue for at least another 6 months, or for at least another 12 months, particularly for another 6 months to 18 months, e.g., about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 18 months, about 18 months, or the like.

The term “regression of indeterminate pulmonary nodules,” as used herein, refers to the treatment results in complete response, partial response or stable disease defined according to Response Evaluation Criteria In Solid Tumors (RECIST), in which a sum of the longest diameters (LD) of all the targeted lesions will be calculated and reported as the baseline sum LD and the baseline sum LD will be used as reference by which to characterize the objective nodules. Furthermore the term “complete response (CR)” refers to the disappearance of all target lesions. The term “partial response (PR)” refers to at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. The term “stable disease (SD)” refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).

Table 7 Evaluation of Target and Non-target Lesions by Response Evaluation

Criteria in Indeterminate Pulmonary Nodules

disease.

* Target lesions: Each pulmonary nodule will be identified and assessed using Brock University criteria described above. Pulmonary nodules with predicted cancer risk > 15% for patients with no history of lung cancer or >10% for patients with history of stage I -II NSCLC who complete surgery and standard adjuvant chemotherapy if indicated will be identified as the targeted lesions. Patients with IPNs that are difficult to uniquely identify or follow will be excluded.

** Nontarget lesions: Other pulmonary nodules that can be uniquely identified and followed, but do not meet the criteria for target lesions will be identified as nontarget lesions.

*** Ground-glass nodules/ opacities will be evaluated and measured on CT lung window setting (WL -600, WW 1500).

In one embodiment, the treatment will continue unless the subject has progressive disease (PD) during the treatment. The term “progressive disease” as used herein, is part of the definition of RECIST, which is understood as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions progression of disease.

Thus, in one aspect, the present invention provides a method of causing the regression of indeterminate pulmonary nodules in a subject comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof.

In one embodiment, of the invention, the subject has achieved complete response, namely the IPNs have completely disappeared, typically for at least a period of 3 months, 6 months, one year or two years, typically examined by CT counted from the beginning of the Treatment of the Invention.

In one embodiment, of the invention, the subject has achieved partial response, namely the indeterminate pulmonary nodules have at least a 30% decrease, preferably at least 50% decrease, preferably at least 60% decrease, in the sum of the LD of target lesions, taking as reference the baseline sum LD, typically for at least a period of 3 months, 6 months, one year or two years, typically examined by CT counted from the beginning of the Treatment of the Invention. In one embodiment, of the invention, the subject has achieved stable disease, namely the IPNs, although not decreased by at least 30%, nor increased by more than 20% in the sum of the LD of target lesions, taking as reference the baseline sum LD, typically for at least a period of 3 months, 6 months, one year or two years, typically examined by CT counted from the beginning of the Treatment of the Invention.

In one embodiment, of the invention, the subject receiving the Treatment of the Invention does not develop lung cancer for at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, e.g., 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 55, 60 months calculated from the onset of the treatment of the present invention. In one embodiment of the invention, the subject receiving the treatment of the present invention does not develop lung cancer for at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months calculated from last treatment of the present invention.

In one embodiment, the incidence of lung cancer in the group of subjects receiving a Treatment of the Invention, is reduced by at least about 5%, reduced by at least about 8%, reduced by at least about 10%, reduced by at least about 15%, preferably by at least about 20%, preferably by at least about 25%, preferably by at least about 30%, preferably by at least about 35%, than the incidence in the groups of subjects not receiving Treatment of the Invention. Typically the groups are created in a clinical setting, testing the efficacy and/or safety of the present invention. Alternatively the groups are created by collecting real world evidence.

In one embodiment, the incidence of lung cancer, in the group of subjects receiving Treatment of the Invention, is reduced by at least about 5%, reduced by at least about 8%, reduced by at least about 10%, reduced by at least about 15%, preferably by at least about 20%, preferably by at least about 25%, preferably by at least about 30%, preferably by at least about 35%, than the expected cancer incidence in a defined population.

A large amount of data has been accumulated worldwide to enable relatively accurate assessment of cancer incidence in a defined population, for example, the incidence of lung cancer in a population of subjects having IPNs. According to N Engl J Med. 2013 Sep 5; 369(10): 910-919, 3.7-5.5% of subjects having IPN would develop lung cancer within 3 years of diagnosis. Benefiting from the combinatio of data sharing, real world evidence and artificial inteligence, the assessment of cancer incidence in a defined population will become even more accurate in the near future. For the sake of clarity and by way of example, in a population with an expected cancer incidence of 10%, save all the other conditions remain comparable, if the Treatment of the Invention can reduced the cancer incidence to 8%, it means the cancer incidence is reduced by 20%.

In one embodiment, in the group of subjects receiving Treatment of the Invention, the period of lung cancer free survival is in average at least one year, or at least 2 years, or at least 3 years longer than the group of subjects not receiving Treatment of the Invention. Typically the groups are created in a clinical setting, testing the efficacy and/or safety of the present invention. Alternatively the groups are created by collecting real world evidence. The term “period of lung cancer free survival” is the measure of time, counted from the beginning of the treatment, during which time no evidence of lung cancer is found. This term can be used for an individual or for a group of people within a study. This term is usually used in the context of scientific research.

In one embodiment, the subject has at least one year, 2 years, 3 years, 4 years, 5 years or 10 years of lung cancer free survival calculated from onset of the Treatment of the Invention.

The term “Treatment of the Invention,” as used in the this application, refers to DRUG of the invention, suitably canakinumab or gevokizumab, administered according to the dosing regimen, as taught in this application.

The word “a” and “an” have been generally defined as “at least one” or “one or more” in the specification. The word “IPN” and “IPNs” are interchangeably used herein without the intention of distinguishing one nodule or more than one nodules in a subject.

The word “subject” refers to a human subject.

The following Examples illustrate the invention described above; they are not, however, intended to limit the scope of the invention in any way.

EXAMPLES

The Example below is set forth to aid in the understanding of the invention but is not intended, and should not be construed, to limit its scope in any way. EXAMPLE 1

Single arm phase II trial using canakinumab for the prevention of lung Cancer (Can- Prevent-Lung)

Inclusion Criteria a. Patients with no history of lung cancer, who have persistent IPNs (on two CT scans at least 3 months apart with no evidence of shrinkage or regression) detected by LDCT- guided lung cancer screening or imaging studies for other reasons (inci dental omas) with 10- 30% cancer probability by Brock University cancer prediction equation below. b. Patients with no history of lung cancer, who have persistent IPNs (on two CT scans at least 3 months apart with no evidence of shrinkage or regression) detected by LDCT- guided lung cancer screening or imaging studies for other reasons (incidental omas) with > 30% cancer probability by Brock University cancer prediction equation below, but biopsy showed no clear evidence of malignancy. c. Patients with history of Stage I-III NSCLC, who have completed treatment with curative intent, who have persistent IPNs (on two CT scans at least 3 months apart with no evidence of shrinkage or regression) with 5-30% cancer probability by Brock University cancer prediction equation as below. d. Patients with history of Stage I-III NSCLC, who have completed treatment with curative intent, who have persistent IPNs (on two CT scans at least 3 months apart with no evidence of shrinkage or regression) with > 30% cancer probability by Brock University cancer prediction equation as below, but biopsy showed no clear evidence of malignancy.

Log odds = (0.0287 * (Age - 62)) + Sex (female= +0.6011; male = 0) + Family History Lung Cancer (yes= + 0.2961; no=0) + Emphysema - (5.3854* ((Nodule size/10)-0.5 - 1.58113883)) + Nodule type + Nodule Upper Lung - (0.0824 * (Nodule count - 4)) + Spiculation - 6.7892.

Cancer probability = 100 * (e(Log odds) / (1 + e(Log odds)))

This calculator estimates the probability that a lung nodule described above will be diagnosed as cancer within a two to four year follow-up period. Equation parameters, such as Sex, have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g., (0.6011), represent the values that will be used. Canakinumab 200 mg will be administered every 3 weeks by subcutaneous (s.c.) injection.

Objective: To determine whether canakinumab increases regression rate of high-risk pulmonary nodules. The regression of pulmonary nodules is based on the modified RECIST criteria.

Hypothesis: Chronic inflammation contributes to malignant transformation of preneoplasia into invasive lung cancers and that modulation of immune and inflammation microenvironment by canakinumab can promote regression of preneoplasia, hence, reduce the lung cancer risk.

Secondary Objective(s) & Hypothesis(es)

(1) To determine whether canakinumab prolongs lung cancer-free survival. The diagnosis of lung cancer is based on histology (diagnosed as lung cancer from subsequent biopsies or final surgical resection).

(2) To determine whether canakinumab decreases the incidence of lung cancers.

Exploratory Objective

Objective: An important aspect of this trial is to identify novel prognostic and predictive markers present at diagnosis, and to determine modulation of markers by canakinumab. Candidate markers to be evaluated may include (depending on tissue availability):

1. To explore the radiographic (including radiomic features) evolution of high-risk IPNs with treatment of canakinumab and to assess their association with risks of lung cancer, as well as their association with clinical benefit/toxi cities in patients treated with canakinumab

2. To explore the TCR repertoire evolution of patients with high-risk IPNs and assess their association with risks of lung cancer as well as their association with clinical benefit/toxicities in patients treated with canakinumab

3. To explore the evolution of serum soluble factors, such as IFN-gamma and interferon inducible factors (such as CXCL9 and CXCL10), IL- 12, TNFa, IL- 10, TGF-0, VEGF, IL-6, IL-8, IL-17, IL-18, C-reactive protein etc.) and assess their association with risks of lung cancer, as well as their association with clinical benefit/toxicities in patients treated with canakinumab.

Claims

1. An IL-iβ binding antibody or a functional fragment thereof for use in a subject in the treatment of indeterminate pulmonary nodules (IPNs).

2. A method of treating indeterminate pulmonary nodules comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof.

3. An IL-iβ binding antibody or a functional fragment thereof for use in a subject in the prevention of lung cancer, wherein the subject has indeterminate pulmonary nodules (IPNs).

4. A method of preventing lung cancer comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof, wherein the subject has indeterminate pulmonary nodules.

5. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, wherein the IPN is high risk IPN.

6. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or claim 5 depending thereof, wherein the subject has multiple indeterminate pulmonary nodules (IPNs).

7. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or claim 5 or 6 depending thereof, wherein the subject has persistent indeterminate pulmonary nodules (IPNs).

8. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims 6 depending thereof, wherein the IPN is at the stage of GGO, AAH, AIS or MIA.

9. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the subject having IPN is with history of cancer.

10. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any of the preceding claims depennding thereof, wherein the subject having IPN has no history of cancer.

11. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the subject having IPN has no history of cancer

12. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the subject is selected from the group consisting of: a. A subject with no history of lung cancer with 10-30% cancer probability by Brock University cancer prediction equation. b. A subj ect with no history of lung cancer with > 30% cancer probability by Brock University cancer prediction equation as following, but biopsy showed no clear evidence of malignancy. c. A subject with history of Stage I-III NSCLC, who have completed treatment with curative intent with 5-30% cancer probability by Brock University cancer prediction equation. d. Patients with history of Stage I-III NSCLC, who have completed treatment with curative intent, with > 30% cancer probability by Brock University cancer prediction equation but biopsy showed no clear evidence of malignancy.

13. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the IPN have at least a partial inflammatory basis.

14. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the subject has high sensitivity C-reactive protein (hsCRP) equal to or greater than about 2 mg/L before first administration of said IL-iβ binding antibody or functional fragment thereof.

15. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the IL-iβ binding antibody or a functional fragment thereof is administered at a dose of about 30 mg to about 400 mg per treatment.

16. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the IL-iβ binding antibody or a functional fragment thereof is administered subcutaneously.

17. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the IL-iβ binding antibody or a functional fragment thereof is administered intravenously.

18. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the IL-iβ binding antibody or a functional fragment thereof is administered in the frequency range from about every 2 weeks to about every 3 months, typically about every 3 weeks, about every 4 weeks (one month), about every 6 weeks, about every 8 weeks (2 months) or about every 3 months.

19. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the IL-iβ binding antibody or a functional fragment thereof is canakinumab or a functional fragment thereof.

20. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein canakinumab is administered at a dose of about 100 mg to about 400 mg per treatment.

21. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein canakinumab is administered at a dose of about 200 mg per treatment.

22. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein canakinumab is administered every 3 weeks, every 4 weeks (one month), every 6 weeks, every 8 weeks (2 months) or every 3 months.

23. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein canakinumab is administered at a dose of about 400 mg per treatment.

24. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein canakinumab is administered every 6 weeks, every 8 weeks (2 months) or every 3 months.

25. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the claims 5 to 18 depending thereof, wherein said IL- ip binding antibody or a functional fragment thereof is gevokizumab or a functional fragment thereof.

26. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the claims 5 to 18 or claim 25 depending thereof, wherein gevokizumab is administered at a dose of about 30mg to about 240mg per treatment.

27. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the claims 5 to 18 depending thereof or claim 25 or 26, wherein gevokizumab is administered at a dose of about 60mg, 90mg, 120mg per treatment.

28. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the claims 5 to 18 depending thereof, or any one of the claims 25 to 27, wherein gevokizumab is administered every 4 weeks (one month), every 8 weeks (two months) or every 12 weeks (three months).

29. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the claims 5 to 18 depending thereof, or any one of the claims 25 to 28, wherein gevokizumab is administered subcutaneously or intravenously.

30. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the high sensitivity C-reactive protein (hsCRP) level of the subject has reduced by at least about 20%, %, at least 30%, at least 50%, at least 70%, compared to baseline assessed after the first administration but before the second administration of the IL-iβ binding antibody or functional fragment thereof.

31. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the interleukin-6 (IL-6) level of the subject has reduced by at least about 20%, at least 30%, at least 50%, at least 70%, compared to baseline assessed after the first administration but before the second administration of the IL-iβ binding antibody or functional fragment thereof.

32. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein said IL-iβ binding antibody or a functional fragment thereof is administered in combination with one or more therapeutic agents.

33. The use or method of claim 32, wherein said one or more therapeutic agent is a PD-1 inhibitor or PD-L1 inhibitor preferably selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, tislelizumab and spartalizumab.

34. The use or method of claim 32, wherein said one or more therapeutic agent is a steroid.

35. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the subject is administered with IL-iβ binding antibody or a functional fragment thereof for at least a duration of 6 months.

36. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, wherein the subject is administered with IL-iβ binding antibody or a functional fragment thereof for at least a duration of 6 months, preferably for at least a duration of 12 months, preferably for at least a duration of 24 months, preferably for a duration of 12 to 24 months. A method of causing the regression of indeterminate pulmonary nodules in a subject comprising the step of administering an effective amount of an IL-iβ binding antibody or a functional fragment thereof into a subject in need thereof. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, or the method of causing regression according to claim 37, wherein the indeterminate pulmonary nodules have completely disappeared, partial responded or stable according to RECIST, assessed at 6 months from the start of the Treatment. The IL-iβ binding antibody or a functional fragment thereof for use according to claim 1 or 3, the method of preventing according to claim 2 or the method of treating according to claim 4, or any one of the preceding claims depending thereof, or the method of causing regression according to claim 37, wherein the indeterminate pulmonary nodules have at least 30% decrease, preferably at least 50% decrease, preferably at least 60% decrease, in the sum of the LD of target lesions, taking as reference the baseline sum LD, assessed at 6 months from the start of the Treatment.