JP2026504942A - Methods and Compositions for Combination Therapy - Google Patents

Abstract

The present disclosure provides compositions and methods for treating a disease, such as a cancer or a tumor, comprising administering a combination therapy comprising a decoy-resistant (DR) IL-18 polypeptide or sequential doses of a DR IL-18 polypeptide and an immune checkpoint inhibitor (ICI) or sequential doses of an ICI.
[Selected Figure] Figure 3

Description

CROSS-REFERENCE This application claims the benefit of U.S. Provisional Patent Application No. 63/481,214, filed January 24, 2023, and U.S. Provisional Patent Application No. 63/488,384, filed March 3, 2023, each of which is incorporated herein by reference in its entirety.

REFERENCE TO ELECTRONICALLY SUBMITTED SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on January 23, 2024, is named "ST-009-WO1_seqlist.xml", and is 159 kb in size.

Despite recent advances in cancer therapy, current statistics on cancer prevalence and mortality in the United States and worldwide indicate that cancer remains a major health challenge. It is estimated that more than 600,000 people will die from cancer in the United States in 2023. Lung cancer remains the leading cause of cancer deaths worldwide. Breast cancer is the most common invasive cancer in women worldwide, accounting for 16% of female cancers and 23% of invasive cancers. In the United States, one in eight women will develop breast cancer in their lifetime. Colorectal cancer is the third most common cancer in men and the second most common cancer in women worldwide. CRC mortality rates are declining in the United States and Canada but are increasing in regions such as Latin America and the Caribbean.

Interleukin-18 (IL-18) is a proinflammatory cytokine capable of stimulating T cells, NK cells, and myeloid cells. IL-18 has been proposed as an immunotherapeutic agent for the treatment of cancer, given its ability to stimulate anti-tumor cells. However, the clinical efficacy of human recombinant IL-18 has been limited.

Immune checkpoint inhibitors (ICIs) are binding proteins that bind to immune checkpoint proteins, thereby enhancing a subject's immune system to combat the subject's cancer. ICIs have demonstrated some clinical success in treating at least a subset of a variety of different cancers, including, for example, non-small cell lung cancer, advanced melanoma, gastric cancer, renal cell carcinoma, glioma, breast cancer brain metastasis, colorectal cancer, bladder cancer, testicular germ cell tumors, cervical squamous cell carcinoma, and head and neck squamous cell carcinoma. However, many cancers develop resistance to ICI treatment and subsequently progress, reducing the therapeutic impact of these agents. For example, while a percentage of patients with lung cancer experience long-term clinical benefit with ICIs, most patients develop disease progression during or after treatment cessation.

Therefore, there is a need for compositions and methods for treating and preventing cancer and other diseases and disorders.

One aspect of the present disclosure provides a method of treating a disease, the method comprising: (a) administering to a subject a composition comprising a decoy-resistant (DR) IL-18 polypeptide or a nucleic acid encoding a DR IL-18 peptide; and (b) administering to the subject a composition comprising an immune checkpoint inhibitor (ICI) other than pembrolizumab. Such methods include, but are not limited to, immune checkpoint inhibitors such as acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enlonstobart, ezabenlimab, phynotlimab, geptanolimab, ipalomulimab, and lipstobart. ipustobart), nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, selplulimab, sintilimab, spartalizumab , tislelizumab, toripalimab, zelvalimab, zimbelelimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiflimab, resabelimab (lesabelimab), rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudubrilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstotug, Fila Firastotug, gotistobart, ipilimumab, muzastotug, nurlimab, porustobart, quavonlimab, sovipostobart, tremelimumab, tubonralimab, vilastobart, zalifrelimab, enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstobart, relatolimab, tuparstobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and a group comprising variants of any of the foregoing, or zimvelerimab, Nivolumab, cemiplimab, dostarimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, pidilizumab, MEDI0680, SSI-361, AMP-224, cetrelimab, prorugolimab, retifanlimab, atezolizumab, avelumab, durvalumab, embajo A variety of ICIs may be used, including the group consisting of limumab, cosibelimab, CA-170, BMS-986189, BMS-936559, sugemalimab, adebulelimab, CBT-502, BGB-A333, pacmilimab, ipilimumab, tremelimumab, relatlimab, enoblituzumab, and variants of any of the foregoing.

One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject (a) a decoy-resistant (DR) IL-18 composition comprising a DR polypeptide or a nucleic acid encoding a DR IL-18 polypeptide, (b) an immune checkpoint inhibitor (ICI) composition comprising an effective amount of an ICI, where the ICI is not pembrolizumab, and (c) an additional treatment comprising a prophylactic agent. Administering such a prophylactic agent may reduce the onset of symptoms of cytokine release syndrome (CRS) in the subject, and thus the additional treatment may comprise CRS prophylaxis. CRS prophylaxis comprises administering one or more agents, CRS prophylactic agents, to the subject prior to the onset of CRS in the subject to prevent or reduce the onset of symptoms of CRS in the subject. CRS preventative agents (and combinations of CRS preventative agents), described in more detail below, may be administered with or before administration of the DR IL-18 composition, including with or before administration of each dose of the DR IL-18 composition when sequential DR IL-18 composition doses are used. Non-limiting examples of useful CRS preventative agents include NSAIDs, acetaminophen, diphenhydramine, histamine H1 antagonists, famotidine, and H2 blockers.

In some embodiments, the prophylactic agent comprises an analgesic. In some embodiments, the analgesic is a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the NSAID is selected from the group consisting of ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, celecoxib, rofecoxib, valdecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin. In some embodiments, the NSAID is ibuprofen. In some embodiments, the NSAID is diclofenac. In some embodiments, the NSAID is about 25 mg to about 60 mg. In some embodiments, the NSAID is about 200 mg to about 600 mg.

In some embodiments, the analgesic is an analgesic. In some embodiments, the analgesic is selected from the group consisting of acetaminophen, aspirin, caffeine, butalbital, isometheptene mucate, magnesium salicylate, codeine, dihydrocodeine, hydrocodone, oxycodone, tramadol, co-codamol, co-codaprine, codidramol, alfentanil, fentanyl, hydromorphone, methadone, morphine, meperidine, and oxymorphone. In some embodiments, the analgesic is acetaminophen. In some embodiments, the analgesic is at least about 500 mg. In some embodiments, the analgesic is at least about 600 mg.

In some embodiments, the prophylactic agent is an antihistamine. In some embodiments, the antihistamine is an H-1 receptor antagonist or an H-2 receptor antagonist. In some embodiments, the antihistamine is an H-1 receptor antagonist. In some embodiments, the H-1 receptor antagonist is selected from the group consisting of brompheniramine, chlorpheniramine, clemastine, cyprofeptadine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine. In some embodiments, the H-1 receptor antagonist is diphenhydramine. In some embodiments, the antihistamine is an H-2 receptor antagonist.

In some embodiments, the H-2 receptor antagonist is selected from the group consisting of cimetidine, famotidine, nizatidine, and ranitidine. In some embodiments, the H-2 receptor antagonist is famotidine. In some embodiments, the antihistamine is at least about 20 mg. In some embodiments, the antihistamine is at least about 40 mg.

In some embodiments, the prophylactic agent is an anti-infective. In some embodiments, the anti-infective is a cytokine inhibitor. In some embodiments, the cytokine inhibitor targets a cytokine receptor. In some embodiments, the cytokine receptor is for TNFα, TNFβ, IFNα, IFNβ, IFNγ, IL-6, or IL-12. In some embodiments, the cytokine receptor is an IL-6 receptor. In some embodiments, the anti-infective is an antibody or a small molecule. In some embodiments, the anti-infective is at least about 500 mg.

In some embodiments, the prophylactic agent comprises a supplemental fluid. In some embodiments, the supplemental fluid is selected from the group consisting of saline, lactated Ringer's solution, dextrose in aqueous solution, sodium chloride solution, and any combination thereof. In some embodiments, the supplemental fluid is up to about 3 liters.

In some embodiments, the prophylactic agent is a steroid. In some embodiments, the steroid is selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone. In some embodiments, the steroid is prednisone. In some embodiments, the steroid is administered at a maximum dose of about 10 mg/day.

In some embodiments, the prophylactic agent is administered at least 2 hours before the DR IL-18 polypeptide and an effective amount of ICI. In some embodiments, the prophylactic agent is administered at least 1 hour before the DR IL-18 polypeptide and an effective amount of ICI. In some embodiments, the prophylactic agent is administered intravenously, intramuscularly, subcutaneously, or orally.

In some aspects of the treatment methods provided herein, the disease comprises cancer. In some embodiments, the cancer is a solid tumor or a liquid tumor. In some embodiments, the solid tumor is selected from the group consisting of melanoma, Merkel cell carcinoma, ovarian cancer, renal cell carcinoma, urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability-high (MSI-H) tumors, high tumor mutation burden (TMB-H) tumors, mismatch repair-deficient tumors, gastric, cervical, endometrial, squamous cell carcinoma of the skin, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof. In some embodiments, the solid tumor is melanoma, renal cell carcinoma, TNBC, NSCLC, SCCHN, or MSI-H tumor. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is renal cell carcinoma. In some embodiments, the solid tumor is TNBC. In some embodiments, the solid tumor is NSCLC. In some embodiments, the solid tumor is SCCHN. In some embodiments, the solid tumor is an MSI-H tumor. In some embodiments, the cancer is resistant to one or more ICIs, i.e., the cancer is ICI-resistant, including, for example, when the ICI-resistant cancer is melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase-positive mutation/fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof. In some embodiments, the cancer is a liquid tumor selected from the group consisting of myeloma, B-cell lymphoma, and acute myeloid leukemia.

In some embodiments, the DR IL-18 polypeptide is administered intravenously or subcutaneously. In some embodiments, the DR IL-18 polypeptide is administered weekly. In some embodiments, the method results in a reduction in tumor size or tumor number in the subject. In some embodiments, the DR IL-18 polypeptide comprises multiple mutations compared to wild-type IL-18, as set forth in SEQ ID NO: 13. In some embodiments, the multiple mutations comprise multiple amino acid substitutions. In some embodiments, the DR IL-18 polypeptide comprises an amino acid sequence selected from any one of SEQ ID NOs: 1-12, or an amino acid sequence having at least 90%, 95%, or 98% sequence identity to any one of SEQ ID NOs: 1-12.

INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

The following detailed description of the present invention will be better understood when read in conjunction with the accompanying drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

The sequences of decoy-resistant (DR) IL-18 polypeptides are shown in SEQ ID NOs: 8-12. The position of each mutation and the corresponding residue in the mature form of wild-type human IL-18 are shown at the top of the table. Shaded residues represent the five most conserved mutations. The top sequence ("WT IL-18") is set forth as SEQ ID NO: 13. Figure 1 shows a substantial reduction in CT26 (colorectal) tumor growth in mice treated with a combination of decoy-resistant (DR) IL-18 polypeptide and an anti-PD-1 immune checkpoint inhibitor (ICI) antibody. The Y-axis is tumor growth in cubic millimeters (mm3) and error bars represent standard deviation. Figure 1 shows substantially reduced CT26 (colorectal) tumor growth in mice treated with a combination of DR-18 and anti-LAG3 ICI antibody. The Y-axis is tumor growth in mm3 and error bars represent standard deviation. Figure 1 shows reduced MC38 (colorectal) tumor growth in mice treated with a combination of DR IL-18 polypeptide and anti-PD-1 ICI antibody compared to either DR IL-18 polypeptide or anti-PD-1 ICI monotherapy. The Y-axis is tumor growth in mm3 and error bars represent standard deviation. The inset provides a magnification of the tumor growth area between 0 and 1000 mm3. 1 shows reduced MC38 (colorectal) tumor growth in mice treated with a combination of DR-18 and anti-LAG3 ICI antibodies compared to anti-LAG3 ICI monotherapy. Y-axis is tumor growth in mm3 and error bars represent standard deviation.

All terms are intended to be understood as understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

While various features of the present disclosure may be described in the context of a single embodiment, these features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein for clarity in the context of separate embodiments, the present disclosure may also be implemented in a single embodiment.

Any reference herein to "some embodiments," "an embodiment," "one embodiment," or "other embodiments" means that a feature, structure, or characteristic described in connection with an embodiment is included in at least some, but not necessarily all, embodiments of the present disclosure.

As used in this specification and claim(s), the words "comprising" (and any form of "comprise" such as "comprise" and "comprises"), "having" (and any form of "having" such as "have" and "has"), "including" (and any form of "includes" and "include"), or "containing" (and any form of "containing" such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is intended that any embodiment discussed in this specification can be implemented with respect to any method or configuration of the disclosure, and vice versa. Furthermore, the compositions of the present disclosure can be used to achieve the methods of the present disclosure.

Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure.

Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the size of the range.

As used herein, the terms "about" or "approximately," when referring to a measurable value, such as a parameter, amount, length of time, etc., are meant to encompass variations of the specified value and of no more than +/-20%, no more than +/-10%, no more than +/-5%, or no more than +/-1% from that value, where such variations are appropriate in the present disclosure. It is to be understood that the value to which the modifier "about" or "approximately" refers is itself specifically disclosed.

As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a sample" includes multiple samples, including mixtures thereof.

The terms "subject," "individual," or "patient" are used interchangeably herein. A "subject" includes a biological entity containing expressed genetic material. In some embodiments, a subject includes an animal, mammal, or human. In some embodiments, a subject is diagnosed with cancer. In some embodiments, a subject has a solid tumor.

As used herein, the terms "treat," "treated," "treating," "treatment," and the like are used in reference to an intervention regimen to obtain a beneficial or desired result in a recipient. Beneficial or desired results include, but are not limited to, therapeutic benefit and/or prophylactic benefit. Therapeutic benefit may refer to prevention or amelioration of the condition or underlying disorder being treated. A therapeutic benefit can also be achieved by prevention or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in a subject, although the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For a prophylactic benefit, subjects at risk of developing a particular disease or condition or reporting one or more physiological symptoms of a disease or condition may be treated.

As used herein, the terms "prevent," "preventing," "prevention," and the like mean avoiding or delaying the onset of symptoms associated with a disease or condition in a subject who has not developed such symptoms at the time administration of an agent or compound is initiated.

The term "therapeutic effect" refers to some degree of alleviation of one or more symptoms of a disorder (e.g., a tumor, a tumor, or an infection by an infectious agent or an autoimmune disease) or its associated pathology. As used herein, "therapeutically effective amount" refers to an amount of an agent that, upon single or multiple administration to a cell or a subject, is effective in prolonging survival of a patient with such a disorder, or in reducing, preventing, or delaying one or more signs or symptoms of the disorder beyond that expected in the absence of such treatment. "Therapeutically effective amount" is intended to identify the amount needed to achieve a therapeutic effect. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the required "therapeutically effective amount" (e.g., ED50) of the pharmaceutical composition.

Typically, the therapeutic agent(s) are administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing regression of such symptom(s) or inhibiting their progression to any clinically measurable extent. The amount of therapeutic agent(s) effective to alleviate any particular disease symptom may vary depending on factors such as the subject's or patient's condition, age, and weight, as well as the ability of the therapeutic biologic to elicit a desired response in the subject or patient. Alleviation of a disease symptom can be assessed by any clinical measurement typically used by a physician or other skilled healthcare provider to assess the severity or progression of that symptom. "Treatment" may include one or more of the following: inducing/increasing an anti-tumor immune response, reducing the number of one or more tumor markers, halting or slowing the growth of a tumor or blood cancer or the progression of a disease such as cancer, stabilizing the disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, reducing the level of one or more tumor markers, alleviating or ameliorating clinical symptoms of the disease, reducing the severity or duration of clinical symptoms, extending survival or patient lifespan compared to expected survival in a similar untreated patient, and inducing complete or partial remission of the cancerous condition, wherein the disease is cancer.

The amount of a therapeutic biologic that is effective in alleviating any particular disease symptom can vary depending on factors such as the subject's or patient's condition, age, and weight, as well as the ability of the therapeutic biologic to elicit a desired response in the subject or patient. Alleviation of a disease symptom can be assessed by any clinical measurement typically used by a physician or other skilled healthcare provider to assess the severity or progression of the condition.

Positive therapeutic effects in cancer can be measured in several ways (see W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, for tumor growth inhibition, according to NCI criteria, a T/C of ≦42% is the minimum level of antitumor activity. A T/C of <10% is considered a high level of antitumor activity, where T/C (%) = median treated tumor volume/median control tumor volume × 100. In some embodiments, treatment achieved by the disclosed therapies is one of the following: partial response (PR), complete response (CR), objective response (OR), progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). PFS, also referred to as "time to tumor progression," indicates the length of time during and after treatment during which the cancer does not grow, and includes the length of time the patient experienced a CR or PR, as well as the amount of time the patient experienced stable disease (SD). DFS refers to the length of time a patient remains disease-free during and after treatment. OS refers to an extension of life expectancy compared to a naive or untreated individual or patient. In some embodiments, the response to both of the present disclosure is either PR, CR, PFS, DFS, or OR as assessed using RECIST 1.1 response criteria. Treatment regimens for the disclosed therapies that are effective in treating cancer patients may vary according to factors such as the patient's disease state, age, and weight, as well as the ability of the therapy to induce an anti-cancer response in the subject. While any embodiment of any aspect of the present disclosure may not be effective in achieving a positive therapeutic effect in all subjects, it should be effective in a statistically significant number of subjects, as determined by any statistical test known in the art, such as Student's t-test, chi-square test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonkheel-Tapstra test, and Wilcoxon test.

The terms "tumor" and "cancer" refer to any disease caused by or resulting from inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. Merkel cell carcinoma is a non-limiting example of cancer. The terms "cancer" or "tumor" or "hyperproliferative disorder" refer to the presence of cells that have characteristics characteristic of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain distinctive morphological features. Cancer cells are often in the form of tumors, but such cells can exist alone in an animal or can be non-tumorigenic cancer cells, such as leukemia cells.

The term "liquid tumor" refers to cancers that arise in bodily fluids or the presence of cancerous cells. Liquid tumors are therefore cancers that affect the blood, bone marrow, and/or lymphatic system. Liquid tumors include, for example, blood cancers (or "heme" or blood) such as leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative disorder, and myeloma. The most common types of blood cancer include leukemia, lymphoma, and myeloma. In contrast, a "solid tumor" refers to a group of cancer cells that form a solid mass within a tissue of interest, such as bone tissue, muscle tissue, epithelial tissue, or organ tissue (e.g., liver, lung, stomach, colon, kidney, or brain tissue). Types of solid tumors include, for example, carcinoma, sarcoma, lymphoma, melanoma, neuroendocrine tumors, germ cell tumors, glioma, etc.

"Agent" can include any type of molecule, including, but not limited to, antibodies, peptides, proteins, polynucleotides (e.g., oligonucleotides, RNA, or DNA), small molecules, derivatives thereof, and analogs thereof.

The terms "peptide," "polypeptide," and "protein" are used interchangeably herein to describe a series of at least two amino acids covalently linked by a peptide bond or a modified peptide bond, such as an isostere. No limit is placed on the maximum number of amino acids that a peptide or protein may comprise. Furthermore, the term "polypeptide" extends to fragments, analogs, and derivatives of a peptide, which fragment, analog, or derivative retains the same biological functional activity as the peptide from which the fragment, derivative, or analog is derived. As used herein, a polypeptide may be encoded by a recombinant nucleic acid.

A "fragment" is a portion of a protein or nucleic acid that is substantially identical to a reference protein or nucleic acid. In some embodiments, the portion retains at least 50%, 75%, or 80%, or 90%, 95%, or even 99% of the biological activity of the reference protein or nucleic acid described herein.

A "functional derivative" or "functional fragment" of a native sequence polypeptide (e.g., an antibody) is a compound that has qualitative biological properties in common with the native sequence polypeptide. Functional derivatives or fragments include, but are not limited to, fragments of native sequences, derivatives of native sequence polypeptides, and fragments thereof, provided that they have a biological activity in common with the corresponding native sequence polypeptide. The terms "derivative" and "fragment" encompass both amino acid sequence variants of a polypeptide and covalent modifications thereof.

As used herein, the term "antibody" refers to any form of immunoglobulin molecule exhibiting the desired biological or binding activity. It is therefore used in the broadest sense and specifically encompasses, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies, and may include post-translational modifications thereof (e.g., C-terminal lysine clipping in heavy chains, conversion of glutamine or glutamic acid to pyroglutamic acid) that may occur when the antibody is recombinantly expressed in host cells (e.g., CHO cells) or during purification/storage. A "parent antibody" is an antibody obtained by exposing the immune system to an antigen prior to modification of the antibody for its intended use, such as humanizing the antibody for use as a human therapeutic. As used herein, the term "antibody" encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, fusion proteins comprising antigen-binding fragments thereof that specifically compete with the intact antibody.

Generally, a basic antibody structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair containing one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain contains a variable region of approximately 100-110 amino acids primarily responsible for antigen recognition. The variable regions of each light/heavy chain pair form the antibody binding site. Thus, an intact antibody generally has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Human heavy chains are further classified as mu, delta, gamma, alpha, or epsilon, defining the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 or more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).

As used herein, "variable region" or "V region" or "V chain" refers to the segment of an IgG chain that is variable in sequence among different antibodies. The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, alone or in combination. The variable domain of the heavy chain may be referred to as " _VH ". The variable domain of the light chain may be referred to as " _VL ".

Typically, both heavy and light chain variable regions contain three hypervariable regions located within relatively conserved framework regions (FRs), also called complementarity-determining regions (CDRs). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. Generally, from N- to C-terminus, both light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. As referred to herein, the light chain CDRs are CDRL1, CDRL2, and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2, and CDRH3, respectively. The assignment of amino acids to each domain generally follows the procedures set forth in Sequences of Proteins of Immunological Interest, Kabat, et al. ; National Institutes of Health, Bethesda, Md.; ;5th ed. ;NIH Publ. No. 91-3242 (1991), Kabat (1978) Adv. Prot. Chem. 32:1-75, Kabat, et al. , (1977) J. Biol. Chem. 252:6609-6616, Chothia, et al. , (1987) J Mol. Biol. 196:901-917, or Chothia, et al. , (1989) Nature 342:878-883.

"CDR" refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of an antibody _VH beta-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of an antibody _VL beta-sheet framework. Thus, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art, and are defined, for example, by Kabat as the most hypervariable regions within an antibody variable domain. CDR region sequences are also structurally defined by Chothia as residues that are not part of the conserved beta-sheet framework and can therefore adopt different conformations. Both terms are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The locations of CDRs within canonical antibody variable regions have been determined by comparison of numerous structures (Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79). Because the number of residues within hypervariable regions varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c, etc. next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is also well known to those of skill in the art. For example, correspondence between numbering systems, including Kabat numbering and the IMGT unique numbering system, is well known to those of skill in the art and is shown in Table 1 below. In some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In still other embodiments, the CDRs are as defined by the AbM numbering system, in still other embodiments, the CDRs are as defined by the Chothia numbering system, and in still other embodiments, the CDRs are as defined by the Contact numbering system.

"Chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain contains sequences derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) are derived from another species (e.g., mouse) or belong to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

"Human antibody" refers to an antibody that contains human immunoglobulin protein sequences or derivatives thereof. If produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell, a human antibody may contain mouse carbohydrate chains. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody that contains only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

"Humanized antibody" refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. Generally, a humanized antibody will contain substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the FR regions being those of a human immunoglobulin. A humanized antibody will also optionally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefixes "hum," "hu," or "h" may be added to antibody clone designations when necessary to distinguish the humanized antibody from the parent rodent antibody. Humanized forms of rodent antibodies generally contain the same CDR sequences as the parent rodent antibody, although certain amino acid substitutions may be included to improve affinity, increase the stability of the humanized antibody, or for other reasons.

"Monoclonal antibody" or "mAb" or "Mab," as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a large number of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present disclosure may be made by the hybridoma method described by Kohler et al. (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibody" also refers to the antibody described, for example, by Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

As used herein, unless otherwise indicated, "antibody fragment" or "antigen-binding fragment" refers to a fragment of an antibody that retains the ability to specifically bind to an antigen, e.g., a fragment that retains one or more CDR regions, and that retains the ability to specifically bind to an antigen. An antibody that "specifically binds" to PD-1 is one that exhibits preferential binding to PD-1 (optionally) relative to other proteins, although this specificity does not require absolute binding specificity. An antibody is considered "specific" for its intended target if its binding determines the presence of the target protein in a sample, without producing undesirable results, e.g., false positives. An antibody, or a binding fragment thereof, binds to a target protein with an affinity that is at least 2-fold, preferably at least 10-fold, more preferably at least 20-fold, and most preferably at least 100-fold higher than its affinity for a non-target protein.

Antigen-binding portions include, for example, Fab, Fab', F(ab')2, Fd, Fv, fragments containing the CDRs, and single-chain variable fragment antibodies (scFv), as well as polypeptides (e.g., PD-1) containing at least a portion of an immunoglobulin sufficient to confer specific antigen binding to an antigen. Antibodies include antibodies of any class, such as IgG, IgA, or IgM (or subclasses thereof); antibodies need not be of any particular class. Depending on the amino acid sequence of the constant region of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM; some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known.

An "antigen" is a structure to which an antibody can selectively bind. The target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, e.g., present on or within a cell, e.g., a cancer cell.

An "intact" antibody is one that comprises an antigen-binding site, as well as a constant domain (CL), and at least a heavy chain constant region, CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, an intact antibody has one or more effector functions.

As used herein, the term "immune response" refers to any one or more of a specific immune response, a non-specific immune response, both specific and non-specific responses, an innate response, a primary immune response, adaptive immunity, a secondary immune response, a memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

Therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral or parenteral route. The term "enteral route" of administration refers to administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal, or intragastric routes. A "parenteral route" of administration refers to a route of administration other than enteral. Examples of parenteral routes include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intrathecal, intraorbital, intracardiac, transtracheal, intraarticular, subthecal, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous, or topical administration. Therapeutic agents and compositions of the present disclosure can be administered using any suitable method, such as oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. Suitable routes and methods of administration may vary depending on several factors, such as the particular therapeutic agent used, the desired absorption rate, the particular formulation or dosage form used, the type or severity of the disorder being treated, the particular site of action, and the condition of the patient, and can be readily selected by one of ordinary skill in the art.

The term "variant," when used with reference to an antibody or an amino acid region within an antibody, may refer to a peptide or polypeptide that contains one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) amino acid sequence substitutions, deletions, and/or additions compared to the native or unmodified sequence. For example, an antibody variant may result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, etc.) changes to the amino acid sequence of a native or previously unmodified antibody. Variants may be naturally occurring or artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecule encoding the variant. In certain embodiments, antibody variants retain at least the functional activity of the antibody.

"Conservatively modified variants" or "conservative substitutions" refer to the substitution of amino acids in a protein with other amino acids having similar properties (e.g., charge, side chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.), and therefore, changes can be made frequently without altering the biological activity of the protein or other desired properties, such as antigen affinity and/or specificity. Those skilled in the art generally recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)). Furthermore, substitution of structurally or functionally similar amino acids is unlikely to destroy biological activity. Exemplary conservative substitutions are shown in Table 2 below.

As used herein, "RECIST 1.1 response criteria" means the definitions set forth in Eisenhauer, E. A. et al., Eur. J. Cancer 45:228-247 (2009), for target lesions or non-target lesions, as appropriate, depending on the context in which response is measured.

"Cytokine release syndrome" or CRS, as used herein, refers to an acute systemic inflammatory syndrome that can be triggered by various factors, such as infection, and can occur after treatment with several types of immunotherapies, such as monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy, as well as some non-protein-based cancer drugs. CRS is characterized by a large and rapid increase in cytokine and inflammatory responses. Signs and symptoms of CRS include fever, fatigue, nausea, headache, rash, joint pain, muscle pain, tachycardia, hypotension, and dyspnea. CRS can progress to an uncontrolled systemic inflammatory response with circulatory shock requiring vasopressors, vascular leak, disseminated intravascular coagulation, and multiple organ system failure. Patients may have a mild reaction, or the reaction may be severe or life-threatening. CRS grading is described, for example, in Lee et al. Transplantation may be performed according to the Consensus American Society for Transplantation and Cellular Therapy (ASTCT) grading system, as described in Biology of Blood and Marrow Transplantation. 25 (2019) 625-639, the disclosure of which is incorporated herein by reference in its entirety.

"Pembrolizumab" (formerly known as MK-3475, SCH900475, and lambrolizumab), alternatively referred to herein as "pembro," is a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013), including, for example, the heavy and light chain amino acid sequences and CDRs as shown in Figure 6 of U.S. Patent Publication No. 20240010727A1 and WO 2018183408A1, the disclosures of which are incorporated herein by reference in their entireties. Pembrolizumab is approved by the U.S. FDA as described in the KEYTRUDA® prescribing information (Merck & Co., Inc., Rahway, NJ USA, initial U.S. approval in 2014 (updated February 2023)). The term pembrolizumab includes mAbs' having the structure shown above (ibid.) but without the C-terminal lysine in the heavy chain.

Methods One aspect of the present disclosure provides methods and compositions for treating disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a liquid tumor. In some embodiments, the method of treating cancer comprises administering to a subject multiple compositions in the form of a combination therapy. In some embodiments, the composition administered comprises a DR IL-18 polypeptide and an ICI, wherein the ICI is not pembrolizumab.

One aspect of the present disclosure provides a method of treating a disease, the method comprising: (a) administering to a subject a composition comprising a DR IL-18 polypeptide; and (b) administering to the subject a composition comprising an ICI, where the ICI is not pembrolizumab. In some embodiments, the method comprises administering a single composition comprising a DR IL-18 polypeptide and an ICI. In some embodiments, the method comprises combination therapy comprising administering separate compositions, such as a first composition comprising a DR IL-18 polypeptide and a second composition comprising an ICI. In some embodiments, the compositions are administered simultaneously. In some embodiments, the compositions are administered sequentially. In some embodiments, the first composition (e.g., the DR IL-18 composition) is administered before the second composition (e.g., the ICI composition). In some embodiments, the first composition (e.g., the DR IL-18 composition) is administered after the second composition (e.g., the ICI composition).

In some embodiments, one composition of the combination therapy or two or more compositions of the combination therapy are administered weekly. In some embodiments, the composition(s) are administered every six days. In some embodiments, the composition(s) are administered twice a week. In some embodiments, the composition(s) are administered daily. In some embodiments, the composition(s) are administered every two weeks. In some embodiments, the composition(s) are administered every three weeks. In some embodiments, the composition(s) are administered monthly. In some embodiments, the composition(s) are administered every two months. In some embodiments, the composition(s) are administered every three months. In some embodiments, the composition(s) are administered every four months. In some embodiments, the composition(s) are administered every six months. In some embodiments, the composition(s) are administered once a year.

In some embodiments, the first and second compositions are administered on the same schedule (e.g., both are administered weekly). In some embodiments, the first and second compositions are administered on different schedules (e.g., the first composition is administered daily and the second composition is administered weekly). For example, the DR IL-18 composition of the combination therapy may be administered weekly, and the ICI composition of the combination therapy may be administered less frequently, e.g., once every 2, 3, or 4 weeks.

The composition may be administered according to any suitable and convenient route, including, for example, orally, subcutaneously, intramuscularly, intravenously, intrathecally, rectally, intravaginally, intranasally, etc. In some embodiments, the composition is injected into the patient without dilution.

In some embodiments, the first and second compositions are administered by the same route (e.g., both subcutaneously). In some embodiments, the first and second compositions are administered by different routes (e.g., the first composition is administered subcutaneously and the second composition is administered intravenously).

In some embodiments, administering the composition results in a reduction in tumor size in the subject. In some embodiments, administering the composition results in a reduction in tumor number in the subject. In some embodiments, administering the composition results in a reduction in tumor size and a reduction in tumor number in the subject.

One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject (a) a DR IL-18 polypeptide and (b) an effective amount of an ICI, where the ICI is not pembrolizumab. In some embodiments, the DR IL-18 polypeptide and the ICI are administered simultaneously. In some embodiments, the DR IL-18 polypeptide and the ICI are administered sequentially. In some embodiments, the DR IL-18 polypeptide is administered before the ICI. In some embodiments, the DR IL-18 polypeptide is administered after the ICI.

In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered weekly. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered every 6 days. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered twice a week. In some embodiments, the composition is administered daily. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered every two weeks. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered every three weeks. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered monthly. In some embodiments, the composition is administered every two months. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered every three months. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered every four months. In some embodiments, the composition is administered every six months. In some embodiments, the DR IL-18 polypeptide, the ICI, or any combination thereof is administered once a year.

In some embodiments, the DR IL-18 polypeptide and the ICI are administered on the same schedule (e.g., both are administered weekly). In some embodiments, the DR IL-18 polypeptide and the ICI are administered on different schedules (e.g., a first composition is administered daily and a second composition is administered weekly).

In some embodiments, the DR IL-18 polypeptide and ICI are fused into a single drug product.

The DR IL-18 polypeptide, ICI, or any combination thereof may be administered by various routes, including, for example, orally, subcutaneously, intramuscularly, intravenously, intrathecally, rectally, intravaginally, intranasally, etc. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered subcutaneously. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered intramuscularly. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is administered intravenously. In some embodiments, the DR IL-18 polypeptide, ICI, or any combination thereof is injected into a patient without dilution.

In some embodiments, the DR IL-18 polypeptide and the ICI are administered by the same route (e.g., both are administered subcutaneously). In some embodiments, the DR IL-18 polypeptide and the ICI are administered by different routes (e.g., a first composition is administered subcutaneously and a second composition is administered intravenously).

In some embodiments, administering a DR IL-18 polypeptide and an ICI to a subject results in a reduction in tumor size in the subject. In some embodiments, administering a DR IL-18 polypeptide and an ICI to a subject results in a reduction in the number of tumors in the subject. In some embodiments, administering a DR IL-18 polypeptide to a subject results in a reduction in tumor size and a reduction in the number of tumors in the subject.

Administering such a combination therapy of an ICI and a DR IL-18 polypeptide as described herein thereby results in one or more improvements in the subject's condition, e.g., stable disease, immunotherapy-induced regression, partial response, complete response, or any combination thereof.

A combination therapy method is provided for treating a subject with cancer, comprising administering to the subject sequential doses of an ICI-containing composition and sequential doses of a DR IL-18-containing composition, wherein the combination therapy results in one or more improvements in the subject's condition, such as, but not limited to, an objective response, a partial response, a complete response, immunotherapy-induced regression of the cancer or tumor, disease stabilization (e.g., stable disease for at least 12 months), etc. Administering such a combination therapy of an ICI and a DR IL-18 polypeptide thereby results in an improvement in the subject's condition that is not achieved by administering the monotherapy alone and/or that is greater than the corresponding improvement in outcome achieved by administering either the ICI or the DR IL-18 polypeptide monotherapy.

The observed improvement in the condition of a subject treated according to the methods described herein can include any result of treating a disease or treating cancer, including any result of treating a disease or treating cancer described herein. For example, the subject may experience an improvement in one or more symptoms of the condition, e.g., an improvement in one or more clinical symptoms of the subject's cancer. In some examples, the subject may experience a reduction in the rate of tumor growth, a reduction in the number of tumors, a reduction in the size of one or more tumors in the subject, a reduction in the clinical stage of the tumors, a combination thereof, etc.

In some examples, a subject may experience stabilization of disease, e.g., stabilization of the subject's cancer, for a period of time, e.g., at least 6 months, at least 12 months, or longer. Stable disease is disease that does not progress, e.g., a tumor that does not show substantial growth, as measured using an appropriate method, such as a computed tomography (CT) or magnetic resonance imaging (MRI) scan, over a defined period of time or between two or more relevant time points, e.g., between initiation of treatment and 6 or 12 months after initiation of treatment. Stable disease also includes improvement of disease in subjects that does not reach the level or criteria of a partial response (PR).

In some instances, a subject may achieve PR in accordance with the RECIST guidelines (version 1.1) for cancer or tumors, where the criteria for PR used herein are defined as at least a 30% reduction in the sum of the diameters of target lesions, referenced to the baseline sum diameter. See, e.g., Eisenhauer et al. (2009) European Journal of Cancer 45:228-247, the disclosure of which is incorporated herein by reference in its entirety.

In some examples, a subject may achieve a complete response (CR), where the criteria for CR used herein with respect to a cancer or tumor are defined as the disappearance of all target lesions with short-axis reduction of any pathological lymph nodes (whether target or non-target) to less than 10 mm, consistent with the RECIST guidelines (version 1.1). In some examples, a subject may achieve an objective response (OR), where achieving an OR generally refers to achieving either a PR or a CR.

In some examples, a subject with a disease such as cancer or a tumor may experience immunotherapy-induced regression of the disease, i.e., immunotherapy-induced regression of the cancer or tumor. Disease regression generally refers to a reduction in the severity of the disease or symptoms of the disease, including without complete absence of the disease. In cancer, regression generally refers to a decrease in tumor size and/or a reduction in the extent of cancer in the subject's body. Disease regression in a subject with cancer or a tumor may manifest as a decrease in the number of tumors, a decrease in the size of one or more tumors, or a combination thereof. Accordingly, cancer or tumor progression and regression can be measured by various means, including, but not limited to, radiological imaging such as CT and MRI scans. Disease progression and regression can generally be measured by various means, including, but not limited to, radiological imaging, clinical biomarkers, biopsies (e.g., needle biopsies and liquid biopsies), combinations thereof, and the like. Immunotherapy-induced regression refers to disease regression resulting from administering one or more immunotherapies to a subject, such as, for example, a combination immunotherapy comprising an ICI composition and a DR IL-18 composition described herein. Thus, with respect to cancer or tumors, immunotherapy-induced regression refers to a decrease in the number of tumors, a decrease in the size of one or more tumors, or a combination thereof, resulting from administering one or more immunotherapies to a subject, such as a combination immunotherapy comprising an ICI composition and a DR IL-18 composition described herein.

Improvement in a subject's condition may be expressed as improvement in an individual subject or for one or more cohorts of multiple subjects. For example, a single subject may achieve stable disease, PR, or CR, or all (i.e., 100%), or a subset or percentage (e.g., at least 10%, 25%, 50%, 75%, etc.) of the subjects in a cohort achieve stable disease, PR, CR, or a combination thereof. In some examples, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the cohort achieve stable disease lasting at least 12 months. In some examples, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients in a cohort achieve OR. In some examples, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients in a cohort achieve PR. In some examples, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients in the cohort achieve a CR. In some examples, the cohort exhibits multiple improvements in different categories, including, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the cohort achieving stable disease and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 patients in the cohort achieving an OR.

Administration of Decoy-Resistant IL-18 Polypeptides The methods of the present disclosure include therapies involving the administration of decoy-resistant (DR) IL-18 polypeptides, including combination therapies that involve administering to a subject a decoy-resistant (DR) IL-18 composition comprising a DR IL-18 polypeptide as part of a combination therapy. Polypeptides that are "decoy-resistant" variants of IL-18 are designed to be impermeable to the decoy receptor IL-18 binding protein (IL-18BP), which blocks IL-18 from interacting with its receptor, thereby blocking the cytokine's immunostimulatory activity. Decoy-resistant IL-18 polypeptides have been shown in preclinical studies to maintain potent immune stimulation in the tumor microenvironment, even in the presence of IL-18BP, and are currently in Phase 1a/2 clinical development as monotherapy in solid tumors.

Decoy-resistant IL-18 polypeptides bind to and signal through the formation of the IL-18Rα (IL-18 receptor α) and IL-18Rβ (IL-18 receptor β) receptor complex. Decoy-resistant IL-18 polypeptides do not bind to IL-18BP or exhibit substantially reduced binding to IL-18BP, such as substantially reduced binding to IL-18BP compared to wild-type (WT) IL-18 (SEQ ID NO: 13) (i.e., compared to the binding of IL-18BP to WT IL-18 (SEQ ID NO: 13)). In some embodiments, the DR IL-18 polypeptides used bind to IL-18Rα and do not bind to IL-18BP. In some embodiments, the DR IL-18 polypeptides used bind to IL-18Rα and have reduced binding to IL-18BP compared to WT IL-18. In some embodiments, the DR IL-18 polypeptide is a modified IL-18 polypeptide that (i) has an amino acid sequence that has 85% or more (e.g., 90%, 95%, or 98%) sequence identity with the amino acid sequence of an IL-18 variant set forth in any one of SEQ ID NOs: 10-12, and (ii) includes mutations at amino acid positions cysteine-38 and cysteine-68 relative to wild-type (WT) IL-18 set forth in SEQ ID NO: 13, thereby promoting IL-18 signaling activity.

DR IL-18 polypeptides and compositions comprising DR IL-18 polypeptides useful in the methods described herein are described in more detail below. Any of the DR IL-18 polypeptides described below may be used in the methods of the present disclosure. In some examples, the methods use a DR IL-18 polypeptide (or a DR IL-18 composition comprising such a polypeptide) comprising an amino acid sequence having 85% or more (e.g., 90%, 95%, or 98%) sequence identity to the amino acid sequence of an IL-18 variant set forth in any one of SEQ ID NOs: 1-12. In some examples, the methods use a DR IL-18 polypeptide (or a DR IL-18 composition comprising such a polypeptide) comprising an amino acid sequence having 85% or more (e.g., 90%, 95%, or 98%) sequence identity to the amino acid sequence of an IL-18 variant set forth in SEQ ID NO: 5.

The methods of the present disclosure include administering to a subject a DR IL-18 polypeptide, wherein the DR IL-18 polypeptide is administered as part of a DR IL-18 polypeptide. In some embodiments, the methods include administering to the subject a dose (or a composition comprising same) of about 10 micrograms of DR IL-18 per kilogram of the subject's body weight (μg/kg) to about 1500 μg/kg. In some embodiments, the method comprises administering to a subject a drug comprising administering to a subject a drug comprising about 10 μg/kg to about 20 μg/kg, about 20 μg/kg to about 30 μg/kg, about 30 μg/kg to about 40 μg/kg, about 40 μg/kg to about 50 μg/kg, about 50 μg/kg to about 60 μg/kg, about 60 μg/kg to about 70 μg/kg, about 70 μg/kg to about 80 μg/kg, about 80 μg/kg to about 90 μg/kg, about 90 μg/kg to about 100 μg/kg, about 100 μg/kg to about 150 μg/kg, about 150 μg/kg to about 200 μg/kg, about 200 μg/kg to about 250 μg/kg, about 250 μg/kg to about 300 μg/kg, or about 300 μg/kg. about 450 μg/kg to about 500 μg/kg, about 500 μg/kg to about 600 μg/kg, about 600 μg/kg to about 700 μg/kg, about 700 μg/kg to about 800 μg/kg, about 800 μg/kg to about 900 μg/kg, about 900 μg/kg to about 1000 μg/kg, about 1000 μg/kg to about 1100 μg/kg, about 1200 μg/kg to about 1300 μg/kg, about 1300 μg/kg to about 1400 μg/kg, or about 1400 μg/kg to about 1500 μg/kg. This involves administering an IL-18 polypeptide (or a composition containing it).

In some embodiments, the method includes administering to the subject at least about 10 μg/kg, at least about 20 μg/kg, at least about 30 μg/kg, at least about 40 μg/kg, at least about 50 μg/kg, at least about 60 μg/kg, at least about 70 μg/kg, at least about 80 μg/kg, at least about 90 μg/kg, at least about 100 μg/kg, at least about 110 μg/kg, at least about 120 μg/kg, at least about 1 30 μg/kg, at least about 140 μg/kg, at least about 150 μg/kg, at least about 160 μg/kg, at least about 170 μg/kg, at least about 180 μg/kg, at least about 190 μg/kg, at least about 200 μg/kg, at least about 210 μg/kg, at least about 220 μg/kg, at least about 230 μg/kg, at least about 240 μg/kg, at least about 250 μg/kg, at least about 260 μg /kg, at least about 270 μg/kg, at least about 280 μg/kg, at least about 290 μg/kg, at least about 300 μg/kg, at least about 310 μg/kg, at least about 320 μg/kg, at least about 330 μg/kg, at least about 340 μg/kg, at least about 350 μg/kg, at least about 360 μg/kg, at least about 370 μg/kg, at least about 380 μg/kg, at least about 390 μg/kg, This involves administering a dose of DR IL-18 polypeptide (or a composition comprising same) of at least about 400 μg/kg, at least about 500 μg/kg, at least about 600 μg/kg, at least about 700 μg/kg, at least about 800 μg/kg, at least about 900 μg/kg, at least about 1000 μg/kg, at least about 1100 μg/kg, at least about 1200 μg/kg, at least about 1300 μg/kg, at least about 1400 μg/kg, at least about 1500 μg/kg, or more.

In some embodiments, the method includes administering to the subject a dose of at most about 1500 μg/kg, at most about 1400 μg/kg, at most about 1300 μg/kg, at most about 1200 μg/kg, at most about 1100 μg/kg, at most about 1000 μg/kg, at most about 900 μg/kg, at most about 800 μg/kg, at most about 700 μg/kg, at most about 600 μg/kg, at most about 500 μg/kg, at most about 400 μg/kg, up to about 390 μg/kg, up to about 380 μg/kg, up to about 370 μg/kg, up to about 360 μg/kg, up to about 350 μg/kg, up to about 340 μg/kg, up to about 330 μg/kg, up to about 320 μg/kg, up to about 310 μg/kg, up to about 300 μg/kg, up to about 290 μg/kg, up to about 280 μg/kg, up to about 270 μg/kg g/kg, up to about 260 μg/kg, up to about 250 μg/kg, up to about 240 μg/kg, up to about 230 μg/kg, up to about 220 μg/kg, up to about 210 μg/kg, up to about 200 μg/kg, up to about 190 μg/kg, up to about 180 μg/kg, up to about 170 μg/kg, up to about 160 μg/kg, up to about 150 μg/kg, up to about 140 μg/kg , up to about 130 μg/kg, up to about 120 μg/kg, up to about 110 μg/kg, up to about 100 μg/kg, up to about 90 μg/kg, up to about 80 μg/kg, up to about 70 μg/kg, up to about 60 μg/kg, up to about 50 μg/kg, up to about 40 μg/kg, up to about 30 μg/kg, up to about 20 μg/kg, up to about 10 μg/kg, or less.

In some embodiments, the method includes administering to the subject about 10 μg/kg, about 20 μg/kg, about 30 μg/kg, about 40 μg/kg, about 50 μg/kg, about 60 μg/kg, about 70 μg/kg, about 80 μg/kg, about 90 μg/kg, about 100 μg/kg, about 110 μg/kg, about 120 μg/kg, about 130 μg/kg, about 140 μg/kg, about 160 μg/kg, about 180 μg/kg, about 190 μg/kg, about 200 μg/kg, about 210 μg/kg, about 220 μg/kg, about 230 μg/kg, about 240 μg/kg, about 250 μg/kg, about 260 μg/kg, about 270 μg/kg, about 280 μg/kg, about 290 μg/kg, about 300 μg/kg, about 310 μg/kg, about 320 μg/kg, about 330 μg/kg, about 340 μg/kg, about 350 μg/kg, about 360 μg/kg, about 370 μg/kg, about 380 μg/kg, about 390 μg/kg, about 400 μg/kg, about 410 μg/kg, about 420 μg/kg, about 430 μg/kg, about 440 μg/kg, about 450 μg/kg, about 460 μg/kg, about 470 μg/kg, about 480 μg/kg, about 490 μg/kg, about 500 μg/kg, about 510 μg/kg, about 520 μg/kg, about 530 μg/ 0μg/kg, about 150μg/kg, about 160μg/kg, about 170μg/kg, about 180μg/kg, about 190μg/kg, about 200μg/kg, about 210μg /kg, about 220 μg/kg, about 230 μg/kg, about 240 μg/kg, about 250 μg/kg, about 260 μg/kg, about 270 μg/kg, about 280 μg/kg The present invention also includes administering a DR-18 polypeptide (or a composition comprising the same) at a dose of about 290 μg/kg, about 300 μg/kg, about 310 μg/kg, about 320 μg/kg, about 330 μg/kg, about 340 μg/kg, about 350 μg/kg, about 360 μg/kg, about 370 μg/kg, about 380 μg/kg, about 390 μg/kg, about 400 μg/kg, about 500 μg/kg, about 600 μg/kg, about 700 μg/kg, about 800 μg/kg, about 900 μg/kg, about 1000 μg/kg, about 1100 μg/kg, about 1200 μg/kg, about 1300 μg/kg, about 1400 μg/kg, or about 1500 μg/kg of the DR-18 polypeptide.

In some embodiments, the method of treating a disease comprises administering about 5 mg/ml to about 29 mg/ml of DR IL-18 polypeptide. In some embodiments, the method of treating a disease comprises administering about 5 mg/ml to about 10 mg/ml, about 10 mg/ml to about 15 mg/ml, about 15 mg/ml to about 20 mg/ml, about 20 mg/ml to about 25 mg/ml, or 25 mg/ml to about 29 mg/ml of DR IL-18 polypeptide.

In some embodiments, a method of treating a disease comprises administering at least about 5 mg/ml, at least about 6 mg/ml, at least about 7 mg/ml, at least about 8 mg/ml, at least about 9 mg/ml, at least about 10 mg/ml, at least about 11 mg/ml, at least about 12 mg/ml, at least about 13 mg/ml, at least about 14 mg/ml, at least about 15 mg/ml, at least about 16 mg/ml, at least about 17 mg/ml, at least about 18 mg/ml, at least about 19 mg/ml, at least about 20 mg/ml, at least about 21 mg/ml, at least about 22 mg/ml, at least about 23 mg/ml, at least about 24 mg/ml, at least about 25 mg/ml, at least about 26 mg/ml, at least about 27 mg/ml, at least about 28 mg/ml, at least about 29 mg/ml, or more of a DR IL-18 polypeptide. In some embodiments, methods of treating a disease comprise administering a DR IL-18 polypeptide at up to about 29 mg/ml, at most about 28 mg/ml, at most about 27 mg/ml, at most about 26 mg/ml, at most about 25 mg/ml, at most about 24 mg/ml, at most about 23 mg/ml, at most about 22 mg/ml, at most about 21 mg/ml, at most about 20 mg/ml, at most about 19 mg/ml, at most about 18 mg/ml, at most about 17 mg/ml, at most about 16 mg/ml, at most about 15 mg/ml, at most about 14 mg/ml, at most about 13 mg/ml, at most about 12 mg/ml, at most about 11 mg/ml, at most about 10 mg/ml, at most about 9 mg/ml, at most about 8 mg/ml, at most about 7 mg/ml, at most about 6 mg/ml, at most about 5 mg/ml, or less. In some embodiments, a method for treating a disease comprises administering about 5 mg/ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, about 10 mg/ml, about 11 mg/ml, about 12 mg/ml, about 13 mg/ml, about 14 mg/ml, about 15 mg/ml, about 16 mg/ml, about 17 mg/ml, about 18 mg/ml, about 19 mg/ml, about 20 mg/ml, about 21 mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml, about 26 mg/ml, about 27 mg/ml, about 28 mg/ml, or about 29 mg/ml of a DR IL-18 polypeptide.

In some embodiments, a subject is administered about 10 mg/ml to about 50 mg/ml of DR IL-18 polypeptide. In some embodiments, a subject is administered at least about 10 mg/ml, at least about 15 mg/ml, at least about 20 mg/ml, at least about 25 mg/ml, at least about 30 mg/ml, at least about 35 mg/ml, at least about 40 mg/ml, at least about 45 mg/ml, at least about 50 mg/ml, or more of DR IL-18 polypeptide. In some embodiments, a subject is administered up to about 50 mg/ml, up to about 45 mg/ml, up to about 40 mg/ml, up to about 35 mg/ml, up to about 30 mg/ml, up to about 25 mg/ml, up to about 20 mg/ml, up to about 15 mg/ml, up to about 10 mg/ml, or less of DR IL-18 polypeptide. In some embodiments, the subject is administered about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, or about 50 mg/ml of DR IL-18 polypeptide.

In some embodiments, the composition comprises about 20 mg/ml of DR IL-18 polypeptide. In some embodiments, the subject is administered about 20 mg/ml of DR IL-18 polypeptide.

In some embodiments, the DR IL-18 polypeptide is a monomer. In some embodiments, the monomer is not present in a protein complex. In some embodiments, the monomer functions as a single polypeptide. In some embodiments, the DR IL-18 polypeptide is unglycosylated. In some embodiments, the DR IL-18 polypeptide is glycosylated. In some embodiments, the DR IL-18 polypeptide is partially glycosylated. In some embodiments, the DR IL-18 polypeptide is at least about 50% glycosylated. In some embodiments, the DR IL-18 polypeptide is up to about 50% glycosylated.

In some embodiments, the DR IL-18 polypeptide accounts for 10% to about 50% of the IL-18 receptors. In some embodiments, the DR IL-18 polypeptide accounts for at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more of the IL-18 receptors. In some embodiments, the DR IL-18 polypeptide accounts for up to about 50%, up to about 45%, up to about 40%, up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, or less of the IL-18 receptors. In some embodiments, the DR IL-18 polypeptide accounts for about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the IL-18 receptors.

In some embodiments, a composition comprising a DR IL-18 polypeptide is administered weekly, every 6 days, twice a week, daily, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, or every 6 months. In some embodiments, a composition comprising a DR IL-18 polypeptide is administered once a year.

In some embodiments, the dose of DR IL-18 polypeptide is from about 10 μg/kg to about 50 μg/kg. In some embodiments, the dose of DR IL-18 polypeptide is at least about 10 μg/kg, at least about 15 μg/kg, at least about 20 μg/kg, at least about 25 μg/kg, at least about 30 μg/kg, at least about 35 μg/kg, at least about 40 μg/kg, at least about 45 μg/kg, at least about 50 μg/kg, or more. In some embodiments, the dose of DR IL-18 polypeptide is up to about 50 μg/kg, up to about 45 μg/kg, up to about 40 μg/kg, up to about 35 μg/kg, up to about 30 μg/kg, up to about 25 μg/kg, up to about 20 μg/kg, up to about 15 μg/kg, up to about 10 μg/kg, or less. In some embodiments, the dose of the DR IL-18 polypeptide is about 10 μg/kg, about 15 μg/kg, about 20 μg/kg, about 25 μg/kg, about 30 μg/kg, about 35 μg/kg, about 40 μg/kg, about 45 μg/kg, or about 50 μg/kg. In some embodiments, the dose of the DR polypeptide is about 20 μg/kg.

In some embodiments, DR IL-18 is administered weekly, every 6 days, twice a week, daily, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, or every 6 months. In some embodiments, DR IL-18 polypeptide is administered once a year.

In some embodiments, the DR IL-18 polypeptide is administered to a subject about twice a week, about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every two months, about once every three months, about once every four months, about once every five months, about once every six months, about once every nine months, or about once every twelve months.

In some embodiments, the DR IL-18 polypeptide is administered to the subject for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

In some embodiments, the DR IL-18 polypeptide is administered until disease progression. In some embodiments, the DR IL-18 polypeptide is administered until unacceptable toxicity. In some embodiments, the DR IL-18 polypeptide is administered until disease recurrence.

In some embodiments, the DR IL-18 polypeptide is administered for up to about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, or about 24 months.

In some embodiments, administering a composition comprising a DR IL-18 polypeptide results in a reduction in tumor size in a subject. In some embodiments, administering a composition comprising a DR IL-18 polypeptide results in a reduction in the number of tumors in a subject. In some embodiments, administering a composition comprising a DR IL-18 polypeptide results in a reduction in tumor size and a reduction in the number of tumors in a subject.

In some embodiments, administering a DR IL-18 polypeptide results in a reduction in tumor size in a subject. In some embodiments, administering a DR IL-18 polypeptide results in a reduction in the number of tumors in a subject. In some embodiments, administering a DR IL-18 polypeptide results in a reduction in tumor size and a reduction in the number of tumors in a subject.

The DR IL-18 polypeptides described herein thereby provide the subject with one or more improvements in the subject's condition, e.g., stable disease, immunotherapy-induced regression, partial response, complete response, or any combination thereof.

Such improvements include, but are not limited to, objective response, partial response, complete response, immunotherapy-induced regression of cancer or tumor, disease stabilization (e.g., stable disease for at least 12 months), etc.

The observed improvement in the condition of a subject treated according to the methods described herein can include any result of treating a disease or treating cancer, including any result of treating a disease or treating cancer described herein. For example, the subject may experience an improvement in one or more symptoms of the condition, e.g., an improvement in one or more clinical symptoms of the subject's cancer. In some examples, the subject may experience a reduction in the rate of tumor growth, a reduction in the number of tumors, a reduction in the size of one or more tumors in the subject, a reduction in the clinical stage of the tumors, a combination thereof, etc.

In some examples, a subject may experience stabilization of disease, e.g., stabilization of the subject's cancer, for a period of time, e.g., at least 6 months, at least 12 months, or longer. Stable disease is disease that does not progress, e.g., a tumor that does not show substantial growth, as measured using an appropriate method, e.g., CT or MRI scan, over a defined period of time or between two or more relevant time points, e.g., at the initiation of treatment and 6 or 12 months after the initiation of treatment.

In some examples, a subject may achieve a PR, where the criteria for PR used herein for cancer or tumor are defined consistent with the RECIST guidelines (version 1.1). In some examples, a subject may achieve a CR, where the criteria for CR used herein for cancer or tumor are defined consistent with the RECIST guidelines (version 1.1). In some examples, a subject may achieve an OR. In some examples, a subject with a disease such as cancer or tumor may experience immunotherapy-induced regression of the disease, i.e., immunotherapy-induced regression of the cancer or tumor.

Administration of Immune Checkpoint Inhibitors The methods of the present disclosure include combination therapy comprising administering to a subject, as part of the combination therapy, an immune checkpoint inhibitor (ICI) composition comprising an ICI, where the ICI is not pembrolizumab. The ICI is a binding protein that binds to immune checkpoint proteins, thereby strengthening the subject's immune system and combating cancer in the subject. Examples of immune checkpoint proteins, including stimulatory and inhibitory molecules, including receptors and ligands, include, but are not limited to, LAG-3, MHC-LL, PD-1, PD-L2, PD-L1, TCR, MHC, TIM-3, Galectin-9, GITR, GRTRL, OX40, OX40L, 4-1BB, 4-1BBL, CD40, CD40L, CD27, CD70, CD28, CD80, CD86, CTLA-4, ICOS, ICOSL, CD155, TIGIT, A2AR, A2BR, B7-H3 (CD276), B7-H4 (VTCN1), BTLA, KIR, NOX2, VISTA, SIGLEC7, and SIGLEC9. An ICI can be a binding antagonist, e.g., binding of the ICI to its target prevents signaling through an immune checkpoint, thereby improving the ability of the subject's immune system to fight cancer in the subject. A variety of binding antagonists find use as ICIs in cancer therapy, including, e.g., small molecule inhibitors, immunoadhesins, antagonist antibodies, antibody fragments, antibody fusions, and the like.

Useful ICIs include therapeutic antibodies and antibody-derived therapeutics, including monospecific and multispecific (e.g., bispecific, trispecific) antibodies and antibody-derived therapeutics. Useful monospecific ICI antibodies and antibody-derived therapeutics target immune checkpoint proteins. Useful multispecific ICI antibodies and antibody-derived therapeutics target at least one immune checkpoint protein. For example, bispecific antibodies or antibody-derived therapeutics that target at least one immune checkpoint protein may be used. In some examples, bispecific antibodies or antibody-derived therapeutics that target two immune checkpoint proteins may be used. Non-limiting examples of therapeutic antibodies and antibody-derived therapeutics useful as ICIs, including the methods and compositions described herein, and the corresponding heavy and light chain amino acid sequences, are provided in Table 3 below.

Useful ICIs include, for example, AMP-224 (a recombinant fusion protein consisting of the extracellular domain of the PD-1 ligand programming death ligand 2 (PD-L2) and the Fc region of human IgG), atezolizumab (a monoclonal antibody used to treat advanced or metastatic urothelial carcinoma with disease progression during or up to 12 months after platinum-containing chemotherapy), AUNP-12 (a peptide antagonist of the PD-1 signaling pathway), avelumab (an anti-PD-L1 monoclonal antibody used to treat metastatic Merkel cell carcinoma, metastatic urothelial carcinoma, or renal cell carcinoma), CA-170 (a selective small molecule inhibitor of PD-L1), and camrelizumab (a PD-1 inhibitor that functions by blocking the interaction between PD-1 and PD-L1). anti-PD-1 antibody), cemiplimab (a programmed death receptor-1 blocking antibody used to treat cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer), cosibelimab (a high-affinity programmed death ligand 1 (PD-L1) blocking antibody), dostarimab (an anti-PD-1 monoclonal antibody used to treat mismatch repair-deficient endometrial cancer and solid tumors with no alternative treatment options), durvalumab (an anti-tumor monoclonal antibody used to treat urothelial carcinoma and locally advanced unresectable non-small cell lung cancer), embafolimab (a single-domain PD-L1 antibody administered by subcutaneous injection), MEDI0680 (a humanized IgG4 specific for human PD-1 that blocks the interaction between PD-L1 and programmed death ligand-2 (PD-L2) mAb), nivolumab (PD-1 blocking antibody used to treat melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and Hodgkin lymphoma), retifanlimab (PD-1 blocking antibody indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma), sintilimab (IgG4 anti-PD-1 monoclonal antibody), spartalizumab (investigational monoclonal antibody directed against the human programmed death-1 (PD-1) receptor), tislelizumab (an IgG4 variant monoclonal antibody against PD-1 indicated for the treatment of unresectable locally advanced or metastatic esophageal squamous cell carcinoma), toripalimab (PD-1 blocking monoclonal antibody used for the treatment of metastatic and recurrent nasopharyngeal carcinoma), cetrelimab (an IgG4 anti-programmed death-1 monoclonal antibody used to treat metastatic and recurrent nasopharyngeal carcinoma). Cell death protein-1 (PD-1) antibody), SSI-361 (anti-PD-1 humanized monoclonal antibody), pidilizumab (humanized IgG-1 kappa recombinant mAb directed against the human inhibitory receptor programmed cell death 1 (PD-1)), INCMGA00012 (humanized, hinge-stabilized, immunoglobulin G4 kappa monoclonal antibody that binds to PD-1), dimvelelimab (fully human IgG4 anti-PD-1 monoclonal antibody that binds to human PD-1), prorugolimab (IgG1 anti-PD-1 monoclonal antibody containing an Fc-silencing "LALA" mutation), BMS-986189 (macrocyclic peptide PD-L1 inhibitor), BMS-936559 (high-affinity, fully human, PD-L1-specific, IgG4 monoclonal antibody), sugemalimab (fully human, full-length, anti-PD-L1 These include those that target the PD-1/PD-L2/PD-L1 immune checkpoint(s), such as pembrolizumab (an IgG4 monoclonal antibody), adebrelimab (a high-affinity, humanized monoclonal antibody against PD-L1), CBT-502 (a humanized IgG1 antibody against PD-L1), BGB-A333 (a humanized monoclonal antibody against PD-L1), and pacmilimab (a probody therapy directed against PD-1). In some embodiments, the methods and compositions of the present disclosure may include an ICI that targets the PD-1/PD-L2/PD-L1 immune checkpoint other than pembrolizumab, such as, for example, one of the anti-PD-1/PD-L2/PD-L1 ICIs described above.

Useful ICIs include those that target the CTLA-4 immune checkpoint, such as ipilimumab (a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody used to treat metastatic or unresectable melanoma) and tremelimumab (an anti-CTLA-4 antibody used in combination with durvalumab to treat unresectable hepatocellular carcinoma). In some embodiments, the methods and compositions of the present disclosure may include an ICI that targets the CTLA-4 immune checkpoint, such as, for example, one of the anti-CTLA-4 ICIs described above.

Useful ICIs include ICIs that target the LAG-3 immune checkpoint, such as relatolimab (a monoclonal antibody targeting LAG-3 used in combination with nivolumab for the treatment of unresectable or metastatic melanoma), enselimab, favezelimab, fianlimab, yeramilimab, miptenalimab, negalstbalt, leratolimab, or tuparstbalt. In some embodiments, the methods and compositions of the present disclosure include ICIs that target the LAG-3 immune checkpoint, such as enselimab, favezelimab, fianlimab, yeramilimab, miptenalimab, negalstbalt, leratolimab, or tuparstbalt.

Useful ICIs include those that target the B7-H3 immune checkpoint, such as, for example, omburtamab (a humanized murine anti-CD276 (B7-H3) antibody) and enoblituzumab (a monoclonal antibody that targets B7-H3 and has been enhanced using MacroGenics' Fc-optimization platform). In some embodiments, the methods and compositions of the present disclosure may include ICIs that target the B7-H3 immune checkpoint, such as, for example, omburtamab and enoblituzumab.

One aspect of the present disclosure is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject (a) a DR IL-18 polypeptide and (b) an ICI that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3, where the ICI is not pembrolizumab.

In some embodiments, the ICI is an antagonist. In some embodiments, the ICI is an immunoadhesin. In some embodiments, the ICI is an antibody or an antigen-binding fragment thereof. In some embodiments, the ICI is a monoclonal antibody or an antigen-binding fragment thereof.

In some embodiments, the ICI is a PD-1 checkpoint inhibitor. In some embodiments, the PD-1 checkpoint inhibitor is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is monoclonal. In some embodiments, the PD-1 checkpoint inhibitor is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is an antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is monoclonal. In some embodiments, the PD-1 antagonist is aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotlimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, prodrug In some embodiments, the PD-1 checkpoint inhibitor is a PD-L1 antagonist selected from the group consisting of lorgolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimverelimab, INCMGA00012, MEDI0680, SSI-361, and AMP-224. In some embodiments, the PD-L1 antagonist is an antibody or antigen-binding fragment thereof. In some embodiments, the antibody is monoclonal. In some embodiments, the PD-L1 antagonist is selected from the group consisting of adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.

In some embodiments, the PD-1 checkpoint inhibitor is CA-170.

One aspect of the present disclosure is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject (a) a DR IL-18 polypeptide and (b) an effective amount of an ICI, wherein the ICI is a PD-L1 or PD-L2 antagonist. In some embodiments, the PD-L1 antagonist comprises adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, or any combination thereof. In some embodiments, the ICI is an anti-PD-1 or anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the ICI is an anti-PD-L2 antibody or antigen-binding fragment thereof.

In some embodiments, the ICI is an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In some embodiments, the ICI is botencilimab, evalstuzumab, filastuzumab, gotistuzumab, ipilimumab, muzastozug, nurlimab, polstuzumab, quavonlimab, sovipostuzumab, tremelimumab, tubonlarimab, vilastuzumab, or zalifrelimab.

In some embodiments, the ICI is an anti-LAG-3 antibody or an antigen-binding fragment thereof. In some embodiments, the ICI is enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, leratolimab, or tuparstbalt.

In some embodiments, the ICI is an anti-B7-H3 antibody or an antigen-binding fragment thereof. In some embodiments, the ICI is enoblituzumab, ifinatamab, mirzotamab, omburtamab, or vovlamitamab.

One aspect of the present disclosure is a method for treating a disease, comprising: (a) administering to a subject a composition comprising a DR IL-18 polypeptide; and (b) administering to the subject a composition comprising a DR IL-18 polypeptide, such as dimverelimab, nivolumab, cemiplimab, dostarimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, pidilizumab, MEDI0680, SSI-361, AMP-224, cetrelimab, prorugolimab, retifanlimab, atezolizumab, abel and administering a composition comprising an ICI selected from the group consisting of mab, durvalumab, embafolimab, cosibelimab, CA-170, BMS-986189, BMS-936559, sugemalimab, adebulerimab, CBT-502, BGB-A333, pacmilimab, ipilimumab, tremelimumab, relatolimab, enoblitutuzumab, and variants of any of the foregoing.

One aspect of the present disclosure is a method for treating a disease, comprising: (a) administering to a subject a composition comprising a DR IL-18 polypeptide; and (b) administering to a subject one of the following: aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt. , prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, selplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimvelerimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embalmab Folimab, galibrimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, suduplilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstotsug, filastotsug, gothistotsug, ipilimumab, muzastotsug, nurlimab, polstotsug, quavonlimab, sovipostotsug administering a composition comprising an ICI selected from the group consisting of tremelimumab, tubonlarimab, bilastbalt, zalifrelimab, enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negallastbalt, relatolimab, tuparlastbalt, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and variants of any of the foregoing.

In some embodiments, the ICI is administered as a solution of about 1-250 mg/mL, about 1-10 mg/mL, about 10-20 mg/mL, about 20-30 mg/mL, about 30-40 mg/mL, about 40-50 mg/mL, about 50-75 mg/mL, about 75-100 mg/mL, about 100-150 mg/mL, or about 150-250 mg/mL.

In some embodiments, the ICI is administered as a solution of at least about 1-250 mg/mL, at least about 1-10 mg/mL, at least about 10-20 mg/mL, at least about 20-30 mg/mL, at least about 30-40 mg/mL, at least about 40-50 mg/mL, at least about 50-75 mg/mL, at least about 75-100 mg/mL, at least about 100-150 mg/mL, or at least about 150-250 mg/mL.

In some embodiments, the ICI is administered as a solution of up to about 1-250 mg/mL, up to about 1-10 mg/mL, up to about 10-20 mg/mL, up to about 20-30 mg/mL, up to about 30-40 mg/mL, up to about 40-50 mg/mL, up to about 50-75 mg/mL, up to about 75-100 mg/mL, up to about 100-150 mg/mL, or up to about 150-250 mg/mL.

In some embodiments, the ICI is administered as a solution of at least about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 12 mg/mL, about 14 mg/mL, about 16 mg/mL, about 18 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 200 mg/mL, or about 250 mg/mL. In some embodiments, the ICI is administered as a 100 mg/4 mL (25 mg/mL) solution.

In some embodiments, the ICI is administered until disease progression. In some embodiments, the ICI is administered until unacceptable toxicity. In some embodiments, the ICI is administered until disease recurrence.

In some embodiments, the ICI is administered for up to about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, about 18 months, about 20 months, or about 24 months.

In some embodiments, the ratio of ICI dose to DR IL-18 polypeptide dose is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, or about 1:180. , about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 mg.

In some embodiments, the ICI is administered to the subject at a dosage of about 0.1 mg/kg to about 20.0 mg/kg of the subject's body weight.

In some embodiments, the ICI is administered to a subject at a dose of 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg of the subject's body weight.

In some embodiments, the ICI is administered to a subject at a dose of at least about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg of the subject's body weight.

In some embodiments, the ICI is administered to a subject at a dose of up to 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg of the subject's body weight.

In some embodiments, the ICI is from about 10 mg/kg to about 50 mg/kg. In some embodiments, the ICI is at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, or more. In some embodiments, the ICI is up to about 50 mg/kg, up to about 45 mg/kg, up to about 40 mg/kg, up to about 35 mg/kg, up to about 30 mg/kg, up to about 25 mg/kg, up to about 20 mg/kg, up to about 15 mg/kg, up to about 10 mg/kg, or less. In some embodiments, the ICI is about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, or about 50 mg/kg. In some embodiments, the ICI is about 20 mg/kg.

In some embodiments, the ICI is administered to a subject at a dose of at least about 5-1600 mg, at least about 5-10 mg, at least about 10-20 mg, at least about 20-40 mg, at least about 40-60 mg, at least about 60-80 mg, at least about 80-100 mg, at least about 100-200 mg, at least about 200-300 mg, at least about 300-400 mg, at least about 400-500 mg, at least about 500-600 mg, at least about 700-800 mg, at least about 800-900 mg, at least about 900-1000 mg, at least about 1000-1200 mg, at least about 1200-1400 mg, or at least about 1400-1600 mg.

In embodiments, the ICI is administered to a subject at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, or about 320 mg. It is administered as a dose of about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 600 mg, about 640 mg, about 680 mg, about 720 mg, about 760 mg, about 800 mg, about 840 mg, about 880 mg, about 920 mg, about 960 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1120 mg, about 1160 mg, about 1200 mg, about 1280 mg, about 1360 mg, about 1440 mg, about 1520 mg, or about 1600 mg.

In some embodiments, the ICI is administered to the subject in an amount of at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 800 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 450 mg, at least about 550 mg, at least about 600 mg, at least about 800 mg, at least about 1 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, at least about 640 mg, at least about 680 mg, at least about 720 mg, at least about 760 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 920 mg, at least about 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1080 mg, at least about 1120 mg, at least about 1160 mg, at least about 1200 mg, at least about 1280 mg, at least about 1360 mg, at least about 1440 mg, at least about 1520 mg, or at least about 1600 mg.

In some embodiments, the ICI is administered to the subject at a dose of up to about 5 mg, up to about 10 mg, up to about 15 mg, up to about 20 mg, up to about 25 mg, up to about 30 mg, up to about 35 mg, up to about 40 mg, up to about 45 mg, up to about 50 mg, up to about 55 mg, up to about 60 mg, up to about 80 mg, up to about 100 mg, up to about 120 mg, up to about 140 mg, up to about 160 mg, up to about 180 mg, up to about 200 mg, up to about 220 mg, up to about 240 mg, up to about 260 mg, up to about 280 mg, up to about 300 mg, up to about 320 mg, up to about 360 mg, up to about 380 mg, up to about 400 mg, up to about 420 mg, or up to about 440 mg. g, up to about 460 mg, up to about 480 mg, up to about 500 mg, up to about 520 mg, up to about 540 mg, up to about 560 mg, up to about 580 mg, up to about 600 mg, up to about 640 mg, up to about 680 mg, up to about 720 mg, up to about 760 mg, up to about 800 mg, up to about 840 mg, up to about 880 mg, up to about 920 mg, up to about 960 mg, up to about 1000 mg, up to about 1040 mg, up to about 1080 mg, up to about 1120 mg, up to about 1160 mg, up to about 1200 mg, up to about 1280 mg, up to about 1360 mg, up to about 1440 mg, up to about 1520 mg, or up to about 1600 mg.

In some embodiments, the ICI is administered to the subject about twice a week, about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every two months, about once every three months, about once every four months, about once every five months, about once every six months, about once every nine months, or about once every twelve months.

In some embodiments, an ICI is administered as an additional recommended dose.

In some embodiments, the ICI is administered to the subject for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.

In some embodiments, the ICI is administered X mg Q8W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q7W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q6W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q5W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q4W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q3W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q2W, where X is 10-1600. In some embodiments, the ICI is administered X mg Q1W, where X is 10-1600. In some embodiments, X is about 240. In some embodiments, X is about 480. In some embodiments, X is about 200, about 400, about 600, or about 800.

In some embodiments, the ICI is administered at X mg/kg Q8W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q7W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q6W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q5W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q4W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q3W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q2W, where X is 0.1-20. In some embodiments, the ICI is administered at X mg/kg Q1W, where X is 0.1-20. In some embodiments, X is about 2. In some embodiments, X is about 3. In some embodiments, X is about 10. In some embodiments, X is about 3, about 5, or about 10. In some embodiments, X is about 15.

In some embodiments, the amount of ICI administered is capped at 200 mg. In some embodiments, the subject is a pediatric patient.

In some embodiments, the ICI is administered for n weeks, where n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

In some embodiments, the ICI is administered to the subject at treatment intervals of about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months.

In some embodiments, the method comprises administering to the subject an ICI according to a dosing regimen of X mg/kg Q1W for n weeks followed by Y mg/kg Q2W, where X is 5-20, Y is 10-20, and n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

In some embodiments, the method comprises administering to the subject an ICI according to a dosing regimen of 400-1600 mg Q1W for n weeks followed by 800-1600 mg Q2W, where n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

In some embodiments, the composition comprising an ICI is administered orally. In some embodiments, the composition comprising an ICI is administered subcutaneously. In some embodiments, the composition comprising an ICI is administered intramuscularly. In some embodiments, the composition comprising an ICI is administered intravenously. In some embodiments, the composition comprising an ICI is administered intrathecally. In some embodiments, the composition comprising an ICI is administered rectally. In some embodiments, the composition comprising an ICI is administered intravaginally. In some embodiments, the composition comprising an ICI is administered intranasally. In some embodiments, the composition comprising an ICI is injected into a patient without dilution.

In some embodiments, the ICI is administered orally. In some embodiments, the ICI is administered subcutaneously. In some embodiments, the ICI is administered intramuscularly. In some embodiments, the ICI is administered intravenously. In some embodiments, the ICI is administered intrathecally. In some embodiments, the ICI is administered rectally. In some embodiments, the ICI is administered intravaginally. In some embodiments, the ICI is administered intranasally. In some embodiments, the ICI is injected into the patient undiluted.

In some embodiments, administering a composition comprising an ICI results in a reduction in tumor size in a subject. In some embodiments, administering a composition comprising an ICI results in a reduction in tumor number in a subject. In some embodiments, administering a composition comprising an ICI results in a reduction in tumor size and a reduction in tumor number in a subject.

In some embodiments, administering the ICI results in a reduction in tumor size in the subject. In some embodiments, administering the ICI results in a reduction in tumor number in the subject. In some embodiments, administering the ICI results in a reduction in tumor size and a reduction in tumor number in the subject.

Administration of Additional Therapies The methods of the present disclosure include combination therapy comprising administering to a subject a DR IL-18 composition comprising a DR IL-18 polypeptide and an ICI composition comprising an ICI, wherein the ICI is not pembrolizumab. In addition to administering the DR IL-18 composition and the ICI composition, the method, in some embodiments, further comprises administering one or more additional therapies to the subject. Useful additional therapies include prophylactic therapies that prevent and/or reduce the onset of symptoms of cytokine release syndrome (CRS) in a subject administered the DR IL-18 composition and the ICI composition.

One aspect of the present disclosure provides methods and compositions for treating a disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a liquid tumor. In some embodiments, the method further comprises administering an additional treatment to the subject. In some embodiments, the additional treatment is a prophylactic or pharmaceutical agent that prevents and/or reduces the manifestation of symptoms of CRS in a subject, e.g., a subject having a solid tumor or a liquid tumor, who is receiving a combination therapy comprising administration of a DR IL-18 composition and an ICI composition.

CRS may occur in a subject after administration of a DR IL-18 composition. In some embodiments, the additional treatment reduces the presentation of CRS symptoms. In some embodiments, administering the additional treatment reduces the presentation of CRS symptoms compared to a comparable subject who did not receive the additional treatment. In some embodiments, administering the additional treatment to a subject results in reduced presentation of CRS symptoms in the subject compared to a comparable subject administered about 30 mg/ml or more of DR IL-18 polypeptide.

One aspect of the present disclosure provides a method of treating a disease, the method comprising: (a) administering to a subject a composition comprising a DR IL-18 polypeptide; (b) administering to a subject a composition comprising an ICI, where the ICI is not pembrolizumab; and (c) administering a composition comprising an additional treatment. In some embodiments, the additional treatment is a prophylactic agent. In some embodiments, the prophylactic agent is a CRS prophylactic agent that reduces the presentation of symptoms of CRS in the subject.

One aspect of the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a DR IL-18 polypeptide; (b) an effective amount of an ICI, where the ICI is not pembrolizumab; and (c) an additional therapy. In some embodiments, the additional therapy is a prophylactic agent. In some embodiments, the prophylactic agent is a CRS prophylactic agent that reduces the presentation of symptoms of CRS in the subject.

Consistent with the above definitions, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical object of the article, and therefore, references herein to the administration of an additional therapeutic or CRS prophylactic agent or dose refer to the administration of one or more agents (i.e., one or more agents), CRS prophylactic agents (i.e., one or more CRS prophylactic agents), the administration of one or more doses (i.e., one or more doses), the administration of at least one agent, the administration of at least one CRS prophylactic agent, or the administration of at least one dose. The administration of one or more CRS prophylactic agents may be referred to herein as CRS prophylaxis.

The CRS prophylaxis or CRS preventative agent can be administered to the subject starting with the first dose of the DR IL-18 composition. In some embodiments, the CRS prophylaxis agent can be administered as a pre- or post-medication to a dose of the DR IL-18 composition. In some embodiments, the method further comprises administering a dose of the CRS prophylaxis agent to the subject with or before each dose of the successive doses of the DR IL-18 composition. In some embodiments, the method further comprises administering a dose of the CRS prophylaxis agent to the subject with or before each dose of the successive doses of the DR IL-18 composition.

One aspect of the present disclosure provides a method for treating a disease in a subject in need thereof. In some embodiments, the cancer is a solid or liquid tumor. One aspect of the present disclosure provides a method for treating cancer in a subject, comprising: (a) administering to the subject sequential doses of an ICI composition, wherein the ICI is not pembrolizumab; (b) administering to the subject sequential doses of a DR IL-18 composition comprising a DR IL-18 polypeptide, wherein the DR IL-18 polypeptide comprises an amino acid sequence set forth in any one of SEQ ID NOs: 1-12; and (c) administering CRS prophylaxis to the subject. In some embodiments, the CRS prophylaxis comprises administering a CRS prophylactic agent with or before the DR IL-18 composition, or with or before each dose or sequential doses of the DR IL-18 composition. In some embodiments, the method further comprises administering to the subject a dose of a CRS prophylactic agent with or before each dose of the sequential doses of the DR IL-18 composition. In some embodiments, the dose of CRS preventative agent comprises at least one of an NSAID, acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, or a fluid administered to the subject. In some embodiments, the dose of CRS preventative agent is administered to the subject orally or intravenously.

In some embodiments, the CRS prophylactic agent is administered orally. In some embodiments, one or more CRS prophylactic agents for CRS prophylaxis are administered orally. In some embodiments, the CRS prophylactic agent is administered subcutaneously. In some embodiments, one or more CRS prophylactic agents for CRS prophylaxis are administered subcutaneously. In some embodiments, the CRS prophylactic agent is administered intramuscularly. In some embodiments, one or more CRS prophylactic agents for CRS prophylaxis are administered intramuscularly. In some embodiments, the CRS prophylactic agent is administered intravenously. In some embodiments, one or more CRS prophylactic agents for CRS prophylaxis are administered intravenously. In some embodiments, the CRS prophylactic agent is administered intrathecally. In some embodiments, the CRS prophylactic agent is administered rectally. In some embodiments, the CRS prophylactic agent is administered intravaginally. In some embodiments, the CRS prophylactic agent is administered intranasally. In some instances, multiple routes of administration are used, including, for example, when one or more CRS prophylactic agents of a CRS prophylactic regimen are administered orally and one or more CRS prophylactic agents of a CRS prophylactic regimen are administered intravenously.

In some embodiments, the CRS prophylactic agent is administered hourly. In some embodiments, the CRS prophylactic agent is administered about every few hours. In some embodiments, the CRS prophylactic agent is administered twice daily. In some embodiments, the CRS prophylactic agent is administered daily. In some embodiments, the CRS prophylactic agent is administered every 6 days. In some embodiments, the CRS prophylactic agent is administered twice weekly. In some embodiments, the CRS prophylactic agent is administered weekly. In some embodiments, the CRS prophylactic agent is administered every 2 weeks. In some embodiments, the CRS prophylactic agent is administered every 3 weeks. In some embodiments, the CRS prophylactic agent is administered monthly. In some embodiments, the CRS prophylactic agent is administered every 2 months. In some embodiments, the CRS prophylactic agent is administered every 3 months. In some embodiments, the CRS prophylactic agent is administered every 4 months. In some embodiments, the CRS prophylactic agent is administered every 6 months. In some embodiments, the CRS prophylactic agent is administered once a year.

In some embodiments, the CRS prophylactic agent reduces the presentation of symptoms of cytokine release syndrome (CRS). In some embodiments, administering the CRS prophylactic agent reduces the presentation of symptoms of CRS compared to a comparable subject who did not receive the CRS prophylactic agent. In some embodiments, administering the CRS prophylactic agent reduces the presentation of symptoms of CRS compared to a corresponding subject who received a comparable treatment but did not receive the CRS prophylactic agent. In some embodiments, administering the CRS prophylactic agent to a subject results in reduced presentation of symptoms of CRS in the subject compared to a comparable subject who received about 30 mg/ml or more of a DR IL-18 composition. In some embodiments, administering the CRS prophylactic agent to a subject results in reduced presentation of symptoms of CRS in the subject compared to a corresponding subject who received a comparable therapy including administration of about 30 mg/ml or more of a DR IL-18 composition. In some embodiments, administering a CRS prophylactic agent to a subject results in reduced presentation of CRS symptoms in the subject compared to a comparable subject administered about 30 μg/kg or more of a DR IL-18 composition. In some embodiments, administering a CRS prophylactic agent to a subject results in reduced presentation of CRS symptoms in the subject compared to a comparable subject receiving a comparable therapy comprising administration of about 30 μg/kg or more of a DR IL-18 composition.

In some embodiments, CRS prevention reduces the presentation of CRS symptoms in a subject administered a combination therapy comprising a DR IL-18 composition, including when the presentation of symptoms is reduced compared to a subject administered the same therapy without CRS prophylaxis. In some embodiments, CRS prevention reduces the presentation of CRS symptoms in a subject administered a combination therapy comprising administering a DR IL-18 composition comprising at least about 30 μg/kg or more of a DR-IL-18 polypeptide, including when the presentation of CRS symptoms is reduced compared to a subject administered the same therapy without CRS prophylaxis. In some embodiments, CRS prevention reduces the presentation of CRS symptoms in a subject administered an ICI composition and a DR IL-18 composition combination therapy, including when the presentation of symptoms is reduced compared to a subject administered the same therapy without CRS prophylaxis.

In some embodiments, administering CRS prophylaxis prevents the onset or progression of CRS in a subject receiving the combination therapy, and the combination therapy comprises administering a DR-IL-18 composition comprising a DR-IL-18 polypeptide (e.g., comprising at least about 30 μg/kg or more of a DR-IL-18 polypeptide). For example, administering CRS prophylaxis can be performed, for example, when CRS grading is performed according to the methods described by Lee et al. Biology of Blood and Marrow Transplantation. Prevent the onset or progression of Grade 5 CRS, Grade 4 CRS or higher, and/or Grade 3 CRS or higher, including when performed according to the Consensus American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS as described in 2019 IEEE International Conference on Transplantation and Cellular Therapy (ISCT) 25 (2019) 625-639. In some instances, the lack of onset or progression of CRS may be indicated by the absence of fever (temperature above 38 degrees Celsius), the absence of hypotension, hypotension requiring only a single vasopressor or no vasopressor, the absence of hypoxia, hypoxia requiring only low-flow nasal cannulae or blow-by, hypoxia requiring high-flow nasal cannulae (or face mask, non-rebreather mask, or Venturi mask) but not positive pressure, or a combination thereof.

In some embodiments, CRS prevention in a subject receiving a combination therapy comprising administration of a DR IL-18 composition comprising a DR-IL-18 polypeptide (e.g., comprising at least about 30 μg/kg or more of a DR-IL-18 polypeptide) negates the need to subsequently treat the subject for CRS. For example, in some instances, CRS prevention in such a scenario means that the administration of immunosuppressants, such as corticosteroids (e.g., glucocorticoids), anti-interleukin-6 (IL-6) agents (e.g., tocilizumab, siltoximab, clazakizumab), TNF-α signaling inhibitors (e.g., etanercept), T-cell depletion antibodies (e.g., alemtuzumab), IL-1R-based inhibitors (e.g., anakinra), cyclophosphamide, Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), or combinations thereof, is not required or administered. In some embodiments, a subject undergoing CRS prophylaxis and receiving combination therapy including administration of a DR IL-18 composition comprising a DR IL-18 polypeptide (e.g., comprising at least about 30 μg/kg or more of a DR IL-18 polypeptide) does not require or receive immunosuppressive agents to treat CRS. For example, in some instances, such a subject does not receive any corticosteroids (e.g., glucocorticoids) and/or any anti-interleukin-6 (IL-6) agents during the cycle of combination therapy or during the entire course of combination therapy.

In some embodiments, the CRS preventative agent is at least one of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, or a fluid.

In some embodiments, the additional treatment is an agent selected from the group consisting of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, tocilizumab, and any combination thereof.

In some embodiments, a single composition comprises an additional treatment, a DR IL-18 polypeptide, and an ICI. In some embodiments, two or more compositions comprise an additional treatment, a DR IL-18 polypeptide, and an ICI. In some embodiments, a method comprises administering a first composition comprising a DR IL-18 polypeptide and an ICI, and a second composition comprising the additional treatment. In some embodiments, a method comprises administering a first composition comprising a DR IL-18 polypeptide and an additional treatment, and a second composition comprising an ICI. In some embodiments, a method comprises administering a first composition comprising a DR IL-18 polypeptide, and a second composition comprising an ICI and the additional treatment.

In some embodiments, the additional treatment, such as CRS prophylaxis, is administered before administration of the DR IL-18 polypeptide. In some embodiments, the additional treatment is administered simultaneously with administration of the DR IL-18 polypeptide. In some embodiments, the additional treatment is administered after administration of the DR IL-18 polypeptide.

In some embodiments, an additional treatment, such as CRS prophylaxis, is administered prior to administration of the ICI. In some embodiments, the prophylactic agent is administered simultaneously with administration of the ICI. In some embodiments, the prophylactic agent is administered after administration of the ICI.

In some embodiments, the additional treatment is administered orally. In some embodiments, the additional treatment is administered subcutaneously. In some embodiments, the additional treatment is administered intramuscularly. In some embodiments, the additional treatment is administered intravenously. In some embodiments, the additional treatment is administered intrathecally. In some embodiments, the additional treatment is administered rectally. In some embodiments, the additional treatment is administered intravaginally. In some embodiments, the additional treatment is administered intranasally.

In some embodiments, the additional treatments are administered hourly. In some embodiments, the additional treatments are administered about every few hours. In some embodiments, the additional treatments are administered twice daily. In some embodiments, the additional treatments are administered daily. In some embodiments, the additional treatments are administered every six days. In some embodiments, the additional treatments are administered twice weekly. In some embodiments, the additional treatments are administered weekly. In some embodiments, the additional treatments are administered every two weeks. In some embodiments, the additional treatments are administered every three weeks. In some embodiments, the additional treatments are administered monthly. In some embodiments, the additional treatments are administered every two months. In some embodiments, the additional treatments are administered every three months. In some embodiments, the additional treatments are administered every four months. In some embodiments, the additional treatments are administered every six months. In some embodiments, the additional treatments are administered once a year.

NSAIDs
In some embodiments, the additional treatment, such as CRS prophylaxis, includes a nonsteroidal anti-inflammatory drug (NSAID), and thus the CRS prophylaxis agent used in the combination therapy is an NSAID. In some embodiments, the NSAID is administered to the subject about 1 to 2 hours before administering a dose of the DR IL-18 composition. In some embodiments, the NSAID is administered to the subject at least about 48 hours after administering the dose of the DR IL-18 composition. In some embodiments, the NSAID comprises indomethacin or ibuprofen. In some embodiments, indomethacin is administered to the subject at 25 mg three times daily. In some embodiments, ibuprofen is administered to the subject at 200 mg to 600 mg every 6 to 8 hours. In some embodiments, the NSAID is administered to the subject orally. In some embodiments, the NSAID is administered to the subject intravenously.

Non-limiting examples of NSAIDs include ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, celecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin. In some embodiments, the NSAID is ibuprofen. In some embodiments, the NSAID is indomethacin. In some embodiments, the NSAID is naproxen. In some embodiments, the NSAID is aspirin. In some embodiments, the NSAID is from about 25 mg to about 600 mg. In some embodiments, the NSAID is about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 3 In some embodiments, the NSAID is about 200 mg to about 325 mg, about 325 mg to about 350 mg, about 350 mg to about 375 mg, about 375 mg to about 400 mg, about 400 mg to about 425 mg, about 425 mg to about 450 mg, about 450 mg to about 475 mg, about 475 mg to about 500 mg, about 500 mg to about 525 mg, about 525 mg to about 550 mg, about 550 mg to about 575 mg, or 575 mg to about 600 mg. In some embodiments, the NSAID is about 200 mg to about 600 mg.

In some embodiments, the NSAID is at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, at least about 500 mg, at least about 525 mg, at least about 550 mg, at least about 575 mg, at least about 600 mg, or more.

In some embodiments, the NSAID is at most about 600 mg, at most about 575 mg, at most about 550 mg, at most about 525 mg, at most about 500 mg, at most about 475 mg, at most about 450 mg, at most about 425 mg, at most about 400 mg, at most about 375 mg, at most about 350 mg, at most about 325 mg, at most about 300 mg, at most about 275 mg, at most about 250 mg, at most about 225 mg, at most about 200 mg, at most about 175 mg, at most about 150 mg, at most about 125 mg, at most about 100 mg, at most about 75 mg, at most about 50 mg, at most about 25 mg, or less.

In some embodiments, the NSAID is about 25 mg, 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, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

Acetaminophen In some embodiments, the additional treatment, such as CRS prophylaxis, includes acetaminophen, and therefore the CRS prophylactic agent used in the combination therapy is acetaminophen. In some embodiments, acetaminophen is administered to the subject at 650 mg every 4 to 6 hours. In some embodiments, acetaminophen is administered at least 24 hours after administration of a single dose of the DR IL-18 composition. In some embodiments, acetaminophen is administered to the subject at 650 mg every 4 to 6 hours, starting 1 hour before administration of a dose of the DR IL-18 composition. In some embodiments, acetaminophen is administered for at least 48 hours after administration of a single dose of the DR IL-18 composition. In some embodiments, acetaminophen is administered to the subject orally or enterally. In some embodiments, acetaminophen is administered to the subject orally or enterally.

In some embodiments, the acetaminophen is from about 200 mg to about 800 mg. In some embodiments, the acetaminophen is from about 600 mg to about 800 mg.

In some embodiments, the acetaminophen is at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, or more. In some embodiments, the acetaminophen is at most about 800 mg, at most about 750 mg, at most about 700 mg, at most about 650 mg, at most about 600 mg, at most about 550 mg, at most about 500 mg, at most about 450 mg, at most about 400 mg, at most about 350 mg, at most about 300 mg, at most about 250 mg, at most about 200 mg, or less. In some embodiments, the acetaminophen is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, the acetaminophen is about 650 mg.

Histamine H1 Antagonist In some embodiments, the additional treatment, such as CRS prophylaxis, includes a histamine H1 antagonist, and thus the CRS prophylactic agent used in the combination therapy is a histamine H1 antagonist. In some embodiments, the histamine H1 antagonist is administered at 50 mg about 30 to 60 minutes prior to administration of the DR IL-18 composition. In some embodiments, the H1 antagonist is administered intravenously. In some embodiments, the H1 antagonist is administered orally.

Non-limiting examples of histamine H1 antagonists include brompheniramine, clemastine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine, mepyramine, chlorpheniramine, promethazine, and cyproheptadine. In some embodiments, the histamine H1 antagonist is about 20 to about 100 mg. In some embodiments, the histamine H1 antagonist is at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, or more. In some embodiments, the histamine H1 antagonist is at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, or less. In some embodiments, the histamine H1 antagonist is at most about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the histamine H1 antagonist is at most about 50 mg.

Diphenhydramine In some embodiments, the additional treatment, such as CRS prophylaxis, includes diphenhydramine, and thus the CRS prophylaxis agent used in the combination therapy is diphenhydramine. In some embodiments, diphenhydramine is administered at 50 mg about 30 to 60 minutes prior to administration of the dose of the DR IL-18 composition. In some embodiments, diphenhydramine is administered intravenously. In some embodiments, diphenhydramine is administered orally.

In some embodiments, the diphenhydramine is about 20 to about 100 mg. In some embodiments, the diphenhydramine is at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, or more. In some embodiments, the diphenhydramine is at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, or less. In some embodiments, the diphenhydramine is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the diphenhydramine is about 50 mg.

H2 Blockers In some embodiments, the additional therapy, such as CRS prophylaxis, includes a histamine H2 antagonist (H2 blocker), and thus the CRS prophylactic agent used in the combination therapy is an H2 blocker. In some embodiments, the H2 blocker is administered at 20 mg about 30 to 60 minutes prior to administration of the DR IL-18 composition. In some embodiments, the H2 blocker is administered intravenously. In some embodiments, the H2 blocker is administered at 20 mg to 40 mg about 30 to 60 minutes prior to administration of a dose of the DR IL-18 composition. In some embodiments, the H2 blocker is administered orally.

In some embodiments, the H2 blocker is famotidine, cimetidine, ranitidine, or nizatidine. In some embodiments, the H2 blocker is famotidine. In some embodiments, the H2 blocker is cimetidine. In some embodiments, the H2 blocker is ranitidine. In some embodiments, the H2 blocker is nizatidine. In some embodiments, the H2 blocker is 10 mg to about 60 mg. In some embodiments, the H2 blocker is about 20 mg to about 40 mg. In some embodiments, the famotidine is at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, or more. In some embodiments, the H2 blocker is at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, at most about 10 mg, or less. In some embodiments, the H2 blocker is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

Famotidine In some embodiments, the additional treatment, such as CRS prophylaxis, includes famotidine, and thus the CRS prophylaxis agent used in the combination therapy is famotidine. In some embodiments, famotidine is administered at 20 mg about 30 to 60 minutes prior to administration of the DR IL-18 composition. In some embodiments, famotidine is administered intravenously. In some embodiments, famotidine is administered at 20 mg to 40 mg about 30 to 60 minutes prior to administration of the dose of the DR IL-18 composition. In some embodiments, famotidine is administered orally.

In some embodiments, the famotidine is between 10 mg and about 60 mg. In some embodiments, the famotidine is between about 20 mg and about 40 mg. In some embodiments, the famotidine is at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, or more. In some embodiments, the famotidine is at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, at most about 10 mg, or less. In some embodiments, the famotidine is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

Fluids In some embodiments, the subject has or is at risk of having low blood pressure. In some embodiments, administering a dose of a CRS preventative agent comprises administering a fluid to the subject. In some embodiments, the fluid comprises up to 3 liters of fluid (e.g., water, juice, sports drink, or IV fluid) within 24 hours after administration of the DR IL-18 composition. In some embodiments, the fluid is administered intravenously. In some embodiments, the fluid is administered orally.

In some embodiments, the additional treatment is tocilizumab. In some embodiments, the tocilizumab is from about 400 mg to about 1000 mg. In some embodiments, the tocilizumab is from about 500 mg to about 900 mg. In some embodiments, the tocilizumab is at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, or more. In some embodiments, tocilizumab is at most about 1000 mg, at most about 950 mg, at most about 900 mg, at most about 850 mg, at most about 800 mg, at most about 750 mg, at most about 700 mg, at most about 650 mg, at most about 600 mg, at most about 550 mg, at most about 500 mg, at most about 450 mg, at least about 400 mg, or less. In some embodiments, tocilizumab is at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, or at most about 1000 mg.

In some embodiments, administering the additional therapy results in reduced display of symptoms of cytokine release syndrome (CRS). Non-limiting examples of symptoms of CRS include fever, chills, fatigue, nausea, vomiting, diarrhea, headache, cough, low blood pressure, joint pain, muscle pain, skin rash, shortness of breath, confusion, dizziness, difficulty swallowing, increased heart rate, decreased heart function, irregular heartbeat, organ failure, and swelling. In some embodiments, administration results in reduced display of symptoms of cytokine release syndrome compared to a comparable subject administered about 30 mg/ml to about 100 mg/ml of a DR IL-18 polypeptide. In some embodiments, administration results in reduced display of symptoms of cytokine release syndrome compared to a corresponding subject administered an equivalent therapy comprising about 30 mg/ml to about 100 mg/ml of a DR IL-18 composition. In some embodiments, administration results in reduced manifestations of CRS symptoms compared to a comparable subject administered about 30 mg/ml to about 40 mg/ml, about 40 mg/ml to about 50 mg/ml, about 50 mg/ml to about 60 mg/ml, about 60 mg/ml to about 70 mg/ml, about 70 mg/ml to about 80 mg/ml, about 80 mg/ml to about 90 mg/ml, or about 90 mg/ml to about 100 mg/ml of a DR IL-18 polypeptide. In some embodiments, administration results in reduced manifestations of CRS symptoms compared to a corresponding subject receiving an equivalent therapy of about 30 mg/ml to about 40 mg/ml, about 40 mg/ml to about 50 mg/ml, about 50 mg/ml to about 60 mg/ml, about 60 mg/ml to about 70 mg/ml, about 70 mg/ml to about 80 mg/ml, about 80 mg/ml to about 90 mg/ml, or about 90 mg/ml to about 100 mg/ml of the DR IL-18 composition.

In some embodiments, administration results in reduced presentation of CRS symptoms compared to a comparable subject administered DR IL-18 polypeptide (or compared to a corresponding subject administered an equivalent therapy) of at least about 30 mg/ml, at least about 35 mg/ml, at least about 40 mg/ml, at least about 45 mg/ml, at least about 50 mg/ml, at least about 55 mg/ml, at least about 60 mg/ml, at least about 65 mg/ml, at least about 70 mg/ml, at least about 75 mg/ml, at least about 80 mg/ml, at least about 85 mg/ml, at least about 90 mg/ml, at least about 95 mg/ml, at least about 100 mg/ml, or more. In some embodiments, administration results in reduced presentation of CRS symptoms compared to a comparable subject administered up to about 100 mg/ml, up to about 95 mg/ml, up to about 90 mg/ml, up to about 85 mg/ml, up to about 80 mg/ml, up to about 75 mg/ml, up to about 70 mg/ml, up to about 65 mg/ml, up to about 60 mg/ml, up to about 55 mg/ml, up to about 50 mg/ml, up to about 45 mg/ml, up to about 40 mg/ml, up to about 35 mg/ml, up to about 30 mg/ml, or less, of a DR IL-18 polypeptide. In some embodiments, administration results in reduced manifestations of CRS symptoms compared to a comparable subject administered about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, or about 100 mg/ml of DR IL-18 polypeptide.

CRS Prophylactic Combinations Any of the groups of CRS prophylactic agents and individual CRS prophylactic agents described herein, and any of the methods described herein using such groups and individual CRS prophylactic agents, may be combined into useful CRS prophylactic combinations.

For example, in some embodiments, CRS prophylaxis administered to a subject includes at least an NSAID and at least a histamine H1 antagonist, at least acetaminophen and at least a histamine H1 antagonist, at least an NSAID and at least acetaminophen, or at least an NSAID, at least a histamine H1 antagonist, and at least acetaminophen. Such NSAIDs, histamine H1 antagonists, and acetaminophen used in such combinations may be administered according to the administration and/or dosing of each agent described herein. In some embodiments, CRS prophylaxis administered to a subject includes at least indomethacin or ibuprofen and at least diphenhydramine, at least acetaminophen and at least diphenhydramine, at least indomethacin or ibuprofen and at least acetaminophen, or at least indomethacin or ibuprofen, at least diphenhydramine, and at least acetaminophen. The indomethacin or ibuprofen, diphenhydramine, and acetaminophen used in such combinations may be administered according to the administration and/or dosing of each agent described herein. In some embodiments, such combinations further include an H2 blocker, including, for example, when the H2 blocker used is famotidine and the famotidine is administered according to the administration and/or dosing described herein.

In some embodiments, CRS prophylaxis includes at least an NSAID, a histamine H1 antagonist, and acetaminophen, including, for example, when (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day (e.g., including 75 mg per day) or oral ibuprofen administered at 600 mg to 2,400 mg per day (e.g., including 800 mg to 1,800 mg per day), (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg (e.g., including a 50 mg dose), and (iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day (e.g., including 650 mg to 3,900 mg per day). In some embodiments, such combinations further include an H2 blocker, including, for example, when the H2 blocker used is famotidine and the famotidine is administered according to the administration and/or dosages described herein.

In some embodiments, the CRS prophylaxis combinations described herein reduce the presentation of one or more symptoms of CRS, including alleviating one or more symptoms, compared to a subject receiving the same treatment protocol without CRS prophylaxis. In some embodiments, the CRS prophylaxis combinations described herein, such as those described above, prevent a subject with cancer treated with a combination therapy comprising administration of a DR IL-18 composition comprising a DR IL-18 polypeptide comprising an amino acid sequence set forth in any one of SEQ ID NOS: 1-12 (e.g., SEQ ID NO: 5) from experiencing one or more (including all) symptoms of Grade 3 or higher CRS or Grade 4 CRS. In some embodiments, CRS prevention combinations described herein, such as those described above, can be used in combination therapy comprising administration of a DR IL-18 composition comprising a polypeptide that is a modified IL-18 polypeptide comprising the amino acid sequence set forth in one of SEQ ID NOS: 1-12 (e.g., SEQ ID NO: 5), to prevent a subject with cancer from requiring treatment for CRS, including treatment with one or more (or any) immunosuppressants, such as, for example, a corticosteroid, an anti-interleukin-6 (IL-6) agent (e.g., tocilizumab), or any combination thereof.

Subject Indications One aspect of the present disclosure provides a method for treating a disease in a subject in need thereof. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor.

In some embodiments, the compositions and methods of the present disclosure are useful for treating tumors or cancers that are resistant to ICIs. Examples of ICIs include anti-PD1 agents such as anti-PD1 antibodies (e.g., aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbart, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbart, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab ... anti-PD-L1 agents such as anti-PD-L1 antibodies (e.g., adjuvant, praducinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimbelelimab, INCMGA00012, MEDI0680, SSI-361, and AMP-224); ... lelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galibrimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333), anti-P anti-PD-L2 agents such as DL-L2 antibodies, anti-CTLA4 (e.g., botencilimab, evalstuzumab, filastuzumab, gotistuzumab, ipilimumab, muzastozug, nurlimab, polstuzumab, quabonlimab, sobipostuzumab, tremelimumab, tubonlarimab, vilastuzumab, and zalifrelimab), anti-TIM3 (e.g., covolimab, sabatolimab, sulzeviclimab, and belzistova), verzistobart, anti-TIGIT (e.g., berrestotug, darzistobart, dombanalimab, etidilimab, lancastotug, osipeliimab, ralzapastotug, renvistobart, tamgibulimab, tiragolumab, and vibostolimab), anti-LAG3 (e.g., encelimab, favezelimab, fianlimab, anti-B7H3 (e.g., enoblitzumab, ifinatamab, mirzotamab, omburtamab, vovramitamab), anti-B7H4 (e.g., arcevalimab, pxitag), anti-VISTA (ombatilimab), anti-BTLA, anti-CD47 (e.g., lemzoparimab, retaplimab, ligufalimab, magrolimab, anti-CD48, anti-CD155, anti-CD160, anti-TREM2 (e.g., iluzanebart), anti-IDO1, anti-adenosine 2A receptor, anti-aryl hydrocarbon receptor, anti-KIR, and anti-LILRB2, among others. Examples of targets of ICI include, but are not limited to, PD-L1, PD1, CTLA4, TIM3, TIGIT, LAG3, B7H3, B7H4, VISTA, BTLA, CD47, SIRPα, CD48, CD155, CD160, TREM2, IDO1, adenosine 2A receptor, aryl hydrocarbon receptor, KIR, and LILRB2, or any combination thereof.

In some embodiments, the disease is cancer. Cancer can be a hyperproliferation of cells that can have unregulated growth, lack of differentiation, local tissue invasion, and/or metastasis. In some embodiments, the cancer is a solid tumor. A tumor can be an abnormal proliferation of cells or tissues (e.g., malignant or benign).

In some embodiments, the cancer is leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma, and/or sarcoma. Non-limiting examples of cancer include lymphoma, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., , hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung cancer, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophageal), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma. Additional non-limiting examples of cancer include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic cancer, These include insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, and prostate cancer.

In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is leukemia. Leukemia can be a progressive malignant disease of the blood-forming organs, potentially distorting the growth and development of white blood cells and their precursors in the blood and bone marrow. Leukemia can generally be classified clinically based on (1) the duration and characteristics of the disease—acute or chronic, (2) the type of cells involved—myeloid (myeloid), lymphoid (lymphatic), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood—leukemic or non-leukemic (subleukemic). Non-limiting examples of leukemias include, for example, acute myeloid leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, Examples of leukemia include lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

In some embodiments, the cancer is a sarcoma. Sarcomas can be tumors that can be composed of a substance like embryonic connective tissue and can consist of closely packed cells embedded in a fibrillar and/or homogeneous substance. Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloromatous sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, and fibrosarcoma. Examples include sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

In some embodiments, the cancer is melanoma. The term "melanoma" can refer to tumors arising from the melanocytic system of the skin and other organs. Non-limiting examples of melanoma include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

In some embodiments, the cancer is a solid tumor. Non-limiting examples of solid tumor cancers include bladder cancer, breast cancer, cervical cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, oral cancer, liver cancer, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, small cell lung cancer, and thyroid cancer.

In some embodiments, the solid tumor is selected from the group consisting of melanoma, Merkel cell carcinoma, renal cell carcinoma, urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability-high (MSI-H) tumors, high tumor mutation burden (TMB-H) tumors, mismatch repair-deficient tumors, gastric, cervical, endometrial, squamous cell skin, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof.

In some embodiments, the solid tumor is melanoma, renal cell carcinoma, triple-negative breast cancer, NSCLC, SCCHN, or an MSI-H tumor. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is renal cell carcinoma. In some embodiments, the solid tumor is TNBC. In some embodiments, the solid tumor is NSCLC. In some embodiments, the solid tumor is SCCHN. In some embodiments, the solid tumor is an MSI-H tumor.

In some embodiments, the cancer or solid tumor is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient cancer (dMMR) cancer, microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC), or Associated with colorectal cancer, gastric cancer, esophagogastric junction cancer, esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof.

In some embodiments, the cancer or solid tumor is resistant to an ICI checkpoint inhibitor and is selected from the group consisting of melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumors or mismatch repair-deficient cancers (dMMR), microsatellite instability-high or mismatch repair-deficient cancers, and cancers with high microsatellite instability or mismatch repair deficiency. Associated with colorectal cancer (CRC), colorectal cancer, gastric cancer, esophagogastric junction cancer, esophagogastric junction adenocarcinoma, locally advanced or metastatic esophagogastric junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof.

In some embodiments, the cancer or solid tumor is associated with melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation/fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer or solid tumor is resistant to a PD-1 checkpoint inhibitor.

In some embodiments, the cancer or solid tumor is associated with platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.

Compositions One aspect of the present disclosure provides therapeutic compositions for treating a disease. In some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the therapeutic composition comprises a DR IL-18 polypeptide. In some embodiments, the therapeutic composition comprises an ICI, wherein the ICI is not pembrolizumab.

One aspect of the present disclosure provides therapeutic compositions comprising (a) a DR IL-18 polypeptide and (b) an ICI, where the ICI is not pembrolizumab. In some embodiments, a single therapeutic composition comprises a DR IL-18 polypeptide and an ICI. In some embodiments, a first therapeutic composition comprises a DR IL-18 polypeptide and a second therapeutic composition comprises an ICI.

In some embodiments, the DR IL-18 polypeptide and ICI are fused into a single drug product.

Compositions Comprising DR IL-18 Polypeptides Provided herein, including for use in the methods described herein, are compositions comprising DR IL-18 polypeptides, i.e., DR IL-18 compositions. Useful DR IL-18 polypeptides, including DR IL-18 polypeptides useful in such DR IL-18 compositions, can vary.

In some embodiments, the DR IL-18 polypeptide has 60-100% sequence identity to any one of SEQ ID NOs:1-12. In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:1. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO:1. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO:1.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 2. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 2. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 2.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 3. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 3. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 3.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:4. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO:4. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO:4.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 5. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 5. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 5.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 6. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 6. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 6.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:7. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO:7. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO:7.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 8. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 8. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 8.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 9. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 9. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 9.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 10. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 10. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 10.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 11. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 11. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 11.

In some embodiments, the DR IL-18 polypeptide has at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 12. In some embodiments, the DR IL-18 polypeptide has about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, about 99%, or about 100% sequence identity to SEQ ID NO: 12. In some embodiments, the DR IL-18 polypeptide is SEQ ID NO: 12.

In some embodiments, the DR IL-18 polypeptide has mutations compared to wild-type (WT) IL-18. In some embodiments, the WT IL-18 is SEQ ID NO: 13. In some embodiments, the IL-18DR polypeptide has at least about two mutations, at least about three mutations, at least about four mutations, at least about five mutations, at least about six mutations, at least about seven mutations, at least about eight mutations, at least about nine mutations, or at least about 10 mutations compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the IL-18DR polypeptide has about two mutations, about three mutations, about four mutations, about five mutations, about six mutations, about seven mutations, about eight mutations, about nine mutations, or about 10 mutations compared to the WT IL-18 set forth in SEQ ID NO: 13.

In some embodiments, the IL-18DR polypeptide has a mutation at amino acid position C38 compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the IL-18DR polypeptide has a mutation at amino acid position C68 compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the IL-18DR polypeptide has mutations at amino acid positions C38 and C68 compared to the WT IL-18 set forth in SEQ ID NO: 13.

In some embodiments, the mutation at amino acid position C38 is a substitution mutation. In some embodiments, the mutation at amino acid position C38 is a C38S substitution relative to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a substitution mutation. In some embodiments, the mutation at amino acid position C68 is a C68S substitution, a C68G substitution, a C68A substitution, a C68V substitution, a C68D substitution, a C68E substitution, or a C68N substitution relative to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68S substitution relative to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68G substitution relative to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68A substitution relative to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68V substitution compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68D substitution compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68D substitution compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68E substitution compared to the WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the mutation at amino acid position C68 is a C68N substitution compared to the WT IL-18 set forth in SEQ ID NO: 13.

In some embodiments, the DR IL-18 polypeptide has at least one mutation (e.g., at least two, at least three, at least four, at least five, or at least six mutations) at an amino acid position selected from the group consisting of Y1, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, D110, N111, M113, V153, and N155 compared to WT IL-18 set forth in SEQ ID NO: 13. In some embodiments, the DR IL-18 polypeptide has at least four mutations relative to the WT IL-18 set forth in SEQ ID NO: 13 at amino acid positions selected from the group consisting of Y1, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, D110, N111, M113, V153, and N155. In some embodiments, the DR IL-18 polypeptide has at least six mutations relative to the WT IL-18 set forth in SEQ ID NO: 13 at amino acid positions selected from the group consisting of Y1, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, D110, N111, M113, V153, and N155. In some embodiments, the DR IL-18 polypeptide has at least one mutation (e.g., at least two, at least three, at least four, at least five, or at least six mutations) at an amino acid position selected from the group consisting of Y1, L5, K8, S55, Q56, P57, G59, E77, Q103, S105, D110, N111, M113, V153, and N155 relative to the WT IL-18 set forth in SEQ ID NO: 13. ... Compared to IL-18, Y1H, Y1R, LSH, L51, LSY, K8Q, K8R, M51T, M51K, M51D, M51N, M51E, M51R, K53R, K53G, K53S, K53T, S55K, S55R, Q56E, Q56A, Q56R, Q56V, Q56G, Q56K, Q56L, P57L, P57G, P57A, P57K, G59T, G59A, M60K, M60Q, M60R, M60L, E77D, Q103E, Q103K, Q103P, Q103A, Q103R, S105R, S105D, S105 The DR IL-18 polypeptide has at least one mutation (e.g., at least two, at least three, at least four, at least five, or at least six mutations) at an amino acid position selected from the group consisting of K, S105N, S105A, D110H, D110K, D110N, D110Q, D110E, D110S, D110G, N111H, N111Y, N111D, N111R, N111S, N111G, M113V, M113R, M113T, M113K, V1531, V153T, V153A, N155K, and N155H. Examples of mutations in the DR IL-18 polypeptide compared to WT IL-18 (SEQ ID NO: 13) are shown in Figure 1.

Decoy-resistant IL-18 polypeptides bind to and signal through the formation of the IL-18Rα (IL-18 receptor α) and IL-18Rβ (IL-18 receptor β) receptor complex. Decoy-resistant IL-18 polypeptides do not bind to IL-18BP or exhibit substantially reduced binding to IL-18BP, such as substantially reduced binding to IL-18BP compared to wild-type (WT) IL-18 (SEQ ID NO: 13) (i.e., compared to the binding of IL-18BP to WT IL-18 (SEQ ID NO: 13)). In some embodiments, DR IL-18 polypeptides do not bind to IL-18 binding protein (IL-18BP). In some embodiments, DR IL-18 polypeptides have reduced binding to IL-18BP compared to WT IL-18. In some embodiments, DR IL-18 polypeptides bind to IL-18Rα and do not bind to IL-18BP. In some embodiments, the DR IL-18 polypeptide binds to IL-18Rα and has reduced binding to IL-18BP compared to WT IL-18. In some embodiments, the DR IL-18 polypeptide is a monomer. In some embodiments, the monomer is not present in a protein complex. In some embodiments, the monomer functions as a single polypeptide. In some embodiments, the DR IL-18 polypeptide is unglycosylated. In some embodiments, the DR IL-18 polypeptide is glycosylated. In some embodiments, the DR IL-18 polypeptide is partially glycosylated. In some embodiments, the DR IL-18 polypeptide is at least about 50% glycosylated. In some embodiments, the DR IL-18 polypeptide is at most about 50% glycosylated.

In some embodiments, the DR IL-18 polypeptide accounts for 10% to about 50% of the IL-18 receptors. In some embodiments, the DR IL-18 polypeptide accounts for at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more of the IL-18 receptors. In some embodiments, the DR IL-18 polypeptide accounts for up to about 50%, up to about 45%, up to about 40%, up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, or less of the IL-18 receptors. In some embodiments, the DR IL-18 polypeptide occupies about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the IL-18 receptors.

In some embodiments, the composition comprises about 10 micrograms per kilogram (μg/kg) of DR IL-18 to about 1500 μg/kg of the subject's body weight. In some embodiments, the composition comprises about 10 μg/kg to about 20 μg/kg, about 20 μg/kg to about 30 μg/kg, about 30 μg/kg to about 40 μg/kg, about 40 μg/kg to about 50 μg/kg, about 50 μg/kg to about 60 μg/kg, about 60 kg/ug to about 70 μg/kg, about 70 μg/kg to about 80 μg/kg, about 80 kg/ug to about 90 μg/kg, about 90 μg/kg to about 100 μg/kg, about 100 μg/kg to about 150 μg/kg, about 150 μg/kg to about 200 μg/kg, about 200 μg/kg to about 250 μg/kg, about 250 μg/kg to about 300 μg/kg, about 300 μg/kg DR of about 550 μg/kg, about 350 μg/kg to about 400 μg/kg, about 400 μg/kg to about 450 μg/kg, about 450 μg/kg to about 500 μg/kg, about 500 μg/kg to about 600 μg/kg, about 600 μg/kg to about 700 μg/kg, about 700 μg/kg to about 800 μg/kg, about 800 μg/kg to about 900 μg/kg, about 900 μg/kg to about 1000 μg/kg, about 1000 μg/kg to about 1100 μg/kg, about 1200 μg/kg to about 1300 μg/kg, about 1300 μg/kg to about 1400 μg/kg, or about 1400 μg/kg to about 1500 μg/kg Contains IL-18 peptide.

In some embodiments, the composition provides a dose of at least about 10 μg/kg, at least about 20 μg/kg, at least about 30 μg/kg, at least about 40 μg/kg, at least about 50 μg/kg, at least about 60 μg/kg, at least about 70 μg/kg, at least about 80 μg/kg, at least about 90 μg/kg, at least about 100 μg/kg, at least about 110 μg/kg, at least about 120 μg/kg, at least about 130 μg/kg, at least about 140 μg/kg, at least about 150 μg/kg, at least about 160 μg/kg, at least about 170 μg/kg, at least about 180 μg/kg, at least about 190 μg/kg, at least about 200 μg/kg, at least about 210 μg/kg, at least about 220 μg/kg, at least about 230 μg/kg, at least about 240 μg/kg, at least about 250 μg/kg, at least about 260 μg/kg, at least about 270 μg/kg, at least about 280 μg/kg, at least about 290 μg/kg, at least about 300 μg/kg, at least about 310 μg/kg, at least about 320 μg/kg, at least about 330 μg/kg, at least about 340 μg/kg, at least about 350 μg/kg, at least about 360 μg/kg, at least about 370 μg/kg, at least about 380 μg/kg, at least about 390 μg/kg, at least about 400 μg/kg, at least about 410 μg/kg, at least about 420 μg/kg, at least about 43 μg/kg, at least about 140 μg/kg, at least about 150 μg/kg, at least about 160 μg/kg, at least about 170 μg/kg, at least about 180 μg/kg, at least about 190 μg/kg, at least about 200 μg/kg, at least about 210 μg/kg, at least about 220 μg/kg, at least about 230 μg/kg, at least about 240 μg/kg, at least about 250 μg/kg, at least about 260 μg/kg /kg, at least about 270 μg/kg, at least about 280 μg/kg, at least about 290 μg/kg, at least about 300 μg/kg, at least about 310 μg/kg, at least about 320 μg/kg, at least about 330 μg/kg, at least about 340 μg/kg, at least about 350 μg/kg, at least about 360 μg/kg, at least about 370 μg/kg, at least about 380 μg/kg, at least about 390 μg/kg g, at least about 400 μg/kg, at least about 500 μg/kg, at least about 600 μg/kg, at least about 700 μg/kg, at least about 800 μg/kg, at least about 900 μg/kg, at least about 1000 μg/kg, at least about 1100 μg/kg, at least about 1200 μg/kg, at least about 1300 μg/kg, at least about 1400 μg/kg, at least about 1500 μg/kg, or more of DR IL-18 polypeptide.

In some embodiments, the composition provides a steroid hormone at a dose of up to about 1500 μg/kg, up to about 1400 μg/kg, up to about 1300 μg/kg, up to about 1200 μg/kg, up to about 1100 μg/kg, up to about 1000 μg/kg, up to about 900 μg/kg, up to about 800 μg/kg, up to about 700 μg/kg, up to about 600 μg/kg, up to about 500 μg/kg, up to about 4 00 μg/kg, up to about 390 μg/kg, up to about 380 μg/kg, up to about 370 μg/kg, up to about 360 μg/kg, up to about 350 μg/kg, up to about 340 μg/kg, up to about 330 μg/kg, up to about 320 μg/kg, up to about 310 μg/kg, up to about 300 μg/kg, up to about 290 μg/kg, up to about 280 μg/kg, up to about 270 μg/kg g/kg, up to about 260 μg/kg, up to about 250 μg/kg, up to about 240 μg/kg, up to about 230 μg/kg, up to about 220 μg/kg, up to about 210 μg/kg, up to about 200 μg/kg, up to about 190 μg/kg, up to about 180 μg/kg, up to about 170 μg/kg, up to about 160 μg/kg, up to about 150 μg/kg, up to about 140 μg/kg g, up to about 130 μg/kg, up to about 120 μg/kg, up to about 110 μg/kg, up to about 100 μg/kg, up to about 90 μg/kg, up to about 80 μg/kg, up to about 70 μg/kg, up to about 60 μg/kg, up to about 50 μg/kg, up to about 40 μg/kg, up to about 30 μg/kg, up to about 20 μg/kg, up to about 10 μg/kg, or less of DR IL-18 polypeptide.

In some embodiments, the composition may be administered at a dose of about 10 μg/kg, about 20 μg/kg, about 30 μg/kg, about 40 μg/kg, about 50 μg/kg, about 60 μg/kg, about 70 μg/kg, about 80 μg/kg, about 90 μg/kg, about 100 μg/kg, about 110 μg/kg, about 120 μg/kg, about 130 μg/kg, about 140 μg/kg, about 150 μg/kg, about 160 μg/kg, about 170 μg/kg, about 180 μg/kg, about 190 μg/kg, about 200 μg/kg, about 210 μg/kg, about 220 μg/kg, about 230 μg/kg, about 240 μg/kg, about 250 μg/kg, or about 260 μg/kg. In some embodiments, the DR IL-18 polypeptide may be administered at about 270 μg/kg, about 280 μg/kg, about 290 μg/kg, about 300 μg/kg, about 310 μg/kg, about 320 μg/kg, about 330 μg/kg, about 340 μg/kg, about 350 μg/kg, about 360 μg/kg, about 370 μg/kg, about 380 μg/kg, about 390 μg/kg, about 400 μg/kg, about 500 μg/kg, about 600 μg/kg, about 700 μg/kg, about 800 μg/kg, about 900 μg/kg, about 1000 μg/kg, about 1100 μg/kg, about 1200 μg/kg, about 1300 μg/kg, about 1400 μg/kg, or about 1500 μg/kg.

In some embodiments, the composition comprises about 20 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 30 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 90 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 180 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 360 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 600 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 900 μg/kg of DR IL-18 polypeptide. In some embodiments, the composition comprises about 1200 μg/kg of DR IL-18 polypeptide per subject's body weight.

In some embodiments, the composition contains about 5 milligrams per milliliter (mg/ml) to about 50 mg/ml of DR IL-18 polypeptide. In some embodiments, the composition contains about 5 mg/ml to about 10 mg/ml, about 10 mg/ml to about 29 mg/ml, or 30 mg/ml to about 50 mg/ml of DR IL-18 polypeptide.

In some embodiments, the composition comprises at least about 5 mg/ml, at least about 6 mg/ml, at least about 7 mg/ml, at least about 8 mg/ml, at least about 9 mg/ml, at least about 10 mg/ml, at least about 11 mg/ml, at least about 12 mg/ml, at least about 13 mg/ml, at least about 14 mg/ml, at least about 15 mg/ml, at least about 16 mg/ml, at least about 17 mg/ml, at least about 18 mg/ml, at least about 19 mg/ml, at least about 20 mg/ml, at least about 21 mg/ml, at least about 22 mg/ml, at least about 23 mg/ml, at least about 24 mg/ml, at least about 25 mg/ml, at least about 26 mg/ml, at least about 27 mg/ml , at least about 28 mg/ml, at least about 29 mg/ml, at least about 30 mg/ml, at least about 31 mg/ml, at least about 32 mg/ml, at least about 33 mg/ml, at least about 34 mg/ml, at least about 35 mg/ml, at least about 36 mg/ml, at least about 37 mg/ml, at least about 38 mg/ml, at least about 39 mg/ml, at least about 40 mg/ml, at least about 41 mg/ml, at least about 42 mg/ml, at least about 43 mg/ml, at least about 44 mg/ml, at least about 45 mg/ml, at least about 46 mg/ml, at least about 47 mg/ml, at least about 48 mg/ml, at least about 49 mg/ml, at least about 50 mg/ml, or more of DR IL-18 polypeptide.

In some embodiments, the composition has a concentration of at most about 50 mg/ml, at most about 49 mg/ml, at most about 49 mg/ml, at most about 48 mg/ml, at most about 47 mg/ml, at most about 46 mg/ml, at most about 45 mg/ml, at most about 44 mg/ml, at most about 43 mg/ml, at most about 43 mg/ml, at most about 42 mg/ml, at most about 41 mg/ml, at most about 40 mg/ml, at most about 39 mg/ml, at most about 38 mg/ml, at most about 37 mg/ml, at most about 36 mg/ml, at most about 35 mg/ml, at most about 34 mg/ml, at most about 33 mg/ml, at most about 32 mg/ml, at most about 31 mg/ml, at most about 30 mg/ml, at most about 29 mg/ml, mg/ml, up to about 28 mg/ml, up to about 27 mg/ml, up to about 26 mg/ml, up to about 25 mg/ml, up to about 24 mg/ml, up to about 23 mg/ml, up to about 22 mg/ml, up to about 21 mg/ml, up to about 20 mg/ml, up to about 19 mg/ml, up to about 18 mg/ml, up to about 17 mg/ml, up to about 16 mg/ml, up to about 15 mg/ml, up to about 14 mg/ml, up to about 13 mg/ml, up to about 12 mg/ml, up to about 11 mg/ml, up to about 10 mg/ml, up to about 9 mg/ml, up to about 8 mg/ml, up to about 7 mg/ml, up to about 6 mg/ml, up to about 5 mg/ml, or less of DR IL-18 polypeptide.

In some embodiments, the composition contains about 5 mg/ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, about 10 mg/ml, about 11 mg/ml, about 12 mg/ml, about 13 mg/ml, about 14 mg/ml, about 15 mg/ml, about 16 mg/ml, about 17 mg/ml, about 18 mg/ml, about 19 mg/ml, about 20 mg/ml, about 21 mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 mg/ml, about 26 mg/ml, about 27 mg/ml , about 28 mg/ml, about 29 mg/ml, about 30 mg/ml, about 31 mg/ml, about 32 mg/ml, about 33 mg/ml, about 34 mg/ml, about 35 mg/ml, about 36 mg/ml, about 37 mg/ml, about 38 mg/ml, about 39 mg/ml, about 40 mg/ml, about 41 mg/ml, about 42 mg/ml, about 43 mg/ml, about 44 mg/ml, about 45 mg/ml, about 46 mg/ml, about 47 mg/ml, about 48 mg/ml, about 49 mg/ml, about 50 mg/ml, or more of DR IL-18 polypeptide.

Formulations The compositions of the present disclosure useful in the methods of the present disclosure may be formulated with a DR IL-18 polypeptide described herein, one or more ICIs, or both a DR IL-18 polypeptide and one or more ICIs. The compositions of the present disclosure may include one or more formulating agents, including, for example, a buffering agent, a stabilizer, a surfactant, an antioxidant, a solvent, or any combination thereof.

In some embodiments, in addition to the amount of DR IL-18 polypeptide, the amount of one or more ICIs, or an amount of both, the composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from the group consisting of: L-histidine, L-histidine hydrochloride, phosphate, Tris, citrate, glycine, diethanolamine (DEA), and any combination thereof. In some embodiments, the buffering agent is L-histidine. In some embodiments, the buffering agent is L-histidine hydrochloride. In some embodiments, the buffering agent is L-histidine and L-histidine hydrochloride.

In some embodiments, the composition comprises about 1 mg/ml to about 2 mg/ml, about 1 mg/ml to about 5 mg/ml, about 5 mg/ml to about 10 mg/ml, about 10 mg/ml to about 20 mg/ml, about 20 mg/ml to about 30 mg/ml, about 30 mg/ml to about 40 mg/ml, or about 40 mg/ml to about 50 mg/ml of buffer. In some embodiments, the composition comprises at least about 1 mg/ml, at least about 2 mg/ml, at least about 3 mg/ml, at least about 4 mg/ml, at least about 5 mg/ml, at least about 6 mg/ml, at least about 7 mg/ml, at least about 8 mg/ml, at least about 9 mg/ml, at least about 10 mg/ml, at least about 15 mg/ml, at least about 20 mg/ml, at least about 25 mg/ml, at least about 30 mg/ml, at least about 35 mg/ml, at least about 40 mg/ml, at least about 45 mg/ml, at least about 50 mg/ml, or more, of buffering agent.

In some embodiments, the composition comprises up to about 50 mg/ml, up to about 45 mg/ml, up to about 40 mg/ml, up to about 35 mg/ml, up to about 30 mg/ml, up to about 35 mg/ml, up to about 30 mg/ml, up to about 25 mg/ml, up to about 20 mg/ml, up to about 15 mg/ml, up to about 10 mg/ml, up to about 9 mg/ml, up to about 8 mg/ml, up to about 7 mg/ml, up to about 6 mg/ml, up to about 5 mg/ml, up to about 4 mg/ml, up to about 3 mg/ml, up to about 2 mg/ml, up to about 1 mg/ml, or less of buffer. In some embodiments, the composition comprises about 1 mg/ml, about 2 mg/ml, about 3 mg/ml, about 4 mg/ml, about 5 mg/ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, or about 50 mg/ml of buffer.

In some embodiments, in addition to the amount of DR IL-18 polypeptide, the amount of one or more ICIs, or both, the composition further comprises a stabilizer. In some embodiments, the stabilizer is selected from the group consisting of glycerol, sucrose, glucose, trehalose, ethylene glycol, glycerol, erythritol, threitol, arabitol, ethylenediaminetetraacetic acid (EDTA), disodium salt of EDTA, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetritol, polyglycitol, and any combination thereof. In some embodiments, the stabilizer is sucrose. In some embodiments, the stabilizer is EDTA. In some embodiments, the stabilizer is disodium salt of EDTA. In some embodiments, the stabilizer comprises sucrose and EDTA. In some embodiments, the stabilizer comprises sucrose and disodium salt of EDTA. In some embodiments, the stabilizer comprises EDTA and the disodium salt of EDTA. In some embodiments, the stabilizer comprises sucrose, EDTA, and the disodium salt of EDTA.

In some embodiments, the composition comprises from about 20 mg/ml to about 200 mg/ml of stabilizer. In some embodiments, the composition comprises from about 20 mg/ml to about 30 mg/ml, from about 30 mg/ml to about 40 mg/ml, from about 40 mg/ml to about 50 mg/ml, from about 50 mg/ml to about 60 mg/ml, from about 60 mg/ml to about 99 mg/ml, from about 60 mg/ml to about 70 mg/ml, from about 70 mg/ml to about 99 mg/ml, from about 70 mg/ml to about 80 mg/ml, from about 90 mg/ml to about 100 mg/ml, from about 100 mg/ml to about 110 mg/ml. 0 mg/ml, about 110 mg/ml to about 120 mg/ml, about 120 mg/ml to about 130 mg/ml, about 130 mg/ml to about 140 mg/ml, about 140 mg/ml to about 150 mg/ml, about 150 mg/ml to about 160 mg/ml, about 160 mg/ml to about 170 mg/ml, about 170 mg/ml to about 180 mg/ml, about 180 mg/ml to about 190 mg/ml, and about 190 mg/ml to about 200 mg/ml of stabilizer.

In some embodiments, the composition comprises at least about 20 mg/ml, at least about 25 mg/ml, at least about 30 mg/ml, at least about 35 mg/ml, at least about 40 mg/ml, at least about 45 mg/ml, at least about 50 mg/ml, at least about 55 mg/ml, at least about 60 mg/ml, at least about 65 mg/ml, at least about 70 mg/ml, at least about 71 mg/ml, at least about 72 mg/ml, at least about 73 mg/ml, at least about 73 mg/ml, at least about 74 mg/ml, at least about 75 mg/ml, at least about 76 mg/ml, at least about 77 mg/ml, at least about 78 mg/ml, at least about 79 mg/ml, at least about 80 mg/ml, at least about 81 mg/ml, at least about 82 mg/ml, at least about 83 mg/ml, at least about 84 mg/ml, at least about 85 mg/ml, at least about 86 mg/ml, at least about 87 mg/ml, at least about 88 mg/ml, at least about 89 mg/ml, at least about 90 mg/ml, at least about 91 mg/ml, at least about 92 mg/ml, at least about 93 mg/ml, at least about 94 mg/ml, at least about 95 mg/ml, at least about 96 mg/ml, at least about 97 mg/ml, at least about 98 mg/ml, at least about 99 mg/ml, at least about 100 mg/ml, at least about 102 mg/ml, at least about 103 mg/ml, at least about 104 mg/ml, at least about 105 mg/ml, at least about 106 mg/ml, at least about 107 mg/ml, at least about 108 mg/ml, at least about 10 Also contains about 85 mg/ml, at least about 86 mg/ml, at least about 87 mg/ml, at least about 88 mg/ml, at least about 89 mg/ml, at least about 90 mg/ml, at least about 91 mg/ml, at least about 92 mg/ml, at least about 93 mg/ml, at least about 94 mg/ml, at least about 95 mg/ml, at least about 96 mg/ml, at least about 97 mg/ml, at least about 98 mg/ml, at least about 99 mg/ml, at least about 100 mg/ml, at least about 110 mg/ml, at least about 120 mg/ml, at least about 130 mg/ml, at least about 140 mg/ml, at least about 150 mg/ml, at least about 160 mg/ml, at least about 170 mg/ml, at least about 180 mg/ml, at least about 190 mg/ml, at least about 200 mg/ml, or more of stabilizer.

In some embodiments, the composition has a concentration of at most about 200 mg/ml, at most about 190 mg/ml, at most about 180 mg/ml, at most about 170 mg/ml, at most about 160 mg/ml, at most about 150 mg/ml, at most about 140 mg/ml, at most about 130 mg/ml, at most about 120 mg/ml, at most about 110 mg/ml, at most about 100 mg/ml, at most about 99 mg/ml, at most about 98 mg/ml, at most about 97 mg/ml, at most about 96 mg/ml, at most about 95 mg/ml, at most about 94 mg/ml, at most about 93 mg/ml, at most about 92 mg/ml, at most about 91 mg/ml, at most about 90 mg/ml, at most about 89 mg/ml, at most about 88 mg/ml, at most about 87 mg/ml, or at most about 86 mg/ml. , up to about 85 mg/ml, up to about 84 mg/ml, up to about 83 mg/ml, up to about 82 mg/ml, up to about 81 mg/ml, up to about 80 mg/ml, up to about 79 mg/ml, up to about 78 mg/ml, up to about 77 mg/ml, up to about 76 mg/ml, up to about 75 mg/ml, up to about 74 mg/ml, up to about 73 mg/ml, up to about 72 mg/ml, up to about 71 mg/ml, up to about 70 mg/ml, up to about 65 mg/ml, up to about 60 mg/ml, up to about 55 mg/ml, up to about 50 mg/ml, up to about 45 mg/ml, up to about 40 mg/ml, up to about 35 mg/ml, up to about 30 mg/ml, up to about 25 mg/ml, up to about 20 mg/ml, or less of a stabilizer.

In some embodiments, the composition may comprise about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 71 mg/ml, about 72 mg/ml, about 73 mg/ml, about 74 mg/ml, about 75 mg/ml, about 76 mg/ml, about 77 mg/ml, about 78 mg/ml, about 79 mg/ml, about 80 mg/ml, about 81 mg/ml, about 82 mg/ml, about 83 mg/ml, about 84 mg/ml, about 85 mg/ml, Contains about 86 mg/ml, about 87 mg/ml, about 88 mg/ml, about 89 mg/ml, about 90 mg/ml, about 91 mg/ml, about 92 mg/ml, about 93 mg/ml, about 94 mg/ml, about 95 mg/ml, about 96 mg/ml, about 97 mg/ml, about 98 mg/ml, about 99 mg/ml, about 100 mg/ml, about 110 mg/ml, about 120 mg/ml, about 130 mg/ml, about 140 mg/ml, about 150 mg/ml, about 160 mg/ml, about 170 mg/ml, about 180 mg/ml, about 190 mg/ml, or about 100 mg/ml of stabilizer.

In some embodiments, in addition to an amount of DR IL-18 polypeptide, an amount of one or more ICIs, or an amount of both, the composition further comprises a surfactant. In some embodiments, the surfactant is an anionic surfactant. Non-limiting examples of anionic surfactants include docusate, perfluorooctane sulfonate, perfluorobutane sulfonate, alkyl aryl phosphate esters, and alkyl phosphate esters. In some embodiments, the surfactant is a cationic surfactant. Non-limiting examples of cationic surfactants include cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide. In some embodiments, the surfactant is a nonionic surfactant. Non-limiting examples of nonionic surfactants include octaethylene glycol monododecyl ether, Triton X-100, polyethoxylated tallowamine, cocamide monoethanolamine, poloxamer, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, Tween 20, Tween 80, decyl glucoside, octyl glucoside, and polysorbate 80. In some embodiments, the surfactant is polysorbate 80.

In some embodiments, the composition comprises 0.01 mg/ml to about 10 mg/ml of surfactant. In some embodiments, the composition comprises between about 0.01 mg/ml to about 0.5 mg/ml, about 0.01 mg/ml to about 1 mg/ml, about 0.01 mg/ml to about 5 mg/ml, about 0.5 mg/ml to about 1 mg/ml, about 1 mg/ml to about 5 mg/ml, or about 5 mg/ml to about 10 mg/ml of surfactant.

In some embodiments, the composition comprises at least about 0.01 mg/ml, at least about 0.05 mg/ml, at least about 0.1 mg/ml, at least about 0.2 mg/ml, at least about 0.3 mg/ml, at least about 0.4 mg/ml, at least about 0.5 mg/ml, at least about 0.6 mg/ml, at least about 0.7 mg/ml, at least about 0.8 mg/ml, at least about 0.9 mg/ml, at least about 1 mg/ml, at least about 2 mg/ml, at least about 3 mg/ml, at least about 4 mg/ml, at least about 5 mg/ml, at least about 6 mg/ml, at least about 7 mg/ml, at least about 8 mg/ml, at least about 9 mg/ml, at least about 10 mg/ml, or more of the surfactant. In some embodiments, the composition comprises at most about 10 mg/ml, at most about 9 mg/ml, at most about 8 mg/ml, at most about 7 mg/ml, at most about 6 mg/ml, at most about 5 mg/ml, at most about 4 mg/ml, at most about 3 mg/ml, at most about 2 mg/ml, at most about 1 mg/ml, at most about 0.9 mg/ml, at most about 0.8 mg/ml, at most about 0.7 mg/ml, at most about 0.6 mg/ml, at most about 0.5 mg/ml, at most about 0.4 mg/ml, at most about 0.3 mg/ml, at most about 0.2 mg/ml, at most about 0.1 mg/ml, at most about 0.05 mg/ml, at most about 0.01 mg/ml, or less, of surfactant.

In some embodiments, the composition comprises about 0.01 mg/ml, about 0.05 mg/ml, about 0.1 mg/ml, about 0.2 mg/ml, about 0.3 mg/ml, about 0.4 mg/ml, about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1 mg/ml, about 2 mg/ml, about 3 mg/ml, about 4 mg/ml, about 5 mg/ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, or about 10 mg/ml of surfactant.

In some embodiments, in addition to the amount of DR IL-18 polypeptide, the amount of one or more ICIs, or the amount of both, the composition further comprises an antioxidant. In some embodiments, the antioxidant is selected from the group consisting of ascorbic acid, glutathione, lipoic acid, uric acid, carotene, α-tocopherol, ubiquinol, and L-methionine. In some embodiments, the antioxidant is L-methionine.

In some embodiments, the composition contains about 0.01 mg/ml to about 10 mg/ml of antioxidant. In some embodiments, the composition contains about 0.01 mg/ml to about 0.5 mg/ml, about 0.01 mg/ml to about 1 mg/ml, about 0.01 mg/ml to about 5 mg/ml, about 0.5 mg/ml to about 1 mg/ml, about 1 mg/ml to about 5 mg/ml, or about 5 mg/ml to about 10 mg/ml of antioxidant.

In some embodiments, the composition comprises at least about 0.01 mg/ml, at least about 0.05 mg/ml, at least about 0.1 mg/ml, at least about 0.15 mg/ml, at least about 0.2 mg/ml, at least about 0.25 mg/ml, at least about 0.3 mg/ml, at least about 0.35 mg/ml, at least about 0.4 mg/ml, at least about 0.45 mg/ml, at least about 0.5 mg/ml, at least about 0.55 mg/ml, at least about 0.6 mg/ml, at least about 0.65 mg/ml, or at least about 0.65 mg/ml. In some embodiments, the antioxidant may be at least about 0.7 mg/ml, at least about 0.75 mg/ml, at least about 0.8 mg/ml, at least about 0.85 mg/ml, at least about 0.9 mg/ml, at least about 0.95 mg/ml, at least about 1 mg/ml, at least about 2 mg/ml, at least about 3 mg/ml, at least about 4 mg/ml, at least about 5 mg/ml, at least about 6 mg/ml, at least about 7 mg/ml, at least about 8 mg/ml, at least about 9 mg/ml, at least about 10 mg/ml, or more. In some embodiments, the composition has a concentration of up to about 10 mg/ml, up to about 9 mg/ml, up to about 8 mg/ml, up to about 7 mg/ml, up to about 6 mg/ml, up to about 5 mg/ml, up to about 4 mg/ml, up to about 3 mg/ml, up to about 2 mg/ml, up to about 1 mg/ml, up to about 0.95 mg/ml, up to about 0.9 mg/ml, up to about 0.85 mg/ml, up to about 0.8 mg/ml, up to about 0.75 mg/ml, up to about 0.7 mg/ml, 1, up to about 0.65 mg/ml, up to about 0.6 mg/ml, up to about 0.55 mg/ml, up to about 0.5 mg/ml, up to about 0.45 mg/ml, up to about 0.4 mg/ml, up to about 0.35 mg/ml, up to about 0.3 mg/ml, up to about 0.25 mg/ml, up to about 0.2 mg/ml, up to about 0.15 mg/ml, up to about 0.1 mg/ml, up to about 0.05 mg/ml, up to about 0.01 mg/ml, or less of antioxidants.

In some embodiments, the composition comprises 0.01 mg/ml, about 0.05 mg/ml, about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, 0.9 mg/ml, about 0.95 mg/ml, about 1 mg/ml, about 2 mg/ml, about 3 mg/ml, about 4 mg/ml, about 5 mg/ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, or about 10 mg/ml of antioxidant.

In some embodiments, in addition to the amount of DR IL-18 polypeptide, the amount of one or more ICIs, or both, the composition further comprises a solvent. Non-limiting examples of solvents include water, ethanol, methanol, acetone, tetrachloroethylene, toluene, methyl acetate, and ethyl acetate. In some embodiments, the solvent is water. In some embodiments, the composition comprises from about 0 mg/ml to about 10 mg/ml of solvent. In some embodiments, the composition comprises from about 0 mg/ml to about 5 mg/ml, or from about 5 mg/ml to about 10 mg/ml of solvent. In some embodiments, the composition comprises at least about 0.01 mg/ml, at least about 0.05 mg/ml, at least about 0.1 mg/ml, at least about 0.15 mg/ml, at least about 0.2 mg/ml, at least about 0.25 mg/ml, at least about 0.3 mg/ml, at least about 0.35 mg/ml, at least about 0.4 mg/ml, at least about 0.45 mg/ml, at least about 0.5 mg/ml, at least about 0.55 mg/ml, at least about 0.6 mg/ml, at least about 0.65 mg/ml ml, at least about 0.7 mg/ml, at least about 0.75 mg/ml, at least about 0.8 mg/ml, at least about 0.85 mg/ml, at least about 0.9 mg/ml, at least about 0.95 mg/ml, at least about 1 mg/ml, at least about 2 mg/ml, at least about 3 mg/ml, at least about 4 mg/ml, at least about 5 mg/ml, at least about 6 mg/ml, at least about 7 mg/ml, at least about 8 mg/ml, at least about 9 mg/ml, or at least about 10 mg/ml of solvent.

In some embodiments, the composition has a concentration of at most about 10 mg/ml, at most about 9 mg/ml, at most about 8 mg/ml, at most about 7 mg/ml, at most about 6 mg/ml, at most about 5 mg/ml, at most about 4 mg/ml, at most about 3 mg/ml, at most about 2 mg/ml, at most about 1 mg/ml, at most about 0.95 mg/ml, at most about 0.9 mg/ml, at most about 0.85 mg/ml, at most about 0.8 mg/ml, at most about 0.75 mg/ml, at most about 0.7 mg/ml, or at most about 0.8 mg/ml. ml, up to about 0.65 mg/ml, up to about 0.6 mg/ml, up to about 0.55 mg/ml, up to about 0.5 mg/ml, up to about 0.45 mg/ml, up to about 0.4 mg/ml, up to about 0.35 mg/ml, up to about 0.3 mg/ml, up to about 0.25 mg/ml, up to about 0.2 mg/ml, up to about 0.15 mg/ml, up to about 0.1 mg/ml, up to about 0.05 mg/ml, up to about 0.01 mg/ml, or less of solvent.

In some embodiments, the composition comprises about 0.01 mg/ml, about 0.05 mg/ml, about 0.1 mg/ml, about 0.15 mg/ml, about 0.2 mg/ml, about 0.25 mg/ml, about 0.3 mg/ml, about 0.35 mg/ml, about 0.4 mg/ml, about 0.45 mg/ml, about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml, about 0.75 mg/ml, about 0.8 mg/ml, about 0.85 mg/ml, about 0.9 mg/ml, about 0.95 mg/ml, about 1 mg/ml, about 2 mg/ml, about 3 mg/ml, about 4 mg/ml, about 5 mg/ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, or about 10 mg/ml of solvent.

Compositions Comprising Immune Checkpoint Inhibitors One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide; and (b) an ICI, wherein the ICI is not pembrolizumab. In some embodiments, the ICI is an antagonist. In some embodiments, the ICI is a binding antagonist that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3. In some embodiments, the ICI is an immunoadhesin. In some embodiments, the binding antagonist is an antibody or antigen-binding fragment thereof. In some embodiments, the antibody is a monoclonal antibody.

In some embodiments, the ICI is a PD-1 checkpoint inhibitor. In some embodiments, the PD-1 checkpoint inhibitor is a PD-1 antagonist (e.g., aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, iparomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, pemprimab). In some embodiments, the ICI is an anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody is monoclonal.

In some embodiments, the PD-1 checkpoint inhibitor is a PD-L1 antagonist (e.g., adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiblimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333). In some embodiments, the ICI is an anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-L1 antibody is monoclonal.

In some embodiments, the immune checkpoint or PD-1 checkpoint inhibitor is a PD-L2 antagonist. In some embodiments, the ICI is an immunoadhesin. In some embodiments, the ICI is an anti-PD-L2 antibody or antigen-binding fragment thereof. In some embodiments, the anti-PD-L2 antibody is monoclonal.

In some embodiments, the ICI is a CTLA-4 antagonist (e.g., botencilimab, evalstuzumab, filastuzumab, gotistozumab, ipilimumab, muzastozug, nurlimab, polstuzumab, quavonlimab, sovipostozumab, tremelimumab, tubonlarimab, vilastozumab, or zalifrelimab). In some embodiments, the ICI is an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-CTLA-4 antibody is monoclonal.

In some embodiments, the ICI is a LAG-3 antagonist (e.g., encelimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, leratolimab, and tuparstbalt). In some embodiments, the ICI is an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody is monoclonal.

In some embodiments, the ICI is a B7-H3 antagonist (e.g., enoblitutumab, ifinatamab, mirzotamab, omburtamab, or vovlamitamab). In some embodiments, the ICI is an anti-B7-H3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-B7-H3 antibody is monoclonal.

In some embodiments, the ICI is selected from the group consisting of gimverelimab, nivolumab, cemiplimab, dostarimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, pidilizumab, MEDI0680, SSI-361, AMP-224, cetrelimab, prorugolimab, retifanlimab, and atezolizumab. Selected from the group consisting of uzumab, avelumab, durvalumab, embafolimab, cosibelimab, CA-170, BMS-986189, BMS-936559, sugemalimab, adebrelimab, CBT-502, BGB-A333, pacmilimab, ipilimumab, tremelimumab, relatolimab, enoblitutuzumab, and variants of any of the foregoing.

In some embodiments, the ICI is aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, prodrug Rugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimvelerimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durba lumab, embafolimab, galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstotsug, filastotsug, gothistotsug, ipilimumab, muzastotsug, nurlimab, polstotsug The compound is selected from the group consisting of quabonlimab, sobipostobart, tremelimumab, tubonlarimab, vilastobart, zalifrelimab, enselimab, favezelimab, fianlimab, yeramilimab, miptenalimab, negallastobart, relatolimab, tuparlastobart, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and variants of any of the foregoing.

One aspect of the present disclosure provides a therapeutic composition comprising (a) a DR IL-18 polypeptide and (b) a PD-L1 or PD-L2 antagonist. In some embodiments, the PD-L1 or PD-L2 antagonist is selected from the group consisting of adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiburimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.

In some embodiments, the therapeutic composition comprises a solution in which the ICI is diluted to a solution concentration of at least about 1-250 mg/mL, about 1-10 mg/mL, 10-20 mg/mL, 20-30 mg/mL, 30-40 mg/mL, 40-50 mg/mL, 50-75 mg/mL, 75-100 mg/mL, 100-150 mg/mL, or 150-250 mg/mL.

In some embodiments, the therapeutic composition comprises a solution of ICI at at least about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 12 mg/mL, about 14 mg/mL, about 16 mg/mL, about 18 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 200 mg/mL, or about 250 mg/mL.

In some embodiments, the therapeutic composition may be administered in a concentration of about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, The ratio of ICI to DR IL-18 polypeptide is about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 mg.

In some embodiments, the therapeutic composition comprises at least about 5-1600 mg, at least about 5-10 mg, at least about 10-20 mg, at least about 20-40 mg, at least about 40-60 mg, at least about 60-80 mg, at least about 80-100 mg, at least about 100-200 mg, at least about 200-300 mg, at least about 300-400 mg, at least about 400-500 mg, at least about 500-600 mg, at least about 700-800 mg, at least about 800-900 mg, at least about 900-1000 mg, at least about 1000-1200 mg, at least about 1200-1400 mg, or at least about 1400-1600 mg of ICI.

In some embodiments, the therapeutic composition comprises at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 4 The ICI may be at least about 40 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, at least about 640 mg, at least about 680 mg, at least about 720 mg, at least about 760 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 920 mg, at least about 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1080 mg, at least about 1120 mg, at least about 1160 mg, at least about 1200 mg, at least about 1280 mg, at least about 1360 mg, at least about 1440 mg, at least about 1520 mg, or at least about 1600 mg.

In some embodiments, the therapeutic composition further comprises axitinib or lenvatinib. In some embodiments, the therapeutic composition further comprises 5 mg of axitinib. In some embodiments, the therapeutic composition further comprises 20 mg of lenvatinib.

One aspect of the present disclosure is a therapeutic composition comprising (a) a DR IL-18 polypeptide and (b) one or more of the following: gimverelimab, nivolumab, cemiplimab, dostarimab, vopratelimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, pidilizumab, MEDI0680, SSI-361, AMP-224, cetrelimab, prorugolimab, retifanlimab, atezolizumab, avelumab, A therapeutic composition is provided, comprising an ICI selected from the group consisting of durvalumab, embafolimab, cosibelimab, CA-170, BMS-986189, BMS-936559, sugemalimab, adebrelimab, CBT-502, BGB-A333, pacmilimab, ipilimumab, tremelimumab, relatolimab, enoblituzumab, and variants of any of the foregoing.

One aspect of the present disclosure is a therapeutic composition comprising (a) a DR IL-18 polypeptide and (b) one or more of the following: aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, or prorugolimab. , pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimvelerimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embaholima , galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, suduplilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstotsug, filastotsug, gothistotsug, ipilimumab, muzastotsug, nurlimab, polstotsug, quavonlimab, sovipos and an ICI selected from the group consisting of thiamin monophosphate, tremelimumab, tubolalimab, bilastovalt, zalifrelimab, enselimab, favezelimab, fianlimab, yeramilimab, miptenalimab, negallastovalt, relatolimab, tuparstovalt, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and variants of any of the foregoing.

Compositions Comprising Additional Therapies The present disclosure provides compositions, including compositions useful for combination therapy, such as a DR IL-18 composition comprising a DR IL-18 polypeptide and an ICI composition comprising an ICI, wherein the ICI is not pembrolizumab. In addition to the DR IL-18 composition and the ICI composition, the present disclosure further provides compositions for administering one or more additional therapies to a subject. Useful additional therapeutic compositions include prophylactic therapeutic compositions that, when administered to a subject, prevent and/or reduce the manifestation of CRS symptoms when the subject is administered the DR IL-18 composition or the DR IL-18 composition and the ICI composition. The compositions of the present disclosure may be formulated separately, for example, a DR IL-18 composition formulated separately from an ICI composition that is formulated separately from an additional therapeutic composition or a CRS prophylactic composition. The compositions of the present disclosure may be co-formulated, for example, a DR-IL18 composition co-formulated with an ICI composition, a DR-IL18 composition co-formulated with an additional therapeutic or CRS-preventing composition, an ICI composition co-formulated with an additional therapeutic or CRS-preventing composition, or a DR-IL18 composition co-formulated with an ICI composition co-formulated with an additional therapeutic or CRS-preventing composition.

One aspect of the present disclosure provides a therapeutic composition comprising: (a) a DR IL-18 polypeptide administered to a subject; (b) an ICI administered to the subject, where the ICI is not pembrolizumab; and (c) an additional therapy. In some embodiments, the additional therapy is a prophylactic agent. In some embodiments, the additional therapy reduces the manifestation of symptoms of cytokine release syndrome (CRS). In some embodiments, the therapeutic composition is for use in treating cancer, and the additional therapy comprises one or more CRS prophylactic agents and provides CRS prophylaxis that reduces the manifestation of symptoms of CRS.

In some embodiments, a single therapeutic composition comprises a prophylactic agent, a DR IL-18 polypeptide, and an ICI. In some embodiments, two or more therapeutic compositions comprise a prophylactic agent, a DR IL-18 polypeptide, and an ICI.

In some embodiments, the additional therapy is a drug or drugs selected from the group consisting of an NSAID, acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, and an H2 blocker. In some embodiments, the additional therapy is a drug or drugs selected from the group consisting of an NSAID, acetaminophen, diphenhydramine, a histamine H1 antagonist, famotidine, an H2 blocker, tocilizumab, and any combination thereof.

In some embodiments, the compositions of the present disclosure include an additional therapeutic agent, such as a CRS prophylactic agent, that is an NSAID. In some embodiments, the NSAID includes indomethacin or ibuprofen. In some embodiments, the indomethacin is formulated to allow administration to a subject of 25 mg three times daily. In some embodiments, the ibuprofen is formulated to allow administration to a subject of 200 mg to 600 mg every 6 to 8 hours. In some embodiments, the NSAID is formulated for oral administration. In some embodiments, the NSAID is formulated for intravenous administration.

Non-limiting examples of useful NSAIDs include ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, rofecoxib, valdecoxib, celecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin. In some embodiments, the NSAID is ibuprofen. In some embodiments, the NSAID is indomethacin. In some embodiments, the NSAID is naproxen. In some embodiments, the NSAID is aspirin. In some embodiments, the NSAID is from about 25 mg to about 600 mg. In some embodiments, the NSAID is about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, about 250 mg to about 275 mg, about 275 mg to about 300 mg, about 3 In some embodiments, the NSAID is about 200 mg to about 325 mg, about 325 mg to about 350 mg, about 350 mg to about 375 mg, about 375 mg to about 400 mg, about 400 mg to about 425 mg, about 425 mg to about 450 mg, about 450 mg to about 475 mg, about 475 mg to about 500 mg, about 500 mg to about 525 mg, about 525 mg to about 550 mg, about 550 mg to about 575 mg, or 575 mg to about 600 mg. In some embodiments, the NSAID is about 200 mg to about 600 mg.

In some embodiments, the NSAID is at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 225 mg, at least about 250 mg, at least about 275 mg, at least about 300 mg, at least about 325 mg, at least about 350 mg, at least about 375 mg, at least about 400 mg, at least about 425 mg, at least about 450 mg, at least about 475 mg, at least about 500 mg, at least about 525 mg, at least about 550 mg, at least about 575 mg, at least about 600 mg, or more.

In some embodiments, the NSAID is at most about 600 mg, at most about 575 mg, at most about 550 mg, at most about 525 mg, at most about 500 mg, at most about 475 mg, at most about 450 mg, at most about 425 mg, at most about 400 mg, at most about 375 mg, at most about 350 mg, at most about 325 mg, at most about 300 mg, at most about 275 mg, at most about 250 mg, at most about 225 mg, at most about 200 mg, at most about 175 mg, at most about 150 mg, at most about 125 mg, at most about 100 mg, at most about 75 mg, at most about 50 mg, at most about 25 mg, or less.

In some embodiments, the NSAID is about 25 mg, 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, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

In some embodiments, the compositions of the present disclosure include an additional therapeutic agent, such as a CRS preventative agent that is acetaminophen. In some embodiments, the acetaminophen is administered to a subject at 650 mg every 4 to 6 hours. In some embodiments, the acetaminophen is formulated to allow administration to a subject of 650 mg every 4 to 6 hours, beginning 1 hour before administration of a single dose of the DR IL-18 composition. In some embodiments, the acetaminophen is formulated for continuous administration for at least 48 hours after administration of a dose of the DR IL-18 composition. In some embodiments, the acetaminophen is formulated for oral administration. In some embodiments, the acetaminophen is formulated for intravenous administration.

In some embodiments, the acetaminophen is from about 200 mg to about 800 mg. In some embodiments, the acetaminophen is from about 600 mg to about 800 mg.

In some embodiments, the acetaminophen is at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, or more. In some embodiments, the acetaminophen is at most about 800 mg, at most about 750 mg, at most about 700 mg, at most about 650 mg, at most about 600 mg, at most about 550 mg, at most about 500 mg, at most about 450 mg, at most about 400 mg, at most about 350 mg, at most about 300 mg, at most about 250 mg, at most about 200 mg, or less. In some embodiments, the acetaminophen is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, the acetaminophen is about 650 mg.

In some embodiments, the compositions of the present disclosure include an additional therapeutic agent, such as a CRS preventative agent, that is a histamine H1 antagonist. In some embodiments, the histamine H1 antagonist is formulated for administration to a subject of about 50 mg. In some embodiments, the histamine H1 antagonist is formulated for intravenous administration. In some embodiments, the histamine H1 antagonist is formulated for oral administration.

Non-limiting examples of histamine H1 antagonists include brompheniramine, clemastine, dexchlorpheniramine dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine, mepyramine, chlorpheniramine, promethazine, and cyproheptadine. In some embodiments, the histamine H1 antagonist is about 20 to about 100 mg. In some embodiments, the histamine H1 antagonist is at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, or more. In some embodiments, the histamine H1 antagonist is at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, or less. In some embodiments, the histamine H1 antagonist is at most about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the histamine H1 antagonist is at most about 50 mg.

In some embodiments, the compositions of the present disclosure include an additional therapeutic agent, e.g., a CRS prophylactic agent, i.e., diphenhydramine. In some embodiments, the diphenhydramine is formulated for administration to a subject of about 50 mg. In some embodiments, the diphenhydramine is formulated for intravenous administration. In some embodiments, the diphenhydramine is formulated for oral administration.

In some embodiments, the diphenhydramine is about 20 to about 100 mg. In some embodiments, the diphenhydramine is at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, or more. In some embodiments, the diphenhydramine is at most about 100 mg, at most about 90 mg, at most about 80 mg, at most about 70 mg, at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, or less. In some embodiments, the diphenhydramine is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the diphenhydramine is about 50 mg.

In some embodiments, the compositions of the present disclosure include an additional therapeutic agent, such as a CRS preventative agent that is a histamine H2 antagonist (H2 blocker). In some embodiments, the H2 blocker is formulated for administration to a subject of 20 mg. In some embodiments, the H2 blocker is formulated for intravenous administration, including, for example, an intravenous administration of 20 mg. In some embodiments, the H2 blocker is formulated for administration to a subject of 20 mg to 40 mg. In some embodiments, the H2 blocker is formulated for oral administration, including, for example, an oral administration of 20 mg to 40 mg.

In some embodiments, the H2 blocker is famotidine, cimetidine, ranitidine, or nizatidine. In some embodiments, the H2 blocker is famotidine. In some embodiments, the H2 blocker is cimetidine. In some embodiments, the H2 blocker is ranitidine. In some embodiments, the H2 blocker is nizatidine. In some embodiments, the H2 blocker is 10 mg to about 60 mg. In some embodiments, the H2 blocker is about 20 mg to about 40 mg. In some embodiments, the famotidine is at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, or more. In some embodiments, the H2 blocker is at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, at most about 10 mg, or less. In some embodiments, the H2 blocker is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

In some embodiments, the compositions of the present disclosure include an additional therapeutic agent, e.g., a CRS preventative agent, namely, famotidine. In some embodiments, the famotidine is formulated for administration to a subject at 20 mg. In some embodiments, the famotidine is formulated for intravenous administration, including, for example, an intravenous administration of 20 mg. In some embodiments, the famotidine is formulated for administration at 20 mg to 40 mg. In some embodiments, the famotidine is formulated for oral administration, including, for example, an oral administration of 20 mg to 40 mg.

In some embodiments, the famotidine is between 10 mg and about 60 mg. In some embodiments, the famotidine is between about 20 mg and about 40 mg. In some embodiments, the famotidine is at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, or more. In some embodiments, the famotidine is at most about 60 mg, at most about 50 mg, at most about 40 mg, at most about 30 mg, at most about 20 mg, at most about 10 mg, or less. In some embodiments, the famotidine is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

In some embodiments, the additional treatment is tocilizumab. In some embodiments, the tocilizumab is from about 400 mg to about 1000 mg. In some embodiments, the tocilizumab is from about 500 mg to about 900 mg. In some embodiments, the tocilizumab is at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, or more. In some embodiments, tocilizumab is at most about 1000 mg, at most about 950 mg, at most about 900 mg, at most about 850 mg, at most about 800 mg, at most about 750 mg, at most about 700 mg, at most about 650 mg, at most about 600 mg, at most about 550 mg, at most about 500 mg, at most about 450 mg, at least about 400 mg, or less. In some embodiments, tocilizumab is at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, or at most about 1000 mg.

Compositions of the present disclosure include compositions comprising combinations of two or more CRS preventative agents. Any of the groups of CRS preventative agents and individual CRS preventative agents described herein can be combined into useful CRS preventative combinations and formulated together in a single composition (e.g., with or without additional components such as a DR IL-18 polypeptide, one or more ICIs, or both).

For example, in some embodiments, a CRS prophylactic composition includes at least an NSAID and at least a histamine H1 antagonist, at least acetaminophen and at least a histamine H1 antagonist, at least an NSAID and at least acetaminophen, or at least an NSAID, at least a histamine H1 antagonist, and at least acetaminophen. Such NSAIDs, histamine H1 antagonists, and acetaminophen may be formulated together in such combinations, where practical and appropriate, in accordance with the dosage and delivery methods of each agent described herein. In some embodiments, a CRS prophylactic composition includes at least indomethacin or ibuprofen and at least diphenhydramine, at least acetaminophen and at least diphenhydramine, at least indomethacin or ibuprofen and at least acetaminophen, or at least indomethacin or ibuprofen, at least diphenhydramine, and at least acetaminophen. Such indomethacin or ibuprofen, diphenhydramine, and acetaminophen may be formulated together in such combinations, where practical and appropriate, according to the dosages and delivery methods of each agent described herein. In some embodiments, such combinations further include an H2 blocker, including, for example, when the H2 blocker used is famotidine, and the famotidine is formulated according to the dosages and administration described herein.

In some embodiments, the CRS preventive composition comprises at least two or more of an NSAID, a histamine H1 antagonist, and acetaminophen, for example, (i) the NSAID is oral or intravenous indomethacin at a dose of 50 mg to 100 mg (e.g., including 75 mg per day) or oral or intravenous ibuprofen at a dose of 600 mg to 2,400 mg (e.g., including 800 mg to 1,800 mg per day), (ii) the histamine H1 antagonist is intravenous or oral diphenhydramine at a dose of 25 mg to 100 mg (e.g., including a 50 mg dose), and (iii) the acetaminophen is oral or intravenous acetaminophen at a dose of 350 mg to 4,000 mg (e.g., including 650 mg to 3,900 mg per day). In some embodiments, such combinations further include an H2 blocker, including, for example, where the H2 blocker used is famotidine, the famotidine is in a dosage and is administered as described herein.

Examples of Non-Limiting Aspects of the Disclosure Aspects, including embodiments of the subject matter described above, may be useful alone or in combination with one or more other aspects or embodiments. Without limiting the foregoing, certain non-limiting aspects of the disclosure are provided below. As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individually numbered aspects may be used and combined with any of the preceding or subsequent individually numbered aspects. This is intended to support all such combinations of aspects, and is not limited to the combinations of aspects explicitly provided below.

Set A (Aspects 1 to 56)
1. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject: (a) a prophylactic agent; (b) a decoy-resistant IL-18 polypeptide or a nucleic acid encoding a decoy-resistant IL-18 polypeptide; and (c) an effective amount of an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is not pembrolizumab.
2. A method for treating a disease, comprising: (a) administering to a subject a composition comprising a nucleic acid encoding a decoy-resistant IL-18 polypeptide or a decoy-resistant IL-18 peptide; and (b) administering to the subject a composition comprising a nucleic acid encoding a decoy-resistant IL-18 polypeptide or a decoy-resistant IL-18 peptide, and administering an immune checkpoint inhibitor selected from the group consisting of mabu, retifanlimab, atezolizumab, avelumab, durvalumab, emvafolimab, cosibelimab, CA-170, BMS-986189, BMS-936559, sugemalimab, adeburelimab, CBT-502, BGB-A333, pacmilimab, ipilimumab, tremelimumab, relatolimab, enoblitzumab, and variants of any of the foregoing.
3. The method of Set A aspect 1, wherein the prophylactic agent comprises an analgesic.
4. The method of Set A Aspect 3, wherein the analgesic agent is a nonsteroidal anti-inflammatory drug (NSAID).
5. The method of Set A aspect 4, wherein the NSAID is selected from the group consisting of ibuprofen, naproxen, diclofenac, diflunisal, fenoprofen, flurbiprofen, ketoprofen, meloxicam, nabumetone, oxaproin, piroxicam, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, celecoxib, rofecoxib, valdecoxib, mefenamic acid, etoricoxib, indomethacin, and aspirin.
6. The method of Set A embodiment 5, wherein the NSAID is ibuprofen.
7. The method of Set A embodiment 5, wherein the NSAID is diclofenac.
8. The method of Set A embodiment 4, wherein the NSAID is from about 25 mg to about 60 mg.
9. The method of Set A embodiment 4, wherein the NSAID is from about 200 mg to about 600 mg.
10. The method of Set A aspect 3, wherein the analgesic comprises an analgesic.
11. The method of Set A aspect 10, wherein the analgesic agent is selected from the group consisting of acetaminophen, aspirin, caffeine, butalbital, isometheptene mucate, magnesium salicylate, codeine, dihydrocodeine, hydrocodone, oxycodone, tramadol, co-codamol, co-codaprine, codidramol, alfentanil, fentanyl, hydromorphone, methadone, morphine, meperidine, and oxymorphone.
12. The method of Set A aspect 11, wherein the analgesic is acetaminophen.
13. The method of Set A aspect 11, wherein the analgesic agent is at least about 500 mg.
14. The method of Set A aspect 11, wherein the analgesic agent is at least about 600 mg.
15. The method of Set A embodiment 1, wherein the prophylactic agent comprises an antihistamine.
16. The method of Set A aspect 15, wherein the antihistamine is an H-1 receptor antagonist or an H-2 receptor antagonist.
17. The method of Set A aspect 16, wherein the antihistamine is an H-1 receptor antagonist.
18. The method of Set A aspect 17, wherein the H-1 receptor antagonist is selected from the group consisting of brompheniramine, chlorpheniramine, clemastine, cyprofeptadine, dexchlorpheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, phenindamine, azelastine, loratadine, cetirizine, desloratadine, and fexofenadine.
19. The method of Set A embodiment 18, wherein the H-1 receptor antagonist is diphenhydramine.
20. The method of Set A aspect 16, wherein the antihistamine is an H-2 receptor antagonist.
21. The method of Set A aspect 20, wherein the H-2 receptor antagonist is selected from the group consisting of cimetidine, famotidine, nizatidine, and ranitidine.
22. The method of Set A aspect 20, wherein the H-2 receptor antagonist is famotidine.
23. The method of Set A aspect 16, wherein the antihistamine is at least about 20 mg.
24. The method of Set A aspect 16, wherein the antihistamine is at least about 40 mg.
25. The method of Set A embodiment 1, wherein the prophylactic agent comprises an anti-infective.
26. The method of Set A aspect 25, wherein the anti-infective agent is a cytokine inhibitor.
27. The method of Set A aspect 26, wherein the cytokine inhibitor targets a cytokine receptor.
28. The method of Set A aspect 27, wherein the cytokine receptor is for TNFα, TNFβ, IFNα, IFNβ, IFNγ, IL-6, or IL-12.
29. The method of Set A aspect 26, wherein the cytokine receptor is an IL-6 receptor.
30. The method of Set A aspect 25, wherein the anti-infective agent is an antibody or a small molecule.
31. The method of Set A aspect 25, wherein the antiinfective is at least about 500 mg.
32. The method of Set A aspect 1, wherein the prophylactic agent comprises a supplemental fluid.
33. The method of Set A aspect 32, wherein the auxiliary fluid is selected from the group consisting of saline, lactated Ringer's solution, dextrose in aqueous solution, sodium chloride solution, and any combination thereof.
34. The method of set A aspect 32, wherein the auxiliary fluid is at most about 3 liters.
35. The method of Set A embodiment 1, wherein the prophylactic agent comprises a steroid.
36. The method of Set A embodiment 35, wherein the steroid is selected from the group consisting of cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone.
37. The method of set A embodiment 36, wherein the steroid is prednisone.
38. The method of Set A aspect 35, wherein the steroid is at most about 10 mg/day.
39. The method of Set A embodiment 1, wherein the prophylactic agent is administered at least 2 hours before the decoy-resistant IL-18 polypeptide and the effective amount of an immune checkpoint inhibitor.
40. The method of Set A embodiment 1, wherein the prophylactic agent is administered at least 1 hour before the decoy-resistant IL-18 polypeptide and the effective amount of an immune checkpoint inhibitor.
41. The method of Set A embodiment 1, wherein the prophylactic agent is administered intravenously, intramuscularly, subcutaneously, or orally.
42. The method of Set A embodiment 1 or 2, wherein the disease comprises cancer.
43. The method of Set A aspect 42, wherein the cancer is a solid tumor or a liquid tumor.
44. The method of Set A aspect 43, wherein the solid tumor is selected from the group consisting of melanoma, Merkel cell carcinoma, renal cell carcinoma, urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability-high (MSI-H) tumors, high tumor mutation burden (TMB-H) tumors, mismatch repair deficient tumors, gastric, cervical, endometrial, squamous cell skin, small cell lung, esophageal, hepatocellular carcinoma (HCC), platinum-resistant ovarian cancer, and any combination thereof.
45. The method of Set A aspect 43, wherein the solid tumor is melanoma, renal cell carcinoma, TNBC, NSCLC, SCCHN, or an MSI-H tumor.
46. The method of Set A embodiment 43, wherein the solid tumor is melanoma.
47. The method of Set A embodiment 43, wherein the solid tumor is renal cell carcinoma.
48. The method of Set A embodiment 43, wherein the solid tumor is TNBC.
49. The method of Set A embodiment 43, wherein the solid tumor is NSCLC.
50. The method of Set A embodiment 43, wherein the solid tumor is SCCHN.
51. The method of set A embodiment 43, wherein the solid tumor is an MSI-H tumor.
52. The method of Set A Aspect 1 or Set A Aspect 2, wherein the decoy-resistant IL-18 polypeptide is administered intravenously or subcutaneously.
53. The method of Set A Aspect 1 or Set A Aspect 2, wherein the decoy resistance is administered weekly.
54. The method of Set A aspect 1 or Set A aspect 2, wherein the method results in a reduction in tumor size or tumor number in the subject.
55. The method of Set A embodiment 1 or 2, wherein the decoy-resistant IL-18 polypeptide comprises multiple mutations relative to the wild-type IL-18 set forth in SEQ ID NO:13.
56. The method of Set A aspect 55, wherein the plurality of mutations comprises a plurality of amino acid substitutions.

Set B (Aspects 1 to 104)
1. A method of treating a disease in a subject in need thereof, comprising administering to the subject (a) a decoy-resistant (DR) IL-18 composition comprising a DR IL-18 polypeptide or a nucleic acid encoding a DR IL-18 polypeptide; and (b) an immune checkpoint inhibitor (ICI) composition, wherein the ICI is not pembrolizumab, and optionally (c) the ICI is not acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotlimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab ... Nprimimab, peresolimab, pidilizumab, pimivalimab, pradu-sinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimbelelimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstbalt, betifisolimab, cosibelimab, dur Valmab, embafolimab, galibrimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, suduplilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstotsug, filastotsug, gothistobald, ipilimumab, muzastobald, nurlimab, polstobald, quavonlimab, sobipostobald, tremelimumab, tubonlarimab, vilast (d) the method comprises administering to the subject an additional treatment that reduces the presentation of symptoms of cytokine release syndrome (CRS); or (e) both (c) and (d).
2. The method of Set B embodiment 1, wherein the method comprises an additional therapy, wherein the additional therapy comprises CRS prophylaxis administered together with or prior to the DR IL-18 composition.
3. The method of Set B embodiment 1 or 2, wherein the method comprises administering successive doses of a DR IL-18 composition and administering an additional treatment with or before each dose of the successive doses of the DR IL-18 composition.
4. The method of any one of the preceding set B aspects, wherein the additional therapy comprises at least one of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, a histamine H1 antagonist, an H2 blocker, or a fluid administered to the subject.
5. The method of any one of the preceding set B aspects, wherein the additional therapy comprises an NSAID, and optionally, the NSAID is an oral NSAID.
6. The method of Set B aspect 5, wherein the additional treatment is administered prior to the DR IL-18 composition or prior to each dose of the DR IL-18 composition in successive doses, optionally at least 1 hour, and optionally 1 to 2 hours.
7. The method of Set B aspect 5 or 6, wherein an NSAID is further administered for at least 24 hours, optionally at least 48 hours, after the sequential doses of the DR IL-18 composition or each dose of the sequential doses of the DR IL-18 composition.
8. The method of any one of Set B aspects 5-7, wherein the NSAID is indomethacin, optionally oral indomethacin.
9. The method of Set B aspect 8, wherein indomethacin is administered at 50 mg to 100 mg per day, optionally 75 mg per day.
10. The method of Set B aspect 8 or 9, wherein indomethacin is administered at a dose of 25 mg, optionally three times daily.
11. The method of any one of Set B aspects 5-7, wherein the NSAID is ibuprofen, optionally oral ibuprofen.
12. The method of Set B aspect 11, wherein ibuprofen is administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day.
13. The method of Set B aspect 11 or 12, wherein ibuprofen is administered in a dose of 200 mg to 600 mg, optionally with 6 to 8 hours between ibuprofen doses.
14. The method of any one of the preceding set B aspects, wherein the additional therapy comprises a histamine H1 antagonist, and optionally the histamine H1 antagonist is an intravenous histamine H1 antagonist or an oral histamine H1 antagonist.
15. The method of Set B aspect 14, wherein the histamine H1 antagonist is administered prior to the DR IL-18 composition or prior to each dose of the DR IL-18 composition in successive doses, optionally at least 30 minutes, and optionally 30 to 60 minutes.
16. The method of Set B aspect 14 or 15, wherein the histamine H1 antagonist is diphenhydramine, optionally intravenous diphenhydramine or oral diphenhydramine.
The method of Set B aspect 16, wherein 25 mg to 100 mg of diphenhydramine is administered, optionally, 50 mg of diphenhydramine is administered.
18. The method of any one of the preceding set B aspects, wherein the additional treatment comprises acetaminophen, and optionally, the acetaminophen is oral acetaminophen.
19. The method of Set B aspect 18, wherein acetaminophen is administered prior to, optionally within 2 hours or 1 hour before, the DR IL-18 composition, or the sequential doses of the DR IL-18 composition.
20. The method of Set B aspect 19, wherein acetaminophen is administered for at least two days after each dose of the DR IL-18 composition, or successive doses of the DR IL-18 composition.
21. The method of Set B aspect 18, wherein acetaminophen is administered within 24 hours of the DR IL-18 composition or each dose of the consecutive doses of the DR IL-18 composition.
22. The method of any one of Set B aspects 18-21, wherein between 350 mg and 4,000 mg of acetaminophen is administered per day, and optionally between 650 mg and 3,900 mg of acetaminophen is administered per day.
23. The method of any one of Set B aspects 18-22, wherein acetaminophen is administered in one or more 650 mg amounts, optionally with 4-6 hours between doses.
24. The method of any one of the preceding set B aspects, wherein the additional therapy comprises an H2 blocker, optionally wherein the H2 blocker is an oral H2 blocker or an intravenous H2 blocker.
25. The method of Set B aspect 24, wherein the H2 blocker is administered only before each successive dose of the DR IL-18 composition, optionally at least 30 minutes before each successive dose of the DR IL-18 composition, optionally 30 to 60 minutes before each successive dose of the DR IL-18 composition.
26. The method of Set B aspect 24 or 25, wherein the H2 blocker is famotidine, optionally oral famotidine, or intravenous famotidine.
27. The method of Set B aspect 26, wherein 20 mg to 40 mg of oral famotidine is administered.
28. The method of Set B aspect 26, wherein 20 mg of intravenous famotidine is administered.
29. The method of any one of the preceding set B aspects, wherein the method comprises administering to the subject multiple doses of a CRS preventative comprising at least one dose of an NSAID and at least one dose of a histamine H1 antagonist, at least one dose of acetaminophen and at least one dose of a histamine H1 antagonist, at least one dose of an NSAID and at least one dose of acetaminophen, or at least one dose of an NSAID, at least one dose of a histamine H1 antagonist, and at least one dose of acetaminophen, optionally wherein the NSAID is selected from indomethacin and ibuprofen, and the histamine H1 antagonist is diphenhydramine.
30. The method of Set B aspect 29, further comprising at least one dose of an H2 blocker, optionally wherein the H2 blocker is famotidine, and optionally wherein the famotidine is oral famotidine administered in a 20 mg to 40 mg dose or intravenous famotidine administered in a 20 mg dose.
31. (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally 75 mg per day, or oral ibuprofen administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day;
(ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg, optionally 50 mg;
(iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day, optionally 650 mg to 3,900 mg per day; or (iv) any combination thereof.
32. The method of any one of the preceding set B aspects, wherein administering the CRS prophylactic agent reduces the presentation of one or more symptoms of CRS compared to a comparable subject who has not received the CRS prophylactic agent.
33. The method of any one of the preceding Set B aspects, wherein administering the CRS prophylactic agent reduces the presentation of one or more symptoms of CRS compared to a subject receiving a comparable treatment comprising administration of about 30 μg/kg or more of a DR IL-18 composition without receiving the CRS prophylactic agent.
34. The method of any one of the preceding set B aspects, wherein the subject does not experience CRS of Grade 4 or higher, and optionally, the subject does not experience CRS of Grade 3 or higher.
35. The method of any one of the preceding set B aspects, wherein the DR IL-18 polypeptide comprises a plurality of mutations relative to the wild-type IL-18 set forth in SEQ ID NO:13.
36. The method of any one of the preceding set B aspects, wherein the DR IL-18 polypeptide comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid substitutions relative to the wild-type IL-18 set forth in SEQ ID NO: 13.
37. The method of Set B aspect 35 or 36, wherein the plurality of mutations comprises mutations at positions selected from Y1, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, D110, N111, M113, V153, and N155.
38. The DR IL-18 polypeptide has any of the following amino acids compared to the wild-type IL-18 set forth in SEQ ID NO: 13: Y1H, Y1R, LSH, L51, LSY, K8Q, K8R, M51T, M51K, M51D, M51N, M51E, M51R, K53R, K53G, K53S, K53T, S55K, S55R, Q56E, Q56A, Q56R, Q56V, Q56G, Q56K, Q56L, P57L, P57G, P57A, P57K, G59T, G59A, M60K, M60Q, M60R, M60L, E77D, Q103E, Q103K , Q103P, Q103A, Q103R, S105R, S105D, S105K, S105N, S105A, D110H, D110K, D110N, D110Q, D110E, D110S, D110G, N111H, N111Y, N111D, N111R, N111S, N111G, M113V, M113R, M113T, M113K, V1531, V153T, V153A, N155K, and N155H.
39. The method of any of the preceding set B aspects, wherein the DR IL-18 polypeptide comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 1-12.
40. The method of any of the preceding set B aspects, wherein the DR IL-18 polypeptide comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 1-12.
41. The method of any of the preceding set B aspects, wherein the DR IL-18 polypeptide comprises an amino acid sequence having at least 98% sequence identity to any one of SEQ ID NOs: 1-12.
42. The method of any of the preceding set B aspects, wherein the DR IL-18 polypeptide comprises an amino acid sequence selected from SEQ ID NOs: 1-12.
43. The method of any one of the preceding set B aspects, wherein the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising the amino acid sequence set forth in SEQ ID NO:5.
44. The method of any one of the preceding Set B aspects, wherein the DR IL-18 polypeptide is a modified IL-18 polypeptide consisting of the amino acid sequence set forth in SEQ ID NO:5.
45. The method of any one of the preceding set B aspects, wherein the DR IL-18 polypeptide is administered at a concentration of about 30 mg/mL.
46. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 15 μg of DR IL-18 polypeptide per kg of body weight of the subject.
47. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 20 μg of DR IL-18 polypeptide per kg of body weight of the subject.
48. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises a DR IL-18 composition comprising at least about 30 μg of DR IL-18 polypeptide per kg of body weight of the subject.
49. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 90 μg of DR IL-18 polypeptide per kg of body weight of the subject.
50. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 180 μg of DR IL-18 polypeptide per kg of body weight of the subject.
51. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 360 μg of DR IL-18 polypeptide per kg of body weight of the subject.
52. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 600 μg of DR IL-18 polypeptide per kg of subject body weight.
53. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 900 μg of DR IL-18 polypeptide per kg of subject body weight.
54. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition comprises at least about 1200 μg of DR IL-18 polypeptide per kg of body weight of the subject.
55. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition, or each dose of the sequential doses of DR IL-18 composition, comprises from about 15 μg to about 1200 μg of DR IL-18 polypeptide per kg of body weight of the subject.
56. The method of any one of the preceding Set B aspects, wherein the DR IL-18 composition, or each dose of the sequential doses of DR IL-18 composition, comprises from about 15 μg to about 30 μg, from about 30 μg to about 90 μg, from about 90 μg to about 180 μg, from about 180 μg to about 360 μg, from about 360 μg to about 600 μg, from about 600 μg to about 900 μg, or from about 900 μg to about 1200 μg of DR IL-18 polypeptide per kg of body weight of the subject.
57. The method of any one of the preceding Set B aspects, wherein the DR IL-18 composition, or each dose of the sequential doses of DR IL-18 composition, comprises about 15 μg, about 30 μg, about 90 μg, about 180 μg, about 360 μg, about 600 μg, about 900 μg, or about 1200 μg of DR IL-18 polypeptide per kg of body weight of the subject.
58. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition is administered to the subject weekly.
59. The method of any one of the preceding set B aspects, wherein the DR IL-18 composition is administered to the subject about every 7 days.
60. The method of any one of the preceding set B aspects, wherein a subsequent dose of the DR IL-18 composition is administered to the subject at least 6 days after the previous dose of the DR IL-18 composition.
61. The method of Set B aspect 60, wherein a subsequent dose of the DR IL-18 composition is administered to the subject up to 9 days after the previous dose of the DR IL-18 composition.
62. The method of any one of the preceding set B aspects, wherein the method comprises administering continuous doses of the ICI composition.
63. The method of any one of the preceding set B aspects, wherein the dose of the ICI composition is administered to the subject at least about 60 minutes before the dose of the DR IL-18 composition is administered to the subject.
64. The method of any one of the preceding set B aspects, wherein the dose of the ICI composition is administered to the subject at least 60 minutes after the dose of the DR IL-18 composition is administered to the subject.
65. The method of any one of the preceding Set B aspects, wherein (a) and (b) are performed sequentially.
66. The method of any one of the preceding Set B aspects, wherein (a) is performed before (b).
67. The method of any one of Set B aspects 1-65, wherein (b) is performed before (a).
68. The method of any one of Set B aspects 1-64, wherein (a) and (b) are performed simultaneously.
69. The method of any one of the preceding set B aspects, wherein the dose of the ICI composition is administered to the subject by intravenous infusion.
70. The method of any one of the preceding set B aspects, wherein each dose of the ICI composition is administered to the subject by intravenous infusion.
71. The method of any one of the preceding set B aspects, wherein the dose of the DR IL-18 composition is administered to the subject by subcutaneous injection.
72. The method of any one of the preceding set B aspects, wherein each dose of the DR IL-18 composition is administered to the subject by subcutaneous injection.
73. The method of any one of the preceding set B aspects, wherein the disease comprises cancer.
74. The method of Set B aspect 73, wherein the cancer is a solid tumor or a liquid tumor.
75. The cancer is melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) tumor or mismatch repair deficient cancer (dMMR) cancer, microsatellite instability-high or mismatch repair deficient colorectal cancer (CRC), colorectal cancer, gastric cancer, esophagogastric junction cancer, esophagogastric cancer, The method of Set B Aspect 74, wherein the cancer is selected from the group consisting of esophageal adenocarcinoma, locally advanced or metastatic gastroesophageal junction (GEJ) cancer, malignant pleural mesothelioma, cervical cancer, ovarian cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), kidney cancer, renal cell carcinoma (RCC), bladder cancer, endometrial cancer, liver cancer, high tumor mutation burden (TMB-H) cancer, squamous cell carcinoma (cSCC), triple-negative breast cancer (TNBC), or any combination thereof.
76. The method of any one of Set B aspects 73-75, wherein the cancer is resistant to one or more ICIs.
77. The method of any one of Set B aspects 73-76, wherein the cancer is selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation/fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and wherein the cancer is resistant to one or more ICIs.
78. The method of any one of Set B aspects 73-76, wherein the cancer is selected from platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.
79. The method of Set B aspect 73, wherein the cancer is a liquid tumor selected from the group consisting of leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative disorder, and myeloma.
80. The method of Set B embodiment 79, wherein the liquid tumor is myeloma.
81. The method of Set B aspect 79, wherein the liquid tumor is a lymphoma, optionally a B-cell lymphoma.
82. The method of Set B aspect 79, wherein the liquid tumor is leukemia, optionally acute myeloid leukemia.
83. A method comprising administering to a subject one or more doses of a CRS prophylactic agent with or before each dose of the sequential doses of a DR IL-18 composition, wherein the CRS prophylactic agent comprises at least one of an NSAID, a histamine H1 antagonist, acetaminophen, or an H2 blocker;
(i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5;
(ii) the dose of the DR IL-18 composition comprises at least about 30 μg of polypeptide per kg of body weight of the subject;
(iii) The method of any one of the preceding Set B aspects, wherein the disease comprises an ICI-resistant solid tumor selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelium, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer.
84. The method of at least one of the preceding set B aspects, wherein the ICI is an ICI that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3.
85. The method of Set B aspect 84, wherein the ICI is an anti-LAG-3 antibody or antigen-binding fragment thereof.
86. The method of Set B aspect 85, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, leratolimab, or tuparstbalt.
87. The method of Set B aspect 84, wherein the ICI is a PD-1 checkpoint inhibitor, optionally a PD-1 antagonist, a PD-L1 antagonist, or a PD-L2 inhibitor.
88. PD-1 checkpoint inhibitors include acrixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofaginlimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, selplulimab, sintilimab, spartalizumab, tislelizumab, and tripa limab, zelvalimab, zimvelerimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adebulerimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, suduplilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.
89. A method comprising administering to a subject one or more CRS prophylactic agents together with or prior to the DR IL-18 composition, wherein the one or more CRS prophylactic agents comprise an NSAID, a histamine H1 antagonist, acetaminophen, an H2 blocker, or a combination thereof;
(i) the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5;
(ii) the DR IL-18 composition comprises at least about 30 μg of polypeptide per kg of patient body weight;
(iii) the ICI composition comprises an ICI that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3;
(iv) The method of any one of Set B aspects 73-88, wherein the disease comprises an ICI checkpoint inhibitor resistant solid tumor selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endocervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum resistant ovarian cancer or microsatellite stable colorectal cancer.
90. The method of any one of Set B aspects 73-89, wherein the ICI is an anti-LAG-3 antibody or antigen-binding fragment thereof, and optionally the cancer is selected from colorectal cancer, myeloma, B-cell lymphoma, and acute myeloid leukemia.
91. The method of any one of Set B aspects 73-89, wherein the ICI is a PD-1 checkpoint inhibitor, and optionally the cancer is selected from colorectal cancer, myeloma, B-cell lymphoma, and acute myeloid leukemia.
92. The method of any one of the preceding set B aspects, wherein the disease is cancer or tumor, and the method thereby results in one or more improvements in the cancer or tumor in the patient.
93. The method of Set B aspect 92, wherein the one or more improvements comprises stable disease for at least 12 weeks.
94. The method of Set B aspect 92 or 93, wherein the one or more improvements comprises immunotherapy-induced regression of cancer or tumor in the patient.
95. The method of any one of Set B aspects 92-94, wherein the one or more improvements comprise a partial response as assessed by RECIST version 1.1.
96. The method of any one of Set B aspects 92-95, wherein the one or more improvements comprise a complete response as assessed by RECIST version 1.1.
97. Use of an ICI composition, a DR IL-18 composition, or a combination thereof, in a method of treating cancer according to any one of the preceding Set B aspects.
98. A therapeutic composition comprising: (a) an effective amount of a decoy-resistant (DR) IL-18 polypeptide; and (b) an effective amount of an ICI, wherein the ICI is not pembrolizumab, optionally wherein the ICI is selected from the group consisting of aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotlimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, novolumab, Fadzinlimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimbelelimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab , avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galibrimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstutuzug, filastutuzug, gothistutuzug, ipilimumab, muzast A therapeutic composition selected from the group consisting of tsugu, nurulimab, polustbalt, quabonlimab, sobipostbalt, tremelimumab, tubonlarimab, vilastbalt, zalifrelimab, enselimab, favezelimab, fianlimab, yeramilimab, miptenalimab, negalustbalt, relatolimab, tuparustbalt, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and variants of any of the foregoing.
99. The ICI is a PD-1 antagonist, optionally the PD-1 antagonist is selected from the group consisting of aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, 99. The therapeutic composition of Set B aspect 98, wherein the compound is selected from the group consisting of pimivalimab, pradusinstvald, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimvelerimab, INCMGA00012, MEDI0680, SSI-361, and AMP-224.
100. The therapeutic composition of Set B aspect 98, wherein the ICI is a PD-L1 antagonist, optionally wherein the PD-L1 antagonist is selected from the group consisting of adebrelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab, embafolimab, galiblimab, resabelimab, lodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333.
101. The therapeutic composition of Set B aspect 98, wherein the ICI is a LAG3 antagonist, optionally wherein the LAG3 antagonist is selected from the group consisting of enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, leratolimab, or tuparstbalt.
102. The therapeutic composition of Set B aspect 98, wherein the ICI is a CTLA4 antagonist, optionally wherein the CTLA4 antagonist is selected from the group consisting of botencilimab, botencilimab, evalstotsug, filastotsug, gotistotsug, ipilimumab, muzastotsug, nurlimab, polstotsug, quavonlimab, sobipostotsug, tremelimumab, tubonlarimab, vilastotsug, or zalifrelimumab.
103. The therapeutic composition of any one of Set B aspects 98-102, wherein the therapeutic composition is formulated for intravenous administration.
104. The therapeutic composition of any one of Set B aspects 98-103, further comprising a buffering agent, a stabilizer, a surfactant, an antioxidant, a solvent, or any combination thereof.

Example #1: Anti-PD-1 Therapy as Monotherapy In an exemplary embodiment, subjects are administered an anti-PD-1 monoclonal antibody by infusion (200 mg Q3W) for up to two years, but not a decoy-resistant IL-18 polypeptide, to treat tumors associated with non-small cell lung cancer. Although the tumors initially shrink, they develop resistance to the anti-PD-1 treatment, leading to disease recurrence and progression after two years of anti-PD-1 monotherapy.

Example #2 Anti-PD-1 Antibody Combination Therapy with DR IL-18 Polypeptide In an exemplary example, a subject receives an anti-PD-1 monoclonal antibody by infusion (200 mg Q3W) and a DR IL-18 polypeptide by subcutaneous injection (e.g., 30 μg/kg of subject's body weight QW), with mandatory CRS prophylaxis given with each dose of DR IL-18 polypeptide.

To determine the maximum tolerated dose, each subject will receive an initial dose of 30 μg/kg of DR IL-18 polypeptide, with the dose escalating as per Table 1 below in the absence of treatment-related AEs of ≧Grade 2. If the initial dose level (30 μg/kg) is not tolerated, lower doses (10, 15, or 20 μg/kg) or less intensive dosing schedules at 30 μg/kg will be evaluated.

Once the desired dose is determined, the subject is so administered for up to two years to treat tumors associated with non-small cell lung cancer. Tumors shrink over the course of treatment, resulting in a reduction in tumor size and number until the patient exhibits signs of complete disease remission after two years of combined treatment.

Example #3: CRS prevention in patients treated with DR IL-18 polypeptide + pembrolizumab combination therapy. The risk of CRS was observed when DR IL-18 polypeptide was administered subcutaneously as monotherapy. All patients now received prophylactic medication before each injection.

The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for CRS is as follows:
Abbreviations: BiPAP = bilevel positive airway pressure, CPAP = continuous positive airway pressure. See also, e.g., Lee et al. Biology of Blood and Marrow Transplantation. 25 (2019) 625-639.

A cohort of three patients who had previously experienced an inadequate response to PD-1 checkpoint inhibitor therapy received weekly subcutaneous DR IL-18 polypeptide in combination with pembrolizumab at 30 μg/kg + 200 mg administered intravenously every three weeks. DR IL-18 polypeptide is administered with CRS prophylaxis given with each dose, which consists of: (a) an oral nonsteroidal anti-inflammatory drug (NSAID) (using indomethacin at 25 mg three times a day or oral ibuprofen at 200 mg to 600 mg every 6 to 8 hours) 1 to 2 hours before and continuing for at least 48 hours after dosing with DR IL-18 polypeptide; (b) 50 mg intravenous or oral diphenhydramine (or an equivalent dose of a next-generation histamine H1 antagonist) 30 to 60 minutes before dosing with DR IL-18 polypeptide; (c) 650 mg oral acetaminophen every 4 to 6 hours as needed for the first 24 hours after dosing; and (d) subsequent DR IL-18 polypeptide prophylaxis, if indicated after the initial DR IL-18 polypeptide dose. This included administration of 20 mg of intravenous famotidine (or other H2 blocker) or 20-40 mg of oral famotidine (or other H2 blocker) 30-60 minutes before IL-18 polypeptide administration. Unless contraindicated by post-administration vital signs, any blood pressure medication was withheld at least 24 hours before and at least 48 hours after DR IL-18 polypeptide administration. For subjects with contraindications to NSAIDs, 650 mg of oral acetaminophen was used every 4-6 hours beginning 1 hour before DR IL-18 polypeptide administration and continued for at least 48 hours after administration. For subjects with or at risk for hypotension, up to 3 liters of oral and/or intravenous fluids were administered within 24 hours after administration.

All patients in the cohort remained on study through the dose-limiting toxicity (DLT) period (i.e., through 21 days of three doses of DR IL-18 polypeptide). No patients in the cohort experienced grade 3 or higher CRS, and no patients in the cohort required steroid administration for CRS.

Example #4: Efficacy in patients treated with DR IL-18 polypeptide + ICI combination therapy As described below, cohorts of patients receive weekly subcutaneous DR IL-18 polypeptide at 30 μg/kg, 60 μg/kg, or other recommended dose (such as the recommended Phase 2 dose obtained from the DR IL-18 polypeptide dose-finding study) plus an ICI intravenously every 1, 2, or 3 weeks (with CRS prophylaxis given with each dose as described in Example 3).

Cohort subjects include those with histologically or cytologically confirmed advanced/metastatic melanoma, Merkel cell carcinoma, renal cell carcinoma (RCC), urothelial, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), any microsatellite instability-high (MSI-H), any high tumor mutation burden (Hi-TMB) or mismatch repair deficient, gastric, cervical, endometrial, squamous cell skin, small cell lung, esophageal, and hepatocellular carcinoma (HCC) cancer/tumor(s) that have experienced an inadequate response to prior ICI therapy, such as checkpoint inhibitor programmed death receptor-1 (PD-1) therapy. TNBC is diagnosed in tumors that do not express estrogen or progesterone receptors and are not human epidermal growth factor receptor 2 (HER2) 3+ by immunohistochemistry (IHC) or negative by fluorescence in situ hybridization (FISH). MSI-high tumors have mutations in 30% or more microsatellites by PCR or are negative for MSH1/2/6 or PMS-2 by IHC. TMB-H-high tumors have 10 or more mutations per megabase (mut/Mb) calculated from whole-genome or whole-exome sequencing. The following tumors are accepted in the expansion cohort: platinum-resistant ovarian cancer and microsatellite-stable colorectal cancer.

Disease assessments are performed using computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis (and other relevant areas if they contain target lesions). Determination of the magnitude and duration of change in tumor size is based on well-established response and progression criteria, as applied to radiological measurements (see Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, Eisenhauer et al. (2009) European Journal of Cancer 45:228-247). Disease assessments are performed every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Clinical laboratory, pharmacodynamic, pharmacogenomic, pharmacokinetic, and other assessments are also performed.

The cohort is expected to demonstrate evidence of pharmacodynamic activity and substantial evidence of tumor regression, including objective responses (CRs and PRs) as assessed by RECIST version 1.1. Stable disease for ≥12 weeks is considered clinically relevant in this patient population.

Example #5: Combination therapy of DR IL-18 polypeptide and anti-PD-1 ICI antibody reduces tumor growth in the CT26 mouse colorectal tumor model.
The antitumor activity of decoy-resistant (DR) IL-18 polypeptides, alone and in combination with anti-PD-1 immune checkpoint inhibitors (ICIs), in colorectal cancer was evaluated using the CT26 mouse colorectal cancer model. CT26 is an N-nitroso-N-methylurethane- (NNMU)-induced undifferentiated colon cancer cell line established from BALB/c mice bearing aggressive colon cancer. CT26 is considered a "warm" tumor model, meaning it lies between immunogenic "hot" tumors and non-immunogenic "cold" tumors in general.

To establish the model, CT26 cells were implanted as xenografts into host mice and allowed to form tumors. Mice were treated with DR IL-18 polypeptide alone (0.32 milligrams per kilogram (mpk) administered by intraperitoneal injection (IP) every other week (BIW) for five doses, with the final dose on study day 15), anti-PD-1 antibody alone (10 mpk administered BIW for five doses), or the combination of DR IL-18 polypeptide and anti-PD-1 (dosed at the same dose as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle only (i.e., without DR IL-18 polypeptide or any ICI). As an assay for cancer growth, tumor size (in cubic millimeters (mm3)) was measured in each animal over time throughout the course of the study.

As can be seen in Figure 2, tumors grew rapidly in untreated vehicle control mice and mice treated with anti-PD-1 monotherapy. Tumor growth was substantially reduced in mice treated with DR IL-18 polypeptide monotherapy compared to vehicle control mice and anti-PD-1 monotherapy-treated mice. However, tumor growth in mice treated with the combination of DR IL-18 polypeptide and anti-PD-1 was substantially reduced, if not stopped, compared to either of the monotherapy treatment conditions. Thus, this example demonstrates that a combination therapy comprising a DR IL-18 polypeptide in combination with an anti-PD-1 antibody ICI has effective anti-tumor activity, significantly reducing, if not stopping, the growth of colorectal tumors. The anti-tumor activity of the combination therapy was substantially greater than either DR IL-18 polypeptide monotherapy or anti-PD-1 ICI monotherapy.

Example #6: Combination therapy of DR IL-18 polypeptide and anti-LAG3 ICI antibody reduces tumor growth in the CT26 mouse colorectal tumor model.
The CT26 mouse colorectal cancer model described in Example #5 was used to evaluate the anti-tumor activity of decoy-resistant IL-18 (DR-18) in combination with an anti-LAG3 immune checkpoint inhibitor (ICI) in colorectal cancer.

Mice bearing established tumors were treated with DR-18 alone (five IP doses at 0.32 mpk BIW, with the final dose on study day 15), anti-LAG3 antibody alone (five IP doses at 10 mpk BIW), or the combination of DR-18 and anti-LAG3 (at the same doses as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle only (i.e., without DR-18 or any ICI). As an assay for cancer growth, tumor size (in cubic millimeters (mm3)) was measured over time in each animal during the course of the study.

As can be seen in Figure 3, tumors grew rapidly in untreated vehicle control mice and mice treated with anti-LAG3 monotherapy. Tumor growth was substantially slowed in mice treated with DR-18 monotherapy compared to vehicle control mice and anti-LAG3 monotherapy-treated mice. However, tumor growth in mice treated with the combination of DR-18 and anti-LAG3 was substantially slowed, if not stopped, compared to either of the monotherapy treatment conditions. Thus, this example demonstrates that a combination therapy comprising DR-18 in combination with the anti-LAG3 antibody ICI has effective anti-tumor activity, significantly reducing, if not stopping, the growth of colorectal tumors. The anti-tumor activity of the combination therapy was substantially greater than either DR-18 or anti-LAG3 ICI monotherapy.

Example #7: Combination therapy of DR IL-18 polypeptide and anti-PD-1 ICI antibody reduces tumor growth in the MC38 mouse colorectal tumor model.
The MC38 mouse colorectal cancer model was used to evaluate the antitumor activity of DR IL-18 alone and in combination with an anti-PD-1 ICI in colorectal cancer. The MC38 tumorigenic epithelial cell line was isolated from a mouse bearing colon adenocarcinoma and expresses high levels of human carcinoembryonic antigen (CEA). MC38 contains a high mutational burden and is sensitive to immune checkpoint immunotherapy.

To establish the model, MC38 cells were implanted as xenografts into host mice and allowed to form tumors. Mice were treated with DR IL-18 polypeptide alone (5 IP doses at 0.32 mpk BIW, with the final dose on study day 15), anti-PD-1 antibody alone (5 IP doses at 10 mpk BIW), or the combination of DR IL-18 polypeptide and anti-PD-1 (at the same doses as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle only (i.e., without DR IL-18 polypeptide or any ICI). As an assay for cancer growth, tumor size was measured (mm3) in each animal over time throughout the course of the study.

As can be seen in Figure 4, tumors grew, on average, to over 2000 mm3 in untreated vehicle control mice. Mice treated with anti-PD-1 monotherapy showed reduced MC38 tumor growth compared to vehicle controls. Tumor growth was reduced in mice treated with DR IL-18 polypeptide monotherapy compared to mice treated with anti-PD-1 monotherapy. However, mice treated with a combination of DR IL-18 polypeptide and anti-PD-1 showed a more substantial reduction in MC38 tumor growth compared to either monotherapy. Thus, this example demonstrates that a combination therapy comprising a DR IL-18 polypeptide in combination with an anti-PD-1 antibody ICI has effective anti-colorectal tumor activity superior to both DR IL-18 polypeptide monotherapy and anti-PD-1 ICI monotherapy.

Example #8: Combination therapy of DR IL-18 polypeptide and anti-LAG3 ICI antibody reduces tumor growth in the MC38 mouse colorectal tumor model.
The MC38 mouse colorectal cancer model described in Example #7 was used to evaluate the anti-tumor activity of DR-18 alone and in combination with an anti-LAG3 ICI in colorectal cancer.

Mice bearing established MC38 tumors were treated with DR-18 alone (five IP doses at 0.32 mpk BIW, with the final dose on study day 15), anti-LAG3 antibody alone (five IP doses at 10 mpk BIW), or the combination of DR-18 and anti-LAG3 (at the same doses as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle only (i.e., without DR-18 or any ICI). As an assay for cancer growth, tumor size (mm3) was measured over time in each animal during the course of the study.

As can be seen in Figure 5, tumors grew rapidly in untreated vehicle control mice and mice treated with anti-LAG3 monotherapy. In comparison, tumor growth was significantly reduced in mice treated with a combination therapy containing DR-18 and an anti-LAG3 antibody. However, it should be noted that DR-18 monotherapy also significantly reduced tumor growth compared to either the vehicle control or anti-LAG3 monotherapy. Collectively, this example demonstrates that combining DR-18 with anti-LAG3 ICI therapy has effective anti-colorectal tumor activity superior to anti-LAG3 ICI therapy alone.

Example #9: Combination therapy of DR IL-18 polypeptide and anti-PD-1 ICI antibody reduces tumor growth and improves treatment response in a mouse heme tumor model.
The antitumor activity of DR IL-18 polypeptides alone and in combination with anti-PD-1 ICIs in hematologic cancers was evaluated using various hematologic tumor mouse models, including MPC-11 (myeloma), A-20 (B-cell lymphoma), and C1498 (acute myeloid leukemia). MPC-11 (Merwin Plasma Cell tumor-11) is a murine plasma cell myeloma with an H-2d haplotype that is commercially available and commonly used for anti-cancer immunotherapy efficacy and other studies. A-20 is a cell line derived from a spontaneous reticulum cell sarcoma that is commercially available and commonly used for B-cell lymphoma studies, including anti-cancer immunotherapy efficacy and other studies. C1498 is an aggressive acute myeloid leukemia (AML) cell line derived from a spontaneous C57BL/6 mouse that is commercially available and commonly used for AML studies, including anti-cancer immunotherapy efficacy and other studies.

To establish the model, MPC-11, A-20, or C1498 cells were implanted as xenografts into host mice and allowed to engraft and form tumors. Mice were treated with DR IL-18 polypeptide alone (5 IP doses at 0.32 mpk BIW, with the final dose on study day 15), anti-PD-1 antibody alone (5 IP doses at 10 mpk BIW), or the combination of DR IL-18 polypeptide and anti-PD-1 (at the same doses as the corresponding monotherapy). Untreated "vehicle" controls received the delivery vehicle only (i.e., without DR IL-18 polypeptide or any ICI).

Both DR IL-18 polypeptide monotherapy and DR IL-18 polypeptide + anti-PD-1 antibody ICI combination therapy demonstrated reduced tumor growth compared to vehicle control and anti-PD-1 antibody ICI monotherapy. In addition to tumor growth inhibition, mice were also evaluated for treatment response using a pseudoclinical scoring scale that correlates with the scoring used for partial response (PR) and complete response (CR) in human clinical trials. In the A-20 tumor model, improved responses were observed in mice treated with combination therapy (DR IL-18 polypeptide + anti-PD-1 antibody ICI) compared to DR IL-18 polypeptide monotherapy. Treatment with DR IL-18 polypeptide monotherapy resulted in 60% CR and 40% PR, while treatment with the combination therapy resulted in 87.5% CR and 12.5% PR. In summary, this example demonstrates that combining a DR IL-18 polypeptide with anti-PD-1 ICI therapy has effective anti-heme (e.g., anti-myeloma, anti-B cell lymphoma, and anti-AML) tumor activity superior to monotherapy with an anti-PD-1 ICI, and results in an improved therapeutic response compared to DR IL-18 polypeptide monotherapy.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Amino acid sequence SEQ ID NO: 1
Variant of SEQ ID NO: 10 (C38S/C68S)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKSEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 1)
SEQ ID NO: 2
Variant of SEQ ID NO: 10 (C38S/C68G)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKGEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 2)
SEQ ID NO: 3
Variant of SEQ ID NO: 10 (C38S/C68A)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKAEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 3)
SEQ ID NO: 4
Variant of SEQ ID NO: 10 (C38S/C68V)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKVEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 4)
SEQ ID NO: 5
Mutant of SEQ ID NO: 10 (C38S/C68D)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKDEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 5)
SEQ ID NO: 6
Variant of SEQ ID NO: 10 (C38S/C68E)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKEEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 6)
SEQ ID NO:7
Variant of SEQ ID NO: 10 (C38S/C68N)
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDSRDNAPRTIFIISKYSDSLARGLAVTISVKNEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 7)
SEQ ID NO:8
Variant of SEQ ID NO: 13 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYGDSGARGLAVTISVKCEKIISTLSCENKIISFKEMNPPDNIKDTKSDIIFFERDVPGHSGKVQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 8)
SEQ ID NO:9
Variant of SEQ ID NO: 13 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYGDSRPRGMAVTISVKCEKIISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRAVPGHNRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 9)
SEQ ID NO: 10
Variant of SEQ ID NO: 13 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSLARGLAVTISVKCEKIISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRDVPGHSRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 10)
SEQ ID NO: 11
Variant of SEQ ID NO: 13 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSRARGLAVTISVKCEKIISTLSCENKIISFKEMNPPDNIKDTKSDIIFFARSVPGHGRKTQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 11)
SEQ ID NO: 12
Variant of SEQ ID NO: 13 YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISKYSDSRARGLAVTISVKCEKIISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRNVPGHGRKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 12)
SEQ ID NO: 13
Wild type IL-18
YFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCEN KIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED
(SEQ ID NO: 13)

Claims (20)

A method of treating a disease in a subject in need of such treatment, the method comprising administering to the subject (a) a decoy-resistant (DR) IL-18 composition comprising a DR IL-18 polypeptide or a nucleic acid encoding the DR IL-18 polypeptide, and (b) an immune checkpoint inhibitor (ICI) composition, wherein the ICI is not pembrolizumab; and optionally, (c) the ICI is selected from the group consisting of aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotlimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, and pembrolizumab. , penprimab, peresolimab, pidilizumab, pimivalimab, pradu-sinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimbelelimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstbalt, betifisolimab, cosibelimab, dur Valmab, embafolimab, galibrimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, suduplilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstotsug, filastotsug, gothistotsug, ipilimumab, muzastotsug, nurlimab, polstotsug, quabonlimab, sobipostotsug, tremelimumab, tubonlarimab, vilastotsug (d) the method is selected from the group consisting of: rituximab, zalifrelimab, enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, relatolimab, tuparstbalt, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and variants of any of the foregoing; (d) the method comprises administering to the subject an additional treatment that reduces the presentation of symptoms of cytokine release syndrome (CRS); or (e) both (c) and (d). The method of claim 1, wherein the method includes an additional treatment, and the additional treatment includes CRS prophylaxis administered together with or prior to the DR IL-18 composition. 3. The method of claim 2, wherein the method comprises administering to the subject multiple doses of a CRS preventative agent comprising at least one dose of an NSAID and at least one dose of a histamine H1 antagonist, at least one dose of acetaminophen and at least one dose of a histamine H1 antagonist, at least one dose of an NSAID and at least one dose of acetaminophen, or at least one dose of an NSAID, at least one dose of a histamine H1 antagonist, and at least one dose of acetaminophen, optionally wherein the NSAID is selected from indomethacin and ibuprofen, and the histamine H1 antagonist is diphenhydramine. (i) the NSAID is oral indomethacin administered at 50 mg to 100 mg per day, optionally 75 mg per day, or oral ibuprofen administered at 600 mg to 2,400 mg per day, optionally 800 mg to 1,800 mg per day;
(ii) the histamine H1 antagonist is intravenous or oral diphenhydramine administered at a dose of 25 mg to 100 mg, optionally 50 mg;
(iii) the acetaminophen is oral acetaminophen administered at 350 mg to 4,000 mg per day, optionally 650 mg to 3,900 mg per day, or (iv) any combination thereof. The method of any one of the preceding claims, wherein administering the CRS prophylactic agent reduces the presentation of one or more symptoms of CRS compared to a comparable subject who has not received the CRS prophylactic agent, a comparable subject who has not received the CRS prophylactic agent and is receiving treatment comprising administration of about 30 μg/kg or more of the DR IL-18 composition, or both. The method of any one of the preceding claims, wherein the DR IL-18 polypeptide comprises multiple mutations compared to wild-type IL-18 as set forth in SEQ ID NO: 13. A method according to any of the preceding claims, wherein the DR IL-18 polypeptide comprises an amino acid sequence having at least 90%, at least 95%, at least 98%, or 100% sequence identity to any one of SEQ ID NOs: 1-12. The method of any one of the preceding claims, wherein the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5. The method of any one of the preceding claims, wherein the DR IL-18 composition comprises at least about 15 μg, at least about 20 μg, or at least about 30 μg of the DR IL-18 polypeptide per kg of the subject's body weight. The method of any one of the preceding claims, wherein the disease comprises cancer. The method of claim 10, wherein the cancer is selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC (without epidermal growth factor receptor, TRK receptor, or anaplastic lymphoma kinase positive mutation/fusion), TNBC, SCCHN, MSI-H, TMB-H or mismatch repair deficient, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, and the cancer is resistant to one or more ICIs, or the cancer is selected from platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. The method of claim 10, wherein the cancer is a liquid tumor selected from the group consisting of myeloma, lymphoma, and leukemia. administering to the subject one or more doses of a CRS prophylactic agent with or before each dose of the sequential doses of the DR IL-18 composition, wherein the CRS prophylactic agent comprises at least one of an NSAID, a histamine H1 antagonist, acetaminophen, or an H2 blocker;
(i) the polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5;
(ii) said dose of said DR IL-18 composition comprises at least about 30 μg of said polypeptide per kg of body weight of said subject;
(iii) The method of any one of the preceding claims, wherein the disease comprises an ICI-resistant solid tumor selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. The method of any one of the preceding claims, wherein the ICI binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3. The method of claim 14, wherein the ICI is an anti-LAG-3 antibody or antigen-binding fragment thereof, and optionally the anti-LAG-3 antibody or antigen-binding fragment thereof is enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, leratolimab, or tuparstbalt. The ICI is a PD-1 checkpoint inhibitor, optionally a PD-1 antagonist, a PD-L1 antagonist, or a PD-L2 inhibitor, and optionally the PD-1 checkpoint inhibitor is aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotrimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sa Sanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimvelerimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstwald, betifisolimab, cosibelimab, durvalumab , emvafolimab, galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, sudublilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, and BGB-A333. administering to the subject one or more CRS prophylactic agents together with or prior to the DR IL-18 composition, wherein the one or more CRS prophylactic agents comprise an NSAID, a histamine H1 antagonist, acetaminophen, an H2 blocker, or a combination thereof;
(i) the DR IL-18 polypeptide is a modified IL-18 polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5;
(ii) the DR IL-18 composition comprises at least about 30 μg of the polypeptide per kg of the patient's body weight;
(iii) the ICI composition comprises an ICI that binds to at least one of PD-1, PD-L1, PD-L2, B7-1, CD28, CTLA-4, LAG-3, or B7-H3;
(iv) The method of any one of claims 10 to 16, wherein the disease comprises an ICI checkpoint inhibitor-resistant solid tumor selected from the group consisting of melanoma, Merkel cell carcinoma, RCC, urothelial, NSCLC, TNBC, SCCHN, MSI-H tumors, TMB-H or mismatch repair deficient tumors, gastric, cervical, endometrial, squamous skin, small cell lung, esophageal, HCC, or any combination thereof, or platinum-resistant ovarian cancer or microsatellite-stable colorectal cancer. The method of any one of the preceding claims, wherein the disease is cancer or tumor, and the method thereby results in one or more improvements in the patient's cancer or tumor. Use of an ICI composition, a DR IL-18 composition, or a combination thereof in a method for treating cancer according to any one of the preceding claims. A therapeutic composition comprising: (a) an effective amount of a decoy-resistant (DR) IL-18 polypeptide; and (b) an effective amount of an ICI, wherein the ICI is not pembrolizumab, and optionally the ICI is selected from the group consisting of aclixolimab, balstilimab, budigalimab, camrelizumab, cemiplimab, cetrelimab, dostarimab, enronstbalt, ezabenlimab, phynotlimab, geptanolimab, ipalomulimab, lipstbalt, nivolumab, nofazinelimab, pembrolizumab, Penprimab, peresolimab, pidilizumab, pimivalimab, pradusinstbalt, prorugolimab, pucotenlimab, retifanlimab, rosnilimab, ruronilimab, sasanlimab, serplulimab, sintilimab, spartalizumab, tislelizumab, toripalimab, zelvalimab, zimbelelimab, INCMGA00012, MEDI0680, SSI-361, AMP-224, adeburelimab, atezolizumab, avelumab, bemmelstbalt, betifisolimab, cosibelimab, durval Mab, embafolimab, galiflimab, resabelimab, rodapolimab, manelimab, opucolimab, pakmilimab, socazolimab, suduplilimab, sugemalimab, tagitanlimab, CA-170, BMS-986189, BMS-936559, CBT-502, BGB-A333, botencilimab, evalstuzumab, filastuzumab, gothistuzumab, ipilimumab, muzastuzumab, nurulimab, polstuzumab, quabonlimab, sobipostuzumab, tremelimumab, tubonlarimab, vilastuzumab, za A therapeutic composition selected from the group consisting of rifrelimab, enselimab, favezelimab, fianlimab, yelamilimab, miptenalimab, negalstbalt, leratolimab, tuparstbalt, enoblituzumab, ifinatamab, mirzotamab, omburtamab, vovlamitamab, and variants of any of the foregoing, optionally formulated for intravenous administration, and optionally further comprising a buffering agent, a stabilizer, a surfactant, an antioxidant, a solvent, or any combination thereof.