Combined therapy of ARM and natural killer cells

Abstract

In particular, the present invention provides techniques involving immune cells and antibody-recruiting molecules. In some embodiments, the immune cells are memory-like natural killer cells. In some embodiments, the provided techniques are particularly useful for conditions, disorders, or diseases such as cancer. In some embodiments, the provided techniques provide high efficacy. In some embodiments, the provided techniques provide fewer or less severe side effects associated with natural killer cell therapy.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority based on U.S. Application No. 62 / 783,036, filed on December 20, 2018, the entire content of which is incorporated herein by reference.

Background Art

[0002] Immune system activity can be utilized to prevent or treat a variety of conditions, disorders, and diseases, including cancer.

Summary of the Invention

[0003] Natural killer (NK) cells can induce cell death of a variety of targets, such as diseased cells like cancer cells. In particular, NK cells (e.g., NK cells expanded and / or pre - activated in vitro) have been developed for use in cancer treatment. In some embodiments, the present invention encompasses the recognition that NK cell therapy can be significantly improved by agents that can facilitate and / or enhance the recognition of targets by NK cells. In some embodiments, the present invention provides technologies (e.g., methods, compositions, etc.) comprising NK cells and such agents. In particular, in some embodiments, the present invention provides technologies comprising NK cells and an antibody recruitment molecule (ARM) that includes (i) one or more antibodies or antibody - binding portions capable of binding to a fragment thereof, (ii) a target - binding portion capable of binding to a cell, and optionally (iii) a linker portion that links the antibody - binding portion and the target - binding portion.

[0004] In some embodiments, the ARM can significantly improve the effectiveness of NK cell therapy, for example, by facilitating the recognition of target cells by NK cells. In some embodiments, the ARM can enhance the interaction between NK cells and their target cells and / or promote the killing of target cells induced by NK cells. In some embodiments, the ARM can promote the activation of NK cells, for example, by recruiting antibodies that can subsequently recruit and activate NK cells to the target cells.

[0005] In addition to or alternatively to this, in some embodiments, the ARM can reduce and / or delay the onset of one or more side effects of NK cell therapy, for example, by guiding NK cells to target cells and reducing off-target effects. In some embodiments, NK cells are typically activated, enriched, and / or increased prior to administration. Such pre-activated NK cells are more potent and may be necessary for the effective killing of target cells. However, due to these activations, these cells can cause a very large number of side effects, for example, unintended cell death. In particular, the present invention provides a technique in which the ARM can guide NK cells to target cells and reduce side effects and toxicity related to NK cell therapy. Furthermore, from the perspective of reducing off-target effects, in some embodiments, more activated NK cells can be utilized to further improve therapeutic effectiveness.

[0006] In particular, the antibody-binding portion (also referred to as the antibody-binding terminus (ABT) in some embodiments) can bind to an antibody (or a fragment thereof). In some embodiments, the antibody-binding portion binds to the variable region. In some embodiments, the antibody-binding portion binds to the Fab region. In some embodiments, the antibody-binding portion recruits diverse antigen-specific antibodies (or fragments thereof) by binding, in particular, to, for example, the Fc region (“universal ABT” or “uABT”). In some embodiments, the use of uABT can avoid undesirable effects that can arise from reliance on a particular antibody population and the diversity of individuals within a particular antibody population. In some embodiments, uABT preferentially enables the recruitment of IgG1, IgG2, and / or IgG4. In some embodiments, the recruitment of antibodies, such as IgG subclasses, is not limited by the amount of ARM administered and / or by the level of antibodies having a particular Fab region in an individual. In some embodiments, the ABT binds to endogenous antibodies and recruits endogenous antibodies. In some embodiments, uABT binds to IgG molecules via IgG molecules, preferably human IgA or IgM. Typically, after being bound by the antibody-binding portion, the antibodies are able to interact with one or more of their immune activities, for example, interact with NK cells that can result in the killing of target cells by the NK cells.

[0007] Typically, the target-binding portion (also referred to as the target-binding terminus (TBT) in certain embodiments) can confer the specificity of the ARM to its target, for example, a diseased cell of interest, by binding to an entity (e.g., a cell surface receptor) that distinguishes the target from non-target cells (e.g., diseased cells derived from other cell types).

[0008] In particular, the ARM can enable target-specific recruitment by ABT of antibodies, such as endogenous antibodies, administered antibodies, etc., and / or induce, generate, promote, and / or enhance NK cell-related immune activities, such as the killing of target cells by NK cells. A variety of techniques, such as assays, reagents, methods, etc. are available for evaluating the antibody binding portion, the target binding portion, and the ARM, and can be utilized according to the present invention.

[0009] In some embodiments, the ARM is: an antibody binding portion, a target binding portion, and optionally a linker portion wherein the antibody binding portion can bind to the Fab region of an antibody.

[0010] In some embodiments, the ARM is: an antibody binding portion, a target binding portion, and optionally a linker portion, wherein the antibody binding portion can bind to the Fc region of an antibody.

[0011] In some embodiments, the ARM is: an antibody binding portion, a target binding portion, and optionally a linker portion wherein the antibody binding portion can bind to two or more antibodies having different Fab regions.

[0012] In some embodiments, the antibody binding portion, such as a universal antibody binding portion, binds to the Fc region of an antibody. In some embodiments, the antibody binding portion, such as a universal antibody binding portion, binds to the conserved Fc region of an antibody. In some embodiments, the antibody binding portion binds to the Fc region of an IgG antibody.

[0013] In some embodiments, the agent of the present invention, such as the ARM, has the formula I:

Chemical formula

[0014] In some embodiments, the agent is of Formula I-a: [Chemical formula] [Wherein each variable group is as defined and described in the present specification] A compound of or a salt thereof. In some embodiments, the agent, such as ARM, is of Formula I-a or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula I-a.

[0015] In some embodiments, the agent is of Formula I-b: [Chemical formula] [Wherein each variable group is as defined and described in the present specification] A compound of or a salt thereof. In some embodiments, the agent, such as ARM, is of Formula I-b or a pharmaceutically acceptable salt thereof. In some embodiments, the provided compound of Formula I is a compound of Formula I-b.

[0016] In some embodiments, the agent, such as ARM, is of Formula II: [Chemical formula] [Wherein each variable group is as defined and described in the present specification] A compound having the structure of or a pharmaceutically acceptable salt thereof. In some embodiments, the agent is a compound of formula II or a salt thereof. In some embodiments, the compound of formula I is a compound of formula II or a salt thereof. In some embodiments, the compound having the structure of formula I-a is a compound of formula II.

[0017] In some embodiments, an agent, such as an ARM, has the formula III:

Chemical formula

[0018] The combination of NK cells and the agent of the present invention, such as an ARM, can be particularly effective in the treatment of various conditions, disorders or diseases. In some embodiments, the present invention provides A population of natural killer cells that are increased, enriched, and / or pre-activated; and An antibody mobilizing molecule (ARM) comprising an antibody binding portion capable of binding to one or more antibodies or fragments thereof, a target binding portion capable of binding to a target, and optionally a linker portion linking the antibody binding portion and the target binding portion A combination agent comprising the same.

[0019] In some embodiments, the present invention provides A plurality of natural killer cells; and An antibody mobilizing molecule (ARM) comprising an antibody binding portion capable of binding to one or more antibodies or fragments thereof, a target binding portion capable of binding to a target, and optionally a linker portion linking the antibody binding portion and the target binding portion Administer one or both of them into the system, expose the system to both, and reduce the number of cells in the system compared to when neither natural killer cells nor antibody mobilizing molecules are present, thereby inducing cell death, inhibiting cell proliferation, and / or reducing the number of cells in the system.

[0020] One of ordinary skill in the art will understand that the techniques provided are appropriate for the various systems described herein. For example, in some embodiments, the system is an organism. In some embodiments, the system is a subject. In some embodiments, the system is a human. In some embodiments, the system is a patient. In some embodiments, the system is a non-human animal. In some embodiments, the system is a non-human animal useful as a disease model. In some embodiments, the system is an organ. In some embodiments, the system is a tissue. In some embodiments, the system is an in vivo system. In some embodiments, the system is an ex vivo system. In some embodiments, the system is an in vitro system. In some embodiments, the system is a cell culture or includes the same.

[0021] In some embodiments, the present invention provides a method for treating cancer in a subject a plurality of natural killer cells; and an antibody mobilizing molecule (ARM) comprising an antibody binding portion capable of binding to one or more antibodies or fragments thereof, a target binding portion capable of binding to cancer cells, and optionally a linker portion linking the antibody binding portion and the target binding portion administering one or both of them and exposing the subject to both.

[0022] In some embodiments, the subject is a human. In some embodiments, the subject is a human patient. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a non-human animal useful as a disease model.

[0023] In some embodiments, the number of cancer cells in a subject is reduced compared to when neither natural killer cells nor antibody mobilizing molecules are present. In some embodiments, the proliferation of cancer cells in a subject is reduced compared to when neither natural killer cells nor antibody mobilizing molecules are present. In some embodiments, the proliferation of cancer cells in a subject is reduced compared to when neither natural killer cells nor antibody mobilizing molecules are present. In some embodiments, the volume of cancer cells in a subject is reduced compared to when neither natural killer cells nor antibody mobilizing molecules are present.

[0024] In some embodiments, the present invention provides a method for treating cancer in a patient comprising a plurality of natural killer cells; and an antibody mobilizing molecule comprising an antibody binding portion capable of binding to one or more antibodies or fragments thereof, a target binding portion capable of binding to cancer cells, and optionally a linker portion linking the antibody binding portion and the target binding portion administering the same.

[0025] In some embodiments, the present invention provides a method for reducing the toxicity or side effects of a treatment using natural killer cells in a subject comprising a plurality of natural killer cells; and an antibody mobilizing molecule comprising an antibody binding portion capable of binding to one or more antibodies or fragments thereof, a target binding portion capable of binding to a treatment target, and optionally a linker portion linking the antibody binding portion and the target binding portion administering the same.

[0026] In some embodiments, the present invention provides an improvement in a method for treating a subject by administering a plurality of natural killer cells, which also comprises administering an antibody mobilizing molecule (ARM) comprising an antibody binding portion capable of binding to one or more antibodies or fragments thereof, a target binding portion capable of binding to a target, and optionally a linker portion linking the antibody binding portion and the target binding portion.

[0027] An agent, for example, the ARM of the present invention, can be administered before, simultaneously with, and / or following NK cells, for example, increased, enriched, and / or pre-activated NK cells.

Brief Description of the Drawings

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Figure 1

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Modes for Carrying Out the Invention

[0032] Detailed Description of Specific Embodiments 1. Specific Embodiments of the Present Invention: As described above, in some embodiments, the present invention provides techniques for inducing cell death, inhibiting cell proliferation, and / or reducing cell numbers within a system. Separately or in addition to this, in some embodiments, the present invention provides techniques for treating cancer and / or reducing the toxicity and / or side effects of cellular immunotherapy (e.g., NK cell therapy).

[0033] In some embodiments, the present invention utilizes an ARM agent in conjunction with a cellular immunotherapy such as NK cell therapy (including, for example, in vitro expansion of NK cells). In some embodiments, one or more of the ARM agents described herein are administered to a subject having or about to have a population of NK cells that have been, are being, or are about to be targeted to a site of interest (e.g., a tumor) by NK cell therapy or by another method. Conversely, in some embodiments, a cellular immunotherapy (e.g., NK cell therapy) is administered to a subject that has received, is receiving, or is about to receive treatment with an ARM agent described herein.

[0034] In some embodiments, the present invention utilizes an ARM agent that includes an antibody-binding portion capable of binding to an antibody (or a fragment thereof) having various Fab structures ("uABT"). In particular, in some embodiments, the relevant ARM agent includes an antibody-binding portion that binds to the Fc region of the antibody; in certain embodiments, such binding to the Fc region of the antibody does not interfere with one or more of the immune activities of the antibody, such as interaction with an Fc receptor (e.g., CD16a), recruitment of effector cells such as NK cells to ADCC, etc. As will be understood by those skilled in the art, the techniques (agents, compounds, compositions, methods, etc.) of the present invention that include uABT can provide various advantages. For example, the techniques provided can utilize antibodies having various Fab regions in the immune system to avoid or minimize the effects of unwanted antibody variations in the patient population, induce and / or enhance immune activity against a target, such as a target disease cell like a cancer cell.

[0035] In some embodiments, the technology of the present invention is useful for recruiting antibodies and NK cells against various targets, such as cancer cells. In some embodiments, the technology provided is useful for modulating the immune activity against a target (such as diseased cells, foreign objects or substances, etc.), such as ADCC involving NK cells. In some embodiments, the technology provided is useful for modulating NK cells against target cells, such as diseased cells like cancer cells. In some embodiments, the target binding portion is an inhibitory portion. In some embodiments, the target binding portion is an enzyme inhibitory portion. In some embodiments, the target binding portion binds to cell surface substances, such as proteins, carbohydrates, lipids, etc.

[0036] In some embodiments, a drug, such as ARM, an antibody binding portion, a target binding portion and optionally a linker portion wherein the antibody binding portion can bind to the Fab region.

[0037] In some embodiments, a drug, such as ARM, an antibody binding portion, a target binding portion and optionally a linker portion, wherein the antibody binding portion can bind to the Fc region.

[0038] In some embodiments, a drug, such as ARM, an antibody binding portion, a target binding portion and optionally a linker portion, wherein the antibody binding portion can bind to two or more antibodies having different Fab regions.

[0039] In some embodiments, the agent useful for the practice of the technology of the present invention comprises two or more antibody-binding moieties. In some embodiments, the useful agent comprises two or more target-binding moieties.

[0040] An antibody-binding moiety can interact with any part of an antibody. In some embodiments, the antibody-binding moiety binds to the Fc region of the antibody. In some embodiments, the antibody-binding moiety binds to the conserved Fc region of the antibody. In some embodiments, the antibody-binding moiety binds to the Fc region of an IgG antibody. As will be appreciated by those skilled in the art, a variety of antibody-binding moieties, linkers and target-binding moieties can be utilized in the present invention. In particular, as shown in the examples, in some embodiments, the present invention is particularly useful and effective for constructing ARM molecules for recruiting antibodies to target cells and / or inducing, generating, promoting, and / or enhancing immune system activity against target cells, such as diseased cells like cancer cells, and provides antibody-binding moieties, linkers and target-binding moieties and combinations thereof.

[0041] In some embodiments, the antibody-binding moiety can bind to an Fc region bound to an Fc receptor, such as FcγRIIIa, CD16a, etc. In some embodiments, the provided moieties and / or agents (e.g., compounds / ARMs of various formulas described herein) comprise an antibody-binding moiety that binds to a complex comprising an Fc region and an Fc receptor. In some embodiments, the complex comprises an antibody-binding moiety, a target-binding moiety, and optionally a linker moiety and an agent comprising, an Fc region and an Fc receptor wherein the antibody-binding moiety of the agent can bind to two or more antibodies having different Fab regions.

[0042] In some embodiments, the Fc region is the Fc region of an endogenous antibody of the subject. In some embodiments, the Fc region is the Fc region of an exogenous antibody. In some embodiments, the Fc region is the Fc region of an administered agent. In some embodiments, the Fc receptor is a diseased cell in the subject. In some embodiments, the Fc receptor is a cancer cell in the subject.

[0043] In certain embodiments, an agent, such as an ARM, has the formula I:

Chemical formula

[0044] In some embodiments, ABT is a universal antibody binding portion.

[0045] In some embodiments, the antibody binding portion comprises one or more amino acid residues. In some embodiments, the antibody binding portion is a peptide portion or comprises the same. In some embodiments, the antibody binding portion is a cyclic peptide portion or comprises the same. In some embodiments, such an antibody binding portion comprises one or more natural amino acid residues. In some embodiments, such an antibody binding portion comprises one or more unnatural natural amino acid residues.

[0046] In some embodiments, the amino acid has the formula A-I:

Chemical formula

[0047] In some embodiments, the antibody binding portion is a cyclic peptide portion. In some embodiments, the compound, such as a drug, an ARM, has the formula I-a:

Chemical formula

[0048] In some embodiments, a is 1. In some embodiments, b is 1. In some embodiments, a is 1 and b is 1, and the compound of formula I-a is

Chemical formula

[0049] In some embodiments, each amino acid residue, e.g., each Xaa in formula I-a, is a residue of an amino acid having the structure of formula A-I. In some embodiments, each Xaa is independently -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -CO-. In some embodiments, two or more side chains in an amino acid residue, e.g., R a2 or R a3 of one amino acid residue and R a2 or R a3may optionally form a cross-link together (e.g., Compound I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.). For example, in some embodiments, two cysteine residues form an -S-S- cross-link as typically found in native proteins. In some embodiments, the cross-link formed has the structure of L b where L b is the L described herein a . In some embodiments, each end of L b independently binds to a backbone atom of the cyclic peptide (e.g., a ring atom of the ring formed by -(Xaa) z - in Formula I-a). In some embodiments, L b contains an R group (e.g., when a methylene unit of L b is substituted with -C(R)2- or -N(R)-), where the R group, together with the R groups (e.g., if R, then R a1 , R a2 , R a3 , etc.) bound to the backbone atoms and the atoms between them, forms a ring. In some embodiments, L b is bound by a side chain of an amino acid residue (e.g., Xaa in Formula I-a) to a ring, e.g., a ring formed by -(Xaa) z - in Formula I-a. In some embodiments, such side chains contain an amino group or a carboxylic acid group.

[0050] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

[0051] In certain embodiments, a compound, such as a drug, an ARM, etc., is of formula II: [Chemical formula] [wherein, R 1 , R 3 and R 5 each is independently hydrogen or C 1-6a group optionally selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R 1 and R 1’ may optionally, together with the carbon atom therebetween, form a saturated or partially unsaturated 3- to 8-membered spirocyclic carbocyclic ring which may be optionally substituted, or a saturated or partially unsaturated 3- to 8-membered spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ may optionally, together with the carbon atom therebetween, form a saturated or partially unsaturated 3- to 8-membered spirocyclic carbocyclic ring which may be optionally substituted, or a saturated or partially unsaturated 3- to 8-membered spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; The R 5 group and the R 5’ group attached to the same carbon atom may optionally, together with the carbon atom therebetween, form a saturated or partially unsaturated 3- to 8-membered spirocyclic carbocyclic ring which may be optionally substituted, or a saturated or partially unsaturated 3- to 8-membered spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or Two R 5 groups may optionally, together with the atom therebetween, form a divalent C 1-10may form a straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently, optionally, -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2- or -Cy 1 -substituted, wherein each -Cy 1 - is independently a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1’ 、R 3’ and R 5’ each of which is independently hydrogen or optionally substituted C 1-3 is aliphatic; R 2 、R 4 and R 6 each of which is independently hydrogen or optionally substituted C 1-4 is aliphatic or: R 2 and R 1 may optionally form a saturated or partially unsaturated 4- to 8-membered monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 may optionally, together with the atoms between them, form a saturated or partially unsaturated 4- to 8-membered monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6 group and the adjacent R 5 group may optionally, together with the atoms between them, form a saturated or partially unsaturated 4- to 8-membered monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; L 1 is

Chemical formula

Chem.

[0052] In some embodiments, the antibody binding moiety is or comprises a peptide moiety. In some embodiments, a compound, such as a drug, an ARM, etc., has the formula I-b:

Chem.

[0053] In some embodiments, a1 is 1. In some embodiments, a2 is 1. In some embodiments, b is 1. In some embodiments, the compound of formula I-b is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0054] In some embodiments, each amino acid residue, for example, each Xaa in formula I-b, is a residue of an amino acid having the structure of formula A-I. In some embodiments, each Xaa is independently -N(R a1 )-L a1 -C(R a2 )(R a3 )-La2 -CO-. In some embodiments, two or more side chains in an amino acid residue, e.g., in a compound of Formula I-a (e.g., R of one amino acid residue a2 or R a3 and R of another amino acid residue a2 or R a3 ) may optionally combine to form a bridge (e.g., compounds I-10, I-12, I-14, I-18, I-19, I-22, I-23, I-25, etc.). For example, in some embodiments, two cysteine residues form an -S-S- bridge, as is typical in native proteins. In some embodiments, the formed bridge has the structure of L b , where L b is L as described herein a . In some embodiments, each end of L b is independently bonded to a backbone atom of the cyclic peptide (e.g., a ring atom of the ring formed by -(Xaa) z - in Formula I-a). In some embodiments, L b contains an R group (e.g., when a methylene unit of L b is replaced by -C(R)2- or -N(R)-), where the R group, together with the R groups (e.g., if R, then R a1 , R a2 , R a3 , etc.) bonded to the backbone atoms and the intervening atoms, forms a ring. In some embodiments, L b is bonded to a ring formed by a side chain of an amino acid residue (e.g., Xaa in Formula I-a), e.g., a ring formed by -(Xaa) z - in Formula I-a. In some embodiments, such side chains contain an amino group or a carboxylic acid group.

[0055] In some embodiments, R c -(Xaa)z- is an antibody-binding portion (R c -(Xaa)z-H binds to an antibody). In some embodiments, R c -(Xaa)z- is a universal antibody-binding portion. In some embodiments, Rc -(Xaa)z- is a universal antibody-binding moiety that can bind to antibodies having different Fab regions. In some embodiments, R c -(Xaa)z- is a universal antibody-binding moiety that can bind to the Fc region. In some embodiments, the antibody-binding moiety, e.g., R c The universal antibody-binding moiety having the structure of -(Xaa)z- can bind to the Fc region bound to the Fc receptor. In some embodiments, R c -(Xaa)z- is

Chemical formula

Chemical formula

[0056] In certain embodiments, a compound, e.g., a drug, an ARM, etc., is of formula III:

Chemical formula

Chemical formula

[0057] 2. Definitions: The compounds of the present invention include the compounds generally described herein and are indicated by the classes, subclasses, and species described herein. Unless otherwise specified, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Further, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March’s Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0058] Administration: As used herein, the term "administration" typically refers to the administration of a composition to a subject or system. One of ordinary skill in the art understands the various routes that can be used for administration to a subject, such as a human, in appropriate circumstances. For example, in some embodiments, administration can be ocular, oral, parenteral, topical, etc. In some specific embodiments, administration can be bronchial (e.g., bronchial instillation), buccal, percutaneous (one or more or including topical administration to the skin, intradermal, subcutaneous, transdermal, etc.), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a particular organ (e.g., within the liver), mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by tracheal instillation), vaginal, vitreous, etc. In some embodiments, administration can include administration that is intermittent (e.g., multiple administrations separated in time) and / or periodic (e.g., multiple independent administrations separated by a common period). In some embodiments, administration can be continuous administration (e.g., perfusion) for at least a selected period of time.

[0059] Agents: Generally, as used herein, the term "agent" can be used to refer to compounds or substances of any chemical classification, including, for example, polypeptides, nucleic acids, carbohydrates, lipids, small molecules, metals, or complexes thereof. In appropriate circumstances, as will be apparent to one of ordinary skill in the art from the context, the term can be used to refer to a cell or organism or a fragment, extract, or component thereof, or a substance containing the same. Separately or in addition thereto, as will be apparent from the context, the term can be used to refer to natural products found in nature and / or obtained from nature. In some instances, again as will be apparent from the context, the term can be used to refer to one or more substances that are designed, developed, and / or manufactured by human handiwork and / or are not found in nature. In some embodiments, the agent is used in isolated or pure form; in some embodiments, the agent can be used in crude form. In some embodiments, potential agents can be used as a collection or library, for example, a collection or library that can be screened to identify and characterize active agents therein. In some cases, the term "agent" refers to a compound or substance that is a polymer or contains a polymer; in some cases, the term can denote a compound or substance containing one or more polymer moieties. In some embodiments, the term "agent" can denote a compound or substance that is not a polymer and / or does not contain substantially any polymer and / or one or more specific polymer moieties. In some embodiments, the term can denote a compound or substance that does not contain a polymer moiety or contains substantially no polymer moieties. In some embodiments, the agent is a compound. In some embodiments, the agent is an ARM as described herein.

[0060] Aliphatic: As used herein, "aliphatic" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a substituted or unsubstituted monocyclic, bicyclic or polycyclic hydrocarbon ring that is fully saturated or contains one or more unsaturated units, or a combination thereof. Unless otherwise specified, aliphatic groups contain from 1 to 100 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain from 1 to 5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3 or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and combinations thereof.

[0061] Alkenyl: As used herein, the term "alkenyl" refers to an aliphatic group as defined herein having one or more double bonds.

[0062] Alkenylene: The term "alkenylene" refers to a divalent alkenyl group.

[0063] Alkyl: As used herein, the term "alkyl" gives its ordinary meaning in the art and can include saturated aliphatic groups including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl groups. In some embodiments, alkyl has from 1 to 100 carbon atoms. In certain embodiments, straight-chain or branched-chain alkyl has about 1 to 20 carbon atoms in its backbone (e.g., C1-C for straight-chain and C2-C for branched-chain). 20 For branched-chain, C2-C20 ) or has from about 1 to 10 carbon atoms. In some embodiments, the cycloalkyl ring has from about 3 to 10 carbon atoms in their ring structure, such rings being monocyclic, bicyclic or polycyclic, or having about 5, about 6 or about 7 carbons in the ring structure. In some embodiments, the alkyl group can be a lower alkyl group containing 1 to 4 carbon atoms (e.g., C1-C4 for straight-chain lower alkyl).

[0064] Alkylene: The term "alkylene" refers to a divalent alkyl group.

[0065] Amino acid: Most broadly, as used herein, refers to a compound and / or substance that can be included in a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid contains an amino group and a carboxylic acid group. In some embodiments, an amino acid has the general structure NH(R’)-C(R’)2-COOH, where each R’ is independently as described herein. In some embodiments, an amino acid has the general structure H2N-C(R’)2-COOH, where each R’ is as described herein. In some embodiments, an amino acid has the general structure H2N-C(H)(R’)-COOH, where each R’ is as described herein. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. "Standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. "Non-standard amino acid" refers to any amino acid other than a standard amino acid, whether synthetically produced or obtained from natural sources. In some embodiments, an amino acid that includes a carboxy and / or amino-terminal amino acid in a polypeptide may include structural modifications compared to the above general structure. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of an amino group, carboxylic acid, one or more protons, one or more hydrogens, and / or a hydroxyl group). In some embodiments, such modifications may change the circulating half-life of a polypeptide containing the modified amino acid compared to a polypeptide containing another identical unmodified amino acid. In some embodiments, such modifications do not significantly change the relative activity of a polypeptide containing the modified amino acid compared to a polypeptide containing another identical unmodified amino acid.As will be apparent from the context, in some embodiments, the term "amino acid" is used to refer to free amino acids; in certain embodiments, it may be used to refer to the amino acid residues of a polypeptide.

[0066] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human of either sex and at any stage of development. In some embodiments, "animal" refers to a non-human animal at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects and / or worms. In some embodiments, an animal can be a transgenic animal, a genetically engineered animal and / or a clone.

[0067] Antibody: As used herein, the term "antibody" refers to a polypeptide that contains standard immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, a naturally produced intact antibody is generally a ~150 kD tetrameric factor consisting of two identical heavy chain polypeptides (each ~50 kD) and two identical light chain polypeptides (each ~25 kD) that bind to each other in what is generally referred to as a "Y-shaped" structure. Each heavy chain consists of at least four domains (each ~110 amino acids in length) - an amino-terminal variable (VH) domain (located at the tip of the Y structure), followed by three constant domains: CH1, CH2, and carboxy-terminal CH3 (located at the base of the Y structure). A short region known as the "switch" links the heavy chain variable region to the constant region. The "hinge" links the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region link the two heavy chain polypeptides in the intact antibody to each other. Each light chain consists of two domains - an amino-terminal variable (VL) domain and a carboxy-terminal constant (CL) domain - separated from each other by another "switch". The intact antibody tetramer consists of two heavy chain-light chain dimers in which the heavy and light chains are bound to each other by a single disulfide bond and two other disulfide bonds link the heavy chain hinge regions to each other, such that the dimer regions are bound to each other and a tetramer is formed. Naturally produced antibodies are also typically glycosylated on the CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold" formed by two β-sheets (e.g., 3-, 4-, or 5-strand sheets) arranged against each other in a compressed antiparallel β-barrel. Each variable domain contains three highly variable loops (CDR1, CDR2, and CDR3) known as "complementarity-determining regions" and four partially invariant "framework" regions (FR1, FR2, FR3, and FR4). When a natural antibody folds, the FR regions form β-sheets that provide a structural framework for the domain, and the CDR loop regions from both the heavy and light chains come together in three-dimensional space to form a single highly variable antigen-binding site located at the tip of the Y structure.The Fc region of a natural antibody binds to elements of the complement system and also binds to receptors on effector cells, such as effector cells that mediate cytotoxicity. As is known in the art, the affinity of the Fc region for Fc receptors and / or other binding attributes can be modulated by glycosylation or other modifications. In some embodiments, the antibodies produced and / or utilized according to the present invention include glycosylated Fc domains, such as Fc domains having such modified or engineered glycosylation. For the purposes of the present invention, in certain embodiments, any polypeptide or polypeptide complex that includes a sufficient immunoglobulin domain sequence as found in natural antibodies, whether such polypeptide is produced naturally (e.g., by an organism in response to an antigen) or by recombinant technology, chemical synthesis, or other artificial systems or methods, can be referred to as and / or used as an "antibody." In some embodiments, the antibody is polyclonal; in some embodiments, the antibody is monoclonal. In some embodiments, the antibody has a constant region sequence characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, as is known in the art, the antibody sequence elements are humanized, primatized, chimeric, etc. Further, as used herein, the term "antibody" can, in appropriate embodiments (unless otherwise specified or clear from the context), refer to constructs or formats known or developed in the art for exploiting the structural and functional characteristics of antibodies in other presentations.For example, in some embodiments, the antibodies utilized by the present invention include, but are not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®); Fab fragments, Fab’ fragments, F(ab’)2 fragments, Fd’ fragments, Fd fragments, and isolated CDRs or combinations thereof; single-chain Fv; polypeptide-Fc fusions; single-domain antibodies (e.g., shark single-domain antibodies such as IgNAR or fragments thereof); camelid antibodies; masked antibodies (e.g., Probodies®); small modular immunopharmaceuticals (“SMIPs”). TM ”); single-chain or tandem bispecific antibodies (TandAb®); VHH; Anticalins®; Nanobodies®; minibodies; BiTE®; ankyrin repeat proteins or DARPIN®; Avimers®; DART; TCR-like antibodies; Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®; Centyrins®; KALBITOR®; CovX-Bodies; and CrossMabs. In some embodiments, the antibody may not have covalent modifications (e.g., glycan attachment) that it would have if naturally produced. In some embodiments, the antibody may include covalent modifications (e.g., attachment of a glycan, a payload [e.g., a detection moiety, a therapeutic moiety, a catalytic moiety, etc.], or another pendant group [e.g., polyethylene glycol, etc.]).

[0068] As used herein, the term "about" or "approximately" as applied to a value of one or more of the objectives refers to a value similar to the recited reference value. In certain embodiments, the term "about" or "approximately" means within 25%, 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less in either direction (greater or less), unless otherwise specified or clear from the context (except where such numbers exceed 100% of the possible values).

[0069] Aryl: The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy", "aryloxyalkyl", etc., refers to a monocyclic, bicyclic or polycyclic ring system having from 5 to 30 ring members in total, wherein at least one ring in the system is aromatic. In some embodiments, the aryl group is a monocyclic, bicyclic or polycyclic ring system having from 5 to 14 ring members in total, wherein at least one ring in the system is aromatic and each ring in the system contains from 3 to 7 ring members. In some embodiments, the aryl group is a biaryl group. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to, but is not limited to, an aromatic ring system such as phenyl, biphenyl, naphthyl, binaphthyl, anthracyl, etc., which may have one or more substituents. In some embodiments, a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phthalimidyl, phenanthridinyl or tetrahydronaphthyl, etc., and the radical or point of attachment is on the aryl ring is also included within the scope of the term "aryl" as used herein.

[0070] Related: As the term is used herein, two events or substances are "related" to each other if the presence, level and / or form of one correlates with that of the other. For example, a particular substance (e.g., a nucleic acid (e.g., genomic DNA, transcript, mRNA, etc.), polypeptide, genetic trait, metabolite, microorganism, cell, etc.) is considered to be related to a particular disease, disorder or condition if its presence, level and / or form correlates with the occurrence of the disease, disorder or condition and susceptibility to the disease, disorder or condition (e.g., across a relevant population).

[0071] Carrier: As used herein, refers to a diluent, adjuvant, excipient or vehicle administered with a composition. In some exemplary embodiments, the carrier can include a sterile liquid, such as water and oils of animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier is or includes one or more solid components.

[0072] Comparable: As used herein, the term "comparable" refers to two or more agents, substances, combinations of situations, conditions, etc. that are not necessarily identical to each other, but are similar enough to allow a comparison between them such that conclusions can be reasonably drawn based on the differences and similarities observed by one of ordinary skill in the art. In some embodiments, comparable combinations of conditions, situations, individuals or populations are characterized by a plurality of substantially identical features or one or a few different features. In context, one of ordinary skill in the art understands the degree of identity required in any given situation for two or more such agents, substances, combinations of situations, conditions, etc. to be considered comparable. For example, one of ordinary skill in the art understands that combinations of situations, individuals or populations are comparable to each other when the differences in the results or observed phenomena obtained under or with those combinations of various situations, individuals or populations are characterized by a sufficient number and variety of substantially identical features to form the basis for a reasonable conclusion that the differences are induced by or derive from the changes in those features that were varied.

[0073] Cycloaliphatic: As used herein, the term "cycloaliphatic" refers to, for example, a saturated or partially unsaturated aliphatic monocyclic, bicyclic, or polycyclic ring system having 3 to 30 ring members, which may optionally be substituted. Cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, the cycloalkyl has 3 to 6 carbons. The term "cycloaliphatic" may also include an aliphatic ring having one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, fused thereto, with the radical or point of attachment being on the aliphatic ring. In some embodiments, the carbocyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, the carbocyclic group is polycyclic. In some embodiments, "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon or C8-C that is either fully saturated or contains one or more units of unsaturation but is not aromatic. 10 A bicyclic hydrocarbon, or a C9-C that is either fully saturated or contains one or more units of unsaturation but is not aromatic. 16 Refers to a tricyclic hydrocarbon.

[0074] Derivative: As used herein, the term "derivative" refers to a structural analog of a reference substance. That is, a "derivative" is a substance that exhibits a significant structural similarity to the reference substance, for example, having a core or common structure but differing in certain distinct ways. In some embodiments, a derivative is a substance that can be formed from the reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be formed by the implementation of a synthetic process that is substantially similar to (e.g., shares a plurality of steps with) the synthetic process that forms the reference substance.

[0075] Form of administration or unit dose: One of ordinary skill in the art will understand that the term "form of administration" can be used to refer to a physically distinct unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is an appropriate unit dose (or a full fractional amount thereof) according to a dosing regimen determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., in a therapeutic dosing schedule). One of ordinary skill in the art will understand that the total amount of a therapeutic composition or agent to be administered to a particular subject is determined by one or more attending physicians and may include administration of multiple forms of administration.

[0076] Dosing regimen: One of ordinary skill in the art will understand that the term "dosing regimen" can typically be used to refer to a combination (typically two or more) of individual doses administered to a subject, separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may include one or more administrations. In some embodiments, the dosing regimen includes multiple administrations, each of which is separated in time from the other administrations. In some embodiments, the individual administrations are separated from each other by the same length of time; in some embodiments, the dosing regimen includes multiple administrations and at least two different times separating the individual administrations. In some embodiments, all administrations within the dosing regimen are the same unit dose. In some embodiments, different administrations within the dosing regimen are different amounts. In some embodiments, the dosing regimen includes an initial administration at an initial dose and one or more additional administrations at a second dose different from the initial dose. In some embodiments, the dosing regimen includes an initial administration at an initial dose and one or more additional administrations at a second dose equal to the initial dose. In some embodiments, when administered to a relevant population (i.e., a therapeutic dosing regimen), the dosing regimen correlates with a desired or beneficial outcome.

[0077] Halogen: The term "halogen" means F, Cl, Br, or I.

[0078] Heteroaliphatic: The term "heteroaliphatic" is given its ordinary meaning in the art and refers to an aliphatic group as described herein in which one or more carbon atoms are replaced by one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.).

[0079] Heteroaryl: The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, such as "heteroalkyl", "heteroalkoxy", "arylalkyl", "aralkoxy", "aryloxyalkyl", refer to, for example, monocyclic, bicyclic or polycyclic ring systems having a total of 5 to 30 ring members, such as 5, 6, 9, 10, 14, etc., at least one ring within the system being aromatic and at least one aromatic ring atom being a heteroatom. In some embodiments, the heteroatom is nitrogen, oxygen or sulfur. In some embodiments, the heteroaryl group has 5 to 14 ring atoms (i.e., monocyclic, bicyclic or polycyclic), and in some embodiments, is a group having 5, 6, 9, 10 or 14 ring atoms. In some embodiments, the heteroaryl group has 6, 10 or 14 π electrons shared in the ring array; and contains 1 to 5 heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. In some embodiments, heteroaryl is a hetero biaryl group, such as bipyridyl, etc. The terms "heteroaryl" and "heteroar-" as used herein also include groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.The heteroaryl group can be monocyclic, bicyclic or polycyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaryl group", and any of these terms includes a ring which may optionally be substituted. The term "heteroalkyl" refers to an alkyl group substituted by a heteroaryl group, where the alkyl and heteroaryl moieties are each independently optionally substituted.

[0080] Heteroatom: The term "heteroatom" means an atom other than carbon and other than hydrogen. In some embodiments, the heteroatom is oxygen, sulfur, nitrogen, phosphorus, boron or silicon (any oxidized form of nitrogen, sulfur, phosphorus or silicon; any basic nitrogen or substitutable nitrogen of a heterocyclic ring (e.g., N as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)) and the like. In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen or sulfur. + In some embodiments, the heteroatom is a quaternized form of the above. In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen or sulfur.

[0081] Heterocyclyl: As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a monocyclic, bicyclic or polycyclic (e.g., 3-30 membered) ring moiety that is saturated or partially unsaturated and contains one or more heteroatom ring atoms. In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen or sulfur. In some embodiments, the heterocyclyl group is a stable 3-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is saturated or partially unsaturated as defined above and has one or more, preferably 1-4, heteroatoms in addition to carbon atoms. When used in reference to the ring atoms of a heterocycle, the term "nitrogen" refers to substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), N (as in pyrrolidinyl) or (as in N-substituted pyrrolidinyl) +It may be NR. The heterocyclic ring can be attached to the pendant group on any heteroatom or carbon atom that provides a stable structure, and any ring atom can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein, and a heterocyclic ring fused to one or more aryl, heteroaryl, or cycloaliphatic rings, with the radical or point of attachment on the heterocyclic aliphatic ring, such as, for example, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclyl group can be monocyclic, bicyclic, or polycyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, and the alkyl and heterocyclyl moieties are each independently optionally substituted.

[0082] "Improved", "increased", or "decreased": As used herein, these terms or terms that are grammatically equivalent thereto as comparisons to others indicate a value compared to a comparable reference measurement. For example, in some embodiments, an evaluation value achieved using a target agent can be "improved" compared to an evaluation value obtained using a comparable reference agent. Separately or in addition thereto, in some embodiments, an evaluation value achieved in a target object or system of interest can be "improved" compared to an evaluation value obtained in the same object or system under different conditions (e.g., before and after an event such as administration of a target agent) or a different, comparable object (e.g., a comparable object or system different from the target object or system of interest in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or a previous exposure to a condition or agent). In some embodiments, the term as a comparison to others refers to a statistically significant difference (e.g., a probability and / or magnitude sufficient to achieve statistical validity). One of ordinary skill in the art can understand and readily determine the degree and / or probability required or sufficient to achieve such statistical significance in a given context.

[0083] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a moiety containing at least one double bond or triple bond. The term "partially unsaturated" is intended to encompass groups having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties.

[0084] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent, e.g., a compound formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose appropriate for administration in a treatment regimen that, when administered to the relevant population, exhibits a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition can be specially formulated for administration in solid or liquid form, including administration adapted to: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., sterile solutions or suspensions or sustained release formulations, e.g., subcutaneous, intramuscular, intravenous or epidural injection; topical application, e.g., creams, ointments or controlled release patches or sprays for application to the skin, lung or mouth; intravaginal or rectal, e.g., as pessaries, creams or foams; sublingual; ocular; transdermal; or nasal, pulmonary and other mucosal surfaces.

[0085] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to that compound, substance, composition and / or dosage form which, within the scope of sound medical judgment, is appropriate for contact with human tissue without excessive toxicity, irritation, allergic response or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0086] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or vehicle such as a liquid or solid diluent, excipient, vehicle or solvent encapsulant that is involved in transporting or delivering the primary compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppositories; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffering solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical formulations.

[0087] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in a pharmaceutical sense, i.e., within the scope of sound medical judgment, salts that are not accompanied by excessive toxicity, irritation, allergic response, etc., and are suitable for use in contact with humans and lower animals, corresponding to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed by other known methods such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic base addition salts, e.g., salts formed by bases with acidic groups of the provided compounds.Representative alkali or alkaline earth metal salts include salts such as sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, the pharmaceutically acceptable salts are ammonium salts (e.g., -N(R)3. + )). In some embodiments, the pharmaceutically acceptable salts are sodium salts. In some embodiments, the pharmaceutically acceptable salts are calcium salts. In some embodiments, the pharmaceutically acceptable salts, when appropriate, are formed using counterions such as halides, hydroxides, carboxyl, sulfuric acid, phosphoric acid, nitric acid, alkyl having 1 to 6 carbon atoms, sulfonic acid, and arylsulfonic acid, including non-toxic ammonium, quaternary ammonium, and amine cations. In some embodiments, the provided compounds are in the form of pharmaceutically acceptable salts.

[0088] Protecting group: As used herein, the term "protecting group" or "protection group" refers to a temporary substituent that protects a potential reactive functional group from unwanted chemical transformation. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. "Si protecting group" is a protecting group containing an Si atom, Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., t-butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl). Generally, the Si protecting group is bonded to an oxygen atom. The field of protecting group chemistry is being reexamined (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Such protecting groups (and related protected moieties) are described in detail below.

[0089] Protected hydroxyl groups are known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is hereby incorporated by reference in its entirety. Examples of suitably protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formate, acetate, propionate, pentanoate, crotonate, and benzoate. Specific examples of suitable esters include formate, benzoylformate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetic acid), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate. Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonate. Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl ether, and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and allyl ether or its derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, β-(trimethylsilyl)ethoxymethyl, and tetrahydropyran-2-yl ether.Examples of suitable aryl alkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2-picolyl and 4-picolyl ether.

[0090] Protected amines are known in the art and include those described in detail in Greene (1999). Suitable mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allylamines, amides, etc. Examples of suitable mono-protected amino moieties include tert-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxycarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethoxycarbonylamino (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, tert-butyldiphenylsilyl, etc. Suitable di-protected amines include amines substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides such as phthalimide, maleimide, succinimide, etc. Suitable di-protected amines also include pyrrole, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine, etc., and azides.

[0091] Protected aldehydes are known in the art and include those described in detail in Greene (1999). Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, etc. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazone and its derivatives.

[0092] Protected carboxylic acids are known in the art and include those described in detail in Greene (1999). Suitable protected carboxylic acids further include, but are not limited to, optionally substituted C 1-6 aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, where each group may optionally be substituted. Further suitable protected carboxylic acids include oxazolines and orthoesters.

[0093] Protected thiols are known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl thioethers and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters.

[0094] Reference: As used herein, describes the standard or control against which a comparison is made. For example, in some embodiments, a drug, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control drug, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a past reference or control and is optionally embodied in a tangible expression medium. Typically, as will be understood by one of ordinary skill in the art, the reference or control is determined or characterized under conditions or circumstances comparable to those under evaluation. One of ordinary skill in the art understands when there is sufficient similarity to justify reliance on and / or comparison to a particular possible reference or control.

[0095] Substitution: As used herein, the compounds of the invention may optionally be substituted and / or may contain substituted moieties. In general, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, whether or not the term "optionally" precedes it. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when two or more positions of any given structure may be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions. The combinations of substituents contemplated by this disclosure are preferably combinations that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to the conditions for the manufacture, detection, and in certain embodiments, the recovery, purification, and use of the compounds for one or more of the purposes described herein.

[0096] Suitable monovalent substituents are halogen; -(CH2) 0-4 R 〇 ; -(CH2) 0-4 OR 〇 ; -O(CH2) 0-4 R 〇 , -O-(CH2) 0-4 C(O)OR 〇 ; -(CH2) 0-4 CH(OR 〇 )2; R 〇 Optionally substituted -(CH2) 0-4 Ph; R 〇 Optionally substituted -(CH2) 0-4 O(CH2) 0-1 Ph; R 〇 Optionally substituted -CH=CHPh; R 〇 Optionally substituted -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R 〇 )2; -(CH2) 0-4 N(R〇 )C(O)R 〇 ;-N(R 〇 )C(S)R 〇 ;-(CH2) 0-4 N(R 〇 )C(O)N(R 〇 )2;-N(R 〇 )C(S)N(R 〇 )2;-(CH2) 0-4 N(R 〇 )C(O)OR 〇 ;-N(R 〇 )N(R 〇 )C(O)R 〇 ;-N(R 〇 )N(R 〇 )C(O)N(R 〇 )2;-N(R 〇 )N(R 〇 )C(O)OR 〇 ;-(CH2) 0-4 C(O)R 〇 ;-C(S)R 〇 ;-(CH2) 0-4 C(O)OR 〇 ;-(CH2) 0-4 C(O)SR 〇 ;-(CH2) 0-4 C(O)OSi(R 〇 )3;-(CH2) 0-4 OC(O)R 〇 ;-OC(O)(CH2) 0-4 SR 〇 、-(CH2) 0-4 SC(O)R 〇 ;-(CH2) 0-4 C(O)N(R 〇 )2;-C(S)N(R 〇 )2;-C(S)SR°;-SC(S)SR°、-(CH2) 0-4 OC(O)N(R 〇 )2;-C(O)N(OR 〇 )R 〇 ;-C(O)C(O)R 〇 ;-C(O)CH2C(O)R 〇 ;-C(NOR 〇 )R 〇 ;-(CH2) 0-4 SSR 〇 ;-(CH2) 0-4S(O)2R 〇 ;-(CH2) 0-4 S(O)2OR 〇 ;-(CH2) 0-4 OS(O)2R 〇 ;-S(O)2N(R 〇 )2;-(CH2) 0-4 S(O)R 〇 ;-N(R 〇 )S(O)2N(R 〇 )2;-N(R 〇 )S(O)2R 〇 ;-N(OR 〇 )R 〇 ;-C(NH)N(R 〇 )2;-Si(R 〇 )3;-OSi(R 〇 )3;-OSi(OR 〇 )3;-P(R 〇 )2;-P(OR 〇 )2;-OP(R 〇 )2;-OP(OR 〇 )2;-N(R 〇 )P(R 〇 )2;-OP(O)(R 〇 )2;-OP(O)(OR 〇 )2;-N(R 〇 )P(O)(R 〇 )2;-N(R 〇 )P(O)(OR 〇 )2;-B(R 〇 )2;-OB(R 〇 )2;-OB(OR 〇 )2;-P(O)(R 〇 )2;-OP(O)(R 〇 )2;-(C 1-4 a straight-chain or branched-chain alkylene)O-N(R 〇 )2; or -(C 1-4 a straight-chain or branched-chain alkylene)C(O)O-N(R 〇 )2; wherein each R 〇 is as defined below and is independently hydrogen, C 1-20 a C having 1 to 5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, sulfur, silicon, and phosphorus 1-20 heteroaliphatic, -CH2-(C 6-14 aryl), -O(CH2)0-1 (C 6-14 aryl), -CH2-(5- to 14-membered heteroaryl ring), a 5- to 20-membered monocyclic, bicyclic or polycyclic, saturated, partially unsaturated or aryl ring having 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, regardless of the above definition, two independently existing Rs 〇 are, together with those atoms, a 3- to 20-membered monocyclic, bicyclic or polycyclic, saturated, partially unsaturated or aryl ring which may be substituted as defined below and which has 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus.

[0097] R 〇 (or the ring formed by two independently existing Rs 〇 being joined together with the atoms therebetween) suitable monovalent substituents on are, independently, halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ●and wherein each R ● is unsubstituted or, when preceded by "halo", is substituted by one or more halogens only and, independently, is selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, and a 5- to 6-membered saturated, partially unsaturated or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Suitable divalent substituents on saturated carbon atoms of R ● include =O and =S.

[0098] Suitable divalent substituents, for example, on suitable carbon atoms, nitrogen atoms, etc., are independently the following: =O, =S, =CR * 2, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, wherein each R * may be substituted as defined below and, independently, is hydrogen, C 1-20 aliphatic, C having from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus 1-20 heteroaliphatic, -CH2-(C 6-20 aryl), -O(CH2) 0-1 (C 6-20 aryl), -CH2-(a 5- to 20-membered heteroaryl ring having from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus), a 5- to 20-membered, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated or aryl ring having from 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus or, regardless of the above definition, two independently occurring Rs *combines with those atoms to form a 3- to 20-membered monocyclic, bicyclic, or polycyclic, saturated, partially unsaturated, or aryl ring that may be substituted as defined below and has 0 to 5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus. Suitable divalent substituents that bond to adjacent substitutable atoms of the "optionally substituted" group include -O(CR * 2) 2-3 O-.

[0099] R * (or, in the case of two independently occurring R * s that combine with the atoms between them to form a ring), suitable monovalent substituents independently include halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ● , where each R ● is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens and, independently, C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. R * Suitable divalent substituents for R include =O and =S.

[0100] In some embodiments, suitable substituents on a replaceable nitrogen of a "optionally substituted" group are -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2 or -N(R † )S(O)2R † ; wherein each R † is independently hydrogen, a C 1-6 aliphatic optionally substituted as defined below, unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two R † existing independently are joined together with the atoms thereof to form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus.

[0101] In some embodiments, suitable substituents on an aliphatic group of R † are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ●is 2 or -NO2, where each R ● is unsubstituted or, when "halo" precedes, is substituted by only one or more halogens and, independently, is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 a 5- to 6-membered saturated, partially unsaturated or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0102] Subject: As used herein, the terms "subject" or "test subject" refer to any organism to which a provided compound or composition is administered for experimental, diagnostic, prophylactic and / or therapeutic purposes, according to the invention. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates and humans; insects; worms, etc.) and plants. In some embodiments, the subject may have and / or be susceptible to a disease, disorder and / or condition. In some embodiments, the subject is human.

[0103] Susceptible to: An individual "susceptible to" a disease, disorder and / or condition is an individual who has a higher risk of developing the disease, disorder and / or condition than the general population. In some embodiments, an individual susceptible to a disease, disorder and / or condition may not be diagnosed with the disease, disorder and / or condition. In some embodiments, an individual susceptible to a disease, disorder and / or condition may exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual susceptible to a disease, disorder and / or condition may not exhibit symptoms of the disease, disorder and / or condition. In some embodiments, a disease, disorder and / or condition progresses in an individual susceptible to the disease, disorder and / or condition. In some embodiments, a disease, disorder and / or condition does not progress in an individual susceptible to the disease, disorder and / or condition.

[0104] Therapeutic agent: As used herein, the term "therapeutic agent" refers to an agent that, when administered to a subject, has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect. In some embodiments, a therapeutic agent can be any substance used to reduce, ameliorate, alleviate, inhibit, prevent, delay the onset of, reduce the severity of, and / or decrease the occurrence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, the compounds provided are useful as therapeutic agents.

[0105] Treatment regimen: As used herein, the term "treatment regimen" refers to an administration regimen where administration to a relevant population may be correlated with a desired or beneficial therapeutic outcome.

[0106] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" means a substance (e.g., a therapeutic agent, composition, and / or formulation) that, when administered as part of a treatment regimen, elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject having or susceptible to the disease, disorder, and / or condition. As will be understood by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, the target cell or tissue, etc. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that reduces, ameliorates, alleviates, inhibits, prevents, delays the onset of, reduces the severity of, and / or decreases the occurrence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered as a single dose; in some embodiments, multiple unit doses are required for delivery of a therapeutically effective amount. In some embodiments, the compounds provided are administered in a therapeutically effective amount, as a single dose or multiple unit doses.

[0107] Treat: As used herein, the terms "treat", "treatment" or "treating" refer to any method used to partially or completely alleviate, improve, relieve, inhibit, prevent, delay the onset of, reduce the severity of, or decrease the occurrence of one or more symptoms or characteristics of a disease, disorder and / or condition. Treatment can be administered to a subject who does not exhibit signs of the disease, disorder and / or condition. In some embodiments, treatment can be administered to a subject who exhibits only early signs of a disease, disorder and / or condition, for example, for the purpose of reducing the risk that the pathology associated with the disease, disorder and / or condition will progress.

[0108] Unit dose: As used herein, the expression "unit dose" refers to the amount administered as a single dose of a pharmaceutical composition and / or in physically discrete units. In many embodiments, the unit dose contains a predetermined amount of the active agent. In some embodiments, the unit dose contains the entire single dose of the drug. In some embodiments, two or more unit doses are administered to achieve the total single dose. In some embodiments, administration of multiple unit doses is required or expected to achieve the desired effect. The unit dose can be, for example, a volume such as a liquid (e.g., an acceptable carrier) containing one or more predetermined therapeutic agents, a solid form of one or more predetermined amounts of therapeutic agents, a sustained release formulation, or a drug delivery device containing one or more predetermined amounts of therapeutic agents. It is understood that the unit dose can be present in a formulation containing a variety of optional components in addition to one or more therapeutic agents. For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc. can be included. One of ordinary skill in the art understands that in many embodiments, the total appropriate daily dosage of a particular therapeutic agent can include one or more unit doses and can be determined by the attending physician within the scope of sound medical judgment. In some embodiments, the specific effective dosage level for any particular subject or organism depends on a variety of factors including the disorder being treated and the severity of the disorder; the specific active compound being used; the specific composition being used; the age, weight, general health, sex, and diet of the subject; the time of administration and the excretion rate of the specific active compound being used; the duration of treatment; drugs and / or additional therapies used in combination with or simultaneously with one or more specific compounds being used, and factors known in the medical arts.

[0109] Unsaturated: As used herein, the term "unsaturated" means that a moiety has one or more unsaturation units.

[0110] Wild type: As used herein, the term "wild type" has the meaning understood in the art to refer to a substance having a structure and / or activity that is naturally found in a "normal" (as opposed to a mutated, diseased, altered, etc.) state or situation. One of ordinary skill in the art will understand that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0111] Unless otherwise specified, salts of the provided compounds (e.g., drugs, ARMs, etc.), such as pharmaceutically acceptable acid or base addition salts, stereoisomeric forms, and tautomers are included. Unless otherwise specified, the structures shown herein also include compounds with various isotopes, e.g., substitution of hydrogen by deuterium or tritium, 13 C or 14 substitution of carbon by

[0112] Unless otherwise apparent from the context, in the present invention, (i) the term "a" may be understood to mean "at least one"; (ii) the term "or" may be understood to mean "and / or"; (iii) the terms "comprising" and "including" may be understood to encompass the separately listed components or steps, which exist alone or together with one or more additional components or steps; (iv) the terms "about" and "approximately" may be understood to allow for the standard variations understood by one of ordinary skill in the art; (v) when ranges are provided, the endpoints are included.

[0113] 3. Cellular immunotherapy A variety of immune cells, particularly NK cells, can be utilized with the agents described herein for treating a variety of conditions, disorders or diseases, including cancer. Such cells are administered before, simultaneously with and / or sequentially to the agents described herein, e.g., the ARM. In some embodiments, such cells, e.g., NK cells, are administered simultaneously with an agent, e.g., the ARM, in the same composition containing both the NK cells and the ARM. In some embodiments, such cells, e.g., NK cells, are administered simultaneously with an agent, e.g., the ARM, in separate compositions, e.g., one composition containing the NK cells but not the ARM and one composition containing the ARM but not the NK cells.

[0114] As will be appreciated by those skilled in the art, useful immune cells such as NK cells can be derived from a variety of sources and / or can be engineered in numerous ways. For example, in some embodiments, NK cells are derived from stem cells. In some embodiments, NK cells are derived from iPSC lines. In some embodiments, NK cells are derived from clonal master iPSC lines. In some embodiments, NK cells are engineered to express a particular receptor, such as a high-affinity and optionally non-cleavable CD16 receptor. In some embodiments, NK cells are engineered to express a chimeric antigen receptor (CAR), for example, in some embodiments, NK cells can be engineered to express an anti-CD19 CAR. In some embodiments, NK cells are CAR-NK cells. In some embodiments, NK cells are engineered to express a cytokine receptor. In some embodiments, NK cells contain an IL-15 receptor fusion that enhances resistance and expansion capabilities without the need for co-administration of a cytokine support. In some embodiments, NK cells are engineered to inhibit the expression of a particular cellular protein, such as a particular cell surface protein. In some embodiments, NK cells are engineered to inhibit the expression of CD38. In some embodiments, NK cells are derived from the placenta. In some embodiments, NK cells are donor NK cells. In some embodiments, NK cells are haplotype-matched donor NK cells. In some embodiments, NK cells are mismatched donor NK cells. In some embodiments, NK cells are related donor NK cells, such as mismatched-related donor NK cells. In some embodiments, NK cells are unrelated donor NK cells. In some embodiments, NK cells are derived from a subject, such as a patient. In some embodiments, the technology provided includes a natural cell engager that binds to natural cells (e.g., NK cells and macrophages) and simultaneously binds to particular tumor cells. In some embodiments, NK cells are derived from umbilical cord blood stem cells and progenitor cells.In some embodiments, the NK cells are derived from the regulation of signaling pathways, such as the Notch signaling pathway. In some embodiments, nanoparticles are utilized to improve and / or maintain the proliferation of NK cells. In some embodiments, the NK cells described herein are produced ex vivo. In some embodiments, the NK cells are cryopreserved and stored as a cell therapy that can be used at any time. Examples of certain such techniques include those utilized by Fate Therapeutics, NantKwest Inc., Celularity, Inc., GC Pharma, Sorrento Therapeutics, Inc., Affimed GmbH / MD Anderson Cancer Center, Gamida Cell Ltd., Nohla Therapeutics, Kiadis Pharma N.V., and the like. Those skilled in the art will understand that antibodies and / or CARs that may optionally be utilized against specific antigens utilized in certain such techniques may not be required for the provided techniques that include the ARM described herein.

[0115] Cell population / preparation In some embodiments, useful cells, such as NK cells, are processed prior to administration to a subject. In many embodiments, NK cells are enriched, pre-activated, and / or expanded in vitro prior to administration to a subject. In some embodiments, a composition comprising NK cells for administration is enriched in NK cells as compared to a reference composition, such as blood from a subject to whom such a composition is administered. In some embodiments, enrichment is or includes an increase in the number of cells per unit volume, e.g., per mL. In some embodiments, enrichment is or includes an increase in the percentage of NK cells in such a composition. In some embodiments, enrichment is or includes an increase in the number of cells per unit volume and an increase in the percentage of NK cells in the composition. In some embodiments, the composition is a composition of substantially pure NK cells in that the non-NK cells in the composition are "impurities" resulting from the manufacturing process (e.g., incomplete isolation, purification, etc.). As will be understood by those skilled in the art, it is rare, if at all, for chemical and biological processes to reach completion and / or proceed completely or achieve or avoid absolute results. Thus, the term "substantially" is used in the present invention to capture the potential lack of perfection inherent in many biological and / or chemical phenomena.

[0116] A variety of techniques for enriching NK cells are available in the art and can be utilized by the present invention. For example, in some embodiments, NK cells are isolated using leukapheresis, optionally with purification steps such as CD3 depletion and / or CD56 positive selection. In some embodiments, NK cells, such as pre-activated memory-like NK cells, are enriched for CD56 and depleted of CD3-expressing cells as compared to a reference population of NK cells (e.g., NK cells in the blood of a donor or subject).

[0117] Prior to administration to a subject, NK cells are typically pre-activated with cytokines such as IL-12, IL-15, and IL-18 for an appropriate time (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 25 hours or more, e.g., about 16 hours). In some embodiments, prior to administration, the NK cells are treated with cytokines. In some embodiments, the NK cells are treated for an appropriate period (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 25 hours or more, e.g., about 16 hours) with an appropriate amount of IL-12 (e.g., about 10 ng / mL), IL-15 (e.g., 50 ng / mL), and IL-18 (e.g., 50 ng / mL) and pre-activated. The conditions for pre-activation of NK cells and the pre-activated NK cells can be evaluated by assessment of one or more markers, such as CD94, NKG2A, NKp46, CD25, NKp30, NKp44, CD62L, CD27, TRAIL, the cytotoxic molecule perforin, and granzyme B. Specific useful markers are described in Romee et al., Blood 120, 4751-4760, (2012); Leong et al., Biol. Blood Marrow Transplant. 20, 463-473 (2014); Romee et al., Sci Transl Med. 2016 Sep 21; 8(357):357ra123. doi: 10.1126 / scitranslmed.aaf2341, etc. In some embodiments, the NK cells are primary human NK cells that have been differentiated in vitro into memory-like NK cells via full activation with pre-activated IL-12, IL-15, and IL-18.

[0118] In particular, such cytokine-induced memory-like NK cells exhibit an enhanced response to cytokine or activating receptor restimulation for several weeks to months after pre-activation, and may be particularly useful for the treatment of diverse conditions, disorders or diseases including cancer. In some embodiments, such pre-activated memory-like NK cells have enhanced interferon-gamma (IFN-γ) production and / or cytotoxicity against cancer cells. Typical methods of manufacture and methods of administration of such NK cells can be found in, for example, Romee et al., Blood 120, 4751-4760, (2012); Leong et al., Biol. Blood Marrow Transplant. 20, 463-473 (2014); Romee et al., Sci Transl Med. 2016 Sep 21; 8(357):357ra123. doi: 10.1126 / scitranslmed.aaf2341. In some embodiments, such NK cells have enhanced proliferation after restimulation (e.g., using cytokines or via activating receptors, etc.) compared to comparable benchmark NK cells, e.g., NK cells that are similarly manufactured but not pre-activated (e.g., not treated with cytokines, treated only with low doses of IL-15, etc.), express the high-affinity IL-2 receptor αβγ or express it at high levels, and / or provide an increase in IFN-γ production.

[0119] Pre-activated memory-like NK cells may have significant differences in the number of protein expressions compared to reference NK cells, such as CD94, NKG2A, NKp46, CD25, NKp30, NKp44, CD62L, CD27, TRAIL, cytotoxic molecule perforin, and granzyme B. In some embodiments, NK cells show a decrease in NKp80 expression. Such markers can be used separately or in combination, inter alia, to enrich, purify, and / or identify memory-like NK cells. Typical useful markers can be identified using various techniques, such as mass cytometry and multidimensional analysis. Typical methods and typical such proteins for identifying proteins that can distinguish pre-activated memory-like NK cells from reference (e.g., control) NK cells are described in Romee et al., Sci Transl Med. 2016 Sep 21;8(357):357ra123. doi: 10.1126 / scitranslmed.aaf2341.

[0120] In some embodiments, immune cells, such as NK cells, are contacted with a GSK3α / β inhibitor. In some embodiments, such cells are pre-activated by a GSK3α / β inhibitor.

[0121] In some embodiments, the immune cells are cytokine-induced memory-like NK cells. In some embodiments, the immune cells are IL-12, IL-15 and IL-18-preactivated NK cells. In some embodiments, the immune cells are allogeneic HLA-haplotypematched IL-12, IL-15 and IL-18-activated NK cells. Although not intended to be limited by any of these, memory-like NK cells after preactivation with IL-12, IL-15 and IL-18 can result in a process that includes differentiation that confers long-term changes in functional capacity. Memory-like NK cells having such functional capacity can be produced by treatment with other agents (e.g., other cytokines or other small molecules, peptides, proteins, etc.). Techniques for evaluating such agents and / or treatment with the resulting NK cells (e.g., protein markers, assays, etc.) are available in the art and can be utilized by the present invention (e.g., the techniques described in Romee et al., Sci Transl Med. 2016 Sep 21;8(357):357ra123. doi: 10.1126 / scitranslmed.aaf2341). In some embodiments, memory-like NK cells increase the expression of inhibitory and activating cytokine receptors (e.g., CD94 / NKG2A, NKp30, NKp44, NKp46, NKG2D, CD62L and CD25, etc.) and / or decrease the expression of specific proteins (e.g., NKp80). In some embodiments, the levels of specific receptors (e.g., KIR, CD57, NKG2C, DNAM-1, CD137, CD11b, etc.) do not substantially change. In some embodiments, the changes in activation, inhibition, cytokine and adhesion receptors are consistent with differentiation. In some embodiments, preactivation with cytokines provides epigenetic regulation of specific genes, such as IFN-γ. For example, in some embodiments, activation with IL-12, IL-15 and IL-18 (e.g., for 5 days) results in a reduction in methylation of the IFN-γ conserved non-coding sequence 1 locus in human NK cells.In some embodiments, certain pre-activated NK cells (e.g., cytokine-induced) cells exist in an enhanced activated state without substantial differentiation.

[0122] In some embodiments, the NK cells are administered within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 5 weeks, within 6 weeks, within 7 weeks, within 8 weeks, within 9 weeks, within 10 weeks, within 11 weeks, within 12 weeks, within 13 weeks, within 14 weeks, within 15 weeks, within 16 weeks, within 17 weeks, within 18 weeks, within 19 weeks, or within 20 weeks, or within 4 months, within 5 months, within 6 months, within 7 months, within 8 months, within 9 months, within 10 months, within 11 months, or within 12 months after pre-activation.

[0123] In particular, the present invention encompasses the recognition that such NK cells having enhanced properties and / or activities that can enhance the inhibition or killing of cancer cells can result in more and / or more severe side effects and / or toxicities, e.g., off-target toxicity to normal cells. Thus, in some embodiments, the present invention provides, inter alia, a technique for reducing such side effects and / or toxicities, including administering one or more agents, particularly ARMs, that promote, increase, and / or enhance the interaction between the NK cells and the target and reduce the side effects and / or toxicities associated with NK cell administration.

[0124] In some embodiments, the NK cells are expanded before, during, and / or after pre-activation. In some embodiments, the NK cells are purified prior to administration, e.g., to remove certain media (or components thereof), activating cytokines, etc.

[0125] In some embodiments, the NK cells administered to a subject are isolated and / or expanded from the subject (autologous). In some embodiments, the NK cells administered to a subject are isolated and / or expanded from another subject (allogeneic; e.g., from a donor with a haplotype match).

[0126] In some embodiments, the NK cells described above are processed (e.g., isolated, purified, pre-activated, etc.) prior to administration. In some embodiments, the NK cell composition for administration comprises a specific artificial medium or its components, such as L-glutamine, HEPES, NEAA, penicillin / streptomycin, and 10% human AB serum, and optionally contains complete RPMI-1640 medium supplemented with rhIL-15 (1 ng / mL) to support survival.

[0127] Administration Immune cells, such as pre-activated memory-like NK cells, are formulated into various forms known in the art for administration to a subject. Depending on the subject and / or the condition, disorder, or disease being treated, an appropriate amount of cells is administered to provide a clinical benefit. In some embodiments, the cell dose level is 10,000 to 100 million, 100,000 to 50 million, 100,000 to 20 million, 100,000 to 10 million, 50,000, 100,000, 200,000, 300,000, 300,000, 500,000, 1 million, 2 million, 3 million, 4 million, 5 million, 6 million, 7 million, 8 million, 9 million, 10 million, 15 million, 20 million, 25 million, 30 million, 35 million, 40 million, 45 million, 50 million, 60 million, 70 million, 80 million, or 90 million per kilogram. In some embodiments, the dose level is 0.5×10 6 kg per kg. In some embodiments, the dose level is 1×10 6 per kg. In some embodiments, the dose level is 10×10 6 or less per kg. As will be understood by those skilled in the art, pre-activated memory-like NK cells can be administered at a lower dose to achieve the same or more clinical benefit or provide more clinical benefit when administered in the same amount compared to non-memory-like (e.g., activated only with IL-2 or IL-15, e.g., treated overnight) non-activated NK cells or pre-activated NK cells.

[0128] In many embodiments, the cells are administered via intravenous infusion. In some embodiments, a composition comprising cells, such as pre-activated NK cells, is administered via infusion. In some embodiments, such a composition is administered by adoptive transfer.

[0129] In some embodiments, a subject, such as an AML patient, is pre-conditioned with a chemotherapeutic agent (e.g., on day 0) for administration of the cells. For example, in some embodiments, an AML patient is pre-conditioned with fludarabine / cyclophosphamide on day 0.

[0130] In some embodiments, immune cells, such as pre-activated NK cells, are administered prior to administration of an agent such as ARM. In some embodiments, they are administered simultaneously with an agent such as ARM. In some embodiments, they are administered sequentially with an agent such as ARM. In some embodiments, when not administered simultaneously, the immune cells, such as pre-activated NK cells and an agent such as ARM, are administered in such a way that the subject is exposed to both. Specific techniques for administration of NK cells are described in Miller et al., Blood 105, 3051-3057 (2005) and can be utilized by the present invention.

[0131] In some embodiments, specific cytokines are administered to support the administered immune cells after or simultaneously with the administration of the immune cells. In some embodiments, rhIL-2 is administered, typically at a low dose, to support memory-like NK cells by the induced high-affinity IL-2Rαβγ. See, for example, Leong, et al., Biol. Blood Marrow Transplant, 20, 463-473 (2014).

[0132] In some embodiments, donor memory-like NK cells are tracked in the subject's blood using informative HLA, for example, using donor- or patient-specific anti-HLA monoclonal antibodies. In some embodiments, such cells peak after infusion, for example, at a frequency of 7 to 14 days, and can decrease in number after recipient T cell recovery. If desired, additional doses of such NK cells can be administered (in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses can be administered). In some embodiments, memory-like NK cells are less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 60%, less than about 70%, less than about 80% or less than about 90% of blood NK cells at a time after administration (e.g., at 7 days). In some embodiments, the level is greater than about 10%. In some embodiments, the level is greater than about 20%. In some embodiments, the level is greater than about 30%. In some embodiments, the level is greater than about 40%. In some embodiments, the level is greater than about 50%. In some embodiments, the level is greater than about 60%. In some embodiments, the level is greater than about 70%. In some embodiments, the level is greater than about 80%. In some embodiments, the level is greater than about 90%. In some embodiments, the total number of memory-like NK cells increases at least 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800-fold, 850-fold, 900-fold, 950-fold or 1000-fold in the blood when comparing day 1 and subsequent time points (e.g., 7 days). In some embodiments, the increase is at least 100-fold. In some embodiments, the increase is at least 200-fold. In some embodiments, the increase is at least 300-fold. In some embodiments, the increase is at least 400-fold. In some embodiments, the increase is at least 500-fold. In some embodiments, the increase is at least 600-fold.In some embodiments, the increase is at least 700-fold. In some embodiments, the increase is at least 800-fold. In some embodiments, the increase is at least 900-fold. In some embodiments, the increase is at least 1000-fold. Typically, the percentage and absolute number (count) of memory-like NK cells also increase after administration of memory-like NK cells (e.g., at 5, 6, 7, 8, 9, 10, 11, 12, 13, and / or 14 days), e.g., to the above percentages (e.g., less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, at least 90%) and total numbers (e.g., 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800-fold, 850-fold, 900-fold, 950-fold, or 1000-fold or more; in some embodiments, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, or more).

[0133] In some embodiments, after administration, memory-like NK cells have enhanced function, as demonstrated, for example, by an increase in IFN-γ production upon stimulation.

[0134] In some embodiments, memory-like NK cells proliferate (Ki-67 + ) after administration (e.g., at 3 and / or 7 days).

[0135] In some embodiments, pre-activated memory-like NK cells are cytokine-induced memory-like NK cells. In some embodiments, memory-like NK cells express inhibitory KIR receptors. In some embodiments, such cells can perform one or more functions (e.g., inhibition and / or killing of target cells such as cancer cells) regardless of KIR-ligand interaction.

[0136] In some embodiments, the administered immune cells, such as memory-like NK cells, are detectable in the subject's blood and bone marrow for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or more. In some embodiments, such cells proliferate and / or expand in vivo after administration to the subject. In some embodiments, such cells differentiate in the subject in vivo and exhibit enhanced functions against targets such as cancer cells (e.g., leukemia cells).

[0137] In some embodiments, immune cells, such as pre-activated NK cells, are administered simultaneously with the ARM. In some embodiments, they are administered in a single composition. In some embodiments, they are administered as separate compositions.

[0138] In some embodiments, an appropriate amount of antibody may also be administered, together with the ARM, in the same composition or in separate compositions (and optionally, before the ARM, simultaneously with the ARM or sequentially with the ARM). In some embodiments, a composition comprising the ARM, pre-activated NK cells and optionally an antibody or a fragment thereof is administered. In some embodiments, a composition comprising the ARM comprising uABT, pre-activated NK cells and optionally IgM is administered. In some embodiments, the provided composition comprises a complex comprising NK cells, an antibody or a fragment thereof and the ARM. In some embodiments, in such complex A, the CD16a receptor of the NK cell interacts with the antibody or a fragment thereof, and the antibody-binding portion of the ARM interacts with the same antibody or a fragment thereof.

[0139] 4. Typical ARM Agents A variety of ARM agents can be utilized according to the present invention. In some embodiments, the ARM comprises an antibody-binding portion that interacts with the Fab region, preferably binds to an antibody (and / or a fragment thereof) comprising such a Fab region, and can mobilize it. In some embodiments, the ARM comprises an antibody-binding portion that interacts with the Fc region (e.g., the uABT described herein), preferably binds to a variety of antibodies (and / or fragments thereof) comprising such an Fc region, and can mobilize it. As will be understood by those skilled in the art, the antibodies (and / or fragments thereof) mobilized by such an ARM can comprise a variety of Fab regions and can have a variety of specificities. In some embodiments, an individual mobilized antibody (or fragment thereof) does not exceed 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80% or 90% of the total mobilized antibodies and their fragments.

[0140] In certain embodiments, a useful ARM is of formula I:

Chemical formula

[0141] In some embodiments, a useful ARM is a compound of formula I-a or a salt thereof. In some embodiments, a useful ARM is a compound of formula I-b or a salt thereof.

[0142] In certain embodiments, a useful ARM is a compound of formula II or a pharmaceutically acceptable salt thereof, R 1 、R 3 and R 5Each of which is independently hydrogen or C 1-6 An optionally substituted group selected from an aliphatic group, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or R 1 and R 1’ may optionally, together with the carbon atoms therebetween, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ may optionally, together with the carbon atoms therebetween, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; The R 5 group and the R 5’ group attached to the same carbon atom may optionally, together with the carbon atoms therebetween, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or; Two R 5 groups may optionally, together with the atoms therebetween, form a divalent C 1-10may form a straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently, optionally, -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2- or -Cy 1 - may be substituted, wherein each -Cy 1 - is independently a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1’ 、R 3’ and R 5’ each of which is independently hydrogen or C 1-3 is aliphatic; R 2 、R 4 and R 6 each of which is independently hydrogen or C 1-4 is aliphatic or: R 2 and R 1 may optionally combine with the atoms therebetween to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 may optionally combine with the atoms therebetween to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or; R 6 group and the adjacent R 5 group may optionally combine with the atoms therebetween to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; L 1 is

Chemical formula

[0143] In certain embodiments, a useful ARM is of formula III: [Chemical formula] [wherein, each R 7 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or the R 7 groups and R 7’The base may optionally form, together with the carbon atoms between them, a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Each R 7’ is independently hydrogen or C 1-3 is aliphatic; Each R 8 is independently hydrogen or C 1-4 is aliphatic or: The R 8 group and the R 7 group adjacent thereto may optionally form, together with the atoms between them, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 9 is hydrogen, C 1-3 aliphatic or -C(O)C 1-3 is aliphatic; L 3 is

Chemical formula

[0144] antibody binding site A variety of antibody binding moieties are known in the art and can be utilized according to the present invention.

[0145] In some embodiments, the antibody binding moiety mainly interacts with the Fab region. In some embodiments, the antibody binding moiety mainly includes a specific Fab structure and / or interacts with an antibody and / or a fragment thereof directed to a specific antigen.

[0146] In some embodiments, the antibody binding portion interacts with the Fc region. In some embodiments, the antibody binding portions described herein, such as uABT, interact with the Fc region and can recruit Fc regions bound to Fab regions having diverse structures and / or antigen specificities. In some embodiments, useful agents include universal antibody binding portions that can bind to antibodies having different Fab regions and different specificities. In some embodiments, the antibody binding portion is a universal antibody binding portion that binds to the Fc region. In some embodiments, binding of the antibody binding portion to an antibody (or fragment thereof), e.g., binding of uABT to the Fc region, can occur simultaneously with binding of the same antibody (or fragment thereof) to an Fc receptor, e.g., CD16a (e.g., when uABT binds to Fc, it can occur at different positions / amino acid residues of the same Fc region). In some embodiments, even when a universal antibody binding portion binds, the Fc region interacts with Fc receptors and mediates, induces, promotes, and / or enhances one or more or all of its immune activities, including recruitment of immune cells (e.g., effector cells such as NK cells), and / or immune system activity against target cells, tissues, subjects, and / or substances, such as antibody-dependent cell cytotoxicity (ADCC) and / or ADCP.

[0147] A variety of universal antibody binding portions can be utilized according to the present invention, and many techniques, such as those described in the Examples, are available for the identification and evaluation of universal antibody binding portions. In some embodiments, the universal antibody binding portion comprises one or more amino acid residues that are each independently natural or non-natural. In some embodiments, the universal antibody binding portion has the structure of

Chemical formula

Chemical formula

[0148] In some embodiments, -(Xaa)z- is [X 1 p1 [X 2 p2 -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -[X 13 p13 -[X 14 p14 [X 15 p15 [X 16 p16 or includes this, where X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 each is independently an amino acid residue, for example, an amino acid residue of formula A-I, and each of p1, p2, p13, p14, p15 and p16 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 each is independently an amino acid residue of the amino acid of formula A-I. In some embodiments, X​​​​​​1 and X 2 and X 3 and X 4 and X 5 and X 6 and X 7 and X 8 and X 9 and X 10 and X 11 and X 12 and X 13 Each of and X is independently a natural amino acid residue. In some embodiments, X 1 and X 2 and X 3 and X 4 and X 5 and X 6 and X 7 and X 8 and X 9 and X 10 and X 11 and X 12 and X 13 One or more of are independently non-natural amino acid residues described herein.

[0149] In some embodiments, the peptide unit contains a functional group capable of reacting with a functional group of another amino acid residue in the amino acid residue. In some embodiments, the peptide unit contains an amino acid residue having a side chain containing a functional group capable of reacting with another functional group of the side chain of another amino acid residue to form a bond (see, for example, the compounds in Table 1). In some embodiments, a certain functional group of a certain amino acid residue binds to a functional group of another amino acid residue to form a bond (or crosslink). The bond is attached to the backbone atoms of the peptide unit and does not contain backbone atoms. In some embodiments, the peptide unit contains a bond formed by the side chains of two non-adjacent amino acid residues. In some embodiments, the bond binds to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, both backbone atoms to which the bond is attached are carbon atoms. In some embodiments, the bond has the structure of L b where L b is the L described herein a where L a is not a covalent bond. In some embodiments, La contains -Cy-. In some embodiments, L a contains -Cy- which is a heteroaryl that may optionally be substituted. In some embodiments, -Cy- is

Chemical formula

Chemical formula

[0150] In some embodiments, the two amino acid residues linked by a bond are separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more than 15 amino acid residues (excluding the two amino acid residues linked by the bond) therebetween. In some embodiments, the number is 1. In some embodiments, the number is 2. In some embodiments, the number is 3. In some embodiments, the number is 4. In some embodiments, the number is 5. In some embodiments, the number is 6. In some embodiments, the number is 7. In some embodiments, the number is 8. In some embodiments, the number is 9. In some embodiments, the number is 10. In some embodiments, the number is 11. In some embodiments, the number is 12. In some embodiments, the number is 13. In some embodiments, the number is 14. In some embodiments, the number is 15.

[0151] In some embodiments, each of p1, p2, p13, p14, p15 and p16 is 0. In some embodiments, -(Xaa)z- is -X3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 - is or includes, where: X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 each of which is independently an amino acid residue; X 6 is Xaa A or Xaa P is; X 9 is Xaa N is; X 12 is Xaa A or Xaa P is. In some embodiments, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 each of which is independently an amino acid residue of the amino acids of formula A-I described herein. In some embodiments, X 5 is Xaa A or Xaa P is. In some embodiments, X 5 is Xaa A is. In some embodiments, X 5 is Xaa P is. In some embodiments, X 5 is an amino acid residue comprising a saturated, partially saturated or aromatic ring, the side chain of which may optionally be substituted. In some embodiments, X5 is [Chem.] . In some embodiments, X 5 is [Chem.] . In some embodiments, X 6 is Xaa A . In some embodiments, X 6 is Xaa P . In some embodiments, X 6 is His. In some embodiments, X 12 is Xaa A . In some embodiments, X 12 is Xaa P . In some embodiments, X 9 is Asp. In some embodiments, X 9 is Glu. In some embodiments, X 12 is [Chem.] . In some embodiments, X 12 is [Chem.] . In some embodiments, X 7 , X 10 and X 11 each independently is an amino acid residue having a hydrophobic side chain (a "hydrophobic amino acid residue", Xaa H ). In some embodiments, X 7 is Xaa H . In some embodiments, X 7 is [Chem.] . In some embodiments, X 7is Val. In some embodiments, X 10 is Xaa H In some embodiments, X 10 is Met. In some embodiments, X 10 is

Chemical formula

Chemical formula

[0152] In some embodiments, -(Xaa)z- is -X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 - or includes this, where X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 and X 12 each independently is an amino acid residue; At least two amino acid residues are linked by one or more linkages L b ; L b is a divalent group optionally substituted when selected from C1-C 20 aliphatic or C1-C having 1 to 5 heteroatoms 20 heteroaliphatic, wherein one or more methylene units of said group are optionally and independently -C(R')2-, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S- or -C(O)O-substituted, where L b binds to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms; X 6 is Xaa A or Xaa P ; X 9 is Xaa N ; X 12 is Xaa A or Xaa P . In some embodiments, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 each is independently an amino acid residue of an amino acid of formula A-I described herein. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, X 5 and X 10 are linked by L b . In some embodiments, one linkage L b is present. In some embodiments, X 6is Xaa A In some embodiments, X 6 is Xaa P In some embodiments, X 6 is His. In some embodiments, X 9 is Asp. In some embodiments, X 9 is Glu. In some embodiments, X 12 is Xaa A In some embodiments, X 12 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0153] In some embodiments, -(Xaa)z- is -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 - or includes this, where X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12Each of them is independently an amino acid residue; At least two amino acid residues are linked by one or more linkages L b ; L b is a divalent group which may be substituted when selected from C1-C 20 aliphatic or C1-C having 1 to 5 heteroatoms 20 heteroaliphatic, wherein one or more methylene units of said group may optionally and independently be substituted by -C(R')2-, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S- or -C(O)O-, where L b binds to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms; X 4 is Xaa A ; X 5 is Xaa A or Xaa P ; X 8 is Xaa N ; X 11 is Xaa A ; In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 are each independently an amino acid residue of an amino acid of formula A-I described herein. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, one linkage L b is present. In some embodiments, X2 and X 12 is L b is linked by L. In some embodiments, L b is -CH2-S-S-CH2-. In some embodiments, L b is -CH2-CH2-S-CH2-. In some embodiments, L b is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0154] In some embodiments, -(Xaa)z- is -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 - or includes this, where X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 each is independently an amino acid residue; at least two amino acid residues are linked by one or more linkages L b ; L b is C1-C 20 aliphatic or C1-C 20 having 1 to 5 heteroatomsA divalent group optionally substituted when selected from heteroaliphatics, wherein one or more methylene units of said group are optionally and independently, -C(R’)2-, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -C(O)S- or -C(O)O-; where L b is bonded to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms; X 5 is Xaa A or Xaa P ; X 8 is Xaa N ; X 11 is Xaa A ; In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 each is independently an amino acid residue of an amino acid of formula A-I described herein. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, one bond L b is present. In some embodiments, two or more bonds L b are present. In some embodiments, two bonds L b are present. In some embodiments, X 2 and X 12 are linked by L b . In some embodiments, X 4 and X 9 are linked by L bis linked by. In some embodiments, X 4 and X 10 are linked by L b In some embodiments, L b is -CH2-S-S-CH2-. In some embodiments, L b is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0155] In some embodiments, -(Xaa)z- is -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 - or includes this, where X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 、X 13 、X 14 、X 15 and X 16 each is independently an amino acid residue; At least two amino acid residues are linked by one or more bonds L b ; L b is C1-C20 An optionally substituted divalent group selected from aliphatic or C1-C having 1 to 5 heteroatoms 20 heteroaliphatic, wherein one or more methylene units of said group are optionally and independently, -C(R')2-, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S- or -C(O)O-; where L b is attached to the backbone atoms of one amino acid residue and the backbone atoms of another amino acid residue and does not contain backbone atoms; X 3 is Xaa N ; X 6 is Xaa A ; X 7 is Xaa A or Xaa P ; X 9 is Xaa N ; X 13 is Xaa A ; In some embodiments, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 and X 12 each is independently an amino acid residue of an amino acid of formula A-I described herein. In some embodiments, two non-adjacent amino acid residues are linked by L b . In some embodiments, one bond L b is present. In some embodiments, two or more bonds L b are present. In some embodiments, two bonds L bexists. In some embodiments, X 2 is linked to X b by L 16 . In some embodiments, X 4 is linked to X b by L 14 . In some embodiments, both X 2 and X 16 are Cys, and the two -SH groups of these side chains form -S-S- (L b is -CH2-S-S-CH2-). In some embodiments, both X 4 and X 14 are Cys, and the two -SH groups of these side chains form -S-S- (L b is -CH2-S-S-CH2-). In some embodiments, L b links the two α-carbon atoms of two different amino acid residues. In some embodiments, X 3 is Asp. In some embodiments, X 3 is Glu. In some embodiments, X 5 is Xaa H . In some embodiments, X 5 is Ala. In some embodiments, X 6 is Xaa A . In some embodiments, X 6 is Tyr. In some embodiments, X 7 is Xaa A . In some embodiments, X 7 is Xaa P . In some embodiments, X 7 is His. In some embodiments, X 8 is Xaa H . In some embodiments, X 8 is Ala. In some embodiments, X 9 is Gly. In some embodiments, X 10 is Asp. In some embodiments, X 10is Glu. In some embodiments, X 11 is Xaa H In some embodiments, X 11 is Leu. In some embodiments, X 12 is Xaa H In some embodiments, X 12 is Val. In some embodiments, X 13 is Xaa A In some embodiments, X 13 is Tyr. In some embodiments, X 15 is an amino acid residue containing a polar uncharged side chain (e.g., at physiological pH, a "polar uncharged amino acid residue", Xaa L ). In some embodiments, X 15 is Val. In some embodiments, p1 is 1. In some embodiments, in some embodiments, X 1 is Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1 is Glu.

[0156] As will be appreciated by those skilled in the art, an amino acid residue can be replaced by another amino acid residue having similar properties. For example, a certain Xaa H (e.g., Val, Leu, etc.) can be replaced by another Xaa H (e.g., Leu, Ile, Ala, etc.), and a certain Xaa A can be replaced by another Xaa A , and a certain Xaa P can be replaced by Xaa P , and a certain Xaa N can be replaced by another Xaa N , and a certain Xaa L can be replaced by another Xaa L and so on.

[0157] In some embodiments, the antibody-binding portion, such as a universal antibody-binding portion, is the universal antibody-binding portion of the compounds in Table 1. In some embodiments, the antibody-binding portion, such as a universal antibody-binding portion, is optionally substituted and has the following structure or includes: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0158] In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-1. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-2. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-3. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-4. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-5. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-6. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-7. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-8. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-9. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-10. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-11. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-12. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-13. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-14. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-15. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-16.In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-17. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-18. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-19. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-20. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-21. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-22. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-23. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-24. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-25. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-26. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-27. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-28. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-29. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-30. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-31. In some embodiments, the universal antibody binding portion is, or comprises, optionally substituted A-32.In some embodiments, the universal antibody binding portion is, or comprises, A-33, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-34, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-35, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-36, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-37, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-38, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-39, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-40, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-41, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-42, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-43, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-44, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-45, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-46, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-47, which may optionally be substituted. In some embodiments, the universal antibody binding portion is, or comprises, A-48, which may optionally be substituted.In some embodiments, the universal antibody binding portion is, or comprises, A-49, which may optionally be substituted. In some embodiments, it is unsubstituted. In some embodiments, it is substituted.

[0159] In some embodiments, the universal antibody binding portion contains peptide units and is linked to the linker portion by the C-terminus of the peptide unit. In some embodiments, it is linked to the linker portion by the N-terminus of the peptide unit. In some embodiments, it is linked to the linker portion from a side chain group of the peptide unit.

[0160] In some embodiments, the antibody binding portion, e.g., the universal antibody binding portion, comprises a small molecule having a molecular weight, e.g., less than 10,000, less than 9,000, less than 8,000, less than 7,000, less than 6,000, less than 5,000, less than 4,000, less than 3,000, less than 2,000, less than 1,500, less than 1,000, etc. Suitable such antibody binding portions include small molecule Fc binding portions, e.g., those described in U.S. Patent No. 9,745,339, U.S. Patent Application Publication No. 20130131321, etc.

[0161] As will be understood by those skilled in the art, antibodies of various properties and activities (e.g., antibodies that recognize different antigens, such as having any modifications, etc.) can be mobilized by the antibody binding portions described herein. In some embodiments, such antibodies include, for example, antibodies administered to a subject for therapeutic purposes. In some embodiments, the antibodies mobilized by the antibody binding portion include antibodies against different antigens. In some embodiments, the antibodies mobilized by the antibody binding portion include antibodies where the antigen is not present on the surface or cell membrane of a target cell (e.g., a target cell such as a cancer cell). In some embodiments, the antibodies mobilized by the antibody binding portion include antibodies that do not target antigens present on the surface or cell membrane of a target cell (e.g., a target cell such as a cancer cell). In some embodiments, antigens on the surface of a target cell can interfere with the structure, conformation, and / or one or more properties and / or activities of the mobilized antibodies that bind to such antigens. In some embodiments, as will be understood by those skilled in the art, the provided technology includes a universal antibody binding portion that mobilizes antibodies of various specificities, and 1% or less, 2% or less, 5% or less, 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, 70% or less, 75% or less, 80% or less, 85% or less, 90% or less, 95% or less, or 99% or less of the mobilized antibodies are antibodies against the same antigen, protein, lipid, carbohydrate, etc. In particular, one advantage of the present invention is that the provided technology including a universal antibody binding portion can utilize the diverse pool of antibodies present in serum. In some embodiments, the universal antibody binding portion of the present invention (e.g., in (e.g., ARM)) contracts with a plurality of antibodies, where 1% or less, 2% or less, 5% or less, 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35%, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, 70% or less, 75% or less, 80% or less, 85% or less, 90% or less, 95% or less, or 99% or less of the plurality of antibodies are antibodies against the same antigen, protein, lipid, carbohydrate, etc.

[0162] Amino acid In some embodiments, useful compounds and, for example, ARM agents may include one or more amino acid moieties, for example, in a universal antibody binding moiety, a linker moiety, and the like. In some embodiments, the amino acid has the formula A-I:

Chemical formula

[0163] In some embodiments, L a1 is a covalent bond. In some embodiments, the compound of formula A-I has the structure NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH.

[0164] In some embodiments, L a2 is a covalent bond. In some embodiments, the compound of formula A-I has the structure NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH.

[0165] In some embodiments, L a1 is a covalent bond and L a2 is a covalent bond. In some embodiments, the compound of formula A-I has the structure NH(R a1 )-C(R a2 )(R a3 )-COOH.

[0166] In some embodiments, L a is a covalent bond. In some embodiments, La is a divalent C which may optionally be substituted 1-6 is aliphatic. In some embodiments, L a is a C which may optionally be substituted 1-6 is alkylene. In some embodiments, L a is -CH2-. In some embodiments, L a is -CH2CH2-. In some embodiments, L a is -CH2CH2CH2-.

[0167] In some embodiments, R’ is R. In some embodiments, R a1 is R, where R is as described herein. In some embodiments, R a2 is R, where R is as described herein. In some embodiments, R a3 is R, where R is as described herein. In some embodiments, R a1 , R a2 and R a3 each independently is R, where R is as described herein.

[0168] In some embodiments, R a1 is hydrogen. In some embodiments, R a2 is hydrogen. In some embodiments, R a3 is hydrogen. In some embodiments, R a1 is hydrogen, and at least one of R a2 and R a3 is hydrogen. In some embodiments, R a1 is hydrogen, and one of R a2 and R a3 is hydrogen and the other is not hydrogen.

[0169] In some embodiments, R a2 is -L a -R, where R is as described herein. In some embodiments, Ra2 is -L a -R, where R is a C 3-30 cycloaliphatic, C 5-30 aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon, a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected therefrom, and a 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group which may be optionally substituted. In some embodiments, R a2 is -L a -R, where R is a C 6-30 aryl and a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group which may be optionally substituted. In some embodiments, R a2 is the side chain of an amino acid. In some embodiments, R a2 is the side chain of a standard amino acid.

[0170] In some embodiments, R a3 is -L a -R, where R is as described herein. In some embodiments, R a3 is -L a -R, where R is a C 3-30 cycloaliphatic, C 5-30 aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon, a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected therefrom, and a 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group which may be optionally substituted. In some embodiments, R a3 is -L a -R, where R is a C 6-30 aryl and a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group which may be optionally substituted. In some embodiments, R a3is the side chain of an amino acid. In some embodiments, R a3 is the side chain of a standard amino acid.

[0171] In some embodiments, R is a cyclic group. In some embodiments, R is an optionally substituted C 3-30 cycloaliphatic group. In some embodiments, R is cyclopropyl.

[0172] In some embodiments, R is an aromatic group, and the amino acid residue of the amino acid of formula A-I is Xaa A . In some embodiments, R is optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is 4-trifluoromethylphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 14-membered heteroaryl having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is

Chemical formula

Chemical formula

[0173] In some embodiments, R’ is -COOH. In some embodiments, the amino acid residue of the compound and the amino acid of formula A-I is Xaa N is.

[0174] In some embodiments, R’ is -NH2. In some embodiments, the amino acid residue of the compound and the amino acid of A-I is Xaa P is.

[0175] In some embodiments, R a2 or R a3 is R, where R is an aliphatic C as described herein 1-20 In some embodiments, the amino acid residue of the compound and the amino acid of A-I is Xaa H is. In some embodiments, R is -CH3. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is cyclopropyl.

[0176] In some embodiments, R a1 , R a2 and R a3 Two or more of are R, and together form an optionally substituted as described herein.

[0177] In some embodiments, R a1 as well as R a2 and R a3 One of is R, and together form an optionally substituted 3- to 6-membered ring having no further ring heteroatoms other than the nitrogen atom to which R a1 is attached. In some embodiments, the formed ring is a 5-membered ring such as exists in proline.

[0178] In some embodiments, R a2 and R a3is R and together forms a 3- to 6-membered ring which may be optionally substituted as described herein. In some embodiments, R a2 and R a3 is R and together forms a 3- to 6-membered ring which may be optionally substituted when having one or more nitrogen ring atoms. In some embodiments, R a2 and R a3 is R and forms a 3- to 6-membered ring which may be optionally substituted when having ring heteroatoms that are 1 or fewer nitrogen atoms. In some embodiments, the ring is a saturated ring.

[0179] In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is a non-natural amino acid. In some embodiments, the amino acid is an α-amino acid. In some embodiments, the amino acid is a β-amino acid.

[0180] Target In some embodiments, the present invention provides a technique for selectively directing an agent comprising a target-binding moiety (e.g., an ARM compound), an antibody, and an immune cell, e.g., an NK cell, to a desired target site comprising one or more targets. As will be understood by those skilled in the art, the technique provided is useful for a variety of types of targets.

[0181] In some embodiments, the target is damaged or missing tissue. In some embodiments, the target is damaged tissue. In some embodiments, the target is missing tissue. In some embodiments, the target is associated with a disease, disorder or condition, such as cancer, wound, etc. In some embodiments, the target is a tumor. In some embodiments, the target is or includes diseased cells. In some embodiments, the target is or includes cancer cells. In some embodiments, the target is a foreign substance. In some embodiments, the target is or includes an infectious agent. In some embodiments, the target is a microorganism. In some embodiments, the target is or includes bacteria. In some embodiments, the target is or includes a virus.

[0182] In many embodiments, the target is tissue and / or cells associated with a disease, disorder or condition, particularly various types of cancer. In some embodiments, the target includes cancer cells. In particular, the present invention provides a technique that is particularly useful for selectively targeting cancer cells by the immune system, for example, via recruitment antibodies (e.g., endogenous antibodies) and immune cells, such as NK cells, by using an ARM.

[0183] In many embodiments, the target is a cancer cell or a proliferative state, disorder or disease. In some embodiments, the cancer or proliferative state, disorder or disease is a benign tumor, malignant tumor, solid tumor, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumor, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon cancer or colorectal adenoma, head and neck tumors, epithelial hyperplasia, psoriasis, prostatic hyperplasia, epithelial neoplasm, adenoma, adenocarcinoma, squamous cell carcinoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin and non-Hodgkin, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, hematological tumors (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphocytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma and intravascular large B-cell lymphoma).

[0184] The target site typically includes one or more physical, chemical and / or biological markers that can be utilized by the target binding moiety of a compound (e.g., an ARM) to selectively direct an antibody and / or its fragment and / or an immune cell to the target.

[0185] In some embodiments, the cells of the target site may include one or more characteristic factors useful for targeting. In some embodiments, such factors are proteins and / or their fragments. In some embodiments, such factors are antigens specifically associated with a disease, disorder or condition.

[0186] For example, in some embodiments, cancer cells may contain one or more tumor-specific antigens or tumor-associated antigens. The target-binding moieties described herein may selectively bind to such markers. In some embodiments, the target-binding moieties of the invention are small molecules useful for binding to cell surface proteins and / or intracellular proteins.

[0187] In some embodiments, for example, characteristic factors such as cells at the target site are or include carbohydrates, such as in glycosylated proteins, for example, carbohydrates on the cell surface. In some embodiments, the characteristic factor is or includes a lipid.

[0188] In some embodiments, for example, characteristic factors such as cells at the target site are extracellular. In some embodiments, the characteristic factor is an extracellular protein. In some embodiments, the characteristic factor is present on the cell surface. In some embodiments, the characteristic factor is a protein present on the cell surface. For example, in many tumor tissues, cell surface and / or extracellular mucins exhibit different glycosylation levels and patterns and can be utilized for targeting.

[0189] In some embodiments, the target site, such as diseased tissue, has one or more physical, biological, and / or chemical properties that can be utilized by the target-binding moiety. In some embodiments, such properties are pH. In some embodiments, such properties are the concentration of one or more chemical substances. For example, the tumor microenvironment is often hypoxic and / or acidic (e.g., pH 6.5 - 6.9 versus 7.2 - 7.4).

[0190] In some embodiments, the target is a peptide or a fragment thereof, or comprises the same. In some embodiments, the target is a protein or a fragment thereof, or comprises the same. In some embodiments, the target is avidin. In some embodiments, the target is streptavidin. In some embodiments, the target is an antigen or comprises the same. In some embodiments, the target is a tumor-specific antigen. In some embodiments, the target is a tumor-associated antigen (TAA) or comprises the same.

[0191] In some embodiments, the tumor-associated antigen is a carbohydrate or comprises the same. In some embodiments, the provided target-binding moiety comprises such a TAA. In some embodiments, the carbohydrate is part of a glycoprotein. In some embodiments, the carbohydrate is a glycolipid. Many conditions, disorders, and diseases, such as various types of cancer, are associated with abnormal glycosylation. In some embodiments, the tumor-associated carbohydrate antigen (TACA) includes, and / or is associated with, altered sialic acid expression, altered Lewis carbohydrate antigen expression, altered ganglioside expression, and the like. In some embodiments, the target-binding moiety of the present invention can target various types of TACAs, including those described in the art, such as Chua and Durrant, Monoclonal Antibodies Against Tumour-Associated Carbohydrate Antigens, Carbohydrate Mahmut Caliskan, IntechOpen, DOI: 10.5772 / 66996.

[0192] In some embodiments, the tumor-associated antigen is a cell surface receptor. In some embodiments, the TAA is BMPR1B (type IB bone morphogenetic protein receptor, Genbank accession number NM_001203), E16 (LAT1, SLC7A5, Genbank accession number NM_003486), STEAP1 (prostate six-transmembrane epithelial antigen, Genbank accession number NM_012449), 0772P (CA125, MUC16, Genbank accession number AF361486), MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession number NM.sub.-005823), Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession number NM_006424), Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, semaphorin 5b Hlog, semadomain, 7 thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain (semaphorin) 5B, Genbank accession number AB040878), PSCA hlg (2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628), ETBR (endothelin B receptor, Genbank accession number AY275463), MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number NM_017763), STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMPI, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, prostate 6 transmembrane epithelial antigen 2, 6 transmembrane prostate protein, Genbank accession number AF455138), TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession number NM_017636), CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession number NP_003203 or NM_003212), CD21 (CR2 (complement receptor 2) or C3DR (C3d / Epstein-Barr virus receptor) or Hs.73792 Genbank accession number M26004), CD79b (CD79B, CD79.β., IGb (immunoglobulin-related β), B29, Genbank accession number NM_000626), FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain including phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession number NM_030764), HER2 (Genbank accession number M1730), NCA (Genbank accession number M18728), MDP (Genbank accession number BC017023), IL20Rα (Genbank accession number AF184971), brevican (Genbank accession number AF229053, EphB2R (Genbank accession number NM_004442), ASLG659 (Genbank accession number AX092328), PSCA (Genbank accession number AJ297436), GEDA (Genbank accession number AY260763, BAFF-R (B cell activation factor receptor, BLyS receptor 3, BR3, NP_443177.1), CD22 (B cell receptor CD22-B isoform, NP_001762.1), CD79a (CD79A, CD79.α., immunoglobulin-related α, Igβ (CD79B) interacts covalently, forms a complex on the surface with IgM molecules, and converts signals involved in B cell differentiation. B cell-specific protein, Genbank accession number NP_001774.1), CXCR5 (Burkitt lymphoma receptor 1, activated by CXCL13 chemokine, functions in lymphocyte migration and humoral defense, and plays a role in HIV-2 infection and possibly the development of AIDS, lymphoma, myeloma, and leukemia. G protein-coupled receptor, Genbank accession number NP_001707.1), HLA-DOB (β subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes, Genbank accession number NP_002111.1), P2X5 (purinergic receptor P2X ligand-gated ion channel 5, an ion channel opened by extracellular ATP that may be involved in neurotransmission and neurogenesis, and its deficiency may contribute to the pathophysiology of idiopathic detrusor instability. Genbank accession number NP_002552.2), CD72 (B-cell differentiation antigen CD72, Lyb-2, Genbank accession number NP_001773.1), LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein of the leucine-rich repeat (LRR) family, which regulates B-cell activation and apoptosis, and loss of function is associated with increased disease activity in patients with systemic lupus erythematosus. Genbank accession number NP_005573.1), FcRH1 (Fc receptor-like protein 1, a receptor predicted for the immunoglobulin Fc domain containing a C2-type Ig-like and ITAM domain, which may have a role in B-lymphocyte differentiation. Genbank accession number NP_443170.1), IRTA2 (immunoglobulin superfamily receptor translocation-associated 2, a putative immunoreceptor that may have a role in B-cell development and lymphoma genesis; deregulation of the gene by translocation occurs in some B-cell malignancies. Genbank accession number NP_112571.1); and TENB2 (a putative transmembrane proteoglycan associated with the EGF / heregulin family of growth factors and follistatin, selected from Genbank accession number AF179274).

[0193] In some embodiments, the target is a nucleic acid or comprises the same.

[0194] In some embodiments, the target is a lipid or comprises the same.

[0195] In some embodiments, the target is a carbohydrate or comprises the same. In some embodiments, the target is a carbohydrate associated with a disease, disorder or condition or comprises the same. In some embodiments, the target is a carbohydrate associated with cancer, e.g., a carbohydrate as a glycan modification of a protein on the surface or extracellularly of a cancer cell or comprises the same.

[0196] Target binding site A variety of types of target-binding moieties and chemical classes can be utilized in the present invention, and many techniques (e.g., assays, reagents, kits, etc.) for identifying and / or evaluating the properties of the target-binding moiety can be utilized in the present invention. Generally, the target-binding moiety interacts with the target site by one or more physical, biological, and / or chemical properties. In some embodiments, the target-binding moiety binds to the characteristic factors described herein. In some embodiments, the target-binding moiety binds to a surface, extracellular and / or intracellular protein, carbohydrate, and / or nucleic acid. In some embodiments, the target-binding moiety binds to the surface protein of the target cell. In some embodiments, the target-binding moiety is a small molecule moiety. In some embodiments, the target-binding moiety is an antibody agent. In some embodiments, the target-binding moiety is a nucleic acid agent such as an aptamer. In some embodiments, the target-binding moiety is a lipid moiety. Specific types of target-binding moieties are described below; those skilled in the art will understand that other types of target-binding moieties, including those well-known in the art, can also be utilized in the present invention.

[0197] In some embodiments, the target-binding moiety binds to the target by one or more proteins, lipids, nucleic acids, carbohydrates, small molecules, etc. of the target. For example, in some embodiments, the target-binding moiety binds to the tumor-specific antigen of the target cancer cell. In some embodiments, the tumor-specific antigen is a carbohydrate or a fragment thereof, or includes the same. In some embodiments, the tumor-specific antigen is a protein or a fragment thereof, or includes the same.

[0198] In some embodiments, the target-binding moiety binds to a cell surface protein, carbohydrate, or lipid. In some embodiments, the target-binding moiety binds to CD19. In some embodiments, the target-binding moiety binds to CD20. In some embodiments, the target-binding moiety binds to CD22. In some embodiments, the target-binding moiety binds to CD30. In some embodiments, the target-binding moiety binds to CD33. In some embodiments, the target-binding moiety binds to CD123.

[0199] a. Small molecule In some embodiments, the target-binding moiety is a small molecule moiety. In some embodiments, the small molecule moiety has a molecular weight of 8000 or less, 7000 or less, 6000 or less, 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1500 or less, 1000 or less, 900 or less, 800 or less, 700 or less, or 600 or less. In some embodiments, the small molecule moiety has a molecular weight of 8000 or less. In some embodiments, the small molecule moiety has a molecular weight of 7000 or less. In some embodiments, the small molecule moiety has a molecular weight of 6000 or less. In some embodiments, the small molecule moiety has a molecular weight of 5000 or less. In some embodiments, the small molecule moiety has a molecular weight of 4000 or less. In some embodiments, the small molecule moiety has a molecular weight of 3000 or less. In some embodiments, the small molecule moiety has a molecular weight of 2000 or less. In some embodiments, the small molecule moiety has a molecular weight of 1500 or less. In some embodiments, the small molecule moiety has a molecular weight of 1000 or less. In some embodiments, the small molecule moiety has a molecular weight of 900 or less. In particular, the present invention encompasses the recognition that a small molecule target-binding moiety may be able to bind to markers outside, on the surface, and / or inside a target, such as a cancer cell.

[0200] In some embodiments, the small molecule target binding moiety is, or comprises, a moiety that selectively binds to a protein or a fragment thereof, such as a cancer antigen. For example, in some embodiments, the target binding moiety is, or comprises, a moiety that selectively binds to prostate specific membrane antigen (PSMA). In some embodiments, the target binding moiety is [Chemical Formula] or comprises the same.

[0201] In some embodiments, the small molecule target binding moiety is, or comprises, a biotin moiety. In some embodiments, the small molecule target binding moiety is [Chemical Formula] or comprises the same. In some embodiments, the small molecule target binding moiety is [Chemical Formula] or comprises the same.

[0202] b. Peptide agent In some embodiments, the target binding moiety is, or comprises, a peptide agent. In some embodiments, the target binding moiety is a peptide moiety. In some embodiments, the peptide moiety can be linear or cyclic. In some embodiments, the target binding moiety is, or comprises, a cyclic peptide moiety. A variety of peptide target binding moieties are known in the art and can be utilized by the present invention.

[0203] In some embodiments, the target binding moiety is, or comprises, a peptide aptamer agent.

[0204] c. Aptamer agent In some embodiments, the target binding moiety is, or comprises, a nucleic acid agent. In some embodiments, the target binding moiety is, or comprises, an oligonucleotide moiety. In some embodiments, the target binding moiety is, or comprises, an aptamer agent. A variety of aptamer agents are known in the art and can be readily developed using common techniques and utilized in the techniques provided by the present invention.

[0205] Linker moiety In some embodiments, the antibody binding moiety may optionally be linked to the target binding moiety by a linker moiety. Linker moieties for a variety of types and / or for a variety of purposes, such as those utilized in antibody-drug conjugates and the like, can be utilized in the present invention.

[0206] The linker moiety can be divalent or polyvalent. In some embodiments, the linker moiety is divalent. In some embodiments, the linker is polyvalent and links three or more moieties.

[0207] In some embodiments, the linker moiety is L. In some embodiments, L is a covalent bond or a divalent or polyvalent straight-chain or branched-chain C optionally substituted when including one or more aliphatic, aryl, heteroaliphatic having 1 to 20 heteroatoms, heteroaromatic having 1 to 20 heteroatoms, or any combination thereof 1-100 group, where one or more methylene units of said group are optionally and independently C 1-6 alkylene, C 1-6 alkenylene, divalent C having 1 to 5 heteroatoms 1-6Optionally substituted with a heteroaliphatic group, -C≡C-, -Cy-, -C(R’)2-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -C(O)C(R’)2N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -C(O)S-, -C(O)O-, -P(O)(OR’)-, -P(O)(SR’)-, -P(O)(R’)-, -P(O)(NR’)-, -P(S)(OR’)-, -P(S)(SR’)-, -P(S)(R’)-, -P(S)(NR’)-, -P(R’)-, -P(OR’)-, -P(SR’)-, -P(NR’)-, or -[(-O-C(R’)2-C(R’)2-) n , where n is from 1 to 20.

[0208] In some embodiments, L is divalent. In some embodiments, L is divalent or C 1-00 An aliphatic and C having 1 to 50 heteroatoms 1-100 A straight-chain or branched-chain group optionally substituted when selected from a heteroaliphatic, where one or more methylene units of said group are optionally and independently C 1-6 Alkylene, C 1-6 Alkenylene, a divalent C having 1 to 5 heteroatoms 1-6 A heteroaliphatic group, -C≡C-, -Cy-, -C(R’)2-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -C(O)C(R’)2N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -C(O)S-, -C(O)O-, -P(O)(OR’)-, -P(O)(SR’)-, -P(O)(R’)-, -P(O)(NR’)-, -P(S)(OR’)-, -P(S)(SR’)-, -P(S)(R’)-, -P(S)(NR’)-, -P(R’)-, -P(OR’)-, -P(SR’)-, -P(NR’)- or -[(-O-C(R’)2-C(R’)2-) n -optionally substituted.

[0209] In some embodiments, L is a covalent bond. In some embodiments, L is an optionally substituted divalent straight or branched chain C 1-100 aliphatic group, wherein one or more methylene units of said group are optionally and independently substituted. In some embodiments, L is a straight or branched chain C 6-100 aryl aliphatic group, wherein one or more methylene units of said group are optionally and independently substituted. In some embodiments, L is an optionally substituted divalent straight or branched chain C having 1 to 20 heteroatoms 5-100 heteroaryl aliphatic group, wherein one or more methylene units of said group are optionally and independently substituted. In some embodiments, L is an optionally substituted divalent straight or branched chain C having 1 to 20 heteroatoms 1-100 heteroaliphatic group, wherein one or more methylene units of said group are optionally and independently substituted.

[0210] In some embodiments, the linker moiety (e.g., L) is or comprises one or more polyethylene glycol units. In some embodiments, the linker moiety is -(CH2CH2O) n -, or comprises this, where n is as described herein. In some embodiments, one or more methylene units of L are independently -(CH2CH2O) n- is replaced. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20.

[0211] In some embodiments, the linker moiety includes one or more moieties that can be utilized for linkage to other moieties, such as amino, carbonyl, etc. In some embodiments, the linker moiety includes one or more -NR'- where R' is as described herein. In some embodiments, -NR'- improves solubility. In some embodiments, -NR'- serves as a point of attachment to another moiety. In some embodiments, R' is -H. In some embodiments, one or more methylene units of L are independently replaced with -NR'- where R' is as described herein.

[0212] In some embodiments, the linker moiety, e.g., L, includes a -C(O)- group that can be used for linkage to a moiety. In some embodiments, one or more methylene units of L are independently replaced with -C(O)-.

[0213] In some embodiments, the linker portion includes one or more ring portions. For example, one or more methylene units of L are replaced by -Cy-. In some embodiments, the linker portion, such as L, includes an aryl ring. In some embodiments, the linker portion, such as L, includes a heteroaryl ring. In some embodiments, the linker portion, such as L, includes an aliphatic ring. In some embodiments, the linker portion, such as L, includes a heterocyclyl ring. In some embodiments, the linker portion, such as L, includes a polycyclic ring. In some embodiments, the ring in the linker portion, such as L, is 3 to 20 membered. In some embodiments, the ring is 5 membered. In some embodiments, the ring is 6 membered. In some embodiments, the ring in the linker is the product of a ring addition reaction (such as click chemistry and its variants) used to bind to different moieties.

[0214] In some embodiments, the linker portion (such as L) is

Chemical formula

Chemical formula

Chemical formula

[0215] In some embodiments, the linker portion is as described in Table 1. Further linker portions include, for example, the linkers described for L 2 including. In some embodiments, L is the L of the present invention 1 as follows. In some embodiments, L is the L described herein 2 as follows. In some embodiments, L is the L described herein 3It is. In some embodiments, L is the L described herein b It is.

[0216] In some embodiments, L is

Chemical Formula

[0217] Specific embodiments of the variable group As an example, typical embodiments of the variable group are described throughout this specification. As will be understood by those skilled in the art, embodiments for various variable groups can optionally be combined.

[0218] As defined above and as described herein, ABT is an antibody binding portion.

[0219] In some embodiments, ABT is an antibody binding portion.

[0220] In some embodiments, ABT is selected from those shown in Table 1 below.

[0221] As defined above and as described herein, L is a bivalent linker moiety that links ABT and TBT.

[0222] In some embodiments, L is a bivalent linker moiety that links ABT and TBT.

[0223] In some embodiments, L is selected from those shown in Table 1 below.

[0224] As defined above and as described herein, TBT is a target binding portion.

[0225] In some embodiments, TBT is a target binding portion.

[0226] In some embodiments, the TBT is selected from those shown in Table 1 below.

[0227] As defined above and as described herein, R 1 R 3 and R 5 each independently is hydrogen or is selected independently from C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted; or R 1 and R 1’ optionally, together with the carbon atom between them, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3’ optionally, together with the carbon atom between them, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 5 groups and R 5’ groups optionally, together with the carbon atom between them, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R 5 groups, together with the atoms between them, form a divalent C 1-10forms a straight or branched chain saturated or unsaturated hydrocarbon chain, where 1 to 3 methylene units of the chain are independently, optionally, -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2- or -Cy 1 - may be substituted, where each -Cy 1 - is independently a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0228] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may optionally be substituted. In some embodiments, R 1 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 1 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is an optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R 1 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 1is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 1 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0229] In some embodiments, R 1 is

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical formula

Chemical formula

[0230] In some embodiments, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0231] In some embodiments, R 1 is

Chem.

Chem.

[0232] In some embodiments, R 1 and R 1’ may optionally, together with the carbon atoms between them, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 1 and R 1’ may optionally, together with the carbon atoms between them, form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0233] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0234] In some embodiments, R is the R 1 described herein. In some embodiments, R a2 is the R 1 described herein. In some embodiments, R a3 is the R 1 described herein.

[0235] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6A group which may be optionally substituted and is selected from an aliphatic group, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 3 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is an optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8- to 10-membered bicyclic aromatic carbocyclic ring. In some embodiments, R 3 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0236] In some embodiments, R 3 is methyl. In some embodiments, R 3 is

Chemical formula

[0237] In some embodiments, R 3 is [Chemical formula] is as follows. In some embodiments, R 3 is [Chemical formula] is as follows. In some embodiments, R 3 has a binding site with (S) stereochemistry [Chemical formula] is as follows. In some embodiments, R 3 has a binding site with (R) stereochemistry [Chemical formula] is as follows. In some embodiments, R 3 has a binding site with (S) stereochemistry [Chemical formula] is as follows. In some embodiments, R 3 has a binding site with (R) stereochemistry [Chemical formula] is as follows.

[0238] In some embodiments, R 3 has a binding site with (S) stereochemistry [Chemical formula] is as follows. In some embodiments, R 3 has a binding site with (R) stereochemistry [Chem.] is.

[0239] In some embodiments, R 3 and R 3’ may optionally, together with the carbon atoms between them, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 3 and R 3’ may optionally, together with the carbon atoms between them, form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0240] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0241] In some embodiments, R is the R 2 described herein. In some embodiments, R a2 is the R 2 described herein. In some embodiments, R a3 is the R 2 described herein.

[0242] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted when selected. In some embodiments, R5 is C, which may be optionally substituted 1-6 and is an aliphatic group. In some embodiments, R 5 is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, which may be optionally substituted. In some embodiments, R 5 is phenyl, which may be optionally substituted. In some embodiments, R 5 is an 8- to 10-membered bicyclic aromatic carbocyclic ring, which may be optionally substituted. In some embodiments, R 5 is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be optionally substituted. In some embodiments, R 5 is a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be optionally substituted. In some embodiments, R 5 is an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be optionally substituted.

[0243] In some embodiments, R 5 is methyl. In some embodiments, R 5 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0244] In some embodiments, R 5 is

Chem.

Chem.

[0245] In some embodiments, R 5 is

Chem.

Chem.

Chemical formula

Chemical formula

[0246] In some embodiments, R 5 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0247] In some embodiments, R 5 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0248] In some embodiments, R and R groups attached to the same carbon atom may optionally combine with the carbon atom between them to form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R and R groups attached to the same carbon atom may optionally combine with the carbon atom between them to form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 and R 5’ groups may optionally combine with the carbon atom between them to form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R and R 5 and R 5’ groups may optionally combine with the carbon atom between them to form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0249] In some embodiments, two R 5 groups combine with the atom between them to form a divalent C 1-10 straight-chain or branched-chain saturated or unsaturated hydrocarbon chain, where 1 to 3 methylene units of the chain are independently optionally substituted by -S-, -SS-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, or -Cy 1 -, where each -Cy 1 - is independently a 5- to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0250] In some embodiments, two R 5 groups combine with the atom between them to

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0251] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0252] In some embodiments, R is the R described herein 5 . In some embodiments, R a2 is the R described herein 5 . In some embodiments, R a3 is the R described herein 5 .

[0253] As defined above and as described herein, each of R 1’ , R 3’ and R 5’ is independently hydrogen or C 1-3 aliphatic.

[0254] In some embodiments, R 1’ is hydrogen. In some embodiments, R 1’ is C 1-3 aliphatic.

[0255] In some embodiments, R 1’ is methyl. In some embodiments, R 1’ is ethyl. In some embodiments, R 1’ is n-propyl. In some embodiments, R 1’ is isopropyl. In some embodiments, R 1’ is cyclopropyl.

[0256] In some embodiments, R1’ is selected from those shown in Table 1 below.

[0257] In some embodiments, R 3’ is hydrogen. In some embodiments, R 3’ is C 1-3 and is aliphatic.

[0258] In some embodiments, R 3’ is methyl. In some embodiments, R 3’ is ethyl. In some embodiments, R 3’ is n-propyl. In some embodiments, R 3’ is isopropyl. In some embodiments, R 3’ is cyclopropyl.

[0259] In some embodiments, R 3’ is selected from those shown in Table 1 below.

[0260] In some embodiments, R 5’ is hydrogen. In some embodiments, R 5’ is C 1-3 and is aliphatic.

[0261] In some embodiments, R 5’ is methyl. In some embodiments, R 5’ is ethyl. In some embodiments, R 5’ is n-propyl. In some embodiments, R 5’ is isopropyl. In some embodiments, R 5’ is cyclopropyl.

[0262] In some embodiments, R 5’ is selected from those shown in Table 1 below.

[0263] As defined above and as described herein, R 2 , R4 and R 6 Each of which is independently hydrogen or C 1-4 is aliphatic, or: R 2 and R 1 may optionally, together with their atoms, form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 may optionally, together with the atoms between them, form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6 group and the adjacent R 5 group may optionally, together with the atoms between them, form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0264] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is C 1-4 is aliphatic. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is n-butyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is tert-butyl.

[0265] In some embodiments, R 2 and R 1combines with the atoms therebetween to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0266] In some embodiments, R 2 and R 1 combine with the atoms therebetween to

Chemical formula

Chemical formula

[0267] In some embodiments, R 2 is selected from those shown in Table 1 below.

[0268] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-4 aliphatic. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is isobutyl. In some embodiments, R 4 is tert-butyl.

[0269] In some embodiments, R 4 and R 3It is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, integrated with the atoms therebetween.

[0270] In some embodiments, R 4 and R 3 are integrated with the atoms therebetween,

Chemical formula

Chemical formula

[0271] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0272] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is C 1-4 aliphatic. In some embodiments, R 6 is methyl. In some embodiments, R 6 is ethyl. In some embodiments, R 6 is n-propyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-butyl. In some embodiments, R 6 is isobutyl. In some embodiments, R 6 is tert-butyl.

[0273] In some embodiments, the R 6 group and the R 5 adjacent theretoThe base, together with the atoms therebetween, forms a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0274] In some embodiments, R 6 group and the R 5 group adjacent thereto, together with the atoms therebetween,

Chemical formula

Chemical formula

[0275] In some embodiments, R 6 is selected from those shown in Table 1 below.

[0276] In some embodiments, R is the R 1’ described herein. In some embodiments, R a2 is the R 1’ described herein. In some embodiments, R a3 is the R 1’ described herein. In some embodiments, R is the R 3’ described herein. In some embodiments, R a2 is the R 3’ described herein. In some embodiments, R a3 is the R 3’ described herein. In some embodiments, R is the R 2 described herein. In some embodiments, R a2 is the R 2 described herein. In some embodiments, R a3 is the R described herein2 It is. In some embodiments, R is the R described herein 4 It is. In some embodiments, R a2 is the R described herein 4 It is. In some embodiments, R a3 is the R described herein 4 It is. In some embodiments, R is the R described herein 6 It is. In some embodiments, R a2 is the R described herein 6 It is. In some embodiments, R a3 is the R described herein 6 It is.

[0277] As defined above and as described herein, L 1 is

Chemical formula

[0278] In some embodiments, L 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0279] In some embodiments, L 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0280] In some embodiments, L 1 is selected from those shown in Table 1 below.

[0281] As defined above and as described herein, L 2 is a covalent bond or a divalent C 1-10A straight-chain or branched-chain saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-,

Chem.

[0282] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is a divalent straight-chain or branched-chain saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally -S-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-,

Chem.

[0283] In some embodiments, L 2 is

Chem.

Chem.

[0284] In some embodiments, L 2 is selected from those shown in Table 1 below.

[0285] In some embodiments, L is the L described herein 2 It is.

[0286] As defined above and as described herein, TBT is a target binding moiety.

[0287] In some embodiments, TBT is a target binding moiety.

[0288] In some embodiments, TBT is [Chemical formula] It is. In some embodiments, TBT is [Chemical formula] It is.

[0289] In some embodiments, TBT is selected from those shown in Table 1 below.

[0290] As defined above and as described herein, each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0291] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0292] In some embodiments, m is selected from those shown in Table 1 below.

[0293] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0294] In some embodiments, n is selected from those shown in Table 1 below.

[0295] As defined above and as described herein, each R 7 is independently hydrogen or C 1-6A group optionally substituted when selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 7 group and R 7’ groups may optionally, together with the carbon atom between them, form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0296] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is 1-6 a group optionally substituted when selected from an aliphatic, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 7 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 7 is an optionally substituted phenyl. In some embodiments, R 7is an 8- to 10-membered bicyclic aromatic carbocyclic ring which may be optionally substituted. In some embodiments, R 7 is an optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0297] In some embodiments, R 7 is methyl. In some embodiments, R 7 is

Chem.

Chem.

Chem.

Chem.

[0298] In some embodiments, R 7 is

Chem.

[0299] In some embodiments, R 7 is [Chemistry] is. In some embodiments, R 7 is [Chemistry] is. In some embodiments, R 7 is [Chemistry] is. In some embodiments, R 7 is [Chemistry] is.

[0300] In some embodiments, R 7 is [Chemistry] is. In some embodiments, R 7 is [Chemistry] is. In some embodiments, R 7 is [Chemistry] is. In some embodiments, R 7 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0301] In some embodiments, the R 7 group and the R 7’ group bonded to the same carbon atom combine with the carbon atom between them to form a 3- to 8-membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, the R 7 group and the R 7’ group bonded to the same carbon atom combine with the carbon atom between them to form a 4- to 8-membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0302] In some embodiments, R 7 is selected from those shown in Table 1 below.

[0303] As defined above and as described herein, each R7’ is independently hydrogen or C 1-3 is aliphatic.

[0304] In some embodiments, R 7’ is hydrogen. In some embodiments, R 7’ is methyl. In some embodiments, R 7’ is ethyl. In some embodiments, R 7’ is n-propyl. In some embodiments, R 7’ is isopropyl.

[0305] In some embodiments, R 7’ is selected from those shown in Table 1 below.

[0306] As defined above and as described herein, each R 8 is independently hydrogen or C 1-4 is aliphatic, or; R 8 groups and the R 7 groups adjacent thereto may optionally form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0307] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is C 1-4 is aliphatic. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is n-propyl. In some embodiments, R 8 is isopropyl. In some embodiments, R 8 is n-butyl. In some embodiments, R 8 is isobutyl. In some embodiments, R 8 is tert-butyl.

[0308] In some embodiments, R 8 group and the R 7 group adjacent thereto combine with the atoms therebetween to form a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0309] In some embodiments, R 8 group and the R 7 group adjacent thereto combine with the atoms therebetween to

Chemical formula

Chemical formula

[0310] In some embodiments, R 8 is selected from those shown in Table 1 below.

[0311] As defined above and as described herein, R 9 is hydrogen, C 1-3 aliphatic, or -C(O)C 1-3 aliphatic.

[0312] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is C 1-3 aliphatic. In some embodiments, R 9 is -C(O)C 1-3 aliphatic.

[0313] In some embodiments, R 9 is methyl. In some embodiments, R 9is ethyl. In some embodiments, R 9 is n-propyl. In some embodiments, R 9 is isopropyl. In some embodiments, R 9 is cyclopropyl.

[0314] In some embodiments, R 9 is -C(O)Me. In some embodiments, R 9 is -C(O)Et. In some embodiments, R 9 is -C(O)CH2CH2CH3. In some embodiments, R 9 is -C(O)CH(CH3)2. In some embodiments, R 9 is -C(O)cyclopropyl.

[0315] In some embodiments, R 9 is selected from those shown in Table 1 below.

[0316] In some embodiments, R is the R described herein 7 In some embodiments, R a2 is the R described herein 7 In some embodiments, R a3 is the R described herein 7 In some embodiments, R is the R described herein 7’ In some embodiments, R a2 is the R described herein 7’ In some embodiments, R a3 is the R described herein 7’ In some embodiments, R is the R described herein 8 In some embodiments, R a2 is the R described herein 8 In some embodiments, R a3 is the R described herein 8It is. In some embodiments, R is the R described herein 8’ It is. In some embodiments, R a2 is the R described herein 8’ It is. In some embodiments, R a3 is the R described herein 8’ It is. In some embodiments, R is the R described herein 9 It is. In some embodiments, R a2 is the R described herein 9 It is. In some embodiments, R a3 is the R described herein 9 It is.

[0317] As defined above and as described herein, L 3 is

Chemical Formula

[0318] In some embodiments, L 3 is

Chemical Formula

[0319] In some embodiments, L 3 is

Chemical Formula

Chemical Formula

Chemical Formula

Chem.

Chem.

Chem.

[0320] In some embodiments, L 3 is selected from those shown in Table 1 below.

[0321] In some embodiments, L is the L described herein 3 as follows.

[0322] As defined above and as described herein, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0323] In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is 5. In some embodiments, o is 6. In some embodiments, o is 7. In some embodiments, o is 8. In some embodiments, o is 9. In some embodiments, o is 10.

[0324] In some embodiments, o is selected from those shown in Table 1 below.

[0325] In certain embodiments, useful agents, such as ARM, are those for which L 2 is

Chem.

[0326] In certain embodiments, a useful agent, e.g., ARM, where L 2 is [Chemical formula] and TBT is [Chemical formula] and thereby formula II-b: [Chemical formula] [wherein, each of L 1 , R 1 , R 1’ , R 2 , R 3 , R 3’ , R 4 , R 5 , R 5’ , R 6 and m is, each independently or in combination, as defined above and as described in the embodiments herein)] is a compound of formula II or a salt thereof that forms a compound of

[0327] In certain embodiments, a useful agent, such as ARM, is L 2 is

Chemical formula

Chemical formula

Chemical formula

[0328] In certain embodiments, a useful agent, such as ARM, is L 2 is

Chemical formula

Chemical formula

Chemical formula

[0329] In certain embodiments, a useful agent, such as ARM, is L 2 is

Chemical formula

Chemical formula

Chemical formula

[0330] In certain embodiments, a useful agent, such as ARM, is L 2 is

Chemical formula

Chemical formula

Chemical formula

[0331] In some embodiments, R a1 is the R described herein. In some embodiments, R a1 is optionally substituted C 1-4 is aliphatic

[0332] In some embodiments, L a1 is the L described herein a . In some embodiments, L a1 is a covalent bond

[0333] In some embodiments, L a2 is the L described herein a . In some embodiments, L a2 is a covalent bond

[0334] In some embodiments, L a is a covalent bond. In some embodiments, L a is C1-C 10 aliphatic or C1-C 10A divalent group, optionally substituted, when selected from heteroaliphatics, wherein one or more methylene units of said group are optionally and independently, -C(R’)2-, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -C(O)S- or -C(O)O-. In some embodiments, L a is a divalent group, optionally substituted, when selected from C1-C5 aliphatics or C1-C5 heteroaliphatics having 1 to 5 heteroatoms, wherein one or more methylene units of said group are optionally and independently, -C(R’)2-, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -C(O)S- or -C(O)O-. In some embodiments, L a is an optionally substituted divalent C1-C5 aliphatic, wherein one or more methylene units of said group are optionally and independently, -C(R’)2-, -Cy-, -O-, -S-, -S-S-, -N(R’)-, -C(O)-, -C(S)-, -C(NR’)-, -C(O)N(R’)-, -N(R’)C(O)N(R’)-, -N(R’)C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R’)-, -C(O)S- or -C(O)O-. In some embodiments, L a is an optionally substituted divalent C1-C5 aliphatic. In some embodiments, L a is an optionally substituted divalent C1-C5 heteroaliphatic having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0335] In some embodiments, R a2 is the R described herein. In some embodiments, Ra2 is the side chain of a natural amino acid. In some embodiments, R a3 is the R described herein. In some embodiments, R a3 is the side chain of a natural amino acid. In some embodiments, R 2a and R 3a one of which is hydrogen.

[0336] In some embodiments, each -Cy- is independently C 3-20 a cycloaliphatic ring, C 6-20 an aryl ring, a 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, which may be optionally substituted. In some embodiments, -Cy- is, for example, a ring which may be optionally substituted as described herein for R and Cy L but is divalent.

[0337] In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- includes a saturated cyclic moiety. In some embodiments, -Cy- includes a partially unsaturated cyclic moiety. In some embodiments, -Cy- includes an aromatic cyclic moiety. In some embodiments, -Cy- includes a combination of saturated, partially unsaturated, and / or aromatic cyclic moieties. In some embodiments, -Cy- is 3-membered. In some embodiments, -Cy- is 4-membered. In some embodiments, -Cy- is 5-membered. In some embodiments, -Cy- is 6-membered. In some embodiments, -Cy- is 7-membered. In some embodiments, -Cy- is 8-membered. In some embodiments, -Cy- is 9-membered. In some embodiments, -Cy- is 10-membered. In some embodiments, -Cy- is 11-membered. In some embodiments, -Cy- is 12-membered. In some embodiments, -Cy- is 13-membered. In some embodiments, -Cy- is 14-membered. In some embodiments, -Cy- is 15-membered. In some embodiments, -Cy- is 16-membered. In some embodiments, -Cy- is 17-membered. In some embodiments, -Cy- is 18-membered. In some embodiments, -Cy- is 19-membered. In some embodiments, -Cy- is 20-membered.

[0338] In some embodiments, -Cy- is a divalent C 3-20 cycloaliphatic ring, optionally substituted. In some embodiments, -Cy- is a divalent, saturated C 3-20 cycloaliphatic ring, optionally substituted. In some embodiments, -Cy- is a divalent, partially unsaturated C 3-20It is a cycloaliphatic ring. In some embodiments, -Cy-H is a cycloaliphatic that may be optionally substituted as described herein, for example, a cycloaliphatic embodiment for R.

[0339] In some embodiments, -Cy- is a C that may be optionally substituted. 6-20 It is an aryl ring. In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene. In some embodiments, -Cy- is an optionally substituted 1,3-phenylene. In some embodiments, -Cy- is an optionally substituted 1,4-phenylene. In some embodiments, -Cy- is an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an aryl that may be optionally substituted as described in the present invention, for example, an aryl embodiment for R.

[0340] In some embodiments, -Cy- is an optionally substituted divalent 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heteroaryl ring having 1 heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-H is an optionally substituted heteroaryl as described herein, for example, an embodiment of heteroaryl for R. In some embodiments, -Cy- is

Chemical formula

[0341] In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 3- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 to 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5- to 6-membered heterocyclyl ring having 1 heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent saturated heterocyclyl group. In some embodiments, -Cy- is an optionally substituted divalent partially unsaturated heterocyclyl group. In some embodiments, -Cy-H is an optionally substituted heterocyclyl as described in the heterocyclyl embodiments of the present invention, for example, for R.

[0342] In some embodiments, each Xaa is independently an amino acid residue. In some embodiments, each Xaa is independently an amino acid residue of an amino acid of A-I.

[0343] In some embodiments, t is 0. In some embodiments, t is from 1 to 50. In some embodiments, t is the z described herein.

[0344] In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some embodiments, z is 9. In some embodiments, z is 10. In some embodiments, z is 11. In some embodiments, z is 12. In some embodiments, z is 13. In some embodiments, z is 14. In some embodiments, z is 15. In some embodiments, z is 16. In some embodiments, z is 17. In some embodiments, z is 18. In some embodiments, z is 19. In some embodiments, z is 20. In some embodiments, z is greater than 20.

[0345] In some embodiments, R c is the R' described herein. In some embodiments, R c is the R described herein. In some embodiments, R c is -N(R')2, where each R' is independently as described herein. In some embodiments, R c is -NH2. In some embodiments, R c is R-C(O)-, where R is as described herein.

[0346] In some embodiments, a is 1. In some embodiments, a is from 2 to 100. In some embodiments, a is 5. In some embodiments, a is 10. In some embodiments, a is 20. In some embodiments, a is 50.

[0347] In some embodiments, b is 1. In some embodiments, b is from 2 to 100. In some embodiments, b is 5. In some embodiments, b is 10. In some embodiments, b is 20. In some embodiments, b is 50.

[0348] In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0349] In some embodiments, a2 is 0. In some embodiments, a2 is 1.

[0350] In some embodiments, L b is the L described herein. a In some embodiments, L b contains -Cy-. In some embodiments, L b contains a double bond. In some embodiments, L b contains -S-. In some embodiments, L b contains -S-S-. In some embodiments, L b contains -C(O)-N(R’)-.

[0351] In some embodiments, R’ is -R, -C(O)R, -C(O)OR or -S(O)2R, where R is as described herein. In some embodiments, R’ is R, where R is as described herein. In some embodiments, R’ is -C(O)R, where R is as described herein. In some embodiments, R’ is -C(O)OR, where R is as described herein. In some embodiments, R’ is -S(O)2R, where R is as described herein. In some embodiments, R’ is hydrogen. In some embodiments, R’ is not hydrogen. In some embodiments, R’ is R, and R is an optionally substituted C 1-20 aliphatic as described herein. In some embodiments, R’ is R, where R is an optionally substituted C 1-20 heteroaliphatic as described herein. In some embodiments, R’ is R, where R is an optionally substituted C 6-20 aryl as described herein. In some embodiments, R’ is R, where R is an optionally substituted C 6-20 arylalkyl as described herein. In some embodiments, R’ is R, where R is an optionally substituted C 6-20 arylheteroalkyl as described herein. In some embodiments, R’ is R, where R is an optionally substituted 5- to 20-membered heteroaryl as described herein. In some embodiments, R’ is R, where R is an optionally substituted 3- to 20-membered heterocyclyl as described herein. In some embodiments, two or more R’s are R and optionally, independently or together, form a ring as described herein that is optionally substituted.

[0352] In some embodiments, each R is independently -H or C 1-30C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 aryl heteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group optionally selected from, optionally substituted, or two R groups may optionally, independently, together form a covalent bond, or: two or more R groups on the same atom may optionally, independently, together with the atom, in addition to that atom, have 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and may form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring; or two or more R groups on two or more atoms may optionally, independently, in addition to the intervening atoms, have 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and may form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring.

[0353] In some embodiments, each R is independently -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30A 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from aryl, heteroaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group which may be optionally substituted, or Two R groups may optionally, independently, combine together to form a covalent bond, or: Two or more R groups on the same atom may optionally, independently, combine with that atom to form, in addition to that atom, an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon; Two or more R groups on two or more atoms may optionally, independently, form, in addition to the atoms between them, an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon.

[0354] In some embodiments, each R is independently -H or C 1-20 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon 1-20 heteroaliphatic, C 6-20 aryl, C 6-20 aryl aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-20 A 5- to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from aryl, heteroaliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3- to 20-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a group which may be optionally substituted, or Two R groups may optionally, independently, combine together to form a covalent bond, or: Two or more R groups on the same atom may, independently, together with that atom, have 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to that atom, and may form an optionally substituted 3- to 20-membered monocyclic, bicyclic, or polycyclic ring; Two or more R groups on two or more atoms may, independently, together with the atoms between them, have 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon in addition to the atoms between them, and may form an optionally substituted 3- to 20-membered monocyclic, bicyclic, or polycyclic ring.

[0355] In some embodiments, each R is independently -H or C 1-30 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 heteroaliphatic, C 6-30 aryl, C 6-30 arylalkyl, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 arylheteroaliphatic, 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and is an optionally substituted group selected therefrom.

[0356] In some embodiments, each R is independently -H or C 1-20 aliphatic, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-20 heteroaliphatic, C 6-20 aryl, C 6-20 arylalkyl, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-20A group selected from 5- to 20-membered heteroaryl having 1 to 10 heteroatoms independently selected from aryl, heteroaliphatic, oxygen, nitrogen, sulfur, phosphorus and silicon and 3- to 20-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, which group may optionally be substituted.

[0357] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is C 1-30 A C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 A group selected from C heteroaliphatic, aryl, 5- to 30-membered heteroaryl rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon and 3- to 30-membered heterocyclic rings having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, which group may optionally be substituted.

[0358] In some embodiments, R is hydrogen or C 1-20 A group selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic rings, 8- to 10-membered bicyclic saturated, partially unsaturated or aryl rings, 5- to 6-membered monocyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic rings having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur or 8- to 10-membered bicyclic heteroaryl rings having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which group may optionally be substituted.

[0359] In some embodiments, R is optionally substituted C 1-30 Aliphatic. In some embodiments, R is optionally substituted C1-20 It is aliphatic. In some embodiments, R is optionally substituted C 1-15 It is aliphatic. In some embodiments, R is optionally substituted C 1-10 It is aliphatic. In some embodiments, R is optionally substituted C 1-6 It is aliphatic. In some embodiments, R is optionally substituted C 1-6 It is alkyl. In some embodiments, R is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments, R is optionally substituted hexyl. In some embodiments, R is optionally substituted pentyl. In some embodiments, R is optionally substituted butyl. In some embodiments, R is optionally substituted propyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is hexyl. In some embodiments, R is pentyl. In some embodiments, R is butyl. In some embodiments, R is propyl. In some embodiments, R is ethyl. In some embodiments, R is methyl. In some embodiments, R is isopropyl. In some embodiments, R is n-propyl. In some embodiments, R is tert-butyl. In some embodiments, R is sec-butyl. In some embodiments, R is n-butyl. In some embodiments, R is -(CH2)2CN.

[0360] In some embodiments, R is optionally substituted C 3-30 It is cycloaliphatic. In some embodiments, R is optionally substituted C 3-20 Cycloaliphatic. In some embodiments, R is optionally substituted C 3-10It is cycloaliphatic. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0361] In some embodiments, R is an optionally substituted saturated or partially unsaturated carbocyclic ring having 3 to 30 members. In some embodiments, R is an optionally substituted saturated or partially unsaturated carbocyclic ring having 3 to 7 members. In some embodiments, R is an optionally substituted saturated or partially unsaturated 3-membered carbocyclic ring. In some embodiments, R is an optionally substituted saturated or partially unsaturated 4-membered carbocyclic ring. In some embodiments, R is an optionally substituted saturated or partially unsaturated 5-membered carbocyclic ring. In some embodiments, R is an optionally substituted saturated or partially unsaturated 6-membered carbocyclic ring. In some embodiments, R is an optionally substituted saturated or partially unsaturated 7-membered carbocyclic ring. In some embodiments, R is an optionally substituted cycloheptyl. In some embodiments, R is cycloheptyl. In some embodiments, R is an optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is an optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is an optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0362] In some embodiments, when R is a ring structure, such as cycloaliphatic, cycloheteroaliphatic, aryl, heteroaryl, etc., or includes the same, the ring structure can be monocyclic, bicyclic or polycyclic. In some embodiments, R is a monocyclic structure or includes the same. In some embodiments, R is a bicyclic structure or includes the same. In some embodiments, R is a polycyclic structure or includes the same.

[0363] In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 1-30 that is heteroaliphatic. In some embodiments, R is an optionally substituted C 1-20 that is heteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, or silicon (optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, or selenium) 1-20 that is heteroaliphatic. In some embodiments, R is

Chemical formula

Chemical formula

[0364] In some embodiments, R is an optionally substituted C 6-30 that is aryl. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is phenyl. In some embodiments, R is a substituted phenyl.

[0365] In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic saturated, partially unsaturated, or aryl ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic partially unsaturated ring. In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic aryl ring. In some embodiments, R is an optionally substituted naphthyl.

[0366] In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5- to 30-membered heteroaryl ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0367] In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, R is a substituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5- to 6-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.

[0368] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0369] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted pyrrolyl, furanyl, or thienyl.

[0370] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom and an additional heteroatom selected from sulfur or oxygen. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0371] In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 to 2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 3 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 2 nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1 nitrogen atom.

[0372] In certain embodiments, R is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0373] In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3- to 30-membered heterocyclic ring having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0374] In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5- to 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5- to 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 4-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, R is an optionally substituted 7-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0375] In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0376] In certain embodiments, R is an optionally substituted 5- to 6-membered partially unsaturated monocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted tetrahydropyridinyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl group.

[0377] In some embodiments, R is an optionally substituted 7- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted indolinyl. In some embodiments, R is an optionally substituted isoindolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroquinolinyl. In some embodiments, R is an optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, R is an optionally substituted azabicyclo[3.2.1]octanyl.

[0378] In some embodiments, R is an optionally substituted 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0379] In some embodiments, R is optionally substituted C 6-30 aryl aliphatic. In some embodiments, R is optionally substituted C 6-20 aryl aliphatic. In some embodiments, R is optionally substituted C 6-10 aryl aliphatic. In some embodiments, the aryl moiety of the aryl aliphatic has 6, 10, or 14 aryl carbon atoms. In some embodiments, the aryl moiety of the aryl aliphatic has 6 aryl carbon atoms. In some embodiments, the aryl moiety of the aryl aliphatic has 10 aryl carbon atoms. In some embodiments, the aryl moiety of the aryl aliphatic has 14 aryl carbon atoms. In some embodiments, the aryl moiety is optionally substituted phenyl.

[0380] In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-30 which is arylheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur 6-30 which is arylheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-20 which is arylheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, and sulfur 6-20 which is arylheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon 6-10 which is arylheteroaliphatic. In some embodiments, R is an optionally substituted C having 1 to 5 heteroatoms independently selected from oxygen, nitrogen, and sulfur 6-10 which is arylheteroaliphatic.

[0381] In some embodiments, two R groups may optionally and independently combine to form a covalent bond. In some embodiments, -C=O is formed. In some embodiments, -C=C- is formed. In some embodiments, -C≡C- is formed.

[0382] In some embodiments, two or more R groups on the same atom may optionally and independently combine with that atom and, in addition to that atom, may form an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and having from 3 to 30 members. In some embodiments, two or more R groups on the same atom may optionally and independently combine with that atom and, in addition to that atom, may form an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and having from 3 to 20 members. In some embodiments, two or more R groups on the same atom may optionally and independently combine with that atom and, in addition to that atom, may form an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and having from 3 to 10 members. In some embodiments, two or more R groups on the same atom may optionally and independently combine with that atom and, in addition to that atom, may form an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and having from 3 to 6 members. In some embodiments, two or more R groups on the same atom may optionally and independently form an optionally substituted monocyclic, bicyclic, or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and having from 3 to 5 members.

[0383] In some embodiments, two or more R groups on two or more atoms may optionally and independently combine with the atoms therebetween and, in addition to the atoms therebetween, may form an optionally substituted 3- to 30-membered, monocyclic, bicyclic or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, two or more R groups on two or more atoms may optionally and independently combine with the atoms therebetween and, in addition to the atoms therebetween, may form an optionally substituted 3- to 20-membered, monocyclic, bicyclic or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, two or more R groups on two or more atoms may optionally and independently combine with the atoms therebetween and, in addition to the atoms therebetween, may form an optionally substituted 3- to 10-membered, monocyclic, bicyclic or polycyclic ring having from 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, two or more R groups on two or more atoms may optionally and independently combine with the atoms therebetween and, in addition to the atoms therebetween, may form an optionally substituted 3- to 10-membered, monocyclic, bicyclic or polycyclic ring having from 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, two or more R groups on two or more atoms may optionally and independently combine with the atoms therebetween and, in addition to the atoms therebetween, may form an optionally substituted 3- to 6-membered, monocyclic, bicyclic or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, two or more R groups on two or more atoms may optionally and independently combine with the atoms therebetween and, in addition to the atoms therebetween, may form an optionally substituted 3- to 5-membered, monocyclic, bicyclic or polycyclic ring having from 0 to 3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0384] In some embodiments, the heteroatom in the structure formed by the R group or two or more R groups integrated together is selected from oxygen, nitrogen, and sulfur. In some embodiments, the ring formed is 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, 17-membered, 18-membered, 19-membered, or 20-membered. In some embodiments, the ring formed is saturated. In some embodiments, the ring formed is partially saturated. In some embodiments, the ring formed is aromatic. In some embodiments, the ring formed contains a saturated, partially saturated, or aromatic ring moiety. In some embodiments, the ring formed contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the ring formed contains 5 or fewer, 6 or fewer, 7 or fewer, 8 or fewer, 9 or fewer, 10 or fewer, 11 or fewer, 12 or fewer, 13 or fewer, 14 or fewer, 15 or fewer, 16 or fewer, 17 or fewer, 18 or fewer, 19 or fewer, or 20 or fewer aromatic ring atoms. In some embodiments, the aromatic ring atoms are selected from carbon, nitrogen, oxygen, and sulfur.

[0385] In some embodiments, the ring formed by two or more R groups integrated together (or two or more groups selected from the variable groups that can be R and R) is C 3-30 cycloaliphatic, C 6-30 aryl, a 5- to 30-membered heteroaryl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or a 3- to 30-membered heterocyclyl having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, a ring as described for R, but a divalent or polyvalent ring.

[0386] Typical compounds of the present invention are shown in Table 1 below. Table 1. Typical Compounds

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

[0387] In some embodiments, a useful ARM is a compound shown in Table 1 above or a pharmaceutically acceptable salt thereof.

[0388] Typical production methods of immune cells and ARM agents A variety of techniques in the art can be utilized to produce immune cells, such as NK cells, and the agents of the present invention. Specific methods, including isolation, purification, pre-activation, characterization, evaluation, etc., are described in Romee et al., Blood 120, 4751-4760, (2012); Leong et al., Biol. Blood Marrow Transplant. 20, 463-473 (2014); Romee et al., Sci Transl Med. 2016 Sep 21;8 (357):357ra123. doi: 10.1126 / scitranslmed.aaf2341, etc.

[0389] An agent such as an ARM can be produced, for example, by the methods shown in the examples.

[0390] For example, in some embodiments, a useful compound, such as an ARM, is constructed by a cycloaddition reaction, such as click chemistry or a modified method thereof.

[0391] In some embodiments, a compound useful for producing a compound, such as an agent of the present invention, such as an ARM, has the formula IV:

Chemical formula

[0392] In some embodiments, a compound, such as a compound useful for making a drug of the present invention, such as an ARM, has the formula IV-a:

Chemical formula

[0393] In some embodiments, a compound, such as a compound useful for making a drug of the present invention, such as an ARM, has the formula IV-b:

Chemical formula

[0394] In some embodiments, a compound, such as a compound useful for making a drug of the present invention, such as an ARM, has the formula IV-c:

Chemical formula

[0395] In some embodiments, a compound, such as a drug of the present invention, such as a compound useful for producing an ARM, has the formula IV-d:

Chemical formula

[0396] In some embodiments, a compound, such as a drug of the present invention, such as a compound useful for producing an ARM, has the formula V:

Chemical formula

[0397] In some embodiments, a method for producing a compound, such as an ARM, includes the following steps: Providing a first compound of formula IV, formula IV-a, formula IV-b, formula IV-c or formula IV-d or a salt thereof, comprising a first reactive moiety; Providing a second compound of formula V or a salt thereof, comprising a second reactive moiety; and Reacting the first compound with the second compound such that the first reactive moiety reacts with the second reactive moiety by a cycloaddition reaction.

[0398] Many cycloaddition reactions can be utilized according to the present invention. In some embodiments, the cycloaddition reaction is a [4+2] reaction. In some embodiments, the cycloaddition reaction is a [3+2] reaction. In some embodiments, the [3+2] reaction is a click chemistry reaction. In some embodiments, the first reactive moiety is -C≡C- and the second reactive moiety is -N3. In some embodiments, the first reactive moiety is -N3 and the second reactive moiety is -C≡C-.

[0399] 6. Use, Formulation, and Administration Pharmaceutically Acceptable Compositions In some embodiments, the present invention provides a composition comprising immune cells, such as pre-activated memory-like NK cells, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a composition comprising a drug and its pharmaceutically acceptable derivatives and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a composition comprising immune cells and a drug and its pharmaceutically acceptable derivatives and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, immune cells and a useful drug, such as ARM, are provided in separate compositions. In some embodiments, immune cells and a useful drug, such as ARM, are provided in separate compositions.

[0400] In many embodiments, the immune cells are administered in an amount sufficient to provide a therapeutic benefit without typically accompanying severe side effects. For example, in some embodiments, the immune cells are administered at 10,000 to 100 million, 100,000 to 50 million, 10,000 to 20 million, 100,000 to 10 million, 50,000, 100,000, 200,000, 300,000, 300,000, 500,000, 1 million, 2 million, 3 million, 4 million, 5 million, 6 million, 7 million, 8 million, 9 million, 10 million, 15 million, 20 million, 25 million, 30 million, 35 million, 40 million, 45 million, 50 million, 60 million, 70 million, 80 million, or 90 million cells per kg of the subject's body weight.

[0401] An agent, such as an ARM, is typically administered in an amount effective to selectively re-direct an endogenous antibody (e.g., an endogenous antibody) and / or a fragment thereof to a target cell, such as a cancer cell, thereby inducing cell-mediated immunity directed against the antibody, such as cytotoxicity. In certain embodiments, the amount of the compound in the composition of the present invention is sufficient to selectively re-direct an endogenous antibody in a biological sample or subject to a target cell, such as a cancer cell, thereby inducing cell-mediated cytotoxicity directed against the antibody. In some embodiments, the amount is from 0.01 to 100 mg / kg body weight. In some embodiments, the amount is from 0.01 to 50 mg / kg body weight. In some embodiments, the amount is from about 1 mg / kg to about 25 mg / kg.

[0402] In some embodiments, the pharmaceutically acceptable carrier, adjuvant or vehicle is a non-toxic carrier, adjuvant or vehicle that together does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate salts, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. In some embodiments, immune cells can be provided in a suitable medium.

[0403] In some embodiments, the agent can be provided as a pharmaceutically acceptable derivative, which can be a non-toxic salt, ester, salt of an ester or other derivative of the compounds of the present disclosure that can provide the agent directly or indirectly upon administration to a receptor.

[0404] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. In some embodiments, parenteral administration includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intraliver, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. Preferably, the composition containing immune cells is administered intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. The suspension can be formulated by techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and physiological saline. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium.

[0405] In some embodiments, a drug, such as ARM, the composition is formulated as a composition for delayed release and / or sustained release. Techniques for sustained release and / or slow absorption are widely available in the art and can be utilized by the present invention.

[0406] In some embodiments, a branded fixed oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids, such as oleic acid and its glyceride derivatives, may be useful in the preparation of injection solutions, and may also be natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. Such oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span and other emulsifiers or bioavailability enhancers commonly used in pharmaceutically acceptable solid, liquid or other dosage forms may also be used for the purposes of the formulation.

[0407] The agent of the present invention, such as a pharmaceutically acceptable composition of ARM, is administered orally in any orally acceptable dosage form, such as capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, may also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifying agent and a suspending agent. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0408] Solid dosage forms, such as for oral administration, include capsules, tablets, pills, powders, and granules. In some embodiments, the agent to be delivered, such as an ARM, is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or, a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0409] Solid compositions may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. In some embodiments, solid dosage forms of tablets, dragees, capsules, pills, and granules may be manufactured using coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art. In some embodiments, the solid composition may optionally include an opacifying agent and may release the agent to be delivered only to, or preferentially to, a particular part of the subject (e.g., a particular part of the digestive tract), optionally in a delayed manner. Examples of implantable compositions used include polymeric materials and waxes.

[0410] In some embodiments, the agent, e.g., ARM, can be in microencapsulated form having one or more of the excipients described above. In some embodiments, solid dosage forms such as tablets, dragees, capsules, pills and granules can be manufactured using coatings and shells, enteric coatings, controlled release coatings and other coatings known in the pharmaceutical field. In such solid dosage forms, the agent to be delivered can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms can also, in the normal practice, contain additional substances, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In some embodiments, in the case of capsules, tablets and pills, the dosage form can contain buffering agents.

[0411] Alternatively, the pharmaceutically acceptable composition can be administered in the form of suppositories for rectal administration. These can be manufactured by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

[0412] The pharmaceutically acceptable composition of the present invention can be administered topically, particularly when the target of treatment includes regions or organs that are readily accessible by topical application, including diseases of the eye, skin or lower gastrointestinal tract. Suitable topical formulations can be readily manufactured for each of these regions or organs.

[0413] For topical application, the pharmaceutically acceptable compositions can be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0414] For ophthalmic use, the pharmaceutically acceptable compositions can be formulated as a suspension micronized in pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride, or preferably as a solution in pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as an ointment such as petrolatum.

[0415] The pharmaceutically acceptable compositions can be administered by nasal aerosol or inhalation. Such compositions can be manufactured by techniques known in the pharmaceutical art and can be manufactured as an aqueous saline solution using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0416] Agents, such as pharmaceutically acceptable compositions of ARM, can be formulated for oral administration. Such formulations can be administered with food or without food. In some embodiments, the pharmaceutically acceptable compositions are administered without food. In other embodiments, the pharmaceutically acceptable compositions are administered with food.

[0417] Specific dosages and treatment regimens for a particular subject will depend on a variety of factors such as the activity of the specific immune cells and / or agents used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician as well as the severity of the particular disease being treated and should also be understood.

[0418] Use In particular, the present invention encompasses the recognition that certain immune cells, such as pre-activated memory-like NK cells, have improved properties and / or activity against their targets, such as cancer cells, and can be particularly effective for treating conditions, disorders or diseases such as cancer. However, such immune cells can induce more severe side effects as an off-target result, for example due to increased cytotoxicity. Thus, in some embodiments, the present invention provides techniques for exposing both such immune cells...

Claims

**Claim 1**: The following structure: 【Chemical 1】 A compound having the same or a pharmaceutically acceptable salt thereof. **Claim 2**: A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to Claim 1 and a pharmaceutically acceptable excipient. **Claim 3**: A pharmaceutical composition comprising a plurality of natural killer cells and a compound having the following structure: 【Chemical 2】 or a pharmaceutically acceptable salt thereof. **Claim 4**: The natural killer cells are memory-like natural killer cells or cytokine-induced memory-like natural killer cells induced by IL-12, IL-15 and IL-18; further comprising an antibody or a fragment thereof or a combination thereof; or being a combination of these The composition according to Claim 3. **Claim 5**: A combination agent for inducing cell death in a system, inhibiting cell proliferation or reducing the number of cells, comprising a plurality of natural killer cells and a compound having the following structure: 【Chemical Formula 3】 or a pharmaceutically acceptable salt thereof. **Claim 6**: A combination agent for treating a condition, disorder or disease, comprising a plurality of natural killer cells and a compound having the following structure: 【Chemical 4】 or a pharmaceutically acceptable salt thereof. **Claim 7**: The combination agent according to Claim 6, wherein the condition, disorder or disease is cancer. **Claim 8**: The combination agent according to Claim 6, wherein the condition, disorder or disease is cancer selected from prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer and lymphoma. **Claim 9**: A combination agent for reducing the side effects of cancer treatment, comprising a plurality of natural killer cells and a compound having the following structure: 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof. **Claim 10**: A combination agent for reducing the toxicity of cancer treatment, comprising a plurality of natural killer cells and a compound having the following structure: 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof. **Claim 11**: The natural killer cells are memory-like natural killer cells or cytokine-induced memory-like natural killer cells induced by IL-12, IL-15 and IL-18; The combination agent further comprises an antibody or a fragment thereof; The natural killer cells and the compound are administered in one composition; or These combinations The combination agent according to any one of claims 5 to 10.

12. The natural killer cells and the compound are administered simultaneously; The natural killer cells are administered prior to the compound; The natural killer cells are administered after the compound; The combination agent according to any one of claims 5 to 10.

13. A combination agent comprising a plurality of natural killer cells and a compound having the following structure: [Chemical Formula 7] or a pharmaceutically acceptable salt thereof.

14. The natural killer cells are memory-like natural killer cells or cytokine-induced memory-like natural killer cells induced by IL-12, IL-15 and IL-18; The combination agent further comprises an antibody or a fragment thereof; or These combinations The combination agent according to claim 13.

15. A method of inducing cell death, inhibiting cell proliferation and / or reducing the number of cells in a system, comprising administering the combination agent according to claim 13, wherein the system is a non-human animal, an ex vivo system or an in vitro system.

16. A method of treating a condition, disorder or disease, comprising administering the combination agent according to claim 13 to a non-human animal having the disease.

17. The condition, disorder or disease is cancer selected from prostate cancer, metastatic prostate cancer, gastric cancer, colon cancer, ovarian cancer, testicular cancer, bladder cancer, kidney cancer, brain / CNS cancer, head and neck cancer, pharyngeal cancer, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, kidney cancer and lymphoma. The method according to claim 16.

18. A method of reducing the side effects or toxicity of cancer treatment, comprising administering the combination agent according to claim 13 to a non-human animal having the disease.

19. The natural killer cells are memory-like natural killer cells or cytokine-induced memory-like natural killer cells induced by IL-12, IL-15, and IL-18; The combination agent further comprises an antibody or a fragment thereof; The natural killer cells and the compound are administered in one composition; or These combinations The method according to any one of claims 15 to 18.

20. The compound is administered together with an antibody or a fragment thereof; The natural killer cells and the compound are administered in one composition; or These combinations The method according to claim 19.

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