Combination therapy of ARM and natural killer cells

Abstract

Among other aspects, the present disclosure provides technologies comprising immune cells and antibody recruitment molecules. In some embodiments, the immune cells are memory-like natural killer cells. In some embodiments, the provided technologies are particularly useful for treating conditions, disorders, or diseases such as cancer. In some embodiments, the provided technologies provide higher efficacy. In some embodiments, the provided technologies provide fewer side effects or less severe side effects associated with natural killer cell therapy.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. application No. 62 / 783,036, filed December 20, 2018, the entire contents of which are incorporated herein by reference. Background Art

[0003] Immune system activity can be used to prevent or treat a variety of conditions, disorders, and diseases, including cancer. Summary of the Invention

[0004] Natural killer (NK) cells are capable of inducing cell death of various targets (e.g., diseased cells such as cancer cells). Among other aspects, NK cells (e.g., in vitro expanded and / or pre-activated NK cells) are being developed for cancer treatment. In some embodiments, the present disclosure encompasses the recognition that NK cell therapy can be significantly improved by agents that help and / or promote NK cells to recognize targets. In some embodiments, the present disclosure provides technologies (e.g., methods, compositions, etc.) comprising NK cells and such agents. In particular, in some embodiments, the present disclosure provides technologies comprising NK cells and antibody recruiting molecules (ARMs), the antibody recruiting molecules comprising (i) an antibody binding portion that can bind to one or more antibodies or fragments thereof, (ii) a target binding portion that can bind to a cell, and optionally (iii) a linker portion connecting the antibody binding portion and the target binding portion.

[0005] In some embodiments, ARM can significantly improve the efficiency of NK cell therapy, for example, by promoting NK cells to recognize target cells. In some embodiments, ARM can enhance the interaction between NK cells and their target cells, and / or promote the death of target cells induced by NK cells. In some embodiments, ARM promotes the activation of NK cells, for example, by recruiting antibodies to target cells, which can then recruit and activate NK cells.

[0006] Additionally or alternatively, in some embodiments, ARM reduces and / or delays 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 amplified before being administered to a subject. Such pre-activated NK cells are more powerful and may be necessary for effectively killing target cells, however, due to their activation, these cells may cause significantly more side effects, for example, killing unintended cells. Among other aspects, the present disclosure provides ARM that can guide NK cells to target cells and reduce the side effects and toxicity associated with NK cell therapy. In addition, in view of the reduced off-target effects, in some embodiments, more activated NK cells can be utilized to further improve treatment efficiency.

[0007] In addition to other aspects, the antibody binding portion (referred to in some embodiments as an antibody binding end (ABT)) can bind to an antibody (or its fragment). 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 ("universal ABT" or "uABT") can (among other aspects) recruit antibodies (or its fragment) with various antigen specificities, for example, by binding to the Fc region. In some embodiments, the use of uABT can avoid dependence on a specific antibody population and adverse effects that may be caused by individual variations in a specific antibody population. In some embodiments, uABT can preferentially recruit IgG1, IgG2, and / or IgG4. In some embodiments, the recruitment of antibodies (e.g., IgG subclasses) is limited by the dose of ARM administered and / or is not limited by the level of antibodies with a specific Fab region in the individual. In some embodiments, ABT binds to and recruits endogenous antibodies. In some embodiments, uABT preferably binds to IgG molecules over human IgA or IgM. Typically, after being bound by an antibody binding moiety, the antibody is still able to carry out one or more of its immunological activities, such as interacting with NK cells, which can result in the killing of target cells by the NK cells.

[0008] Typically, the target binding portion (in some embodiments, referred to as a target binding terminus (TBT)) can confer specificity to the ARM for its target (e.g., a diseased cell of interest) by, for example, binding to an entity (e.g., a cell surface receptor) that distinguishes targets from non-targets (e.g., diseased cells from other cell types).

[0009] Among other things, ARM can achieve target-specific antibody (e.g., endogenous antibodies, administered antibodies, etc.) recruitment by ABT, and / or trigger, generate, encourage and / or enhance NK cell-related immune activity, e.g., NK cells kill target cells. Various techniques (e.g., assays, reagents, methods, etc.) can be used to evaluate antibody binding portions, target binding portions, and ARM, and can be used according to the present disclosure.

[0010] In some embodiments, the ARM comprises:

[0011] Antibody binding portion,

[0012] a target binding moiety, and

[0013] an optional linker moiety,

[0014] The antibody binding portion can bind to the Fab region of an antibody.

[0015] In some embodiments, the ARM comprises:

[0016] Antibody binding portion,

[0017] a target binding moiety, and

[0018] an optional linker moiety,

[0019] The antibody binding portion can bind to the Fc region of an antibody.

[0020] In some embodiments, the ARM comprises:

[0021] Antibody binding portion,

[0022] a target binding moiety, and

[0023] an optional linker moiety,

[0024] The antibody binding portion may bind to two or more antibodies having different Fab regions.

[0025] In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) binds to the Fc region of an antibody. In some embodiments, the antibody binding portion (e.g., 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.

[0026] In some embodiments, an agent (eg, ARM) of the present disclosure is a compound having the structure of Formula I:

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the pharmaceutical agent is a compound of Formula I or a salt thereof.

[0029] In some embodiments, the pharmaceutical agent is a compound of Formula Ia:

[0030]

[0031] or a salt thereof, wherein each variable is as defined and described in the present disclosure. In some embodiments, the agent (e.g., ARM) is Formula Ia or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is a compound of Formula Ia.

[0032] In some embodiments, the pharmaceutical agent is a compound of Formula Ib:

[0033]

[0034] or a salt thereof, wherein each variable is as defined and described in the present disclosure. In some embodiments, the agent (e.g., ARM) is Formula Ib or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I provided is a compound of Formula Ib.

[0035] In some embodiments, the pharmaceutical agent (eg, ARM) is a compound having the structure of Formula II:

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the pharmaceutical 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 Ia is a compound of Formula II.

[0038] In some embodiments, the pharmaceutical agent (eg, ARM) is a compound having the structure of Formula III:

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. In some embodiments, the pharmaceutical agent is a compound of Formula III or a salt thereof. In some embodiments, the compound of Formula I is a compound of Formula III or a salt thereof. In some embodiments, the compound having the structure of Formula Ib is a compound of Formula III.

[0041] The combination of NK cells and agents (e.g., ARM) of the present disclosure can be particularly effective in treating various conditions, disorders, or diseases including cancer. In some embodiments, the present disclosure provides the following combination, comprising:

[0042] Expanded, enriched and / or pre-activated natural killer cell populations; and

[0043] Antibody Recruiting Molecule (ARM), wherein:

[0044] The ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to a target entity, and optionally a linker portion connecting the antibody binding portion and the target binding portion.

[0045] In some embodiments, the present disclosure provides methods for inducing cell death, inhibiting cell growth, and / or reducing cell number in a system, comprising administering to the system:

[0046] One or both of the following:

[0047] multiple natural killer cells; and

[0048] Antibody Recruiting Molecule (ARM),

[0049] wherein the ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to a cell, and optionally a linker portion connecting the antibody binding portion and the target binding portion;

[0050] The system is then exposed to both, and the number of cells in the system is reduced compared to when the natural killer cells and the antibody recruiting molecule are not present.

[0051] Those skilled in the art will appreciate that the provided technology is applicable to various systems as 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 that can be used 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 or comprises a cell culture.

[0052] In some embodiments, the present disclosure provides methods for treating cancer comprising administering to a subject having cancer:

[0053] One or both of the following:

[0054] multiple natural killer cells; and

[0055] Antibody Recruiting Molecule (ARM),

[0056] The ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to cancer cells, and optionally a linker portion connecting the antibody binding portion and the target binding portion.

[0057] The subjects were then exposed to both.

[0058] 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 that can be used as a disease model.

[0059] In some embodiments, the number of cancer cells in the subject is reduced compared to in the absence of natural killer cells and antibody recruitment molecules. In some embodiments, the growth of cancer cells in the subject is reduced compared to in the absence of natural killer cells and antibody recruitment molecules. In some embodiments, the proliferation of cancer cells in the subject is reduced compared to in the absence of natural killer cells and antibody recruitment molecules. In some embodiments, the volume of cancer cells in the subject is reduced compared to in the absence of natural killer cells and antibody recruitment molecules.

[0060] In some embodiments, the present disclosure provides methods for treating cancer comprising administering to a subject having cancer:

[0061] multiple natural killer cells; and

[0062] Antibody recruitment molecules,

[0063] The ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to cancer cells, and optionally a linker portion connecting the antibody binding portion and the target binding portion.

[0064] In some embodiments, the present disclosure provides methods for reducing toxicity or side effects of treatment with natural killer cells, comprising administering to a subject:

[0065] multiple natural killer cells; and

[0066] Antibody recruitment molecules,

[0067] The ARM comprises an antibody binding portion that can bind to one or more antibodies or fragments thereof, a target binding portion that can bind to a therapeutic target entity, and optionally a linker portion connecting the antibody binding portion and the target binding portion.

[0068] In some embodiments, the present disclosure provides improvements in methods of treating a subject by administering a plurality of natural killer cells, the improvements further comprising administering an antibody recruitment molecule (ARM), wherein the ARM comprises an antibody binding portion that can bind one or more antibodies or fragments thereof, a target binding portion that can bind a target entity, and optionally a linker portion that connects the antibody binding portion to the target binding portion.

[0069] An agent of the present disclosure (e.g., ARM) can be administered before, simultaneously with, and / or after NK cells (e.g., expanded, enriched, and / or pre-activated NK cells). BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 The provided technology has low toxicity. A. Frequency of dead NK cells. B. Frequency of dead NK cells normalized to DMSO-treated controls.

[0071] Figure 2 The provided technology can effectively kill cancer cells. A. Frequency of dead SUDHL-4 cells in NK-SUDHL-4 co-cultures. B. Frequency of dead SUDHL-4 cells in NK-SUDHL-4 co-cultures normalized to DMSO-treated controls.

[0072] Figure 3 .The technology provided can reduce the number of plasma cells.

[0073] Figure 4 .The technology provided does not cause unwanted NK cell cannibalism or causes low levels of unwanted NK cell cannibalism. DETAILED DESCRIPTION

[0074] 1. General Description of Certain Embodiments of the Invention:

[0075] As described above, in some embodiments, the present disclosure provides techniques for inducing cell death, inhibiting cell growth and / or reducing cell number in a system. Alternatively or additionally, in some embodiments, the present disclosure provides techniques for treating cancer and / or for reducing the toxicity and / or side effects of cellular immunotherapy (e.g., NK cell therapy).

[0076] In some embodiments, the present disclosure utilizes ARM medicaments together with cellular immunotherapies such as NK cell therapy (e.g., involving in vitro expansion of NK cells). In some embodiments, one or more ARM medicaments as described herein are administered to a subject who has, is, or will receive NK cell therapy, or who additionally has or will have a NK cell population targeting a site of interest (e.g., a tumor). Conversely, in some embodiments, cellular immunotherapy (e.g., NK cell therapy) is administered to a subject who has, is, or will receive an ARM medicament therapy as described herein.

[0077] In some embodiments, the present disclosure uses an ARM agent comprising an antibody binding portion, which can bind to antibodies (or fragments thereof) with different Fab structures. In particular, in some embodiments, the relevant ARM agent comprises an antibody binding portion that binds to the Fc region of an antibody; in certain embodiments, such binding to the Fc region of an antibody does not interfere with one or more immune activities of the antibody, for example, interaction with Fc receptors (e.g., CD16a), recruitment of effector cells (such as NK cells for ADCC), etc. As will be appreciated by those skilled in the art, the technology (agents, compounds, compositions, methods, etc.) comprising uABTs provided by the present disclosure can provide a variety of advantages. For example, the technology provided can utilize antibodies with different Fab regions in the immune system to avoid or minimize the adverse effects of antibody variation in a patient population, and can trigger and / or enhance immune activity against a target, for example, killing target diseased cells, such as cancer cells.

[0078] In some embodiments, the technology of the present disclosure can be used to recruit antibodies and NK cells to various targets (e.g., cancer cells). In some embodiments, the technology provided can be used to regulate the immune activity (e.g., ADCC involving NK cells) against targets (disease cells, foreign objects, or entities, etc.). In some embodiments, the technology provided can be used to regulate the activity of NK cells against target cells (e.g., diseased cells, such as cancer cells). In some embodiments, the target binding moiety is an inhibitor moiety. In some embodiments, the target binding moiety is an enzyme inhibitor moiety. In some embodiments, the target binding moiety is combined with cell surface entities (e.g., proteins, carbohydrates, lipids, etc.).

[0079] In some embodiments, the pharmaceutical agent (e.g., ARM) comprises:

[0080] Antibody binding portion,

[0081] a target binding moiety, and

[0082] an optional linker moiety,

[0083] The antibody binding portion may bind to the Fab region.

[0084] In some embodiments, the pharmaceutical agent (e.g., ARM) comprises:

[0085] Antibody binding portion,

[0086] a target binding moiety, and

[0087] an optional linker moiety,

[0088] The antibody binding portion can bind to the Fc region.

[0089] In some embodiments, the pharmaceutical agent (e.g., ARM) comprises:

[0090] Antibody binding portion,

[0091] a target binding moiety, and

[0092] an optional linker moiety,

[0093] The antibody binding portion may bind to two or more antibodies having different Fab regions.

[0094] In some embodiments, agents for practicing the technology of the present disclosure comprise two or more antibody binding moieties.In some embodiments, useful agents comprise two or more target binding moieties.

[0095] The antibody binding portion can interact with any part of the antibody. In some embodiments, the antibody binding portion binds to the Fc region of the antibody. In some embodiments, the antibody binding portion binds to the conserved Fc region of the antibody. In some embodiments, the antibody binding portion binds to the Fc region of the IgG antibody. As will be appreciated by those skilled in the art, various antibody binding portions, linkers and target binding portions can be used according to the present disclosure. In addition to other aspects, as demonstrated in the examples, in some embodiments, the present disclosure provides antibody binding portions, linkers and target binding portions and combinations thereof, which are particularly useful and effective for constructing ARM molecules to recruit antibodies to target cells and / or trigger, produce, encourage and / or enhance immune system activity against target cells (e.g., diseased cells, such as cancer cells).

[0096] In some embodiments, the antibody binding portion can bind to an Fc region that binds to an Fc receptor (e.g., FcγRIIIa, CD16a, etc.). In some embodiments, provided moieties and / or agents (e.g., compounds / ARMs of various formulae as described in this disclosure) comprise an antibody binding portion that binds to a complex comprising an Fc region and an Fc receptor. In some embodiments, the complex comprises:

[0097] A medicament comprising:

[0098] Antibody binding portion,

[0099] a target binding moiety, and

[0100] an optional linker moiety,

[0101] Fc region, and

[0102] Fc receptors,

[0103] The antibody binding portion of the agent may bind to two or more antibodies having different Fab regions.

[0104] In some embodiments, the Fc region is an Fc region of an endogenous antibody of the subject. In some embodiments, the Fc region is an Fc region of an exogenous antibody. In some embodiments, the Fc region is an Fc region of an administered agent. In some embodiments, the Fc receptor is from a diseased cell of the subject. In some embodiments, the Fc receptor is from a cancer cell of the subject.

[0105] In certain embodiments, the agent (eg, ARM) has Formula I:

[0106]

[0107] or a pharmaceutically acceptable salt thereof, wherein:

[0108] ABT is the antibody binding portion;

[0109] L is a divalent linker moiety connecting ABT and TBT; and

[0110] TBT is the target binding moiety.

[0111] In some embodiments, the ABT is a universal antibody binding moiety.

[0112] In some embodiments, the antibody binding portion comprises one or more amino acid residues. In some embodiments, the antibody binding portion is or comprises a peptide portion. In some embodiments, the antibody binding portion is or comprises a cyclic peptide portion. In some embodiments, such antibody binding portions comprise one or more natural amino acid residues. In some embodiments, such antibody binding portions comprise one or more non-natural natural amino acid residues.

[0113] In some embodiments, the amino acid has the structure of Formula AI:

[0114] NH(R a1 )-L a1 -C(R a2 )(Ra3 )-L a2 -COOH,

[0115] AI

[0116] or a salt thereof, wherein:

[0117] R a1 、R a2 、R a3 Each independently is -L a -R';

[0118] L a1 and L a2 Each is independently L a ;

[0119] Each L a are independently covalent bonds or selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20 a heteroaliphatic optionally substituted divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')-, -Cy-, -O-, -S-, -SS-, -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)-, -S(O)N(R')-, -C(O)S-, or -C(O)O-;

[0120] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 Alicyclic ring, C 6-20 aryl rings, 5-20 membered heteroaryl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0121] Each R' is independently -R, -C(O)R, -CO2R, or -SO2R;

[0122] Each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0123] Two R groups optionally and independently form together a covalent bond, or:

[0124] two or more R groups on the same atom are optionally and independently taken together with the atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

[0125] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0126] In some embodiments, the antibody binding portion is a cyclic peptide portion. In some embodiments, the compound (e.g., agent, ARM) is Formula Ia:

[0127]

[0128] or a salt thereof, wherein:

[0129] Each Xaa is independently an amino acid residue;

[0130] t is 0-50;

[0131] z is 1-50;

[0132] L is the connector part;

[0133] TBT is the target binding moiety;

[0134] Each R c Independently -L a -R';

[0135] a and b are each independently 1-200;

[0136] Each L a are independently covalent bonds or selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20a heteroaliphatic optionally substituted divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')-, -Cy-, -O-, -S-, -SS-, -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)-, -S(O)N(R')-, -C(O)S-, or -C(O)O-;

[0137] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 Alicyclic ring, C 6-20 aryl rings, 5-20 membered heteroaryl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0138] Each R' is independently -R, -C(O)R, -CO2R, or -SO2R;

[0139] Each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0140] Two R groups optionally and independently form together a covalent bond, or:

[0141] two or more R groups on the same atom are optionally and independently taken together with the atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

[0142] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0143] 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 Ia has structure.

[0144] In some embodiments, each amino acid residue, such as each Xaa in Formula Ia, is independently an amino acid residue having the structure of Formula AI. In some embodiments, each Xaa independently has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 In some embodiments, two or more side chains (e.g., R of an amino acid residue) of an amino acid residue (e.g., in a compound of Formula Ia) are a2 or R a3 R with another amino acid residue a2 or R a3 ) are optionally joined together 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, the two cysteine ​​residues form an -SS- bridge, as commonly observed in natural proteins. In some embodiments, the bridge formed has L b The structure of L b is L as described in this disclosure a In some embodiments, L b Each end of the cyclic peptide is independently connected to the main chain atom (for example, -(Xaa) in Formula Ia) z -ring atoms of the ring formed). In some embodiments, L b Contains an R group (for example, when L b When the methylene unit is replaced by -C(R)2- or -N(R)-), wherein the R group is the same as the R group attached to the main chain atom (e.g., R a1 、R a2 、R a3 In some embodiments, L b The amino acid residue (e.g., Xaa in Formula Ia) is linked to the ring via the side chain of the amino acid residue (e.g., Xaa in Formula Ia), e.g., by -(Xaa) z In some embodiments, such side chains comprise an amino group or a carboxylic acid group.

[0145] In some embodiments, Is the antibody binding portion ( In some embodiments, is a universal antibody binding portion. In some embodiments, is a universal antibody binding portion that can bind antibodies with different Fab regions. In some embodiments, is a general antibody binding portion that can bind to the Fc region. In some embodiments, the antibody binding portion (e.g., having In some embodiments, the antibody binding portion (e.g., having a structure of The antibody binding portion of the structure of In some embodiments, have structure.

[0146] In certain embodiments, the compound (eg, agent, ARM, etc.) has Formula II:

[0147]

[0148] or a pharmaceutically acceptable salt thereof, wherein:

[0149] R 1 、R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0150] R 1 and R 1 'optionally together with the intervening carbon atoms form a 3-8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0151] R 3 and R 3’ optionally together with the intervening carbon atoms thereof form a 3-8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0152] R 5 group and R attached to the same carbon atom 5’The group optionally forms together with its intervening carbon atom a 3-8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0153] Two R's 5 The group optionally forms together with its intervening atoms a C 1-10 An optionally substituted divalent linear or branched saturated or unsaturated hydrocarbon chain wherein 1 to 3 methylene units of the chain are independently and optionally replaced 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 -C(O)-. 1 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0154] R 1’ 、R 3’ and R 5’ are each independently hydrogen or optionally substituted C 1-3 aliphatic;

[0155] R 2 、R 4 and R 6 are each independently hydrogen or optionally substituted C 1-4 Aliphatic, or:

[0156] R 2 and R 1 optionally taken together with its intervening atoms to form a 4-8 membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0157] R 4 and R 3 optionally taken together with its intervening atoms to form a 4-8 membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0158] R 6 Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4-8 membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0159] L 1 is connected A trivalent linker portion;

[0160] L2 Is a covalent bond or C 1-30 An optionally substituted divalent linear or branched saturated or unsaturated hydrocarbon chain wherein 1 to 10 methylene units of the chain are independently and optionally replaced by -S-, -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 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0161] TBT is a target binding moiety; and

[0162] m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0163] In some embodiments, the antibody binding portion is or comprises a peptide portion. In some embodiments, the compound (e.g., agent, ARM, etc.) has a structure of Formula Ib:

[0164]

[0165] or a salt thereof, wherein:

[0166] Each Xaa is independently an amino acid residue;

[0167] Each z is independently 1-50;

[0168] Each L is independently a linker moiety;

[0169] TBT is the target binding moiety,

[0170] Each R c Independently -L a -R';

[0171] a1 and a2 are each independently 0 or 1, wherein at least one of a1 and a2 is not 0;

[0172] a and b are each independently 1-200;

[0173] Each L a are independently covalent bonds or selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20a heteroaliphatic optionally substituted divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')-, -Cy-, -O-, -S-, -SS-, -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)-, -S(O)N(R')-, -C(O)S-, or -C(O)O-;

[0174] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 Alicyclic ring, C 6-20 aryl rings, 5-20 membered heteroaryl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0175] Each R' is independently -R, -C(O)R, -CO2R, or -SO2R;

[0176] Each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0177] Two R groups optionally and independently form together a covalent bond, or:

[0178] two or more R groups on the same atom are optionally and independently taken together with the atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

[0179] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0180] 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 Ib has In some embodiments, the compound of Formula Ib has In some embodiments, the compound of Formula Ib has In some embodiments, the compound of Formula Ib has structure.

[0181] In some embodiments, each amino acid residue, such as each Xaa in Formula Ib, is independently an amino acid residue having the structure of Formula AI. In some embodiments, each Xaa independently has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 In some embodiments, two or more side chains (e.g., R of an amino acid residue) of an amino acid residue (e.g., in a compound of Formula Ia) are a2 or R a3 R with another amino acid residue a2 or R a3 ) are optionally joined together 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, the two cysteine ​​residues form an -SS- bridge, as commonly observed in natural proteins. In some embodiments, the bridge formed has L b The structure of L b is L as described in this disclosure a In some embodiments, L b Each end of the cyclic peptide is independently connected to the main chain atom (for example, -(Xaa) in Formula Ia) z -ring atoms of the ring formed). In some embodiments, L b Contains an R group (for example, when L b When the methylene unit is replaced by -C(R)2- or -N(R)-), wherein the R group is the same as the R group attached to the main chain atom (e.g., R a1 、R a2 、R a3 In some embodiments, L b The amino acid residue (e.g., Xaa in Formula Ia) is linked to the ring via the side chain of the amino acid residue (e.g., -(Xaa) in Formula Ib). zIn some embodiments, such side chains comprise an amino group or a carboxylic acid group.

[0182] In some embodiments, R c -(Xaa)z- is the antibody binding portion (R c -(Xaa)zH binding antibody). In some embodiments, R c -(Xaa)z- is a universal antibody binding portion. In some embodiments, R c -(Xaa)z- is a universal antibody binding portion that can bind antibodies with different Fab regions. c -(Xaa)z- is a general antibody binding portion that can bind to an Fc region. In some embodiments, the antibody binding portion (e.g., having R c -(Xaa)z- structure) can bind to the Fc region that binds to the Fc receptor. In some embodiments, R c -(Xaa)z- has In some embodiments, R c -(Xaa)zL- has structure.

[0183] In certain embodiments, the compound (eg, agent, ARM, etc.) has Formula III:

[0184]

[0185] or a pharmaceutically acceptable salt thereof, wherein:

[0186] Each R 7 are independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0187] R 7 group and R attached to the same carbon atom 7’ The group optionally forms, together with its intervening carbon atom, a 3-8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered optionally substituted saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0188] Each R7' is independently hydrogen or optionally substituted C1-3 aliphatic;

[0189] Each R8 is independently hydrogen or optionally substituted C1-4 aliphatic, or:

[0190] R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4-8 membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0191] R 9 is hydrogen, optionally substituted C 1-3 Aliphatic or -C(O)-(optionally substituted C 1-3 aliphatic);

[0192] L3 is the connection a divalent linker moiety with TBT;

[0193] TBT is a target binding moiety; and

[0194] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0195] 2. Definitions:

[0196] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version), Handbook of Chemistry and Physics (75th edition). In addition, 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 edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0197] Administration: As used herein, the term "administer" generally refers to administering a composition to a subject or system. One of ordinary skill in the art will appreciate that, where appropriate, a variety of routes can be used to administer to a subject (e.g., a human). For example, in some embodiments, administration can be ocular, oral, parenteral, topical, and the like. In certain specific embodiments, administration can be intrabronchial (e.g., by bronchial instillation), buccal, dermal (which can be or include, for example, one or more topical administrations to the dermis, intradermal, interdermal, transdermal, and the like), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic)), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, and the like. In some embodiments, administration can involve intermittent (e.g., multiple doses separated by time) administration and / or periodic (e.g., single doses separated by a common time period) administration. In some embodiments, administration can involve continuous dosing (eg, infusion) for at least a selected period of time.

[0198] Pharmaceutical Agent: Generally speaking, as used herein, the term "agent" may be used to refer to a compound or entity of any chemical class, including, for example, polypeptides, nucleic acids, carbohydrates, lipids, small molecules, metals, or combinations or complexes thereof. Where appropriate, as would be clear from the context to one skilled in the art, the term may be used to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof. Alternatively or additionally, as would be clear from the context, the term may be used to refer to a natural product, as it is found in and / or obtained from nature. In some instances, again as would be clear from the context, the term may be used to refer to one or more artificial entities, as it is produced by human manipulation and / or is not found in nature. In some embodiments, the agent may be used in isolated or pure form; in some embodiments, the agent may be used in crude form. In some embodiments, potential agents may be provided as a collection or library, for example, which may be screened to identify or characterize active agents therein. In some cases, the term "agent" may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises one or more polymer moieties. In some embodiments, the term "agent" may refer to a compound or entity that is not a polymer and / or is substantially free of any polymer and / or one or more specific polymer moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymer moieties. In some embodiments, the agent is a compound. In some embodiments, the agent is an ARM as described herein.

[0199] Aliphatic: As used herein, "aliphatic" means a straight (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, an aliphatic group contains 1-100 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-20 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-9 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-7 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof.

[0200] Alkenyl: As used herein, the term "alkenyl" refers to an aliphatic group, as defined herein, having one or more double bonds.

[0201] Alkenylene: The term "alkenylene" refers to a divalent alkenyl group.

[0202] Alkyl: As used herein, the term "alkyl" is given its ordinary meaning in the art and may 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, an alkyl group has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl group has about 1-20 carbon atoms in its backbone (e.g., C1-C2 for a straight chain). 20 ; For branched chains, C2-C 20 ), and alternatively have about 1-10 carbon atoms. In some embodiments, the cycloalkyl ring has about 3-10 carbon atoms in its ring structure (wherein such ring is monocyclic, bicyclic or polycyclic), and alternatively has about 5, 6 or 7 carbons in the ring structure. In some embodiments, the alkyl group can be a lower alkyl group, wherein the lower alkyl group contains 1-4 carbon atoms (e.g., C1-C4 for straight chain lower alkyl).

[0203] Alkylene: The term "alkylene" refers to a divalent alkyl group.

[0204] Amino acid: in its broadest sense, as used herein, refers to any compound and / or substance that can be incorporated into a polypeptide chain (e.g., by forming one or more peptide bonds). In some embodiments, an amino acid comprises an amino group and a carboxylic acid group. In some embodiments, an amino acid has the general structure NH(R')-C(R')2-COOH, wherein each R' is independently as described in the present disclosure. In some embodiments, an amino acid has the general structure H2N-C(R')2-COOH, wherein R' is as described in the present disclosure. In some embodiments, an amino acid has the general structure H2N-C(H)(R')-COOH, wherein R' is as described in the present disclosure. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a non-natural amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any of the twenty 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 prepared or obtained from a natural source. In some embodiments, the amino acids in the polypeptide, including the carboxyl and / or amino terminal amino acids, may contain structural modifications compared to the general structure described above. For example, in some embodiments, the amino acids may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., an amino group, a carboxylic acid group, one or more protons, one or more hydrogens, and / or hydroxyl groups are substituted) compared to the general structure. In some embodiments, such modifications may, for example, alter the circulatory half-life of the polypeptide containing the modified amino acid compared to a polypeptide containing an otherwise identical unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of the polypeptide containing the modified amino acid compared to a polypeptide containing an otherwise identical unmodified amino acid. As will be clear from the context, in some embodiments, the term "amino acid" may be used to refer to a free amino acid; in some embodiments, it may be used to refer to an amino acid residue of a polypeptide.

[0205] Animal: As used herein, refers to any member of the animal kingdom. In some embodiments, "animal" refers to a human of any sex 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., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or worms. In some embodiments, animals can be transgenic animals, genetically engineered animals, and / or clones.

[0206] Antibody: As used herein, the term "antibody" refers to a polypeptide comprising sufficient standard immunoglobulin sequence elements to confer specific binding to a particular target antigen. As is known in the art, naturally occurring intact antibodies are tetrameric agents of approximately 150 kD, consisting of two identical heavy chain polypeptides (each approximately 50 kD) and two identical light chain polypeptides (each approximately 25 kD), which associate with each other in a structure commonly referred to as a "Y-shaped" structure. Each heavy chain comprises at least four domains (each approximately 110 amino acids long) - an amino-terminal variable (VH) domain (located at the top of the Y structure), followed by three constant domains: CH1, CH2, and carboxyl-terminal CH3 (located at the base of the Y stem). A short region called the "switch" connects the heavy chain variable and constant regions. The "hinge" connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in the hinge region connect the two heavy chain polypeptides in the intact antibody to each other. Each light chain contains two domains - an amino-terminal variable (VL) domain, followed by a carboxyl-terminal constant (CL) domain, separated from each other by another "switch". A complete antibody tetramer contains two heavy chain-light chain dimers, in which the heavy and light chains are connected to each other by a disulfide bond; two additional disulfide bonds connect the heavy chain hinge regions to each other, thereby connecting the dimers to each other and forming a tetramer. Naturally produced antibodies are also glycosylated, usually on the CH2 domain. Each domain in a natural antibody has a structure characterized as an "immunoglobulin fold", which is composed of two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) stacked against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops, called "complementarity determining regions" (CDR1, CDR2, and CDR3), and four relatively invariant "framework" regions (FR1, FR2, FR3, and FR4). When a natural antibody folds, the FR regions form a beta sheet that provides a structural framework for the domain, and the CDR loop regions from the heavy and light chains come together in three-dimensional space to create a single hypervariable antigen-binding site located at the top of the Y structure. The Fc region of a naturally occurring antibody binds to elements of the complement system and also binds to receptors on effector cells (including, for example, effector cells that mediate cytotoxicity). As is known in the art, the affinity and / or other binding properties of the Fc region for Fc receptors can be modulated by glycosylation or other modifications. In some embodiments, the antibodies produced and / or utilized according to the present disclosure comprise a glycosylated Fc domain, including Fc domains having such modified or engineered glycosylation. For the purposes of the present disclosure, in certain embodiments, any polypeptide or polypeptide complex comprising sufficient immunoglobulin domain sequences found in natural antibodies may be referred to and / or used as an "antibody," regardless of whether such polypeptides are naturally produced (e.g., produced by an organism in reaction with an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods.In some embodiments, the antibody is a polyclonal antibody; in some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody has a constant region sequence unique to a mouse, rabbit, primate, or human antibody. In some embodiments, the antibody sequence elements are humanized, primatized, chimeric, etc., as known in the art. In addition, the term "antibody" as used herein may refer to a construct or form known or developed in any art in appropriate embodiments (unless otherwise indicated or the context clearly indicates) for utilizing antibody structure and function characteristics in alternative presentations. For example, in some embodiments, the antibody used in accordance with the present disclosure is in the following form, selected from, but not limited to: a complete IgA, IgG, IgE, or IgM antibody; a bispecific or multispecific antibody (e.g., . etc.); Antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments and isolated CDRs or collections 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., ); Small modular immunopharmaceuticals (“SMIPs TM ”); single-chain or tandem diabodies ( );VHH; microantibodies; Ankyrin repeat protein or DART;TCR-like antibody; microbial proteins; CovX-Bodies; and CrossMab. In some embodiments, an antibody may lack covalent modifications (e.g., attachment of glycans) that it would have if it were naturally produced. In some embodiments, an antibody may contain covalent modifications (e.g., attachment of glycans, payloads [e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.], or other side groups [e.g., polyethylene glycol, etc.]).

[0207] Approximately: As used herein, the term "approximately" or "about" when applied to one or more values ​​of interest refers to a value similar to the reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of either direction (greater than or less than) of the reference value, unless otherwise stated or otherwise apparent from the context (unless such number exceeds 100% of the possible values).

[0208] Aryl: The term "aryl" used alone or as part of a larger moiety (as in "aralkyl," "aralkoxy," "aryloxyalkyl," and the like) refers to a monocyclic, bicyclic, or polycyclic ring system having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic, or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, an aryl group is a biaryl group. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracenyl, and the like, which may have one or more substituents. In some embodiments, also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, among others, where the radical or point of attachment is on the aryl ring.

[0209]

[00155] Association: Two events or entities are "associated with" one another, as the term is used herein, if the presence, level, and / or form of one event or entity is correlated with the presence, level, and / or form of another event or entity. For example, a particular entity (e.g., a nucleic acid (e.g., genomic DNA, transcript, mRNA, etc.), polypeptide, genetic signature, metabolite, microorganism, cell, etc.) is considered associated with a particular disease, disorder, or condition if the presence, level, and / or form of the entity is correlated with the incidence and / or susceptibility of the disease, disorder, or condition (e.g., in a relevant population).

[0210] Carrier: As used herein, refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers may include sterile liquids such as water and oils, including oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In some embodiments, a carrier is or comprises one or more solid components.

[0211] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, condition groups, etc. that may be different from each other but are similar enough to allow comparisons to be made between them, such that one skilled in the art will understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, comparable condition groups, environments, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of different features. One of ordinary skill in the art will understand that, in context, in any given case, how much identity of two or more such agents, entities, situations, condition groups is required to be considered comparable. For example, one of ordinary skill in the art will understand that when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in the results or observed phenomena obtained under different environment groups, individuals, or populations are caused by or indicate changes in the features of these changes, the environment groups, individuals, or populations are comparable to each other.

[0212] Alicyclic: As used herein, the term "alicyclic" refers to a saturated or partially unsaturated aliphatic monocyclic, bicyclic or polycyclic ring system having, for example, 3 to 30 members, wherein the alicyclic ring system is optionally substituted. Alicyclic 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 group has 3-6 carbon atoms. The term "alicyclic" may also include alicyclic rings fused to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, wherein the group or point of attachment is located on the alicyclic 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, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon or C8-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units that are not aromatic. 10 Bicyclic hydrocarbons, either fully saturated or containing one or more unsaturated units which are not aromatic, C9-C 16 Tricyclic hydrocarbons.

[0213] 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 significant structural similarity to a reference substance, such as sharing a core or common structure, but also differs in some manner of isolation. In some embodiments, a derivative is a substance that can be produced from a reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be produced by performing a synthetic method that is substantially similar (e.g., shares multiple steps) to the synthetic method used to produce the reference substance.

[0214] Dosage form or unit dosage form: It will be understood by those skilled in the art that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic agent or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, such an amount is a unit dose (or a whole portion thereof) suitable for administration according to a dosing regimen that has been determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., administered with a therapeutic dosing regimen). It will be understood by those of ordinary skill in the art that the total amount of a therapeutic composition or medicament administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0215] Dosing regimen: Those skilled in the art will understand that the term "dosing regimen" can be used to refer to a group of unit doses (usually more than one) that are administered separately to a subject, typically separated by time periods. In some embodiments, a given therapeutic agent has a recommended dosing regimen that can include one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each dose separated in time from the other doses. In some embodiments, the individual doses are separated by time periods of the same length; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within a dosing regimen have the same unit dose amount. In some embodiments, different doses within a dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is different from the first dose amount. In some embodiments, the dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is the same as the first dose amount. In some embodiments, the dosing regimen is associated with a desired or beneficial outcome when administered to a relevant population (i.e., is a therapeutic dosing regimen).

[0216] Halogen: The term "halogen" means F, Cl, Br or I.

[0217] 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.).

[0218] Heteroaryl: The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to a monocyclic, bicyclic, or polycyclic ring system having, for example, 5 to 30 (e.g., 5, 6, 9, 10, 14, etc.) ring members, wherein at least one ring in the system is aromatic and at least one aromatic ring atom is a heteroatom. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, a heteroaryl group is a group having 5 to 14 ring atoms (i.e., monocyclic, bicyclic, or polycyclic); in some embodiments, a group having 5, 6, 9, 10, or 14 ring atoms. In some embodiments, a heteroaryl group has 6, 10, or 14 pi electrons in common in the cyclic array; and has from one to five heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furyl, 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 heterobiaryl, such as bipyridyl and the like. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the group or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl 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 term "heteroaryl ring" or "heteroaryl group", any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0219] Heteroatom: The term "heteroatom" means an atom that is neither carbon nor hydrogen. In some embodiments, the heteroatom is oxygen, sulfur, nitrogen, phosphorus, boron, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any basic nitrogen or quaternized form of a substitutable nitrogen of a heterocyclic ring (e.g., N as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +( 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, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur.

[0220] Heterocyclyl: As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a monocyclic, bicyclic, or polycyclic moiety (e.g., 3-30 members) that is saturated or partially unsaturated and has 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, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, the heterocyclyl group is a stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (preferably one to four) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen," when used to refer to the ring atoms of a heterocycle, includes substituted nitrogens. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine Oxazolin thiazolinone The terms "heterocycle / heterocyclyl ring", "heterocyclyl", "heterocyclic group / heterocyclic radical", "heterocyclic moiety" are used interchangeably herein and also include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or alicyclic rings (such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl), wherein the group or point of attachment is on the heteroaliphatic ring. The heterocyclyl group can be monocyclic, bicyclic, or polycyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0221] "Improve", "increase" or "decrease": as used herein, these terms or grammatically comparable comparative terms represent the value relative to a comparable reference measurement result. For example, in some embodiments, relative to the evaluation value obtained with a comparable reference agent, the evaluation value obtained with the purpose agent can be "improved". Alternatively or additionally, in some embodiments, relative to the evaluation value obtained under different conditions (for example, before or after an event such as administering the purpose agent) in the same subject or system or in different comparable subjects (for example, in a comparable subject or system different from the purpose subject or system, in the presence of one or more indicators of a particular disease, disorder or condition, or before being exposed to a condition or agent, etc.), the evaluation value obtained in the purpose subject or system can be "improved". In some embodiments, comparative terms refer to statistically relevant differences (for example, with prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will know or can easily determine the degree and / or prevalence of difference (which is required or sufficient to achieve such statistical significance) in a given context.

[0222] Partially unsaturated: As used herein, the term "partially unsaturated" refers to a moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass groups having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0223] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent (e.g., a compound) formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage amount suitable for administration in a therapeutic regimen, which unit dosage amount shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical compositions can be specially formulated for administration in solid or liquid forms, including those suitable for: oral administration, e.g., drench (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those directed for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for administration to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin, lungs, or mouth; intravaginally or intrarectally, e.g., as a pessary, cream, or foam; sublingually; ophthalmically; transdermally; or through the nose, lungs, and other mucosal surfaces.

[0224] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and with a reasonable benefit / risk ratio commensurate.

[0225] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that participates in delivering or transporting the subject 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 materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffered solutions; polyesters, polycarbonates, and / or polyanhydrides; and other nontoxic, compatible substances employed in pharmaceutical formulations.

[0226] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of compounds that are suitable for use in a pharmaceutical setting, i.e., salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known. For example, S.M. Berge et al. describe 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, which are salts formed by an amino group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other known methods (e.g., 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, dodecylsulfate, 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, such as salts formed by acidic groups of the provided compounds and bases. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. In some embodiments, pharmaceutically acceptable salts are ammonium salts (e.g., -N(R)3 + ). In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations formed using counterions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls with 1 to 6 carbon atoms, sulfonates, and arylsulfonates) when appropriate. In some embodiments, the compounds provided are in the form of pharmaceutically acceptable salts.

[0227] Protecting group:As used herein, phrase " protecting group (protecting group or protection group) " refers to the temporary substituent that protects potential reactive functional group from undesirable chemical transformation.The example of such protecting group includes ester of carboxylic acid, silyl ether of alcohol and acetal and ketal of aldehyde and ketone respectively. " Si protecting group " is the protecting group that comprises Si atom, such as Si-trialkyl (for example, trimethylsilyl, tributylsilyl, tert-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (for example, tert-butyldiphenylsilyl) or Si-aryl-dialkyl (for example, Si-phenyldialkyl).Usually, Si protecting group is attached to oxygen atom. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis [protective group in organic synthesis], 2nd edition; Wiley [Wiley Press]: New York, 1991). Such protecting group (and related protected part) are described in detail below.

[0228] Protected hydroxyl groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. Examples of suitable protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, propionates, valerates, crotonates, and benzoates. Specific examples of suitable esters include formates, benzoyl formates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivalate (trimethylacetate), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoate, 2,4,6-trimethylbenzoate. Examples of suitable carbonates include 9-fluorenylmethyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, vinyl carbonate, allyl carbonate, and p-nitrobenzyl carbonate. Examples of suitable silyl ethers include trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, triisopropylsilyl ether and other trialkylsilyl ethers. Examples of suitable alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, tert-butyl ether and allyl ether, or derivatives thereof. Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, β-(trimethylsilyl)ethoxymethyl ether and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl ether, p-methoxybenzyl (MPM) ether, 3,4-dimethoxybenzyl ether, o-nitrobenzyl ether, p-nitrobenzyl ether, p-halobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2-picolyl ether, and 4-picolyl ether.

[0229] Protected amines are well known in the art and include those described in detail in Greene (1999). Suitable mono-protected amines further include, but are not limited to, arylalkylamines, carbamates, allylamines, amides, and the like. Examples of suitable mono-protected amino moieties include tert-butoxycarbonylamino (-NHBOC), ethoxycarbonylamino, methoxycarbonylamino, trichloroethoxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxycarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethoxycarbonylamino (-NHFmoc), formamido, acetamido, chloroacetamido, dichloroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, tert-butyldiphenylsilyl, and the like. Suitable diprotected amines include amines substituted with two substituents (independently selected from those listed above as monoprotected amines), and further include cyclic imides such as phthalimide, maleimide, succinimide, etc. Suitable diprotected amines also include pyrrole, etc., 2,2,5,5-tetramethyl-[1,2,5]azadithiarolidine, etc., and azides.

[0230] Protected aldehydes are well 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, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazones, and derivatives thereof.

[0231] Protected carboxylic acids are well 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, etc. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, each of which is optionally substituted. Other suitable protected carboxylic acids include oxazolines and orthoesters.

[0232] Protected thiols are well 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 thioether, and trichloroethoxycarbonylthioesters, to name a few.

[0233] Reference: As used herein, describes a standard or control with which comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the test or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as will be understood by those skilled in the art, a reference or control is determined or characterized under conditions or circumstances comparable to those under evaluation. Those skilled in the art will understand that reliance on and / or comparison to a particular possible reference or control is only justified when there is sufficient similarity.

[0234] Substitution: As described herein, the compounds of the present disclosure may contain optionally substituted / substituted moieties. In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituents at each position may be the same or different. Combinations of substituents envisioned in accordance with the present disclosure are preferably combinations of substituents that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions permitted by their production, detection, and in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0235] Suitable monovalent substituents include halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2; can be R o Substituted -(CH2) 0-4 Ph; can be R o Substituted -(CH2) 0-4 O(CH2) 0-1 Ph; can be R o Substituted -CH=CHPh; can be R o Substituted -(CH2) 0-4 O(CH2) 0-1-pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)N(R o )2; -N(R o )C(S)N(R o )2; -(CH2) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)N(R o )2; -N(R o )N(R o )C(O)OR o [[ID=四十八]]; -(CH2)[[ID=四十九]] 0-4 [[ID=五十]]C(O)R[[ID=五十一]] o [[ID=五十二]]; -C(S)R[[ID=五十三]] o [[ID=五十四]]; -(CH2)[[ID=五十五]] 0-4 [[ID=五十六]]C(O)OR[[ID=五十七]] o [[ID=五十八]]; -(CH2)[[ID=五十九]] 0-4 [[ID=六十]]C(O)SR[[ID=六十一]]<反映出 o [[ID=六十二]]; -(CH2)[[ID=六十三]] 0-4 [[ID=六十四]]C(O)OSi(R[[ID=六十五]] o [[ID=六十六]])3; -(CH2)[[ID=六十七]] 0-4 [[ID=六十八]]OC(O)R[[ID=六十九]] o [[ID=七十]]; -OC(O)(CH2)[[ID=七十一]] 0-4 [[ID=七十二]]SR[[ID=七十三]] o [[ID=七十四]]; -(CH2)[[ID=七十五]] 0-4 [[ID=七十六]]SC(O)R[[ID=七十七]] o [[ID=七十八]]; -(CH2)[[ID=七十九]] 0-4 [[ID=八十]]C(O)N(R[[ID=八十一]] o [[ID=八十二]])2; -C(S)N(R[[ID=八十三]] o [[ID=八十四]])2; -C(S)SR[[ID=八十五]] o [[ID=八十六]]; -SC(S)SR[[ID=八十七]] o [[ID=八十八]]; -(CH2)[[ID=八十九]] 0-4 [[ID=九十]]OC(O)N(R[[ID=九十一]] o [[ID=九十二]])2; -C(O)N(OR[[ID=九十三]] o [[ID=九十四]])R[[ID=九十五]]<000反映出000214>[[ID=九十六]]; -C(O)C(O)R[[ID=九十七]] o [[ID=九十八]]; -C(O)CH2C(O)R Note: There seems to be an error in the provided text where some tags are not in the correct format (e.g., "反映出" instead of proper tags). This might affect the overall understanding and correct translation. The above translation is done based on the best understanding of the text with the given tags.o ;-C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ;-S(O)2N(R o )2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2N(R o )2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)N(R o )2;-Si(R o )3;-OSi(R o )3;-OSi(OR o )3;-P(R o )2;-P(OR o )2;-OP(R o )2;-OP(OR o )2;-N(R o )P(R o )2;-OP(O)(R o )2;-OP(O)(OR o )2;-N(R o )P(O)(R o )2;-N(R o )P(O)(OR o )2;-B(R o )2;-OB(R o )2;-OB(OR o )2;-P(O)(R o )2;-OP(O)(R o )2;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2; where each R o may be substituted as defined below and are independently hydrogen, C 1-20aliphatic, C having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus 1-20 Heteroaliphatic, -CH2-(C 6-14 aryl), -O(CH2) 0-1 (C 6-14 aryl), -CH2-(5-14 membered heteroaryl ring), a 5-20 membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the above definition, two independent occurrences of o Together with its one or more intervening atoms, it forms a 3-20 membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below.

[0236] R o (or by combining two independent occurrences of R o Suitable monovalent substituents on the ring (together with the intervening atoms thereof) are independently hydrogen, -(CH2) 0-2 R λ 、-(halogenated R λ ), -(CH2) 0-2 OH, -(CH2) 0-2 OR λ 、-(CH2) 0-2 CH(OR λ )2、-O(halogenated R λ )、-CN、-N3、-(CH2) 0-2 C(O)R λ 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR λ 、-(CH2) 0-2 SR λ 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR λ 、-(CH2) 0-2 NR λ 2. -NO2, -SiR λ 3. -OSiR λ 3. -C(O)SR λ 、-(C 1-4 linear or branched alkylene)C(O)OR λ , or -SSR λ , where each R λunsubstituted or preceded by "halo" which is substituted only with one or more halogens and independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph and a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0237] Suitable divalent substituents (eg, on suitable carbon atoms, nitrogen atoms, etc.) independently include the following: =O, =S, =CR * 2. =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2- 3O-, or -S(C(R * 2)) 2-3 S-, where each R * may be substituted as defined below and are independently hydrogen, C 1-20 aliphatic, C having 1-5 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 5-20 membered heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus), a 5-20 membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, or, notwithstanding the above definitions, two independent occurrences of R * Together with its one or more intervening atoms, it forms a 3-20 membered monocyclic, bicyclic or polycyclic saturated, partially unsaturated or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon and phosphorus, which may be substituted as defined below. Suitable divalent substituents bound to the ortho-substitutable atoms of the "optionally substituted" group include: -O(CR * 2) 2-3 O-.

[0238] R * (or by combining two independent occurrences of R * Suitable monovalent substituents on the ring (together with the intervening atoms thereof) are independently hydrogen, -(CH2) 0-2 Rλ 、-(halogenated R λ ), -(CH2) 0-2 OH, -(CH2) 0-2 OR λ 、-(CH2) 0-2 CH(OR λ )2、-O(halogenated R λ )、-CN、-N3、-(CH2) 0-2 C(O)R λ 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR λ 、-(CH2) 0-2 SR λ 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR λ 、-(CH2) 0-2 NR λ 2. -NO2, -SiR λ 3. -OSiR λ 3. -C(O)SR λ 、-(C 1-4 linear or branched alkylene)C(O)OR λ , or -SSR λ , where each R λ unsubstituted or preceded by "halo" which is substituted only with one or more halogens and independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph and a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. * Suitable divalent substituents of include =0 and =S.

[0239] In some embodiments, suitable substituents on the substitutable nitrogen of an "optionally substituted" group include Each of these are independently hydrogen, C which may be substituted as defined below 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with its one or more intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0240] In some embodiments, Suitable substituents on the aliphatic group are independently halogen, -R λ 、-(halogenated R λ ), -OH, -OR λ 、-O(halogenated R λ )、-CN、-C(O)OH、-C(O)OR λ 、-NH2、-NHR λ 、-NR λ 2, or -NO2, where each R λ unsubstituted or preceded by "halo" which is substituted only with one or more halogens and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0241] Subject: As used herein, the term "subject" or "test subject" refers to any organism to which a provided compound or composition according to the present disclosure is administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. 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 a disease, disorder, and / or condition, and / or be susceptible to a disease, disorder, and / or condition. In some embodiments, the subject is a human.

[0242] Susceptible: An individual who is susceptible to a disease, disorder, and / or condition is an individual who is at a higher risk of developing the disease, disorder, and / or condition than a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not be diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0243] Therapeutic agent: As used herein, the phrase "therapeutic agent" refers to an agent that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect when administered to a subject. In some embodiments, a therapeutic agent is any substance that can be used to alleviate, ameliorate, alleviate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, provided compounds are useful as therapeutic agents.

[0244] Therapeutic regimen: As used herein, the term "therapeutic regimen" refers to a regimen of dosages, the administration of which in the relevant population is likely to be associated with desired or beneficial therapeutic outcomes.

[0245] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. 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 suffering from or susceptible to the disease, disorder, and / or condition. As will be understood by one of ordinary skill in the art, the effective amount of a substance may vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue, and the like. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, ameliorates, relieves, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver the therapeutically effective amount. In some embodiments, the provided compound is administered in a therapeutically effective amount in a single dose or multiple unit doses.

[0246] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method for partially or completely alleviating, ameliorating, alleviating, inhibiting, preventing, delaying the onset of, reducing the severity of, and / or reducing the incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment can be administered to subjects who do not exhibit signs of the disease, disorder, and / or condition. In some embodiments, treatment can be administered to subjects who exhibit only early signs of the disease, disorder, and / or condition, for example, for the purpose of reducing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0247] Unit dose: As used herein, the expression "unit dose" refers to an amount administered as a single dose and / or as a physically discrete unit of a pharmaceutical composition. In many embodiments, a unit dose comprises a predetermined amount of an active agent. In some embodiments, a unit dose comprises an entire single dose of an agent. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, it is necessary or anticipated that multiple unit doses will be administered to achieve the desired effect. A unit dose can be, for example, a volume of a liquid (e.g., an acceptable carrier) containing a predetermined amount of one or more therapeutic agents, a predetermined amount of one or more solid forms of therapeutic agents, a sustained-release formulation, or a drug delivery device containing a predetermined amount of one or more therapeutic agents. It should be understood that a unit dose can be present in a formulation containing any of a variety of components in addition to one or more therapeutic agents. For example, an acceptable carrier (e.g., a pharmaceutically acceptable carrier), a diluent, a stabilizer, a buffer, a preservative, etc. can be included as described below. One skilled in the art will appreciate that, in many embodiments, the total appropriate daily dose of a particular therapeutic agent can include a portion or multiple unit doses, and this can be determined, for example, by an attending physician within the scope of sound medical judgment. In some embodiments, the specific effective dosage level for any particular subject or organism may depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific active compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration and rate of excretion of the specific active compound employed; the duration of the treatment; drugs and / or additional therapies used in combination or concomitantly with the specific compound or compounds employed, and like factors well known in the medical arts.

[0248] Unsaturated: As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0249] Wild-type: As used herein, the term "wild-type" has its art-understood meaning and refers to an entity having structure and / or activity as found in nature in a "normal" (as compared to mutated, diseased, altered, etc.) state or environment. One of ordinary skill in the art will understand that wild-type genes and polypeptides typically exist in a variety of different forms (e.g., alleles).

[0250] Unless otherwise indicated, salts (such as pharmaceutically acceptable acid or base addition salts), stereoisomeric forms, and tautomeric forms of the provided compounds (e.g., agents, ARMs, etc.) are also included. Unless otherwise indicated, structures depicted herein also include structures containing various isotopes (e.g., hydrogen replaced by deuterium or tritium, carbon replaced by 13 C or 14In some embodiments, the compositions comprising the compounds comprise an isotope at an enriched level in the compound. Such compounds and compositions can be used, among other things, as analytical tools, probes in biological assays, or therapeutic agents.

[0251] Unless otherwise clear from the context, in this disclosure, (i) the term "a / 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 cover the itemized components or steps, whether presented alone or with one or more additional components or steps; (iv) the terms "about" and "approximately" may be understood to allow for standard variations known to those of ordinary skill in the art; and (v) where ranges are provided, the endpoints are included.

[0252] 3. Cellular immunotherapy

[0253] Various immune cells, particularly NK cells, can be used together with the agents described herein to treat various conditions, disorders or diseases including cancer. Such cells can be administered before, simultaneously with and / or after the agents described herein (e.g., ARM). In some embodiments, such cells (e.g., NK cells) and agents (e.g., ARM) are administered simultaneously with the same composition comprising both NK cells and ARM. In some embodiments, such cells (e.g., NK cells) and agents (e.g., ARM) are administered simultaneously with separate compositions (e.g., a composition comprising NK cells but not comprising ARM and a composition comprising ARM but not comprising NK cells).

[0254] As will be appreciated by those skilled in the art, useful immune cells such as NK cells can be from various sources and / or engineered by a variety of methods. 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 cloned master iPSC lines. In some embodiments, NK cells are engineered to express certain receptors, for example, high-affinity, optionally non-cleavable CD16 receptors. In some embodiments, NK cells are engineered to express chimeric antigen receptors (CARs), for example, in some embodiments, NK cells can be engineered to express anti-CD19 CARs. In some embodiments, NK cells are CAR-NK cells. In some embodiments, NK cells are engineered to express cytokine receptors. In some embodiments, NK cells include IL-15 receptor fusions, which enhance persistence and amplification capacity without the need for co-administration of cytokine support. In some embodiments, NK cells are engineered to prevent the expression of certain cell proteins (for example, certain cell surface proteins). In some embodiments, NK cells are engineered to prevent the expression of CD38. In some embodiments, NK cells are derived from placenta. In some embodiments, NK cells are donor NK cells. In some embodiments, NK cells are haploid identical donor NK cells. In some embodiments, NK cells are mismatched donor NK cells. In some embodiments, NK cells are related donor NK cells, for example, mismatched related donor NK cells. In some embodiments, NK cells are unrelated donor NK cells. In some embodiments, NK cells are derived from subjects, for example, patients. In some embodiments, provided technology includes innate cell conjugates, for example, innate cell conjugates that are combined with innate cells (for example, NK cells and macrophages) and simultaneously combined with specific tumor cells. In some embodiments, NK cells are derived from cord blood stem cells and progenitor cells. In some embodiments, NK cells are obtained by regulating signal transduction pathways (for example, Notch signal transduction pathways). In some embodiments, nanoparticles are used to improve and / or maintain the growth of NK cells. In some embodiments, as described herein, NK cells are produced in vitro. In some embodiments, NK cells can be used as ready-made cell therapies with multiple doses of cryopreservation and storage.Examples of certain such technologies include those used by Fate Therapeutics, NantKwest Inc., Celularity, Inc., GCPharma, Sorrento Therapeutics, Inc., Affimed GmbH / MD Anderson Cancer Center, Gamida Cell Ltd., Nohla Therapeutics, Kiadis Pharma NV, etc. One skilled in the art will appreciate that antibodies and / or CARs directed against the specific antigens used in certain such technologies may not be required in the provided technologies comprising the ARMs described herein and may optionally be used.

[0255] Cell populations / preparations

[0256] In some embodiments, useful cells (e.g., NK cells) are processed before being applied to a subject. In many embodiments, NK cells are enriched, preactivated, and / or amplified in vitro before being applied to a subject. In some embodiments, compared with a reference composition (e.g., from the blood of a subject to whom such a composition is to be applied), the composition comprising NK cells for application is enriched in NK cells. In some embodiments, enrichment is or comprises an increase in the number of cells per unit volume (e.g., per mL). In some embodiments, enrichment is or comprises an increase in the percentage of NK cells in such compositions. In some embodiments, enrichment is or comprises 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 substantially pure NK cell composition because the non-NK cells in the composition are "impurities" (e.g., due to incomplete separation, purification, etc.) from the production process. As understood by those skilled in the art, chemical and biological processes rarely (if ever) complete and / or proceed to completion or achieve or avoid absolute results. Therefore, the term "substantially" is used in this disclosure to obtain inherent integrity that is potentially lacking in many biological and chemical phenomena.

[0257] Various techniques for enriching NK cells are available in the art and can be used according to the present disclosure. For example, in some embodiments, NK cells are separated using leukocyte apheresis, optionally with a purification step, such as CD3 depletion and / or CD56 positive selection. In some embodiments, NK cells (e.g., pre-activated memory-like NK cells) are enriched in CD56 and depleted of CD3 expressing cells compared to a reference NK cell population (e.g., NK cells in donor or subject blood).

[0258] Prior to administration to a subject, NK cells are typically preactivated, e.g., with cytokines (e.g., IL-12, IL-15, and IL-18) for a suitable period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 or more hours, e.g., about 16 hours). In some embodiments, NK cells are treated with cytokines prior to administration. In some embodiments, NK cells are processed 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) for a suitable time period (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 or more hours, e.g., about 16 hours) to pre-activate them. The pre-activation conditions of NK cells and pre-activated NK cells can be assessed by assessing one or more markers (e.g., CD94, NKG2A, NKp46, CD25, NKp30, NKp44, CD62L, CD27, TRAIL, cytotoxic molecules perforin and granzyme B, etc.). Some useful markers are described in the following literature: 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 are differentiated into memory-like NK cells in vitro via pre-activation with IL-12, IL-15, and IL-18.

[0259] Among other things, this cytokine-induced memory-like NK cell shows an enhanced response to cytokine or activating receptor restimulation within weeks to months after pre-activation, and can be particularly used to treat various conditions, disorders or diseases including cancer. In some embodiments, such pre-activated memory-like NK cells have enhanced interferon-γ (IFN-γ) production and / or cytotoxicity for target cells (e.g., cancer cells). Exemplary procedures for preparing, evaluating and administering such NK cells can be found in the following literature: 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. September 21, 2016; 8 (357): 357ra123.doi: 10.1126 / scitranslmed.aaf2341; etc. In some embodiments, such NK cells have enhanced proliferation, express or express higher levels of high affinity IL-2 receptor αβγ, and / or provide increased IFN-γ production upon restimulation (e.g., with cytokines or via activating receptors, etc.), compared to comparable reference NK cells (e.g., similarly prepared but not pre-activated (e.g., not treated with cytokines, treated only with low dose IL-15, etc.)).

[0260] Compared with reference NK cells, pre-activated memory-like NK cells may have significant differences in the expression of many proteins (e.g., CD94, NKG2A, NKp46, CD25, NKp30, NKp44, CD62L, CD27, TRAIL, cytotoxic molecules perforin and granzyme B, etc.). In some embodiments, such NK cells show a decrease in NKp80 expression. Among other aspects, such markers can be used to enrich, purify and / or identify memory-like NK cells alone or in combination. Exemplary useful markers can be identified using a variety of techniques, for example, a large number of cell counting methods and multidimensional analysis. Exemplary procedures and exemplary 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. September 21, 2016; 8(357):357ra123.doi:10.1126 / scitranslmed.aaf2341.

[0261] In some embodiments, immune cells (e.g., NK cells) are contacted with a GSK3α / β inhibitor. In some embodiments, such cells are pre-activated by a GSK3α / β inhibitor.

[0262] In some embodiments, immune cells are cytokine-inducible memory-like NK cells. In some embodiments, immune cells are IL-12, IL-15 and IL-18 pre-activated NK cells. In some embodiments, immune cells are allogeneic, HLA-haploid identical, IL-12, IL-15 and IL-18 pre-activated NK cells. The present invention is not subject to any restriction, and the memory-like NK cells after IL-12, IL-15 and IL-18 pre-activation may be produced by a process including differentiation, and the differentiation produces long-term functional capacity changes. Memory-like NK cells with this functional capacity can be prepared by processing with other agents (e.g., other cytokines, or other small molecules, peptides, proteins, etc.). For assessing the technology (for example, protein markers, determination etc.) of the treatment of such as medicament and / or result NK cell, it is available in the art and can be used according to the present disclosure (for example, Romee et al., Sci Transl Med. 2016 Sep 21st; 8(357): those described in 357ra123.doi:10.1126 / scitranslmed.aaf2341). In some embodiments, memory-like NK cells have inhibitory receptors, activating receptors and cytokine receptors (for example, CD94 / NKG2A, NKp30, NKp44, NKp46, NKG2D, CD62L and CD25 etc.) increased expression, and / or the expression of certain proteins (for example, NKp80) reduction. In some embodiments, the level of certain receptors is substantially unchanged (for example, KIR, CD57, NKG2C, DNAM-1, CD137, CD11b etc.). In some embodiments, the changes of activation, inhibition, cytokine and adhesion receptors are consistent with differentiation. In some embodiments, cytokine pre-activation provides epigenetic regulation of certain genes (e.g., IFN-γ). For example, in some embodiments, IL-12, IL-15, and IL-18 activation (e.g., for 5 days) result in reduced methylation of 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 activation state without substantial differentiation.

[0263] In some embodiments, the NK cells are administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or 4, 5, 6, 7, 8, 9, 10, 11 months, or several months after pre-activation.

[0264] Among other things, the present disclosure includes the recognition that such NK cells with enhanced properties and / or activity can provide enhanced cancer cell inhibition or killing, potentially leading to more and / or more severe side effects and / or toxicity, for example, off-target toxicity to normal cells. Accordingly, in some embodiments, the present disclosure provides techniques for reducing such side effects and / or toxicity, comprising administering one or more agents (particularly ARMs) that can, among other things, promote, encourage, and / or enhance the interaction of NK cells with their targets and reduce side effects and / or toxicity associated with NK cell administration.

[0265] In some embodiments, NK cells are expanded, for example, before, during and / or after pre-activation.In some embodiments, NK cells are purified before administration to remove, for example, certain culture media (or components thereof), activating cytokines, etc.

[0266] In some embodiments, the NK cells to be administered to a subject are isolated and / or expanded from the subject (autologous). In some embodiments, the NK cells to be administered to a subject are isolated and / or expanded from another subject (allogeneic; e.g., from an HLA-haploid identical donor).

[0267] In some embodiments, NK cells are treated (e.g., isolated, purified, pre-activated, etc.) as described above prior to administration. In some embodiments, the NK cell composition for administration comprises certain artificial culture media or components thereof, e.g., complete RPMI-1640 medium containing L-glutamine, HEPES, NEAA, penicillin / streptomycin, and 10% human AB serum, optionally supplemented with rhIL-15 (1 ng / mL) to support survival.

[0268] Application

[0269] Immune cells (e.g., pre-activated memory-like NK cells) can be formulated in various forms known in the art for use in subjects. Depending on the subject and / or condition, disorder, or disease to be treated, a suitable amount of cells is administered to provide clinical benefit. In some embodiments, the cell dosage level is 0.01-100, 0.1-50, 0.1-20, 0.1-10, 0.05, 0.1, 0.2, 0.3, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90 million / kg. In some embodiments, the dosage level is 0.5x10 6 In some embodiments, the dosage level is 1x10 6 In some embodiments, the dosage level does not exceed 10x106 As will be appreciated by those skilled in the art, pre-activated memory-like NK cells can be administered at lower levels to achieve the same or greater clinical benefit, or provide greater clinical benefit when administered at the same level, compared to unactivated NK cells or non-memory-like pre-activated NK cells (e.g., treated with only IL-2 or IL-15, for example, overnight).

[0270] In many embodiments, cells are administered via intravenous infusion. In some embodiments, a composition comprising cells (e.g., pre-activated NK cells) is administered via infusion. In some embodiments, such compositions are administered by adoptive transfer.

[0271] In some embodiments, the subject (e.g., AML patient) is pretreated with a chemotherapeutic drug (e.g., on day 0) prior to administration of the cells. For example, in some embodiments, the AML patient is pretreated on day 0 with fludarabine / cyclophosphamide.

[0272] In some embodiments, immune cells (e.g., pre-activated NK cells) are administered before administering a medicament such as ARM. In some embodiments, they are administered simultaneously with a medicament such as ARM. In some embodiments, they are administered after a medicament such as ARM. In some embodiments, when not administered simultaneously, immune cells (e.g., pre-activated NK cells) and a medicament such as ARM are administered in a manner such that the subject is exposed to both. Some techniques for administering NK cells are described in Miller et al., Blood 105, 3051-3057 (2005), and can be used according to the present disclosure.

[0273] In some embodiments, after or simultaneously with the administration of immune cells, certain cytokines are administered to support the administered immune cells. In some embodiments, a generally low dose of rhIL-2 is administered to support memory-like NK cells by the high affinity IL-2Rαβγ induced by it. For example, see Leong et al., Biol. Blood Marrow Transplant, 20, 463-473 (2014).

[0274] In some embodiments, for example, donor or patient-specific anti-HLA monoclonal antibodies are used to track donor memory-like NK cells in the blood of a subject with informative HLA. In some embodiments, such cells reach a frequency peak on the 7th to 14th day after, for example, infusion, and the number may decrease after the recipient T cells recover. If necessary, additional doses of such NK cells (in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more dosages may be administered) can be administered. In some embodiments, at a certain time after administration (for example, on the 7th day), memory-like NK cells include no less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80% or 90% of blood NK cells. In some embodiments, the level exceeds about 10%. In some embodiments, the level exceeds about 20%. In some embodiments, the level exceeds about 30%. In some embodiments, the level exceeds about 40%. In some embodiments, the level exceeds about 50%. In some embodiments, the level exceeds about 60%. In some embodiments, the level exceeds about 70%. In some embodiments, the level exceeds about 80%. In some embodiments, the level exceeds about 90%. In some embodiments, for example, compared to the 1st day and a later time point (for example, the 7th day), the count of memory-like NK cells in the blood increases by at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 times. In some embodiments, the increase is at least 100 times. In some embodiments, the increase is at least 200 times. In some embodiments, the increase is at least 300 times. In some embodiments, the increase is at least 400 times. In some embodiments, the increase is at least 500 times. In some embodiments, the increase is at least 600 times. 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, after administration of memory-like NK cells (e.g., on days 5, 6, 7, 8, 9, 10, 11, 12, 13, and / or 14), the percentage and absolute number (count) of memory-like NK cells also increase, for example, to the above-mentioned percentages (e.g., not less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, at least 90%) and counts (e.g., 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000-fold or more; in some embodiments, 100, 200, 300, 400, 500, 600-fold or more).

[0275] In some embodiments, the memory-like NK cells have enhanced function following administration, e.g., as demonstrated by increased IFN-γ production following stimulation.

[0276] In some embodiments, memory-like NK cells have increased proliferation (Ki-67 + ).

[0277] In some embodiments, pre-activated memory-like NK cells are cytokine-inducible memory-like NK cells. In some embodiments, memory-like NK cells express inhibitory KIR receptors. In some embodiments, no matter how KIR-ligands interact, such cells can perform one or more functions (e.g., inhibit and / or kill target cells such as cancer cells).

[0278] In some embodiments, the immune cells (e.g., memory-like NK cells) administered are detectable in the blood and bone marrow of the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or longer. In some embodiments, such cells proliferate and / or amplify in vivo after being administered to the subject. In some embodiments, such cells differentiate in the subject and show enhanced functionality for targets such as cancer cells (e.g., leukemia cells).

[0279] In some embodiments, immune cells (e.g., pre-activated NK cells) are administered simultaneously with ARM. In some embodiments, they are administered with a single composition. In some embodiments, they are administered as separate compositions.

[0280] In some embodiments, an appropriate amount of antibody can also be administered together with ARM, in the same composition or in a separate composition (and optionally can be administered before, simultaneously with, or after ARM). In some embodiments, a composition comprising ARM, preactivated NK cells, and optional antibodies or fragments thereof is administered. In some embodiments, a composition comprising ARM, preactivated NK cells, and optional IgM is administered, and the ARM comprises uABT. In some embodiments, the composition provided comprises a complex comprising NK cells, antibodies, or fragments thereof, and ARM. In some embodiments, in such a complex, the CD16a receptor of the NK cell interacts with the antibody or fragment thereof, and the antibody binding portion of the ARM interacts with the same antibody or fragment thereof.

[0281] 4. Exemplary ARM Agents

[0282] Various ARM agents can be used according to the present disclosure. In some embodiments, ARM comprises an antibody binding portion that interacts with the Fab region, and can preferably bind to and recruit antibodies (and / or fragments thereof) containing such Fab regions. In some embodiments, ARM comprises an antibody binding portion that interacts with the Fc region (e.g., uABT as described herein), and can bind to and recruit various antibodies (and / or fragments thereof) containing such Fc regions. As will be appreciated by those skilled in the art, the antibodies (and / or fragments thereof) recruited by such ARMs can contain different Fab regions and can have different specificities. In some embodiments, no single recruited antibody (or fragment thereof) has more than 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 recruited antibodies and fragments thereof.

[0283] In certain embodiments, useful ARMs are compounds of Formula I:

[0284]

[0285] or a pharmaceutically acceptable salt thereof, wherein:

[0286] ABT is the antibody binding portion;

[0287] L is a divalent linker moiety connecting ABT and TBT; and

[0288] TBT is the target binding moiety.

[0289] In some embodiments, a useful ARM is a compound of Formula Ia or a salt thereof. In some embodiments, a useful ARM is a compound of Formula Ib or a salt thereof.

[0290] In certain embodiments, a useful ARM is a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein:

[0291] R 1 、R 3 and R 5 are each independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0292] R 1 and R 1' Optionally, together with the intervening carbon atoms, they form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0293] R 3 and R 3’ Optionally, together with the intervening carbon atoms, they form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0294] R 5 group and R attached to the same carbon atom 5’ The group optionally forms, together with its intervening carbon atom, a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0295] Two R's 5 The group optionally forms together with its intervening atoms a C 1-10 A divalent linear or branched saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced 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 -C(O)-. 1 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0296] R 1’、R 3’ and R 5’ are each independently hydrogen or C 1-3 aliphatic;

[0297] R 2 、R 4 and R 6 are each independently hydrogen or C 1-4 Aliphatic, or:

[0298] R 2 and R 1 optionally together with its intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0299] R 4 and R 3 optionally together with its intervening atoms form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0300] R 6 Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0301] L 1 is connected of

[0302] trivalent linker moiety;

[0303] L 2 Is a covalent bond or C 1-10 A divalent straight or branched saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -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 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0304] TBT is a target binding moiety; and

[0305] m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0306] In certain embodiments, a useful ARM is a compound of Formula III:

[0307]

[0308] or a pharmaceutically acceptable salt thereof, wherein:

[0309] Each R 7 are independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or:

[0310] R 7 group and R attached to the same carbon atom 7’ The group optionally forms, together with its intervening carbon atom, a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0311] Each R 7' are independently hydrogen or C 1-3 aliphatic;

[0312] Each R 8 are independently hydrogen or C 1-4 Aliphatic, or:

[0313] R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0314] R 9 It is hydrogen, C 1-3 Aliphatic or -C(O)C 1-3 aliphatic;

[0315] L 3 is connected a divalent linker moiety with TBT;

[0316] TBT is a target binding moiety; and

[0317] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0318] Antibody binding portion

[0319] Various antibody binding portions are known in the art and can be used in accordance with the present disclosure.

[0320] In some embodiments, the antibody binding portion interacts primarily with the Fab region.In some embodiments, the antibody binding portion interacts primarily with antibodies and / or fragments thereof comprising certain Fab structures and / or directed against certain antigens.

[0321] In some embodiments, the antibody binding portion interacts with the Fc region. In some embodiments, the antibody binding portion described herein (e.g., uABT) interacts with the Fc region and can recruit the Fc region that has been connected to the Fab region with different structures and / or antigenic specificities. In some embodiments, a useful agent comprises a universal antibody binding portion that can bind to antibodies with 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, the binding of the antibody binding portion to the antibody (or its fragment) (e.g., the binding of uABT to the Fc region) can occur simultaneously with the binding of the Fc receptor (e.g., CD16a) to the same antibody (or its fragment) (e.g., in the case of uABT binding to Fc, it can occur at different positions / amino acid residues in the same Fc region). In some embodiments, after binding to a universal antibody binding portion, the Fc region can still interact with an Fc receptor and carry out one or more or all of its immune activities, including recruitment of immune cells (e.g., effector cells, such as NK cells), and / or triggering, generating, encouraging and / or enhancing immune system activities against target cells, tissues, objects and / or entities, for example, antibody-dependent cell-mediated cytotoxicity (ADCC) and / or ADCP.

[0322] A variety of universal antibody binding portions can be used in accordance with the present disclosure, and a number of techniques (e.g., those described in the Examples) can be used to identify and / or evaluate universal antibody binding portions. In some embodiments, the universal antibody binding portion comprises one or more amino acid residues, each of which is independently natural or non-natural. In some embodiments, the universal antibody binding portion has the structure or a salt thereof. In some embodiments, the universal antibody binding portion has the structure or a salt thereof. In some embodiments, the universal antibody binding portion is or comprises a peptide portion, for example, having structure R c In some embodiments, the universal antibody binding portion is or comprises a cyclic peptide portion, for example, having the structure In some embodiments, the universal antibody binding portion is R c -(Xaa)z- or and is or comprises a Peptide unit. In some embodiments, -(Xaa)z- is or comprises a Peptide unit. In some embodiments, the Peptide unit comprises an amino acid residue, e.g., an amino acid residue of Formula AI having a positively charged side chain (e.g., at physiological pH about 7.4, a "positively charged amino acid residue," Xaa P In some embodiments, the Peptide unit comprises R. In some embodiments, at least one Xaa is R. In some embodiments, the Peptide unit is or comprises APAR. In some embodiments, the Peptide unit is or comprises RAPA. In some embodiments, the Peptide unit comprises an amino acid residue, e.g., an amino acid residue of Formula AI having a side chain comprising an aromatic group ("aromatic amino acid residue," Xaa A In some embodiments, the peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit comprises W. In some embodiments, the peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, the peptide unit is or comprises Xaa A XaaXaa P Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P XaaXaa A In some embodiments, the peptide unit is or comprises Xaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises two or more Xaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa A Xaa P XaaXaa P Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P Xaa A Xaa A Xaa P In some embodiments, the peptide unit is or comprises Xaa P Xaa P Xaa P Xaa A In some embodiments, the peptide unit is or comprises two or more Xaa A Xaa A Xaa P. In some embodiments, the peptide residue comprises one or more proline residues. In some embodiments, the peptide unit is or comprises HWRGWA. In some embodiments, the peptide unit is or comprises WGRR. In some embodiments, the peptide unit is or comprises RRGW. In some embodiments, the peptide unit is or comprises NRFRGKYK. In some embodiments, the peptide unit is or comprises NARKFYK. In some embodiments, the peptide unit comprises positively charged amino acid residues, aromatic amino acid residues, and the following amino acid residues, for example, amino acid residues of formula AI having a negatively charged side chain (e.g., at physiological pH of about 7.4, "negatively charged amino acid residues", Xaa N In some embodiments, the peptide residue is RHRFNKD. In some embodiments, the peptide unit is TY. In some embodiments, the peptide unit is TYK. In some embodiments, the peptide unit is RTY. In some embodiments, the peptide unit is RTYK. In some embodiments, the peptide unit is or comprises a sequence selected from PAM. In some embodiments, the peptide unit is WHL. In some embodiments, the peptide unit is ELVW. In some embodiments, the peptide unit is or comprises a sequence selected from AWHLGELVW. In some embodiments, the peptide unit is or comprises a sequence selected from DCAWHLGELVWCT, in which the two cysteine ​​residues can form a disulfide bond as found in natural proteins. In some embodiments, the peptide unit is or comprises a sequence selected from Fc-III. In some embodiments, the peptide unit is or comprises a sequence selected from DpLpAWHLGELVW. In some embodiments, the peptide unit is or comprises a sequence selected from FcBP-1. In some embodiments, the peptide unit is or comprises a sequence selected from DpLpDCAWHLGELVWCT. In some embodiments, the peptide unit is or comprises a sequence selected from FcBP-2. In some embodiments, the peptide unit is or comprises a sequence selected from CDCAWHLGELVWCTC, wherein the first and last cysteines and the two cysteines in the middle of the sequence can each independently form a disulfide bond as in a natural protein. In some embodiments, the peptide unit is or comprises a sequence selected from Fc-III-4c. In some embodiments, the peptide unit is or comprises a sequence selected from FcRM. In some embodiments, the peptide unit is or comprises a cyclic peptide unit. In some embodiments, the cyclic peptide unit comprises an amide group formed by an amino group in the side chain and a -COOH at the C-terminus.

[0323] In some embodiments, -(Xaa)z- is or comprises [X 1 ] p1 [X 2 ] p2 -X 3 X 4 X5 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 , 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, e.g., an amino acid residue of Formula AI, and p1, p2, p13, p14, p15, and p16 are each 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 an amino acid of formula AI. 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 independently is a natural amino acid residue. In some embodiments, X 1 、X 2 、X 3 、X4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 、X 11 、X 12 and X 13 One or more of are independently a non-natural amino acid residue as described in the present disclosure.

[0324] In some embodiments, the peptide unit includes a functional group that can react with the functional group of another amino acid residue in the amino acid residue. In some embodiments, the peptide unit includes an amino acid residue with a side chain, and the side chain includes a functional group that can react with another functional group of the side chain of another amino acid residue to form a linkage (for example, see the compounds in Table 1). In some embodiments, one functional group of an amino acid residue is connected to the functional group of another amino acid residue to form a linkage (or bridge). The linkage is bonded to the backbone atoms of the peptide unit and does not include backbone atoms. In some embodiments, the peptide unit includes a linkage formed by two side chains of non-adjacent amino acid residues. In some embodiments, the linkage is bonded to two backbone atoms of two non-adjacent amino acid residues. In some embodiments, the two backbone atoms bonded to the linkage are both carbon atoms. In some embodiments, the linkage has L b The structure of L b is L as described in this disclosure a , where L a In some embodiments, L a Contains -Cy-. In some embodiments, L a Contains -Cy-, wherein -Cy- is an optionally substituted heteroaryl. In some embodiments, -Cy- is In some embodiments, L a yes In some embodiments, such L a Can be formed by the -N3 group of the side chain of one amino acid residue and the -≡- of the side chain of another amino acid residue. In some embodiments, the linkage is formed by connecting two thiol groups (e.g., two cysteine ​​residues). In some embodiments, L a Contains -SS-. In some embodiments, L a In some embodiments, the linkage is formed by connecting an amino group (e.g., -NH2 in the side chain of a lysine residue) and a carboxylic acid group (e.g., -COOH in the side chain of an aspartic acid or glutamic acid residue). aContains -C(O)-N(R')-. In some embodiments, L a Contains -C(O)-NH-. In some embodiments, L a is -CH2CONH-(CH2)3-. In some embodiments, L a Contains -C(O)-N(R')-, wherein R' is R and together with the R groups on the peptide backbone form a ring (eg, in 1-27). In some embodiments, L a In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene. In some embodiments, L a yes In some embodiments, L a yes In some embodiments, L a is an optionally substituted divalent C 2-20 In some embodiments, L a is optionally substituted -(CH2)9-CH=CH-(CH2)9-. In some embodiments, L a It is -(CH2)3-CH=CH-(CH2)3-.

[0325] In some embodiments, the two amino acid residues bonded to the linkage 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 between them (excluding the two amino acid residues bonded to the linkage). 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.

[0326] In some embodiments, p1, p2, p13, p14, p15, and p16 are each 0. In some embodiments, -(Xaa)z- is or comprises -X 3 X 4 X 5 X 6 X7 X 8 X 9 X 10 X 11 X 12 -,in:

[0327] 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;

[0328] X 6 It's Xaa A or Xaa P ;

[0329] X 9 It's Xaa N ;and

[0330] X 12 It's Xaa A or Xaa P .

[0331] 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 AI as described in the present disclosure. In some embodiments, X 5 It's Xaa A or Xaa P In some embodiments, X 5 It's Xaa A In some embodiments, X 5 It's Xaa P In some embodiments, X 5 is an amino acid residue whose side chain comprises an optionally substituted saturated ring, partially saturated ring, or aromatic ring. 5 yes In some embodiments, X 5 yes In some embodiments, X 6 It's XaaA In some embodiments, X 6 It's Xaa P In some embodiments, X 6 In some embodiments, X 12 It's Xaa A In some embodiments, X 12 It's Xaa P In some embodiments, X 9 is Asp. In some embodiments, X 9 In some embodiments, X 12 yes In some embodiments, X 12 yes In some embodiments, X 7 、X 10 and X 11 Each is independently an amino acid residue having a hydrophobic side chain ("hydrophobic amino acid residue", Xaa H ). In some embodiments, X 7 It's Xaa H In some embodiments, X 7 yes In some embodiments, X 7 Is Val. In some embodiments, X 10 It's Xaa H In some embodiments, X 10 In some embodiments, X 10 yes In some embodiments, X 11 It's Xaa H In some embodiments, X 11 yes In some embodiments, X 8 In some embodiments, X 4 In some embodiments, X 3 In some embodiments, X 12 -COOH and Lys(X 3 ) forms an amide bond with the side chain amino group of Lys(X 3 ) is linked to a linker moiety and then to a target binding moiety.

[0332] In some embodiments, -(Xaa)z- is or comprises -X 3 X 4 X 5 X 6 X 7 X8 X 9 X 10 X 11 X 12 -,in:

[0333] 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;

[0334] At least two amino acid residues are linked by one or more linkages L b connect;

[0335] L b Is selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20 a heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue and does not contain a backbone atom;

[0336] X 6 It's Xaa A or Xaa P ;

[0337] X 9 It's Xaa N ;and

[0338] X 12 It's Xaa A or Xaa P .

[0339] 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 AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are separated by L b In some embodiments, X 5 and X 10 By L b In some embodiments, there is a linker L b In some embodiments, X 6 It's Xaa A In some embodiments, X 6 is XaaP. In some embodiments, X 6 In some embodiments, X 9 is Asp. In some embodiments, X 9 In some embodiments, X 12 It's Xaa A In some embodiments, X 12 yes In some embodiments, X 12 yes In some embodiments, X 12 yes In some embodiments, X 4 、X 7 and X 11 Each is independently Xaa H In some embodiments, X 4 It's Xaa H In some embodiments, X 4 is Ala. In some embodiments, X 7 It's Xaa H In some embodiments, X 7 yes In some embodiments, X 11 It's Xaa H In some embodiments, X 11 yes In some embodiments, X 8 In some embodiments, X 3 In some embodiments, X 12 -COOH and Lys(X 3 ) forms an amide bond with the side chain amino group of Lys(X 3 ) is linked to a linker moiety and then to a target binding moiety. In some embodiments, L b yes In some embodiments, L b yes In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 5 and X 10 Both are Cys, and the two -SH groups in their side chains form -SS-(L b is -CH2-SS-CH2-).

[0340] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -,in:

[0341] 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;

[0342] At least two amino acid residues are linked by one or more linkages L b connect;

[0343] L b Is selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20 a heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue and does not contain a backbone atom;

[0344] X 4 It's Xaa A ;

[0345] X 5 It's Xaa A or Xaa P ;

[0346] X 8 It's Xaa N ;and

[0347] X 11 It's Xaa A .

[0348] 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 AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are separated by L b In some embodiments, there is a linker L b In some embodiments, X 2 and X 12 By L b In some embodiments, L b Is -CH2-SS-CH2-. In some embodiments, L b Is -CH2-CH2-S-CH2-. In some embodiments, L b yes In some embodiments, L b yes In some embodiments, L b In some embodiments, R' together with the R groups on the backbone atoms to which -N(R')-CH2CH2- is bonded forms a ring, for example, as in I-27. In some embodiments, the ring formed is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the ring formed is a monocyclic ring. In some embodiments, the ring formed is a saturated ring. In some embodiments, L b yes

[0349] In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 4 It's Xaa A In some embodiments, X 4 In some embodiments, X 5 It's Xaa A In some embodiments, X 5 is XaaP. In some embodiments, X 5 In some embodiments, X 8 is Asp. In some embodiments, X 8 It's Glu. X 11 In some embodiments, X 2 and X 12 Both are Cys, and the two -SH groups in their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 3 、X 6 、X 9 and X 10 Each is independently Xaa H In some embodiments, X 3 It's Xaa H In some embodiments, X 3 is Ala. In some embodiments, X 6 It's Xaa H In some embodiments, X 6 In some embodiments, X 9 It's Xaa H In some embodiments, X 9 In some embodiments, X 9 yes In some embodiments, X 10 It's Xaa H In some embodiments, X 10 Is Val. In some embodiments, X 10 yes In some embodiments, X 7 In some embodiments, p1 is 1. In some embodiments, X 1 is Asp. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X 13 is an amino acid residue containing a polar uncharged side chain (e.g., at physiological pH, a "polar uncharged amino acid residue," XaaL ). In some embodiments, X 13 is Val. In some embodiments, p13 is O. In some embodiments, R c is -NHCH2CH(OH)CH3. In some embodiments, R c is (R)-NHCH2CH(OH)CH3. In some embodiments, R c It is (S)-NHCH2CH(OH)CH3.

[0350] In some embodiments, -(Xaa)z- is or comprises -X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 -,in:

[0351] 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;

[0352] At least two amino acid residues are linked by one or more linkages L b connect;

[0353] L b Is selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20 a heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue and does not contain a backbone atom;

[0354] X 5 It's Xaa A or Xaa P ;

[0355] X 8 It's Xaa N ;and

[0356] X 11 It's Xaa A .

[0357] 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 AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are separated by L b In some embodiments, there is a linker L b In some embodiments, there are two or more linkages L b In some embodiments, there are two linkages L b In some embodiments, X 2 and X 12 By L b In some embodiments, X 4 and X 9 By L b In some embodiments, X 4 and X 10 By L b In some embodiments, L b Is -CH2-SS-CH2-. In some embodiments, L b yes In some embodiments, L b yes In some embodiments, X 2 and X 12 Both are Cys, and the two -SH groups in their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 4 and X 10 Both are Cys, and the two -SH groups in their side chains form -SS-(L bis -CH2-SS-CH2-). In some embodiments, X 4 and X 9 By L b Connection, where L b yes In some embodiments, X 4 and X 9 By L b Connection, where L b yes

[0358] In some embodiments, X 5 It's Xaa A In some embodiments, X 5 is XaaP. In some embodiments, X 5 In some embodiments, X 8 is Asp. In some embodiments, X 8 In some embodiments, X 11 In some embodiments, X 11 yes In some embodiments, X 2 and X 12 By L b Connection, where L b Is -CH2-S-CH2CH2-. In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 3 、X 6 and X 9 Each is independently Xaa H In some embodiments, X 3 It's Xaa H In some embodiments, X 3 is Ala. In some embodiments, X 6 It's Xaa H In some embodiments, X 6 In some embodiments, X 6 yes In some embodiments, X 9 It's Xaa H In some embodiments, X 9 In some embodiments, X 9 yes In some embodiments, X 10 It's Xaa H In some embodiments, X 10Is Val. In some embodiments, X 7 In some embodiments, p1 is 1. In some embodiments, X 1 It's Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1 is Glu. In some embodiments, p13 is 1. In some embodiments, p14, p15, and p16 are 0. In some embodiments, X 13 It's Xaa L In some embodiments, X 13 It's Val.

[0359] In some embodiments, -(Xaa)z- is or comprises -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 -,in:

[0360] 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;

[0361] At least two amino acid residues are linked by a linkage L b connect;

[0362] L b Is selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20a heteroaliphatic optionally substituted divalent radical wherein one or more methylene units of the radical are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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-, wherein L b is bonded to a backbone atom of an amino acid residue and a backbone atom of another amino acid residue and does not contain a backbone atom;

[0363] X 3 It's Xaa N ;

[0364] X 6 It's Xaa A ;

[0365] X 7 It's Xaa A or Xaa P ;

[0366] X 9 It's Xaa N ;and

[0367] X 13 It's Xaa A .

[0368] 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 AI as described in the present disclosure. In some embodiments, two non-adjacent amino acid residues are separated by L b In some embodiments, there is a linker L b In some embodiments, there are two or more linkages L b In some embodiments, there are two linkages L b In some embodiments, X 2 By L b Connect to X 16 In some embodiments, X 4 By Lb Connect to X 14 In some embodiments, X 2 and X 16 Both are Cys, and the two -SH groups in their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, X 4 and X 14 Both are Cys, and the two -SH groups in their side chains form -SS-(L b is -CH2-SS-CH2-). In some embodiments, L b Two α-carbon atoms connecting two different amino acid residues. In some embodiments, X 3 is Asp. In some embodiments, X 3 In some embodiments, X 5 It's Xaa H In some embodiments, X 5 is Ala. In some embodiments, X 6 It's Xaa A In some embodiments, X 6 In some embodiments, X 7 It's Xaa A In some embodiments, X 7 It's Xaa P In some embodiments, X 7 In some embodiments, X 8 It's Xaa H In some embodiments, X 8 is Ala. In some embodiments, X 9 In some embodiments, X 10 is Asp. In some embodiments, X 10 In some embodiments, X 11 It's Xaa H In some embodiments, X 11 In some embodiments, X 12 It's Xaa H In some embodiments, X 12 Is Val. In some embodiments, X 13 It's Xaa A In some embodiments, X 13 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," XaaL ). In some embodiments, X 15 Is Val. In some embodiments, p1 is 1. In some embodiments, In some embodiments, X 1 It's Xaa N In some embodiments, X 1 is Asp. In some embodiments, X 1 It's Glu.

[0369] As will be appreciated by those skilled in the art, an amino acid residue may be substituted with another amino acid residue having similar properties, e.g., an Xaa H (e.g., Val, Leu, etc.) can be replaced by another Xaa H (e.g., Leu, Ile, Ala, etc.) substituted with an Xaa A Can be used by another Xaa A Replacement, an Xaa P Can be used by another Xaa P Replacement, an Xaa N Can be used by another Xaa N Replacement, an Xaa L Can be used by another Xaa L Alternative, etc.

[0370] In some embodiments, the antibody binding portion (e.g., universal antibody binding portion) is a universal antibody binding portion of the compounds in Table 1. In some embodiments, the antibody binding portion (e.g., universal antibody binding portion) is or comprises an optionally substituted.

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380] 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 an optionally substituted A-26. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-27. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-28. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-29. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-30. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-31. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-32.In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-33. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-34. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-35. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-36. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-37. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-38. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-39. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-40. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-41. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-42. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-43. In some embodiments, the universal antibody binding portion is or comprises optionally substituted A-44. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-45. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-46. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-47. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-48. In some embodiments, the universal antibody binding portion is or comprises an optionally substituted A-49. In some embodiments, it is unsubstituted. In some embodiments, it is substituted.

[0381] In some embodiments, the universal antibody binding portion comprises a peptide unit and is connected to a linker portion via the C-terminus of the peptide unit. In some embodiments, it is connected to a linker portion via the N-terminus of the peptide unit. In some embodiments, it is connected via a side chain group of the peptide unit.

[0382] In some embodiments, the antibody binding portion (e.g., a universal antibody binding portion) is or comprises a small molecule entity, for example, having a molecular weight of less than 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, etc. Suitable such antibody binding portions include small molecule Fc binding portions, for example, those described in US 9,745,339, US20130131321, etc.

[0383] As will be appreciated by those skilled in the art, antibodies with various characteristics and activities (e.g., antibodies that recognize different antigens, have optional modifications, etc.) can be raised by the antibody binding moieties described in this disclosure. In some embodiments, such antibodies include antibodies that are administered to a subject, for example, for therapeutic purposes. In some embodiments, the antibodies raised by the antibody binding moiety include antibodies directed against different antigens. In some embodiments, the antibodies raised by the antibody binding moiety include antibodies whose antigens are 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 raised by the antibody binding moiety include antibodies that do not target an antigen that is 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 antigens on the target cell surface may interfere with the structure, conformation, and / or one or more characteristics and / or activity of the antibodies raised in conjunction with such antigens. In some embodiments, as will be appreciated by those skilled in the art, the provided technology comprises universal antibody binding portions that recruit antibodies with different specificities, and no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the recruited antibodies are directed against the same antigen, protein, lipid, carbohydrate, etc. Among other things, one advantage of the present disclosure is that the provided technology comprising universal antibody binding portions can utilize diverse antibody repertoires, such as those present in serum. In some embodiments, the universal antibody binding portions of the present disclosure (e.g., those in ARM) are contacted with a plurality of antibodies, wherein no more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the plurality of antibodies are directed against the same antigen, protein, lipid, carbohydrate, etc.

[0384] amino acids

[0385] In some embodiments, useful compounds and agents (e.g., ARM) may comprise one or more amino acid moieties, such as those found in common antibody binding moieties, linker moieties, and the like. The amino acid moieties may be natural amino acids or non-natural amino acids. In some embodiments, the amino acids have the structure of Formula AI:

[0386] NH(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 -COOH,

[0387] AI

[0388] or a salt thereof, wherein each variable is independently as described in the present disclosure. In some embodiments, the amino acid residue has -N(R a1 )-L a1 -C(R a2 )(R a3 )-L a2 The structure of -CO-.

[0389] In some embodiments, L a1 is a covalent bond. In some embodiments, the compound of Formula AI has NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH structure.

[0390] In some embodiments, L a2 is a covalent bond. In some embodiments, the compound of Formula AI has NH(R a1 )-C(R a2 )(R a3 )-L a2 -COOH structure.

[0391] In some embodiments, L a1 is a covalent bond and L a2 is a covalent bond. In some embodiments, the compound of Formula AI has NH(R a1 )-C(R a2 )(R a3 )-COOH structure.

[0392] In some embodiments, L a is a covalent bond. In some embodiments, L a is an optionally substituted C 1-6 In some embodiments, L a is an optionally substituted C 1-6 In some embodiments, L a In some embodiments, L a is -CH2CH2-. In some embodiments, L a It is -CH2CH2CH2-.

[0393] In some embodiments, R' is R. In some embodiments, R a1 is R, wherein R is as described in the present disclosure. In some embodiments, R a2 is R, wherein R is as described in the present disclosure. In some embodiments, R a3is R, wherein R is as described in the present disclosure. In some embodiments, R a1 、R a2 and R a3 Each is independently R, wherein R is as described in this disclosure.

[0394] In some embodiments, R a1 In some embodiments, R a2 In some embodiments, R a3 In some embodiments, R a1 is hydrogen, and R a2 and R a3 In some embodiments, at least one of R a1 is hydrogen, R a2 and R a3 One is hydrogen and the other is not hydrogen.

[0395] In some embodiments, R a2 Yes-L a -R, wherein R is as described in the present disclosure. In some embodiments, R a2 Yes-L a -R, wherein R is an optionally substituted group selected from C 3-30 Alicyclic, C 5-30 aryl, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. a2 Yes-L a -R, wherein R is an optionally substituted group selected from C 6-30 aryl and 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. a2 is the side chain of an amino acid. a2 are the side chains of standard amino acids.

[0396] In some embodiments, R a3 Yes-L a -R, wherein R is as described in the present disclosure. In some embodiments, R a3 Yes-L a -R, wherein R is an optionally substituted group selected from C 3-30 Alicyclic, C 5-30 aryl, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.a3 Yes-L a -R, wherein R is an optionally substituted group selected from C 6-30 aryl and 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. a3 is the side chain of an amino acid. a3 are the side chains of standard amino acids.

[0397] In some embodiments, R is a cyclic group. In some embodiments, R is an optionally substituted C 3-30 In some embodiments, R is cyclopropyl.

[0398] In some embodiments, R is an aromatic group and the amino acid residue of the amino acid of Formula AI is Xaa A In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is a phenyl group. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is 4-trifluoromethylphenyl. In some embodiments, R is 4-phenylphenyl. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-14 membered heteroaryl group having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is In some embodiments, R is an optionally substituted pyridyl. In some embodiments, R is a 1-pyridyl. In some embodiments, R is a 2-pyridyl. In some embodiments, R is a 3-pyridyl. In some embodiments, R is

[0399] In some embodiments, R' is -COOH. In some embodiments, the compound of the amino acid of formula AI and the amino acid residue is Xaa N .

[0400] In some embodiments, R' is -NH2. In some embodiments, the compound wherein the amino acid residue of the amino acid of formula AI is Xaa P .

[0401] In some embodiments, R a2 or R a3 is R, wherein R is C as described in the present disclosure 1-20 In some embodiments, the amino acid residue of the amino acid of formula AI is Xaa HIn some embodiments, R is -CH3. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is cyclopropyl.

[0402] In some embodiments, R a1 、R a2 and R a3 Two or more of are R and together form an optionally substituted ring as described in the disclosure.

[0403] In some embodiments, R a1 and R a2 and R a3 One of them is R and together they form an optionally substituted 3-6 membered ring, said ring except for R a1 Besides the bonded nitrogen atom, there are no additional ring heteroatoms. In some embodiments, the ring formed is a 5-membered ring as in proline.

[0404] In some embodiments, R a2 and R a3 is R and together form an optionally substituted 3-6 membered ring as described in the present disclosure. In some embodiments, R a2 and R a3 is R and together form an optionally substituted 3-6 membered ring having one or more nitrogen ring atoms. In some embodiments, R a2 and R a3 is R and together form an optionally substituted 3-6 membered ring having one and no more than one ring heteroatom which is a nitrogen atom. In some embodiments, the ring is a saturated ring.

[0405] In some embodiments, the amino acid is a natural amino acid. In some embodiments, the amino acid is an unnatural amino acid. In some embodiments, the amino acid is an α-amino acid. In some embodiments, the amino acid is a β-amino acid.

[0406] Target

[0407] In some embodiments, the present disclosure provides techniques for selectively directing agents (e.g., ARM compounds), antibodies, and immune cells (e.g., NK cells) comprising a target binding portion to a desired target site comprising one or more targets. As will be appreciated by those skilled in the art, the techniques provided can be used for various types of targets.

[0408] In some embodiments, the target is damaged or defective tissue. In some embodiments, the target is damaged tissue. In some embodiments, the target is defective tissue. In some embodiments, the target is associated with a disease, disorder, or condition (e.g., cancer, wound, etc.). In some embodiments, the target is a tumor. In some embodiments, the target is or comprises a diseased cell. In some embodiments, the target is or comprises a cancer cell. In some embodiments, the target is a foreign object. In some embodiments, the target is or comprises an infectious pathogen. In some embodiments, the target is a microorganism. In some embodiments, the target is or comprises a bacterium. In some embodiments, the target is or comprises a virus.

[0409] In many embodiments, the target is a tissue and / or cell associated with a disease, disorder or condition, particularly various types of cancer. In some embodiments, the target is or comprises a cancer cell. Among other aspects, the disclosure provides techniques that are particularly suitable for selectively targeting cancer cells by the immune system, for example, by raising antibodies (e.g., endogenous antibodies) and immune cells (e.g., NK cells), using ARM.

[0410] In many embodiments, the target is a cell of a cancer or proliferative condition, disorder or disease. In some embodiments, the cancer or proliferative condition, disorder or disease is selected from benign tumors, malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumors, 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 or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer (especially colon cancer or colorectal adenoma), neck and head tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial characteristics, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's disease and non-Hodgkin's disease, mammary cancer (mammary carcinoma), follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, hematologic malignancies (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, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma).

[0411] A target site typically comprises one or more physical, chemical and / or biological markers, which can be used, for example, by the target binding portion of a compound (e.g., ARM) to selectively recruit antibodies and / or fragments thereof, and / or to recruit immune cells to the target.

[0412] In some embodiments, cells at the target site contain one or more characteristic agents that can be used for targeting. In some embodiments, such agents are proteins and / or fragments thereof. In some embodiments, such agents are antigens specifically associated with a disease, disorder, or condition.

[0413] For example, in some embodiments, cancer cells may contain one or more tumor-specific antigens or tumor-associated antigens. Target binding moieties as described herein can selectively bind to such markers. In some embodiments, the target binding moieties of the present disclosure are small molecules that bind to cell surface proteins and / or intracellular proteins.

[0414] In some embodiments, the characteristic agent (e.g., a characteristic agent of a cell having a target site, etc.) is or comprises a carbohydrate, e.g., those on the surface of a cell, in a glycosylated protein, etc. In some embodiments, the characteristic agent is or comprises a lipid.

[0415] In some embodiments, the characteristic agent (e.g., a characteristic agent of a cell having a target site, etc.) is extracellular. In some embodiments, the characteristic agent is an extracellular protein. In some embodiments, the characteristic agent is on the cell surface. In some embodiments, the characteristic agent 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 / or patterns and can be used for targeting.

[0416] In some embodiments, the target site (e.g., diseased tissue, etc.) has one or more physical, biological, and / or chemical properties that can be exploited by a targeting moiety. In some embodiments, such a property is pH. In some embodiments, such a property is the concentration of one or more chemical substances. For example, the tumor microenvironment is typically hypoxic and / or acidic (e.g., pH 6.5-6.9 vs. 7.2-7.4).

[0417] In some embodiments, the target is or comprises a peptide or a fragment thereof. In some embodiments, the target is or comprises a protein or a fragment thereof. In some embodiments, the target is avidin. In some embodiments, the target is streptavidin. In some embodiments, the target is or comprises an antigen. In some embodiments, the target is or comprises a tumor-specific antigen. In some embodiments, the target is or comprises a tumor-associated antigen (TAA).

[0418] In some embodiments, the tumor-associated antigen is or comprises a carbohydrate. In some embodiments, the target binding portion provided targets such TAAs. In some embodiments, the carbohydrate is part of a glycoprotein. In some embodiments, the carbohydrate is part of a glycolipid. Many conditions, disorders, and diseases (e.g., various types of cancer) are associated with abnormal glycosylation. In some embodiments, tumor-associated carbohydrate antigens (TACAs) include altered sialic acid expression, altered Lewis sugar antigen expression, altered ganglioside expression, and / or are associated therewith. In some embodiments, the target binding portion of the present disclosure can target various types of TACAs, including those described in the art, for example, in Chua and Durrant, Monoclonal Antibodies Against Tumour-Associated Carbohydrate Antigens, Carbohydrate Mahmut Caliskan, Intech Open, DOI: 10.5772 / 66996.

[0419] In some embodiments, the tumor-associated antigen is a cell surface receptor. In some embodiments, the TAA is selected from BMPR1B (bone morphogenetic protein receptor-IB type, Genbank accession number NM.sub.-001203); E16 (LAT1, SLC7A5, Genbank accession number NM.sub.-003486); STEAP1 (six-transmembrane prostate epithelial antigen, Genbank accession number NM.sub.-012449); 0772P (CA125, MUC16, Ge Genbank accession number AF361486); MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession number NM.sub.-005823); Napi3b (NAPI-3B, NPTIIb, SLC34A2, soluble carrier family 34 (sodium phosphate) member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession number NM.sub.-006424); Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5bHlog, sema domain, seven 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 type B receptor, Genbank accession number AY275463); MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number NM.sub.-017763); STEAP2 (HGNC.sub.-8639, IPCA-1, PCANAP1, STAMPI, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, six-transmembrane prostate epithelial antigen 2, six-transmembrane prostate protein, Ge Genbank accession number AF455138); TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M member 4, Genbank accession number NM.sub.-017636); CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratoma-derived growth factor, Genbank accession number NP.sub.-003203 or NM.sub.-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 protein β), B29, Genbank accession number NM.sub.-000626); FcRH2 (IFGP4, IRTA4, SPAP1A (phosphatase anchoring protein 1a SH2 domain containing), SPAP1B, SPAP1C, Genbank accession number NM.sub.-030764); HER2 (Genbank accession number M1730); NCA (Genbank accession number M18728); MDP (Genbank accession number BC017023); IL20Rα (Genbank accession number AF184971); Brevican (G sub.-004442); ASLG659 (Genbank accession number AX092328); PSCA (Genbank accession number AJ297436); GEDA (Genbank accession number AY260763); BAFF-R (B cell activating factor receptor, BLyS receptor 3, BR3, NP.sub.-443177.1); CD22 (B cell receptor CD22-B isoform, NP.sub.-001762.1); CD79a (CD79A, CD79.α., immunoglobulin-associated protein α, a B cell-specific protein that covalently interacts with Igβ (CD79B) and binds to Ig on the surface). M molecules form complexes that transduce signals involved in B cell differentiation, Genbank accession number NP.sub.--001774.1); CXCR5 (Burkitt lymphoma receptor 1, a G protein-coupled receptor that is activated by the CXCL13 chemokine and plays a role in lymphocyte migration and humoral defense, and plays a role in HIV-2 infection and possibly the development of AIDS, lymphoma, myeloma, and leukemia, Genbank accession number NP.sub.-001707.1); HLA-DOB (MHC The β subunit of the class II molecule (Ia antigen), which binds and presents peptides to CD4+ T lymphocytes, Genbank accession number NP.sub.-002111.1); P2X5 (purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, which may be involved in synaptic transmission and neurogenesis, and its deficiency may contribute to the pathophysiology of idiopathic detrusor instability, Genbank accession number NP.sub.-002552.2); CD72 (B cell differentiation antigen CD72, Lyb-2, Genbank accession number NP.sub.-001773.1); LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein of the leucine-rich repeat (LRR) family that regulates B cell activation and apoptosis, and its loss of function is associated with increased disease activity in patients with systemic lupus erythematosus, Genbank accession number NP.sub.--005573.1); FcRH1 (Fc receptor-like protein 1, a putative receptor for the Fc domain of immunoglobulins, containing a C2-type Ig-like domain and an ITAM domain, which may play a role in B lymphocyte differentiation, G 179274).

[0420] In some embodiments, the target is or comprises a nucleic acid.

[0421] In some embodiments, the target is or comprises a lipid.

[0422] In some embodiments, the target is or comprises a carbohydrate. In some embodiments, the target is or comprises a carbohydrate associated with a disease, disorder, or condition. In some embodiments, the target is or comprises a carbohydrate associated with cancer, e.g., a carbohydrate that is a glycan modification of a protein, e.g., on the surface of a cancer cell or outside of the cell.

[0423] Target binding moiety

[0424] Various types and chemical classes of target binding moieties can be used in accordance with the present disclosure, and a variety of techniques (e.g., assays, reagents, kits, etc.) for identifying and / or evaluating the properties of target binding moieties can be used in accordance with the present disclosure. Typically, a target binding moiety interacts with a target site through one or more physical, biological, and / or chemical properties. In some embodiments, the target binding moiety binds to a characteristic agent as described in the present disclosure. In some embodiments, the target binding moiety binds to surface, extracellular, and / or intracellular proteins, carbohydrates, and / or nucleic acids. In some embodiments, the target binding moiety binds to a surface protein of a 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. Certain types of target binding moieties are described below; those skilled in the art will appreciate that other types of target binding moieties (including many known in the art) can be used in accordance with the present disclosure.

[0425] In some embodiments, the targeting binding moiety binds to the target through one or more proteins, lipids, nucleic acids, carbohydrates, small molecules, etc. in the target. For example, in some embodiments, the target binding moiety binds to a tumor-specific antigen of a target cancer cell. In some embodiments, the tumor-specific antigen is or comprises a carbohydrate or a fragment thereof. In some embodiments, the tumor-specific antigen is or comprises a protein or a fragment thereof.

[0426] 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.

[0427] a. Small character

[0428] In some embodiments, the target binding moiety is a small molecule moiety. In some embodiments, the molecular weight of the small molecule moiety does not exceed 8000, 7000, 6000, 5000, 4000, 3000, 2000, 1500, 1000, 900, 800, 700, or 600. In some embodiments, the molecular weight of the small molecule moiety does not exceed 8000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 7000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 6000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 5000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 4000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 3000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 2000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 1500. In some embodiments, the molecular weight of the small molecule moiety does not exceed 1000. In some embodiments, the molecular weight of the small molecule moiety does not exceed 900.

[0014] The present disclosure encompasses, among other things, the recognition that small molecule target binding moieties may be capable of binding to markers external to, on the surface of, and / or internal to a target (eg, a cancer cell).

[0429] In some embodiments, the small molecule target binding moiety is or comprises a moiety that selectively binds a protein or fragment thereof (e.g., a cancer antigen). For example, in some embodiments, the target binding moiety is or comprises a moiety that selectively binds prostate specific membrane antigen (PSMA). In some embodiments, the target binding moiety is or comprises a moiety that selectively binds

[0430] 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 or comprises a In some embodiments, the small molecule target binding moiety is or comprises

[0431] b. Peptide agents

[0432] 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. Various peptide target binding moieties are known in the art and can be used in accordance with the present disclosure.

[0433] In some embodiments, the target binding moiety is or comprises a peptide aptamer.

[0434] c. Aptamers

[0435] 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. Various aptamers are known in the art or can be readily developed using common techniques and can be used in the provided technology according to this disclosure.

[0436] Connector

[0437] In some embodiments, the antibody binding moiety is optionally linked to the target binding moiety via a linker moiety. Linker moieties of various types and / or for various purposes can be used in accordance with the present disclosure, e.g., linker moieties for use in antibody-drug conjugates, etc.

[0438] The linker moiety can be divalent or multivalent. In some embodiments, the linker moiety is divalent. In some embodiments, the linker is multivalent and connects more than two moieties.

[0439] In some embodiments, the linker moiety is L. In some embodiments, L is a covalent bond or an optionally substituted divalent or multivalent linear or branched C containing one or more aliphatic, aromatic, heteroaliphatic having 1-20 heteroatoms, heteroaromatic having 1-20 heteroatoms, or any combination thereof. 1-100 A group wherein one or more methylene units of the group are optionally and independently replaced by C 1-6 Alkylene, C 1-6 Alkenylene, divalent C 1-6 Heteroaliphatic groups, -C≡C-, -Cy-, -C(R')2-, -O-, -S-, -SS-, -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 -[(-OC(R')2-C(R')2-) n ]-substituted, where n is 1-20.

[0440] In some embodiments, L is divalent. In some embodiments, L is a divalent or optionally substituted linear or branched group selected from C 1-00 Aliphatic and C with 1-50 heteroatoms 1-100 Heteroaliphatic, wherein one or more methylene units of the group are optionally and independently replaced by C 1-6 Alkylene, C 1-6 Alkenylene, divalent C 1-6 Heteroaliphatic groups, -C≡C-, -Cy-, -C(R')2-, -O-, -S-, -SS-, -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 -[(-OC(R')2-C(R')2-) n ]-alternative.

[0441] In some embodiments, L is a covalent bond. In some embodiments, L is an optionally substituted divalent linear or branched C 1-100 An aliphatic group wherein one or more methylene units of the group are optionally and independently replaced. In some embodiments, L is an optionally substituted divalent linear or branched C 6-100 An aryl aliphatic group wherein one or more methylene units of the group are optionally and independently replaced. In some embodiments, L is an optionally substituted divalent linear or branched C 5-100 Heteroaryl aliphatic groups, wherein one or more methylene units of the group are optionally and independently replaced. In some embodiments, L is an optionally substituted divalent linear or branched C having 1-20 heteroatoms. 1-100 A heteroaliphatic group wherein one or more methylene units of the group are optionally and independently replaced.

[0442] 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 or comprises -(CH2CH2O) n-, wherein n is as described in the present disclosure. In some embodiments, one or more methylene units of L are independently -(CH2CH2O) n - substitution. 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.

[0443] In some embodiments, the linker moiety comprises one or more moieties that can be used to connect to other moieties, e.g., amino, carbonyl, etc. In some embodiments, the linker moiety comprises one or more -NR'-, wherein R' is as described in the present disclosure. 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 by -NR'-, wherein R' is as described in the present disclosure.

[0444] In some embodiments, the linker moiety (e.g., L) comprises a -C(O)- group, which can be used to attach to a moiety. In some embodiments, one or more methylene units of L are independently replaced by -C(O)-.

[0445] In some embodiments, the linker moiety is or comprises one or more ring moieties, for example, one or more methylene units of L are replaced by -Cy-. In some embodiments, the linker moiety (e.g., L) comprises an aryl ring. In some embodiments, the linker moiety (e.g., L) comprises a heteroaryl ring. In some embodiments, the linker moiety (e.g., L) comprises an aliphatic ring. In some embodiments, the linker moiety (e.g., L) comprises a heterocyclyl ring. In some embodiments, the linker moiety (e.g., L) comprises a polycyclic ring. In some embodiments, the ring in the linker moiety (e.g., L) is a 3-20 ring. In some embodiments, the ring is a 5-membered ring. In some embodiments, the ring is a 6-membered ring. In some embodiments, the ring in the joint is the product of a cycloaddition reaction (e.g., click chemistry and its variants) for connecting different parts together.

[0446] In some embodiments, the linker moiety (e.g., L) is or comprises In some embodiments, the methylene units of L are In some embodiments, -Cy- is

[0447] In some embodiments, the linker moieties are as described in Table 1. Additional linker moieties include, for example, 2 In some embodiments, L is L described in this disclosure. 1 In some embodiments, L is L as described in the present disclosure. 2 In some embodiments, L is L as described in the present disclosure. 3 In some embodiments, L is L as described in the present disclosure. b .

[0448] In some embodiments, L is

[0449] Certain implementations of variables

[0450] As examples, exemplary embodiments of variables are described throughout this disclosure. As will be appreciated by those skilled in the art, embodiments of different variables may be optionally combined.

[0451] As defined above and described herein, an ABT is an antibody binding portion.

[0452] In some embodiments, the ABT is an antibody binding portion.

[0453] In some embodiments, the ABT is selected from those depicted in Table 1 below.

[0454] As defined above and described herein, L is a divalent linker moiety that connects ABT to TBT.

[0455] In some embodiments, L is a divalent linker moiety that connects ABT to TBT.

[0456] In some embodiments, L is selected from those depicted in Table 1 below.

[0457] As defined above and described herein, TBT is a target binding moiety.

[0458] In some embodiments, TBT is a target binding moiety.

[0459] In some embodiments, TBT is selected from those depicted in Table 1 below.

[0460] As defined above and described herein, R 1 、R3 and R 5 are each independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R 1 and R 1 'Optionally together with the intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 3 and R 3 'Optionally together with the intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 5 group and R attached to the same carbon atom 5’ The group optionally forms together with its intervening carbon atom a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring or a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R 5 The group optionally forms together with its intervening atoms a C 1-10 A divalent linear or branched saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced 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 -C(O)-. 1 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0461] In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted group selected from C 1-6aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 1 is an optionally substituted C 1-6 In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 1 is an optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. 1 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 1 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 1 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0462] In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0463] In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0464] In some embodiments, R 1 yes In some embodiments, R 1 yes

[0465] In some embodiments, R 1 and R 1 ' optionally together with its intervening carbon atoms form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 1 and R 1 ' is optionally taken together with its intervening carbon atoms to form a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0466] In some embodiments, R 1 Select from those depicted in Table 1 below.

[0467] In some embodiments, R is as described in the present disclosure. 1 In some embodiments, R a2 is R as described in this disclosure 1 In some embodiments, R a3 is R as described in this disclosure 1 .

[0468] In some embodiments, R 3 In some embodiments, R 3 is an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 3 is an optionally substituted C 1-6In some embodiments, R 3 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 3 is an optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. 3 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 3 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 3 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0469] In some embodiments, R 3 In some embodiments, R 3 yes In some embodiments, R 3 yes

[0470] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (R) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (R) stereochemistry.

[0471] In some embodiments, R 3 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 3 yes wherein the attachment site has an (R) stereochemistry.

[0472] In some embodiments, R 3 and R 3’ Optionally, together with the intervening carbon atoms, they form a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring. 3and R 3’ Optionally, together with the intervening carbon atoms, they form a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0473] In some embodiments, R 3 Select from those depicted in Table 1 below.

[0474] In some embodiments, R is as described in the present disclosure. 2 In some embodiments, R a2 is R as described in this disclosure 2 In some embodiments, R a3 is R as described in this disclosure 2 .

[0475] In some embodiments, R 5 In some embodiments, R 5 is an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 5 is an optionally substituted C 1-6 In some embodiments, R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 5 is an optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. 5 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 5 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0476] In some embodiments, R 5 In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 5 yes wherein the attachment site has an (R) stereochemistry. In some embodiments, R 5 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 5 yes wherein the attachment site has an (R) stereochemistry. In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0477] In some embodiments, R 5 yes In some embodiments, R 5 yes

[0478] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0479] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes

[0480] In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 4 5 In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 5 yes In some embodiments, R 4 yes wherein the attachment site has an (S) stereochemistry. In some embodiments, R 4 yes wherein the attachment site has an (R) stereochemistry.

[0481] In some embodiments, R 5 and R attached to the same carbon atom 5 The group optionally forms a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring together with its intervening carbon atoms. 5 and R attached to the same carbon atom 5 The ' group optionally together with its intervening carbon atom forms a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0482] In some embodiments, both R 5 The group together with its intervening atoms forms a C 1-10A divalent linear or branched saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced 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 -C(O)-. 1 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0483] In some embodiments, both R 5 The group together with its intervening atoms forms In some embodiments, both R 5 The group together with its intervening atoms forms In some embodiments, both R 5 The group together with its intervening atoms forms In some embodiments, both R 5 The group together with its intervening atoms forms

[0484] In some embodiments, R 5 Select from those depicted in Table 1 below.

[0485] In some embodiments, R is as described in the present disclosure. 5 In some embodiments, R a2 is R as described in this disclosure 5 In some embodiments, R a3 is R as described in this disclosure 5 .

[0486] As defined above and described herein, R 1 '、R 3 ' and R 5 ' are each independently hydrogen or C 1-3 Fatty.

[0487] In some embodiments, R 1’ In some embodiments, R 1’ It is C 1-3 Fatty.

[0488] In some embodiments, R 1’ In some embodiments, R 1’ In some embodiments, R 1’ In some embodiments, R 1’ In some embodiments, R1’ It is cyclopropyl.

[0489] In some embodiments, R 1’ Select from those depicted in Table 1 below.

[0490] In some embodiments, R 3’ In some embodiments, R 3’ It is C 1-3 Fatty.

[0491] In some embodiments, R 3’ In some embodiments, R 3’ In some embodiments, R 3’ In some embodiments, R 3’ In some embodiments, R 3’ It is cyclopropyl.

[0492] In some embodiments, R 3’ Select from those depicted in Table 1 below.

[0493] In some embodiments, R 5’ In some embodiments, R 5’ It is C 1-3 Fatty.

[0494] In some embodiments, R 5’ In some embodiments, R 5’ In some embodiments, R 5’ In some embodiments, R 5’ In some embodiments, R 5’ It is cyclopropyl.

[0495] In some embodiments, R 5’ Select from those depicted in Table 1 below.

[0496] As defined above and described herein, R 2 、R 4 and R 6 are each independently hydrogen or C 1-4 Aliphatic, or: R 2 and R 1 Optionally, together with its intervening atoms, it forms a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 4 and R 3 optionally together with its intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or R 6Group and its adjacent R 5 The group is optionally taken together with its intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0497] In some embodiments, R 2 In some embodiments, R 2 It is C 1-4 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is tert-butyl.

[0498] In some embodiments, R 2 and R 1 Together with the intervening atoms, it forms a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0499] In some embodiments, R 2 and R 1 Together with the intervening atoms, In some embodiments, R 2 and R 1 Together with the intervening atoms,

[0500] In some embodiments, R 2 Select from those depicted in Table 1 below.

[0501] In some embodiments, R 4 In some embodiments, R 4 It is C 1-4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is tert-butyl.

[0502] In some embodiments, R 4 and R 3 Together with the intervening atoms, it forms a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0503] In some embodiments, R 4 and R 3 Together with the intervening atoms, In some embodiments, R 4 and R 3 Together with the intervening atoms,

[0504] In some embodiments, R 4 Select from those depicted in Table 1 below.

[0505] In some embodiments, R 6 In some embodiments, R 6 It is C 1-4 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 It is tert-butyl.

[0506] In some embodiments, R 6 Group and its adjacent R 5 The group together with its intervening atoms forms a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0507] In some embodiments, R 6 Group and its adjacent R 5 The group together with its intervening atoms forms In some embodiments, R 6 Group and its adjacent R 5 The group together with its intervening atoms forms

[0508] In some embodiments, R 6 Select from those depicted in Table 1 below.

[0509] In some embodiments, R is as described in the present disclosure. 1’In some embodiments, R a2 is R as described in this disclosure 1’ In some embodiments, R a3 is R as described in this disclosure 1’ In some embodiments, R is as described in the present disclosure. 3’ In some embodiments, R a2 is R as described in this disclosure 3’ In some embodiments, R a3 is R as described in this disclosure 3’ In some embodiments, R is as described in the present disclosure. 2 In some embodiments, R a2 is R as described in this disclosure 2 In some embodiments, R a3 is R as described in this disclosure 2 In some embodiments, R is as described in the present disclosure. 4 In some embodiments, R a2 is R as described in this disclosure 4 In some embodiments, R a3 is R as described in this disclosure 4 In some embodiments, R is as described in the present disclosure. 6 In some embodiments, R a2 is R as described in this disclosure 6 In some embodiments, R a3 is R as described in this disclosure 6 .

[0510] As defined above and described herein, L 1 is connected The trivalent linker portion.

[0511] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0512] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0513] In some embodiments, L 1 Select from those depicted in Table 1 below.

[0514] As defined above and described herein, L 2 Is a covalent bond or C 1-10 A divalent straight or branched saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -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 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0515] In some embodiments, L 2 is a covalent bond. In some embodiments, L2 It is C 1-10 A divalent straight or branched saturated or unsaturated hydrocarbon chain in which 1 to 3 methylene units of the chain are independently and optionally replaced by -S-, -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 -substitution, where each -Cy 1 - is independently a 5-6 membered heteroarylene group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0516] In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes In some embodiments, L 2 yes

[0517] In some embodiments, L 2 Select from those depicted in Table 1 below.

[0518] In some embodiments, L is L described in this disclosure. 2 .

[0519] As defined above and described herein, TBT is a target binding moiety.

[0520] In some embodiments, TBT is a target binding moiety.

[0521] In some embodiments, TBT is In some embodiments, TBT is

[0522] In some embodiments, TBT is selected from those depicted in Table 1 below.

[0523] As defined above and described herein, m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0524] 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.

[0525] In some embodiments, m is selected from those depicted in Table 1 below.

[0526] 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.

[0527] In some embodiments, n is selected from those depicted in Table 1 below.

[0528] As defined above and described herein, each R 7 are independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; or: R 7 The R7' group and the R7' group attached to the same carbon atom optionally form together with the intervening carbon atom a 3-8 membered saturated or partially unsaturated spirocyclic carbocycle or a 4-8 membered saturated or partially unsaturated spirocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0529] In some embodiments, R 7 In some embodiments, R 7 is an optionally substituted group selected from C 1-6 aliphatic, 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, 8-10 membered bicyclic aromatic carbocycle, 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R 7 is an optionally substituted C 1-6In some embodiments, R 7 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 7 is an optionally substituted phenyl. In some embodiments, R 7 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. 7 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 7 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 7 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0530] In some embodiments, R 7 In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0531] In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0532] In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0533] In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0534] In some embodiments, R 7 group and R attached to the same carbon atom 7 ' group together with its intervening carbon atom forms a 3-8 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R 7 group and R attached to the same carbon atom 7 The ' group together with its intervening carbon atom forms a 4-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0535] In some embodiments, R 7 Select from those depicted in Table 1 below.

[0536] As defined above and described herein, each R 7 ' are independently hydrogen or C 1-3 Fatty.

[0537] In some embodiments, R 7’ In some embodiments, R 7’ In some embodiments, R 7’ In some embodiments, R 7’ In some embodiments, R 7’ It is isopropyl.

[0538] In some embodiments, R 7’ Select from those depicted in Table 1 below.

[0539] As defined above and described herein, each R 8 are independently hydrogen or C 1-4 Aliphatic, or: R 8 Group and its adjacent R 7 The group is optionally taken together with its intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0540] In some embodiments, R 8 In some embodiments, R 8It is C 1-4 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is tert-butyl.

[0541] In some embodiments, R 8 Group and its adjacent R 7 The group together with its intervening atoms forms a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0542] In some embodiments, R 8 Group and its adjacent R 7 The group together with its intervening atoms forms In some embodiments, R 8 Group and its adjacent R 7 The group together with its intervening atoms forms

[0543] In some embodiments, R 8 Select from those depicted in Table 1 below.

[0544] As defined above and described herein, R 9 It is hydrogen, C 1-3 Aliphatic or -C(O)C 1-3 Fatty.

[0545] In some embodiments, R 9 In some embodiments, R 9 It is C 1-3 In some embodiments, R 9 Yes-C(O)C 1-3 Fatty.

[0546] In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 It is cyclopropyl.

[0547] In some embodiments, R9 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 It is -C(O)cyclopropyl.

[0548] In some embodiments, R 9 Select from those depicted in Table 1 below.

[0549] In some embodiments, R is as described in the present disclosure. 7 In some embodiments, R a2 is R as described in this disclosure 7 In some embodiments, R a3 is R as described in this disclosure 7 In some embodiments, R is as described in the present disclosure. 7’ In some embodiments, R a2 is R as described in this disclosure 7’ In some embodiments, R a3 is R as described in this disclosure 7’ In some embodiments, R is as described in the present disclosure. 8 In some embodiments, R a2 is R as described in this disclosure 8 In some embodiments, R a3 is R as described in this disclosure 8 In some embodiments, R is as described in the present disclosure. 8’ In some embodiments, R a2 is R as described in this disclosure 8’ In some embodiments, R a3 is R as described in this disclosure 8’ In some embodiments, R is as described in the present disclosure. 9 In some embodiments, R a2 is R as described in this disclosure 9 In some embodiments, R a3 is R as described in this disclosure 9 .

[0550] As defined above and described herein, L 3 is connected A divalent linker moiety with TBT.

[0551] In some embodiments, L 3 is connected A divalent linker moiety with TBT.

[0552] In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes In some embodiments, L 3 yes

[0553] In some embodiments, L 3 Select from those depicted in Table 1 below.

[0554] In some embodiments, L is L described in this disclosure. 3 .

[0555] As defined above and described herein, o is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0556] 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.

[0557] In some embodiments, o is selected from those depicted in Table 1 below.

[0558] In certain embodiments, useful agents (eg, ARMs) are compounds of Formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-a:

[0559]

[0560] or a pharmaceutically acceptable salt thereof, wherein, alone or in combination, L 1 、R 1 、R 1’ 、R 2 、R 3 、R3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and as described in the embodiments herein.

[0561] In certain embodiments, useful agents (eg, ARMs) are compounds of Formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-b:

[0562]

[0563] or a pharmaceutically acceptable salt thereof, wherein, alone or in combination, L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and as described in the embodiments herein.

[0564] In certain embodiments, useful agents (eg, ARMs) are compounds of Formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-c:

[0565]

[0566] or a pharmaceutically acceptable salt thereof, wherein, alone or in combination, L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and as described in the embodiments herein.

[0567] In certain embodiments, useful agents (eg, ARMs) are compounds of Formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-d:

[0568]

[0569] or a pharmaceutically acceptable salt thereof, wherein, alone or in combination, L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and as described in the embodiments herein.

[0570] In certain embodiments, useful agents (eg, ARMs) are compounds of Formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-e:

[0571]

[0572] or a pharmaceutically acceptable salt thereof, wherein, alone or in combination, L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and as described in the embodiments herein.

[0573] In certain embodiments, useful agents (eg, ARMs) are compounds of Formula II, wherein L 2 yes And TBT is Thus forming a compound of formula II-f:

[0574]

[0575] or a pharmaceutically acceptable salt thereof, wherein, alone or in combination, L 1 、R 1 、R 1’ 、R 2 、R 3 、R 3’ 、R 4 、R 5 、R 5’ 、R 6 and m are each as defined above and as described in the embodiments herein.

[0576] In some embodiments, R a1 is R as described in the present disclosure. In some embodiments, R a1 is an optionally substituted C 1-4 Fatty.

[0577] In some embodiments, L a1 is the L described in this disclosure a In some embodiments, L a1 It is a covalent bond.

[0578] In some embodiments, L a2 is the L described in this disclosure a In some embodiments, L a2 It is a covalent bond.

[0579] In some embodiments, L a is a covalent bond. In some embodiments, L a Is selected from C1-C 10 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 10 A heteroaliphatic optionally substituted divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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 group selected from C1-C5 aliphatic or C1-C5 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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 ais an optionally substituted divalent C1-C5 aliphatic, wherein one or more methylene units of the group are optionally and independently replaced by -C(R')2-, -Cy-, -O-, -S-, -SS-, -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. a is an optionally substituted C1-C5 heteroaliphatic having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0580] In some embodiments, R a2 is R as described in the present disclosure. In some embodiments, R a2 is a side chain of a natural amino acid. a3 is R as described in the present disclosure. In some embodiments, R a3 is a side chain of a natural amino acid. 2a and R 3a One is hydrogen.

[0581] In some embodiments, each -Cy- is independently an optionally substituted divalent group selected from C 3-20 Alicyclic ring, C 6-20 aryl rings, 5-20 membered heteroaryl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, -Cy- is an optionally substituted ring as described in the present disclosure, for example, for R and Cy L , but it is a divalent ring.

[0582] 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- comprises a saturated cyclic moiety. In some embodiments, -Cy- comprises a partially unsaturated cyclic moiety. In some embodiments, -Cy- comprises an aromatic cyclic moiety. In some embodiments, -Cy- comprises 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.

[0583] In some embodiments, -Cy- is an optionally substituted divalent C 3-20 In some embodiments, -Cy- is an optionally substituted divalent saturated C 3-20 In some embodiments, -Cy- is an optionally substituted divalent partially unsaturated C 3-20 In some embodiments, -Cy-H is an optionally substituted alicyclic ring as described in the present disclosure, for example, an alicyclic embodiment of R.

[0584] In some embodiments, -Cy- is optionally substituted C 6-20 In some embodiments, -Cy- is an optionally substituted phenylene ring. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene ring. In some embodiments, -Cy- is an optionally substituted 1,3-phenylene ring. In some embodiments, -Cy- is an optionally substituted 1,4-phenylene ring. In some embodiments, -Cy- is an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an optionally substituted aryl ring as described in the present disclosure, for example, an aryl embodiment of R.

[0585] In some embodiments, -Cy- is an optionally substituted divalent 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heteroaryl ring having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy-H is an optionally substituted heteroaryl as described in the disclosure, for example, a heteroaryl embodiment of R. In some embodiments, -Cy- is

[0586] In some embodiments, -Cy- is an optionally substituted divalent 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 3-6 membered heterocyclyl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heterocyclyl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heterocyclyl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heterocyclyl ring having 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 membered heterocyclyl ring having one heteroatom independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted saturated divalent heterocyclyl group. In some embodiments, -Cy- is an optionally substituted partially unsaturated divalent heterocyclyl group. In some embodiments, -Cy-H is an optionally substituted heterocyclyl as described in the present disclosure, for example, the heterocyclyl embodiment of R.

[0587] 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 Formula AI.

[0588] In some embodiments, t is 0. In some embodiments, t is 1 to 50. In some embodiments, t is z as described in the disclosure.

[0589] 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.

[0590] In some embodiments, R c is R' as described in the present disclosure. In some embodiments, R c is R as described in the present disclosure. In some embodiments, R c is -N(R')2, wherein each R' is independently as described in the present disclosure. In some embodiments, R c is -NH2. In some embodiments, R c is RC(O)-, wherein R is as described in this disclosure.

[0591] In some embodiments, a is 1. In some embodiments, a is 2-100. In some embodiments, a is 5. In some embodiments, a is 10. In some embodiments, a is 20. In some embodiments, a is 50.

[0592] In some embodiments, b is 1. In some embodiments, b is 2-100. In some embodiments, b is 5. In some embodiments, b is 10. In some embodiments, b is 20. In some embodiments, b is 50.

[0593] In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0594] In some embodiments, a2 is 0. In some embodiments, a2 is 1.

[0595] In some embodiments, L b is L described in this disclosure aIn 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 -SS-. In some embodiments, L b Contains -C(O)-N(R')-.

[0596] In some embodiments, R' is -R, -C(O)R, -C(O)OR, or -S(O)2R, wherein R is as described in the disclosure. In some embodiments, R' is R, wherein R is as described in the disclosure. In some embodiments, R' is -C(O)R, wherein R is as described in the disclosure. In some embodiments, R' is -C(O)OR, wherein R is as described in the disclosure. In some embodiments, R' is -S(O)2R, wherein R is as described in the disclosure. In some embodiments, R' is hydrogen. In some embodiments, R' is not hydrogen. In some embodiments, R' is R, wherein R is an optionally substituted C as described in the disclosure. 1-20 In some embodiments, R' is R, wherein R is an optionally substituted C 1-20 In some embodiments, R' is R, wherein R is an optionally substituted C 6-20 In some embodiments, R' is R, wherein R is an optionally substituted C 6-20 In some embodiments, R' is R, wherein R is an optionally substituted C 6-20 In some embodiments, R' is R, wherein R is an optionally substituted 5-20 membered heteroaryl as described in the present disclosure. In some embodiments, R' is R, wherein R is an optionally substituted 3-20 membered heterocyclyl as described in the present disclosure. In some embodiments, two or more R's are R, and optionally and independently together form an optionally substituted ring as described in the present disclosure.

[0597] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0598] Two R groups optionally and independently form together a covalent bond, or:

[0599] two or more R groups on the same atom are optionally and independently taken together with the atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

[0600] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0601] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0602] Two R groups optionally and independently form together a covalent bond, or:

[0603] two or more R groups on the same atom optionally and independently taken together with said atoms form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to said atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0604] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0605] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-20 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-20 Heteroaliphatic, C 6-20 Aryl, C 6-20 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-20 arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0606] Two R groups optionally and independently form together a covalent bond, or:

[0607] two or more R groups on the same atom optionally and independently taken together with said atoms form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having, in addition to said atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0608] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0609] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 Arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0610] In some embodiments, each R is independently -H or an optionally substituted group selected from C 1-20 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-20 Heteroaliphatic, C 6-20 Aryl, C 6-20Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-20 Arylheteroaliphatic, 5-20 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0611] In some embodiments, R is hydrogen. In some embodiments, R is not hydrogen. In some embodiments, R is an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, 5-30 membered heteroaryl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclic rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0612] In some embodiments, R is hydrogen or an optionally substituted group selected from C 1-20 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0613] In some embodiments, R is optionally substituted C 1-30 In some embodiments, R is an optionally substituted C 1-20 In some embodiments, R is an optionally substituted C 1-15 In some embodiments, R is an optionally substituted C 1-10 In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is an optionally substituted C 1-6In some embodiments, R is an optionally substituted hexyl, pentyl, butyl, propyl, ethyl, or methyl group. In some embodiments, R is an optionally substituted hexyl group. In some embodiments, R is an optionally substituted pentyl group. In some embodiments, R is an optionally substituted butyl group. In some embodiments, R is an optionally substituted propyl group. In some embodiments, R is an optionally substituted ethyl group. In some embodiments, R is an optionally substituted methyl group. In some embodiments, R is a hexyl group. In some embodiments, R is a pentyl group. In some embodiments, R is a butyl group. In some embodiments, R is a propyl group. In some embodiments, R is an ethyl group. In some embodiments, R is a methyl group. In some embodiments, R is an isopropyl group. In some embodiments, R is an n-propyl group. In some embodiments, R is a tert-butyl group. In some embodiments, R is a sec-butyl group. In some embodiments, R is an n-butyl group. In some embodiments, R is -(CH2)2CN.

[0614] In some embodiments, R is optionally substituted C 3-30 In some embodiments, R is an optionally substituted C 3-20 In some embodiments, R is an optionally substituted C 3-10 In some embodiments, R is an optionally substituted cyclohexyl group. In some embodiments, R is a cyclohexyl group. In some embodiments, R is an optionally substituted cyclopentyl group. In some embodiments, R is a cyclopentyl group. In some embodiments, R is an optionally substituted cyclobutyl group. In some embodiments, R is a cyclobutyl group. In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R is a cyclopropyl group.

[0615] In some embodiments, R is an optionally substituted 3-30 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 6 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 7 membered saturated or partially unsaturated 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.

[0616] In some embodiments, when R is or comprises a ring structure (e.g., cycloaliphatic, cycloheteroaliphatic, aryl, heteroaryl, etc.), the ring structure can be monocyclic, bicyclic, or polycyclic. In some embodiments, R is or comprises a monocyclic structure. In some embodiments, R is or comprises a bicyclic structure. In some embodiments, R is or comprises a polycyclic structure.

[0617] In some embodiments, R is an optionally substituted C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 In some embodiments, R is an optionally substituted C 1-20 In some embodiments, R is an optionally substituted C having 1-10 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 In some embodiments, R is an optionally substituted C 1-30 Heteroaliphatic, comprising 1-10 groups independently selected from: -N=, ≡N, -S-, -S(O)-, -S(O)2-, -O-, =O,

[0618] In some embodiments, R is optionally substituted C 6-30 In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is a phenyl group. In some embodiments, R is a substituted phenyl group.

[0619] In some embodiments, R is an optionally substituted 8-10 membered bicyclic saturated ring, partially unsaturated ring, or aryl ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic partially unsaturated ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R is an optionally substituted naphthyl.

[0620] In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 5-30 membered heteroaryl ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0621] In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, R is a substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.

[0622] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0623] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted pyrrolyl, furanyl, or thienyl.

[0624] 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 additional heteroatoms 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.

[0625] In some embodiments, R is an optionally substituted 6-membered heteroaryl ring with 1-4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring with 1-3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring with 1-2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring with four nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring with three nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring with two nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring with one nitrogen atom.

[0626] In certain embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0627] In some embodiments, R is a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is a 3-30 membered heterocyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is a 3-30 membered heterocyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0628] In some embodiments, R is an optionally substituted 3-7 yuan saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is a substituted 3-7 yuan saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an unsubstituted 3-7 yuan saturated or partially unsaturated heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R is an optionally substituted 5-7 yuan partially unsaturated monocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R is an optionally substituted 5-6 yuan partially unsaturated monocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R is an optionally substituted 5 yuan partially unsaturated monocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocycle with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocycle with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 3-membered heterocycle with one heteroatom selected from nitrogen, oxygen or sulfur. In some embodiments, R is an optionally substituted 4-membered heterocycle with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 5-membered heterocycle with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 6-membered heterocycle with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 7-membered heterocycle with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0629] In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0630] In certain embodiments, R is an optionally substituted 5-6 membered partially unsaturated monocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted tetrahydropyridinyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl.

[0631] In some embodiments, R is an optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 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]octyl.

[0632] In some embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0633] In some embodiments, R is optionally substituted C 6-30 In some embodiments, R is an optionally substituted C 6-20 In some embodiments, R is an optionally substituted C 6-10 In some embodiments, the aryl moiety of the arylaliphatic has 6, 10, or 14 aryl carbon atoms. In some embodiments, the aryl moiety of the arylaliphatic has 6 aryl carbon atoms. In some embodiments, the aryl moiety of the arylaliphatic has 10 aryl carbon atoms. In some embodiments, the aryl moiety of the arylaliphatic has 14 aryl carbon atoms. In some embodiments, the aryl moiety is an optionally substituted phenyl.

[0634] In some embodiments, R is an optionally substituted C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 In some embodiments, R is an optionally substituted C having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-30 In some embodiments, R is an optionally substituted C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-20 In some embodiments, R is an optionally substituted C having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-20 In some embodiments, R is an optionally substituted C having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-10 In some embodiments, R is an optionally substituted C having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 6-10 Arylheteroaliphatic.

[0635] In some embodiments, two R groups optionally and independently form a covalent bond together. In some embodiments, -C=O is formed. In some embodiments, -C=C- is formed. In some embodiments, -C≡C- is formed.

[0636] In some embodiments, two or more R groups on the same atom optionally and independently form together with the atom an optionally substituted 3-30 yuan monocycle, bicycle or polycycle, and the monocycle, bicycle or polycycle also has 0-10 heteroatoms independently selected from oxygen, nitrogen, sulphur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form together with the atom an optionally substituted 3-20 yuan monocycle, bicycle or polycycle, and the monocycle, bicycle or polycycle also has 0-10 heteroatoms independently selected from oxygen, nitrogen, sulphur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form together with the atom an optionally substituted 3-10 yuan monocycle, bicycle or polycycle, and the monocycle, bicycle or polycycle also has 0-5 heteroatoms independently selected from oxygen, nitrogen, sulphur, phosphorus and silicon in addition to the atom. In some embodiments, two or more R groups on the same atom optionally and independently form together with the atoms an optionally substituted 3-6 membered monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atoms. In some embodiments, two or more R groups on the same atom optionally and independently form together with the atoms an optionally substituted 3-5 membered monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the atoms.

[0637] In some embodiments, two or more R groups on two or more atoms optionally and independently form together with their intervening atoms an optionally substituted 3-30 yuan monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form together with their intervening atoms an optionally substituted 3-20 yuan monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form together with their intervening atoms an optionally substituted 3-10 yuan monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form together with their intervening atoms an optionally substituted 3-10 membered monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form together with their intervening atoms an optionally substituted 3-6 membered monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms. In some embodiments, two or more R groups on two or more atoms optionally and independently form together with their intervening atoms an optionally substituted 3-5 membered monocycle, bicycle or polycycle, wherein the monocycle, bicycle or polycycle has 0-3 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon in addition to the intervening atoms.

[0638] In some embodiments, the heteroatoms in the R group or in the structure formed by two or more R groups are selected from oxygen, nitrogen and sulfur. In some embodiments, the ring formed is a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring. In some embodiments, the ring formed is a saturated ring. In some embodiments, the ring formed is a partially saturated ring. In some embodiments, the ring formed is an aromatic ring. In some embodiments, the ring formed comprises a saturated ring portion, a partially saturated ring portion or an aromatic ring portion. In some embodiments, the ring formed comprises 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 no more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 aromatic ring atoms. In some embodiments, the aromatic ring atoms are selected from carbon, nitrogen, oxygen, and sulfur.

[0639] In some embodiments, the ring formed by two or more R groups (or two or more groups selected from R and variables that can be R) together is C 3-30 Alicyclic, C 6-30 Aryl, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; the ring is as described for R, but is divalent or multivalent.

[0640] Exemplary compounds of the present invention are listed in Table 1 below.

[0641] Table 1. Exemplary compounds

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658] In some embodiments, useful ARMs are compounds listed in Table 1 above, or pharmaceutically acceptable salts thereof.

[0659] 5. Exemplary Methods for Preparing Immune Cells and ARM Agents

[0660] Various techniques in the art can be used to prepare immune cells, for example, NK cells and agents of the present disclosure. Certain methods (including separation, purification, pre-activation, characterization, evaluation, etc.) are described in the following documents: 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.

[0661] Agents such as ARMs can be prepared, for example, by the synthetic methods exemplified in the Examples.

[0662] For example, in some embodiments, useful compounds (eg, ARMs) are constructed via cycloaddition reactions (eg, click chemistry or variations thereof).

[0663] In some embodiments, for example, compounds useful in the preparation of the agents (eg, ARMs) of the present disclosure have the structure of Formula IV:

[0664]

[0665] or a salt thereof, wherein

[0666] ABT is the antibody binding portion;

[0667] L is the connector part;

[0668] R d Yes-L a -R', where R d Contains -C≡C- or -N3;

[0669] Each L a are independently covalent bonds or selected from C1-C 20 Aliphatic or C1-C2-C3-C4-C6-C1-C2-C1 ... 20 a heteroaliphatic optionally substituted divalent group wherein one or more methylene units of the group are optionally and independently replaced by -C(R')-, -Cy-, -O-, -S-, -SS-, -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)-, -S(O)N(R')-, -C(O)S-, or -C(O)O-;

[0670] Each -Cy- is independently an optionally substituted divalent group selected from C 3-20 Alicyclic ring, C 6-20 aryl rings, 5-20 membered heteroaryl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-20 membered heterocyclyl rings having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

[0671] Each R' is independently -R, -C(O)R, -CO2R, or -SO2R;

[0672] Each R is independently -H or an optionally substituted group selected from C 1-30 aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 1-30 Heteroaliphatic, C 6-30 Aryl, C 6-30 Aryl aliphatic, C having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon 6-30 arylheteroaliphatic, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

[0673] Two R groups optionally and independently form together a covalent bond, or:

[0674] two or more R groups on the same atom are optionally and independently taken together with the atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

[0675] Two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted 3-30 membered monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

[0676] In some embodiments, for example, compounds useful in the preparation of the agents (eg, ARMs) of the present disclosure have the structure of Formula IV-a:

[0677]

[0678] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0679] In some embodiments, for example, compounds useful in the preparation of agents (eg, ARMs) of the present disclosure have the structure of Formula IV-b:

[0680] R c -(Xaa) z -LR d ,

[0681] IV-b

[0682] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0683] In some embodiments, for example, compounds useful in the preparation of agents (eg, ARMs) of the present disclosure have the structure of Formula IV-c:

[0684]

[0685] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0686] In some embodiments, for example, compounds useful in the preparation of the agents (eg, ARMs) of the present disclosure have the structure of Formula IV-d:

[0687]

[0688] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0689] In some embodiments, compounds useful, for example, in the preparation of agents (eg, ARMs) of the present disclosure have the structure of Formula V:

[0690]

[0691] or a salt thereof, wherein each variable is independently as described in the present disclosure.

[0692] In some embodiments, the method for preparing a compound (e.g., ARM) comprises the following steps:

[0693] providing a first compound of Formula IV, IV-a, IV-b, IV-c, or IV-d, or a salt thereof, wherein the compound comprises a first reactive moiety;

[0694] providing a second compound of Formula V or a salt thereof comprising a second reactive moiety; and

[0695] The first compound is reacted with the second compound, wherein the first reactive moiety reacts with the second reactive moiety via a cycloaddition reaction.

[0696] Many cycloaddition reactions can be used according to the present disclosure. 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-.

[0697] 6. Use, formulation and application

[0698] Pharmaceutically acceptable compositions

[0699] In some embodiments, the present disclosure provides a composition comprising immune cells (e.g., pre-activated memory-like NK cells) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a composition comprising a medicament and a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a composition comprising immune cells and a medicament and a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, immune cells and useful agents (e.g., ARM) are provided as separate compositions. In some embodiments, immune cells and useful agents (e.g., ARM) are provided as the same composition.

[0700] In many embodiments, immune cells are typically administered in an amount sufficient to provide therapeutic benefit without serious side effects. For example, in some embodiments, immune cells are administered at 0.01-100, 0.1-50, 0.1-20, 0.1-10, 0.05, 0.1, 0.2, 0.3, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90 million cells / kg body weight of the subject.

[0701] The agent (e.g., ARM) is typically administered in an amount that effectively redirects endogenous antibodies (e.g., endogenous antibodies) and / or fragments thereof selectively to target cells (e.g., cancer cells) to induce antibody-directed, cell-mediated immunity (e.g., cytotoxicity). In certain embodiments, the amount of the compound in the compositions of the present disclosure is such that they effectively redirect endogenous antibodies selectively to cancer cells, thereby inducing antibody-directed, cell-mediated cytotoxicity in a biological sample or subject. In some embodiments, the amount is 0.01-100 mg / kg body weight. In some embodiments, the amount is 0.01-50 mg / kg body weight. In some embodiments, the amount is from about 1 mg / kg to about 25 mg / kg.

[0702] In some embodiments, pharmaceutically acceptable carrier, adjuvant or vehicle are non-toxic carriers, adjuvants or vehicles that will not destroy the pharmacological activity of the compound prepared therewith.Pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present invention include but are not limited to ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum protein (such as human serum albumin), buffer material (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), silica sol, magnesium trisilicate, polyvinyl pyrrolidone, based on cellulose material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.In some embodiments, immunocyte can be provided in suitable culture medium.

[0703] In some embodiments, the pharmaceutical agent may be provided as a pharmaceutically acceptable derivative, which may be a non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present disclosure, which is capable of providing the pharmaceutical agent directly or indirectly upon administration to a recipient.

[0704] The compositions of the present disclosure 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, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Preferably, the composition comprising immune cells is administered intravenously. The sterile injectable form of the compositions of the present disclosure can be an aqueous or oily suspension. Suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0705] In some embodiments, the agent (eg, ARM) is formulated as a composition for delayed and / or sustained release. Technologies for sustained release and / or slow absorption are widely available in the art and can be used in accordance with the present disclosure.

[0706] In some embodiments, gentle fixed oils can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and glyceride derivatives thereof can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. Such oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants that are generally used to prepare pharmaceutically acceptable dosage forms (including emulsions and suspensions). For the purpose of preparation, other conventional surfactants can also be used, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, which are generally used to make pharmaceutically acceptable solids, liquids or other dosage forms.

[0707] The pharmaceutically acceptable compositions of the medicaments (e.g., ARM) of the present disclosure can be orally administered in any orally acceptable dosage form (e.g., 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 desired for oral use, the active ingredient is combined with an emulsifier and / or a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0708] For example, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the pharmaceutical agent to be delivered (e.g., ARM) is mixed with at least one pharmaceutically acceptable inert excipient or carrier (e.g., sodium citrate or calcium hydrogen phosphate) and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; 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 a buffer.

[0709] Solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules that use excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (other coatings as known in the art of enteric coatings and pharmaceutical formulations). In some embodiments, solid compositions can optionally contain an emulsifier and can only or preferentially release the medicament to be delivered in a delayed manner in a certain position (e.g., a certain position in the intestinal tract) of the subject. The example of operable embedded compositions includes polymeric substances and waxes.

[0710] In some embodiments, medicament (for example, ARM) can be in the form of microencapsulation with one or more excipients as described above. In some embodiments, the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (such as enteric coatings, controlled release coatings and other coatings known in the art of pharmaceutical formulations). In such solid dosage forms, the medicament to be delivered can be mixed with at least one inert diluent (such as sucrose, lactose or starch). Such dosage forms can also include additional substances as in normal practice, for example, 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 include a buffer.

[0711] Alternatively, the pharmaceutically acceptable compositions can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore dissolve in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0712] The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment comprises areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0713] For topical application, pharmaceutically acceptable compositions can be formulated in a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compound of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing an 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0714] For ophthalmic use, the pharmaceutically acceptable composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline (with or without a preservative such as benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated in an ointment such as petrolatum.

[0715] Pharmaceutically acceptable compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents, and can be prepared as solutions in saline.

[0716] Pharmaceutically acceptable compositions of agents (e.g., ARMs) can be formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions are administered without food. In other embodiments, pharmaceutically acceptable compositions are administered with food.

[0717] It will also be understood that the specific dosage and treatment regimen 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, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated.

[0718] use

[0719] Among other things, the present disclosure encompasses the recognition that certain immune cells (such as pre-activated memory-like NK cells) have improved properties and / or activity toward their targets (e.g., cancer cells) and can be particularly effective in treating conditions, disorders, or diseases (such as cancer); however, such immune cells may also cause more severe side effects, for example, due to their increased cytotoxicity, such as by causing off-target effects. Therefore, in some embodiments, the present disclosure provides techniques for exposing a subject to both such immune cells and an agent (e.g., ARM) that can promote immune cell targeting of a desired target (e.g., cancer cells) and reduce the side effects of such immune cell therapies.

[0720] In some embodiments, useful agents selectively direct antibodies (e.g., endogenous antibodies) to diseased cells (e.g., cancer cells), thereby inducing and / or promoting an antibody-directed, cell-mediated immune response, e.g., cytotoxicity produced by immune cells (e.g., pre-activated memory-like NK cells (e.g., cytokine-inducible memory-like NK cells)). In some embodiments, the antibodies raised include one or more endogenous antibodies. In some embodiments, the antibodies raised are specific for one or more antigens. In some embodiments, the antibodies raised are specific for one or more peptide antigens or proteins. In some embodiments, the antibodies raised are heterogeneous in that they are not antibodies to the same antigen or protein.

[0721] In some embodiments, useful agents (e.g., ARM) trigger, produce encouragement and / or enhance one or more immune system activities for target. In some embodiments, immune system activity is or includes ADCC produced by NK cells. In some embodiments, immune system activity is or includes ADCC produced by pre-activated memory-like NK cells (e.g., cytokine-induced memory-like NK cells). In some embodiments, target is a cancer cell. In some embodiments, target is a cancer cell in a subject.

[0722] As described herein, administration of immune cells (such as pre-activated memory-like NK cells, for example, cytokine-inducible memory-like NK cells) and agents (such as ARM) allows the subject to be exposed to both. In some embodiments, the immune cells (or their dosage) are administered before the ARM agent (or its dosage). In some embodiments, the immune cells (or their dosage) are administered after the ARM agent (or its dosage). In some embodiments, the immune cells (or their dosage) are administered simultaneously with the ARM agent (or its dosage). When administered simultaneously, the immune cells and ARM can be administered in one composition or as separate compositions. In some embodiments, the immune cells and the ARM are administered within 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of each other, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks. The immune cells and the agent (e.g., ARM) can be administered separately as a single dose or in multiple doses. In some embodiments, the administered immune cells (e.g., pre-activated memory-like NK cells) form a complex with the administered ARM together with a target (e.g., a cancer cell) and the antibody (or fragment thereof) in the subject, wherein the antibody (or fragment thereof) interacts with the immune cells and the ARM, and the ARM interacts with the antibody (or fragment thereof) and the target (e.g., cancer cell).

[0723] In some embodiments, "treating" or "treatment" as used herein includes reversing, alleviating, delaying the onset of a condition, disorder, or disease, or one or more symptoms thereof, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment may also be continued after symptoms subside, for example, to prevent or delay their recurrence.

[0724] In some embodiments, the present invention provides methods for treating one or more disorders, diseases and / or conditions, wherein the disorder, disease or condition is cancer. Among other aspects, the provided technology (e.g., compounds, compositions, methods, etc.) is particularly useful for preventing and / or treating cancer.

[0725] In some embodiments, cancer is a pathological process that leads to the formation and growth of cancerous or malignant tumors, that is, abnormal tissue that grows by cell proliferation, usually faster than normal tissue and continues to grow after the stimulus that initiated new growth has ceased. Malignant tumors can show partial or complete loss of structural organization and functional coordination with normal tissue, and most malignant tumors invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and cause the patient's death unless adequately treated. In some embodiments, as used herein, the term neoplasia includes all cancerous disease states and includes or encompasses pathological processes associated with hematological malignancies, ascites tumors, and solid tumors. Representative cancers include, for example, prostate cancer, metastatic prostate cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine corpus cancer, ovarian cancer, testicular cancer, bladder cancer, renal cancer, brain / CNS cancer, head and neck cancer, throat cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myeloid leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, oral / pharyngeal cancer, esophageal cancer, larynx cancer, kidney cancer, and lymphoma, among others, which can be treated with one or more compounds according to the present invention.

[0726] In some embodiments, the cancer is leukemia. In some embodiments, the provided technology is particularly useful for treating leukemia. In some embodiments, the provided technology is particularly useful for treating acute myeloid leukemia (AML). In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is melanoma.

[0727] In some embodiments, before administering the therapy of the present invention (e.g., being exposed to administered pre-activated memory-like NK cells and ARM), the subject may have been treated with another therapy (e.g., chemotherapy, immunotherapy, surgery, etc.). In some embodiments, the subject is susceptible to relapsed or refractory cancer, or suffers from relapsed or refractory cancer. In some embodiments, the subject is susceptible to relapsed or refractory leukemia, or suffers from relapsed or refractory leukemia. In some embodiments, the subject is susceptible to relapsed or refractory AML, or suffers from relapsed or refractory AML.

[0728] In some embodiments, treatment can be administered to a subject undergoing a lymphocyte removal regimen. In some embodiments, removal of immune regulatory elements (e.g., using cytotoxic agents or whole-body irradiation) can enhance the activity of administered immune cells. In some embodiments, cytotoxic agents such as fludarabine, cyclophosphamide, and / or alemtuzumab are administered to a subject.

[0729] Combination therapy

[0730] In certain embodiments, provided technology (e.g., technology comprising immune cells (e.g., memory-like NK cells) and ARM) is administered in combination with one or more other therapies. In some embodiments, in addition to immune cells (e.g., memory-like NK cells) and ARM agents, another therapy is administered to the subject. In some embodiments, the subject has cancer, and such another therapy is a cancer therapy, e.g., chemotherapy, immunotherapy, surgery, etc.

[0731] In addition to other aspects, the technology of the present disclosure including immune cells (e.g., memory-like NK cells) and ARM can be used in combination with other therapies, that is, such technology can be used simultaneously with one or more other therapeutic agents or medical procedures, before or after them, particularly for the treatment of various cancers. In some embodiments, such technology can be used in combination with other antiproliferative compounds. In some embodiments, the therapeutic agent that can be used for combination is a chemotherapeutic agent or an antiproliferative compound. Exemplary chemotherapeutic agents include but are not limited to alkylating agents, nitrosourea agents, antimetabolites, antitumor antibiotics, alkaloids derived from plants, topoisomerase inhibitors, hormone therapy drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapy drugs, and other anticancer agents. In addition, the technology provided can be used for patient's QOL recovery together with leukopenia (neutrophil) drugs, thrombocytopenia drugs, antiemetic drugs and cancer pain drugs as cancer treatment adjuvants, or make a mixture with them. In some embodiments, the therapeutic agent is an antibody. In some embodiments, the therapeutic agent is an immunomodulator. In some embodiments, the cell surface signaling molecules on the immunomodulator targeting immune cells. In some embodiments, the immunomodulator targets cell surface signaling molecules on immune cells, wherein the agent is an antagonist that blocks a co-inhibitory pathway. In some embodiments, the immunomodulator is a checkpoint blocker. In some embodiments, the immunomodulator is an antibody targeting a cell surface signaling protein expressed by an immune cell. In some embodiments, the immunomodulator is an antibody targeting a protein selected from the group consisting of PD-1, PD-L1, CTLA4, TIGIT, BTLA, TIM-3, LAG3, B7-H3, and B7-H4. In some embodiments, the immunomodulator is a PD-1 antibody (e.g., nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL328OA, etc.). In some embodiments, the immunomodulator is a PD-L1 antibody. In some embodiments, the immunomodulator is a CTLA4 antibody (e.g., ipilimumab). In some embodiments, the immunomodulator is a TIGIT antibody. In some embodiments, the immunomodulator is a BTLA antibody. In some embodiments, the immunomodulator is a Tim-3 antibody. In some embodiments, the immunomodulator is a LAG3 antibody. In some embodiments, the immunomodulator is a B7-H3 antibody. In some embodiments, the immunomodulator is a B7-H4 antibody. In some embodiments, the immunomodulator targets a cell surface signaling molecule on an immune cell, wherein the agent is an agonist that participates in a co-stimulatory pathway. In some embodiments, such an immunomodulator is or comprises an antibody that targets a co-stimulatory receptor. In some embodiments, the antibody activates a T cell co-stimulatory receptor.In some embodiments, the antibody targets a member of the tumor ne...

Claims

1. Use of an antibody recruiting molecule (ARM) and a plurality of natural killer cells in the preparation of a medicament for inducing cell death of cancer cells, inhibiting cancer cell growth and / or reducing the number of cancer cells in a patient, wherein the ARM is a compound of the formula: or a pharmaceutically acceptable salt thereof, and The cancer is selected from the group consisting of multiple myeloma, leukemia, lymphoma and melanoma.

2. Use of an antibody recruiting molecule (ARM) in the preparation of a medicament for inducing cell death of cancer cells, inhibiting cancer cell growth and / or reducing the number of cancer cells in a patient, wherein the ARM is a compound of the formula: or a pharmaceutically acceptable salt thereof, and The cancer is selected from the group consisting of multiple myeloma, leukemia, lymphoma and melanoma.

3. Use of an antibody recruiting molecule (ARM) and a plurality of natural killer cells in the preparation of a medicament for treating a condition, disorder or disease, wherein the ARM is a compound of the formula: or a pharmaceutically acceptable salt thereof, and The cancer is selected from the group consisting of multiple myeloma, leukemia, lymphoma and melanoma.

4. The use according to any one of claims 1 to 3, wherein the cancer is selected from multiple myeloma, leukemia and lymphoma.

5. The use according to claim 1 or 3, wherein the medicament is used to reduce the side effects of treatment using natural killer cells in a subject.

6. The use according to claim 1 or 3, wherein the medicament is used to reduce the toxicity of a treatment using natural killer cells.

7. The use according to claim 1 or 3, wherein the natural killer cells are memory-like natural killer cells.

8. The use according to claim 1 or 3, wherein the natural killer cells are cytokine-inducible memory-like natural killer cells induced by IL-12, IL-15 and IL-18.

9. The use according to claim 1 or 3, wherein the natural killer cells and the ARM are administered simultaneously in one composition.

10. The use according to claim 1 or 3, wherein the natural killer cells are administered before or after the ARM.

11. Use of an antibody recruiting molecule (ARM), a plurality of natural killer cells and an antibody in the preparation of a medicament for treating a condition, disorder or disease, wherein the ARM is a compound of the formula: or a pharmaceutically acceptable salt thereof, and wherein the condition, disorder or disease is a cancer selected from the group consisting of multiple myeloma, leukemia, lymphoma and melanoma.

12. A combination product, comprising: multiple natural killer cells; and Antibody Recruiting Molecule (ARM), wherein the ARM is a compound of the formula: or a pharmaceutically acceptable salt thereof.

13. The combination product according to claim 12, wherein the natural killer cells are the natural killer cells according to any one of claims 1, 3 and 5-10.

14. The combination product according to claim 13, further comprising an antibody.

15. A composition comprising: multiple natural killer cells; and Antibody Recruiting Molecule (ARM), wherein the ARM is a compound of the formula: or a pharmaceutically acceptable salt thereof.

16. The composition of claim 15, further comprising an antibody.

17. An antibody recruiting molecule (ARM) having the formula, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the antibody recruiting molecule (ARM) according to claim 17 and a pharmaceutically acceptable excipient.

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