Il-18 binding protein (il-18BP) and methods of using same

Abstract

Provided herein are methods for preparing a subject for a conditioning treatment and / or reducing the toxicity of a conditioning treatment in a subject, wherein the subject is in need of a hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT). Also provided are methods for increasing the recovery of a subject administered a HSCT or BMT. The subject in need of the HSCT or the BMT can, for example, be suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT.

Description

Attorney Docket No. 069069.11011 / 5WO1IL-18 BINDING PROTEIN (IL-18BP) AND METHODS OF USING SAMECROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 682,635, filed August 13, 2024, the disclosure of which is herein incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present invention provides means and methods for preparing a subject for a conditioning treatment and / or reducing the toxicity of a conditioning treatment in a subject, wherein the subject is in need of a hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT). Also provided are means and methods for increasing the recovery of a subject administered a HSCT or BMT. The subject in need of the HSCT or the BMT can, for example, be suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The contents of the electronic sequence listing (069069.5WO1 Sequence Listing. xml; Size is 2,103 bytes; Date of Creation: August 5, 2025) is herein incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0004] Multiple categories of diseases can be treated by hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT). The categories can include refractory rheumatic disease, hematologic malignant disorders, and monogenic conditions involving blood, myeloid, or lymphoid cells. In order to prepare a patient for an HSCT or BMT, a conditioning regiment is required. Prior to the conditioning regiment, the subject in need of the HSCT or BMT can be suffering from the symptoms of the disease or disorder requiring the HSCT or BMT. Additionally, administration of the conditioning regiment can further result in toxicities in the subject requiring the HSCT or BMT. Finally, after administration of the HSCT or BMT, the subject can be suffering from the effects of the disease prior to the conditioning regimen, a relapse for disease, a persistence of disease symptomology, the toxicities associated with the conditioning regiment, a delay of bone marrow recovery, acute graft-vs-host disease, and any effects due to the HSCT or BMT procedures.Attorney Docket No. 069069.11011 / 5WO1

[0005] Thus, there is an unmet need for agents that are capable of preparing a subject for the conditioning treatments used prior to administration of HSCT or BMT, reducing the toxi cities associated with the conditioning treatments, and increasing the recovery of a subject after administration of the HSCT or BMT.BRIEF SUMMARY OF THE INVENTION

[0006] In one general aspect, the invention relates to methods for preparing a subject for a conditioning treatment, wherein the subject is in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT). The methods can comprise administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to the conditioning treatment, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof prior to the conditioning treatment prepares the subject for the conditioning treatment.

[0007] Also provided are methods of reducing the toxicity of a conditioning treatment in a subject in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT). The methods can comprise co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, whereby co-administration of the conditioning treatment and the pharmaceutical composition comprising the IL-18BP or active fragment thereof reduces the toxicity of the conditioning treatment in the subject.

[0008] Also provided are methods of increasing the recovery in a subject administered a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT). The methods comprising administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof after the HSCT or BMT increases the recovery of the HSCT or BMT in the subject.

[0009] Also provided are methods of optimizing the outcome of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT) in a subject in need thereof, the method comprising: (a) administering to the subject a pharmaceutical composition comprising anAttorney Docket No. 069069.11011 / 5WO1IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to a conditioning treatment for the HSCT or BMT, wherein administration of the pharmaceutical composition prior to the conditioning treatment prepares the subject for the conditioning treatment prior to the HSCT or BMT; and / or (b) co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL- 18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, wherein coadministration of the conditioning treatment and the pharmaceutical composition reduces the toxicity of the conditioning treatment in the subject prior to the HSCT or BMT; and / or (c) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL- 18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

[0010] In certain embodiments, the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT. The disease or condition associated with increased inflammation can, for example, be selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn error of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

[0011] The cancer can, for example be selected from adult solid tumors, such as breast and prostate cancer, and pediatric solid tumors, such as neuroblastoma, Ewing sarcoma, and Wilms tumor.

[0012] The refractory rheumatic disease or disorder can, for example, be selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophage activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So-JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP- MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).

[0013] The hematologic malignant disease or disorder can, for example, be selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosisAttorney Docket No. 069069.11011 / 5WO1 fungoides and Sezary syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

[0014] The non-malignant hematologic disorder can, for example, be selected from (a) hemoglobinopathies, such as, e.g., Sickle Cell Disease, and Thalassemia major, including alpha and beta Thalassemia; (b) inherited bone marrow failures, such as, e.g., Amegakaryocytic thrombocytopenia (Amega), Diamond Blackfan anemia (DBA), Dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, Severe congenital neutropenia (SCN, also known as Kostman Diease), Shwachman Diamond syndrome (SDS), Thrombocytopenia absent radii (TAR), Epstein Barr virus-associated HLH, and other bone marrow failure syndromes.

[0015] Inborn errors of immunity resulting in immunodeficiencies can, for example, be selected from (a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others; (b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others; (c) a phagocytic deficiency disorder, wherein the phagocytic deficiency disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; (d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others.

[0016] Inborn errors of immunity resulting in hyperactivation with inflammatory damage can, for example, be selected from the group consisting of X-linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, Proline-serine-threonine phosphatase- interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, DOCK1 1 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (DOCK8), Actin relatedAttorney Docket No. 069069.11011 / 5WO1 protein IB (ARP1B), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome-associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (N0D2 mutation), Majeed syndrome, and others.

[0017] In certain embodiments, the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT. In certain embodiments, the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week. In certain embodiments, the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month. In certain embodiments, the pharmaceutical composition is administered to the subject once every two days (e.g., every 48 hours).

[0018] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. In certain embodiments, a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight. In certain embodiments, a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0019] In certain embodiments, the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.

[0020] In certain embodiments, the methods further comprise co-administration of a conditioning treatment and a pharmaceutical composition comprising the IL-18BP or active fragment thereof and pharmaceutically acceptable carrier to reduce the toxicity of the conditioning treatment.Attorney Docket No. 069069.11011 / 5WO1

[0021] In certain embodiments, after administration of the HSCT or BMT to the subject, the method further comprises administering to the subject a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject. The administration of the pharmaceutical composition after the HSCT or BMT can, for example, accelerate bone marrow recovery in the subject, facilitate engraftment of cells in the subject, reduce post-transplant cytopenia in the subject, and / or increase the proliferative rate of hematopoietic progenitor cells in the subject.

[0022] In certain embodiments, the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT. In certain embodiments, the pharmaceutical composition is administered for about 4 weeks after administration of the HSCT or BMT.

[0023] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. In certain embodiments, a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight. In certain embodiments, a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0024] In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month. In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week. In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT as one dose every two days (e.g., every 48 hours).

[0025] In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises the amino acid sequence of SEQ ID NO: 1.Attorney Docket No. 069069.11011 / 5WO1

[0026] In certain embodiments, the administration of the IL-18BP blocks free IL-18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / ml or lower in the subject prior to, during, or after the HSCT or BMT.DETAILED DESCRIPTION OF THE INVENTION

[0027] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

[0029] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0030] Unless otherwise stated, any numerical values, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Likewise, a concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0031] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention.

[0032] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains” or “containing,” or any other variation thereof, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or groupAttorney Docket No. 069069.11011 / 5WO1 of integers and are intended to be non-exclusive or open-ended. For example, a composition, a mixture, a process, a method, an article, or an apparatus that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0033] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0034] As used herein, the term “consists of,” or variations such as “consist of’ or “consisting of,” as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, but that no additional integer or group of integers can be added to the specified method, structure, or composition.

[0035] As used herein, the term “consists essentially of,” or variations such as “consist essentially of’ or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially change the basic or novel properties of the specified method, structure or composition. See M.P.E.P. § 2111.03.

[0036] As used herein “patient” or “subject” for the purposes of the present invention is used interchangeably and meant to include both humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In the preferred embodiment the patient or subject is a mammal, and in the most preferred embodiment the patient or subject is a human.Attorney Docket No. 069069.11011 / 5WO1

[0037] The words “right,” “left,” “lower,” and “upper” designate directions in the drawings to which reference is made.

[0038] It should also be understood that the terms “about,” “approximately,” “generally,” “substantially,” and like terms, used herein when referring to a dimension or characteristic of a component of the preferred invention, indicate that the described dimension / characteristic is not a strict boundary or parameter and does not exclude minor variations therefrom that are functionally the same or similar, as would be understood by one having ordinary skill in the art. At a minimum, such references that include a numerical parameter would include variations that, using mathematical and industrial principles accepted in the art (e.g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.), would not vary the least significant digit.

[0039] The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences (e.g., IL-18 binding proteins or active fragments thereof), refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection.

[0040] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0041] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 1981; 2:482, by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 1970; 48:443, by the search for similarity method of Pearson & Lipman, Proc. NatT. Acad. Sci. USA 1988; 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by visual inspection (see generally, Current Protocols in Molecular Biology, F.M. Ausubel et al., eds., Current Protocols, a joint venture between Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., 1995 Supplement (Ausubel)).Attorney Docket No. 069069.11011 / 5WO1

[0042] Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., J. Mol. Biol. 1990; 215: 403-410 and Altschul et al., Nucleic Acids Res. 1997; 25: 3389-3402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al, supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased.

[0043] Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). Lor amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. Lor amino acid sequences, the BLASTP program uses as defaults a wordlength (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 1989; 89:10915).

[0044] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat’l. Acad. Sci. USA 1993; 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. Lor example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.Attorney Docket No. 069069.11011 / 5WO1

[0045] A further indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.

[0046] As used herein, the term “isolated” means a biological component (such as a nucleic acid, peptide or protein) has been substantially separated, produced apart from, or purified away from other biological components of the organism in which the component naturally occurs, i.e., other chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides and proteins that have been “isolated” thus include nucleic acids and proteins purified by standard purification methods. “Isolated” nucleic acids, peptides and proteins can be part of a composition and still be isolated if the composition is not part of the native environment of the nucleic acid, peptide, or protein. The term also embraces nucleic acids, peptides and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids.

[0047] As used herein, the terms “peptide,” “polypeptide,” or “protein” can refer to a molecule comprised of amino acids and can be recognized as a protein by those of skill in the art. The conventional one-letter or three-letter code for amino acid residues is used herein. The terms “peptide,” “polypeptide,” and “protein” can be used interchangeably herein to refer to polymers of amino acids of any length. The polymer can be linear or branched, it can comprise modified amino acids, and it can be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art.

[0048] The peptide sequences described herein are written according to the usual convention whereby the N-terminal region of the peptide is on the left and the C-terminal region is on the right. Although isomeric forms of the amino acids are known, it is the L-form of the amino acid that is represented unless otherwise expressly indicated.Attorney Docket No. 069069.11011 / 5WO1

[0049] As used herein, the expression “IL- 18 Binding Protein (IL-18BP)” includes the full-length protein, a mutein, fragment, peptide, functional derivative, functional fragment, fraction, circularly permuted derivative, fused protein, isoform or a salt thereof. IL-18BPs are described in WO2015 / 032932 and WO2016 / 139297. Each reference is incorporated by reference herein in its entirety.

[0050] As used herein, the term “free IL- 18” means monomeric, soluble and non-complexed interleukin- 18 protein.

[0051] As used herein, the terms “treatment,” “treating” and variations thereof generally mean obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of partially or completely curing a disease and / or adverse effects attributed to the disease. The term “treatment” as used herein covers any treatment of a disease in a subject and includes: (a) preventing a disease, i.e., related to an undesired immune response from occurring in a subject which may be predisposed to the disease; (b) inhibiting the disease, i.e. arresting its development; or (c) relieving the disease, i.e. causing regression of the disease (d) reversing the disease symptoms, i.e. leading to recovery of damaged tissue.

[0052] As used herein, the terms “pharmaceutical composition” and “therapeutical composition” are used interchangeably in the widest sense. They are meant to refer, for the purposes of the present invention, to a therapeutically effective amount of the active ingredient, i.e., the IL-18BP and, optionally, a pharmaceutically acceptable carrier or diluent.

[0053] It embraces compositions that are suitable for the curative treatment, the control, the amelioration, an improvement of the condition or the prevention of a disease or disorder in a human being or a non-human animal. Thus, it embraces pharmaceutical compositions for the use in the area of human or veterinary medicine. Such a “therapeutic composition” is characterized in that it embraces at least one IL-18BP or active fragment thereof or a physiologically acceptable salt thereof, and optionally a carrier or excipient whereby the salt and the carrier and excipient are tolerated by the target organism that is treated therewith.

[0054] As used herein, the term “therapeutically effective amount” refers to that amount which provides a therapeutic effect for a given condition and administration regimen. In particular, a “therapeutically effective amount” means an amount that is effective to prevent, reverse, alleviate or ameliorate symptoms of the disease or prolong the survival of the subject being treated, which mayAttorney Docket No. 069069.11011 / 5WO1 be a human or non-human animal. Determination of a therapeutically effective amount is within the skill of the person skilled in the art. In particular, in the present case a “therapeutically or prophylactically effective amount” refers to the amount of protein or peptide, mutein, functional derivative, fraction, circularly permuted derivative, fused protein, isoform or a salt thereof, and compound or pharmaceutical composition which, when administered to a human or animal, leads to a therapeutic or prophylactic effect in said human or animal. The effective amount is readily determined by one of skill in the art following routine procedures. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the relevant art. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.

[0055] As used herein, the term “transmucosal administration” refers to various administration routes wherein the compound is absorbed by the mucosa of any part of the body. Transmucosal administration comprises, but is not limited to, i.e., intranasal, buccal, oral transmucosal, intratracheal, intraurinary tract, intrarectal, intravaginal, sublingual, intrabronchial, intrapulmonary and transdermal administration.

[0056] As used herein, the term “pharmaceutically acceptable” is meant to encompass any carrier, excipient, diluent or vehicle, which does not interfere with effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.

[0057] As used herein, the term “fused protein” refers to a polypeptide comprising an IL-18BP or a mutein or fragment thereof, fused with another protein, which, e.g., has an extended residence time in body fluids. An IL-18BP can, thus, be fused to another protein, polypeptide or the like, e.g., an immunoglobulin or a fragment thereof.

[0058] The isoforms, muteins, fused proteins or functional derivatives retain the biological activity of IL-18BP, in particular the binding to IL- 18, and preferably have essentially at least an activity similar to IL-18BP. Ideally, such isoforms, muteins, fused proteins, functional derivatives or proteins have a biological activity which is even increased in comparison to unmodified IL-18BP. Preferred active fractions have an activity which is better than the activity of IL-18BP, or which have further advantages, like a better stability or a lower toxicity or immunogenicity, or they are easier to produce in large quantities, or easier to purify.Attorney Docket No. 069069.11011 / 5WO1

[0059] As used herein, the term “interleukin- 18 binding protein” comprises also an IL-18BP mutein, functional derivative, fraction, biologically active peptide, circularly permuted derivative, fused protein, isoform and a salt thereof.

[0060] As used herein, the term “muteins” refers to analogs of an IL-18BP, in which one or more of the amino acid residues of a natural IL-18BP are replaced by different amino acid residues, or are deleted, or one or more amino acid residues are added to the natural sequence of an IL-18BP, without changing considerably the activity of the resulting products as compared with the wild type IL-18BP. These muteins are prepared by known synthesis and / or by site-directed mutagenesis techniques, high throughput mutagenesis, DNA shuffling, protein evolution techniques, or any other known technique suitable therefore.

[0061] Any such mutein preferably has a sequence of amino acids sufficiently duplicative of that of an IL-18BP, such as to have substantially similar activity to IL-18BP. One activity of IL-18BP is its capability of binding IL- 18. As long as the mutein has substantial binding activity to IL- 18, it can be used in the purification of IL- 18, such as by means of affinity chromatography, and thus can be considered to have substantially similar activity to IL-18BP. Thus, it can be determined whether any given mutein has substantially the same activity as IL-18BP by means of routine experimentation comprising subjecting such a mutein, e. g. to a simple sandwich competition assay to determine whether or not it binds to an appropriately labeled IL- 18, such as radioimmunoassay or ELISA assay.

[0062] Muteins of IL-18BP polypeptides, which can be used in accordance with the present invention, or nucleic acids capable of encoding muteins of IL-18BP polypeptides, include a finite set of substantially corresponding sequences as substitution peptides or polynucleotides which can be routinely obtained by one of ordinary skill in the art, without undue experimentation, based on the teachings and guidance presented herein.

[0063] Preferred changes for muteins in accordance with the present invention are what are known as “conservative” substitutions. Conservative amino acid substitutions of IL-18BP polypeptides, can include synonymous amino acids within a group which have sufficiently similar physicochemical properties that substitution between members of the group will preserve the biological function of the molecule (Grantham, 1974). It is clear that insertions and deletions of amino acids may also be made in the above-defined sequences without altering their function, particularly if the insertions or deletions only involve a few amino acids, e.g., under thirty, and preferably under ten, and do notAttorney Docket No. 069069.11011 / 5WO1 remove or displace amino acids which are critical to a functional conformation, e.g., cysteine residues. Proteins and muteins produced by such deletions and / or insertions come within the purview of the present invention.

[0064] As used herein, the term “functional derivatives” refers to derivatives of IL-18BPs and their muteins and fused proteins, which may be prepared from the functional groups which occur as side chains on the residues or the N-or C-terminal groups, by means known in the art, and are included in the invention as long as they remain pharmaceutically acceptable, i.e., they do-not destroy the activity of the protein which is substantially similar to the activity of IL-18BP, and do not confer toxic properties on compositions containing it.

[0065] These derivatives may, for example, include polyethylene glycol side-chains, which may mask antigen sites and extend the residence of an IL-18BP in body fluids. Other derivatives include aliphatic esters of the carboxyl groups, amides of the carboxyl groups by reaction with ammonia or with primary or secondary amines, N-acyl derivatives of free amino groups of the amino acid residues formed with acyl moieties (e. g. alkanol or carbocyclic aroyl groups) or O-acyl derivatives of free hydroxyl groups (for example that of seryl or threonyl residues) formed with acyl moieties.

[0066] As used herein, a “functional fragment” of an IL-18BP, mutein and fused protein refers to any fragment or precursors of the polypeptide chain of the IL-18BP protein molecule alone or together with associated molecules or residues linked thereto, e. g., sugar or phosphate residues, or aggregates of the protein molecule or the sugar residues by themselves, provided said fraction has substantially similar activity to IL-18BP.

[0067] As used herein, the term “salts” refers to both salts of carboxyl groups and to acid addition salts of amino groups of the IL-18BP molecule or analogs thereof. Salts of a carboxyl group may be formed by means known in the art and include inorganic salts, for example, sodium, calcium, ammonium, ferric or zinc salts, and the like, and salts with organic bases as those formed, for example, with amines, such as triethanolamine, arginine or lysine, piperidine, procaine and the like. Acid addition salts include, for example, salts with mineral acids, such as, for example, hydrochloric acid or sulfuric acid, and salts with organic acids, such as, for example, acetic acid or oxalic acid. Of course, any such salts must retain the biological activity of IL-18BP, e. g. the ability to bind IL- 18.

[0068] As used herein, the term “isoforms” of IL-18BP refers to proteins capable of binding IL- 18 or fragment thereof, which may be produced by alternative splicing.Attorney Docket No. 069069.11011 / 5WO1

[0069] As used herein, the term “circularly permuted derivatives” refers to a linear molecule in which the termini have been joined together, either directly or through a linker, to produce a circular molecule, and then the circular molecule is opened at another location to produce a new linear molecule with termini different from the termini in the original molecule. Circular permutations include those molecules whose structure is equivalent to a molecule that has been circularized and then opened. Thus, a circularly permuted molecule may be synthesized de novo as a linear molecule and never go through a circularization and opening step. The preparation of circularly permutated derivatives is described in W095 / 27732.

[0070] The expression “abnormal levels of free IL- 18” refers to increased or decreased levels of IL- 18 compared to the values detected in body fluids of a healthy control subject. In particular, these abnormal levels mean increased values of IL- 18. In particular, said abnormal level of free IL- 18 in the body fluids exceeds the level in body fluids of a healthy control subject by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%. In certain embodiments of the invention the reference or control value is the normal, non-pathologic base value for free IL- 18 determined in the patient to be treated.

[0071] The expression “abnormal ratio of free IL-18 / IL-18BP” refers to an increased ratio of IL- 18 to IL-18BP compared to values found in body fluids of a healthy control subject. In particular, said abnormal ratio of free IL- 18 to IL-18BP in the body fluids exceeds the ratio in body fluids of a healthy control subject by 1%, 2.5%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%. In certain embodiments of the invention the reference or control value is the normal, non-pathologic base value for free IL- 18 determined in the patient to be treated.

[0072] The expression “IL-18 / IL-18BP imbalance” relates to the dysregulation of mutual interaction of IL- 18 and IL-18BP, which finally leads to an elevated level of unbound IL- 18.

[0073] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated, then the health of the animal continues to deteriorate. A “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the state of health of the animal is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the state of health of the animal.

[0074] A disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a subject, or both, are reduced.Attorney Docket No. 069069.11011 / 5WO1

[0075] As used herein, the term “preparing the subject” or “preparing a subject” generally means that the subject is treated or administered a pharmacological agent or undergoes irradiation treatment to reduce a disease condition (e.g., reducing an undergoing inflammatory process) prior to a subsequent treatment. By way of a non-limiting example, preparing a subject for a conditioning treatment can comprise reducing the levels of inflammatory IL- 18 in the subject prior to the conditioning treatment by administration of an IL- 18 binding protein (IL-18BP) prior to the conditioning treatment.

[0076] As used herein “reducing the toxicity of a conditioning treatment” generally means that a subject to be administered a conditioning treatment to prepare for an HSCT or BMT will be administered an additional therapeutic agent, e.g., a pharmaceutical composition comprising an IL- 18BP or active fragment thereof. Administration of the additional therapeutic agent can reduce the toxicities associated with the conditioning treatment, e.g., multi-organ damage; mucositis; graft versus host disease (GVHD); chemotherapy- induced nausea vomiting (CINV); transplant- associated thrombotic microangiopathy (TA-TMA); sinusoidal obstruction syndrome (also known as veno-occlusive disease) (SOS / VOD); myelosuppression, including neutropenia; thrombocytopenia; anemia; infections; liver toxicities manifested as transaminitis; sinusoidal obstruction syndrome; pulmonary toxicity with the risk of developing acute respiratory distress syndrome or interstitial pneumonitis; kidney damage / failure; cardiotoxicity; diarrhea; anorexia; interstitial lung disease; pulmonary fibrosis; SNC toxicity and peripheral neuropathy; electrolyte imbalances; alopecia; osteonecrosis; cognitive dysfunction jaundice; nausea; vomiting; fatigue; lower blood counts; liver damage; rash; itchy skin; and / or hives.

[0077] As used herein “increasing the recovery in a subject” generally means that a subject administered an HSCT or BMT will be administered an additional therapeutic agent, e.g., a pharmaceutical composition comprising an IL-18BP or active fragment thereof. Administration of the additional therapeutic agent can increase the recovery in the subject. Increasing the recovery in the subject can, for example, comprise accelerating bone marrow recovery in the subject, facilitating engraftment of cells in the subject, reducing post-transplant cytopenia in the subject, restituting immunocompetence, and / or increasing the proliferative rate of hematopoietic progenitor cells in the subject.

[0078] As used herein, “optimizing the outcome” generally means to optimize the success of the treatment, i.e., the HSCT or BMT. By optimizing the success is meant that for the subject, there isAttorney Docket No. 069069.11011 / 5WO1 an increased survival (i.e., mortality), increased healing, increased facilitation of post-transplant engraftment of cells, increased percentage of cells engrafted, and / or reduced risk of infections. Optimizing the outcome can involve treatment of the subject in need of an HSCT or BMT with a pharmaceutical composition comprising an IL-18BP or active fragment thereof prior to the conditioning treatment, concurrently with the conditioning treatment, and / or after the administration of the HSCT or BMT.

[0079] Methods of preparing a subject for a conditioning treatment in a subject in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation

[0080] In one general aspect, the invention relates to methods for preparing a subject for a conditioning treatment, wherein the subject is in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT). The methods can comprise administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to the conditioning treatment, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof prior to the conditioning treatment prepares the subject for the conditioning treatment.

[0081] In certain embodiments, the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT. The disease or condition associated with increased inflammation can, for example, be selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn error of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

[0082] The cancer can, for example be selected from adult solid tumors, such as breast and prostate cancer, and pediatric solid tumors, such as neuroblastoma, Ewing sarcoma, and Wilms tumor.

[0083] The refractory rheumatic disease or disorder can, for example, be selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophage activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So-JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP- MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).Attorney Docket No. 069069.11011 / 5WO1

[0084] The hematologic malignant disease or disorder can, for example, be selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosis fungoides and Sezary syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

[0085] The non-malignant hematologic disorder can, for example, be selected from (a) hemoglobinopathies, such as, e.g., Sickle Cell Disease, and Thalassemia major, including alpha and beta Thalassemia; (b) inherited bone marrow failures, such as, e.g., Amegakaryocytic thrombocytopenia (Amega), Diamond Blackfan anemia (DBA), Dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, Severe congenital neutropenia (SCN, also known as Kostman Diease), Shwachman Diamond syndrome (SDS), Thrombocytopenia absent radii (TAR), Epstein Barr virus-associated HLH, and other bone marrow failure syndromes.

[0086] Inborn errors of immunity resulting in immunodeficiencies can, for example, be selected from (a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others; (b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others; (c) a phagocytic deficiency disorder, wherein the phagocytic deficiency disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; (d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others.

[0087] Inborn errors of immunity resulting in hyperactivation with inflammatory damage can, for example, be selected from the group consisting of X-linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Higashi syndrome, Griscelli syndrome,Attorney Docket No. 069069.11011 / 5WO1Hermansky-Pudlak syndrome, Proline-serine-threonine phosphatase- interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, D0CK1 1 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (D0CK8), Actin related protein IB (ARP1B), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome-associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (N0D2 mutation), Majeed syndrome, and others.

[0088] In certain embodiments, the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT. The pharmaceutical composition can, for example, be administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or any value in between in advance of the administration of the conditioning treatment for HSCT or BMT.

[0089] In certain embodiments, the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week. In certain embodiments, the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0090] In certain embodiments, the pharmaceutical composition is administered to the subject as one dose every two days (e.g., every 48 hours).

[0091] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. A single dose of the pharmaceutical composition can comprise about 50 mg to about 500 mg, about 100 mg to about 450 mg, about 150 mg to about 400 mg, about 200 mg to about 350 mg, or any value in between of IL- 18BP or an active fragment thereof. The single dose can, for example, comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400Attorney Docket No. 069069.11011 / 5WO1 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IL-18BP or an active fragment thereof.

[0092] In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. A single dose of the pharmaceutical composition can, for example, comprise about 0.5 to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.0 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, or any number in between, per kg body weight. The single dose can, for example, comprise about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg per kg body weight.

[0093] In certain embodiments, the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy. Conditioning treatments for HSCT or BMT are known in the art, see, e.g., Gyurkocza and Sandmaier, Blood 124(3):344-53 (2014); Bohm et al., Blood 143(10) : 872-881 (2024); Jagadeesh et al., Cancer 126(10): 2279- 87 (2020); Kang et al., J. Cell. Mol. Med. 25(22): 10770-3 (2021); Allen et al., Blood 132(13): 1438-51 (2018); Zain et al., Blood Advances (2024); and Braniecki et al., Frontiers in Neurology 15: 1-12 (2024).

[0094] In certain embodiments in which the subject is administered a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier to prepare the subject for a conditioning treatment, the method further comprises co-administration of a conditioning treatment and a pharmaceutical composition comprising the IL-18BP or active fragment thereof and pharmaceutically acceptable carrier to reduce the toxicity of the conditioning treatment.

[0095] In certain embodiments, the subject is administered the HSCT or BMT, and after administration of the HSCT or BMT, the method further comprises administering to the subject a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject. The administration of the pharmaceutical composition after the HSCT or BMT can, for example, accelerate bone marrow recovery in theAttorney Docket No. 069069.11011 / 5WO1 subject, facilitate engraftment of cells in the subject, reduce post-transplant cytopenia in the subject, and / or increase the proliferative rate of hematopoietic progenitor cells in the subject.

[0096] In certain embodiments, the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT. The pharmaceutical composition can, for example, be administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or any value in between after administration of the HSCT or BMT.

[0097] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. A single dose of the pharmaceutical composition can comprise about 50 mg to about 500 mg, about 100 mg to about 450 mg, about 150 mg to about 400 mg, about 200 mg to about 350 mg, or any value in between of IL- 18BP or an active fragment thereof. The single dose can, for example, comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IL-18BP or an active fragment thereof.

[0098] In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. A single dose of the pharmaceutical composition can, for example, comprise about 0.5 to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.0 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, or any number in between, per kg body weight. The single dose can, for example, comprise about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg per kg body weight.

[0099] In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month. In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0100] In certain embodiments, the pharmaceutical composition is administered to the subject once every two days (e.g., every 48 hours).Attorney Docket No. 069069.11011 / 5WO1

[0101] In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the ammo acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises the amino acid sequence of SEQ ID NO: 1.

[0102] In certain embodiments, the administration of the IL-18BP blocks free IL-18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / mL or lower in the subject prior to, during, or after the HSCT or BMT. The amount of free IL- 18 in serum of a healthy subject, particularly a healthy human is < 5 pg / mL, particularly < 4 pg / mL, particularly < 3 pg / ml, particularly < 2 pg / ml, particularly < 1 pg / mL, particularly < 0.5 pg / mL, or particularly below the detection level.

[0103] Methods of reducing the toxicity of a conditioning treatment in a subject in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation

[0104] In another general aspect, the invention relates to methods of reducing the toxicity of a conditioning treatment in a subject in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT). The methods can comprise co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL- 18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, whereby coadministration of the conditioning treatment and the pharmaceutical composition comprising the IL- 18BP or active fragment thereof reduces the toxicity of the conditioning treatment in the subject.

[0105] In certain embodiments, the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.

[0106] In certain embodiments, after the subject is administered the conditioning treatment, the subject is administered the HSCT or BMT. After administration of the HSCT or BMT, the method further comprises administering to the subject a pharmaceutical composition comprising an IL- 18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject. The administration of the pharmaceutical composition after the HSCT or BMT can, forAttorney Docket No. 069069.11011 / 5WO1 example, accelerate bone marrow recovery in the subject, facilitate engraftment of cells in the subject, reduce post-transplant cytopenia in the subject, reduce the risk of infections in the subject, and / or increase the proliferative rate of hematopoietic progenitor cells in the subject.

[0107] In certain embodiments, the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT. The pharmaceutical composition can, for example, be administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or any value in between after administration of the HSCT or BMT.

[0108] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. A single dose of the pharmaceutical composition can comprise about 50 mg to about 500 mg, about 100 mg to about 450 mg, about 150 mg to about 400 mg, about 200 mg to about 350 mg, or any value in between of IL- 18BP or an active fragment thereof. The single dose can, for example, comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IL-18BP or an active fragment thereof.

[0109] In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. A single dose of the pharmaceutical composition can, for example, comprise about 0.5 to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.0 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, or any number in between, per kg body weight. The single dose can, for example, comprise about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg per kg body weight.

[0110] In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month. In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0111] In certain embodiments, the pharmaceutical composition is administered to the subject once every two days (e.g., every 48 hours).Attorney Docket No. 069069.11011 / 5WO1

[0112] In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the ammo acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises the amino acid sequence of SEQ ID NO: 1.

[0113] In certain embodiments, the administration of the IL-18BP blocks free IL-18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / mL or lower in the subject prior to, during, or after the HSCT or BMT. The amount of free IL- 18 in serum of a healthy subject, particularly a healthy human is < 5 pg / mL, particularly < 4 pg / mL, particularly < 3 pg / ml, particularly < 2 pg / ml, particularly < 1 pg / mL, particularly < 0.5 pg / mL, or particularly below the detection level.

[0114] Methods of increasing the recovery in a subject administered a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT)

[0115] In another general aspect, the invention relates to methods of increasing the recovery in a subject administered a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT). The methods comprise administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof after the HSCT or BMT increases the recovery of the HSCT or BMT in the subject.

[0116] The administration of the pharmaceutical composition after the HSCT or BMT can, for example, accelerate bone marrow recovery in the subject, facilitate engraftment of cells in the subject, reduce post-transplant cytopenia in the subject, and / or increase the proliferative rate of hematopoietic progenitor cells in the subject.

[0117] In certain embodiments, the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT. The pharmaceutical composition can, for example, be administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or any value in between after administration of the HSCT or BMT.

[0118] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. A single dose of theAttorney Docket No. 069069.11011 / 5WO1 pharmaceutical composition can comprise about 50 mg to about 500 mg, about 100 mg to about 450 mg, about 150 mg to about 400 mg, about 200 mg to about 350 mg, or any value in between of IL- 18BP or an active fragment thereof. The single dose can, for example, comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IL-18BP or an active fragment thereof.

[0119] In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. A single dose of the pharmaceutical composition can, for example, comprise about 0.5 to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.0 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, or any number in between, per kg body weight. The single dose can, for example, comprise about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg per kg body weight.

[0120] In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month. In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0121] In certain embodiments, the pharmaceutical composition is administered to the subject once every two days (e.g., every 48 hours).

[0122] In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the ammo acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises the amino acid sequence of SEQ ID NO: 1.

[0123] In certain embodiments, the administration of the IL-18BP blocks free IL-18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / mL or lower in the subject prior to, during, or after the HSCT or BMT. The amount of free IL- 18 in serum of aAttorney Docket No. 069069.11011 / 5WO1 healthy subject, particularly a healthy human is < 5 pg / mL, particularly < 4 pg / mL, particularly < 3 pg / ml, particularly < 2 pg / ml, particularly < 1 pg / mL, particularly < 0.5 pg / mL, or particularly below the detection level.

[0124] Methods of optimizing the outcome of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation in a subject in need thereof

[0125] In another general aspect, the invention relates to methods of optimizing the outcome of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT) in a subject in need thereof, the method comprising: (a) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to a conditioning treatment for the HSCT or BMT, wherein administration of the pharmaceutical composition prior to the conditioning treatment prepares the subject for the conditioning treatment prior to the HSCT or BMT; and / or (b) coadministering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, wherein co-administration of the conditioning treatment and the pharmaceutical composition reduces the toxicity of the conditioning treatment in the subject prior to the HSCT or BMT; and / or (c) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

[0126] In certain embodiments, the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT. The disease or condition associated with increased inflammation can, for example, be selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn error of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

[0127] The cancer can, for example be selected from adult solid tumors, such as breast and prostate cancer, and pediatric solid tumors, such as neuroblastoma, Ewing sarcoma, and Wilms tumor.

[0128] The refractory rheumatic disease or disorder can, for example, be selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophageAttorney Docket No. 069069.11011 / 5WO1 activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So-JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP- MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).

[0129] The hematologic malignant disease or disorder can, for example, be selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosis fungoides and Sezary syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

[0130] The non-malignant hematologic disorder can, for example, be selected from (a) hemoglobinopathies, such as, e.g., Sickle Cell Disease, and Thalassemia major, including alpha and beta Thalassemia; (b) inherited bone marrow failures, such as, e.g., Amegakaryocytic thrombocytopenia (Amega), Diamond Blackfan anemia (DBA), Dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, Severe congenital neutropenia (SCN, also known as Kostman Diease), Shwachman Diamond syndrome (SDS), Thrombocytopenia absent radii (TAR), Epstein Barr virus-associated HLH, and other bone marrow failure syndromes.

[0131] Inborn errors of immunity resulting in immunodeficiencies can, for example, be selected from (a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others; (b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others; (c) a phagocytic deficiency disorder, wherein the phagocytic deficiency disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; (d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others.Attorney Docket No. 069069.11011 / 5WO1

[0132] Inborn errors of immunity resulting in hyperactivation with inflammatory damage can, for example, be selected from the group consisting of X-linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, Proline-serine-threonine phosphatase- interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, DOCK1 1 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (DOCK8), Actin related protein IB (ARP1B), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome-associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (NOD2 mutation), Majeed syndrome, and others.

[0133] In certain embodiments, the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT. The pharmaceutical composition can, for example, be administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or any value in between in advance of the administration of the conditioning treatment for HSCT or BMT.

[0134] In certain embodiments, the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week. In certain embodiments, the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0135] In certain embodiments, the pharmaceutical composition is administered to the subject once every two days (e.g., every 48 hours).

[0136] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. A single dose of the pharmaceutical composition can comprise about 50 mg to about 500 mg, about 100 mg to about 450 mg, about 150 mg to about 400 mg, about 200 mg to about 350 mg, or any value in between of IL- 18BP or an active fragment thereof. The single dose can, for example, comprise about 50 mg, aboutAttorney Docket No. 069069.11011 / 5WO175 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IL-18BP or an active fragment thereof.

[0137] In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. A single dose of the pharmaceutical composition can, for example, comprise about 0.5 to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.0 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, or any number in between, per kg body weight. The single dose can, for example, comprise about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg per kg body weight.

[0138] In certain embodiments, the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.

[0139] In certain embodiments in which the subject is administered a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier to prepare the subject for a conditioning treatment, the method further comprises co-administration of a conditioning treatment and a pharmaceutical composition comprising the IL-18BP or active fragment thereof and pharmaceutically acceptable carrier to reduce the toxicity of the conditioning treatment.

[0140] In certain embodiments, the subject is administered the HSCT or BMT, and after administration of the HSCT or BMT, the method further comprises administering to the subject a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject. The administration of the pharmaceutical composition after the HSCT or BMT can, for example, accelerate bone marrow recovery in the subject, facilitate engraftment of cells in the subject, reduce post-transplant cytopenia in the subject, and / or increase the proliferative rate of hematopoietic progenitor cells in the subject.Attorney Docket No. 069069.11011 / 5WO1

[0141] In certain embodiments, the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT. The pharmaceutical composition can, for example, be administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or any value in between after administration of the HSCT or BMT.

[0142] In certain embodiments, a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof. A single dose of the pharmaceutical composition can comprise about 50 mg to about 500 mg, about 100 mg to about 450 mg, about 150 mg to about 400 mg, about 200 mg to about 350 mg, or any value in between of IL- 18BP or an active fragment thereof. The single dose can, for example, comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of IL-18BP or an active fragment thereof.

[0143] In certain embodiments, a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight. A single dose of the pharmaceutical composition can, for example, comprise about 0.5 to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.0 mg, about 2.0 mg to about 3.5 mg, about 2.5 mg to about 3.0 mg, or any number in between, per kg body weight. The single dose can, for example, comprise about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg per kg body weight.

[0144] In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month. In certain embodiments, the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0145] In certain embodiments, the pharmaceutical composition is administered to the subject once every two days (e.g., every 48 hours).

[0146] In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%,Attorney Docket No. 069069.11011 / 5WO187%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the IL-18BP comprises the amino acid sequence of SEQ ID NO: 1.

[0147] In certain embodiments, the administration of the IL-18BP blocks free IL-18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / mL or lower in the subject prior to, during, or after the HSCT or BMT. The amount of free IL- 18 in serum of a healthy subject, particularly a healthy human is < 5 pg / mL, particularly < 4 pg / mL, particularly < 3 pg / ml, particularly < 2 pg / ml, particularly < 1 pg / mL, particularly < 0.5 pg / mL, or particularly below the detection level.

[0148] Pharmaceutical Compositions

[0149] In another general aspect, the invention relates to a pharmaceutical composition, comprising an IL-18BP or active fragment thereof and a pharmaceutically acceptable carrier.

[0150] The term “pharmaceutical composition” as used herein means a product comprising an IL- 18BP or active fragment thereof of the invention together with a pharmaceutically acceptable carrier. IL-18BPs or active fragments thereof of the invention and compositions comprising them are also useful in the manufacture of a medicament for therapeutic applications mentioned herein.

[0151] As used herein, the term “carrier” refers to any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, oil, lipid, lipid containing vesicle, microsphere, liposomal encapsulation, or other material well known in the art for use in pharmaceutical formulations. It will be understood that the characteristics of the carrier, excipient or diluent will depend on the route of administration for a particular application. As used herein, the term “pharmaceutically acceptable carrier” refers to a non-toxic material that does not interfere with the effectiveness of a composition according to the invention or the biological activity of a composition according to the invention. According to particular embodiments, in view of the present disclosure, any pharmaceutically acceptable carrier suitable for use in a polypeptide pharmaceutical composition can be used in the invention.

[0152] The formulation of pharmaceutically active ingredients with pharmaceutically acceptable carriers is known in the art, e.g., Remington: The Science and Practice of Pharmacy (e.g.21st edition (2005), and any later editions). Non-limiting examples of additional ingredients include buffers, diluents, solvents, tonicity regulating agents, preservatives, stabilizers, and chelating agents. One or more pharmaceutically acceptable carrier(s) can be used in formulating the pharmaceutical compositions of the invention.Attorney Docket No. 069069.11011 / 5WO1

[0153] In one embodiment of the invention, the pharmaceutical composition is a liquid formulation. A preferred example of a liquid formulation is an aqueous formulation, i.e., a formulation comprising water. The liquid formulation can comprise a solution, a suspension, an emulsion, a microemulsion, a gel, and the like. An aqueous formulation typically comprises at least 50% w / w water, or at least 60%, 70%, 75%, 80%, 85%, 90%, or at least 95% w / w of water.

[0154] In one embodiment, the pharmaceutical composition can be formulated as an injectable which can be injected, for example, via an injection device (e.g., a syringe or an infusion pump). The injection can be delivered subcutaneously, intramuscularly, intraperitoneally, intravitr eally, or intravenously, for example.

[0155] In another embodiment, the pharmaceutical composition is a solid formulation, e.g., a freeze-dried or spray-dried composition, which can be used as is, or whereto the physician or the patient adds solvents, and / or diluents prior to use. Solid dosage forms can include tablets, such as compressed tablets, and / or coated tablets, and capsules (e.g., hard or soft gelatin capsules). The pharmaceutical composition can also be in the form of sachets, dragees, powders, granules, lozenges, or powders for reconstitution, for example.

[0156] The dosage forms may be immediate release, in which case they can comprise a water- soluble or dispersible carrier, or they can be delayed release, sustained release, or modified release, in which case they can comprise water-insoluble polymers that regulate the rate of dissolution of the dosage form in the gastrointestinal tract or under the skin.

[0157] In other embodiments, the pharmaceutical composition can be delivered intranasally, intrabuccally, or sublingually.

[0158] The pH in an aqueous formulation can be between pH 3 and pH 10. In one embodiment of the invention, the pH of the formulation is from about 7.0 to about 9.5. In another embodiment of the invention, the pH of the formulation is from about 3.0 to about 7.0.

[0159] In another embodiment of the invention, the pharmaceutical composition comprises a buffer. Non-limiting examples of buffers include: arginine, aspartic acid, bicine, citrate, disodium hydrogen phosphate, fumaric acid, glycine, glycylglycine, histidine, lysine, maleic acid, malic acid, sodium acetate, sodium carbonate, sodium dihydrogen phosphate, sodium phosphate, succinate, tartaric acid, tricine, and tris(hydroxymethyl)-aminomethane, and mixtures thereof. The buffer can be present individually or in the aggregate, in a concentration from about 0.01 mg / ml to about 50Attorney Docket No. 069069.11011 / 5WO1 mg / ml, for example from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific buffers constitute alternative embodiments of the invention.

[0160] In another embodiment of the invention, the pharmaceutical composition comprises a preservative. Non-limiting examples of preservatives include: benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butyl 4-hydroxybenzoate, chlorobutanol, chlorocresol, chlorohexidine, chlorphenesin, o-cresol, m-cresol, p-cresol, ethyl 4-hydroxybenzoate, imidurea, methyl 4- hydroxybenzoate, phenol, 2-phenoxyethanol, 2-phenylethanol, propyl 4-hydroxybenzoate, sodium dehydroacetate, thiomerosal, and mixtures thereof. The preservative can be present individually or in the aggregate, in a concentration from about 0.01 mg / ml to about 50 mg / ml, for example from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific preservatives constitute alternative embodiments of the invention.

[0161] In another embodiment of the invention, the pharmaceutical composition comprises an isotonic agent. Non-limiting examples of isotonic agents include a salt (such as sodium chloride), an amino acid (such as glycine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine), an alditol (such as glycerol, 1,2-propanediol propyleneglycol), 1,3-propanediol, and 1,3- butanediol), polyethyleneglycol (e.g. PEG400), and mixtures thereof. Another example of an isotonic agent includes a sugar. Non-limiting examples of sugars may be mono-, di-, or polysaccharides, or water-soluble glucans, including for example fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, dextran, pullulan, dextrin, cyclodextrin, alpha and beta-HPCD, soluble starch, hydroxyethyl starch, and sodium carboxymethylcellulose. Another example of an isotonic agent is a sugar alcohol, wherein the term “sugar alcohol” is defined as a C(4-8) hydrocarbon having at least one -OH group. Non-limiting examples of sugar alcohols include mannitol, sorbitol, inositol, galactitol, dulcitol, xylitol, and arabitol. The isotonic agent can be present individually or in the aggregate, in a concentration from about 0.01 mg / ml to about 50 mg / ml, for example from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific isotonic agents constitute alternative embodiments of the invention.

[0162] In another embodiment of the invention, the pharmaceutical composition comprises a chelating agent. Non-limiting examples of chelating agents include citric acid, aspartic acid, salts of ethylenediaminetetraacetic acid (EDTA), and mixtures thereof. The chelating agent can be present individually or in the aggregate, in a concentration from about 0.01 mg / ml to about 50 mg / ml, forAttorney Docket No. 069069.11011 / 5WO1 example from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific chelating agents constitute alternative embodiments of the invention.

[0163] In another embodiment of the invention, the pharmaceutical composition comprises a stabilizer. Non-limiting examples of stabilizers include one or more aggregation inhibitors, one or more oxidation inhibitors, one or more surfactants, and / or one or more protease inhibitors.

[0164] In another embodiment of the invention, the pharmaceutical composition comprises a stabilizer, wherein said stabilizer is carboxy- / hydroxy cellulose and derivatives thereof (such as HPC, HPC-SL, HPC-L and HPMC), cyclodextrins, 2-methylthioethanol, polyethylene glycol (such as PEG 3350), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, salts (such as sodium chloride), sulphur-containing substances such as monothioglycerol), or thioglycolic acid. The stabilizer can be present individually or in the aggregate, in a concentration from about 0.01 mg / ml to about 50 mg / ml, for example from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific stabilizers constitute alternative embodiments of the invention.

[0165] In further embodiments of the invention, the pharmaceutical composition comprises one or more surfactants, preferably a surfactant, at least one surfactant, or two different surfactants. The term “surfactant” refers to any molecules or ions that are comprised of a water-soluble (hydrophilic) part, and a fat-soluble (lipophilic) part. The surfactant can, for example, be selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants, and / or zwitterionic surfactants. The surfactant can be present individually or in the aggregate, in a concentration from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific surfactants constitute alternative embodiments of the invention.

[0166] In a further embodiment of the invention, the pharmaceutical composition comprises one or more protease inhibitors, such as, e.g., EDTA, and / or benzamidine hydrochloric acid (HC1). The protease inhibitor can be present individually or in the aggregate, in a concentration from about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions comprising each one of these specific protease inhibitors constitute alternative embodiments of the invention.

[0167] Pharmaceutical compositions comprising IL-18BP or active fragments thereof and methods of administering the pharmaceutical compositions are described in WO2015 / 032932 and WO2016 / 139297, each of which is herein incorporated by reference in its entirety.Attorney Docket No. 069069.11011 / 5WO1EMBODIMENTS

[0168] The invention provides also the following non-limiting embodiments.

[0169] Embodiment 1 is a method for preparing a subject for a conditioning treatment, wherein the subject is in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT), the method comprising: administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to the conditioning treatment, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof prior to the conditioning treatment prepares the subject for the conditioning treatment.

[0170] Embodiment 2 is the method of embodiment 1, wherein the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT.

[0171] Embodiment 3 is the method of embodiment 2, wherein the disease or condition associated with increased inflammation is selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn error of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

[0172] Embodiment 4 is the method of embodiment 3, wherein the cancer is selected from adult solid tumors and pediatric solid tumors.

[0173] Embodiment 4a is the method of embodiment 4, wherein the adult solid tumor is selected from a breast cancer or a prostate cancer, and the pediatric solid tumor is selected from a neuroblastoma, a Ewing sarcoma, and a Wilms tumor.

[0174] Embodiment 5 is the method of embodiment 3, wherein the refractory rheumatic disease or disorder is selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophage activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So- JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP-MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).

[0175] Embodiment 6 is the method of embodiment 3, wherein the hematologic malignant disease or disorder is selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma,Attorney Docket No. 069069.11011 / 5WO1 follicular lymphoma, mantle cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosis fungoides and Sezary syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

[0176] Embodiment 7 is the method of embodiment 3, wherein the non-malignant hematologic disorder is selected from a hemoglobinopathy or an inherited bone marrow failure disorder.

[0177] Embodiment 7a is the method of embodiment 7, wherein:(a) the hemoglobinopathy is selected from the group consisting of Sickle cell disease, Thalassemia major, alpha thalassemia, and beta thalassemia; and(b) the inherited bone marrow disorder is selected from the group consisting of Amegakaryocytic thrombocytopenia (Amega), Diamond Blackfan anemia (DBA), Dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, Severe congenital neutropenia (SCN, also known as Kostman Diease), Shwachman Diamond syndrome (SDS), Thrombocytopenia absent radii (TAR), Epstein Barr virus-associated HLH, and other bone marrow failure syndromes.

[0178] Embodiment 8 is the method of embodiment 3, wherein the inborn errors of immunity resulting in immunodeficiencies is selected from:(a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others;(b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others;(c) a phagocytic deficiency disorder, wherein the disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; orAttorney Docket No. 069069.11011 / 5WO1(d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others.

[0179] Embodiment 8a is the method of embodiment 3, wherein the inborn errors of immunity resulting in hyperactivation with inflammatory damage is selected from the group consisting of X- linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, Proline-serine- threonine phosphatase-interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, DOCK11 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (DOCK8), Actin related protein IB (ARP IB), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome- associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (NOD2 mutation), Majeed syndrome, and others.

[0180] Embodiment 9 is the method of any one of embodiments 1-8, wherein the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT.

[0181] Embodiment 10 is the method of any one of embodiments 1 -9, wherein the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0182] Embodiment 11 is the method of any one of embodiments 1 -9, wherein the pharmaceutical composition is administered as one dose every two days (e.g., every 48 hours).

[0183] Embodiment 12 is the method of any one of embodiments 1-11, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.Attorney Docket No. 069069.11011 / 5WO1

[0184] Embodiment 13 is the method of any one of embodiments 1-11, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0185] Embodiment 13a is the method of any one of embodiments 1-11, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

[0186] Embodiment 13b is the method of any one of embodiments 1-11, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0187] Embodiment 14 is the method of any one of embodiments 1-13, wherein the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0188] Embodiment 15 is the method of any one of embodiments 1-14, wherein the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.

[0189] Embodiment 16 is the method of any one of embodiments 1-15, wherein the method further comprises co-administration of a conditioning treatment and a pharmaceutical composition comprising the IL-18BP or active fragment thereof and pharmaceutically acceptable carrier to reduce the toxicity of the conditioning treatment.

[0190] Embodiment 17 is the method of any one of embodiments 1-16, wherein after administration of the HSCT or BMT to the subject, the method further comprises administering to the subject a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

[0191] Embodiment 18 is the method of embodiment 17, wherein administration of the pharmaceutical composition after the HSCT or BMT accelerates bone marrow recovery in the subject, facilitates engraftment of cells in the subject, reduces post transplant cytopenia in the subject, and / or increases the proliferative rate of hematopoietic progenitor cells in the subject.Attorney Docket No. 069069.11011 / 5WO1

[0192] Embodiment 19 is the method of embodiment 17 or 18, wherein the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT.

[0193] Embodiment 20 is the method of embodiment 19, wherein the pharmaceutical composition is administered for about 4 weeks after administration of the HSCT or BMT.

[0194] Embodiment 21 is the method of any one of embodiments 17-20, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

[0195] Embodiment 22 is the method of any one of embodiments 17-20, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0196] Embodiment 22a is the method of any one of embodiments 17-20, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

[0197] Embodiment 22b is the method of any one of embodiments 17-20, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0198] Embodiment 23 is the method of any one of embodiments 17-22, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0199] Embodiment 24 is the method of any one of embodiments 17-22, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0200] Embodiment 25 is the method of any one of embodiments 17-22, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT as one dose every two days (e.g., every 48 hours).

[0201] Embodiment 26 is a method of reducing the toxicity of a conditioning treatment in a subject in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT), the method comprising:Attorney Docket No. 069069.11011 / 5WO1 co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, whereby co-administration of the conditioning treatment and the pharmaceutical composition comprising the IL-18BP or active fragment thereof reduces the toxicity of the conditioning treatment in the subject.

[0202] Embodiment 27 is the method of embodiment 26, wherein the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT.

[0203] Embodiment 28 is the method of embodiment 27, wherein the disease or condition associated with increased inflammation is selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn errors of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

[0204] Embodiment 29 is the method of embodiment 28, wherein the cancer is selected from adult solid tumors and pediatric solid tumors.

[0205] Embodiment 29a is the method of embodiment 29, wherein the adult solid tumor is selected from a breast cancer or a prostate cancer, and the pediatric solid tumor is selected from a neuroblastoma, a Ewing sarcoma, and a Wilms tumor.

[0206] Embodiment 30 is the method of embodiment 28, wherein the refractory rheumatic disease or disorder is selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophage activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So- JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP-MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).

[0207] Embodiment 31 is the method of embodiment 28, wherein the hematologic malignant disease or disorder is selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosis fungoides and Sezary syndrome, acute myeloid leukemia, acuteAttorney Docket No. 069069.11011 / 5 WO 1 lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

[0208] Embodiment 32 is the method of embodiment 28, wherein the non-malignant hematologic disorder is selected from a hemoglobinopathy or an inherited bone marrow failure disorder.

[0209] Embodiment 32a is the method of embodiment 32, wherein:(a) the hemoglobinopathy is selected from the group consisting of Sickle cell disease, Thalassemia major, alpha thalassemia, and beta thalassemia; and(b) the inherited bone marrow disorder is selected from the group consisting of Amegakaryocytic thrombocytopenia (Amega), Diamond Blackfan anemia (DBA), Dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, Severe congenital neutropenia (SCN, also known as Kostman Diease), Shwachman Diamond syndrome (SDS), Thrombocytopenia absent radii (TAR), Epstein Barr virus-associated HLH, and other bone marrow failure syndromes.

[0210] Embodiment 33 is the method of embodiment 28, wherein the inborn errors of immunity resulting in immunodeficiencies is selected from:(a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others;(b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others;(c) a phagocytic deficiency disorder, wherein the disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; or(d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others

[0211] Embodiment 33a is the method of embodiment 28, wherein the monogenic condition involving blood, myeloid, or lymphoid cells is selected from the group consisting of X-linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Attorney Docket No. 069069.11011 / 5WO1Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, Proline-serine-threonine phosphatase-interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, D0CK11 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (D0CK8), Actin related protein IB (ARP IB), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome-associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (N0D2 mutation), Majeed syndrome, and others.

[0212] Embodiment 34 is the method of any one of embodiments 26-33, wherein the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT.

[0213] Embodiment 35 is the method of any one of embodiments 26-34, wherein the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0214] Embodiment 36 is the method of any one of embodiments 26-34, wherein the pharmaceutical composition is administered as one dose every two days (e.g., every 48 hours).

[0215] Embodiment 37 is the method of any one of embodiments 26-35, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

[0216] Embodiment 38 is the method of any one of embodiments 26-35, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0217] Embodiment 38a is the method of any one of embodiments 26-35, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.Attorney Docket No. 069069.11011 / 5WO1

[0218] Embodiment 38b is the method of any one of embodiments 26-35, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0219] Embodiment 39 is the method of any one of embodiments 26-38, wherein the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0220] Embodiment 40 is the method of any one of embodiments 26-39, wherein the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.

[0221] Embodiment 41 is the method of any one of embodiments 26-40, wherein after administration of the HSCT or BMT to the subject, the method further comprises administering to the subject a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

[0222] Embodiment 42 is the method of embodiment 41, wherein administration of the pharmaceutical composition after the HSCT or BMT accelerates bone marrow recovery in the subject, facilitates engraftment of cells in the subject, reduces post transplant cytopenia in the subject, and / or increases the proliferative rate of hematopoietic progenitor cells in the subject.

[0223] Embodiment 43 is the method of embodiment 41 or 42, wherein the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT.

[0224] Embodiment 44 is the method of embodiment 43, wherein the pharmaceutical composition is administered for about 4 weeks after administration of the HSCT or BMT.

[0225] Embodiment 45 is the method of any one of embodiments 42-44, wherein the pharmaceutical composition is administered as one dose every two days (e.g., every 48 hours).

[0226] Embodiment 46 is the method of any one of embodiments 41-45, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.Attorney Docket No. 069069.11011 / 5WO1

[0227] Embodiment 47 is the method of any one of embodiments 41-45, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0228] Embodiment 47a is the method of any one of embodiments 41-45, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

[0229] Embodiment 47b is the method of any one of embodiments 41-45, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0230] Embodiment 48 is the method of any one of embodiments 41-47, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0231] Embodiment 49 is the method of any one of embodiments 41-47, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0232] Embodiment 50 is the method of any one of embodiments 41-47, wherein the pharmaceutical composition is administered to the subject as one dose every two days (e.g., every 48 hours).

[0233] Embodiment 51 is a method of increasing the recovery in a subject administered a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT), the method comprising: administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof after the HSCT or BMT increases the recovery of the HSCT or BMT in the subject.

[0234] Embodiment 52 is the method of embodiment 51 , wherein increasing the recovery in a subject administered a HSCT or BMT comprises accelerating bone marrow recovery in the subject, facilitating engraftment of cells in the subject, reducing post transplant cytopenia in the subject, and / or increasing the proliferative rate of hematopoietic progenitor cells in the subject.Attorney Docket No. 069069.11011 / 5WO1

[0235] Embodiment 53 is the method of embodiment 51 or 52, wherein the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT.

[0236] Embodiment 54 is the method of embodiment 53, wherein the pharmaceutical composition is administered for about 4 weeks after administration of the HSCT or BMT.

[0237] Embodiment 55 is the method of any one of embodiments 51-54, wherein the pharmaceutical composition is administered to the subject as one dose every two days (e.g., every 48 hours).

[0238] Embodiment 56 is the method of any one of embodiments 51-55, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

[0239] Embodiment 57 is the method of any one of embodiments 51-55, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0240] Embodiment 57a is the method of any one of embodiments 51-55, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

[0241] Embodiment 57b is the method of any one of embodiments 51-55, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0242] Embodiment 58 is the method of any one of embodiments 51-57, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0243] Embodiment 59 is the method of any one of embodiments 51-57, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0244] Embodiment 60 is the method of any one of embodiments 51-57, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT as one dose every two days (e.g., every 48 hours).Attorney Docket No. 069069.11011 / 5WO1

[0245] Embodiment 61 is a method of optimizing the outcome of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT) in a subject in need thereof, the method comprising:(a) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to a conditioning treatment for the HSCT or BMT, wherein administration of the pharmaceutical composition prior to the conditioning treatment prepares the subject for the conditioning treatment prior to the HSCT or BMT; and / or(b) co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, wherein co-administration of the conditioning treatment and the pharmaceutical composition reduces the toxicity of the conditioning treatment in the subject prior to the HSCT or BMT; and / or(c) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

[0246] Embodiment 62 is the method of embodiment 61, wherein the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT.

[0247] Embodiment 63 is the method of embodiment 62, wherein the disease or condition associated with increased inflammation is selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn error of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

[0248] Embodiment 64 is the method of embodiment 63, wherein the cancer is selected from adult solid tumors and pediatric solid tumors.

[0249] Embodiment 64a is the method of embodiment 64, wherein the adult solid tumor is selected from a breast cancer or a prostate cancer, and the pediatric solid tumor is selected from a neuroblastoma, a Ewing sarcoma, and a Wilms tumor.Attorney Docket No. 069069.11011 / 5 WO 1

[0250] Embodiment 65 is the method of embodiment 63, wherein the refractory rheumatic disease or disorder is selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophage activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So- JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP-MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).

[0251] Embodiment 66 is the method of embodiment 63, wherein the hematologic malignant disease or disorder is selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosis fungoides and Sezary syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

[0252] Embodiment 67 is the method of embodiment 63, wherein the non-malignant hematologic disorder is selected from a hemoglobinopathy or an inherited bone marrow failure disorder.

[0253] Embodiment 67a is the method of embodiment 67, wherein:(a) the hemoglobinopathy is selected from the group consisting of Sickle cell disease, Thalassemia major, alpha thalassemia, and beta thalassemia; and(b) the inherited bone marrow disorder is selected from the group consisting of Amegakaryocytic thrombocytopenia (Amega), Diamond Blackfan anemia (DBA), Dyskeratosis congenita (DC), Fanconi anemia (FA), Pearson syndrome, Severe congenital neutropenia (SCN, also known as Kostman Diease), Shwachman Diamond syndrome (SDS), Thrombocytopenia absent radii (TAR), Epstein Barr virus-associated HLH, and other bone marrow failure syndromes.

[0254] Embodiment 68 is the method of embodiment 63, wherein the inborn errors of immunity resulting in immunodeficiencies is selected from:Attorney Docket No. 069069.11011 / 5WO1(a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others;(b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others;(c) a phagocytic deficiency disorder, wherein the disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; or(d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others

[0255] Embodiment 68a is the method of embodiment 63, wherein the inborn errors of immunity resulting in hyperactivation with inflammatory damage is selected from the group consisting of X- linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, Proline-serine- threonine phosphatase-interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, DOCK11 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (DOCK8), Actin related protein IB (ARP IB), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome- associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (NOD2 mutation), Majeed syndrome, and others.

[0256] Embodiment 69 is the method of any one of embodiments 61-68, wherein the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT.Attorney Docket No. 069069.11011 / 5WO1

[0257] Embodiment 70 is the method of any one of embodiments 61-68, wherein the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0258] Embodiment 71 is the method of any one of embodiments 61-68, wherein the pharmaceutical composition is administered to the subject as one dose every two days (e.g., every 48 hours).

[0259] Embodiment 72 is the method of any one of embodiments 61-71, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

[0260] Embodiment 73 is the method of any one of embodiments 61-71, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0261] Embodiment 73 a is the method of any one of embodiments 61-71, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

[0262] Embodiment 73b is the method of any one of embodiments 61-71, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0263] Embodiment 74 is the method of any one of embodiments 61-73, wherein the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0264] Embodiment 75 is the method of any one of embodiments 61-74, wherein the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.

[0265] Embodiment 76 is the method of embodiment 61, wherein increasing the recovery in a subject administered a HSCT or BMT comprises accelerating bone marrow recovery in the subject, facilitating engraftment of cells in the subject, reducing post transplant cytopenia in the subject, and / or increasing the proliferative rate of hematopoietic progenitor cells in the subject.Attorney Docket No. 069069.11011 / 5WO1

[0266] Embodiment 77 is the method of embodiment 61 or 76, wherein the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT.

[0267] Embodiment 78 is the method of embodiment 77, wherein the pharmaceutical composition is administered for about 4 weeks after administration of the HSCT or BMT.

[0268] Embodiment 79 is the method of any one of embodiments 61 and 76-78, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

[0269] Embodiment 80 is the method of any one of embodiments 61 and 76-78, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

[0270] Embodiment 80a is the method of any one of embodiments 61 and 76-78, wherein a single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

[0271] Embodiment 80b is the method of any one of embodiments 61 and 76-78, wherein a single dose of the pharmaceutical composition comprises about 3 mg of IL-18BP or an active fragment thereof per kg body weight.

[0272] Embodiment 81 is the method of any one of embodiments 61 and 76-80, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

[0273] Embodiment 82 is the method of any one of embodiments 61 and 76-80, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

[0274] Embodiment 83 is the method of any one of embodiments 61 and 76-80, wherein the pharmaceutical composition is administered to the subject as one dose every two days (e.g., every 48 hours).

[0275] Embodiment 84 is the method of any one of embodiments 1-83, wherein the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1.Attorney Docket No. 069069.11011 / 5 WO 1

[0276] Embodiment 85 is the method of any one of embodiments 1-84, wherein the administration of the IL-18BP blocks free IL- 18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / mL or lower in the subject prior to, during, or after the HSCT or BMT.EXAMPLES

[0277] Example 1: Prevention and management of toxicities during pre-BMT transplantation in monogenic inflammatory conditions.

[0278] Background.

[0279] Patients suffering from monogenic inborn errors of immunity that can cause hemophagocytic lymphohistiocytosis (HLH) have been traditionally treated with allogeneic HSCT as a potential curative way for life-threatening conditions.

[0280] Patients receiving HSCT have to undergo conditioning regimens. Conditioning, also known as preparative regimen, is an obligatory step before HSCT and involves the use of chemotherapy, radiation therapy, or a combination of both. The rationale for conditioning prior to HSCT includes several objectives: (a) eradication of cells carrying the pathological gene trait; (2) suppression of patient’s immune system to prevent the rejection of the donor cells; and creation of physical space in the bone marrow to allow the healthy stem cells to establish and proliferate for the recovery of hematopoiesis and lymphopoiesis

[0281] Conditioning regimens vary in intensity and can be associated with different toxicities: (1) myeloablative conditioning involves high doses of chemotherapy and / or radiotherapy aiming to completely eradicate the patient bone marrow cells; and (2) reduced-intensity conditioning (non- myeloablative) involves lower doses of chemotherapy with lower toxicity at the expense of noncomplete eradication of the pathological stem cells.

[0282] The more intense the depletion of the patient’s bone marrow, the more frequent toxicities are observed:(1) Hematologic Toxicity: Bone marrow aplasia produces severe pancytopenia, anemia, increased susceptibility to infections, and bleeding until engraftment occurs. Graft failure, although rare, may result in low production of new blood cells after transplant, necessitating further intervention.(2) Gastrointestinal Toxicity: Mucositis, nausea and vomiting, diarrhea and enteritis.Attorney Docket No. 069069.11011 / 5 WO 1(3) Pulmonary Toxicity: Interstitial pneumonitis: sometimes progressing to fibrosis and chronic respiratory failure, infection: related to immunosuppression.(4) Hepatic Toxicity: Elevation of transaminases. Sinusoidal obstruction syndrome (SOS) or veno-occlusive disease (VOD): characterized by the obstruction of small veins in the liver, leading to hepatomegaly, jaundice, ascites, and liver failure.(5) Renal Toxicity: Nephrotoxicity of certain chemotherapeutic agents or radiation can cause kidney damage, leading to reduced kidney function.(6) Neurologic Toxicity: Encephalopathy and peripheral Neuropathy.

[0283] A common denominator to observed toxicities is the systemic inflammation produced during cytoablative chemotherapy treatments. Released cell debris can provoke TLR4 cell signaling, and cell damage molecular patterns can also produce the activation of the inflammasome pathway. It has been observed that in pre-transplant serum samples the inflammatory reaction is frequently associated with high levels of IL- 18 and a correlation has been established between the levels of IL- 18 and a complicated outcome of the transplantation with higher morbidity and slower bone marrow recovery. The objective of the study is to explore the efficacy of Tadekinig alfa in preventing or managing bone marrow toxicity associated with conditioning treatment.

[0284] METHODS

[0285] Human clinical trial: Enroll, randomly in a 1: 1 ratio, patients suffering from any of the following monogenic autoinflammatory conditions, Familia mediterranean fever, cryopyrin associated periodic syndrome (CAPS), Hyperimmunoglobulin-D syndrome (mevalonate kinase deficiency, IL- Ira deficiency (DIRA), Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) disease, Proteasome- Associated Autoinflammatory Syndrome (PRAAS) syndrome, Majeed syndrome, XI AP deficiency, and require bone marrow transplant (BMT) as therapeutic option.

[0286] The experimental group receives the conditioning protocol preceded by or in combination with IL- 18BP whereas the control arm receives the same conditioning protocol in combination or preceded by a placebo.

[0287] The objective of the study is to explore the efficacy of rhIL-18BP (Tadekinig alfa) in preventing or managing hematologic toxicity and mucositis associated with conditioning treatment.Attorney Docket No. 069069.11011 / 5 WO 1

[0288] The level of hematologic toxicity is graded according to the Common Terminology Criteria for Adverse Evens (CTCAE) with special interest in neutropenia and thrombocytopenia.

[0289] Neutropenia (Low Neutrophil Count)• Grade 1 : Neutrophil count < LLN (Lower Limit of Normal) - 1.5 x 10A9 / L• Grade 2: Neutrophil count < 1.5 - 1.0 x 10A9 / L• Grade 3: Neutrophil count < 1.0 - 0.5 x 10A9 / L• Grade 4: Neutrophil count < 0.5 x 10A9 / L• Grade 5: Death

[0290] Thrombocytopenia (Low Platelet Count)• Grade 1 : Platelet count < LLN - 75 x 10A9 / L• Grade 2: Platelet count < 75 - 50 x 10A9 / L• Grade 3 : Platelet count < 50 - 25 x 10A9 / L• Grade 4: Platelet count < 25 x 10A9 / L• Grade 5: Death

[0291] Lor the grading of mucositis severity, the CTCAE is used for the assessment of oral and gastrointestinal mucositis.

[0292] Oral MucositisGrade 1: a. Asymptomatic or mild symptoms. b. Intervention not indicated.Grade 2: a. Moderate pain or ulcer that does not interfere significantly with oral intake. b. Modified diet indicated.Grade 3: a. Severe pain or ulcer interfering with oral intake. b. Significant impact on oral intake.Grade 4: a. Life-threatening consequences. b. Urgent intervention indicated.Grade 5: a. Death.Attorney Docket No. 069069.11011 / 5 WO 1

[0293] Gastrointestinal Mucositis (General GI)Grade 1: a. Asymptomatic or mild symptoms. b. Intervention not indicated.Grade 2: a. Moderate pain or change in bowel habits (e.g., diarrhea, constipation) that does not interfere significantly with function.Grade 3: a. Severe pain or change in bowel habits, interfering significantly with function. Grade 4: a. Life-threatening consequences. b. Urgent intervention indicated.Grade 5: a. Death.

[0294] For the comparison of the two groups a Fisher’s exact test is applied.

[0295] Example 2: Prevention and management of toxicities post-BMT transplantation in hematologic malignancies.

[0296] Background.

[0297] Allogenic stem cell transplantation is an established medical approach for patients suffering from hematologic malignancies. Persistence or recurrence of the underlying disease is observed, unfortunately, in a proportion of cases. In addition, several complications, unrelated to disease persistence or relapse, can occur post BMT including infections, hemorrhages, acute graft- vs-host disease and other toxicities related to endothelial cell damage.

[0298] It has been noticed that increased IL- 18 levels, released as a consequence of the collateral tissue damage induced by conditioning treatment pre-BMT, are associated with higher morbidity and mortality independent of a relapse of the underlying hematological malignance. The association of high IL- 18 with non- relapse morbi-mortality, including severe infections (including sepsis), hemorrhages, acute graft-vs-hist disease, and cardiovascular (CV) events has been established and the poor or lack of bone marrow recovery is a common denominator of those complications.Attorney Docket No. 069069.11011 / 5WO1

[0299] The recovery of a donor-derived hematopoietic system in the recipient is associated with a lower incidence of complications after allogeneic BMT and a significantly improved outcome for the patients.

[0300] The aim of this study is to block high IL- 18 levels and the presence of free IL- 18 with rhlL- 18BP (Tadekinig alfa) during the conditioning treatment and post BMT until 28 days posttransplant.METHODS

[0301] Human clinical trial: Enroll patients suffering from myeloid malignant disorders including acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Patients are treated with non-myeloablative conditioning (i.e., cyclophosphamide + fludarabine + TBI 2 Gy, but not exclusively), mycophenolate mofetil prophylaxis and demonstrate high IL- 18 levels at the start of the conditioning protocol, i.e. > 500 pg / ml.

[0302] All patients receive Tadekinig alfa, s.c., at 2 mg / kg every 48 hours during the conditioning period and in combination with the conditioning protocol and until 28 days post-transplant.

[0303] The objective of the study is to explore the efficacy of Tadekinig alfa in the recovery of bone marrow post allogeneic stem cell transplantation.

[0304] The primary endpoint is the platelet recovery at 28 days post BMT (> 100 / nl).

[0305] Secondary endpoints include:1. Reduction of hematologic toxicity during the conditioning. Toxicities are graded according to the Common Terminology Criteria for Adverse Evens (CTCAE).

[0306] Neutropenia (Low Neutrophil Count)• Grade 1 : Neutrophil count < LLN (Lower Limit of Normal) - 1.5 x 10A9 / L• Grade 2: Neutrophil count < 1.5 - 1.0 x 10A9 / L• Grade 3: Neutrophil count < 1.0 - 0.5 x 10A9 / L• Grade 4: Neutrophil count < 0.5 x 10A9 / L• Grade 5: Death

[0307] Thrombocytopenia (Low Platelet Count)• Grade 1 : Platelet count < LLN - 75 x 10A9 / L• Grade 2: Platelet count < 75 - 50 x 10A9 / L• Grade 3 : Platelet count < 50 - 25 x 10A9 / LAttorney Docket No. 069069. 11011 / 5 WO 1• Grade 4: Platelet count < 25 x 10A9 / L• Grade 5: Death2. Recovery of white blood cells counts at 28 days post BMT.3. Recovery of red blood cells and hemoglobin at 28 days post BMT.4. Reduction in the incidence of infectious events post BMT.5. Reduction in the incidence of hemorrhages post BMR.6. Reduction in the incidence of acute graft-vs-host disease port BMT.SEQ ID NO:1 (IL-18BP)ThrPro V al S er GlnThr Thr Thr Ala AlaThr AlaS erV al ArgS erThrLy s AspProCy sPr oS erGlnProPr o V alPh eProAlaAlaLysGlnCysProAlaLeuGluValThrTrpProGluValGluValProLeuAsnGlyThrLeuSerLeuSer CysValAlaCysSerArgPheProAsnPheSerlleLeuTyrTrpLeuGlyAsnGlySerPhelleGluHisLeuProGlyAr gLeuTrpGluGlySerThrSerArgGluArgGlySerThrGlyThrGlnLeuCysLysAlaLeuValLeuGluGlnLeuT hrPro AlaLeuHis S er Thr AsnPheS erCy s V alLeuV al AspProGluGlnV al V alGlnArgHis V al V alLeu AlaGl nLeuTrp AlaGlyLeuArg AlaThrLeuProPr oThrGlnGlu AlaLeuProS er S erHis S er S erProGlnGlnGlnGlyTPVSQTTTAATASVRSTKDPCPSQPPVFPAAKQCPALEVTWPEVEVPLNGTLSLSCVACSRFPNFS ILYWLGN GS FI EHLPGRLWEGSTSRERGSTGTQLCKALVLEQLT PALHSTNFSCVLVDPEQVVQRHWLAQLWAGLRATL PPTQEALPS SHSS PQQQG

Claims

Attorney Docket No. 069069.11011 / 5WO1CLAIMSIt is claimed:

1. A method for preparing a subject for a conditioning treatment, wherein the subject is in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT), the method comprising: administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to the conditioning treatment, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof prior to the conditioning treatment prepares the subject for the conditioning treatment.

2. A method of reducing the toxicity of a conditioning treatment in a subject in need of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT), the method comprising: co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, whereby co-administration of the conditioning treatment and the pharmaceutical composition comprising the IL-18BP or active fragment thereof reduces the toxicity of the conditioning treatment in the subject.

3. A method of increasing the recovery in a subject administered a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT), the method comprising: administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, whereby administration of the pharmaceutical composition comprising the IL-18BP or active fragment thereof after the HSCT or BMT increases the recovery of the HSCT or BMT in the subject.

4. A method of optimizing the outcome of a hematopoietic stem cell transplantation (HSCT) or a bone marrow transplantation (BMT) in a subject in need thereof, the method comprising:Attorney Docket No. 069069.11011 / 5WO1(a) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier prior to a conditioning treatment for the HSCT or BMT, wherein administration of the pharmaceutical composition prior to the conditioning treatment prepares the subject for the conditioning treatment prior to the HSCT or BMT; and / or(b) co-administering to the subject a conditioning treatment and a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier, wherein co-administration of the conditioning treatment and the pharmaceutical composition reduces the toxicity of the conditioning treatment in the subject prior to the HSCT or BMT; and / or(c) administering to the subject a pharmaceutical composition comprising an IL- 18 binding protein (IL-18BP) or an active fragment thereof and a pharmaceutically acceptable carrier after the administration of the HSCT or BMT, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

5. The method of claim 1 or 4, wherein the subject in need of the HSCT or the BMT is suffering from a disease or condition associated with increased inflammation prior to the HSCT or BMT.

6. The method of claim 5, wherein the disease or condition associated with increased inflammation is selected from a cancer, a refractory rheumatic disease or disorder, a hematologic malignant disease or disorder, a non-malignant hematologic disorder, or an inborn error of immunity resulting in immunodeficiencies or hyperactivation with inflammatory damage.

7. The method of claim 6, wherein the cancer is selected from an adult solid tumor or a pediatric solid tumor.

8. The method of claim 6, wherein the refractory rheumatic disease or disorder is selected from the group consisting of refractory systemic juvenile idiopathic arthritis (JIA) with recurrent macrophage activation episodes, systemic juvenile idiopathic arthritis (SJIA), systemic-onset juvenile idiopathic arthritis (So- JIA), IL- 18 mediated pulmonary alveolar proteinosis with recurrent MAS (IL-18PAP-MAS), and periodic fevers with aphthous stomatitis pharyngitis and adenitis (PFAPA).

9. The method of claim 6, wherein the hematologic malignant disease or disorder is selected from the group consisting of a B cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantleAttorney Docket No. 069069.11011 / 5 WO 1 cell lymphoma, large B cell lymphoma, marginal-zone lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, T-cell lymphoma, NK cell lymphomas, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphomas like mycosis fungoides and Sezary syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma, Waldenstrom macroglobulinemia, primary myelofibrosis, and related myelodysplastic / myeloproliferative syndromes such as polycythemia vera, essential thrombocytopenia, refractory anemia, aplastic anemia, refractory cytopenia with single or multilineage dysplasia, and others.

10. The method of claim 6, wherein the non-malignant hematologic disorder is selected from a hemoglobinopathy or an inherited bone marrow failure disorder.

11. The method of claim 6, wherein the inborn errors of immunity resulting in immunodeficiencies is selected from:(a) a severe combined immunodeficiency (SCID) disorder, wherein the SCID disorder is selected from adenosine deaminase deficiency (ADA), X-linked SCID, Janus kinase 3 deficiency (JAK3-SCID), RAG1 and RAG2 deficiency, or others;(b) a combined immunodeficiency (CID) disorder, wherein the CID disorder is selected from Bare lymphocyte syndrome (BLS), CD40 ligand deficiency, MHC I deficiency, or others;(c) a phagocytic deficiency disorder, wherein the disorder is selected from chronic granulomatous disease, Leukocyte adhesion deficiency (LAD), or others; or(d) an inherited autoimmune condition, wherein the condition is selected from Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, the Autoimmune poly endocrine syndrome (AIRE mutation or APS-1), or others12. The method of claim 6, wherein the inborn errors of immunity resulting in hyperactivation with inflammatory damage is selected from the group consisting of X-linked lymphoproliferative syndrome (XLP1), X-linked inhibitor of apoptosis (XIAP) deficiency, Chediak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, Proline-serine-threonine phosphatase-interacting protein 1 (PSTPiPl) mutation resulting in the Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome, Cell division cycle 42 (CDC42) mutation associated with NOCARH syndrome, DOCK11 mutation, and other actinopathies associated with mutations in cofilin 1 (CFL1), WASP actin nucleation promoting factor (WAS), Dedicator of cytokinesis 8 (DOCK8),Attorney Docket No. 069069.11011 / 5WO1Actin related protein IB (ARP IB), Rac family small GTPase2 (RAC2), WD repeat domain 1 (WDR1), Cryopyrin associated periodic syndrome (CAPS), Proteosome-associated autoinflammatory syndrome (PRAAS), Familial mediterranean fever, Hyper-IgD syndrome / Mevalonate kinase deficiency, Tumor Necrosis factor receptor-associated periodic syndrome (TRAPS), Deficiency of IL-1 receptor antagonist (DIRA), IL-36RA mutation (DITRA syndrome, pustular psoriasis), Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Blau syndrome (N0D2 mutation), Majeed syndrome, and others.

13. The method of any one of claims 1 and 4 to 12, wherein the pharmaceutical composition is administered about 2 weeks to about 6 weeks in advance of the administration of the conditioning treatment for HSCT or BMT.

14. The method of any one of claims 1 and 4 to 12, wherein the pharmaceutical composition is administered in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

15. The method of any one of claims 1 and 4 to 12, wherein the pharmaceutical composition is administered to the subject as one dose every two days.

16. The method of any one of claims 1 and 4 to 15, wherein a single dose of the pharmaceutical composition comprises 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

17. The method of any one of claims 1 and 4 to 13, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

18. The method of claim 17, wherein the single dose of the pharmaceutical composition comprises about 2 mg of IL-18BP or an active fragment thereof per kg body weight.

19. The method of any one of claims 1 and 4 to 18, wherein the pharmaceutical composition is administered to the subject in need of the HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

20. The method of any one of claims 1 , 2, and 4 to 20, wherein the conditioning treatment is selected from the group consisting of a total body irradiation treatment, a myeloablative non-total body irradiation (TBI) conditioning treatment, a reduced intensity and reduced toxicity conditioning treatment, a nonmyeloablative conditioning treatment, and a chemotherapy.Attorney Docket No. 069069.11011 / 5WO121. The method of claim 1 or 4, wherein the method further comprises co-administration of a conditioning treatment and a pharmaceutical composition comprising the IL-18BP or active fragment thereof and pharmaceutically acceptable carrier to reduce the toxicity of the conditioning treatment.

22. The method of any one of claims 1, 2, or 4 to 21, wherein after administration of the HSCT or BMT to the subject, the method further comprises administering to the subject a pharmaceutical composition comprising an IL-18BP or an active fragment thereof and a pharmaceutically acceptable carrier, wherein administration of the pharmaceutical composition after the HSCT or BMT increases the recovery of the subject.

23. The method of claim 3 or 22, wherein administration of the pharmaceutical composition after the HSCT or BMT accelerates bone marrow recovery in the subject, facilitates engraftment of cells in the subject, reduces post transplant cytopenia in the subject, and / or increases the proliferative rate of hematopoietic progenitor cells in the subject.

24. The method of claim 22 or 23, wherein the pharmaceutical composition is administered for about 2 weeks to about 6 weeks after administration of the HSCT or BMT.

25. The method of claim 24, wherein the pharmaceutical composition is administered for about 4 weeks after administration of the HSCT or BMT.

26. The method of any one of claims 22 to 25, wherein a single dose of the pharmaceutical composition comprises about 50 mg to about 500 mg of IL-18BP or an active fragment thereof.

27. The method of any one of claims 22 to 25, wherein a single dose of the pharmaceutical composition comprises about 0.5 mg of IL-18BP or an active fragment thereof per kg body weight and about 5 mg of IL-18BP or an active fragment thereof per kg body weight.

28. The method of any one of claims 22 to 27, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in multiple doses per day, in multiple doses per week, or in multiple doses per month.

29. The method of any one of claims 22 to 27, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT in one dose per week, in two doses per week, in three doses per week, or in four doses per week.

30. The method of any one of claims 22 to 27, wherein the pharmaceutical composition is administered to the subject after HSCT or BMT as one dose every two days.Attorney Docket No. 069069.11011 / 5WO131. The method of any one of claims 1 to 30, wherein the IL-18BP comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 1.

32. The method of any one of claims 1 to 31, wherein the administration of the IL-18BP blocks free IL- 18 in the subject, preferably the administration of the IL-18BP results in a level of free IL- 18 of 5 pg / mL or lower in the subject prior to, during, or after the HSCT or BMT.