Novel cancer treatment using IL-2 conjugates

Abstract

The present invention relates to an IL-2 conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the IL-2 conjugate is administered in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg, and the IL-2 conjugate is of formula (I); and related embodiments.

Description

[Technical Field]

[0001] The present invention relates to an IL-2 conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the IL-2 conjugate is administered in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg, and the IL-2 conjugate is of formula (I); and related embodiments. [Background technology]

[0002] In healthy individuals, the immune system can often distinguish between healthy and cancerous cells. When it identifies a given cell as cancerous, the immune system typically eliminates it. However, if the immune system is impaired or overwhelmed, for example due to acute or chronic defects, cancer can develop because the impaired immune system is unable to distinguish and eliminate cancer cells. In patients with cancer, administering immunomodulatory proteins can help activate the patient's immune system to enhance its ability to eliminate cancer cells. In this way, cancer may be slowed down, its potential for expansion suppressed, or even eliminated.

[0003] One such immunomodulatory protein used to treat patients with certain cancers is interleukin-2 (IL-2). IL-2 is a naturally occurring cytokine that acts as a stimulant for both natural killer (NK) cells and T cells, resulting in proliferation and functional activity. IL-2 plays a central role in the generation, differentiation, survival, and homeostasis of immune effector cells. IL-2 is activated by CD4 + Synthesized by helper T cells, IL-2 can modulate the immune response toward immunity or tolerance through different receptor interactions.

[0004] IL-2 acts by binding to the IL-2 receptor (IL-2R). The association of the α(CD25), β(CD122), and common γ(γc,CD132)-subunits results in the high-affinity trimer IL-2Rα / β / γ. The medium-affinity dimeric IL-2Rβ / γ consists of the β- and γ-subunits and binds to IL-2 with 1 / 50th the affinity. CD25 is not required for IL-2 signaling but confers high-affinity binding to the trimer receptor, while the β- and γ-subunits mediate signaling. IL-2Rβ / γ is used by NK cells, monocytes, macrophages, and resting CD4 cells. + and CD8 + Although expressed on T cells, IL-2Rα / β / γ are transiently induced on activated T and NK cells and constitutively expressed on regulatory T cells. IL-2's ability to proliferate and activate innate and adaptive effector cells is the basis of its antitumor activity.

[0005] In patients, IL-2, when administered at high doses (i.e., 600,000–720,000 IU / kg body weight three times daily, up to 14 doses / cycle in humans), can stimulate antitumor efficacy characterized by an increase in cytotoxic lymphocytes, including effector T and NK cells. Presumably, during this treatment, all T cells are stimulated by IL-2 after high-dose administration, and once the treatment cycle ends and IL-2 levels decline at some point, regulatory T (Treg) cells expressing IL-2Rα / β / γ will overcome effector T cells expressing IL-2Rβ / γ with respect to the remaining wild-type IL-2.

[0006] Aldesleukin, a recombinant human IL-2, was the first cancer immunotherapy approved by the FDA in 1992. With appropriate supportive care, aldesleukin demonstrated complete cancer regression in approximately 10% of patients treated for metastatic melanoma and renal cancer. Approximately 70% of patients with a complete response were cured and maintained complete regression for more than 25 years after initial treatment.

[0007] Based on its antitumor efficacy, high-dose aldezleukin is approved for the treatment of patients with metastatic renal cell carcinoma and malignant melanoma. Aldesleukin is currently administered in doses of 37 μg / kg every 8 hours via 15-minute intravenous (IV) infusion, with a maximum of 14 doses, and the schedule may be repeated for another 14 doses after a 9-day rest period.

[0008] However, the antitumor immunity of IL-2 is limited in dose due to severe cardiovascular, pulmonary, hepatic, gastrointestinal, neurological, and hematological side effects, and therefore it is administered only to patients in specialized facilities. Furthermore, if the administered IL-2 level falls below the level required for IL-2Rβ / γ activity, activation of Tregs expressing high-affinity IL-2Rα / β / γ may be prioritized, limiting the antitumor immunity. For this reason, it is essential that the dose of IL-2 is sufficiently high to maintain IL-2 levels above the required threshold while ensuring tolerable side effects.

[0009] Preclinical experiments have shown that IL-2-induced pulmonary edema (as a model of vasoleap syndrome) can be induced by the interaction of IL-2 with CD25 on pulmonary endothelial cells, and that this can be reversed by the use of CD25 blocking antibodies, gene disruption, or IL-2 antibody conjugates. Another proposed mechanism by which IL-2 induces vasoleap syndrome involves eosinophil activation, as these cells can express IL-2Rα / β / γ, and IL-2 therapy in patients is accompanied by systemic elevations of eosinophil and IL-5 levels.

[0010] When administering long-acting IL-2, it is especially important to avoid excessively high doses, as excessively high doses can lead to more severe side effects than, for example, aldezleukin. [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] Therefore, there is a need for a more effective and safer treatment with an IL-2 conjugate, which is to at least partially overcome the drawbacks of the current cancer treatment using aldesleukin and the drawbacks observed for IL-2 conjugates that have been tested clinically for cancer treatment such as NKTR-214 and THOR-707. This is the object of the present invention.

Means for Solving the Problems

[0012] In a first aspect, the present invention relates to an IL-2 conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the IL-2 conjugate is administered at a dose in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg, and the IL-2 conjugate is of formula (I): D-L 1 -L 2 -Z (I) [Wherein, -D is -D'-M mod and where -D'- is the IL-2 moiety; -M mod is the first polymer moiety stably conjugated to the side chain of the amino acid residue of -D'; -L 1 - is a linker moiety covalently and reversibly attached to -D'; -L 2 - is either absent or a spacer moiety; -Z is the second polymer moiety].

[0013] The dose given as "X μg IL-2 / kg of IL-2 conjugate" means X μg of the IL-2 moiety -D' present in the IL-2 conjugate, i.e., the dosage for the IL-2 conjugate is given only with respect to -D', and other components present in the IL-2 conjugate, such as the first polymer moiety-M mod , the second polymer moiety -Z and any moiety -L 1- and -L 2 -Exclude

[0014] In a second aspect, the present invention relates to a method for treating a patient with cancer, comprising the step of administering to the patient an IL-2 conjugate of formula (I) or a pharmaceutically acceptable salt thereof in a dose ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg: DL 1 -L 2 -Z (I) [In the formula, -D is -D'-M mod And, Here, -D'- is the IL-2 part; -M mod This is the first polymer moiety stably conjugated to the side chain of the -D'- amino acid residue; -L 1 - is a linker portion covalently and reversibly bonded to -D'-; -L 2 - indicates either non-existent or a spacer portion; -Z is the second polymer portion.

[0015] In a third aspect, the present invention relates to an IL-2 conjugate or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical for the treatment of cancer, wherein the IL-2 conjugate is administered in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg, and the IL-2 conjugate is of formula (I), and the present invention relates to an IL-2 conjugate or a pharmaceutically acceptable salt thereof: DL 1 -L 2 -Z (I) [In the formula, -D is -D'-M mod And, Here, -D'- is the IL-2 part; -M mod This is the first polymer moiety stably conjugated to the side chain of the -D'- amino acid residue; -L 1- is a linker portion covalently and reversibly bonded to -D'-; -L 2 - indicates either non-existent or a spacer portion; -Z is the second polymer portion.

[0016] In a fourth aspect, the present invention relates to a unit dosage form comprising a unit dose of an IL-2 conjugate or a pharmaceutically acceptable salt thereof, comprising 80 μg / kg to 160 μg / kg IL-2, wherein the IL-2 conjugate is of formula (I): DL 1 -L 2 -Z (I) [In the formula, -D is -D'-M mod And, Here, -D'- is the IL-2 part; -M mod This is the first polymer moiety stably conjugated to the side chain of the -D'- amino acid residue; -L 1 - is a linker portion covalently and reversibly bonded to -D'-; -L 2 - indicates either non-existent or a spacer portion; -Z is the second polymer portion.

[0017] Surprisingly, doses of the IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg were found to be both safe and effective. This was unexpected, as other IL-2 drugs are administered at lower doses. For example, NKTR-214 is an IL-2 conjugate consisting of aldesleukin reversibly conjugated to six PEG chains. The highest dose of NKTR-214 tested was 12 μg IL-2 / kg, which caused dose-limiting toxicity, and the recommended phase 2 dose (RP2D) for NKTR-214 is 6 μg IL-2 / kg administered every three weeks (Bentebibel, et al. Cancer Discov. 2019;9(6):711-721). Another example is THOR-707 (SAR444245), which is an IL-2 conjugate consisting of an IL-2 protein in which the proline at position 65 is substituted with the unnatural amino acid N6-(2-azidoethoxy)-carbonyl-l-lysine (AzK) and which is stably PEGylated by a 30kDa mPEG moiety. THOR-707 was tested in dose-escalation studies up to a maximum dose of 40 μg IL-2 / kg every two or three weeks, and the RP2D for THOR-707 was 24 μg IL-2 / kg every two or three weeks for monotherapy and in combination with pembrolizumab (Falchook, et al. Journal for ImmunoTherapy of Cancer, 2021;9:doi: 10.1136 / jitc-2021-SITC2021.481;Falchook, et al. Annals of Oncology, 2022, 33, S885-S886; Clinical trial registration number NCT04009681).

[0018] Within the scope of the meaning of this invention, the terms are used as follows:

[0019] The term "patient" refers to a subject, particularly a human subject, who is the subject of treatment or prevention according to the present invention.

[0020] As used herein, the term “dose” refers to a predetermined amount of a drug, such as IL-2, administered at a single time point to produce a certain degree of biological response in a patient. The phrase “at a single time point” is understood to include the fact that the dose may be administered to a patient in one or more doses, and that these two or more doses may be administered sequentially or concurrently. In the case of sequential administration, the time between the two doses may range from 10 seconds to 8 hours, for example, from 1 minute to 4 hours, 2 minutes to 2 hours, or 5 minutes to 1 hour.

[0021] As used herein, the term "unit dose" refers to the amount of drug administered to a patient in a single dose.

[0022] A "unit dosage form" refers to a dosage form configured for a single dose to a patient. For example, a unit dosage form may be a single vial or other container containing a suitable amount of drug for a single dose, such as a dual-chamber cartridge, ampoule, or syringe. An infusion bag may also be a suitable container.

[0023] As used herein, the term “medication regimen” refers to a combination of dose and frequency by which a drug is administered. A medication regimen may also include the route of administration (e.g., intravenous) and / or the duration of administration.

[0024] As used herein, the term “therapeutic dose” refers to an amount sufficient to cure, alleviate, or partially cessate the clinical symptoms of a given disease and its complications. The effective dose for each purpose will depend on the severity of the disease or injury, as well as the subject’s weight and overall condition. Within the scope of the present invention, “therapeutic dose” refers to a dose that achieves a therapeutic effect over a long period of time, i.e., at least one day, e.g., two days, e.g., three days, e.g., one week, e.g., two weeks, e.g., three weeks, e.g., four weeks, e.g., eight weeks or longer.

[0025] As used herein, the term “drug” refers to a substance used to treat, cure, prevent or diagnose a disease, or otherwise enhance a patient’s physical or mental health. When a drug, such as IL-2, is conjugated to another part, the resulting product derived from the drug is referred to as the “drug part.”

[0026] Any reference in this specification to a biological drug, i.e., a drug manufactured in, extracted from, or semi-synthesized from, a biological source, such as a protein drug, also applies to a biosimilar version of said drug.

[0027] The IL-2 conjugate of the present invention is understood to be a prodrug.

[0028] As used herein, the term “prodrug” refers to a drug moiety reversibly and covalently linked to a special protecting group via a reversible prodrug linker moiety, which is a linker moiety containing a reversible bond to the drug moiety, the special protecting group altering or removing undesirable properties in the parent molecule. This also includes enhancing desired properties and suppressing undesirable properties in the drug. The special non-toxic protecting group may also be referred to as a “carrier,” such as -Z. The prodrug releases the reversibly and covalently linked drug moiety in the form of its corresponding drug. In other words, the prodrug is, for example, -L 1 -A conjugate comprising a drug moiety covalently and reversibly conjugated to a carrier moiety via a reversible linker moiety such as -L, wherein the covalent and reversible conjugation of the carrier to the reversible linker moiety is direct or, for example, -L 2- Via spacers such as. Reversible linkers may also be referred to as "reversible linkers" or "reversible prodrug linkers." Such conjugates can release the previously conjugated drug portion in the form of a free drug, in which case the reversible linker or reversible prodrug linker is a traceless linker. The free drug released from the conjugate of the present invention is, in relation to it, a portion M mod It is understood that this is an IL-2 protein that is covalently conjugated.

[0029] A "reversible bond" is a bond that can be degraded, or cleaved, under physiological conditions (aqueous buffer at pH 7.4 and 37°C) in the absence of enzymes, with a half-life ranging from 1 hour to 3 months. A "stable bond" is a bond that has a half-life of more than 3 months under physiological conditions (aqueous buffer at pH 7.4 and 37°C) in the absence of enzymes.

[0030] As used herein, the term “free form” of a drug refers to the drug in its unmodified, pharmacologically active form, for example, after it has been released from an IL-2 conjugate or a pharmaceutically acceptable salt thereof. The free drug released from the conjugate of the present invention is, in contrast, a partial M mod It is understood that this is an IL-2 protein that is covalently conjugated.

[0031] As used herein, the term “spacer” refers to a portion that connects at least two other portions to one another.

[0032] Generally, the term "interleukin-2" or "IL-2" refers to all IL-2 proteins, including those of mammalian origin, such as primate species, particularly human IL-2 proteins, as well as their variants, analogs, orthologues, homologs, derivatives, and fragments, characterized by their central role in lymphocyte generation, survival, and homeostasis. It also includes naturally occurring variants of IL-2, such as splicing variants or allele variants. Human wild-type IL-2 has the amino acid sequence of SEQ ID NO: 29: TIFF2026517863000001.tif23169

[0033] As used herein, the term “bias IL-2” means the K of bias IL-2 relative to IL-2Rβ. D K of the bias IL-2 relative to IL-2Rα D The ratio of is the ratio of aldesleukin of sequence number 2 to IL-2Rβ. D K for aldesleukin against IL-2Rα D This refers to a modified IL-2 with a ratio greater than [the specified value]. This is described by the following formula:

[0034]

number

number

[0035] Aldesleukin has the following sequence (SEQ ID NO: 2): TIFF2026517863000004.tif26169

[0036] K of bias IL-2 relative to IL-2Rα D , K for IL-2Rβ of biased IL-2 D , K of aldesleukin against IL-2Rα D , and K for aldesleukin against IL-2Rβ D The binding affinity / kinetics necessary to determine this can be evaluated using surface plasmon resonance (SPR) measured with a Biacore instrument (GE Healthcare) as follows: A human Fc capture surface on a CM5 (or alternatively C1 or CM4) chip is prepared by covalent coating with an anti-human Fc antibody, or alternatively, a Protein A chip is used. Next, IL-2Rβ-Fc or IL-2Rα-Fc is immobilized on the chip. To measure the affinity / kinetic constant, serial dilutions of the sample are prepared with respect to the IL-2 compound, for example, between 1 nM and 2 μM, or starting from 30 nM and 500 nM. Each sample is exposed to the receptor-modified chip for a suitable time, e.g., 1 to 30 minutes (which may be 2 minutes or 3 minutes), and then washed off for a suitable time, e.g., 2 to 60 minutes (which may be 10 minutes). The coupling curves obtained from the dilution series are fitted to a 1:1 kinetic model, and the observed response unit (R) is used as the coupling rate constant and dissociation rate constant k. a and k d To associate:

[0037]

number

[0038] When determined via a kinetic 1:1 model, the ratio of dissociation rate to binding rate is given by the equilibrium dissociation constant K. D To provide.

[0039] Alternatively, the binding curve obtained from the dilution series can be used to determine the steady-state binding level (R) relative to the sample concentration (C). eq ) plot regarding K for 1:1 interaction D A 1:1 steady-state interaction model to calculate:

[0040]

number

[0041] It should be understood that not every calculation method is necessarily possible for every biased IL-2 molecule. For example, if the reaction is too fast, it may not be possible to use a 1:1 kinetic model, and a 1:1 steady-state interaction model may be used instead. For example, if equilibrium is not obtained, it may not be possible to use a 1:1 interaction model, and a 1:1 kinetic model may be used instead.

[0042] As used herein, the term “affinity” refers to the sum of the non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). Unless otherwise indicated herein, “affinity” refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., between a receptor and a ligand). The affinity of a molecule X for its partner Y is generally expressed by the dissociation rate constant and binding rate constant (k, respectively) measured at equilibrium. d and k a The equilibrium dissociation constant (K) is the ratio of (K) to (K). D It can be expressed by ). Therefore, equivalent affinity may include different rate constants, as long as the ratio of rate constants remains the same. Affinity can be measured by well-established methods known in the art, including the methods described herein.

[0043] As used herein, the terms “α-subunit of the IL-2 receptor” and “IL-2Rα” refer to human CD25. As used herein, the terms “β-subunit of the IL-2 receptor” and “IL-2Rβ” refer to human CD122. As used herein, the terms “γ-subunit of the IL-2 receptor” and “IL-2Rγ” refer to human CD132.

[0044] "Treating" means curing, reducing, or inhibiting the further worsening of at least one sign or symptom of the disease, or stabilizing at least one sign or symptom of the disease. Treatment can be determined by comparing the signs and symptoms of an individual patient before and after treatment (baseline), or by comparing a group of treated patients to a control group as in clinical trials or studies in animal models.

[0045] As used herein, the terms “PD-L1 positive” or “PD-L1 expression positive” refer to tumor tissue in which at least 1 percent of all tumor cells express PD-L1, for example, a test tissue sample.

[0046] As used herein, the terms “PD-L1 negative” or “PD-L1 expression negative” refer to tumor tissue in which less than 1% of all tumor cells express PD-L1, for example, a test tissue sample.

[0047] As used herein, the term "PD-L1 expression" refers to a detectable level of either PD-L1 protein expression on the cell surface or PD-L1 messenger RNA (mRNA) expression within cells or tissues. PD-L1 protein expression can be detected using a diagnostic PD-L1 antibody in an immunohistochemistry (IHC) assay of tumor tissue sections or by flow cytometry. Alternatively, PD-L1 protein expression by tumor cells can be detected by positron emission tomography (PET) imaging using a binder such as an antibody fragment or affibody that specifically binds to PD-L1. Techniques for detecting and measuring PD-L1 mRNA expression include real-time polymerase chain reaction (RT-PCR) and quantitative RT-PCR.

[0048] As used herein, the terms “PD-1 positive” or “PD-1 expression positive” in relation to programmed cell death protein 1 (PD-1) expression mean cells that express PD-1, for example, CD8 + This refers to tumor tissue, such as a test tissue sample, that is scored for expressing PD-1 based on the proportion, for example, the percentage, of immune cells such as T cells and other tumor-infiltrating lymphocytes.

[0049] As used herein, the terms “PD-1 negative” or “PD-1 expression negative” refer to tumor tissue, such as a test tissue sample, that is not scored as expressing PD-1.

[0050] As used herein, the term "PD-1 expression" refers to a detectable level of either PD-1 protein expression on the cell surface or PD-1 mRNA expression within cells or tissues. PD-1 protein expression can be detected using a diagnostic PD-1 antibody in an IHC assay of tumor tissue sections or by flow cytometry. Alternatively, PD-1 protein expression by immune cells can be detected by PET imaging using a binder such as an antibody fragment or affibody that specifically binds to PD-1. Techniques for detecting and measuring PD-1 mRNA expression include RT-PCR and real-time quantitative RT-PCR.

[0051] As used herein, the term “intratumor administration” refers to a mode of administration in which a drug is administered directly into tumor tissue. In certain embodiments, the term “intratumor administration” may also refer to administration into or on the tumor bed before or after resection. Where the tumor boundary is not clearly defined, intratumor administration is also understood to include administration to tissue adjacent to tumor cells (“peritumor administration”). Exemplary tumors for intratumor administration are solid tumors and lymphomas, which are disclosed in more detail elsewhere herein. Administration may be carried out by injection.

[0052] "Prevention" means preventing, reducing the risk of, or delaying the onset of at least one sign or symptom of a disease in a population of patients (or animal models) at risk of the disease being administered according to the present invention, compared to a control population (or animal model) of patients at risk of the disease not being treated with the drug according to the present invention. A dose is also considered preventively effective if an individual treated patient achieves a more favorable outcome than the mean outcome in a control population of equivalent patients not treated by the method of the present invention.

[0053] As used herein, the term “reagent” means a compound containing at least one functional group for reaction with the functional group of another compound or drug. A drug containing a functional group (e.g., a primary or secondary amine, or a hydroxyl functional group) is also understood to be a reagent.

[0054] As used herein, the term “part” means a portion of a molecule that lacks one or more atoms compared to the corresponding reagent. For example, when a reagent of the formula “HXH” reacts with another reagent to become a portion of a reaction product, the corresponding portion of the reaction product has the structure “HX-” or “-X-”, where each “-” indicates a bond to another portion. Thus, the drug portion is released as a drug from a reversible bond.

[0055] Given an arrangement or chemical structure of atoms bonded to or interspersed between two parts, it is understood that such arrangement or chemical structure can bond to these two parts in either direction, unless otherwise explicitly stated. For example, part "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 It can be joined to two parts as either )C(O)- or intercepted in a part. Similarly, part [ka] teeth, [ka] or [ka] It can be joined to two parts as either one of them, or it can be inserted into a part.

[0056] As used herein, the term “substituted” means that one or more -H atoms in a molecule or part are replaced by different atoms or groups of atoms called “substituents.”

[0057] As used herein, the term "substituent" in certain embodiments refers to halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 , -C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 , -S(O)R x1 , -N(R x1 ), -N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R x1a ), -N(R x1 ), -N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-50 alkyl, C, 2-50 alkenyl, and C 2-50 alkynyl, where -T 0 , C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted by one or more -R x2 s, and C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3)-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- is optionally interrupted by one or more units selected from the group consisting of, -R x1 ,-R x1a ,-R x1b -H, -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 They are independently selected from a group consisting of alkynnyls, where -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has one or more -Rs, which may be the same or different. x2 Replaced by optional means, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-;-S(O)2-,-S(O)-,-N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- is optionally interrupted by one or more units selected from the group consisting of, Each T 0Phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl, each T 0 is one or more -Rs, which may be the same or different. x2 It is independently and arbitrarily replaced by, Each-R x2 These are halogen, -CN, oxo (=O), and -COOR. x4 , -OR x4 , -C(O)R x4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different. Each-R x3 ,-R x3a ,-R x4 ,-R x4a ,-R x4b -H and C 1-6Independently selected from the group consisting of alkyls, where C 1-6 The alkyl group is optionally substituted with one or more halogens, either the same or different.

[0058] In certain embodiments, up to six -H atoms of the optionally substituted molecule are independently replaced by substituents, for example, five -H atoms are independently replaced by substituents, four -H atoms are independently replaced by substituents, three -H atoms are independently replaced by substituents, two -H atoms are independently replaced by substituents, or one -H atom is independently replaced by a substituent.

[0059] As used herein, the term “peptide” refers to a chain of at least two and no more than 50 amino acid monomer moieties linked by peptide (amide) bonds. The term “peptide” also includes peptide mimes, such as D-peptides, peptoids, or beta-peptides, and encompasses such peptide mimetic chains having no more than 50 monomer moieties.

[0060] As used herein, the term “protein” refers to a chain of more than 50 amino acid monomer moieties (which may also be called “amino acid residues”) linked by peptide bonds, in certain embodiments, 12,000 or fewer amino acid monomers, e.g., 10,000 or fewer amino acid monomer moieties, 8,000 or fewer amino acid monomer moieties, 5,000 or fewer amino acid monomer moieties, or 2,000 or fewer amino acid monomer moieties linked by peptide bonds.

[0061] In the context of amino acid sequences, it is understood that each letter represents a single-letter code for an amino acid and does not represent a chemical atom.

[0062] The deletion or insertion of one or more amino acids in a sequence, such as sequence number 1, may alter the number, i.e., the position, of a particular amino acid within that sequence, and in such cases, it is understood that a corresponding, i.e., homologous amino acid position is included. This may be indicated by the phrase "or the corresponding position of its homolog or variant," but such corresponding positions are included even in the absence of this phrase.

[0063] As used herein, the terms “identical” and “identity” percentage in the context of two or more polynucleotide or polypeptide / protein sequences refer to two or more sequences or subsequences having the same or identical percentage of nucleotide or amino acid residues when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm. An example of such an algorithm preferred for determining sequence identity percentages is the BLAST algorithm (Altschul et al., J. Mol. Biol., 215: 403-410 (1990); Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA, 89: 10915 (1989); Karlin & Altschul, Proc. Natl. Acad. Sci. USA, 90: 5873 5787 (1993)). Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information.

[0064] As used herein, the terms “about” or “approximately” in combination with a number are used to indicate a range (inclusive) of plus or minus 10% of the number. For example, the phrase “about 200” is used to mean a range (inclusive) of 200 ± 10%, i.e., a range (inclusive) of 180 to 220. A percentage indicated as “about 50%” is understood to mean a range (inclusive) of 45 to 55%, i.e., a range (inclusive) of plus or minus 10% of the number 50, rather than “50% ± 10%,” i.e., a range (inclusive) of 40 to 60%.

[0065] As used herein, the term “polymer” means a molecule comprising repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, cross-linked, or dendrimer manner, or in combination thereof, which may be of synthetic origin, bio-origin, or a combination of both. It is understood that polymers may also contain one or more other chemical groups and / or parts(s), such as one or more functional groups. Similarly, peptides or proteins are also understood to be polymers, although the side chains of the individual amino acid residues may differ. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, for example, at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, in certain embodiments the polymer may have molecular weights of up to 1000 kDa, e.g., up to 750 kDa, e.g., up to 500 kDa, e.g., up to 300 kDa, e.g., up to 200 kDa, e.g., up to 100 kDa. For insoluble polymers such as hydrogels, it is understood that a meaningful molecular weight range cannot be provided.

[0066] As used herein, the term “polymer” means a reagent or part comprising one or more polymers or polymer parts / parts. A polymer reagent or part may optionally also contain one or more other parts / parts, which in certain embodiments are selected from the group consisting of: ·C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and • Joins selected from the following groups: [ka] [In the formula, The dashed line indicates binding to a portion or the remainder of the reagent. -R and -R a [These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl.]

[0067] Those skilled in the art will understand that polymerization products obtained from polymerization reactions do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Therefore, as used herein, molecular weight range, molecular weight, monomer number range in a polymer, and monomer number in a polymer refer to the number-average molecular weight and monomer number average, i.e., the arithmetic mean of the molecular weight of the polymer or polymer portion, and the arithmetic mean of the monomer number of the polymer or polymer portion.

[0068] Therefore, in a polymer portion containing "x" monomer units, any integer substituted for "x" corresponds to the arithmetic mean of the monomers. Any range of integers substituted for "x" provides a range of integers in which the arithmetic mean of the monomers exists. An integer "x" expressed as "approximately x" means that the arithmetic mean of the monomers lies within the integer range of x ± 10%.

[0069] As used herein, the term “number-mean molecular weight” means the usual arithmetic mean of the molecular weights of individual polymers.

[0070] As used herein, the term “PEG-based” with respect to a portion or reagent means that the portion or reagent contains PEG. In certain embodiments, the PEG-based portion or reagent contains at least 10% (w / w) PEG, e.g., at least 20% (w / w) PEG, e.g., at least 30% (w / w) PEG, e.g., at least 40% (w / w) PEG, e.g., at least 50% (w / w) PEG, e.g., at least 60% (w / w) PEG, e.g., at least 70% (w / w) PEG, e.g., at least 80% (w / w) PEG, e.g., at least 90% (w / w) PEG, e.g., at least 95% (w / w) PEG. The remaining weight percentage of the PEG-based portion or reagent is other portions, which in certain embodiments are selected from the following portions and combinations: ·C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and • Joins selected from the group including the following: [ka] [In the formula, The dashed line indicates binding to a portion or the remainder of the reagent. -R and -R a[These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl.]

[0071] The term "hyaluronic acid-based" is used accordingly.

[0072] As used herein, the term “PEG system containing at least X% PEG” means that the part or reagent contains at least X% (w / w) ethylene glycol units (-CH2CH2O-), which may be arranged alternately in blocks or randomly distributed within the part or reagent, in a particular embodiment all of the ethylene glycol units of the part or reagent being in one block, and the remaining weight percentage of the PEG system part or reagent being another part, which in a particular embodiment is selected from the following parts and combinations: ·C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl, and • Joins selected from the group including the following: [ka] [In the formula, The dashed line indicates binding to a portion or the remainder of the reagent. -R and -R a[These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl.]

[0073] The term "hyaluronic acid-based product containing at least X% hyaluronic acid" is used accordingly.

[0074] The term "interrupted" means that a portion is inserted between two carbon atoms, or, if the insertion is at one of the ends of the portion, between a carbon or heteroatom and a hydrogen atom.

[0075] As used herein, the term "C 1-4 "Alkyl" refers to a linear or branched alkyl moiety, either alone or in combination, having 1 to 4 carbon atoms. When present at the end of a molecule, it refers to a linear or branched C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Two parts of the molecule are C 1-4 If bonded by alkyl, such C 1-4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-4 Each hydrogen atom of the alkyl carbon may be optionally replaced by a substituent as defined above. Optionally, C 1-4 The alkyl group may be interrupted by one or more parts as defined below.

[0076] As used herein, the term "C 1-6 "Alkyl" refers to a linear or branched alkyl moiety, either alone or in combination, having 1 to 6 carbon atoms. When present at the end of a molecule, it refers to linear and branched C 1-6Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. Two parts of the molecule are C 1-6 If bonded by an alkyl group, such C 1-6 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-6 Each hydrogen atom of carbon may be optionally replaced by a substituent as defined above. 1-6 The alkyl group may be interrupted by one or more parts as defined below.

[0077] Therefore, "C 1-10 Alkyl," "C 1-20 "Alkyl" or "C 1-50 "Alkyl" refers to an alkyl chain having 1 to 10, 1 to 20, or 1 to 50 carbon atoms, respectively. 1-10 , C 1-20 or C 1-50 Each hydrogen atom of carbon may be optionally replaced by a substituent as defined above. 1-10 or C 1-50 The alkyl group may be interrupted by one or more parts as defined below.

[0078] As used herein, the term "C 2-6 An "alkenyl" refers to a straight-chain or branched hydrocarbon moiety, either alone or in combination, containing 2 to 6 carbon atoms and at least one carbon-carbon double bond. When present at the ends of a molecule, examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. Two parts of a molecule are C 2-6 When bonded by an alkenyl group, such C 2-6An example of an alkenil is -CH=CH-. 2-6 Each hydrogen atom in the alkenyl moiety may be optionally replaced by a substituent as defined above. Optionally, C 2-6 An alkenil may be interrupted by one or more parts as defined below.

[0079] Therefore, the term "C 2-10 Alkenil, "C 2-20 "Alkenil" or "C 2-50 "Alkenyl" means a linear or branched hydrocarbon moiety, either alone or in combination, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms and containing at least one carbon-carbon double bond. 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may be optionally replaced by a substituent as defined above. Optionally, C 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 An alkenil may be interrupted by one or more parts as defined below.

[0080] As used herein, the term "C 2-6 "Alkynyl" refers to a linear or branched hydrocarbon moiety, either alone or in combination, containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond. When present at the end of a molecule, examples include -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of a molecule are linked by an alkynyl group, an example is -C≡C-. 2-6 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 Alkinyl may be interrupted by one or more parts as defined below.

[0081] Therefore, as used herein, the term "C 2-10 Alkinyl, C2-20 "Alkinyl" and "C 2-50 "Alkynyl" means a linear or branched hydrocarbon moiety, either alone or in combination, containing at least one carbon-carbon triple bond, each having 2 to 10, 2 to 20, or 2 to 50 carbon atoms, respectively. 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Each hydrogen atom of the alkynyl group may be optionally replaced by a substituent as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Alkinyl may be interrupted by one or more parts as defined below.

[0082] As mentioned above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 Alkenil, C 2-10 Alkenil, C 2-20 Alkenil, C 2-50 Alkenil, C 2-6 Alkinyl, C 2-10 Alkinyl, C 2-20 Alkenyl or C 2-50 The alkynyl may optionally be interrupted by one or more parts, the one or more parts preferably [ka] [In the formula, The dashed line indicates binding to the portion or the remainder of the reagent. -R and -R a [H is independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.] It is selected from the group consisting of the following.

[0083] As used herein, the term "C 3-10"Cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of a cycloalkyl carbon may be replaced by a substituent as defined above. 3-10 "Cycloalkyl" also includes cross-linked birings such as norbornane or norbornene.

[0084] The term "8-30 membered carbopolycyclil" or "8-30 membered carbon polycyclic" refers to a cyclic portion of two or more rings having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom, and which may contain up to the maximum number of double bonds (aromatic or non-aromatic rings that are fully saturated, partially saturated, or unsaturated). Preferably, an 8-30 membered carbopolycyclil refers to a cyclic portion of 2, 3, 4, or 5 rings, more preferably 2, 3, or 4 rings.

[0085] As used herein, the terms “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” mean a ring (a fully saturated, partially saturated, or unsaturated aromatic or non-aromatic ring) having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms and potentially containing up to a maximum number of double bonds, wherein at least one ring atom and up to four ring atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule by carbon or nitrogen atoms. Examples of 3- to 10-membered heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxilen, thiirane, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazoline, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazoline, thiadiazole, thiadiazole, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, sulforane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyridine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be replaced by a substituent as defined below.

[0086] As used herein, the terms “8-11 membered heterobicyryl” or “8-11 membered heterobicycle” mean a bicyclic heterocyclic portion (a fully saturated, partially saturated, or unsaturated aromatic or aromatic ring) having 8 to 11 ring atoms, with at least one ring atom shared by both rings, and potentially containing up to a maximum number of double bonds, wherein at least one ring atom, and up to six ring atoms, are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule by carbon or nitrogen atoms. Examples of 8- to 11-membered heterobicyclic rings include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic ring also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocyclic rings such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicyclic carbon may be replaced by a substituent as defined below.

[0087] Similarly, the term “8-30 membered heteropolycyclil” or “8-30 membered heteropolycycle” means a heterocyclic moiety of two or more rings, preferably 3, 4, or 5 rings (aromatic or aromatic rings that are fully saturated, partially saturated, or unsaturated) having 8 to 30 ring atoms, with two adjacent rings sharing at least one ring atom, and potentially containing up to a maximum number of double bonds, wherein at least one ring atom, up to a maximum of 10 ring atoms, is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the ring is bonded to the remainder of the molecule by carbon or nitrogen atoms.

[0088] structure: [ka] Regarding the part, "Pair R x / R y Together with the atoms to which they are bonded, C 3-10 The phrase "forms a cycloalkyl or 3-10 membered heterocycline" is R x and R y However, it is understood that this means forming the following structure: [ka] [In the formula, R is C 3-10 [They are cycloalkyl or 3-10 membered heterocyclines.]

[0089] structure: [ka] Regarding the part, "Pair R x / R y The phrase "they, together with the atoms to which they are bonded, form ring A" is R x and R y However, it is also understood that this means forming the following structure: [ka]

[0090] As used herein, "halogen" means fluoro, chloro, bromo, or iodine. The halogen is generally preferred to be fluoro or chloro.

[0091] As used herein, the term “functional group” means a group of atoms that can react with other groups of atoms. Exemplary functional groups include, for example, carboxylic acids (-(C=O)OH), primary or secondary amines (-NH2, -NH-), maleimides, thiols (-SH), sulfonic acids (-(O=S=O)OH), carbonates, carbamates (-O(C=O)N<), hydroxyls (-OH), aldehydes (-(C=O)H), ketones (-(C=O)-), hydrazines (>NN<), isocyanates, isothiocyanates, phosphoric acids (-O(P=O)OHOH), phosphonic acids (-O(P=O)OHH), haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfuric acids, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziridines.

[0092] If the IL-2 conjugate of the present invention contains one or more acidic or basic groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salt thereof, in particular the pharmaceutically usable salt thereof. Accordingly, the IL-2 conjugate of the present invention containing an acidic group can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. The IL-2 conjugate of the present invention containing one or more basic groups, i.e., protonable groups, can exist in the form of its addition salt with an inorganic or organic acid and can be used according to the present invention. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods for converting basic groups to cations are known to those skilled in the art, such as alkylation of amine groups that yield suitable counterions for positively charged ammonium groups and salts. When the IL-2 conjugate of the present invention contains both an acidic and a basic group, the present invention also includes intramolecular salts or betaines (zwitterionic) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these conjugates with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the IL-2 conjugates of the present invention, which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or to prepare pharmaceutically acceptable salts.

[0093] The term "pharmaceutically acceptable" means a substance that does not cause harm when administered to a patient and is preferably approved by a regulatory authority, such as the EMA (European) and / or FDA (United States) and / or any other national regulatory authority, for use in animals, for example, in humans.

[0094] As used herein, the term “excipient” refers to a diluent, adjuvant, or medium with which a therapeutic agent, such as a drug or prodrug, is administered. Such pharmaceutically excipients may be sterile solutions, such as water, and oils, such as those of petroleum, animal, plant, or synthetic origin, such as, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a preferred excipient when a pharmaceutical composition is administered orally. Saline solution and aqueous dextrose are preferred excipients when a pharmaceutical composition is administered intravenously. Saline solution and aqueous dextrose and glycerol solution are preferably used as liquid excipients for injectable solutions. Suitable pharmaceutically excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. If desired, the pharmaceutical composition may also contain trace amounts of wetting agents or emulsifiers, pH buffers, etc., such as acetates, succinates, tris, carbonates, phosphates, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or surfactants, such as Tween, poloxamer, poloxamine, CHAPS, Igepal, or amino acids, such as glycine, lysine, or histidine. These pharmaceutical compositions may take the form of liquids, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The pharmaceutical compositions can be formulated as suppositories with common binders and excipients, such as triglycerides. Oral formulations may contain standard excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions contain a therapeutically effective amount of drug or bioactive portion, along with a suitable amount of excipients to provide a form for appropriate administration to a patient. The formulation should be adapted to the mode of administration.

[0095] As used herein, the term “liquid pharmaceutical formulation” refers to a mixture comprising a water-soluble compound such as the IL-2 conjugate of the present invention and one or more solvents such as water.

[0096] As used herein, the term “dried pharmaceutical formulation” refers to a pharmaceutical composition provided in a dry form. Preferred methods for drying are spray drying and freeze-drying, i.e., freeze-drying. Such a dried composition has a residual moisture content of less than 5%, or less than 2%, to a maximum of 10%, as measured according to Karl Fischer. In certain embodiments, such a dried pharmaceutical composition is dried by freeze-drying.

[0097] As used herein, the term “percent (w / w)” or “% (w / w)” means a percentage expressed with respect to the weight of a compound, substance, component or drug in a composition, divided by the total weight of the composition and multiplied by 100%.

[0098] As used herein, the term “percent (v / v)” or “%(v / v)” means a percentage expressed with respect to the total liquid volume of a solvent, compound, substance, component, or agent in a composition, divided by the total liquid volume of the composition and multiplied by 100%.

[0099] Generally, the terms "comprise" or "comprising" also encompass "consist of" or "consisting of."

[0100] The IL-2 conjugate of equation (I) emits partial DH. Such partial DH can be biased IL-2.

[0101] In certain embodiments, the doses of the first to third embodiments are in the range of 100 μg IL-2 / kg to 140 μg IL-2 / kg. In certain embodiments, the doses of the first to third embodiments are in the range of 110 μg IL-2 / kg to 130 μg IL-2 / kg. In certain embodiments, the doses of the first to third embodiments are approximately 120 μg IL-2 / kg. In certain embodiments, the doses of the first to third embodiments are 120 μg IL-2 / kg.

[0102] The dose may be administered once or multiple times. For multiple doses, the interval between two consecutive doses may range from 2 to 8 weeks. In certain embodiments, the IL-2 conjugate of formula (I) is administered to the patient every 3 weeks. In certain embodiments, the IL-2 conjugate of formula (I) is administered to the patient every 6 weeks. In certain embodiments, the IL-2 conjugate of formula (I) is administered at a frequency corresponding to disease progression. The IL-2 conjugate of formula (I) may be administered for at least 6 months, 1 year, 2 years, or indefinitely. Treatment may be initiated immediately upon diagnosis of cancer or thereafter. Treatment with the IL-2 conjugate of formula (I) may be a first-line treatment, or a second-line, third-line, or further-line treatment.

[0103] The IL-2 conjugate of formula (I) may be administered topically, by injection or infusion, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intratympanic, intravesical, intracardiac, transtracheal, subepidermal, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion; direct delivery to the brain via an implantable device (e.g., an Onmyer reservoir) that enables delivery of the IL-2 conjugate to brain tissue or cerebral fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related regions, injection into the subchoroidal space, posterior orbital injection or ophthalmic instillation. In certain embodiments, the IL-2 conjugate of formula (I) is administered intravenously, for example, via intravenous infusion or intravenous injection.

[0104] In certain embodiments, the IL-2 conjugate of formula (I) is administered to a patient in the form of a pharmaceutical formulation, such as a dry or liquid pharmaceutical formulation. Such a pharmaceutical formulation comprises at least one IL-2 conjugate of formula (I) and one or more excipients. The dry formulation is resuspended in a liquid, such as sterile water or sterile buffer, before administration to the patient.

[0105] The IL-2 conjugate of formula (I) can be administered to a patient once or multiple times. In certain embodiments, the IL-2 conjugate is administered to the patient once. In certain embodiments, the IL-2 conjugate is administered multiple times, for example, two, three, four, five, eight, ten, twelve, fourteen times, or as many times as needed.

[0106] In certain embodiments, the third embodiment of the pharmaceutical product is in unit dosage form, details of which are provided elsewhere in this specification.

[0107] In certain embodiments, the unit dosage form contains 100 μg IL-2 / kg to 140 μg IL-2 / kg. In certain embodiments, the unit dosage form of the fourth embodiment contains 110 μg IL-2 / kg to 130 μg IL-2 / kg. In certain embodiments, the unit dosage form of the fourth embodiment contains approximately 120 μg IL-2 / kg. In certain embodiments, the unit dosage form of the fourth embodiment contains 120 μg IL-2 / kg.

[0108] In certain embodiments, the unit dosage form is a vial, for example, a stoppered vial. In certain embodiments, the unit dosage form is a Type 1 glass vial equipped with a chlorobutyl rubber stopper and an aluminum sealing cap. In certain embodiments, the unit dosage form is a Type 1 glass vial equipped with a bromobutyl rubber stopper and an aluminum sealing cap.

[0109] In certain embodiments, the unit dosage form of the fourth embodiment is for use in the treatment of cancer. Such cancer embodiments are described elsewhere in this specification.

[0110] When determining the dosage for a particular drug, such as the reversible conjugate of IL-2 of formula (I), the dosage of other reversible conjugates can be used as a guide for other reversible conjugates of IL-2, such that the dosage of other reversible conjugates is the same as that of the IL-2 conjugate of formula (I) in terms of the moles of IL-2. Such guidance is particularly useful when the other conjugate releases the IL-2 portion with a release half-life within plus / minus 20% of that of the IL-2 conjugate of formula (I).

[0111] The method of the present invention can be used to treat or prevent cancer in patients who have cancer or are at risk of having it (e.g., genetic risk). The method of the present invention can also be used to treat a population of patients who have such a disease or are at risk of having it. Such a population may include at least 10, 100, or 1000 patients, or may represent all patients in a particular facility.

[0112] Clinical trials may be useful for determining new doses and drug regimens, but the method of the present invention can also be performed outside of the course of clinical trials.

[0113] In a particular embodiment, -D'- has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 1 has the following sequence: TIFF2026517863000018.tif30162

[0114] In certain embodiments, -D'- has at least 96% sequence identity with the amino acid sequence of SEQ ID NO: 1. In certain embodiments, -D'- has at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 1. In certain embodiments, -D'- has at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 1. In certain embodiments, -D'- has at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 1.

[0115] In a particular embodiment, -D'- comprises the amino acid sequence of SEQ ID NO: 1, in which one amino acid residue selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72 is replaced with a proteinogenic or non-proteinogenic amino acid residue.

[0116] In certain embodiments, -D'- lacks an N-terminal alanine, i.e., -D'- contains an A1del mutation. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 2, which optionally contains one or more mutations at positions selected from the group consisting of K34, R37, M38, T40, F41, K42, F43, E61, P64, E67, V68, and L71.

[0117] In certain embodiments, -D'- comprises the amino acid sequence of Sequence ID No. 1, in which two amino acid residues selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72 are replaced with proteinogenic or non-proteinogenic amino acid residues. The proteinogenic amino acid can be selected from the group consisting of cysteine, methionine, histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, asparagine, glutamine, and arginine. In certain embodiments, the proteinogenic amino acid is cysteine. In certain embodiments, the proteinogenic amino acid is methionine. In certain embodiments, the proteinogenic amino acid is histidine. In certain embodiments, the proteinogenic amino acid is lysine. In certain embodiments, the proteinogenic amino acid is tryptophan. In certain embodiments, the proteinogenic amino acid is serine. In certain embodiments, the proteinogenic amino acid is threonine. In certain embodiments, the proteinogenic amino acid is tyrosine. In certain embodiments, the proteinogenic amino acid is aspartic acid. In certain embodiments, the proteinogenic amino acid is glutamic acid. In certain embodiments, the proteinogenic amino acid is glutamine. In certain embodiments, the proteinogenic amino acid is arginine.

[0118] In certain embodiments, non-proteinogenic amino acids have a functional group in their side chain selected from the group consisting of carbonyl (including keto and dicarbonyl groups); carbonyl derivatives, such as carbonyl-like groups, labeled carbonyl groups, and protected carbonyl groups; azides; oximes; hydrazines, hydrazides; semicarbazides; alkynes; and hydroxylamines.

[0119] In certain embodiments, the non-proteinogenic amino acid is selected from the group consisting of lysine analogs, cysteine ​​analogs, and histidine analogs.

[0120] In certain embodiments, the non-proteinogenic amino acid includes an aromatic side chain, an azide group, an alkyne group, an aldehyde group, or a ketone group. In certain embodiments, the non-proteinogenic amino acid does not include an aromatic side chain.

[0121] In certain embodiments, non-proteinogenic amino acids are the D-stereoisomers of each proteinogenic amino acid, pyrrolidine (Pyl, O), selenocysteine ​​(Sec, U), 2-aminoadipic acid (2-AAA), 3-aminoadipic acid (bAad), β-alanine (bAla), 2-aminobutyric acid (Abu), 4-aminobutyric acid (4Abu), 6-aminocaproic acid (Acp), 2-aminoheptanoic acid (Ahe), 2-aminoisobutyric acid (Aib), 3-aminoisobutyric acid (bAib), 2-aminopimeric acid (Apm), 2,4-diaminobutyric acid (Dbu), desmosine (Des), and 2,2'-diaminopimeric acid. The following substances are selected from the group consisting of hydroxyl (Dpm), 2,3-diaminopropionic acid (Dpr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), hydroxylysine (Hyl), allohydroxylysine (aHyl), 3-hydroxyproline (3Hyp), 4-hydroxyproline (4Hyp), isodesmosine (Ide), alloisoleucine (alle), N-methylglycine (MeGly), N-methylisoleucine (Melle), 6-N-methyllysine (MeLys), N-methylvaline (MeVal), norvaline (Nva), norleucine (Nle), and ornithine (Orn). The abbreviations for each are provided in parentheses.

[0122] In certain embodiments, non-proteinogenic amino acids include N6-((2-azidoethoxy)-carbonyl)-L-lysine, N6-azidoethoxy-L-lysine, N6-propargylethoxy-L-lysine, BCN-L-lysine, norbornenyllysine, trans-cyclooctene (TCO)-lysine, methyltetrazinyllysine, allyloxycarbonyllysine, 2-amino-8-oxononanoic acid, 2-amino-8-oxooctanoic acid, p-acetyl-L-phenylalanine, p-azidomethyl-L-phenylalanine, p-iodo-L-phenylalanine, m-acetylphenylalanine, 2-amino-8-oxononanoic acid, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, 3-methylphenylalanine, L-Dopa, and fluorinated phenylalanine. Selected from the group consisting of nyalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, O-allyl tyrosine, O-methyl-L-tyrosine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, phosphonotyrosine, tri-O-acetyl-GlcNAcp-serine, L-phosphoserine, phosphonoserine, L-3-(2-naphthyl)alanine, 2-amino-3-((2-((3-(benzyloxy)-3-oxopropyl)amino)ethyl)ceranyl)propanoic acid, 2-amino-3-(phenylceranyl)propanoic acid, and serranocysteine.

[0123] In certain embodiments, such non-proteinogenic amino acids are those described in International Publication No. 2006 / 069246A2, which is incorporated herein by reference. In certain embodiments, the non-proteinogenic amino acid is the structure described in formulas (I)

[0265] to

[0283] , formula (XXX)

[0284] , formula (XXX-A)

[0285] , formula (XXX-B)

[0286] , formula (XXXI)

[0287] , formula (XXXI)

[0288] , formula (XXXI-A)

[0289] , formula (XXXI-B)

[0290] , formula (XXXII)

[0291] , formula (XXXII-A)

[0292] , formula (XXXII-B)

[0293] , and formula (XXXX)

[0294] in International Publication No. 2006 / 069246A2 (the non-proteinogenic amino acid is incorporated herein by reference). The structure of XI), the incorrectly displayed paragraph

[0100] , i.e., the structure of formula (XXXXII) in the paragraph between

[0294] and

[0295] , the structure of formula (XXXXIII) in

[0295] and

[0296] , the structure of formula (XIV) in

[0302] to

[0305] , the structure of formula (XV) in

[0306] and

[0307] , the structure of formula (XI) in

[0310] to

[0312] It has the structure of (XII) in

[0313] , the structure of the formulas (XII) in

[0314] and

[0315] , the structure of the formula (XIV) in

[0316] , the structure of the formula (XVI) in

[0317] , the structure of the formulas (XVI) in

[0318] and

[0319] , the structure of the formulas (XVIII) in

[0320] and

[0321] , or the structure of the formula (XXIX) in

[0530] .

[0124] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 1, in which one amino acid residue selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72 is replaced by a cysteine ​​residue.

[0125] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 1, in which two amino acid residues selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72 are replaced by cysteine ​​residues.

[0126] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 2, in which one amino acid residue selected from the group consisting of K34, R37, M38, T40, F41, K42, F43, E61, P64, E67, V68, and L71 is replaced by a cysteine ​​residue.

[0127] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 2, in which two amino acid residues selected from the group consisting of K34, R37, M38, T40, F41, K42, F43, E61, P64, E67, V68, and L71 are replaced by cysteine ​​residues.

[0128] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 3: TIFF2026517863000019.tif26162

[0129] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 4 TIFF2026517863000020.tif26162

[0130] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: TIFF2026517863000021.tif26162

[0131] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 6 TIFF2026517863000022.tif26162

[0132] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 7 TIFF2026517863000023.tif26162

[0133] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 8 TIFF2026517863000024.tif26162

[0134] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 9 TIFF2026517863000025.tif26162

[0135] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 10 TIFF2026517863000026.tif11162TIFF2026517863000027.tif17162

[0136] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 11: TIFF2026517863000028.tif23163

[0137] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 12: TIFF2026517863000029.tif23163

[0138] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 13: TIFF2026517863000030.tif23163

[0139] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 14: TIFF2026517863000031.tif23163

[0140] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 15: TIFF2026517863000032.tif23163

[0141] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 16: TIFF2026517863000033.tif23163

[0142] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 17: TIFF2026517863000034.tif23163

[0143] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 18: TIFF2026517863000035.tif23163

[0144] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 19: TIFF2026517863000036.tif23163

[0145] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 20: TIFF2026517863000037.tif23163

[0146] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 21: TIFF2026517863000038.tif23163

[0147] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 22: TIFF2026517863000039.tif23163

[0148] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 23: TIFF2026517863000040.tif23163

[0149] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 24: TIFF2026517863000041.tif23163

[0150] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 25: TIFF2026517863000042.tif23163

[0151] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 26: TIFF2026517863000043.tif23163

[0152] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 27: TIFF2026517863000044.tif23163

[0153] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 28: TIFF2026517863000045.tif23163

[0154] -M mod This is a polymer portion. Such polymer portions may include linear, branched, or multi-arm polymers. In certain embodiments, -M mod It is a linear polymer. In certain embodiments, -M mod This is a branched polymer, for example, a branched polymer having 1, 2, 3, 4, or 5 branching points, from which 2, 3, or 4 polymer arms may extend. In another embodiment, -M mod This refers to a multi-arm polymer, for example, a multi-arm polymer having 3, 4, 5, 6, 7, or 8 polymer arms.

[0155] In a particular embodiment, -M modIt has a molecular weight in the range of 0.5kDa to 20kDa, for example 1kDa to 20kDa, for example 2kDa to 10kDa, 3kDa to 7kDa, or 4kDa to 6kDa. In a particular embodiment, -M mod It has a molecular weight of approximately 0.5 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 1 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 2 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 3 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 4 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 5 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 6 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 7 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 8 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 9 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 10 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 15 kDa. In certain embodiments, -M mod It has a molecular weight of approximately 20 kDa. In certain embodiments, -M mod It has a molecular weight of 0.5 kDa. In certain embodiments, -M mod It has a molecular weight of 1 kDa. In certain embodiments, -M mod It has a molecular weight of 2 kDa. In certain embodiments, -M mod It has a molecular weight of 3 kDa. In certain embodiments, -M mod It has a molecular weight of 4 kDa. In certain embodiments, -M mod It has a molecular weight of 5 kDa. In certain embodiments, -M mod It has a molecular weight of 6 kDa. In certain embodiments, -M mod It has a molecular weight of 7 kDa. In certain embodiments, -Mmod It has a molecular weight of 8 kDa. In certain embodiments, -M mod It has a molecular weight of 9 kDa. In certain embodiments, -M mod It has a molecular weight of 10 kDa. In certain embodiments, -M mod It has a molecular weight of 15 kDa. In certain embodiments, -M mod It has a molecular weight of 20 kDa.

[0156] In a particular embodiment, -M mod It has a molecular weight of 5±25%kDa. In certain embodiments, -M mod It has a molecular weight of 5±20%kDa. In certain embodiments, -M mod It has a molecular weight of 5 ± 15% kDa.

[0157] In a particular embodiment, -M modThis includes poly(2-methacryloyloxyethylphosphoryl(phosphoyl)choline), poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly(hydroxy The polymer is selected from the group consisting of propyl oxazoline, poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropylmethylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, alginate, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0158] In a particular embodiment, -M mod It is a PEG-based polymer.

[0159] -M modThe bond to -D'- is via a stable bond, which in certain embodiments is an amide bond. In certain embodiments, -D'- and -M mod The join between the following is: [ka]

[0160] -M mod The binding can be a -D'- proteogenic or non-proteogenic amino acid residue. In certain embodiments, -M mod The binding occurs at a proteogenic amino acid. In certain embodiments, such proteogenic amino acid residues are selected from the group consisting of cysteine, methionine, histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, glutamine, and arginine. In certain embodiments, -M mod The binding occurs with non-proteinogenic amino acids. In this case, it is understood that such non-proteinogenic amino acid residues are artificially introduced into -D'-. Such non-proteinogenic amino acid residues are then linked to -M mod This can be any non-proteinogenic amino acid residue having a functional group available for conjugation to -D'-. In certain embodiments, such a non-proteinogenic amino acid has a functional group in its side chain selected from the group consisting of carbonyl; carbonyl derivatives, e.g., carbonyl-like groups, labeled carbonyl groups and protected carbonyl groups; azides; oximes; and hydroxylamines.

[0161] In certain embodiments, such non-proteinogenic amino acids are non-proteinogenic amino acids as described elsewhere in this specification.

[0162] In a particular embodiment, -M mod The binding occurs at the -D'- cysteine ​​residue. In certain embodiments, -M mod The binding occurs at the -D'- lysine residue. In certain embodiments, -M modThe binding occurs at the -D'- threonine residue. In certain embodiments, -M mod The binding occurs at the serine residue of -D'-. In certain embodiments, -M mod The binding occurs at the -D'- tyrosine residue. In certain embodiments, -M mod The binding occurs at the -D'- histidine residue. In certain embodiments, -M mod The binding occurs at the -D'- tryptophan residue. In certain embodiments, -M mod The binding occurs at the -D'- aspartic acid residue. In certain embodiments, -M mod The binding occurs at the glutamic acid residue of -D'-. In certain embodiments, -M mod The binding occurs at the -D'- arginine residue. In certain embodiments, -M mod The binding occurs at the -D'- methionine residue. In certain embodiments, -M mod The binding occurs at the -D'- glutamine residue.

[0163] In a particular embodiment, -M mod The binding occurs at an amino acid position of the IL-2 protein that is known to be involved in binding to IL-2Rα. Thus, in certain embodiments, -M mod The binding of -D'- results in a reduction in the affinity of -D'- for IL-2Rα / β compared to aldesleukin (SEQ ID NO: 2), i.e., a biased IL-2 moiety is introduced.

[0164] In a particular embodiment, -M mod The binding occurs at an amino acid position selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72, or at the corresponding position of its homolog or variant, based on Sequence ID No. 1.

[0165] In a particular embodiment, -M modThe binding occurs at the amino acid position of -D'- selected from the group consisting of R38, F42, Y45, E62, P65, and L72, based on SEQ ID NO: 1, or at the corresponding position of its homolog and variant.

[0166] All of these amino acid positions are -M mod It does not contain functional groups that enable direct conjugation of -M at these amino acid positions, for example, by replacing naturally occurring amino acids with different proteinogenic or non-proteinogenic amino acids, or by performing specific chemical modifications. mod It is understood that certain steps may be required before joining. Therefore, -M mod The binding can occur at either naturally occurring amino acids or amino acids in which naturally occurring amino acids are replaced at those positions, and the binding site can be a proteogenic or non-proteogenic amino acid, both embodiments of which are described herein.

[0167] In a particular embodiment, -M mod The binding occurs at amino acid position K35 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position R38 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position M39 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position T41 of SEQ ID NO: 1 or the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position F42 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position K43 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M modThe binding occurs at amino acid position F44 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position Y45 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position E62 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position P65 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant. In certain embodiments, -M mod The binding occurs at amino acid position L72 of SEQ ID NO: 1 or at the corresponding position of its homolog or variant.

[0168] In a particular embodiment, -D'- has the amino acid sequence of SEQ ID NO: 3, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 35. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 38. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 5, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 39. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 6, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 41. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 7, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 42. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 8, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 43. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 9, and -M modIt is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 44. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 10, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 45. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 11, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 62. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 12, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 65. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 13, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 68. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 14, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 69. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 15, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 72. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 16, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 34. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 17, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 37. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 18, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 38. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 19, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 40. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 20, and -M modIt is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 41. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 21, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 42. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 22, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 43. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 23, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 44. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 24, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 61. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 25, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 64. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 26, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 67. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 27, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 68. In certain embodiments, -D'- has the amino acid sequence of SEQ ID NO: 28, and -M mod It is stably conjugated to the sulfur atom of the cysteine ​​side chain at position 71.

[0169] Optionally, -D'- is one or more further parts -M that are stably conjugated to -D. mod It may include, and it may be the same or different part - M mod These may be one or more further parts - M mod -M mod As stated in the document.

[0170] In a particular embodiment, -M mod is equation (A-1) [ka] [In the formula, -FG- is a bond, -SP- is the spacer part. -POL is a polymer. It belongs to them.

[0171] -FG- in equation (A-1) is, for example, [ka] TIFF2026517863000049.tif28164[In the formula, The dashed lines indicate connections to -D'- and -SP-, respectively. -R and -R a [These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl] These could be any bond used in chemistry, such as a bond selected from the group consisting of [the specified elements].

[0172] In a particular embodiment, -FG- in formula (A-1) is equivalent to formula (FG-1a) [ka] [In the formula, The dashed lines marked with an asterisk indicate bonds to the sulfur atoms in the side chain of -D'- cysteine, while the unmarked dashed lines indicate bonds to -SP-. It belongs to them.

[0173] In a particular embodiment, the formula (FG-1a) has a part-M having part-FG- modThe IL-2 conjugate containing is incubated for several hours, for example, at least 10 hours or at least 12 hours, at a high pH such as pH 9 and a high temperature such as 25°C to promote ring opening.

[0174] Therefore, in a particular embodiment, -FG- in formula (A-1) is equivalent to formula (FG-1d) [ka] [In the formula, The dashed lines marked with an asterisk indicate binding to the sulfur in the side chain of the -D'- cysteine ​​residue, while the unmarked dashed lines indicate binding to -SP-. It belongs to them.

[0175] Alternatively, or further, in a particular embodiment, -FG- in formula (A-1) is formula (FG-1e) [ka] [In the formula, The dashed lines marked with an asterisk indicate binding to the sulfur in the side chain of the -D'- cysteine ​​residue, while the unmarked dashed lines indicate binding to -SP-. It belongs to them.

[0176] When the IL-2 conjugate is incubated at the high pH described above, -FG- exists as a mixture of formulas (FG-1d) and (FG-1e). Trace amounts of -FG- of formula (FG-1a) may be present as a result of incomplete ring opening.

[0177] In a particular embodiment, -SP- in formula (A-1) is C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls, where C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more R, either the same or different. 9 Replaced by optional means, C 1-50 Alkyl, C2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-,-S(O)2N(R 10 )-,-S(O)N(R 10 )-, -S(O)2-, -S(O)-, -N(R 10 )S(O)2N(R 10a )-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )- is optionally interrupted by one or more units selected from the group consisting of, Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each T is the same or different of one or more R 9 It is independently and arbitrarily replaced by, Each-R 9 These are halogen, -CN, oxo (=O), and -COOR. 11 , -OR 11 , -C(O)R 11 ,-C(O)N(R 11 R 11a ), -S(O)2N(R 11 R 11a ), -S(O)N(R 11 R 11a ), -S(O)2R 11 ,-S(O)R 11 , -N(R 11 )S(O)2N(R 11a R 11b ), -SR 11 , -N(R 11 R 11a ), -NO2, -OC(O)R 11 , -N(R 11 )C(O)R 11a , -N(R 11 )S(O)2R11a , -N(R 11 )S(O)R 11a , -N(R 11 )C(O)OR 11a , -N(R 11 )C(O)N(R 11a R 11b ), -OC(O)N(R 11 R 11a ), and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different. Each-R 10 ,-R 10a ,-R 11 ,-R 11a , and -R 11b -H and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 The alkyl group is optionally substituted with one or more halogens, either the same or different.

[0178] In a particular embodiment, -SP- in formula (A-1) is C 1-20 It is alkyl, C 1-20 Alkyl is one or more -R 9 Replaced by optional means, C 1-20 Alkyl is -O-, -C(O)N(R 10 )-, -S(O)2-, -S(O)-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )- is optionally interrupted by one or more groups selected from the group consisting of -R, where each -R 9 C 1-6 Selected from the group consisting of alkyl groups, each -R 10 and -R 10a -H and C 1-6 It is independently selected from the group consisting of alkyl groups.

[0179] In a particular embodiment, -SP- in formula (A-1) is C 1-10 It is alkyl, C 1-10 Alkyl is one or more -R 9 Replaced by optional means, C 1-10 Alkyl is -O-, -C(O)N(R 10 )-, -S(O)2-, -S(O)-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )- is optionally interrupted by one or more groups selected from the group consisting of -R, where each -R 9 C 1-6 Selected from the group consisting of alkyl groups, each -R 10 and -R 10a -H and C 1-6 It is independently selected from the group consisting of alkyl groups.

[0180] In certain embodiments, -POL in formula (A-1) is a PEG-based polymer. In certain embodiments, -POL is formula (A-1i) [ka] [In the formula, The dashed line indicates a connection to -SP-. m is either 0 or 1. p is an integer in the range of approximately 10 to approximately 540. q is selected from the group consisting of 1, 2, 3, 4, 5, and 6. It belongs to them.

[0181] In a particular embodiment, m in equation (A-1i) is 0. In a particular embodiment, m in equation (A-1i) is 1.

[0182] In a particular embodiment, p in equation (A-1i) is an integer in the range of about 10 to about 450, for example, about 22 to about 340, about 45 to about 230, about 65 to about 160, about 90 to about 140, for example, about 95 to about 135, or for example, about 100 to about 125.

[0183] In a particular embodiment, q in formula (A-1i) is 1. In a particular embodiment, q in formula (A-1i) is 2. In a particular embodiment, q in formula (A-1i) is 3. In a particular embodiment, q in formula (A-1i) is 4. In a particular embodiment, q in formula (A-1i) is 5. In a particular embodiment, q in formula (A-1i) is 6.

[0184] In a particular embodiment, -M mod is equation (A-1a) [ka] [In the formula, The dashed lines marked with an asterisk indicate the binding of the side chain of the -D'- cysteine ​​residue to the sulfur. b1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b2 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b3 is an integer in the range of approximately 10 to 540. It belongs to them.

[0185] In a particular embodiment, -M mod This is the formula (A-1a), where the dashed line marked with an asterisk indicates the binding of the side chain of the cysteine ​​residue at position 38 of sequence number 4 to the sulfur.

[0186] In a particular embodiment, b1 in formula (A-1a) is an integer in the range of 1 to 8. In a particular embodiment, b1 in formula (A-1a) is an integer in the range of 1 to 6. In a particular embodiment, b1 in formula (A-1a) is an integer in the range of 1 to 4. In a particular embodiment, b1 in formula (A-1a) is 1. In a particular embodiment, b1 in formula (A-1a) is 2. In a particular embodiment, b1 in formula (A-1a) is 3. In a particular embodiment, b1 in formula (A-1a) is 4. In a particular embodiment, b1 in formula (A-1a) is 5. In a particular embodiment, b1 in formula (A-1a) is 6.

[0187] In a particular embodiment, b2 in formula (A-1a) is an integer in the range of 1 to 8. In a particular embodiment, b2 in formula (A-1a) is an integer in the range of 1 to 6. In a particular embodiment, b2 in formula (A-1a) is an integer in the range of 1 to 4. In a particular embodiment, b2 in formula (A-1a) is 1. In a particular embodiment, b2 in formula (A-1a) is 2. In a particular embodiment, b2 in formula (A-1a) is 3. In a particular embodiment, b2 in formula (A-1a) is 4. In a particular embodiment, b2 in formula (A-1a) is 5. In a particular embodiment, b2 in formula (A-1a) is 6.

[0188] In a particular embodiment, b3 in formula (A-1a) is an integer in the range of about 10 to about 450, for example, about 22 to about 340, about 45 to about 230, about 65 to about 160, about 90 to about 140, about 95 to about 135, or for example, about 100 to about 125.

[0189] In a particular embodiment, b1 of formula (A-1a) is 2, b2 of formula (A-1a) is 2, and b3 of formula (A-1a) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 of formula (A-1a) is 3, b2 of formula (A-1a) is 2, and b3 of formula (A-1a) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 of formula (A-1a) is 2, b2 of formula (A-1a) is 3, and b3 of formula (A-1a) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 of formula (A-1a) is 3, b2 of formula (A-1a) is 3, and b3 of formula (A-1a) is in the range of approximately 90 to approximately 140.

[0190] In a particular embodiment, b1 of formula (A-1a) is 2, b2 of formula (A-1a) is 2, and b3 of formula (A-1a) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 of formula (A-1a) is 3, b2 of formula (A-1a) is 2, and b3 of formula (A-1a) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 of formula (A-1a) is 2, b2 of formula (A-1a) is 3, and b3 of formula (A-1a) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 of formula (A-1a) is 3, b2 of formula (A-1a) is 3, and b3 of formula (A-1a) is in the range of approximately 95 to approximately 135.

[0191] In a particular embodiment, b1 in formula (A-1a) is 2, b2 in formula (A-1a) is 2, and b3 in formula (A-1a) is in the range of approximately 100 to approximately 125. In a particular embodiment, b1 in formula (A-1a) is 3, b2 in formula (A-1a) is 2, and b3 in formula (A-1a) is in the range of approximately 100 to approximately 125. In a particular embodiment, b1 in formula (A-1a) is 2, b2 in formula (A-1a) is 3, and b3 in formula (A-1a) is in the range of approximately 100 to approximately 125. In a particular embodiment, b1 in formula (A-1a) is 3, b2 in formula (A-1a) is 3, and b3 in formula (A-1a) is in the range of approximately 100 to approximately 125.

[0192] In a particular embodiment, -M mod is equation (A-1d) [ka] [In the formula, The dashed lines marked with an asterisk indicate the binding of the -D'- cysteine ​​residue to the sulfur. b1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b2 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b3 is an integer in the range of approximately 10 to 540. It belongs to them.

[0193] In a particular embodiment, -M mod This is the formula (A-1d), where the dashed line marked with an asterisk indicates the binding of the side chain of the cysteine ​​residue at position 38 of sequence number 4 to the sulfur.

[0194] In a particular embodiment, b1 in formula (A-1d) is an integer in the range of 1 to 8. In a particular embodiment, b1 in formula (A-1d) is an integer in the range of 1 to 6. In a particular embodiment, b1 in formula (A-1d) is an integer in the range of 1 to 4. In a particular embodiment, b1 in formula (A-1d) is 1. In a particular embodiment, b1 in formula (A-1d) is 2. In a particular embodiment, b1 in formula (A-1d) is 3. In a particular embodiment, b1 in formula (A-1d) is 4. In a particular embodiment, b1 in formula (A-1d) is 5. In a particular embodiment, b1 in formula (A-1d) is 6.

[0195] In a particular embodiment, b2 in equation (A-1d) is an integer in the range of 1 to 8. In a particular embodiment, b2 in equation (A-1d) is an integer in the range of 1 to 6. In a particular embodiment, b2 in equation (A-1d) is an integer in the range of 1 to 4. In a particular embodiment, b2 in equation (A-1d) is 1. In a particular embodiment, b2 in equation (A-1d) is 2. In a particular embodiment, b2 in equation (A-1d) is 3. In a particular embodiment, b2 in equation (A-1d) is 4. In a particular embodiment, b2 in equation (A-1d) is 5. In a particular embodiment, b2 in equation (A-1d) is 6.

[0196] In a particular embodiment, b3 in equation (A-1d) is an integer in the range of about 10 to about 450, for example, about 22 to about 340, about 45 to about 230, about 65 to about 160, about 90 to about 140, about 95 to about 135, or for example, about 100 to about 125.

[0197] In a particular embodiment, b1 in formula (A-1d) is 2, b2 in formula (A-1d) is 2, and b3 in formula (A-1d) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 in formula (A-1d) is 3, b2 in formula (A-1d) is 2, and b3 in formula (A-1d) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 in formula (A-1d) is 2, b2 in formula (A-1d) is 3, and b3 in formula (A-1d) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 in formula (A-1d) is 3, b2 in formula (A-1d) is 3, and b3 in formula (A-1d) is in the range of approximately 90 to approximately 140.

[0198] In a particular embodiment, b1 in formula (A-1d) is 2, b2 in formula (A-1d) is 2, and b3 in formula (A-1d) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 in formula (A-1d) is 3, b2 in formula (A-1d) is 2, and b3 in formula (A-1d) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 in formula (A-1d) is 2, b2 in formula (A-1d) is 3, and b3 in formula (A-1d) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 in formula (A-1d) is 3, b2 in formula (A-1d) is 3, and b3 in formula (A-1d) is in the range of approximately 95 to approximately 135.

[0199] In a particular embodiment, b1 in formula (A-1d) is 2, b2 in formula (A-1d) is 2, and b3 in formula (A-1d) is in the range of approximately 100 to approximately 125. In a particular embodiment, b1 in formula (A-1d) is 3, b2 in formula (A-1d) is 2, and b3 in formula (A-1d) is in the range of approximately 100 to approximately 125. In a particular embodiment, b1 in formula (A-1d) is 2, b2 in formula (A-1d) is 3, and b3 in formula (A-1d) is in the range of approximately 100 to approximately 125. In a particular embodiment, b1 in formula (A-1d) is 3, b2 in formula (A-1d) is 3, and b3 in formula (A-1d) is in the range of approximately 100 to approximately 125.

[0200] In a particular embodiment, -M mod is equation (A-1e) [ka] [In the formula, The dashed lines marked with an asterisk indicate the binding of the side chain of the -D'- cysteine ​​residue to the sulfur. b1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b2 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b3 is an integer in the range of 12 to 540. It belongs to them.

[0201] In a particular embodiment, -M mod This is the formula (A-1e), where the dashed line marked with an asterisk indicates the binding of the side chain of the cysteine ​​residue at position 38 of sequence number 4 to the sulfur.

[0202] In a particular embodiment, b1 in formula (A-1e) is an integer in the range of 1 to 8. In a particular embodiment, b1 in formula (A-1e) is an integer in the range of 1 to 6. In a particular embodiment, b1 in formula (A-1e) is an integer in the range of 1 to 4. In a particular embodiment, b1 in formula (A-1e) is 1. In a particular embodiment, b1 in formula (A-1e) is 2. In a particular embodiment, b1 in formula (A-1e) is 3. In a particular embodiment, b1 in formula (A-1e) is 4. In a particular embodiment, b1 in formula (A-1e) is 5. In a particular embodiment, b1 in formula (A-1e) is 6.

[0203] In a particular embodiment, b2 in equation (A-1e) is an integer in the range of 1 to 8. In a particular embodiment, b2 in equation (A-1e) is an integer in the range of 1 to 6. In a particular embodiment, b2 in equation (A-1e) is an integer in the range of 1 to 4. In a particular embodiment, b2 in equation (A-1e) is 1. In a particular embodiment, b2 in equation (A-1e) is 2. In a particular embodiment, b2 in equation (A-1e) is 3. In a particular embodiment, b2 in equation (A-1e) is 4. In a particular embodiment, b2 in equation (A-1e) is 5. In a particular embodiment, b2 in equation (A-1e) is 6.

[0204] In a particular embodiment, b3 in formula (A-1e) is an integer in the range of 10 to 450, for example 22 to 340, 45 to 230, 65 to 160, 90 to 140, 95 to 135, or for example 100 to 125.

[0205] In a particular embodiment, b1 of formula (A-1e) is 2, b2 of formula (A-1e) is 2, and b3 of formula (A-1e) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 of formula (A-1e) is 3, b2 of formula (A-1e) is 2, and b3 of formula (A-1e) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 of formula (A-1e) is 2, b2 of formula (A-1e) is 3, and b3 of formula (A-1e) is in the range of approximately 90 to approximately 140. In a particular embodiment, b1 of formula (A-1e) is 3, b2 of formula (A-1e) is 3, and b3 of formula (A-1e) is in the range of approximately 90 to approximately 140.

[0206] In a particular embodiment, b1 of formula (A-1e) is 2, b2 of formula (A-1e) is 2, and b3 of formula (A-1e) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 of formula (A-1e) is 3, b2 of formula (A-1e) is 2, and b3 of formula (A-1e) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 of formula (A-1e) is 2, b2 of formula (A-1e) is 3, and b3 of formula (A-1e) is in the range of approximately 95 to approximately 135. In a particular embodiment, b1 of formula (A-1e) is 3, b2 of formula (A-1e) is 3, and b3 of formula (A-1e) is in the range of approximately 95 to approximately 135.

[0207] In a particular embodiment, b1 in formula (A-1e) is 2, b2 in formula (A-1e) is 2, and b3 in formula (A-1e) is in the range of about 100 to about 125. In a particular embodiment, b1 in formula (A-1e) is 3, b2 in formula (A-1e) is 2, and b3 in formula (A-1e) is in the range of about 100 to about 125. In a particular embodiment, b1 in formula (A-1e) is 2, b2 in formula (A-1e) is 3, and b3 in formula (A-1e) is in the range of about 100 to about 125. In a particular embodiment, b1 in formula (A-1e) is 3, b2 in formula (A-1e) is 3, and b3 in formula (A-1e) is in the range of about 100 to about 125.

[0208] In multiple IL-2 conjugates, some conjugates have part M of equation (A-1d). mod It can include part of formula (A-1e) -M mod It can contain, i.e., multiple IL-2 conjugates are a mixture. Optionally, a certain proportion of IL-2 conjugates is part of formula (A-1a) - M mod It can include part of formula (A-1a) -M mod In such IL-2 conjugates, it is understood that hydrolysis of the thiosuccinimide ring did not occur. Multiple IL-2 conjugates may be present, for example, in a batch of IL-2 conjugates or in a pharmaceutical composition containing such IL-2 conjugates.

[0209] In multiple IL-2 conjugates, part M of equation (A-1d) mod IL-2 conjugate including part (A-1e) -M mod The total number of IL-2 conjugates including is, in a particular embodiment, at least 70% of all IL-2 conjugates. In multiple IL-2 conjugates, part of formula (A-1d) -M mod IL-2 conjugate including part (A-1e) -M mod The total number of IL-2 conjugates including is, in a particular embodiment, at least 80% of all IL-2 conjugates. In multiple IL-2 conjugates, part of formula (A-1d) -M mod IL-2 conjugate including part (A-1e) -M mod The total number of IL-2 conjugates including is, in a particular embodiment, at least 90% of all IL-2 conjugates. In multiple IL-2 conjugates, part of formula (A-1d) -M mod IL-2 conjugate including part (A-1e) -M mod In a particular embodiment, the total number of IL-2 conjugates including this one is at least 95% of all IL-2 conjugates.

[0210] In multiple IL-2 conjugates, some conjugates have part M of equation (A-1a). mod It can include the part of formula (A-1d) -M mod It can include the part of formula (A-1e) -M mod It can include: In multiple IL-2 conjugates, part M of formula (A-1d) mod IL-2 conjugate including part (A-1e) -M mod The total of IL-2 conjugates including is, in a particular embodiment, at least 70% of all IL-2 conjugates, and the remaining IL-2 conjugates are part of equation (A-1a) -M mod This includes the part of equation (A-1d) -M in multiple IL-2 conjugates. mod IL-2 conjugate including part (A-1e) -M mod In a particular embodiment, the total number of IL-2 conjugates including is at least 80% of all IL-2 conjugates, and the remaining IL-2 conjugates are part of equation (A-1a) -M mod This includes the part of equation (A-1d) -M in multiple IL-2 conjugates. mod IL-2 conjugate including part (A-1e) -M mod The total of IL-2 conjugates including is, in a particular embodiment, at least 90% of all IL-2 conjugates, and the remaining IL-2 conjugates are part of equation (A-1a) -M mod This includes the part of equation (A-1d) -M in multiple IL-2 conjugates. mod IL-2 conjugate including part (A-1e) -M mod The total of IL-2 conjugates including is, in a particular embodiment, at least 95% of all IL-2 conjugates, and the remaining IL-2 conjugates are part of equation (A-1a) -M mod Includes.

[0211] The IL-2 conjugate of formula (I) contains a polymer moiety-Z that is reversibly bonded by at least one covalent bond.

[0212] The addition of such a polymer moiety, which is reversibly bonded by at least one covalent bond, may optionally be present in the cyclic half-life of the IL-2 moiety. mod It provides an extension that exceeds the extension brought about by the other factor, and its reversible binding ensures sufficient pharmacokinetic activity.

[0213] In certain embodiments, -Z has a molecular weight in the range of about 20 kDa to about 60 kDa, for example, about 25 kDa to about 55 kDa, about 30 kDa to about 50 kDa, or about 35 kDa to about 45 kDa. In certain embodiments, -Z has a molecular weight of about 40 kDa.

[0214] In certain embodiments, -Z in formula (I) is poly(2-methacryloyl-oxyethylphosphoryl(phosphoyl)choline), poly(acrylic acid), poly(acrylate), poly(acrylamide), poly(alkyloxy)polymer, poly(amide), poly(amideamine), poly(amino acid), poly(acid anhydride), poly(aspartamide), poly(butyric acid), poly(glycolic acid), polybutylene terephthalate, poly(caprolactone), poly(carbonate), poly(cyanoacrylate), poly(dimethylacrylamide), poly(ester), poly(ethylene), poly(ethylene glycol), poly(ethylene oxide), poly(ethyl phosphate), poly(ethyl oxazoline), poly(glycolic acid), poly(hydroxyethyl acrylate), poly(hydroxyethyl oxazoline), poly(hydroxymethacrylate), poly(hydroxypropyl methacrylamide), poly(hydroxypropyl methacrylate), poly( The polymer portion comprises a polymer selected from the group consisting of hydroxypropyl oxazoline, poly(iminocarbonate), poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(methacrylamide), poly(methacrylate), poly(methyloxazoline), poly(organophosphazene), poly(orthoester), poly(oxazoline), poly(propylene glycol), poly(siloxane), poly(urethane), poly(vinyl alcohol), poly(vinylamine), poly(vinyl methyl ether), poly(vinylpyrrolidone), silicone, cellulose, carbomethylcellulose, hydroxypropylmethylcellulose, chitin, chitosan, dextran, dextrin, gelatin, hyaluronic acid and its derivatives, functionalized hyaluronic acid, alginate, mannan, pectin, rhamnogalacturonan, starch, hydroxyalkyl starch, hydroxyethyl starch and other carbohydrate-based polymers, xylan, and copolymers thereof.

[0215] In certain embodiments, -Z in formula (I) is a PEG system portion, such as a linear, branched, or multi-arm PEG system portion. In certain embodiments, -Z is a branched PEG system portion, such as a branched PEG system portion having 1, 2, 3, 4, 5, or 6 branch points. In certain embodiments, -Z is a branched PEG system portion having 1, 2, or 3 branch points. In certain embodiments, -Z is a branched PEG system portion having 1 branch point. In certain embodiments, -Z is a branched PEG system portion having 2 branch points. In certain embodiments, -Z is a branched PEG system portion having 3 branch points.

[0216] Each branch point can be independently selected from the group consisting of -N<, -CH<, and >C<.

[0217] In a particular embodiment, -Z in equation (I) is equal to equation (A) [ka] [In the formula, -BP 1 <, -BP 2 <, -BP 3 < is -N< and -C(R 8 Selected independently from the group consisting of )<, -R 8 is -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls, -P 1 , -P 2 , -P 3 , -P 4 These are PEG-based chains that independently contain at least 40% PEG and have a molecular weight in the range of approximately 5 to approximately 15 kDa. -C 1 -, -C 2 - is C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected independently from the group consisting of alkynnyls, C 1-50 Alkyl, C 2-50 Alkenyl and C2-50 Alkinyl is one or more R, either the same or different. 9 Replaced by optional means, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 10 )-,-S(O)2N(R 10 )-,-S(O)N(R 10 )-, -S(O)2-, -S(O)-, -N(R 10 )S(O)2N(R 10a )-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )- is optionally interrupted by one or more units selected from the group consisting of, Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each T is the same or different of one or more R 9 It is independently and arbitrarily replaced by, Each R 9 These are halogen, -CN, oxo (=O), and -COOR. 11 , -OR 11 , -C(O)R 11 ,-C(O)N(R 11 R 11a ), -S(O)2N(R 11 R 11a ), -S(O)N(R 11 R 11a ), -S(O)2R 11 ,-S(O)R 11 , -N(R 11 )S(O)2N(R 11a R 11b ), -SR 11 , -N(R 11 R 11a ), -NO2, -OC(O)R11 , -N(R 11 )C(O)R 11a , -N(R 11 )S(O)2R 11a , -N(R 11 )S(O)R 11a , -N(R 11 )C(O)OR 11a , -N(R 11 )C(O)N(R 11a R 11b ), -OC(O)N(R 11 R 11a ), and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different. Each-R 10 ,-R 10a ,-R 11 ,-R 11a , and -R 11b -H and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different. This includes the part.

[0218] In a particular embodiment, -P of formula (A) 1 , -P 2 , -P 3 , -P 4 These are PEG-based chains that independently contain at least 50% PEG and have molecular weights in the range of about 5 to about 15 kDa, for example, in the range of about 6.25 kDa to about 13.75 kDa, for example, in the range of about 7.5 kDa to about 12.5 kDa or in the range of about 8.75 kDa to about 11.25 kDa. In certain embodiments, -P of formula (A) 1 , -P 2 , -P 3 , -P 4 These are PEG-based chains that independently contain at least 50% PEG and have a molecular weight of approximately 10 kDa.

[0219] In a particular embodiment, -P of formula (A) 1, -P 2 , -P 3 , and -P 4 They have the same structure.

[0220] In a particular embodiment, the BP of formula (A) 1 -N < .

[0221] In a particular embodiment, the BP of formula (A) 2 and BP 3 They have the same structure. In a particular embodiment, the BP of formula (A) 2 and BP 3 All of these are -CH<.

[0222] In a particular embodiment, -C of formula (A) 1 - and -C 2 - has the same structure. In a particular embodiment, -C of formula (A) 1 - and -C 2 - is -O-, -C(O)N(R 10 )-, and C interrupted by one or more groups selected from the group consisting of 3- to 10-membered heterocyclines 1-50 It is alkyl, where a 3- to 10-membered heterocyclyl is substituted by at least one oxo (=O).

[0223] In a particular embodiment, -C of formula (A) 1 - and -C 2 - is equation (Aa) [ka] [In the formula, The dashed line with a star indicates BP 1 This shows a binding to, The dashed lines without markings are, respectively, BP 2 or BP 3 It shows a binding to, q1 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. q2 is selected from the group consisting of 1, 2, 3, 4, and 5. q3 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. q4 is selected from the group consisting of 1, 2, and 3. It belongs to them.

[0224] In a particular embodiment, q1 in formula (Aa) is selected from the group consisting of 4, 5, 6, 7, and 8. In a particular embodiment, q1 in formula (Aa) is selected from the group consisting of 5, 6, and 7. In a particular embodiment, q1 in formula (Aa) is 1. In a particular embodiment, q1 in formula (Aa) is 2. In a particular embodiment, q1 in formula (Aa) is 3. In a particular embodiment, q1 in formula (Aa) is 4. In a particular embodiment, q1 in formula (Aa) is 5. In a particular embodiment, q1 in formula (Aa) is 6. In a particular embodiment, q1 in formula (Aa) is 7. In a particular embodiment, q1 in formula (Aa) is 8.

[0225] In a particular embodiment, q2 in formula (Aa) is selected from the group consisting of 1, 2, and 3. In a particular embodiment, q2 in formula (Aa) is 1. In a particular embodiment, q2 in formula (Aa) is 2. In a particular embodiment, q2 in formula (Aa) is 3. In a particular embodiment, q2 in formula (Aa) is 4. In a particular embodiment, q2 in formula (Aa) is 5.

[0226] In a particular embodiment, q3 of formula (Aa) is selected from the group consisting of 2, 3, 4, and 5. In a particular embodiment, q3 of formula (Aa) is selected from the group consisting of 2, 3, and 4. In a particular embodiment, q3 of formula (Aa) is 1. In a particular embodiment, q3 of formula (Aa) is 2. In a particular embodiment, q3 of formula (Aa) is 3. In a particular embodiment, q3 of formula (Aa) is 4. In a particular embodiment, q3 of formula (Aa) is 5. In a particular embodiment, q3 of formula (Aa) is 6. In a particular embodiment, q3 of formula (Aa) is 7. In a particular embodiment, q3 of formula (Aa) is 8.

[0227] In a particular embodiment, q4 in equation (Aa) is 1. In a particular embodiment, q4 in equation (Aa) is 2. In a particular embodiment, q4 in equation (Aa) is 3.

[0228] In a particular embodiment, -P of formula (A) 1 , -P 2 , -P 3 and -P 4 These are independent of each other and form equation (Ab) [ka] [In the formula, The dashed line indicates the connection to the remainder of -Z. m is either 0 or 1. p is an integer in the range of 110 to 345. q is selected from the group consisting of 1, 2, 3, 4, 5, and 6. It belongs to them.

[0229] In a particular embodiment, m in equation (Ab) is 0. In a particular embodiment, m in equation (Ab) is 1.

[0230] In certain embodiments, p in formula (Ab) is an integer in the range of 140 to 315. In certain embodiments, p in formula (Ab) is an integer in the range of 170 to 285. In certain embodiments, p in formula (Ab) is an integer in the range of 195 to 255. In certain embodiments, p in formula (Ab) is an integer in the range of 200 to 250. In certain embodiments, p in formula (Ab) is an integer in the range of 210 to 250. In certain embodiments, p in formula (Ab) is an integer in the range of 220 to 240.

[0231] In a particular embodiment, q in equation (Ab) is 1. In a particular embodiment, q in equation (Ab) is 2. In a particular embodiment, q in equation (Ab) is 3. In a particular embodiment, q in equation (Ab) is 4. In a particular embodiment, q in equation (Ab) is 5. In a particular embodiment, q in equation (Ab) is 6.

[0232] In a particular embodiment, -Z in equation (I) is equation (Ac): [ka] [In the formula, p1, p2, p3, and p4 are independent integers in the range of 110 to 345. This includes the part.

[0233] In a particular embodiment, -Z is part of the expression (Ac).

[0234] In certain embodiments, p1, p2, p3, and p4 in formula (Ac) are integers in the range of 140 to 315, independently of each other. In certain embodiments, p1, p2, p3, and p4 in formula (Ac) are integers in the range of 170 to 285, independently of each other. In certain embodiments, p1, p2, p3, and p4 in formula (Ac) are integers in the range of 195 to 255, independently of each other. In certain embodiments, p1, p2, p3, and p4 in formula (Ac) are integers in the range of 200 to 250, independently of each other. In certain embodiments, p1, p2, p3, and p4 in formula (Ac) are integers in the range of 210 to 250, independently of each other. In certain embodiments, p1, p2, p3, and p4 in formula (Ac) are integers in the range of 220 to 240, independently of each other.

[0235] Part-M mod is part -L 1 -L 2 It is bound to an amino acid residue with the -D'- designation, which is different from -Z.

[0236] -L 1- can be bound to a proteinogenic or non-proteinogenic amino acid residue of -D'-. In certain embodiments, -L 1 - is bound to a proteinogenic amino acid residue of -D'-, for example, a proteinogenic amino acid residue selected from the group consisting of cysteine, methionine, histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, glutamine, and arginine. In certain embodiments, such a proteinogenic amino acid residue is selected from the group consisting of cysteine, histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid, and arginine. In certain embodiments, -L 1 The - bond is to a non-proteinogenic amino acid residue of -D'-. Examples of such non-proteinogenic amino acid residues are described elsewhere in this specification.

[0237] In a particular embodiment, -L 1 - is bound to the cysteine ​​residue of -D'-. In certain embodiments, -L 1 - is bound to the histidine residue of -D'-. In certain embodiments, -L 1 - is bound to the lysine residue of -D'-. In certain embodiments, -L 1 - is bound to the tryptophan residue of -D'-. In certain embodiments, -L 1 - is bound to the serine residue of -D'-. In certain embodiments, -L 1 - is bound to the threonine residue of -D'-. In certain embodiments, -L 1 - is bound to the tyrosine residue of -D'-. In certain embodiments, -L 1 - is bound to the aspartic acid residue of -D'-. In certain embodiments, -L 1 - is bound to the glutamate residue of -D'-. In certain embodiments, -L 1 - is bound to the arginine residue of -D'-.

[0238] Part-L1 - can be linked to -D'- through any type of bond, as long as it is reversible. In a particular embodiment, -L 1 - is linked to -D'- through a bond selected from the group consisting of amides, esters, carbamates, acetals, aminals, imines, oximes, hydrazones, disulfides, and acylguanidines. In certain embodiments, -L 1 - is linked to -D'- via a bond selected from the group consisting of amides, esters, carbamates, and acylguanidines. These bonds do not have to be reversible themselves, but reversibility is -L 1 -It is understood that this may be due to the action of a specific group of atoms or parts present within it. In a particular embodiment, -L 1 - is linked to -D'- through a carbamate bond. In certain embodiments, -L 1 - is linked to -D'- through an amide bond.

[0239] In a particular embodiment, -L 1 - is linked to -D'- via the nitrogen of the ε-amino group of the lysine residue of -D'- or via the nitrogen of the N-terminal amine of -D'-. In certain embodiments, -L 1 - is linked to -D'- via the nitrogen of the ε-amino group of the lysine residue or via the nitrogen of the N-terminal amine, and -D'- and -L 1 The bond formed between - and is a carbamate.

[0240] In a particular embodiment, -L 1 - is linked to -D'- via the nitrogen of the ε-amino group of the lysine residue of -D'-. In certain embodiments, -L 1 - is linked to -D'- via the nitrogen of the ε-amino group of the lysine residue of -D'-, and -D'- and -L 1 The bond formed between - and is a carbamate.

[0241] In a particular embodiment, -L 1- is linked to -D'- via the nitrogen of the N-terminal amine of -D'-. In certain embodiments, -L 1 - is linked to -D'- via the nitrogen of the N-terminal amine of -D'-, and -D'- and -L 1 The bond formed between - and is a carbamate.

[0242] In a particular embodiment, -L 1 - has the structure disclosed in International Publication No. 2009 / 095479A2. Therefore, in certain embodiments, part -L 1 - is equation (II): [ka] [In the formula, The dashed line indicates the bond of -D'- to nitrogen by forming an amide bond. -X- is -C(R 4 R 4a )-,-N(R 4 )-, -O-, -C(R 4 R 4a )-C(R 5 R 5a )-,-C(R 5 R 5a )-C(R 4 R 4a )-,-C(R 4 R 4a )-N(R 6 )-,-N(R 6 )-C(R 4 R 4a )-,-C(R 4 R 4a )-O-, -OC(R 4 R 4a )-, or -C(R 7 R 7a )- and, X 1 is C, or S(O), -X 2 - is -C(R 8 R 8a )-, or -C(R 8 R 8a )-C(R 9 R 9a)- and, =X 3 is =O, =S, or =N-CN, -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 4 ,-R 4a ,-R 5 ,-R 5a ,-R 6 ,-R 8 ,-R 8a ,-R 9 ,-R 9a -H and C 1-6 Independently selected from the group consisting of alkyls, -R 3 ,-R 3a -H and C 1-6 Independently selected from the group consisting of alkyl, except -R 3 ,-R 3a If one or both of them are not -H, then they are SP to the N to which they are bonded. 3 Linked through hybrid carbon atoms, -R 7 is -N(R 10 R 10a ), or -NR 10 -(C=O)-R 11 And, -R 7a ,-R 10 ,-R 10a ,-R 11 These are, independently of each other, -H or C 1-6 It is alkyl, Optional: Pair-R 1a / -R 4a ,-R 1a / -R 5a ,-R 1a / -R 7a ,-R 4a / -R 5a ,-R 8a / -R 9a One or more of them form a chemical bond, Optional: Pair-R 1 / -R 1a ,-R 2 / -R 2a,-R 4 / -R 4a ,-R 5 / -R 5a ,-R 8 / -R 8a ,-R 9 / -R 9a One or more of them, together with the atom they are bonded to, C 3-10 Forming cycloalkyl or 3-10 membered heterocyclines, Optional: Pair-R 1 / -R 4 ,-R 1 / -R 5 ,-R 1 / -R 6 ,-R 1 / -R 7a ,-R 4 / -R 5 ,-R 4 / -R 6 ,-R 8 / -R 9 ,-R 2 / -R 3 One or more of these, together with the atoms to which they are bonded, form ring A. Optionally, R 3 / R 3a These, together with the nitrogen atoms to which they are bonded, form a 3- to 10-membered heterocycle. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 [Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl] It is, -L 1 - is at least one -L 2 -Z is replaced, and optionally, -L 1 - is further substituted, except that the hydrogen marked with an asterisk in equation (II) is -L 2 -Z cannot be replaced by a substituent.

[0243] Preferably, -L of formula (II) 1 - is one part -L 2 Replaced with -Z

[0244] In one embodiment, -L of formula (II) 1 - is not further replaced.

[0245] -R in equation (II) 3 / -R 3a However, when they combine with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is SP 3 It is understood that only such 3- to 10-membered heterocycles, which are hybrid carbon atoms, can be formed. In other words, -R 3 / -R 3a Such 3- to 10-membered heterocycles, formed by these atoms and the nitrogen atoms to which they are bonded, have the following structure: [ka] [In the formula, The dashed line is -L 1 - indicates the bond to the remainder, The ring contains 3 to 10 atoms, including at least one nitrogen atom. R # and R ## SP 3 [Represents hybrid carbon atoms].

[0246] It is also understood that 3- to 10-membered complex rings may be further substituted.

[0247] -R in equation (II) 3 / -R 3a Exemplary embodiments of preferred 3- to 10-membered heterocycles formed by these atoms and the nitrogen atoms to which they are bonded are as follows: [ka] [In the formula, The dashed lines indicate bonding to the rest of the molecule. -R is -H and C 1-6 Selected from the group consisting of alkyl groups.

[0248] -L in equation (II) 1- may be further substituted at will. In general, any substituent may be used as long as it does not affect the principle of cleavage, that is, the asterisked hydrogen in formula (II) is not substituted, and part of formula (II) [ka] The nitrogen remains as part of a primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a These are either -H independently of each other, or sp 3 It is linked to -N< through hybridized carbon atoms.

[0249] In a particular embodiment, -L 1 - has the structure disclosed in International Publication No. 2016 / 020373A1. Therefore, in certain embodiments, part -L 1 - is equation (III): [ka] [In the formula, The dashed lines indicate the bonding of -D'- to a primary or secondary amine or hydroxyl group by forming an amide or ester bond, respectively. -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 3 and -R 3a is -H, -C(R 8 R 8a R 8b ), -C(=O)R 8 -C≡N, -C(=NR) 8 )R 8a ,-CR 8 (=CR 8a R 8b ), -C≡CR 8 and -T are independently selected from the group, -R 4 ,-R 5 and -R 5a is -H, -C(R 9 R 9a R 9b) and -T are independently selected from the group, a1 and a2 are independently 0 or 1. Each-R 6 ,-R 6a ,-R 7 ,-R 7a ,-R 8 ,-R 8a ,-R 8b ,-R 9 ,-R 9a ,-R 9b -H, HALogen, -CN, -COOR 10 , -OR 10 , -C(O)R 10 ,-C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)2R 10 ,-S(O)R 10 , -N(R 10 )S(O)2N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO2, -OC(O)R 10 , -N(R 10 )C(O)R 10a , -N(R 10 )S(O)2R 10a , -N(R 10 )S(O)R 10a , -N(R 10 )C(O)OR 10a , -N(R 10 )C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 They are independently selected from a group consisting of alkynnyls, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl has one or more -Rs, which may be the same or different.11 Replaced by optional means, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-,-N(R 12 )C(O)N(R 12a )-, and -OC(O)N(R 12 )- is optionally interrupted by one or more units selected from the group consisting of, Each-R 10 ,-R 10a ,-R 10b -H, -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Independently selected from the group consisting of alkynyls, -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl has one or more -Rs, which may be the same or different. 11 Replaced by optional means, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-,-N(R 12 )C(O)N(R 12a )-, and -OC(O)N(R 12) interrupted optionally by one or more groups selected from the group consisting of Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, and each T is independently optionally substituted by one or more of the same or different -R 11 Each -R 11 is halogen, -CN, oxo (=O), -COOR 13 , -OR 13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O)2N(R 13 R 13a ), -S(O)N(R 13 R 13a ), -S(O)2R 13 , -S(O)R 13 , -N(R 13 )S(O)2N(R 13a R 13b ), -SR 13 , -N(R 13 R 13a ), -NO2, -OC(O)R 13 , -N(R 13 )C(O)R 13a , -N(R 13 )S(O)2R 13a , -N(R 13 )S(O)R 13a , -N(R 13 )C(O)OR 13a , -N(R 13 )C(O)N(R 13a R 13b ), -OC(O)N(R 13 R 13a ), and C 1-6 alkyl are independently selected from each other, and C 1-6 alkyl is optionally substituted by one or more of the same or different halogens, each -R 12 , -R 12a , -R 13 , -R 13a , -R​13b is independently selected from the group consisting of -H and C 1-6 alkyl, and C 1-6 alkyl is optionally substituted by one or more of the same or different halogens, optionally, pair -R 1 / -R 1a , -R 2 / -R 2a , -R 3 / -R 3a , -R 6 / -R 6a , -R 7 / -R 7a one or more of which, together with the atoms to which they are attached, form C 3-10 cycloalkyl or a 3- to 10-member heterocyclyl, optionally, pair -R 1 / -R 2 , -R 1 / -R 3 , -R 1 / -R 4 , -R 1 / -R 5 , -R 1 / -R 6 , -R 1 / -R 7 , -R 2 / -R 3 , -R 2 / -R 4 , -R 2 / -R 5 , -R 2 / -R 6 , -R 2 / -R 7 , -R 3 / -R 4 , -R 3 / -R 5 , -R 3 / -R 6 , -R 3 / -R 7 , -R 4 / -R 5 , -R 4 / -R 6 , -R 4 / -R 7 , -R 5 / -R 6 , -R 5 / -R7 ,-R 6 / -R 7 One or more of these, together with the atoms to which they are bonded, form ring A. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 [Selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, and 8-11 membered heterobicyclyl] It is, -L 1 - is at least one -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0250] -L in equation (III) 1 Further optional substituents of are preferably as described above.

[0251] Preferably, -L of formula (III) 1 - is one part -L 2 Replaced with -Z

[0252] In one embodiment, -L of formula (III) 1 - is not further replaced.

[0253] In another embodiment, -L 1 - has the structure disclosed in European Patent No. 1536334 B1, International Publication No. 2009 / 009712 A1, International Publication No. 2008 / 034122 A1, International Publication No. 2009 / 143412 A2, International Publication No. 2011 / 082368 A2, and U.S. Patent No. 8,618,124 B2, which are incorporated herein by reference.

[0254] In a particular embodiment, -L 1 - has the structure disclosed in U.S. Patent No. 8,946,405 B2 and U.S. Patent No. 8,754,190 B2. Therefore, in certain embodiments, -L 1 - is equation (IV): [ka] [In the formula, The dashed lines indicate bonding to -D'- through a functional group of -D'- selected from the group consisting of -OH, -SH, and -NH2. m is either 0 or 1. -R 1 and -R 2 At least one or both of are -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 ,-S(O)R 3 -S(O)2R 3 , and -SR 4 Selected independently from a group consisting of, -R 1 and -R 2 One or only one of these is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. -R 3 -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 Selected from the group consisting of )2, -R 4 This is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Each-R 5 It is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. -R 9 It is selected from the group consisting of -H and optionally substituted alkyl groups, -Y- does not exist, -X- is either -O- or -S-, or -Y- is -N(Q)CH2-, and -X- is -O-, Q is selected from the group consisting of optionally substituted alkyls, optionally substituted aryls, optionally substituted arylalkyls, optionally substituted heteroaryls, and optionally substituted heteroarylalkyls. Optionally, -R 1 and -R 2 They may come together to form a 3- to 8-membered ring. Optionally, both -R 9 [These atoms, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring.] It is, -L 1 - is, -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0255] The term used only in relation to equation (IV) has the following meanings: As used herein, the term "alkyl" includes a linear, branched, or cyclic saturated hydrocarbon group comprising 1 to 8 carbon atoms, or in some embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0256] The term "alkoxy" includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar groups.

[0257] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon double bond.

[0258] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon triple bond.

[0259] The term "aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" includes aromatic rings with 3 to 15 carbon atoms and at least one N, O, or S atom, preferably 3 to 7 carbon atoms and at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar groups.

[0260] In some cases, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the rest of the molecule through an alkylene bond. In these situations, the substituent is referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety is located between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0261] The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0262] The term "heterocyclic ring" refers to a 4-8 membered aromatic or aromatic ring containing 3-7 carbon atoms and at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term "heteroaryl."

[0263] When the ring system is optionally substituted, preferred substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or further rings, each of which may be optionally further substituted. Optional substituents for any of the above groups include halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, and -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups cooperate with the atom to which they are bonded to form a ring.

[0264] Preferably, -L of formula (IV) 1 - is one part -L 2 It is replaced with -Z.

[0265] In a particular embodiment, -L 1 - has the structure disclosed in International Publication No. 2013 / 036857A1. Therefore, in certain embodiments, -L 1 - is equation (V): [ka] [In the formula, The dashed line indicates the bond to -D'- through the amine functional group of -D'-. -R 1 These include optionally substituted C1-C6 linear, branched or cyclic alkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, alkoxy groups, and -NR groups. 5 Selected from a group consisting of 2, -R 2 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 3 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R4 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each-R 5 These are independently selected from the group consisting of -H, optionally substituted C1-C6 alkyls, optionally substituted aryls, and optionally substituted heteroaryls, or, if they cooperate, two -R 5 [This can be a cycloalkyl or cycloheteroalkyl] It is, -L 1 - is, -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0266] The terms used only in relation to equation (V) have the following meanings: "Alkyl," "alkenyl," and "alkynyl" are linear, branched, or cyclic hydrocarbon groups comprising 1 to 8, 1 to 6, or 1 to 4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 carbon atoms.

[0267] "Aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, including groups such as phenyl, naphthyl, and anthracene. "Heteroaryl" includes aromatic rings with 3 to 15 carbon atoms and at least one N, O, or S atom, preferably 3 to 7 carbon atoms and at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar groups.

[0268] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains one or more substituents in place of one or more hydrogen atoms. Substituents generally include halogens (including F, Cl, Br, and I), lower alkyls (including linear, branched, and cyclic), lower haloalkyls (including fluoroalkyls, chloroalkyls, bromoalkyls, and iodoalkyls), OH, lower alkoxys (including linear, branched, and cyclic), SH, lower alkylthios (including linear, branched, and cyclic), aminos, alkylaminos, dialkylaminos, silyls (including alkylsilyls, alkoxysilyls, and arylsilyls), nitros, cyanos, carbonyls, carboxylic acids, carboxylic acid esters, carboxylic acid amides, aminocarbonyls, aminoacyls, carbamates, ureas, and thiocarbas. The following can be selected: mates, thioureas, ketones, sulfones, sulfonamides, aryls (including phenyl, naphthyl, and anthracenyl), and heteroaryls (including five-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole; six-membered heteroaryls such as pyridine, pyrimidine, and pyrazine; and condensed heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole, and benzoisothiazole).

[0269] In a particular embodiment, the -L of formula (V) 1 - is one part -L 2 Replaced with -Z

[0270] In a particular embodiment, -L 1 - has the structure disclosed in U.S. Patent No. 7,585,837 B2. Therefore, in certain embodiments, -L 1 - is represented by the following equation (VI): [ka] [In the formula, The dashed line indicates the bond to -D'- through the amine functional group of -D'-. R 1 and R 2 Hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkalyl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 Independently selected from the group consisting of amino, ammonium, carboxyl, PO3H2 and OPO3H2, R 3 , R 4 and R 5 [The element is independently selected from the group consisting of hydrogen, alkyl, and aryl atoms.] It is, -L 1 - is, -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0271] Preferred substituents for formula (VI) are alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 Alkenyl), Alkinyl (for example, C 2-6 The moiety is an alkynyl, aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., an aromatic 4-7 membered heterocycle), or halogen moiety.

[0272] The terms used only in relation to equation (VI) have the following meanings: The terms "alkyl," "alkoxy," "alkoxyalkyl," "aryl," "alkalil," and "aralkyl" refer to alkyl radicals with 1 to 8 carbon atoms, preferably 1 to 4, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl radicals with 6 to 10 carbon atoms, such as phenyl and naphthyl. The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0273] In a particular embodiment, the -L of formula (VI) 1 - is one part -L2 It is replaced with -Z.

[0274] In a particular embodiment, -L 1 - has the structure disclosed in International Publication No. 2002 / 089789A1. Therefore, in certain embodiments, -L 1 - is represented by the following equation (VII): [ka] [In the formula, The dashed line indicates the bond to -D'- through the amine functional group of -D'-. Y1 and Y2 are independently O, S, or NR 7 And, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen, C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituting alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6 Independently selected from the group consisting of heteroalkoxys, When Ar is included in formula (VII), it is the part that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group. X is a chemical bond, or a portion that is actively transported to the target cell, a hydrophobic portion, or a combination thereof. y is either 0 or 1. It is, -L 1 - is, -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0275] The term used only in relation to equation (VII) has the following meanings: The term "alkyl" is used, for example, in alkoxy, C 3-8 Linear, branched, and substituted carbon atoms, including cycloalkyl or substituted cycloalkyl groups. 1-12 It will be understood that it contains alkyl.

[0276] The term "substituted" should be understood to include the addition of one or more different atoms, or the replacement of one or more atoms within a functional group or compound with one or more different atoms.

[0277] Substituted alkyls include carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl; substituted cycloalkyls include parts such as 4-chlorocyclohexyl; aryls include parts such as naphthyl; substituted aryls include parts such as 3-bromophenyl; aralkyls include parts such as toluyl; heteroalkyls include parts such as ethylthiophene; substituted heteroalkyls include parts such as 3-methoxythiophene; alkoxys include parts such as methoxy; and phenoxys include parts such as 3-nitrophenoxy. Halos are understood to include fluoro, chloro, iodine, and bromo.

[0278] In a particular embodiment, the -L of formula (VII) 1 - is one part - L 2 It is replaced with -Z.

[0279] In a particular embodiment, -L 1 - is a substructure of equation (VIII) [ka] [In the formula, The dashed lines marked with asterisks indicate the bonding of -D'- to the nitrogen atom due to the formation of an amide bond. Dashed lines without a mark are -L 1- Indicates the connection to the remainder. Includes, -L 1 - is, -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0280] In certain embodiments, the -L of formula (VIII) 1 - is one part -L 2 It is replaced with -Z.

[0281] In certain embodiments, the -L of formula (VIII) 1 - is not further replaced.

[0282] In a particular embodiment, -L 1 - is a substructure of equation (IX) [ka] [In the formula, The dashed lines marked with asterisks indicate the bonding of -D'- to nitrogen through the formation of a carbamate bond. Dashed lines without a mark are -L 1 - Indicates the connection to the remainder. Includes, -L 1 - is, -L 2 -Z is replaced, and optionally, -L 1 - is further replaced.

[0283] In a particular embodiment, the -L of formula (IX) 1 - is one part -L 2 Replaced with -Z

[0284] In a particular embodiment, the -L of formula (IX) 1 - is not further replaced.

[0285] In a particular embodiment, -L 1 - is equation (IX-a) [ka] [In the formula, The dashed lines marked with an asterisk indicate the bond to nitrogen in -D'-, while the unmarked dashed lines indicate -L 2 Shows the bond to -Z, n is 0, 1, 2, 3, or 4. =Y1 is selected from the group consisting of =O and =S, -Y2- is selected from the group consisting of -O- and -S-, -Y3- is selected from the group consisting of -O- and -S-, -Y4- is -O-, -NR 5 -, and -C(R 6 R 6a Selected from the group consisting of )-, =Y5 is selected from the group consisting of =O and =S, -R 3 ,-R 5 ,-R 6 ,-R 6a These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. -R 4 This is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. -W- is C 3-10 Cycloalkyl, 8-30 membered carbopolycyclyl, 3-10 membered heterocyclyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S-, and -N(R 7 C is optionally interrupted by one or more groups selected from the group consisting of )- 1-20 Selected from the group consisting of alkyl groups, -Nu is -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH, [ka] A nucleophile selected from the group consisting of, -Ar- is, [ka] (In the formula, The dashed line is -L 1 - indicates the bond to the remainder, -Z 1 - is -O-, -S-, and -N(R 7 Selected from the group consisting of )-, -Z 2 - is -N(R 7 )-is) Selected from the group consisting of, -R 7 ,-R 7a ,-R 7b is -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 [Selected independently from the group consisting of alkinyls] It is, -L 1 - can be optionally replaced further.

[0286] In a particular embodiment, -L 1 - represents formula (IX-a), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0287] In a particular embodiment, -L 1 - represents equation (IX-a), where the dashed line marked with an asterisk indicates the bond of the ε-amino group of the -D'- lysine residue to the nitrogen.

[0288] In a particular embodiment, -L 1 - is from equation (IX-a), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0289] In a particular embodiment, the -L of formula (IX-a) 1 - is not further replaced.

[0290] In a particular embodiment, -L 1 - is equation (IX-b): [ka] [In the formula, The dashed lines marked with an asterisk indicate the bond to nitrogen in -D'-, while the unmarked dashed lines indicate -L 2 Shows the bond to -Z, n is 0, 1, 2, 3, or 4. =Y1 is selected from the group consisting of =O and =S, -Y2- is selected from the group consisting of -O- and -S-, -Y3- is selected from the group consisting of -O- and -S-, -Y4- is -O-, -NR 5 -, and -C(R 6 R 6a Selected from the group consisting of )-, =Y5 is selected from the group consisting of =O and =S, -R 2 ,-R 3 ,-R 5 ,-R 6 ,-R 6a These are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. -R 4This is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylpropyl. -W- is C 3-10 Cycloalkyl, 8-30 membered carbopolycyclyl, 3-10 membered heterocyclyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S-, and -N(R 7 C is optionally interrupted by one or more groups selected from the group consisting of )- 1-20 Selected from the group consisting of alkyl groups, -Nu is -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH, [ka] A nucleophile selected from the group consisting of, -Ar- is, [ka] (In the formula, The dashed line is -L 1 - indicates the bond to the remainder, -Z 1 - is -O-, -S-, and -N(R 7 Selected from the group consisting of )-, -Z 2 - is -N(R 7 )-is) Selected from the group consisting of, -R 7 ,-R 7a ,-R 7b is -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6[Selected independently from the group consisting of alkinyls] It is, -L 1 - can be optionally replaced further.

[0291] In a particular embodiment, -L 1 - represents formula (IX-b), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0292] In a particular embodiment, -L 1 - represents equation (IX-b), where the dashed line marked with an asterisk indicates the bond of the ε-amino group of the -D'- lysine residue to the nitrogen.

[0293] In a particular embodiment, -L 1 - is from equation (IX-b), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0294] In a particular embodiment, the -L of formula (IX-b) 1 - is not substituted.

[0295] In a particular embodiment, equations (IX-a) and (IX-b) = Y 1 The answer is = O.

[0296] In certain embodiments, formulas (IX-a) and (IX-b)-Y 2 - is -O-.

[0297] In certain embodiments, the -Y in formulas (IX-a) and (IX-b) 3 - is -O-.

[0298] In certain embodiments, the -Y in formulas (IX-a) and (IX-b) 4 - is, -NR 5 - is

[0299] In a particular embodiment, equations (IX-a) and (IX-b) = Y 5 The answer is = O.

[0300] In certain embodiments, n in formulas (IX-a) and (IX-b) is 0 or 1. In certain embodiments, n in formulas (IX-a) and (IX-b) is 0. In certain embodiments, n in formulas (IX-a) and (IX-b) is 1.

[0301] In a particular embodiment, (IX-b) -R 2 The group is selected from -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain embodiments, the -R of formula (IX-b) 2 The -R of formula (IX-b) is selected from the group consisting of -H, methyl, ethyl, n-propyl, and isopropyl. In certain embodiments, the -R of formula (IX-b) is selected. 2 is selected from -H, methyl, and ethyl. In certain embodiments, -R of formula (IX-b) 2 It is -H.

[0302] In certain embodiments, the -R in formulas (IX-a) and (IX-b) 3 The -R is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) 3 The -R is selected from the group consisting of -H, methyl, ethyl, n-propyl, and isopropyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) is selected. 3 is selected from -H, methyl, and ethyl. In certain embodiments, -R of formulas (IX-a) and (IX-b) 3 It is -H.

[0303] In certain embodiments, each of the -R in formulas (IX-a) and (IX-b) 4is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) 4 The -R of formulas (IX-a) and (IX-b) is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) is selected. 4 It is selected from methyl and ethyl.

[0304] In certain embodiments, the -R in formulas (IX-a) and (IX-b) 5 The -R is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) 5 The -R is selected from the group consisting of -H, methyl, ethyl, n-propyl, and isopropyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) is selected. 5 The -R of formulas (IX-a) and (IX-b) is selected from methyl and ethyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) is selected. 5 It is methyl.

[0305] In certain embodiments, the -R in formulas (IX-a) and (IX-b) 6 and -R 6a -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain embodiments, -R of formulas (IX-a) and (IX-b) 6 and -R 6a -H, methyl, ethyl, n-propyl, and isopropyl are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, and isopropyl. In certain embodiments, -R of formulas (IX-a) and (IX-b) 6 and -R 6a The -R is independently selected from -H, methyl, and ethyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) is selected. 6 and -R 6a All of these are -H.

[0306] In certain embodiments, the -Ar- in formulas (IX-a) and (IX-b) is phenyl. In certain embodiments, the -Ar- in formulas (IX-a) and (IX-b) is [ka] [In the equation, the dashed line indicates the combination of parts (IX-a) and (IX-b) with respect to the remainder.] That is the case.

[0307] In a particular embodiment, -W- in formulas (IX-a) and (IX-b) is C 3-10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S-, and -N(R 7 )- which can be optionally interrupted by C 1-20 It is alkyl. In certain embodiments, -W- in formulas (IX-a) and (IX-b) is C 3-10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S-, and -N(R 7 )- which can be optionally interrupted by C 1-10 It is alkyl. In certain embodiments, -W- in formulas (IX-a) and (IX-b) is C 3-10 Cycloalkyl, -C(O)-, -C(O)N(R) 7 )-, -O-, -S-, and -N(R 7 )- which can be optionally interrupted by C 1-6 It is alkyl. In certain embodiments, -W- in formulas (IX-a) and (IX-b) is [ka] [In the formula, The dashed lines indicate the connections to the remainder of the part of equation (IX-a) or (IX-b), respectively. That is the case.

[0308] In a particular embodiment, -Nu in formulas (IX-a) and (IX-b) is -N(R 7 R7a )

[0309] In certain embodiments, the -R in formulas (IX-a) and (IX-b) 7 ,-R 7a , and -R 7b The -R of formulas (IX-a) and (IX-b) is independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In certain embodiments, the -R of formulas (IX-a) and (IX-b) is independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl 7 ,-R 7a , and -R 7b -H, methyl, ethyl, n-propyl, and isopropyl are independently selected from each other. In certain embodiments, -R of formulas (IX-a) and (IX-b) 7 ,-R 7a , and -R 7b The -R of formulas (IX-a) and (IX-b) is selected independently from each other. In certain embodiments, the -R 7 ,-R 7a , and -R 7b All of them are methyl.

[0310] In a particular embodiment, -L 1 - is equation (IX-c) [ka] [In the formula, The dashed lines marked with an asterisk indicate the bond between -D'- and nitrogen. Dashed lines without a mark are -L 2 Shows the bond to -Z, s1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. It belongs to them.

[0311] In a particular embodiment, -L 1 - represents formula (IX-c), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0312] In a particular embodiment, -L 1 - represents equation (IX-c), where the dashed line marked with an asterisk indicates the bond of the ε-amino group of the -D'- lysine residue to the nitrogen.

[0313] In a particular embodiment, -L 1 - is from equation (IX-c), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0314] In a particular embodiment, s1 in equation (IX-c) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In a particular embodiment, s1 in equation (IX-c) is 1. In a particular embodiment, s1 in equation (IX-c) is 2. In a particular embodiment, s1 in equation (IX-c) is 3. In a particular embodiment, s1 in equation (IX-c) is 4. In a particular embodiment, s1 in equation (IX-c) is 5.

[0315] In a particular embodiment, -L 1 - is equation (IX-d) [ka] [In the formula, The dashed lines marked with an asterisk indicate the bond between -D'- and nitrogen. Dashed lines without a mark are -L 2 - Indicates a bond to Z] It belongs to them.

[0316] In a particular embodiment, -L 1 - represents formula (IX-d), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0317] In a particular embodiment, -L 1 - represents equation (IX-d), where the dashed line marked with an asterisk indicates the bond of the ε-amino group of the -D'- lysine residue to the nitrogen.

[0318] In a particular embodiment, -L 1 - represents equation (IX-d), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0319] In a particular embodiment, -L 1 - has the structure disclosed in International Publication No. 2020 / 206358A1. Therefore, in certain embodiments, part -L 1 - is equation (X): [ka] [In the formula, Unmarked dashed lines indicate connections to -D'-. The dashed line with an asterisk indicates -L 2 Shows the bond to -Z, n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. -R 1 and -R 2 These are independently electron-withdrawing groups, alkyl groups, or -H groups, and -R 1 or -R 2 At least one of them is an electron-withdrawing group, Each-R 4 These are independently either C1-C3 alkyl or two-R 4 However, together with the carbon atoms to which they are bonded, they form a 3-6 membered ring. If -D'- is a drug moiety linked via an amine, then -Y- is absent, or if -D'- is a drug moiety linked via a phenol, alcohol, thiol, thiophenol, imidazole, or non-basic amine, then -Y- is -N(R 6 )CH2-, where -R 6 [This is a C1-C6 alkyl group that is optionally substituted, an aryl group that is optionally substituted, or a heteroaryl group that is optionally substituted.] It belongs to them.

[0320] The terms used only in relation to equation (X) have the following meanings: The term "alkyl" refers to a linear, branched, or cyclic saturated hydrocarbon group having 1 to 20, 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In certain embodiments, alkyl groups can be linear or branched. Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. In certain embodiments, alkyl groups are cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.

[0321] The term "alkoxy" refers to alkyl groups that are bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.

[0322] The term "alkenyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon double bond and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0323] The term "alkynyl" refers to a non-aromatic unsaturated hydrocarbon having a carbon-carbon triple bond and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.

[0324] The term "aryl" refers to aromatic hydrocarbon groups with 6 to 18 carbon atoms, preferably 6 to 10, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to aromatic rings containing 3 to 15 carbon atoms and at least one N, O, or S atom, preferably 3 to 7 carbon atoms and at least one N, O, or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indol, and indenyl.

[0325] In certain embodiments, the alkenyl, alkynyl, aryl, or heteroaryl moiety may be coupled to the remainder of the molecule through an alkyl bond. In these circumstances, the substituent is referred to as alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety is between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is coupled.

[0326] The term "halogen" refers to bromo, fluoro, chloro, and iodine.

[0327] The term “heterocyclic ring” or “heterocyclyl” refers to a 3- to 15-membered aromatic or non-aromatic ring containing at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided above for the term “heteroaryl.” In certain embodiments, the heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments, the heterocyclic ring or heterocyclyl is aromatic.

[0328] The term "optionally substituted" refers to a group that may not be substituted, or may be substituted with one or more (e.g., one, two, three, four, or five) substituents that may be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, and -OR. aa , -SR aa , -NR aa R bb -NO2, -C=NH(OR aa ), -C(O)R aa -OC(O)R aa , -C(O)OR aa -C(O)NR aa R bb -OC(O)NR aa R bb , -NR aa C(O)R bb , -NR aaC(O)OR bb ,-S(O)R aa -S(O)2R aa , -NR aa S(O)R bb -C(O)NR aa S(O)R bb , -NR aa S(O)2R bb -C(O)NR aa S(O)2R bb -S(O)NR aa R bb -S(O)2NR aa R bb , -P(O)(OR aa )(OR bb Examples include heterocyclyl, heteroaryl, or aryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently -R cc It is optionally replaced by -R aa and -R bb Each of these is independently -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -R aa and -R bb They cooperate with the nitrogen atom to which they are bonded to form a heterocycline, which is optionally substituted with alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy or -CN, and each -R cc These are independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN, or -NO2.

[0329] In a particular embodiment, -L 2 - is the spacer portion. In a particular embodiment, -L 2 - does not exist.

[0330] In a particular embodiment, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(Ry1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls, where -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has one or more -Rs, which may be the same or different. y2 Replaced by optional means, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- is optionally interrupted by one or more units selected from the group consisting of, -R y1 and -R y1a -H, -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 They are independently selected from a group consisting of alkynnyls, where -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different one or more -R y2Replaced by optional means, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- is optionally interrupted by one or more units selected from the group consisting of, Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each T is the same or different one or more -R y2 It is independently and arbitrarily replaced by, Each-R y2 These are halogen, -CN, oxo (=O), and -COOR. y5 , -OR y5 , -C(O)R y5 ,-C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 ,-S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)Ry5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different. Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b are -H and C 1-6 Independently selected from the group consisting of alkyls, where C 1-6 The alkyl group is optionally substituted with one or more halogens, either the same or different.

[0331] In a particular embodiment, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls, where -T-, C 1-20 Alkyl, C 2-20Alkenyl and C 2-20 Alkinyl has one or more -Rs, which may be the same or different. y2 Replaced by optional means, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- is optionally interrupted by one or more units selected from the group consisting of, -R y1 and -R y1a -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 They are independently selected from a group consisting of alkynnyls, where -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl has one or more -Rs, which may be the same or different. y2 Replaced by optional means, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a)-, and -OC(O)N(R y4 )- is optionally interrupted by one or more units selected from the group consisting of, Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, each T is the same or different one or more -R y2 It is independently and arbitrarily replaced by, -R y2 These are halogen, -CN, oxo (=O), and -COOR. y5 , -OR y5 , -C(O)R y5 ,-C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 ,-S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more halogens, either the same or different. Each-R y3 ,-Ry3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b are -H and C 1-6 They are independently selected from the group consisting of alkyls, where C 1-6 Alkyl atoms are optionally substituted with one or more halogens, either the same or different.

[0332] In a particular embodiment, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls, where -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has one or more -Rs, which may be the same or different. y2 Replaced by optional means, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a)-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- is optionally interrupted by one or more units selected from the group consisting of, -R y1 and -R y1a -H, -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Independently selected from the group consisting of alkinyls, Each T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl, Each-R y2 is halogen and C 1-6 Independently selected from the group consisting of alkyls, Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b -H and C 1-6 They are independently selected from the group consisting of alkyls, where C 1-6 The alkyl group is optionally substituted with one or more halogens, either the same or different.

[0333] In a particular embodiment, -L 2 - is C 1-20 These are alkyl chains, which include -O-, -C(O)-, -T-, and -C(O)N(R) y1 )- is optionally suspended by one or more bases independently selected from C 1-20 The alkyl chain consists of -OH, -T, and -C(O)N(R) y6 R y6a ) is optionally replaced by one or more elements independently selected from, where -R y1 ,-R y6 ,-R y6a H and C 1-4Independently selected from the group consisting of alkyls, T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 The group is selected from cycloalkyl, 3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl.

[0334] In a particular embodiment, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0335] In a particular embodiment, -L 2 -teeth, [ka] TIFF2026517863000084.tif140160[In the formula, The dashed lines represent -L 1 -, -L 2 - indicates the remainder of - or a bond to -Z, -R and -R a [These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.] Includes a portion selected from the group consisting of

[0336] In a particular embodiment, -L 2 - is equation (IX-e): [ka] [In the formula, the dashed line marked with an asterisk represents -L] 1 - indicates a bond to -, Unmarked dashed lines indicate connections to -Z. s2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. It belongs to them.

[0337] In a particular embodiment, s2 in equation (IX-e) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a particular embodiment, s2 in equation (IX-e) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. In a particular embodiment, s2 in equation (IX-e) is 1. In a particular embodiment, s2 in equation (IX-e) is 2. In a particular embodiment, s2 in equation (IX-e) is 3. In a particular embodiment, s2 in equation (IX-e) is 4. In a particular embodiment, s2 in equation (IX-e) is 5. In a particular embodiment, s2 in equation (IX-e) is 6. In a particular embodiment, s2 in equation (IX-e) is 7. In a particular embodiment, s2 in equation (IX-e) is 8.

[0338] In a particular embodiment, part-L 1 -L 2 - is equation (IX-f) [ka] [In the formula, The dashed lines marked with an asterisk indicate the bond between -D'- and nitrogen. Unmarked dashed lines indicate connections to -Z. s1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. s2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. It belongs to them.

[0339] In a particular embodiment, -L 1 - represents equation (IX-f), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0340] In a particular embodiment, -L 1- represents equation (IX-f), where the dashed line marked with an asterisk indicates the bond of the ε-amino group of the -D'- lysine residue to the nitrogen.

[0341] In a particular embodiment, -L 1 - is from equation (IX-f), where the dashed line marked with an asterisk indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0342] Therefore, the molar -L formed in the compound of formula (IX-f) 1 The bond between -D'- is a carbamate.

[0343] In a particular embodiment, s1 in equation (IX-f) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In a particular embodiment, s1 in equation (IX-f) is 1. In a particular embodiment, s1 in equation (IX-f) is 2. In a particular embodiment, s1 in equation (IX-f) is 3. In a particular embodiment, s1 in equation (IX-f) is 4. In a particular embodiment, s1 in equation (IX-f) is 5.

[0344] In a particular embodiment, s2 in formula (IX-f) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a particular embodiment, s2 in formula (IX-f) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. In a particular embodiment, s2 in formula (IX-f) is 1. In a particular embodiment, s2 in formula (IX-f) is 2. In a particular embodiment, s2 in formula (IX-f) is 3. In a particular embodiment, s2 in formula (IX-f) is 4. In a particular embodiment, s2 in formula (IX-f) is 5. In a particular embodiment, s2 in formula (IX-f) is 6. In a particular embodiment, s2 in formula (IX-f) is 7. In a particular embodiment, s2 in formula (IX-f) is 8.

[0345] In a particular embodiment, s1 in equation (IX-f) is 3, and s2 in equation (IX-f) is 3.

[0346] In a particular embodiment, part-L 1 -L 2 -Z is given by equation (XI) [ka] [In the formula, The dashed line indicates the bond of -D'- to nitrogen. s1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. s2 is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. p1, p2, p3, and p4 are independent integers in the range of 110 to 345. It belongs to them.

[0347] In a particular embodiment, -L 1 -L 2 -Z is from formula (XI), where the asterisked dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0348] In a particular embodiment, -L 1 -L 2 -Z is from formula (XI), where the asterisked dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue.

[0349] In a particular embodiment, -L 1 -L 2 -Z is from equation (XI), where the asterisked dashed line indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0350] Therefore, the molar formed in the compound of formula (XI) is -L 1 -L 2 The bond between -Z and -D'- is a carbamate.

[0351] In a particular embodiment, s1 in equation (XI) is an integer selected from the group consisting of 1, 2, 3, 4, and 5. In a particular embodiment, s1 in equation (XI) is 1. In a particular embodiment, s1 in equation (XI) is 2. In a particular embodiment, s1 in equation (XI) is 3. In a particular embodiment, s1 in equation (XI) is 4. In a particular embodiment, s1 in equation (XI) is 5.

[0352] In a particular embodiment, s2 in formula (XI) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In a particular embodiment, s2 in formula (XI) is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. In a particular embodiment, s2 in formula (XI) is 1. In a particular embodiment, s2 in formula (XI) is 2. In a particular embodiment, s2 in formula (XI) is 3. In a particular embodiment, s2 in formula (XI) is 4. In a particular embodiment, s2 in formula (XI) is 5. In a particular embodiment, s2 in formula (XI) is 6. In a particular embodiment, s2 in formula (XI) is 7. In a particular embodiment, s2 in formula (XI) is 8.

[0353] In a particular embodiment, s1 in equation (XI) is 3, and s2 in equation (XI) is 3.

[0354] In certain embodiments, p1, p2, p3, and p4 in equation (XI) are integers in the range of 140 to 315, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI) are integers in the range of 170 to 285, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI) are integers in the range of 195 to 255, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI) are integers in the range of 200 to 250, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI) are integers in the range of 210 to 250, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI) are integers in the range of 220 to 240, independently of each other.

[0355] In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and p1, p2, p3, and p4 are in the range of 195 to 255. In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and p1, p2, p3, and p4 are in the range of 200 to 250. In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and p1, p2, p3, and p4 are in the range of 210 to 250. In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and p1, p2, p3, and p4 are in the range of 220 to 240.

[0356] In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and the molecular weight of the PEG arm is in the range of 8 to 12 kDa. In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and the molecular weight of the PEG arm is in the range of 9 to 11 kDa. In certain embodiments, p1, p2, p3, and p4 in formula (XI) are identical, and the molecular weight of the PEG arm is approximately 10 kDa.

[0357] The term "PEG arm" in relation to p1, p2, p3 and p4 in formula (XI) or (XI-a) is a partial [ka] [In the formula, pX is one of p1, p2, p3, or p4] It refers to.

[0358] In a particular embodiment, part-L 1 -L 2 -Z is given by equation (XI-a) [ka] [In the formula, The dashed line indicates the bond of -D to nitrogen. p1, p2, p3, and p4 are independent integers in the range of 110 to 345. It belongs to them.

[0359] In a particular embodiment, -L 1 -L 2 -Z is from formula (XI-a), where the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of -D'-.

[0360] In a particular embodiment, -L 1 -L 2 -Z is from formula (XI-a), where the dashed line indicates the bond of the ε-amino group of the lysine residue -D'- to the nitrogen.

[0361] In a particular embodiment, -L 1 -L 2 -Z is from equation (XI-a), where the dashed line indicates the bond to the nitrogen of the N-terminal amine of -D'-.

[0362] In a particular embodiment, -L 1 -L 2 -Z is from formula (XI-a), where the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue having the amino acid sequence of SEQ ID NO: 4, or to the nitrogen of the N-terminal amine of -D'-.

[0363] In a particular embodiment, -L1 -L 2 -Z is from formula (XI-a), where the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue having the amino acid sequence of SEQ ID NO: 4.

[0364] In a particular embodiment, -L 1 -L 2 -Z is from formula (XI-a), where the dashed line indicates the bond to the nitrogen of the N-terminal amine of -D'- having the amino acid sequence of SEQ ID NO: 4.

[0365] Therefore, the part formed in the compound of formula (XI-a) -L 1 -L 2 The bond between -Z and -D'- is a carbamate.

[0366] In certain embodiments, p1, p2, p3, and p4 in equation (XI-a) are integers in the range of 140 to 315, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI-a) are integers in the range of 170 to 285, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI-a) are integers in the range of 195 to 255, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI-a) are integers in the range of 200 to 250, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI-a) are integers in the range of 210 to 250, independently of each other. In certain embodiments, p1, p2, p3, and p4 in equation (XI-a) are integers in the range of 220 to 240, independently of each other.

[0367] In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and p1, p2, p3, and p4 are in the range of 195 to 255. In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and p1, p2, p3, and p4 are in the range of 200 to 250. In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and p1, p2, p3, and p4 are in the range of 210 to 250. In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and p1, p2, p3, and p4 are in the range of 220 to 240.

[0368] In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and the molecular weight of the PEG arm is in the range of 8 to 12 kDa. In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and the molecular weight of the PEG arm is in the range of 9 to 11 kDa. In certain embodiments, p1, p2, p3, and p4 in formula (XI-a) are identical, and the molecular weight of the PEG arm is approximately 10 kDa.

[0369] In a particular embodiment, the IL-2 conjugate is of formula (I), where -D- is -D'-M mod -D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod (A-1d) or (A-1e) [ka] [In the formula, The dashed line marked with an asterisk indicates the bond to the sulfur atom of the cysteine ​​side chain at position 38. b1 is 2, b2 is 2, b3 is in the range of 90-140, 95-135, or 100-125. -L 1 -L 2 -Z is represented by equation (XI-a). [ka] (In the formula, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of the -D'-, p1, p2, p3, and p4 are independent integers in the ranges of 110-345, 140-315, 170-285, 195-255, 200-250, 210-250, or 220-240. [It belongs to] It has the structure of [the object].

[0370] In certain embodiments, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue.

[0371] In certain embodiments, the IL-2 conjugate is of formula (I), where -D is -D'-M mod -D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod (A-1d) or (A-1e) [ka] [In the formula, The dashed line marked with an asterisk indicates the bond to the sulfur atom of the cysteine ​​side chain at position 38. b1 is 3, b2 is 2, b3 is in the range of 90-140, 95-135, or 100-125. -L 1 -L 2 -Z is represented by equation (XI-a). [ka] (In the formula, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of the -D'-, p1, p2, p3, and p4 are independent integers in the ranges of 110-345, 140-315, 170-285, 195-255, 200-250, 210-250, or 220-240. [It belongs to] It has the structure of [the object].

[0372] In certain embodiments, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue.

[0373] In a particular embodiment, the IL-2 conjugate is of formula (I), where -D- is -D'-M mod -D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod (A-1d) or (A-1e) [ka] [In the formula, The dashed line marked with an asterisk indicates the bond to the sulfur atom of the cysteine ​​side chain at position 38. b1 is 2, b2 is 3, b3 is in the range of 90-140, 95-135, or 100-125. -L 1 -L 2 -Z is represented by equation (XI-a). [ka] (In the formula, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of the -D'-, p1, p2, p3, and p4 are independent integers in the ranges of 110-345, 140-315, 170-285, 195-255, 200-250, 210-250, or 220-240. [It belongs to] It has the structure of [the object].

[0374] In certain embodiments, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue.

[0375] In certain embodiments, the IL-2 conjugate is of formula (I), where -D is -D'-M mod -D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod (A-1d) or (A-1e) [ka] [In the formula, The dashed line marked with an asterisk indicates the bond to the sulfur atom of the cysteine ​​side chain at position 38. b1 is 3, b2 is 3, b3 is in the range of 90-140, 95-135, or 100-125. -L 1 -L 2 -Z is represented by equation (XI-a). [ka] (In the formula, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue or to the nitrogen of the N-terminal amine of the -D'-, p1, p2, p3, and p4 are independent integers in the ranges of 110-345, 140-315, 170-285, 195-255, 200-250, 210-250, or 220-240. [It belongs to] It has the structure of [the object].

[0376] In certain embodiments, the dashed line indicates the bond to the nitrogen of the ε-amino group of the -D'- lysine residue.

[0377] First stably bonded polymer moiety M mod The combination of the first and second reversibly bonded polymer moiety-Z offers the advantages of both modes of conjugation (stable and reversible). On the other hand, the first stably bonded polymer moiety M mod For example, by altering its receptor binding affinity through steric hindrance, the functional properties of the IL-2 protein can be permanently altered. On the other hand, the second reversibly bound polymer moiety-Z may alter the bioavailability of IL-2, for example, by extending its half-life or blocking its biological activity in circulation while subsequently releasing the protein in its free form.

[0378] In all aspects of the present invention, in certain embodiments, cancer may be selected from the group consisting of humoral tumors, solid tumors, and lymphomas.

[0379] Humorous neoplasms may include leukemia or myeloid neoplasms, such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia, lymphoblastic leukemia, myeloid leukemia, plasma cell leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-related high-risk MDS or AML, chronic myeloid leukemia in the acute transformation phase, multiple myeloma, myelodysplastic syndrome, chronic myeloproliferative disorder, plasma cell neoplasms, and Waldenström macroglobulinemia.

[0380] Solid tumors or lymphomas include lip and oral cancer, oral cancer, liver cancer / hepatocellular carcinoma, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastatic squamous neck cancer of unknown primary origin, multiple endocrine neoplasia syndrome in children, mycosis fungoides, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, neurological cancers, breast cancer, bronchial adenoma / carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma, and rectal rectum The group may be selected from the following: intestinal cancer, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gestational trophoblastoma, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma (pancreatic endocrine part), kidney cancer / renal cell carcinoma, laryngeal cancer, pleuropulmonary blastoma, prostate cancer, renal pelvis-ureter transitional cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, Sézary syndrome, small intestine cancer, genitourinary cancer, malignant thymoma, thyroid cancer, Wilms' tumor, bile duct cancer, and the early stages of abnormal cell proliferation associated with them, such as dysplasia, adenoma, and carcinoma in situ.

[0381] In certain embodiments, the cancer is liver cancer / hepatocellular carcinoma. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is malignant thymoma. In certain embodiments, the cancer is skin cancer. In certain embodiments, the cancer is metastatic squamous neck cancer of unknown primary origin. In certain embodiments, the cancer is neuroblastoma. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is bile duct cancer. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is neurosurgical cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is gastrointestinal carcinoid tumor. In certain embodiments, the cancer is carcinoma. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is extrahepatic bile duct cancer. In certain embodiments, the cancer is gallbladder cancer. In certain embodiments, the cancer is stomach cancer. In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the cancer is kidney cancer / renal cell carcinoma. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is sarcoma. In certain embodiments, the cancer is small intestine cancer. In certain embodiments, the cancer is genitourinary cancer. In certain embodiments, the cancer is salivary gland cancer.

[0382] Examples of salivary gland cancers include mucoepidermoid carcinoma, acinar cell carcinoma, adenoid cystic carcinoma, and pleomorphic adenocarcinoma. In certain embodiments, the cancer is mucoepidermoid carcinoma. In certain embodiments, the cancer is acinar cell carcinoma. In certain embodiments, the cancer is adenoid cystic carcinoma. In certain embodiments, the cancer is pleomorphic adenocarcinoma.

[0383] In certain embodiments, the cancer is PD-L1-positive acinar cell carcinoma.

[0384] Examples of endometrial cancer include endometrioid adenocarcinoma, clear cell carcinoma, serous carcinoma of the uterine body, clear cell carcinoma of the uterus, carcinosarcoma of the uterus, and uterine sarcoma.

[0385] In certain embodiments, the cancer is mismatch repair deficiency (dMMR) endometrial cancer.

[0386] Examples of lung cancer include non-small cell lung cancer and small cell lung cancer. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is small cell lung cancer (SCLC).

[0387] Examples of lymphoma include AIDS-associated lymphoma, primary central nervous system lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, and angioimmunoblastic lymphoma.

[0388] Examples of skin cancers include melanoma and Merkel cell carcinoma. In certain embodiments, the cancer is skin cancer. In certain embodiments, the cancer is Merkel cell carcinoma. In certain embodiments, the cancer is melanoma.

[0389] Ovarian cancer can be, for example, an epithelial cancer, a germ cell tumor, or a low-grade tumor. In certain embodiments, ovarian cancer is an epithelial cancer. In certain embodiments, ovarian cancer is a germ cell tumor. In certain embodiments, ovarian cancer is a low-grade tumor.

[0390] In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the ovarian cancer is platinum-resistant ovarian cancer (PROC).

[0391] Pancreatic cancer can be, for example, an exocrine / adenocarcinoma of the pancreas, an endocrine (PET) pancreatic tumor, or a neuroendocrine (NET) pancreatic tumor. In certain embodiments, the cancer is an exocrine / adenocarcinoma of the pancreas. In certain embodiments, the cancer is an endocrine tumor of the pancreas. In certain embodiments, the cancer is a neuroendocrine tumor of the pancreas.

[0392] In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is microsatellite-stable pancreatic cancer. In certain embodiments, the cancer is high-frequency microsatellite-instability (MSI-H) pancreatic cancer. In certain embodiments, the cancer is low-frequency microsatellite-instability (MSI-L) pancreatic cancer. In certain embodiments, the cancer is microsatellite-stable (MSS) pancreatic cancer.

[0393] Examples of cancers of the brain and nervous system include medulloblastoma, such as pediatric medulloblastoma, astrocytoma, ependymoma, neuroectodermal tumor, schwannoma, meningioma, pituitary adenoma, and glioma. In certain embodiments, the cancer is a medulloblastoma. In certain embodiments, the cancer is a pediatric medulloblastoma. In certain embodiments, the cancer is an astrocytoma. In certain embodiments, the cancer is an ependymoma. In certain embodiments, the cancer is a neuroectodermal tumor. In certain embodiments, the cancer is a schwannoma. In certain embodiments, the cancer is a meningioma. In certain embodiments, the cancer is a pituitary adenoma. In certain embodiments, the cancer is a glioma.

[0394] Astrocytomas include giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, primary pediatric glioblastoma, oligodendroglioma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytic tumor, oligoastrocytoma, anaplastic oligodendroglioma, and oligodendroglioma. It may be selected from the group consisting of astrocytic tumor, oligoastrocytoma, anaplastic oligoastrocytoma, anaplastic astrocytoma, pilocytic astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, and cerebellar astrocytoma.

[0395] Examples of neuroectodermal tumors include pineal primitive neuroectodermal tumors and supratentorial primitive neuroectodermal tumors.

[0396] Ependymomas can be selected from the group consisting of subependymal ependymomas, ependymomas, myxopapillary ependymomas, and anaplastic ependymomas.

[0397] Meningiomas may be atypical meningiomas or anaplastic meningiomas.

[0398] Gliomas may be selected from the group consisting of glioblastoma multiforme, paraganglioma, supratentorial undifferentiated primitive ectoderm tumor (sPNET), brainstem glioma, pediatric brainstem glioma, hypothalamic optic tract glioma, pediatric hypothalamic optic tract glioma, and malignant glioma.

[0399] Examples of breast cancer include breast cancer during pregnancy, triple-negative breast cancer, ductal carcinoma in situ (DCIS), invasive ductal carcinoma in situ (IDC), tubular carcinoma of the breast, medullary carcinoma of the breast, mucinous carcinoma of the breast, papillary carcinoma of the breast, cribriform carcinoma of the breast, invasive lobular carcinoma in situ (ILC), inflammatory breast cancer, lobular carcinoma in situ (LCIS), male breast cancer, Paget's disease of the nipple, phyllodes tumor of the breast, and metastatic breast cancer. In certain embodiments, the cancer is breast cancer during pregnancy. In certain embodiments, the cancer is triple-negative breast cancer. In certain embodiments, the cancer is ductal carcinoma in situ. In certain embodiments, the cancer is invasive ductal carcinoma. In certain embodiments, the cancer is tubular carcinoma of the breast. In certain embodiments, the cancer is medullary carcinoma of the breast. In certain embodiments, the cancer is mucinous carcinoma of the breast. In certain embodiments, the cancer is papillary carcinoma of the breast. In certain embodiments, the cancer is cribriform carcinoma of the breast. In certain embodiments, the cancer is invasive lobular carcinoma. In certain embodiments, the cancer is inflammatory breast cancer. In certain embodiments, the cancer is non-invasive lobular carcinoma. In certain embodiments, the cancer is male breast cancer. In certain embodiments, the cancer is nipple-Paget's disease. In certain embodiments, the cancer is phyllodes tumor of the breast. In certain embodiments, the cancer is metastatic breast cancer.

[0400] In a particular embodiment, the cancer is triple-negative breast cancer (TNBC).

[0401] Examples of carcinomas include neuroendocrine carcinoma, adrenocortical carcinoma, and islet cell carcinoma. In certain embodiments, the cancer is neuroendocrine carcinoma. In certain embodiments, the cancer is adrenocortical carcinoma. In certain embodiments, the cancer is islet cell carcinoma.

[0402] Examples of colorectal cancer include colon cancer and rectal cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is rectal cancer.

[0403] In certain embodiments, the cancer is high-frequency microsatellite instability (MSI-H) colorectal cancer. In certain embodiments, the cancer is low-frequency microsatellite instability (MSI-L) colorectal cancer. In certain embodiments, the cancer is microsatellite stable (MSS) colorectal cancer.

[0404] Examples of kidney cancer / renal cell carcinoma include clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC), chromophobic renal cell carcinoma (chRCC), clear cell papillary renal cell carcinoma (ccpRCC), collecting duct renal cell carcinoma (cdRCC), and renal medullary carcinoma (RMC). In certain embodiments, the cancer is clear cell renal cell carcinoma (ccRCC). In certain embodiments, the cancer is papillary renal cell carcinoma (PRCC). In certain embodiments, the cancer is chromophobic renal cell carcinoma (chRCC). In certain embodiments, the cancer is clear cell papillary renal cell carcinoma (ccpRCC). In certain embodiments, the cancer is collecting duct renal cell carcinoma (cdRCC). In certain embodiments, the cancer is renal medullary carcinoma (RMC).

[0405] In certain embodiments, the cancer is clear cell renal cell carcinoma (ccRCC) that is refractory to treatment with PD-1 or PD-L1 inhibitor therapy. In certain embodiments, the cancer that is refractory to treatment with PD-1 inhibitors is clear cell renal cell carcinoma (ccRCC). In certain embodiments, the cancer that is refractory to treatment with PD-L1 inhibitors is clear cell renal cell carcinoma (ccRCC).

[0406] The sarcoma may be selected from the group consisting of Kaposi's sarcoma, osteosarcoma / malignant fibrous histiocytoma of bone, soft tissue sarcoma, Ewing's sarcoma family tumors, rhabdomyosarcoma, tenosynovial clear cell sarcoma, central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, and uterine sarcoma. In certain embodiments, the cancer may be Kaposi's sarcoma. In certain embodiments, the cancer may be osteosarcoma / malignant fibrous histiocytoma of bone. In certain embodiments, the cancer may be soft tissue sarcoma. In certain embodiments, the cancer may be Ewing's sarcoma family tumor. In certain embodiments, the cancer may be rhabdomyosarcoma. In certain embodiments, the cancer may be tenosynovial clear cell sarcoma. In certain embodiments, the cancer may be central chondrosarcoma. In certain embodiments, the cancer may be central and periosteal chondroma. In certain embodiments, the cancer may be fibrosarcoma. In certain embodiments, the cancer may be uterine sarcoma.

[0407] Examples of genitourinary cancers include testicular cancer, urethral cancer, vaginal cancer, cervical cancer, penile cancer, and vulvar cancer. In certain embodiments, the cancer may be testicular cancer. In certain embodiments, the cancer may be urethral cancer. In certain embodiments, the cancer may be vaginal cancer. In certain embodiments, the cancer may be cervical cancer. In certain embodiments, the cancer may be penile cancer. In certain embodiments, the cancer may be vaginal cancer.

[0408] In certain embodiments, the solid tumor is selected from the group consisting of squamous cell carcinoma (SCCHN) of the head and neck; HPV-related cancers such as anal, vulvar, cervical, penile, and vaginal cancer; and melanoma, pancreatic cancer, and breast cancer, such as triple-negative breast cancer (TNBC).

[0409] In certain embodiments, the solid tumor is selected from the group consisting of melanoma, cervical cancer, pancreatic cancer, renal cell carcinoma, colorectal cancer, ovarian cancer, breast cancer, salivary gland cancer, endometrial cancer, and lung cancer.

[0410] In a particular embodiment, the solid tumor is selected from the group consisting of pancreatic cancer, renal cell carcinoma, colorectal cancer, ovarian cancer, breast cancer, acinar cell carcinoma, endometrial cancer, and lung cancer.

[0411] In a particular embodiment, the solid tumor is selected from the group consisting of pancreatic cancer, renal cell carcinoma (RCC), colorectal cancer (CRC), ovarian cancer, and breast cancer.

[0412] In a particular embodiment, the solid tumor is selected from the group consisting of colorectal cancer, lung cancer, and ovarian cancer.

[0413] In a particular embodiment, the solid tumor is selected from the group consisting of melanoma, cervical cancer, colorectal cancer, lung cancer, and ovarian cancer.

[0414] Early clinical data showed that difficult-to-treat cancers, such as pancreatic cancer or small cell lung cancer, responded surprisingly well to treatment with formula (I) IL-2 conjugate, either as monotherapy or in combination with pembrolizumab.

[0415] In certain embodiments, the cancer was not subjected to a prior treatment regimen. In certain embodiments, the cancer had been previously treated with standard treatment. In certain embodiments, the cancer had been previously treated with chemotherapy, such as platinum-based chemotherapy.

[0416] In certain embodiments, the cancer has been previously treated with an immune checkpoint inhibitor. In certain embodiments, the cancer has been previously treated with a PD-1 or PD-L1 inhibitor. In certain embodiments, the cancer has been previously treated with a PD-1 inhibitor. In certain embodiments, the cancer has been previously treated with a PD-L1 inhibitor. In certain embodiments, the cancer has been previously treated with an anti-PD-1 antibody. In certain embodiments, the cancer has been previously treated with an anti-PD-L1 antibody. In certain embodiments, the cancer has been previously treated with pembrolizumab. In certain embodiments, the cancer has been previously treated with nivolumab. In certain embodiments, the cancer has been previously treated with atezolizumab.

[0417] In certain embodiments, the cancer previously treated with a PD-1 or PD-L1 inhibitor is lung cancer. In certain embodiments, the cancer previously treated with a PD-1 or PD-L1 inhibitor is small cell lung cancer (SCLC). In certain embodiments, the cancer previously treated with a PD-1 or PD-L1 inhibitor is non-small cell lung cancer (NSCLC).

[0418] In a particular embodiment, the cancer that has been previously treated with a PD-1 or PD-L1 inhibitor is melanoma.

[0419] Surprisingly, cancers that were refractory to PD-1 or PD-L1 inhibitors were also found to respond to treatment with formula (I) IL-2 conjugate, either as monotherapy or in combination with pembrolizumab.

[0420] In certain embodiments, cancer is treated with the IL-2 conjugate of formula (I) as neoadjuvant therapy. In certain embodiments, cancer is treated with the IL-2 conjugate of formula (I) as adjuvant therapy.

[0421] In certain embodiments, the cancer treated with neoadjuvant therapy is melanoma. In certain embodiments, the cancer treated with neoadjuvant therapy is non-small cell lung cancer.

[0422] In certain embodiments, the cancer is PD-1 positive. In certain embodiments, the cancer is PD-1 negative. In certain embodiments, the cancer is PD-L1 positive. In certain embodiments, the cancer is PD-L1 negative.

[0423] In certain embodiments, the IL-2 conjugate or pharmaceutical composition of the present invention is administered to a patient before, simultaneously with, or after the administration of one or more further drugs, the one or more further drugs being, in certain embodiments, pattern recognition receptor agonists (PRRAs), cytotoxic / chemotherapeutic agents, immune checkpoint inhibitors or antagonists, immune checkpoint agonists, immune-activating receptor agonists, multispecific drugs, antibody-drug conjugates (ADCs), antibody-adjuvant conjugates (AACs), radionuclides or targeted radionuclide therapeutics, DNA damage repair inhibitors, tumor metabolism inhibitors, pattern recognition receptor agonists, protein kinase inhibitors, chemokines and chemokine receptor agonists, chemokines or chemokine receptor agonists Selected from the group consisting of antagonists, cytokine receptor agonists, cell death receptor agonists, CD47 or SIRPα antagonists, oncolytics, signal-converting proteins, epigenetic modifiers, tumor peptides or tumor vaccines, heat shock protein (HSP) inhibitors, proteases, ubiquitin and proteasome inhibitors, adhesion molecule antagonists, hormones including hormone peptides and synthetic hormones, and adoptive cell therapies, such as tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) therapy, T cell therapy, natural killer (NK) cell therapy, CAR-T therapy, CAR-NK therapy, CAR-γδ therapy, CAR-macrophage therapy, or any other cell therapies using genetically modified or unmodified immune cell types.

[0424] PRRAs can be selected from the group consisting of Toll-like receptor (TLR) agonists, NOD-like receptor agonists (NLR), RIG-I-like receptor agonists, cytoplasmic DNA sensor agonists, STING agonists, and aryl hydrocarbon receptor agonists (AhR).

[0425] In certain embodiments, PRRA is a Toll-like receptor agonist, e.g., TLR1 / 2 agonists, e.g., peptidoglycan, lipoprotein, Pam3CSK4, Amplivant, SLP-AMPLIVANT, HESPECTA, ISA101, ISA201; TLR2 agonists, e.g., LAM-MS, LPS-PG, LTA-BS, LTA-SA, PGN-BS, PGN-EB, PGN-EK, PGN-SA, CL429, FSL-1, Pam2CSK4, Pam3CSK4, Zymosan, CBLB612, SV-283, ISA204, SMP105, heat-killed Listeria (Listeria) monocytogenes; TLR3 agonists, e.g., poly(A:U), poly(I:C) (poly-ICLC), rintatolimod, apoxxim, IPH3102, poly-ICR, PRV300, RGCL2, RGIC.1, riboxxim (RGC100, RGIC100), riboxxol (RGIC50), synthetic natural or modified double-stranded RNA, synthetic natural or modified nucleic acid oligomers and riboxon; TLR4 agonists, e.g., lipopolysaccharide (LPS), neoseptin-3, glucopyranosyllipid adjuvant (GLA), GLA-SE, G100, GLA-AF, clinical center reference endotoxin (CCRE), monophosphoryl lipid A, grass MATA MPL (grass MATA MPL), PEPA10, ONT-10 (PET-Lipid A, Oncothyreon), G-305, ALD046, CRX527, CRX675 (RC527, RC590), GSK1795091, OM197MPAC, OM294DP, tumor-targeting TLR4 agonists, and SAR439794; TLR2 / 4 agonists, e.g., Lipid A, OM174, and PGN007; TLR5 agonists, e.g., Flagellin, Entrimodo, Mobilan, Protectan CBLB501; TLR6 / 2 agonists, e.g., diacylated lipoproteins, diacylated lipopeptides, FSL-1, MALP-2, and CBLB613;TLR7 agonists, for example, CL264, CL307, imiquimod (R837), TMX-101, TMX-201, TMX-202, TMX302, gardiquimod, S-27609, 851, UC-IV150, 852A (3M-001, PF-04878691), loxoribine, polyuridylic acid, GSK2245035, GS-9620, RO6864018 (ANA773, RG7795), RO7020531, Isatrevin, AN0331, ANA245, ANA971, ANA975, DSP0509, DSP3025 (AZD8848), GS986, MBS2, MBS5, RG7863 (RO6870868), Sotilimod, SZU101, synthetic natural or modified single-stranded RNA, synthetic nucleic acids, synthetic natural or modified nucleic acid oligomers, tumor-targeted TLR7 agonists, and TQA3334;TLR8 Agonists, e.g., ssPolyUridine, ssRNA40, TL8-506, XG-1-236, VTX-2337 (Motrimod), VTX-1463, VTX378, VTX763, DN1508052, SBT6050, synthetic natural or modified single-stranded RNA, synthetic nucleic acids, synthetic natural or modified nucleic acid oligomers, tumor-targeted TLR8 agonists and GS9688; agonists of TLR7 / 8, e.g., T ransCon (trademark) TLR7 / 8 agonists, CL075, CL097, poly(dT), reciquimod (R-848, VML600, S28463), MEDI9197 (3M-052), NKTR262, DV1001, IMO4200, IPH3201, synthetic natural or modified single-stranded RNA, synthetic nucleic acids, synthetic nucleic acid oligomers, BDC-1001, other tumor-targeting TLR7 / 8 agonists and VTX1463;TLR9 agonists, e.g., CpG DNA, CpG ODN, Refitrimod (MGN1703), SD-101, QbG10, CYT003, CYT003-QbG10, DUK-CpG-001, CpG-7909 (PF-3512676), GNKG168, EMD 1201081, IMO-2125, IMO-2055, CpG10104, AZD1419, AST008, IMO2134, MGN1706, IRS 954, 1018 Toll-like receptor agonists selected from the group consisting of ISS, actilon (CPG10101), ATP00001, AVE0675, AVE7279, CMP001, DIMS0001, DIMS9022, DIMS9054, DIMS9059, DV230, DV281, EnanDIM, heplisav (V270), kappaproct (DIMS0150), NJP834, NPI503, SAR21609, synthetic natural or modified nucleic acid oligomers and tolamba; and TLR7 / 9 agonists, such as DV1179. In certain embodiments, one or more further drugs are TLR7 / 8 agonists such as rexiquimod.

[0426] In a particular embodiment, one or more further drugs are given by formula (A-3) [ka] [In the formula, "hydrogel" is represented by formula (A-4): [ka] (In the formula, n is in the range of approximately 25 to 29, and the dashed line represents a portion.) [ka] ,portion [ka] Or formula (A-5): [ka] (In the formula, m is in the range of approximately 41 to 45, and the dashed line in (A-5) indicates the connection to the skeletal part of formula (A-4).) (Shows binding to the crosslinking agent) It is a hydrogel containing the skeletal structure. It belongs to them.

[0427] In a particular embodiment, one or more further drugs are given by formula (A-6) [ka] [In the formula, m is in the range of approximately 25-29. n is in the range of approximately 41 to 45. "a" represents the skeletal portion, "b" represents the crosslinking agent portion, "c" represents the reversibly conjugated reximod portion, and "d" represents the acetamide portion. The ratio of parts "a":"b":"c":"d" in the conjugate is approximately 1:13:2:4 or approximately 1:13:2.4:3.6. It belongs to them.

[0428] In a particular embodiment, one or more further drugs are given by formula (Ai-6) [ka] [In the formula, m is in the range of approximately 25-29. n is in the range of approximately 41 to 45. "a" represents the skeletal portion, "b" represents the crosslinking agent portion, "c" represents the reversibly conjugated reximod portion, and "d" represents the acetamide portion. The ratio of parts "a":"b":"c":"d" in the conjugate is approximately 1:13:c:d (c+d=6), for example, approximately 1:13:3:3, or approximately 1:13:2:4, or approximately 1:13:4:2. It belongs to them.

[0429] The drugs of formula (A-3), (A-6), or (Ai-6) may be administered once or multiple times as 0.5 mg per tumor lesion by intratumoral administration, for example, by intratumoral injection. For multiple administrations, the interval between two consecutive administrations may range from 2 to 8 weeks.

[0430] In certain embodiments, one or more additional drugs of formula (A-3), (A-6), or (Ai-6) are administered via intratumoral administration at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate. In certain embodiments, one or more additional drugs of formula (A-3), (A-6), or (Ai-6) are administered via intratumoral administration at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate. In certain embodiments, one or more additional drugs of formula (A-3), (A-6), or (Ai-6) are administered via intratumoral administration at a dose of 0.5 mg per lesion together with, together with, the IL-2 conjugate. In certain embodiments, one or more additional drugs of formula (A-3), (A-6), or (Ai-6) are administered via intratumoral administration at a dose of 0.5 mg per lesion after, together with, or after administration of the IL-2 conjugate.

[0431] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is for use in the treatment of cancer, and the IL-2 conjugate is administered in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered via intratumoral administration at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate.

[0432] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is for use in the treatment of cancer, and the IL-2 conjugate is administered in doses ranging from 100 μg IL-2 / kg to 140 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered via intratumoral administration at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate.

[0433] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is for use in the treatment of cancer, and the IL-2 conjugate is administered in doses ranging from 110 μg IL-2 / kg to 130 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered via intratumoral administration at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate.

[0434] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered at a dose of approximately 120 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered via intratumoral administration at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate.

[0435] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is for use in the treatment of cancer, and the IL-2 conjugate is administered at a dose of 120 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered every three weeks via intratumoral administration at a dose of 0.5 mg per lesion, before, together with, or after administration of the IL-2 conjugate.

[0436] In certain embodiments, the drug of formula (A-3), (A-6), or (Ai-6) is administered to the patient every three weeks. In certain embodiments, the drug of formula (A-3), (A-6), or (Ai-6) is administered to the patient every six weeks. In certain embodiments, the drug of formula (A-3), (A-6), or (Ai-6) is administered at a frequency corresponding to the progression of the disease.

[0437] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered at a dose of approximately 120 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered via intratumoral injection every three weeks at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate.

[0438] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered at a dose of approximately 120 μg IL-2 / kg as co-therapy with a drug of formula (A-3), (A-6), or (Ai-6), and the drug of formula (A-3), (A-6), or (Ai-6) is administered via intratumoral injection every 6 weeks at a dose of 0.5 mg per lesion before, together with, or after administration of the IL-2 conjugate.

[0439] In certain embodiments, IL-2 conjugates or pharmaceutically acceptable salts thereof for use in the treatment of cancer are administered via intravenous infusion as co-therapy with drugs of formula (A-3), (A-6), or (Ai-6).

[0440] Examples of CpG ODNs include ODN 1585, ODN 2216, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN BW006, ODN D-SL01, ODN 2395, ODN M362, and ODN D-SL03.

[0441] In certain embodiments, PRRA is a NOD-like receptor agonist. If one or more further drugs are NOD-like receptor agonists, such NOD-like receptor agonists may be selected from the group consisting of NOD1 agonists, e.g., C12-iE-DAP, C14-Tri-LAN-Gly, iE-DAP, iE-Lys, and Tri-DAP; and NOD2 agonists, e.g., L18-MDP, MDP, M-TriLYS, murabutide, and N-glycolyl-MDP. In certain embodiments, one or more further drugs are NOD1 agonists. In certain embodiments, one or more further drugs are NOD2 agonists.

[0442] In certain embodiments, PRRA is a RIG-I-like receptor agonist. If one or more further drugs are RIG-I-like receptor agonists, such RIG-I-like receptor agonists may be selected from the group consisting of 3p-hpRNA, 5'ppp-dsRNA, 5'ppp RNA (M8), kinked 5'OH RNA (CBS-13-BPS), 5'ppp SLR, KIN100, KIN101, KIN1000, KIN1400, KIN1408, KIN1409, KIN1148, KIN131A, poly(dA:dT), SB9200, RGT100, and hiltonol.

[0443] In certain embodiments, PRRA is a cytoplasmic DNA sensor agonist. If one or more further drugs are cytoplasmic DNA sensor agonists, such cytoplasmic DNA sensor agonists may be selected from the group consisting of cGAS agonists, dsDNA-EC, G3-YSD, HSV-60, ISD, ODN TTAGGG(A151), poly(dG:dC), and VACV-70.

[0444] In certain embodiments, PRRA is a STING agonist. If one or more further drugs are STING agonists, such STING agonists include MK-1454, ADU-S100 (MIW815), 2'3'-cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, cAIMP (CL592), cAIMP difluoro (CL614), cAIM(PS)2 difluoro (Rp / Sp) (CL656), 2'2'- The following can be selected: cGAMP, 2'3'-cGAM(PS)2(Rp / Sp), fluorinated 3'3'-cGAM, fluorinated c-di-AMP, 2'3'-c-di-AMP, 2'3'-c-di-AM(PS)2(Rp,Rp), fluorinated c-di-GMP, 2'3'-c-di-GMP, c-di-IMP, c-di-UMP, and DMXAA (badimesane, ASA404). In certain embodiments, one or more further drugs are MK-1454. In certain embodiments, one or more further drugs are ADU-S100(MIW815). In certain embodiments, one or more further drugs are 2'3'-cGAMP.

[0445] In certain embodiments, PRRA is an aryl hydrocarbon receptor agonist. If one or more further drugs are aryl hydrocarbon receptor (AhR) agonists, such AhR agonists may be selected from the group consisting of FICZ, ITE, and L-kynurenine.

[0446] In certain embodiments, one or more additional drugs are cytotoxic / chemotherapeutic agents. In certain embodiments, one or more additional drugs are immune checkpoint inhibitors or antagonists. In certain embodiments, one or more additional drugs are immune-activating receptor agonists. In certain embodiments, one or more additional drugs are multispecific drugs. In certain embodiments, one or more additional drugs are antibody-drug conjugates (ADCs). In certain embodiments, one or more additional drugs are antibody-adjuvant conjugates (AACs). In certain embodiments, one or more additional drugs are radionuclides or targeted radionuclide therapeutic agents. In certain embodiments, one or more additional drugs are DNA damage repair inhibitors. In certain embodiments, one or more additional drugs are tumor metabolism inhibitors. In certain embodiments, one or more additional drugs are pattern recognition receptor agonists. In certain embodiments, one or more additional drugs are protein kinase inhibitors. In certain embodiments, one or more additional drugs are chemokine and chemoattractant receptor agonists. In certain embodiments, one or more further drugs are chemokines or chemokine receptor antagonists. In certain embodiments, one or more further drugs are cytokine receptor agonists. In certain embodiments, one or more further drugs are cell death receptor agonists. In certain embodiments, one or more further drugs are CD47 antagonists. In certain embodiments, one or more further drugs are SIRPα antagonists. In certain embodiments, one or more further drugs are oncolytic agents. In certain embodiments, one or more further drugs are signal-converting proteins. In certain embodiments, one or more further drugs are epigenetic modifiers. In certain embodiments, one or more further drugs are oncopeptides or oncovaccines. In certain embodiments, one or more further drugs are heat shock protein (HSP) inhibitors. In certain embodiments, one or more further drugs are proteases. In certain embodiments, one or more further drugs are ubiquitin and proteasome inhibitors.In certain embodiments, one or more additional drugs are adhesion molecule antagonists. In certain embodiments, one or more additional drugs are hormones, including hormone peptides and synthetic hormones.

[0447] Cytotoxic or chemotherapeutic agents may be selected from the group consisting of alkylating agents, anthracyclines, pyrrolobenzodiazepines, nitrogen mustard, platinum preparations, antimetabolites, antimicrotubule agents, topoisomerase inhibitors, cytotoxic antibiotics, auristatin, engine, lexitropsin, duocalmycin, cyclopropylpyrroloindole, puromycin, drastatin, meitansine derivatives, alkyl sulfonates, triazenes, and piperazines.

[0448] Alkylating agents may be selected from the group consisting of nitrogen mustards, e.g., mechloretamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, and busulfan; nitrosoureas, e.g., N-nitroso-N-methylurea, carmustine, lomustine, semustine, fotemustine, and streptozotocin; tetrazines, e.g., dacarbazine, mitozolomide, and temozolomide; ethyleneimines, e.g., altoretamine; aziridines, e.g., thiotepa, mitomycin, and diazicone; cisplatins and derivatives, e.g., cisplatin, carboplatin, oxaliplatin; and non-classical alkylating agents, e.g., procarbazine and hexamethylmelamine.

[0449] Antimetabolites may be selected from the group consisting of antifolic acid agents, e.g., methotrexate and pemetrexed; fluoropyrimidines, e.g., fluorouracil and capecitabine; deoxynucleoside analogs, e.g., cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nerarabine, cladribine, clofarabine and pentostatin; and thiopurines, e.g., thioguanine and mercaptopurine.

[0450] In certain embodiments, one or more additional drugs are pemetrexed.

[0451] Antimicrotubule agents may be selected from the group consisting of vinca alkaloids, e.g., vincristine, vinblastine, vinorelbine, vindesine, and vinflunin; taxanes, e.g., paclitaxel and docetaxel; podophyllotoxins and derivatives, e.g., podophyllotoxin, etoposide, and teniposide; stilbenoid phenols and derivatives, e.g., diprestat (CA4P); and BNC105.

[0452] In certain embodiments, one or more additional drugs are paclitaxel.

[0453] In certain embodiments, one or more additional drugs are docetaxel.

[0454] In a particular embodiment, paclitaxel is 80 mg / m². 2 It is administered in the following doses. In certain embodiments, paclitaxel is administered every two weeks. In certain embodiments, paclitaxel is administered every three weeks. In certain embodiments, paclitaxel is administered intravenously. In certain embodiments, paclitaxel is administered at a dose of 80 mg / m² every two or three weeks. 2 It is administered intravenously at the specified dose.

[0455] In a particular embodiment, docetaxel is 75 mg / m² 2 It is administered in the following doses. In certain embodiments, docetaxel is administered every three weeks. In certain embodiments, docetaxel is administered intravenously. In certain embodiments, docetaxel is administered at a dose of 75 mg / m² every three weeks. 2 It is administered intravenously at the specified dose.

[0456] In a particular embodiment, pemetrexed is administered at 500 mg / m². 2It is administered in the following doses. In certain embodiments, pemetrexed is administered every three weeks. In certain embodiments, pemetrexed is administered intravenously. In certain embodiments, pemetrexed is administered at a dose of 500 mg / m² every three weeks. 2 It is administered intravenously at the specified dose.

[0457] The topoisomerase inhibitor may be selected from the group consisting of topoisomerase I inhibitors, such as irinotecan, topotecan, and camptothecin; and topoisomerase II inhibitors, such as etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, melbaron, and acralubicin.

[0458] In certain embodiments, one or more additional drugs are doxorubicin.

[0459] Cytotoxic antibiotics may be selected from the group consisting of anthracyclines, such as doxorubicin, daunorubicin, epirubicin, and idarubicin; pirarubicin, acralubicin, bleomycin, mitomycin C, mitoxantrone, actinomycin, dactinomycin, adriamycin, mitramycin, and tirapazamine.

[0460] Auristatin can be selected from the group consisting of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).

[0461] The engine may be selected from the group consisting of neocardinostatin, ridamycin (C-1027), calicheamicin, esperamicin, dynemycin, and golfomycin A.

[0462] Maytansine derivatives may be selected from the group consisting of ansamitosine, meltansine (emtansine, DM1), and labtansine (solabtansine, DM4).

[0463] Immune checkpoint inhibitors or antagonists include CTLA-4 (cytotoxic T lymphocyte-associated protein 4) inhibitors, such as ipilimumab, tremelimumab, MK-1308, FPT155, PRS010, BMS-986249, BPI-002, CBT509, JS007, ONC392, TE1254, IBI310, BR02001, CG0161, KN044, PBI5D3H5, BCD145, ADU1604, AGEN1884, AGEN1181, CS1002, and CP675206; PD-1 (program details) Inhibitors of splenic cell death protein1), e.g., pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, semiprimab, and PDR001; inhibitors of PD-L1 (programmed cell death ligand 1), e.g., MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559, and durvalumab; inhibitors of PD-L2 (programmed cell death ligand 2); inhibitors of KIR (killer cell immunoglobulin-like receptor), e.g., lirilumab (IPH2102) and IP H2101; B7-H3 inhibitors, e.g., MGA271; B7-H4 inhibitors, e.g., FPA150; BTLA (B and T lymphocyte attenuator) inhibitors; LAG3 (lymphocyte activator gene 3) inhibitors, e.g., IMP321 (eftiragimod α), lilatrimab, MK-4280, AVA017, BI754111, ENUM006, GSK2831781, INCAGN2385, LAG3Ig, LAG525, REGN3767, Sym016, Sym022, TSR033, TSR075, and XmAb2284 1; Inhibitors of TIM-3 (T cell immunoglobulin and mucin-domain-containing T-3), e.g., LY3321367, MBG453, and TSR-022; Inhibitors of VISTA (V-domain Ig suppressor for T cell activation), e.g., JNJ-61610588; Inhibitors of ILT2 / LILRB1 (Ig-like transcript 2 / leukocyte Ig-like receptor 1); Inhibitors of ILT3 / LILRB4 (Ig-like transcript 3 / leukocyte Ig-like receptor 4); Inhibitors of ILT4 / LILRB2 (Ig-like transcript 4 / leukocyte Ig-like receptor 2), e.g., MK-4830;Inhibitors of TIGIT (T cell immune receptors having an Ig domain and an ITIM domain), such as MK-7684, PTZ-201, RG6058, and COM902; inhibitors of NKG2A, such as IPH-2201; and inhibitors of PVRIG, such as COM701, may be selected from this group.

[0464] In certain embodiments, one or more additional drugs are inhibitors of PD-1 or PD-L1. In certain embodiments, one or more additional drugs are inhibitors of PD-1. In certain embodiments, one or more additional drugs are inhibitors of PD-L1. In certain embodiments, one or more additional drugs are anti-PD-1 antibodies. In certain embodiments, one or more additional drugs are anti-PD-L1 antibodies. In certain embodiments, one or more additional drugs are pembrolizumab. During development, pembrolizumab was known as MK3475 and lambrolizumab and marketed as Keytruda®.

[0465] Pembrolizumab can be administered as prescribed, for example, 200 mg of pembrolizumab per intravenous infusion every three weeks. Infusion time can range from 15 minutes to 4 hours, for example, from 30 minutes to 1 hour, and is typically around 30 minutes. Generally, pembrolizumab is administered according to the approved dose, frequency, and form of administration for the given indication.

[0466] In certain embodiments, one or more additional drugs are pembrolizumab administered every three weeks at a dose of 200 mg via intravenous infusion before, together with, or after administration of an IL-2 conjugate. In certain embodiments, pembrolizumab is administered every three weeks at a dose of 200 mg via intravenous infusion before administration of an IL-2 conjugate. In certain embodiments, pembrolizumab is administered every three weeks at a dose of 200 mg via intravenous infusion together with administration of an IL-2 conjugate. In certain embodiments, pembrolizumab is administered every three weeks at a dose of 200 mg via intravenous infusion after administration of an IL-2 conjugate.

[0467] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered in co-therapy with pembrolizumab in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg, with pembrolizumab administered at a dose of 200 mg every three weeks before, together with, or after administration of the IL-2 conjugate.

[0468] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered in co-therapy with pembrolizumab in doses ranging from 100 μg IL-2 / kg to 140 μg IL-2 / kg, while pembrolizumab is administered at a dose of 200 mg every three weeks before, together with, or after administration of the IL-2 conjugate.

[0469] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered in co-therapy with pembrolizumab in doses ranging from 110 μg IL-2 / kg to 130 μg IL-2 / kg, with pembrolizumab administered at a dose of 200 mg every three weeks before, together with, or after administration of the IL-2 conjugate.

[0470] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered in co-therapy with pembrolizumab at a dose of approximately 120 μg IL-2 / kg, with pembrolizumab administered at a dose of 200 mg every three weeks before, together with, or after administration of the IL-2 conjugate.

[0471] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof is intended for use in the treatment of cancer, and the IL-2 conjugate is administered in co-therapy with pembrolizumab at a dose of 120 μg IL-2 / kg, with pembrolizumab administered at a dose of 200 mg every three weeks before, together with, or after administration of the IL-2 conjugate.

[0472] In certain embodiments, IL-2 conjugates or pharmaceutically acceptable salts thereof for use in the treatment of cancer are administered via intravenous infusion as co-therapy with pembrolizumab.

[0473] In certain embodiments, pembrolizumab is administered via intravenous infusion at a dose of 200 mg every three weeks, either before, together with, or after the administration of the IL-2 conjugate. In certain embodiments, pembrolizumab is administered via intravenous infusion at a dose of 200 mg before the administration of the IL-2 conjugate. In certain embodiments, pembrolizumab is administered via intravenous infusion at a dose of 200 mg together with the administration of the IL-2 conjugate. In certain embodiments, pembrolizumab is administered via intravenous infusion at a dose of 200 mg after the administration of the IL-2 conjugate.

[0474] Immune-activating receptor agonists include CD27 agonists, e.g., HERA-CD27L and recombinant CD70 such as varylumab (CDX-1127); CD28 agonists, e.g., recombinant CD80, recombinant CD86, TGN1412, and FPT155; CD40 agonists, e.g., recombinant CD40L, CP-870, CP-893, dacetuzumab (SGN-40), and Chi Lob. A selection may be made from the group consisting of 7 / 4, ADC-1013, and CDX1140; agonists of 4-1BB (CD137), e.g., recombinant 4-1BBL, urelumab, utomirumab, and ATOR-1017; agonists of OX40, e.g., recombinant OX40L, MEDI0562, GSK3174998, MOXR0916, and PF-04548600; agonists of GITR, e.g., recombinant GITRL, TRX518, MEDI1873, INCAGN01876, MK-1248, MK-4166, GWN323, and BMS-986156; and agonists of ICOS, e.g., recombinant ICOSL, JTX-2011, and GSK3359609.

[0475] Multispecific agents may be selected from a group consisting of biologics and small molecule immune checkpoint inhibitors. Examples of biologics include multispecific immune checkpoint inhibitors, e.g., CD137 / HER2 multispecific agents, PD-(L)1 / LAG3 antagonists (e.g., FS118, MGD013), CTLA4 / LAG3 antagonists (e.g., XmAb22841), and CTLA4 / PD-(L)1 antagonists (e.g., XmAb20717, MGD019); multispecific immune-activating receptor agonists, immune cytokines, and multispecific immune checkpoint agonists. Such multispecific immune checkpoint agonists include Ig superfamily agonists, e.g., ALPN-202, FPT155, TGN1412, GSK3359609, JTX-2011; TNF superfamily agonists, e.g., FAP-4-1BBL (RG7826), OX40-41BB (FS120), ATOR-1015, ATOR-1144, ALG, APV-527, Lipocalin / PRS-343, PRS344 / ONC0055, FAP-CD40 DARPin, MP0310 DARPin, FAP-0X40 DARPin, EGFR-CD40 DARPin, EGFR41BB / CD137 DARPin, EGFR-0X40 / DARFPin, HER2-CD40 DARPin, HER2-41BB / CD137 DARPin, HER2-0X40 DARPin, fibronectin ED-B-CD40 DARPin, fibronectin ED-B-41BB / CD137, and fibronectin ED-B-0X40 DARPin;CD3 multispecific agonists, e.g., blinatumomab, solitomab, MEDI-565, erzmakisomab, anti-HER2 / CD3, 1Fab-immunoglobulin G TDB, GBR 1302, MGD009, MGD007, EGFRBi, EGFR-CD probody, RG7802, PF-06863135, PF-06671008, AMG212 / BAY2010112, CD3-5T4, XmAb14045, XmAb13676, XmAb18087, S80880, REGN1979, REGN5458, REGN4018, RG6026, mosnetuzumab, EM801, ERY974, RG6194, AMG420, AMG330, AMG 212, AMG596, AMG160, AMG427, AMG562, AMG673, AMG701, AMG757, AFM13, AMF24, AFM26, AFM11, TNB-486, TNB-383B, GEN3013, JNJ- 63709178, JNJ-63898081, JNJ-64007957, JNJ-64407564, JNJ-67571244, AMV564, APVO414(MOR209, ES414), APVO436, HPN424, HP Other multispecific CD3 agonists or T cell receptor (TCR) agonists, including N536, HPN217, HPN328, and γδTCR agonists that target T cell activity against tumor cell antigens or viral antigens or expressing cells; natural killer (NK) cell receptor multispecific agonists that target activated NK receptors and target tumor cell antigens, e.g., NKG2D multispecific agonist, NKp30 multispecific agonist, NKp44 multispecific agonist, N Kp46 multispecific agonists, NKp80 multispecific agonists, NKG2C multispecific agonists, 2B4 (CD244) multispecific agonists, CD32a multispecific agonists, CD64 multispecific agonists, multispecific agonists that bind to tumor antigens as well as activating receptors such as NKG2D or NKp30 or other NK receptors listed above, and further bind to Fc receptors such as TriNKeTs, and CD16 multispecific agonists such as 1633 BiKE, 161533 TriKE, OXS-3550, OXS-C3550, AFM13 and AFM24;Furthermore, the group may be selected from other therapeutic antibodies that can bind to Fc receptors, such as CD16, CD32a, and CD64, in addition to the target antigen.

[0476] Other examples of immune-activating receptor agonists include dectin agonists (Imprime PGG), recombinant NKG2D ligands, ligands or modulators of γδTCR signaling, such as anti-BTN3A1 mAbs or anti-BTN2A1 mAbs, or Vγ9 / Vδ2 TCR activating ligands, such as phosphoantigens and pyrophosphate antigens, or agents that increase endogenous Vγ9 / Vδ2 ligands, such as bisphosphonates, such as pamidronic acid and zoledronic acid.

[0477] An example of a small molecule immune checkpoint inhibitor is CA-327 (TIM3 / PD-L1 antagonist).

[0478] Antibody-drug conjugates include ADCs targeting hematopoietic malignancies, such as gemtuzumab-ozogamicin, brentuximab-vedotin, inotuzumab-ozogamicin, SAR3419, BT062, SGN-CD19A, IMGN529, MDX-1203, polatuzumab-vedotin (RG7596), pinatuzumab-vedotin (RG7593), RG7598, milatuzumab-doxorubicin, and OXS-1550; and ADCs targeting solid tumor antigens, such as trastuzumab-emtansine, glenvatumomab-vedotin, and SAR566. 58, AMG-172, AMG-595, BAY-94-9343, BIIB015, Borsetuzumab-Mahodotin (SGN-75), ABT-414, ASG-5ME, Enfortumab-Vedotin (ASG-22ME), ASG-16M8F, IMGN853, Indusatuzumab-Vedotin (MLN-0264), Vadortuzumab-Vedotin (RG7450), Sofituzumab-Vedotin (RG7458), Rifastuzumab-Vedotin (RG7599), RG7600, DEDN6526A (RG7636), PSMA The group may be selected from TTC, Progenics Pharmaceuticals' 1095, lorbotuzumab-meltansine, lorbotuzumab-emtansine, IMMU-130, sacituzumab-govitecan (IMMU-132), PF-06263507, and MEDI0641.

[0479] The antibody-adjuvant conjugate may be a bolt body, for example, the bolt bodies described in International Publication No. 2018112108A1 and International Publication No. 2018009916A1, which are incorporated herein by reference. In certain embodiments, the bolt body is selected from the group consisting of BDC-1001 and BDC-2034. In certain embodiments, the bolt body is BDC-1001. In certain embodiments, the bolt body is BDC-2034.

[0480] In a particular embodiment, one or more further drugs are beta emitters, for example, 177 ruthenium, 166 holmium,186 rhenium, 188 rhenium, 67 copper, 149 promethium, 199 gold, 77 bromine, 153 samarium, 105 rhodium, 89 strontium, 90 yttrium, 131 Iodine; alpha emitters, for example, 213 Bismuth 223 radium, 225 Actinium, 211 Astatine; an Auger electron-emitting nuclide, for example. 77 bromine, 111 indium, 123 Iodine, and 125 It is a radioactive nuclide that can be selected from the group consisting of iodine.

[0481] Targeted radionuclide therapeutic drugs include Zevalin ( 90 Y-Ibritumomab-Chiuxetane), Vexar ( 131 I-tositumomab), Oncolim ( 131 I-Lym 1), Lymphocide ( 90 Y-epratuzumab), Kotara ( 131 I-chTNT-1 / B), rabetsumab ( 90 Y or 131 I-CEA), theragyn 90 Y-pemtumomab, licartin 131 I-methuximab, radretumab 131 I-L19)PAM4( 90 Y-cribatuzumab-tetraxetan), Xofigo ( 223 Ra dichloride), Rutatera ( 177 Lu-DOTA-Tyr 3 -Octreotete), and 131 The group consisting of I-MIBG may be selected.

[0482] DNA damage repair inhibitors include poly(ADP-ribose) polymerase (PARP) inhibitors, e.g., olaparib, lucaparib, niraparib, veliparib, CEP 9722, and E7016; CHK1 / CHK2 dual inhibitors, e.g., AZD7762, V158411, CBP501, and XL844; CHK1 selective inhibitors, e.g., PF477736, MK8776 / SCH900776, CCT244747, CCT245737, LY2603618, LY2606368 / prexasertib, AB-IsoG, ARRY575, AZD7762, CBP93872, ESP01, GDC0425, SA The following may be selected: R020106, SRA737, V158411 and VER250840; CHK2 inhibitors, e.g., CCT241533 and PV1019; ATM inhibitors, e.g., AZD0156, AZD1390, KU55933, M3541 and SX-RDS1; ATR inhibitors, e.g., AZD6738, BAY1895344, M4344 and M6620 (VX-970); and DNA-PK inhibitors, e.g., M3814.

[0483] Tumor metabolism inhibitors may be selected from the group consisting of adenosine pathway inhibitors, tryptophan metabolism inhibitors, and arginine pathway inhibitors.

[0484] Examples of adenosine pathway inhibitors include A2AR (adenosine A2A receptor) inhibitors, such as ATL-444, istradefylline (KW-6002), MSX-3, preradianant (SCH-420,814), SCH-58261, SCH412,348, SCH-442,416, ST-1535, caffeine, VER-6623, VER-6947, VER-7835, bipadenan (BIIB-014), ZM-241,385, PBF-509, and V81444; CD73 inhibitors, such as IPH53 and SRF373; and CD39 inhibitors, such as IPH52.

[0485] Examples of tryptophan metabolism inhibitors include IDO inhibitors, e.g., indoximod (NLG8189), epacadostat, navoximod, BMS-986205, and MK-7162; TDO inhibitors, e.g., 680C91; and IDO / TDO dual inhibitors.

[0486] Examples of arginine pathway inhibitors include arginase inhibitors, such as INCB001158.

[0487] Protein kinase inhibitors may be selected from the group consisting of receptor tyrosine kinase inhibitors, intracellular kinase inhibitors, cyclin-dependent kinase inhibitors, phosphoinositide-3 kinase inhibitors, mitogen-activated protein kinase inhibitors, nuclear factor κ-β kinase (IKK) inhibitors, and Wee-1 inhibitors.

[0488] Examples of receptor tyrosine kinase inhibitors include EGF receptor inhibitors, e.g., afatinib, cetuximab, erlotinib, gefitinib, pertuzumab, and margetuximab; VEGF receptor inhibitors, e.g., axitinib, lenvatinib, pegaptanib, and linifanib (ABT-869); C-KIT receptor inhibitors, e.g., CDX0158 (KTN0158); and ERBB2 (HER2) inhibitors (inhibitory). r) For example, Herceptin (trastuzumab); ERBB3 receptor inhibitors, for example, CDX3379 (MEDI3379, KTN3379) and AZD8931 (sapitinib); FGF receptor inhibitors, for example, erdafitinib; AXL receptor inhibitors, for example, BGB324 (BGB324, R428, R428, vemcentinib) and SLC391; and MET receptor inhibitors, for example, CGEN241.

[0489] Examples of intracellular kinase inhibitors include Bruton's tyrosine kinase (BTK) inhibitors, e.g., ibrutinib, acalabrutinib, GS-4059, spebratinib, BGB-3111, HM71224, zanubrutinib, ARQ531, BI-BTK1, and becabrutinib; spleen tyrosine kinase inhibitors, e.g., hostamatinib; Bcr-Abl tyrosine kinase inhibitors, e.g. These include imatinib and nilotinib; Janus kinase inhibitors, such as ruxolitinib, tofacitinib, and fedratinib; and multispecific tyrosine kinase inhibitors, such as bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, lapatinib, mbritinib, pazopanib, sorafenib, sunitinib, SU6656, and vandetanib.

[0490] Examples of cyclin-dependent kinase inhibitors include ribociclib, palbociclib, abemaciclib, trilaciclib, pluvalanol A, olomucine II, and MK-7965.

[0491] Examples of phosphoinositide-3-kinase inhibitors include IPI549, GDc-0326, pictilisib, ceravelisib, IC-87114, AMG319, ceretalisib, idialisib, and CUDC907.

[0492] Examples of mitogen-activated protein kinase inhibitors include Ras / farnesyltransferase inhibitors, e.g., tipirafenib and LB42708; Raf inhibitors, e.g., regorafenib, encorafenib, vemurafenib, dabrafenib, sorafenib, PLX-4720, GDC-0879, AZ628, rifilafenib, PLX7904, and RO5126766; MEK inhibitors, e.g., cobimetinib, trametinib, binimetinib, selumetinib, pimacertib, refametinib, and PD0325901; and ERK inhibitors, e.g., MK-8353, GDC-0994, urixertinib, and SCH772984.

[0493] Examples of inhibitors of nuclear factor κ-β kinase (IKK) include BPI-003 and AS602868.

[0494] An example of a Wee-1 inhibitor is adavocertib.

[0495] Chemokine receptor and chemoattractant receptor agonists may be selected from the group consisting of CXC chemokine receptors, CC chemokine receptors, C chemokine receptors, CX3C chemokine receptors, and chemoattractant receptors.

[0496] CXC chemokine receptors may be selected from the group consisting of CXCR1 agonists, e.g., recombinant CXCL8 and recombinant CXCL6; CXCR2 agonists, e.g., recombinant CXCL8, recombinant CXCL1, recombinant CXCL2, recombinant CXCL3, recombinant CXCL5, recombinant CXCL6, MGTA 145, and SB251353; CXCR3 agonists, e.g., recombinant CXCL9, recombinant CXCL10, recombinant CXCL11, and recombinant CXCL4; CXCR4 agonists, e.g., recombinant CXCL12, ATI2341, CTCE0214, CTCE0324, and NNZ4921; CXCR5 agonists, e.g., recombinant CXCL13; CXCR6 agonists, e.g., recombinant CXCL16; and CXCL7 agonists, e.g., recombinant CXCL11.

[0497] CC chemokine receptors include CCR1 agonists, e.g., recombinant CCL3, ECI301, recombinant CCL4, recombinant CCL5, recombinant CCL6, recombinant CCL8, recombinant CCL9 / 10, recombinant CCL14, recombinant CCL15, recombinant CCL16, recombinant CCL23, PB103, PB105, and MPIF1; CCR2 agonists, e.g., recombinant CCL2, recombinant Recombinant CCL8, recombinant CCL16, PB103, and PB105; CCR3 agonists, e.g., recombinant CCL11, recombinant CCL26, recombinant CCL7, recombinant CCL13, recombinant CCL15, recombinant CCL24, recombinant CCL5, recombinant CCL28, and recombinant CCL18; CCR4 agonists, e.g., recombinant CCL3, ECI301, recombinant CCL5, recombinant The following groups may be selected: recombinant CCL17 and recombinant CCL22; CCR5 agonists, e.g., recombinant CCL3, ECI301, recombinant CCL5, recombinant CCL8, recombinant CCL11, recombinant CCL13, recombinant CCL14, recombinant CCL16, PB103, and PB105; CCR6 agonists, e.g., recombinant CCL20; CCR7 agonists, e.g., recombinant CCL19 and recombinant CCL21; CCR8 agonists, e.g., recombinant CCL1, recombinant CCL16, PB103, and PB105; CCR9 agonists, e.g., recombinant CCL25; CCR10 agonists, e.g., recombinant CCL27 and recombinant CCL28; and CCR11 agonists, e.g., recombinant CCL19, recombinant CCL21, and recombinant CCL25.

[0498] The C chemokine receptor may be an XCR1 agonist, such as recombinant XCL1 or recombinant XCL2.

[0499] The CX3C chemokine receptor can be a CX3CR1 agonist, such as recombinant CX3CL1.

[0500] The chemoattractant receptor may be selected from the group consisting of formylpeptide receptor agonists, e.g., N-formylpeptide, N-formylmethionine-leucyl-phenylalanine, enfuvirtide, T21 / DP107, annexin A1, Ac2-26, and Ac9-25; C5a receptor agonists; and chemokine-like receptor 1 agonists, e.g., chemerin.

[0501] Chemokine antagonists include inhibitors of CXCL chemokines, e.g., UNBS5162; inhibitors of CXCL8, e.g., BMS986253 and PA620; inhibitors of CXCL10, e.g., TM110, erderumab, and NI0801; inhibitors of CXCL12, e.g., NOX-A12 and JVS100; inhibitors of CXCL13, e.g., VX5; inhibitors of CCL2, e.g., PA508, ABN912, AF2838, BN83250, BN83470, C243, CGEN54, CNTO888, NOXE 36, VT224, and SSR150106; inhibitors of CCL5, e.g., HGS1025 and NI0701; inhibitors of CCL2 / CCL5, e.g., BKTP46; inhibitors of CCL5 / FMLP receptors, e.g., RAP160; inhibitors of CCL11, e.g., vertilimmab and RAP701; inhibitors of CCL5 / CXCL4, e.g., CT2008 and CT2009; inhibitors of CCL20, e.g., GSK3050002; and inhibitors of CX3CL1, e.g., quetomolimab may be selected from this group.

[0502] Chemokine receptor antagonists include CXCR1 inhibitors, e.g., repertaxin, CCX832, FX68, and KB03; CXCR2 inhibitors, e.g., AZD5069, AZD5122, AZD8309, GSK1325756, GSK1325756H, PS291822, SB332235, and SB656933; CXCR1 / CXCR2 inhibitors, e.g., DF1970, DF2156A, DF2162, DF2755A, reparixin, SX576, SX682, PACG31P, AZD 4721, and PA401; CXCR3 inhibitors; CXCR4 inhibitors, e.g., BL8040; CXCR4 / E-selectin inhibitors, e.g., GMI1359; CXCR6 inhibitors, e.g., CCX5224; CCR1 inhibitors, e.g., AZD4818, BAY865047, BMS817399, CCX354, CCX634, CCX9588, CP481715, MLN3701, MLN3897, PS031291, PS375179, and PS386113; CCR2 inhibitors, e.g., AZD 2423, BL2030, BMS741672, CCX140, CCX598, CCX872, CCX915, CNTX6970, INCB3284, INCB3344, INCB8696, JNJ17166864, JNJ27141491, MK0812, OPLCCL2LPM, PF4136309, Celocion, STIB0201, STIB0211, STIB0221, STIB0232, STIB0234, TAK202, TPI526; CCR2 / CCR5 inhibitors, e.g., PF046348 17. RAP103 and TBR652; inhibitors of CCR2 / CCR5 / CCR8, e.g., RAP310; inhibitors of CCR3, e.g., ASM8, AXP1275, BMS639623, CM101, DPC168, GW766994, GW824575, MT0814, OPLCCL11LPM, and QAP642; inhibitors of CCR4, e.g., AT008, AZD2098, CCX6239, FLX193, FLX475, GBV3019, GSK2239633, IC487892, and Poteligeo;CCR5 inhibitors, e.g., 5P12-RANTES, AZD5672, AZD8566, CMPD167, ESN196, GSK706769, GW873140, HGS004, INCB15050, INCB9471, L872; bactericides, PF232798, PRO140, RAP101, SAR113244, SCH350634, SCH351125, SCH417690; Cellgentri, TAK779, TBR220, TD0232, and VX286; CCR5 / CXCR4 inhibitors, e.g., AMD887, ND401, and SP01A; CCR6 inhibitors, e.g., CCX507, CCX9664, and STIB100X; CCR6 inhibitors, e.g., CCX025, CCX507, CCX807, eut22, MLN3126, POL7085, trough Traficet-EN; CXCR3 inhibitors, e.g., AMG487, AT010, STIA120X; CXCR4 inhibitors, e.g., AD114, AD214, ALX0651, ALX40-4C, AMD070, AT007, AT009, BKT170, BMS936564, celixafor, CTCE9908, GBV4086, GSK8 The following may be selected: 12397, KRH2731, KRH3140, LY2510924, LY2624587, Mozovir, OPLCXCL12LPM, PF06747143, POL6326, Q122, Revixil, TG0054, USL311, X4P001, and X4P002; and inhibitors of CXCR7, such as CCX650 and CCX662.

[0503] Cytokine receptor agonists include mRNA, DNA, or plasmids encoding genes for IL-2, IL-15, IL-7, IL-10, IL-12, IL-21, IFNα, IL-17, IFNβ, IFNγ, IL-18, IL-27, TNFα, GM-CSF, FLT3L, LTα, LTβ, and TRAIL, as well as recombinant proteins, such as IL-2 / IL-15β / γ receptor agonists and IL-1 The agonist may be selected from the group consisting of 0 receptor agonists, IL-12 receptor agonists, IL-18 receptor agonists, IL-21 receptor agonists, IL-7 receptor agonists, IFNα / β receptor agonists, IFNγ receptor agonists, FLT3 receptor agonists, GM-CSF receptor agonists, LTα receptor agonists, LTβ receptor agonists, and TNFα receptor agonists.

[0504] Examples of IL-10 receptor agonists include AG011, decavir, EG10, IL10Nanocap, ilodecaquin, AM0010, tenovir, and VT310 VIRON.

[0505] Examples of IL-12 receptor agonists include recombinant IL-12 p70, recombinant IL-12 p35, AM0012, AS1409, dodequin, HemaMax, LipoVIL12, MSB0010360N, Ad-RTS-hIL-12, tavokinogene telseplasmid, exoIL-12, and NHS-IL12.

[0506] An example of an IL-18 receptor agonist is SB485232.

[0507] An example of an IL-21 receptor agonist is BMS982470 (denenikoquine).

[0508] Examples of IL-7 receptor agonists include CYT107, CYT99007, and GX-I7.

[0509] An example of an agonist for FLT3R is the CDX-301.

[0510] Examples of TNFα receptor agonists include L19-TNFα, aurimune, beromun, BreMel / TNFα, fibromun, refnot, and TNFPEG20.

[0511] Cell death receptor agonists may be selected from the group consisting of TRAILR1 / DR4 agonists, e.g., AMG951 (Duranermin), APG350, APG880, HGSETR1 (Mapatumumab), and SL231; and TRAILR2 / DR5 agonists, e.g., AMG655, DS8273, HGSETR2 (Lexatumumab), HGSTR2J, IDD004 / GEN1029, INBRX109, LBY135, MEDI3039, PRO95780, RG7386, and TAS266.

[0512] The CD47 antagonist can be selected from the group consisting of ALX148, CC-90002, Hu5F9G4, SRF231, TI061, TTI-621, TTI-622, AO176, IBI188, IMC002, recombinant SIRPα, and LYN00301.

[0513] Examples of SIRPα antagonists include FSI89 or recombinant CD47.

[0514] Examples of oncolytic agents include CAVATAK, BCG, Mobilan, TG4010, Pexa-Vec (JX-594), JX-900, JX-929, and JX-970.

[0515] Examples of signal conversion proteins include Fn14-TRAIL (KAHR101), CD80-Fc (FTP155), CTLA4-FasL (KAHR102), PD1-41BBL (DSP105), PD-L1-41BB (PRS-344, NM21-1480, FS222), PD1-CD70 (DSP106), and SIRPα-41BBL (DSP107).

[0516] Epigenetic modifiers may be selected from the group consisting of DNA methyltransferase inhibitors, lysine-specific demethylase 1 inhibitors, Zeste homolog 2 inhibitors, bromodomains, and extra-terminal motif (BET) protein inhibitors, such as GSK525762, and histone deacetylase (HDAC) inhibitors, such as Bereodak, SNDX275, and CKD-M808.

[0517] Examples of tumor peptides / vaccines include NY-ESO, WT1, MART-1, IO102, and PF-06753512, as well as personalized cancer vaccines using patient-derived tumor sequences or neoantigens.

[0518] Examples of heat shock protein (HSP) inhibitors include HSP90 inhibitors such as PF-04929113 (SNX-5422).

[0519] Examples of proteolytic enzymes include recombinant hyaluronidases, such as rHuPH20 and PEGPH20.

[0520] Ubiquitin and proteasome inhibitors may be selected from the group consisting of ubiquitin-specific protease (USP) inhibitors, e.g., P005091; 20S proteasome inhibitors, e.g., bortezimib, carfilzomib, ixazomib, oprozomib, delanzomib, and cerastrol; and immunoproteasome inhibitors, e.g., ONX-0914.

[0521] Adhesion molecule antagonists can be selected from the group consisting of β2-integrin antagonists and selectin antagonists.

[0522] The hormone can be selected from a group consisting of hormone receptor agonists and hormone receptor antagonists.

[0523] Examples of hormone receptor agonists include somatostatin receptor agonists, such as somatostatin, lanreotide, octreotide, FX125L, FX141L, and FX87L.

[0524] Examples of hormone receptor antagonists include antiandrogens, antiestrogens, and antiprogestogens. Examples of antiandrogens include steroidal antiandrogens, such as cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, oxendrone, and osaterone acetate; nonsteroidal antiandrogens, such as flutamide, bicalutamide, nilutamide, topirutamide, enzalutamide, and apalutamide; androgen synthesis inhibitors, such as ketoconazole, abiraterone acetate, ceviteronel, aminoglutethimide, finasteride, dutasteride, epristeride, and alpha-estradiol. Examples of anti-estrogens include selective estrogen receptor modulators (SERMs), such as tamoxifen, clomiphene, fareston, and raloxifene; ER silent antagonists and selective estrogen receptor degraders (SERDs), such as fulvestrant; aromatase inhibitors, such as anastrozole, letrozole, exemestane, volozol, formestan, and fadrozol; and antigonadotropins, such as testosterone, progestogens, and GnRH analogs. Examples of antiprogestogens include mifepristone, lilopristone, and onapristone.

[0525] Examples of cell therapies include CAR therapies, such as CAR-T therapies, such as tisagenlecroicel, axicaptagen-shiroleicel, bb21217, LCAR-B38M, JCARH125, MCARH171, JNJ-4528, idekabutadiene-bicloicel (bb2121), SCRI-CAR19x22; CAR therapies targeting tumor antigens, such as CAR therapies targeting CD19-expressing cells, CAR therapies targeting CD22-expressing cells, CAR therapies targeting BCMA-expressing cells, CAR therapies targeting HER2-expressing cells, CAR therapies targeting CD138-expressing cells, CAR therapies targeting CD133-expressing cells, CAR therapies targeting BCMA-expressing cells, and CEA-expressing cells. Examples of CAR therapies include cell-targeting CAR therapies, claudin 18.2-expressing cell-targeting CAR therapies, EGFR-expressing cell-targeting CAR therapies, EGFRvIII-expressing cell-targeting CAR therapies, Eph2A-expressing cell-targeting CAR therapies, EpCAM-expressing cell-targeting CAR therapies, GD2-expressing cell-targeting CAR therapies, GPC3-expressing cell-targeting CAR therapies, MSLN-expressing cell-targeting CAR therapies, 5T4-expressing cell-targeting CAR therapies, LMP1-expressing cell-targeting CAR therapies, PD-L1-expressing cell-targeting CAR therapies, PSMA-expressing cell-targeting CAR therapies, FRα-expressing cell-targeting CAR therapies, and MUC1-expressing cell-targeting CAR therapies. Examples of cell therapies include TIL therapy, NK therapy, cytokine-induced memory NK cell therapy, and NK cell therapy using ex vivo proliferating cells. Examples of cell therapies include therapies using αβ or γδ T cells that can be genetically engineered to express tumor antigen or tumor neoantigen-specific T cell receptors, or that can proliferate in relation to tumor antigen or tumor neoantigen.

[0526] In certain embodiments, one or more additional drugs are administered in approved doses.

[0527] In a particular embodiment, one or more additional drugs are standard treatments for a particular cancer, such as standard therapeutic chemotherapy.

[0528] In a fifth aspect, the present invention relates to a kit comprising an IL-2 conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the kit comprises an IL-2 conjugate or a pharmaceutically acceptable salt thereof and at least one container.

[0529] In certain embodiments, at least one container of the kit is a sterile container for holding IL-2 conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the sterile container is selected from the group consisting of ampoules, bottles, vials, test tubes, bags, pouches, blister packs, syringes, dual-chamber syringes and other suitable container forms known in the art. Such sterile containers may be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding pharmaceuticals. In certain embodiments, the sterile container is a glass vial.

[0530] In certain embodiments, the kit further includes instructions in a readable medium relating to the administration and / or administration of IL-2 conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the readable medium can be read by a human or a machine. In certain embodiments, the human-readable medium is selected from the group consisting of brochures, accompanying documents, and other document forms. In certain embodiments, the machine-readable medium is selected from the group consisting of read-only memory (ROM) such as CD-ROMs; random-access memory (RAM); magnetic disk storage media; quick-response codes (QR codes®) or other matrix barcodes; optical storage media; and flash memory devices such as USB drives.

[0531] In certain embodiments, the kit includes an IL-2 conjugate or a pharmaceutically acceptable salt thereof provided in a glass vial, and instructions in a readable medium relating to the dosing and / or administration of the IL-2 conjugate or a pharmaceutically acceptable salt thereof.

[0532] In certain embodiments, the kit optionally further includes components and / or devices necessary or suitable for administering IL-2 conjugate or a pharmaceutically acceptable salt thereof, such as needles, applicators, and injection devices, including syringes.

[0533] In certain embodiments, the kit optionally further comprises a re-prepared solution. In certain embodiments, the re-prepared solution may contain further excipients, such as preservatives and / or antimicrobial agents, such as benzyl alcohol and cresol, and is a sterile liquid, such as phosphate-buffered saline, isotonic saline, water for injection, or other buffer solution.

[0534] In certain embodiments, the kit comprises a unit dosage form of IL-2 conjugate or a pharmaceutically acceptable salt thereof as described elsewhere in this specification. In certain embodiments, the kit comprises a unit dosage form of IL-2 conjugate or a pharmaceutically acceptable salt thereof as described elsewhere in this specification, and instructions in readable medium relating to the dosing and / or administration of IL-2 conjugate or a pharmaceutically acceptable salt thereof.

[0535] In certain embodiments, the kit comprises an IL-2 conjugate or a pharmaceutically acceptable salt thereof and one or more of the above-mentioned further drugs. In certain embodiments, the kit comprises an IL-2 conjugate or a pharmaceutically acceptable salt thereof and a drug of formula (A-3), (A-6), or (Ai-6). In certain embodiments, the kit comprises an IL-2 conjugate or a pharmaceutically acceptable salt thereof and pembrolizumab.

[0536] In certain embodiments, IL-2 conjugate or a pharmaceutically acceptable salt thereof and one or more further drugs are contained in one container. In certain embodiments, IL-2 conjugate or a pharmaceutically acceptable salt thereof and drugs of formula (A-3), (A-6), or (Ai-6) are contained in one container. In certain embodiments, IL-2 conjugate or a pharmaceutically acceptable salt thereof and pembrolizumab are contained in one container.

[0537] In certain embodiments, the kit comprises a first container containing an IL-2 conjugate or a pharmaceutically acceptable salt thereof and a second container containing one or more further drugs. In certain embodiments, the kit comprises a first container containing an IL-2 conjugate or a pharmaceutically acceptable salt thereof and a second container containing a drug of formula (A-3), (A-6), or (Ai-6). In certain embodiments, the kit comprises a first container containing an IL-2 conjugate or a pharmaceutically acceptable salt thereof and a second container containing pembrolizumab.

[0538] In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof and one or more additional drugs provided in the kit are intended to be administered simultaneously, separately, or sequentially. In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof and drugs of formula (A-3), (A-6), or (Ai-6) provided in the kit are intended to be administered simultaneously, separately, or sequentially. In certain embodiments, the IL-2 conjugate or a pharmaceutically acceptable salt thereof and pembrolizumab provided in the kit are intended to be administered simultaneously, separately, or sequentially.

[0539] In certain embodiments, the kit further includes instructions in a readable medium regarding the dosing and / or administration of IL-2 conjugate or a pharmaceutically acceptable salt thereof and one or more further drugs. In certain embodiments, the kit further includes instructions in a readable medium regarding the dosing and / or administration of IL-2 conjugate or a pharmaceutically acceptable salt thereof and a drug of formula (A-3), (A-6), or (Ai-6). In certain embodiments, the kit further includes instructions in a readable medium regarding the dosing and / or administration of IL-2 conjugate or a pharmaceutically acceptable salt thereof and pembrolizumab.

[0540] In a sixth aspect, the present invention relates to a kit for use in the treatment of cancer, as described elsewhere in this specification, comprising an IL-2 conjugate or a pharmaceutically acceptable salt thereof, or a unit dosage form of an IL-2 conjugate or a pharmaceutically acceptable salt thereof, as described elsewhere in this specification.

[0541] In a seventh aspect, the present invention relates to a method for synthesizing IL-2 conjugate or a pharmaceutically acceptable salt thereof. In certain embodiments, the IL-2 conjugate is synthesized as described in International Publication No. 2021 / 245130, Example 5, Compound 6. In certain embodiments, the IL-2 conjugate is synthesized as described in Example 1 of this specification.

[0542] In a particular embodiment, the IL-2 conjugate of formula (I) DL 1 -L 2 -Z (I) teeth, (a)(a)i. At least one reagent ZL 2 -L 1 -FG; (a)ii. A liquid containing at least one organic solvent; and (a)iii. One or more drug DH Steps to provide; (b) At least one reagent ZL from step (a)i.2 -L 1 -A step of incubating FG, the liquid from step (a)ii. and one or more drugs DH from step (a)iii. together to obtain the IL-2 conjugate of formula (I); and (c) Optionally, a step to purify the IL-2 conjugate of formula (I) obtained in step (b). Synthesized by a method including, At this time, -D, -L 1 -, -L 2 - and -Z are defined as set forth elsewhere in this specification; DH is the free form of -D; -FG is the functional group portion.

[0543] In certain embodiments, the liquid in step (a)ii. contains at least about 5% (v / v), for example, in the range of about 5% to about 80% (v / v), in the range of about 10% to about 60% (v / v), or in the range of about 20% to about 50% (v / v).

[0544] In certain embodiments, the organic solvent in step (a)ii. is selected from the group consisting of acetaldehyde, acetic acid, acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2-butoxyethanol, butyric acid, dimethoxyethane, dimethyl sulfoxide, dimethylformamide, 1,4-dioxane, ethanol, ethylene glycol, formic acid, furfuryl alcohol, glycerol, 2-methyl-2,4-pentanediol, methanol, methyl isocyanide, n-methyl-2-pyrrolidone, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol, propanoic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol.

[0545] In certain embodiments, the organic solvent in step (a)ii. is selected from the group consisting of acetonitrile, dimethyl sulfoxide, 1,4-dioxane, and 2-methyl-2,4-pentanediol.

[0546] In certain embodiments, the liquid in step (a)ii. contains about 20% (v / v), about 30% (v / v), about 40% (v / v), or about 50% (v / v) acetonitrile, dimethyl sulfoxide, 1,4-dioxane, or 2-methyl-2,4-pentanediol. In certain embodiments, the liquid in step (a)ii. contains 20% (v / v), 30% (v / v), 40% (v / v), or 50% (v / v) acetonitrile, dimethyl sulfoxide, 1,4-dioxane, or 2-methyl-2,4-pentanediol. In certain embodiments, the liquid in step (a)ii. contains about 20% (v / v), about 30% (v / v), about 40% (v / v), or about 50% (v / v) acetonitrile. In certain embodiments, the liquid in step (a)ii. contains 20% (v / v), 30% (v / v), 40% (v / v), or 50% (v / v) acetonitrile. In certain embodiments, the liquid in step (a)ii. contains about 30% (v / v) acetonitrile. In certain embodiments, the liquid in step (a)ii. contains 30% (v / v) acetonitrile.

[0547] In a particular embodiment, the liquid in step (a)ii is a mixture of at least one organic solvent and water, or a mixture of at least one organic solvent and an aqueous solution, such as a buffer solution.

[0548] In certain embodiments, the aqueous solution is an aqueous buffer solution. In certain embodiments, the aqueous buffer comprises borates; for example, orthoborates, metaborates, or tetraborates; phosphates; bicarbonates; N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid; 3-(N-morpholino)propanesulfonic acid; (4-2-hydroxyethyl)-1-piperazineethanesulfonic acid; 3-N-bis(hydroxyethyl)-amino-2-hydroxypropanesulfonic acid; 3-(N-morpholino)propanesulfonic acid; (2-hydroxyethyl)-piperazine-N-2-hydroxypropanesulfonic acid; piperazine-1,4-bis(2-hydroxypropanesulfonic acid); 3-[4-(2-hydroxyethyl)piperazine-1-yl]propane-1-sulfonic acid; bicine; N-(2-hydroxyethyl)piperazine-N'-(4-butanesulfonic acid); or any combination thereof.

[0549] In a particular embodiment, the aqueous buffer solution has a pH in the range of about 7 to about 11, for example, about 7.5 to about 10.5, about 8 to about 10, about 8.5 to about 9.5, or a pH of about 9.

[0550] In certain embodiments, the mixture of at least one organic solvent and water, or the mixture of at least one organic solvent and aqueous solution, comprises about 20% (v / v), about 30% (v / v), about 40% (v / v), or about 50% (v / v) acetonitrile, dimethyl sulfoxide, 1,4-dioxane, or 2-methyl-2,4-pentanediol. In certain embodiments, the mixture comprises 20% (v / v), 30% (v / v), 40% (v / v), or 50% (v / v) acetonitrile, dimethyl sulfoxide, 1,4-dioxane, or 2-methyl-2,4-pentanediol. In certain embodiments, the mixture comprises about 20% (v / v), about 30% (v / v), about 40% (v / v), or about 50% (v / v) acetonitrile. In certain embodiments, the mixture contains 20% (v / v), 30% (v / v), 40% (v / v), or 50% (v / v) acetonitrile.

[0551] In certain embodiments, the mixture contains about 30% (v / v) acetonitrile in water.

[0552] In a particular embodiment, at least one reagent ZL is used in step (b). 2 -L 1 -FG and one or more partial DHs are combined in a molar ratio ranging from 10:1 to 1:10, for example, 9:1 to 1:9, 8:1 to 1:8, 7:1 to 1:7, 6:1 to 1:6, 5:1 to 1:5, 4:1 to 1:4, 3:1 to 1:3, 2:1 to 1:2, or 1:1. In certain embodiments, ZL 2 -L 1 -The molar ratio of FG to DH is in the range of 4:1 to 1:1. In certain embodiments, ZL 2 -L 1 - The molar ratio of FG to DH is 3:1.

[0553] In a particular embodiment, step (b) is: step (b)i.~(b)iii.: (b)i. At least one reagent ZL from step (a)i. 2 -L 1 - The step of mixing FG with the liquid from step (a)ii.; (b)ii. Adding one or more drugs DH from step (a)iii. to the mixture from step (b)i.; and (b)iii. Incubate the mixture from step (b)ii for at least 10 minutes. Includes.

[0554] In a particular embodiment, step (b)iii. is carried out over a period of about 10 minutes to about 24 hours, for example, about 30 minutes to about 6 hours or about 2 to about 5 hours.

[0555] In a particular embodiment, step (b)iii. is carried out at a temperature in the range of about 0°C to about 40°C, for example, in the range of about 5°C to about 30°C, in the range of about 10°C to about 20°C, in the range of about 11°C to about 17°C, or at a temperature of about 14°C.

[0556] In certain embodiments, the IL-2 conjugate of formula (I) in step (c) is purified by sterile filtration, chromatography, or ultrafiltration. In certain embodiments, the IL-2 conjugate of formula (I) in step (c) is purified by mixed-mode chromatography.

[0557] In certain embodiments, -FG is (methylsulfonyl)oxy, [(nonafluorobutyl)sulfonyl]oxy, [(trifluoromethyl)sulfonyl]oxy, [2-(trimethylsilyl)ethoxy]methylacetal, 1-hydroxybenzotriazole, 4-methoxybenzenesulfonamide, 4-methoxybenzyl ether, 4-nitrophenolate, 9-fluorenylmethylcarbamate, azide, benzyloxy, benzyloxycarbonyl, brosilate, dichlorophenolate, difluorophenolate, dihalophosphinoloxy, ethanesulfonyloxy, ethoxyethyl ether, hydroxysuccinimide The following are selected from the group consisting of imidazole, methanesulfonylate / mesylate, methanesulfonyloxy, methoxymethyl ether, monofluorophenolate, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, nitrophenolate, pentafluorophenolate, phenyl, p-toluenesulfonylate (tosylate), tert-butyldimethylsilyl ether, tetrachlorophenolate, tetrafluorophenolate, tetrahydropyranyl ether, thienyloxy, triflate, trifluoroacetoxy, trifluoromethylmethanesulfonylate, and trityl(triphenylmethyl) ether.

[0558] In certain embodiments, -FG is selected from the group consisting of 4-nitrophenolate, pentafluorophenolate, and N-hydroxysuccinimide. In certain embodiments, -FG is pentafluorophenolate.

[0559] In a particular embodiment, the IL-2 conjugate of formula (I) is: (a)(a)i. At least one reagent of formula (XII) [ka] [In the formula, p1, p2, p3, and p4 are integers in the ranges of 110-345, 140-315, 170-285, 195-255, 200-250, 210-250, or 220-240, independently of each other.] (a)ii. A mixture of about 30% (v / v) acetonitrile in water; and (a)iii. Solution containing DH Steps to provide; (b) A step of mixing at least one of the reagents from step (a)i with the mixture from step (a)ii; (c) A step in which the mixture from step (b) is mixed with the solution from step (a)iii, wherein the molar ratio of the reagent of formula (XII) to DH is in the range of 4:1 to 1:1; (d) Incubating the mixture from step (c) at a temperature in the range of 10°C to 20°C for 1 to 5 hours to obtain the IL-2 conjugate of formula (I); and (e) Optionally, a step to purify the IL-2 conjugate of formula (I) from the incubated mixture of step (d). It is synthesized by a method that includes [a specific component].

[0560] DH is the free form of -D, which is further described elsewhere in this specification.

[0561] In a particular embodiment, method DH is D'-M mod-D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod (A-1d) or (A-1e) [ka] [In the formula, The dashed line marked with an asterisk indicates the bond to the sulfur atom of the cysteine ​​side chain at position 38. b1 is either 2 or 3. b2 is either 2 or 3. b3 is in the range of 90-140, 95-135, or 100-125. It has the structure of [the object].

[0562] Surprisingly, it was found that dissolving the reagent in step (a)i. in an aqueous mixture of organic solvents reduced the amount of reagent required to synthesize the IL-2 conjugate of formula (I) with similar yield and purity compared to dissolution in pure water. Furthermore, surprisingly, it was found that dissolving the reagent in step (a)i. in an aqueous mixture of organic solvents reduced the dissolution time and reduced the hydrolysis of the reagent in step (a)i. compared to dissolution in pure water.

[0563] Surprisingly, the IL-2 conjugate of formula (I) increased the levels of soluble CD25 (sCD25) and / or CD8 in patients with cancer. + To effectively increase T cell levels, and furthermore, to increase sCD25 levels and / or CD8 levels. + Elevated T-cell levels were found to correlate with favorable treatment outcomes, including stable disease for at least six months, partial response, or complete response. To the best of the applicant's knowledge, this is the first IL-2 conjugate for which such correlations have been observed in patients with cancer at the time of filing.

[0564] In the eighth aspect, the present invention is (a) Measuring the level of sCD25 in a biological sample obtained from a patient after administration of at least one dose of an IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg to the patient; and / or (b) CD8 in biological samples obtained from patients after administration of at least one dose of the IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg to the patient. + A step of measuring the level and / or proliferation of T cells; (c) A step of comparing the level from step (a) and / or the level from step (b) and / or the increase in sCD25 and / or CD8 compared to the reference, wherein the increased level of sCD25 and / or CD8 + A step demonstrating that elevated levels and / or proliferation of T cells indicate that the patient is likely to benefit from treatment with the IL-2 conjugate of formula (I); and (d) The patient, (i) If the patient has elevated levels of sCD25 compared to the reference, administer to the patient one or more additional doses of IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg; and / or (ii) Compare CD8 with the reference + If the patient has elevated levels and / or proliferation of T cells, administer one or more additional doses of IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg to the patient. Step This relates to methods for treating cancer or slowing its progression in patients, including the following.

[0565] The IL-2 conjugate of formula (I) in the eighth aspect is defined as set forth elsewhere in this specification.

[0566] In certain embodiments, the dose in steps (a), (b), and (d) of the eighth aspect is in the range of 100 μg IL-2 / kg to 140 μg IL-2 / kg. In certain embodiments, the dose in steps (a), (b), and (d) of the eighth aspect is in the range of 110 μg IL-2 / kg to 130 μg IL-2 / kg. In certain embodiments, the dose in steps (a), (b), and (d) of the eighth aspect is approximately 120 μg IL-2 / kg. In certain embodiments, the dose in steps (a), (b), and (d) of the eighth aspect is 120 μg IL-2 / kg.

[0567] In certain embodiments, the biological sample in step (a) and / or step (b) is obtained after administration of a first dose of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is obtained after administration of a second dose of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is obtained after administration of a third dose of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is obtained after administration of a fourth dose of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is obtained after administration of a fifth dose of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is obtained after administration of any dose administered after the fifth dose of the IL-2 conjugate of formula (I).

[0568] In certain embodiments, the biological sample in step (a) and / or step (b) is taken 1 to 6 weeks after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 1 day after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 2 days after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 3 days after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 4 days after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 5 days after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 6 days after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 1 week after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 2 weeks after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 3 weeks after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 4 weeks after administration of the IL-2 conjugate of formula (I). In certain embodiments, the biological sample in step (a) and / or step (b) is taken 5 weeks after administration of the IL-2 conjugate of formula (I). In a particular embodiment, the biological samples in step (a) and / or step (b) are taken 6 weeks after administration of the IL-2 conjugate of formula (I).

[0569] In certain embodiments, the biological samples in step (a) and step (b) are the same biological sample. In certain embodiments, the biological samples in step (a) and step (b) are different biological samples.

[0570] In certain embodiments, the biological sample in step (a) and / or step (b) is a blood sample or a tumor sample. In certain embodiments, the biological sample in step (a) and / or step (b) is a blood sample. In certain embodiments, the biological sample in step (a) and / or step (b) is a tumor sample.

[0571] In certain embodiments, the blood sample includes peripheral blood mononuclear cells (PBMCs).

[0572] In a particular embodiment, the level of sCD25 is measured. In a particular embodiment, CD8 + The level of T cells is measured. In a particular embodiment, CD8 + T cell proliferation is measured. In certain embodiments, the levels of sCD25 and CD8 + The level of T cells is measured. In certain embodiments, the levels of sCD25 and CD8 + T cell proliferation is measured. In a particular embodiment, CD8 + T cell level and CD8 + T cell proliferation is measured. In certain embodiments, the levels of sCD25 and CD8 are measured. + T cell level and CD8 + T cell proliferation is measured.

[0573] In a particular embodiment, CD8 + T cell levels and / or proliferation are measured by flow cytometry. In certain embodiments, CD8 + T cell proliferation is CD8 + It is measured by detecting the expression of cell or nuclear proliferation-related antigens on T cells. In certain embodiments, CD8+ T cell proliferation is measured by detecting Ki-67.

[0574] In certain embodiments, the reference includes a biological sample obtained from a patient prior to administration of the IL-2 conjugate of formula (I). In certain embodiments, the reference includes a standard derived from a population of known non-responders to treatment with the IL-2 conjugate of formula (I). In certain embodiments, the reference includes a standard derived from a population of known responders to treatment with the IL-2 conjugate of formula (I). In certain embodiments, the reference is data collected across multiple patients. In certain embodiments, the reference is a healthy subject.

[0575] In certain embodiments, one or more additional doses in step (d) are administered when the absolute level of sCD25 in the biological sample is elevated compared to the reference, such as measured in pg / mL. In certain embodiments, one or more additional doses in step (d) are administered when the relative level of sCD25 in the biological sample is elevated compared to the reference, such as indicated by the rate of change.

[0576] In a particular embodiment, one or more additional doses in step (d) are CD8 in a biological sample, such as those measured in cells / μL. + It is administered when the absolute level of T cells is elevated compared to the reference. In certain embodiments, one or more further doses in step (d) are CD8 in a biological sample, such as those indicated by the change factor. + It is administered when the relative level of T cells is elevated compared to the reference level.

[0577] In certain embodiments, one or more additional doses in step (d) are proliferative CD8 in a biological sample, such as those measured in cells / μL. +It is administered when the absolute number of T cells is increased compared to the reference. In certain embodiments, one or more further doses in step (d) are CD8 in a biological sample, such as those indicated by the change factor. + It is administered when the relative proliferation of T cells is increased compared to the reference level.

[0578] Steps (a), (b), and (c) involve the elevated level of sCD25 and / or CD8 + This can be repeated until T cell levels and / or proliferation are observed.

[0579] The present invention is further described by the following non-limiting items.

[0580] 1. IL-2 conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the IL-2 conjugate is administered in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg, and the IL-2 conjugate is of formula (I), the above IL-2 conjugate or a pharmaceutically acceptable salt thereof: DL 1 -L 2 -Z (I) [In the formula, -D is -D'-M mod And, Here, -D'- is the IL-2 part; -M mod This is the first polymer moiety stably conjugated to the side chain of the -D'- amino acid residue; -L 1 - is a linker portion covalently and reversibly bonded to -D'-; -L 2 - indicates either non-existent or a spacer portion; -Z is the second polymer portion.

[0581] 2. IL-2 conjugate for use in item 1, with a dosage in the range of 100 μg IL-2 / kg to 140 μg IL-2 / kg.

[0582] 3. IL-2 conjugates for use in item 1 or 2, with a dosage in the range of 110 μg IL-2 / kg to 130 μg IL-2 / kg.

[0583] 4. An IL-2 conjugate for use in any one of items 1-3, with a dose of approximately 120 μg IL-2 / kg.

[0584] 5. An IL-2 conjugate for use in any one of items 1-4, with a dose of 120 μg IL-2 / kg.

[0585] 6. IL-2 conjugate for use in any one of items 1-5, administered in multiple doses.

[0586] 7. An IL-2 conjugate for use in any one of items 1-6, with an interval of 2-8 weeks between two consecutive doses.

[0587] 8. IL-2 conjugate for use of any one of items 1-7, with an interval of 3 weeks between two consecutive doses.

[0588] 9. IL-2 conjugate for use of any one of items 1-7, with an interval of 6 weeks between two consecutive doses.

[0589] 10. IL-2 conjugate for use in any one of items 1-6, administered at a frequency corresponding to disease progression.

[0590] 11. IL-2 conjugate for use in any one of items 1-5, administered as a single dose.

[0591] 12. Treatment should be initiated immediately upon diagnosis of cancer, using one of the following IL-2 conjugates:

[0592] 13. IL-2 conjugate for use of any one of items 1-12, where the treatment is the first-line treatment.

[0593] 14. IL-2 conjugate for use of any one of items 1-12, where the treatment is a second-line, third-line, or further-line treatment.

[0594] 15. IL-2 conjugate for use in any one of items 1-14, administered by topical use, injection or infusion, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intrasacral, intraorbital, intratympanic, intravesical, intracardiac, transtracheal, subepidermal, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion; direct delivery to the brain via an implantable device (e.g., Onmyya reservoir) that enables delivery of IL-2 conjugate to brain tissue or cerebral fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related region, injection into the subchoroidal space, posterior orbital injection or ophthalmic instillation.

[0595] 16. IL-2 conjugate to be administered intravenously, IL-2 conjugate for use in any one of items 1-15.

[0596] 17. IL-2 conjugate administered subcutaneously, IL-2 conjugate for use in any one of items 1-15.

[0597] 18. An IL-2 conjugate for use in any one of items 1-17, wherein -D'- has at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 1.

[0598] 19. An IL-2 conjugate for use in any one of items 1-18, wherein -D'- has at least 96% sequence identity with respect to the amino acid sequence of SEQ ID NO: 1.

[0599] 20. An IL-2 conjugate for use in any one of items 1-19, wherein -D'- has at least 97% sequence identity with respect to the amino acid sequence of SEQ ID NO: 1.

[0600] 21. An IL-2 conjugate for use in any one of items 1-20, wherein -D'- has at least 98% sequence identity with respect to the amino acid sequence of SEQ ID NO: 1.

[0601] 22. An IL-2 conjugate for use in any one of items 1-21, wherein -D'- has at least 99% sequence identity with respect to the amino acid sequence of SEQ ID NO: 1.

[0602] 23. An IL-2 conjugate for use in any one of items 1 to 22, comprising the amino acid sequence of SEQ ID NO: 1, wherein -D'- is replaced by a proteinogenic or non-proteinogenic amino acid residue selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72.

[0603] 24. An IL-2 conjugate for use in any one of items 1-23, in which -D'- contains the A1del mutation.

[0604] 25. An IL-2 conjugate for use in any one of items 1-23, comprising the amino acid sequence of SEQ ID NO: 1, wherein -D'- is replaced by a cysteine ​​residue, with one amino acid residue selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72.

[0605] 26. An IL-2 conjugate for use in any one of items 1-23 or 25, having the amino acid sequence of SEQ ID NO: 1, wherein -D'- is replaced by a cysteine ​​residue in one amino acid residue selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72.

[0606] 27. An IL-2 conjugate for use in any one of items 1-23, 25, or 26, wherein -D'- has the amino acid sequence of SEQ ID NO: 4.

[0607] 28. -M mod IL-2 conjugate for use in any one of items 1 to 27, having a molecular weight in the range of 0.5 kDa to 20 kDa.

[0608] 29. -M mod IL-2 conjugate for use in any one of items 1 to 28, having a molecular weight in the range of 1 kDa to 20 kDa.

[0609] 30. -M mod IL-2 conjugate for use in any one of items 1-29, having a molecular weight in the range of 2kDa to 10kDa.

[0610] 31. -M mod IL-2 conjugate for use in any one of items 1-30, having a molecular weight in the range of 3kDa to 7kDa.

[0611] 32. -M mod IL-2 conjugate for use in any one of items 1-31, having a molecular weight of 5±25%kDa.

[0612] 33. -M mod IL-2 conjugate for use in any one of items 1-32, having a molecular weight in the range of 4kDa to 6kDa.

[0613] 34. -M mod IL-2 conjugate for use in any one of items 1-32, having a molecular weight of 5±20%kDa.

[0614] 35. -M mod IL-2 conjugate for use in any one of items 1-34, having a molecular weight of 5±15%kDa.

[0615] 36. -M mod IL-2 conjugate for use with any one of items 1-35, having a molecular weight of approximately 5 kDa.

[0616] 37. -M mod IL-2 conjugate for use in any one of items 1-36, which is a PEG-based polymer.

[0617] 38. -M mod An IL-2 conjugate for use in any one of items 1-37, wherein the binding occurs at an amino acid position selected from the group consisting of K35, R38, M39, T41, F42, K43, F44, Y45, E62, P65, E68, V69, and L72.

[0618] 39. -D'- has the amino acid sequence of SEQ ID NO: 4, and -M mod IL-2 conjugate for use in either item 1-23 or 25-38, in which the sulfur atom of the cysteine ​​side chain at position 38 is stably conjugated.

[0619] 40. -M mod Equation (A-1) [ka] [In the formula, -FG- is a bond, -SP- is the spacer part. -POL is a polymer. An IL-2 conjugate for use in any one of items 1-39.

[0620] 41. -FG- in equation (A-1) is equal to equation (FG-1a) [ka] [In the formula, The dashed lines marked with an asterisk indicate the bond to the sulfur in the cysteine ​​side chain of -D'-, while the unmarked dashed lines indicate the bond to -SP-. IL-2 conjugate for use of item 40.

[0621] 42. -FG- in equation (A-1) is equal to (FG-1d) or (FG-1e) [ka] [In the formula, The dashed lines marked with an asterisk indicate binding to the sulfur of the -D'- cysteine ​​residue, while the dashed lines without an asterisk indicate binding to the -SP- residue. IL-2 conjugate for use of item 40.

[0622] 43. -SP- is C 1-10 It is alkyl, C 1-10 Alkyl is one or more -R 9 Replaced by optional means, C 1-10 Alkyl is -O-, -C(O)N(R 10 )-, -S(O)2-, -S(O)-, -S-, -N(R 10 )-, -OC(OR 10 )(R 10a )-,-N(R 10 )C(O)N(R 10a )-, and -OC(O)N(R 10 )- is optionally interrupted by one or more groups selected from the group consisting of -R, where each -R 9 C 1-6 Selected from the group consisting of alkyl groups, each -R 10 and -R 10a -H and C 1-6 An IL-2 conjugate for use of any one of items 40-42, independently selected from the group consisting of alkyls.

[0623] 44. -POL is given by equation (A-1i) [ka] [In the formula, The dashed line indicates a connection to -SP-. m is either 0 or 1. p is an integer in the range of approximately 10 to approximately 540. q is selected from the group consisting of 1, 2, 3, 4, 5, and 6. An IL-2 conjugate for use with any one of items 40-43.

[0624] 45. -M mod However, equation (A-1a) [ka] [In the formula, The dashed lines marked with an asterisk indicate the binding of the -D'- cysteine ​​residue to the sulfur. b1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b2 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b3 is an integer in the range of approximately 10 to 540. An IL-2 conjugate for use in any one of items 1-41, 43, or 44.

[0625] 46. ​​-M mod However, formula (A-1d) or (A-1e) [ka] [In the formula, The dashed lines marked with an asterisk indicate the binding of the -D'- cysteine ​​residue to the sulfur. b1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b2 is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20. b3 is an integer in the range of approximately 10 to 540. An IL-2 conjugate for use with either item 1-40 or 42-44.

[0626] 47. An IL-2 conjugate for use of item 45 or 46, where b1 is an integer in the range of 1 to 4.

[0627] 48. An IL-2 conjugate for use in any one of items 45-47, where b1 is 2.

[0628] 49. IL-2 conjugate for use of any one of items 45-47, where b1 is 3.

[0629] 50. IL-2 conjugate for use of any one of items 45-49, where b2 is 2.

[0630] 51. IL-2 conjugate for use of any one of items 45-49, where b2 is 3.

[0631] 52. An IL-2 conjugate for use of any one of items 45-51, where b3 is an integer in the range of 10-450.

[0632] 53. An IL-2 conjugate for use of any one of items 45-52, where b3 is an integer in the range of 22-340.

[0633] 54. An IL-2 conjugate for the use of any one of items 45-53, where b3 is an integer in the range of 45-230.

[0634] 55. An IL-2 conjugate for the use of any one of items 45-54, where b3 is an integer in the range of 65-160.

[0635] 56. -M mod IL-2 conjugate for use in any one of items 45-55, b3 is selected so that it has a molecular weight of 5±25%kDa.

[0636] 57. An IL-2 conjugate for use in any one of items 45-56, where b3 is an integer in the range of 90-140.

[0637] 58. -M mod IL-2 conjugate for use in any one of items 45-57, where b3 is selected so that it has a molecular weight in the range of approximately 4 kDa to approximately 6 kDa.

[0638] 59. -M mod IL-2 conjugate for use in any one of items 45-58, b3 is selected so that it has a molecular weight of 5±20%kDa.

[0639] 60. An IL-2 conjugate for the use of any one of items 45-59, where b3 is an integer in the range of 95-135.

[0640] 61. -M mod IL-2 conjugate for use in any one of items 45-60, b3 is selected so that it has a molecular weight of 5±15%kDa.

[0641] 62. An IL-2 conjugate for use of any one of items 45-61, where b3 is an integer in the range of 100-125.

[0642] 63. -M mod IL-2 conjugate for use in any one of items 45-62, where b3 is selected so that it has a molecular weight of approximately 5 kDa.

[0643] 64. IL-2 conjugate for use in any one of items 1-63, wherein -Z has a molecular weight in the range of approximately 20 kDa to approximately 60 kDa.

[0644] 65. IL-2 conjugate for use in any one of items 1-64, where -Z has a molecular weight in the range of approximately 25 kDa to approximately 55 kDa.

[0645] 66. IL-2 conjugate for use in any one of items 1-65, wherein -Z has a molecular weight in the range of approximately 30 kDa to approximately 50 kDa.

[0646] 67. IL-2 conjugate for use in any one of items 1-66, wherein -Z has a molecular weight in the range of approximately 35 kDa to approximately 45 kDa.

[0647] 68. IL-2 conjugate for use in any one of items 1-67, where -Z has a molecular weight in the range of approximately 40 kDa.

[0648] 69. -Z is the expression (Ac): [ka] [In the formula, p1, p2, p3, and p4 are independent integers in the range of 110 to 345. An IL-2 conjugate for use in any one of items 1-68, including the portion marked with [this].

[0649] 70. An IL-2 conjugate for the use of item 69, where p1, p2, p3, and p4 of expression (Ac) are integers in the range of 140 to 315, independently of each other.

[0650] 71. An IL-2 conjugate for the use of any one of items 69-70, where p1, p2, p3, and p4 of expression (Ac) are integers in the range of 170-285, independently of each other.

[0651] 72. An IL-2 conjugate for the use of any one of items 69-71, where p1, p2, p3, and p4 of expression (Ac) are integers in the range of 195-255, independently of each other.

[0652] 73. An IL-2 conjugate for use of any one of items 69-72, where p1, p2, p3, and p4 of expression (Ac) are integers in the range of 200-250, independently of each other.

[0653] 74. An IL-2 conjugate for use of any one of items 69-73, where p1, p2, p3, and p4 of expression (Ac) are integers in the range of 210-250, independently of each other.

[0654] 75. An IL-2 conjugate for use of any one of items 69-74, where p1, p2, p3, and p4 of expression (Ac) are integers in the range of 220-240, independently of each other.

[0655] ...

Claims

1. IL-2 conjugate or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the IL-2 conjugate is administered in doses ranging from 80 μg IL-2 / kg to 160 μg IL-2 / kg, and the IL-2 conjugate is of formula (I), the above IL-2 conjugate or a pharmaceutically acceptable salt thereof: D-L 1 -L 2 -Z (I) [In the formula, -D is -D'-M mod And, Here, -D'- is the IL-2 part; -M mod This is a first polymer moiety stably conjugated to the side chain of the -D'- amino acid residue; -L 1 - is a linker portion covalently and reversibly bonded to -D'-; -L 2 - is either non-existent or a spacer; -Z is the second polymer portion.

2. An IL-2 conjugate for use according to claim 1, wherein the dose is in the range of 100 μg IL-2 / kg to 140 μg IL-2 / kg.

3. An IL-2 conjugate for use according to claim 1 or 2, wherein the dose is in the range of 110 μg IL-2 / kg to 130 μg IL-2 / kg.

4. An IL-2 conjugate for use according to any one of claims 1 to 3, wherein the dose is approximately 120 μg IL-2 / kg.

5. An IL-2 conjugate for use according to any one of claims 1 to 4, wherein the dose is 120 μg IL-2 / kg.

6. An IL-2 conjugate for use according to any one of claims 1 to 5, wherein the dose is administered multiple times.

7. An IL-2 conjugate for use according to any one of claims 1 to 6, wherein the interval between two consecutive doses is in the range of 2 to 8 weeks.

8. An IL-2 conjugate for use according to any one of claims 1 to 7, wherein the interval between two consecutive doses is three weeks.

9. An IL-2 conjugate for use according to any one of claims 1 to 7, wherein the interval between two consecutive doses is 6 weeks.

10. An IL-2 conjugate for use according to any one of claims 1 to 6, wherein the IL-2 conjugate is administered at a frequency corresponding to the progression of the disease.

11. An IL-2 conjugate for use according to any one of claims 1 to 5, wherein the dose is administered as a single dose.

12. An IL-2 conjugate for use according to any one of claims 1 to 11, wherein treatment is initiated directly on diagnosis of cancer.

13. An IL-2 conjugate for use according to any one of claims 1 to 12, wherein the treatment is a first-line treatment.

14. An IL-2 conjugate for use according to any one of claims 1 to 12, wherein the treatment is a second-line, third-line, or further-line treatment.

15. IL-2 conjugate for use according to any one of claims 1 to 14, administered by topical use, injection or infusion, including intra-articular, peri-articular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intrasternal, intratracheal, subepidermal, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion; direct delivery to the brain via an implantable device (e.g., an Onmyya reservoir) enabling delivery of IL-2 conjugate to brain tissue or cerebral fluid, direct intraventricular injection or infusion, injection or infusion into the brain or brain-related region, injection into the subchoroidal space, posterior orbital injection or ophthalmoscopy.

16. An IL-2 conjugate for use according to any one of claims 1 to 15, wherein the IL-2 conjugate is administered intravenously.

17. A method for synthesizing IL-2 conjugates, (a)(a)i. At least one reagent of formula (XII) 【Chemistry 1】 [In the formula, p1, p2, p3, and p4 are integers in the ranges of 110–345, 140–315, 170–285, 195–255, 200–250, 210–250, or 220–240, independently of each other.] (a)ii. A mixture of about 30% (v / v) acetonitrile in water; and (a)iii. D'-M mod A solution containing, -D'- has the amino acid sequence of SEQ ID NO: 4, -M mod (A-1d) or (A-1e) 【Chemistry 2】 [In the formula, The dashed line marked with an asterisk indicates the bond to the sulfur atom of the cysteine ​​side chain at position 38. b1 is either 2 or 3. b2 is either 2 or 3. b3 is in the range of 90-140, 95-135, or 100-125. Solution having the structure Steps to provide; (b) A step of mixing at least one of the reagents from step (a)i with the mixture from step (a)ii; (c) A step of mixing the mixture of step (b) with the solution of step (a) iii., wherein the molar ratio of the reagent of formula (XII) to D'-M mod is in the range of 4:1 to 1:1; (d) Incubating the mixture from step (c) at a temperature in the range of 10°C to 20°C for 1 to 5 hours to obtain the IL-2 conjugate of formula (I); and (e) Optionally, a step to purify the IL-2 conjugate of formula (I) from the incubated mixture of step (d). The above method, including.

18. (a) Measuring the level of sCD25 in a biological sample obtained from a patient after administration of at least one dose of formula (I) IL-2 conjugate in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg to the patient; and / or (b) CD8 in biological samples obtained from patients after administration of at least one dose of the IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg to the patient. + A step of measuring the level and / or proliferation of T cells; (c) A step of comparing the level from step (a) and / or the level from step (b) and / or the increase in sCD25 and / or CD8 compared to the reference, wherein the increased level of sCD25 and / or CD8 + A step demonstrating that elevated levels and / or proliferation of T cells indicate that the patient is likely to benefit from treatment with the IL-2 conjugate of formula (I); and (d) The patient, (i) If the patient has elevated levels of sCD25 compared to the reference, administer to the patient one or more additional doses of IL-2 conjugate of formula (I) in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg; and / or (ii) Compare CD8 with the reference + If the patient has elevated levels and / or proliferation of T cells, administer one or more additional doses of formula (I) IL-2 conjugate in the range of 80 μg IL-2 / kg to 160 μg IL-2 / kg to the patient. Step A method for treating cancer or slowing its progression in a patient, including [the specified method].

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