Agents and methods for targeted delivery to cells

Abstract

The invention relates to agents and methods for targeted delivery of payloads to cells. The payload comprises immunomodulators as further specified herein. In some embodiments, the invention involves providing to a subject a compound comprising a payload moiety and at least one tag (e.g., at least two tags) (tag conjugate) and a compound binding to the tag(s) of the tag conjugate and a target antigen, e.g., a cell surface antigen on a target cell, (docking compound).

Description

[0001] AGENTS AND METHODS FOR TARGETED DELIVERY TO CELLS

[0002] The invention relates to agents and methods for targeted delivery of payloads to cells. The payload comprises immunomodulators as further specified herein. In some embodiments, the invention involves providing to a subject a compound comprising a payload moiety and at least one tag (e.g., at least two tags) (tag conjugate) and a compound binding to the tag(s) of the tag conjugate and a target antigen, e.g., a cell surface antigen on a target cell, (docking compound). In some embodiments, the docking compound comprises a peptide or polypeptide. In some embodiments, the docking compound comprises a binding moiety binding to target cells (primary targeting moiety) and a further binding moiety binding to the tag(s) of the tag conjugate. The tag(s) of the tag conjugate may bind to its (their) binding moiety on the docking compound and the primary targeting moiety of the docking compound may bind to a target antigen on target cells such as an antigen on cancer cells to thereby precisely deliver a payload to the target cells. In some embodiments, the docking compound is provided to a subject by administering nucleic acid, e.g., RNA, encoding the docking compound. In some embodiments, the docking compound is provided to a subject by administering the docking compound. In some embodiments, a preformed complex wherein the docking compound is bound to the tag conjugate is provided to a subject by administration.

[0003] In many areas of medical therapy and diagnosis, it is desired to selectively deliver an agent, such as a therapeutic agent (a drug) or a diagnostic agent (e.g. an imaging agent), to a specific cell in the body of a subject such as a patient.

[0004] Active targeting of a cell may be achieved by the direct or indirect conjugation of the desired payload to a targeting moiety, which binds to cell surface antigens on the target cell of interest. The targeting moieties are typically constructs that have affinity for cell surface targets, e.g., membrane proteins, and include antibodies or antibody fragments.

[0005] The present invention relates to an approach wherein a docking compound that binds to target cells, e.g., by binding to a cell surface antigen, is used. The docking compound further comprises a moiety, which binds to a compound comprising a payload and being equipped with at least one tag (e.g., at least two tags) which is (are) targeted by the moiety on the docking compound. In some embodiments, a docking compound which binds to a tag conjugate comprising a payload is administered in the form of nucleic acid encoding the docking compound for expressing of the docking compound in a subject. The docking compound may bind to target cells, e.g., by binding to a cell surface antigen, thus resulting in targeting of the payload. Common examples for pairs of interacting moieties on the docking compound and on the tag conjugate are antibody / tag systems. The concept described herein allows to use a single type of tag conjugate for targeting a wide range of target cells, i.e., by using a single type of tag conjugate in combination with different docking compounds targeting different primary targets. The concept described herein is of further advantage, as the primary targeting using a single docking compound can be carried out in combination with different tag conjugates comprising different payloads.

[0006] Summary

[0007] The invention relates to agents and methods for targeted delivery of payloads to cells. The payload comprises an immunomodulator as specified herein. Targeted delivery of a payload is achieved using a tag conjugate described herein comprising the payload and a docking compound binding to the tag conjugate via its tag(s), said docking compound comprising a targeting molecule for targeting an antigen on target cells.

[0008] In one aspect, the invention relates to a kit comprising:

[0009] (i) a compound comprising a binding moiety binding to a target antigen and a binding moiety for a tag, or a nucleic acid encoding said compound; and

[0010] (ii) a compound comprising a payload moiety and a tag to which the binding moiety for a tag binds, wherein the payload comprises a STING agonist.

[0011] In some embodiments, the STING agonist has the following Formula (XX): wherein:

[0012] Ring A is selected from the group consisting of

[0013] G and Gi are independently N, CH, or C-X1-R2; or when G and Gi are each C-X1-R2, the R2 groups are optionally linked to form L2;

[0014] G' and G2 are independently N or CH;

[0015] X is N-R, O, or S;

[0016] X' is N or CH; Xi is CH2, 0 or S;

[0017] R is hydrogen or C1-4 alkyl;

[0018] L1and L2are each independently C2-4 alkylene or C2-4 alkenylene;

[0019] R2 is selected from the group consisting of hydrogen, C2-4 cyclic ether, C1.4 alkylene-(C2-4 cyclic

[0020] 0 o

[0021] H2N^M^ HOAA ether), C3-4 cycloalkyl, C1-4 alkylene-(C34 cycloalkyl), C1-4 alkyl,

[0022] Ri and R3 are independently selected from the group consisting of

[0023] Ring B is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 2 heteroatoms independently selected from N, 0, and S;

[0024] Rs is -OH or -NR9R10;

[0025] R9 and Rio are independently selected from hydrogen and C1-6 alkyl;

[0026] X2 and X3 are independently NH or S;

[0027] Yi and Y2 are independently a 5-membered heteroaryl or heterocyclic ring, wherein the 5- membered heteroaryl or heterocyclic ring (i) has 1 to 4 heteroatoms independently selected from N, O, and S, (ii) is attached to the remainder of the STING agonist via a C ring atom of the 5-membered heteroaryl or heterocyclic ring, and (iii) is optionally substituted with 1 to 4 R21, wherein each R21 is independently C1-4 alkyl (such as methyl, ethyl, propyl, or butyl); Rs, Re, and R7 are independently selected from hydrogen, Ci-e alkyl, C2-6 alkenyl, , or Rs and Re are optionally connected to form a 5- or 6- membered heterocyclic ring;

[0028] Ris is -OH or -NR9R10;

[0029] Ring C is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 ring heteroatoms independently selected from N, 0, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 4 ring heteroatoms independently selected from N, O, and S; n, p, q, q', t, and v are independently an integer from 2 to 6 (i.e., 2, 3, 4, 5, or 6, such as 2, 3, 4, or 5, e.g., 2, 3, or 4); and k, I, m, o, u, and w are independently an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6, such as 1, 2, 3, 4, or 5, e.g., 1, 2, 3, or 4).

[0030] In some preferred embodiments, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX). In some preferred embodiments, the payload moiety comprises a STING agonist moiety of Formula (XX1) as disclosed herein.

[0031] Preferred embodiments of the STING agonist of Formula (XX) and / or of the STING agonist moiety of Formula (XX') are disclosed herein and include: (1) any one of Formulas (XXA), (XXB), (XXC), (XXD), (XXE), (XXF), (XXG), (XXH), (XXJ), (XXK), (XX-I) to (XX-LXII), (XX-1) to (XX-73), (XX- 6'), (XX-18'), (XX-51'), (XX-531), (XX-73'a), and (XX-73'b); (2) the embodiments of substituents specified herein with respect to any one of Formulas (XX), (XXA), (XXB), (XXC), (XXD), (XXE), (XXF), (XXG), (XXH), (XXJ), (XXK), and (XX-I) to (XX-LXII) (e.g., that in some embodiments of Formula (XX), G? is CH); and (iii) the embodiments of substituents specified herein with respect to any one of Formulas (XX1), (XXA'), (XXB'), (XXC), (XXD'), (XXE'), (XXF1), (XXG'), (XXH'), (XXJ'), (XXK1), (XX-6'), (XX-18'), (XX-511), (XX-53'), (XX-73'a), and (XX-73'b) (e.g., that in some embodiments of Formula (XX1), one of the monovalent substituents present in the STING agonist of Formula (XX) (e.g., R2 being hydrogen or C1-4 alkyl; or Ri being N(R6)(R?)N(Rs)C(0)-) has been replaced by a corresponding divalent substituent (e.g., R2 has been replaced by R21, wherein R2' is a bond (if R2 was hydrogen) or C1-4 alkylene (if R2 was a C1-4 alkyl); or Ri has been replaced by Rr, wherein Rr is selected from the group consisting of *-N(Re)N(Rs)C(O)-#, *- N (Rs)C(O)-#, and -C(0)-, wherein * represents the attachment point of R2' and Rr, respectively, to the remainder of the compound under (ii); and#represents the attachment point of R2' and Rr, respectively, to the remainder of the STING agonist moiety of Formula (XX')).

[0032] In some embodiments, the STING agonist of Formula (XX) has Formula (XXA) as disclosed herein, wherein G is CH, C-SCH3, C-OCH3, or N. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXA), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXA1).

[0033] In some embodiments, the STING agonist of Formula (XX) has Formula (XXB) as disclosed herein, wherein G is CH, C-SCH3, C-OCH3, or N; Rs is -OH or -NH2; Yi and Y2 are independently oxazolyl, pyrazolyl, thiazolyl, or imidazolyl, each of which is optionally substituted with 1 or 2 R21. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXB), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXB1).

[0034] In some embodiments, the STING agonist of Formula (XX) has Formula (XXC) as disclosed herein, wherein Yi and Y2 are independently oxazolyl, pyrazolyl, thiazolyl, or imidazolyl, each of which is optionally substituted with 1 or 2 R21. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXC), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXC).

[0035] In some embodiments, the STING agonist of Formula (XX) has Formula (XXD) as disclosed herein, wherein R?r is hydrogen or C1-4 alkyl. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXD), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXD1).

[0036] In some embodiments, the STING agonist of Formula (XX) has Formula (XXE) as disclosed herein, wherein X is S or O. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXE), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXE').

[0037] In some embodiments, the STING agonist of Formula (XX) has Formula (XXF) as disclosed herein, wherein G is CH, C-SCH3, C-OCH3, or N. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXF), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXF').

[0038] In some embodiments, the STING agonist of Formula (XX) has Formula (XXG) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXG), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXG1).

[0039] In some embodiments, the STING agonist of Formula (XX) has Formula (XXH) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXH), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXH1).

[0040] In some embodiments, the STING agonist of Formula (XX) has Formula (XXJ) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXJ), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXJ').

[0041] In some embodiments, the STING agonist of Formula (XX) has Formula (XXK) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXK), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXK1).

[0042] In some preferred embodiments, the STING agonist of Formula (XX) has Formula (XXH) or (XXK) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXH') or (XXK1).

[0043] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-181) as disclosed herein, wherein R2' is a bond, -(CHz)3-,#- (CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-*, preferably Rz is -(CH2)3-,#-(CH2)3N(CH3)-*, or#- (CH2)sN(CH3)NH-*, more preferably Rz is#-(CH2)3N(CH3)NH-*, wherein * represents the attachment point of Rz to the remainder of the compound under (ii); and * represents the attachment point of Rz to the remainder of the STING agonist moiety.

[0044] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-511) as disclosed herein, wherein Rr is a bond, -C(O)-,#-C(O)NH-*, or#-C(O)NHNH-*, preferably Rr is#-C(O)NHNH-*, wherein * represents the attachment point of Rr to the remainder of the compound under (ii); and#represents the attachment point of Rr to the remainder of the STING agonist moiety.

[0045] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-73'a), wherein Rz is a bond, -(CH2)3-, or#-(CH2)3(piperazin-l,4-diyl)- *, preferably Rz is#-(CH2)3(piperazin-l,4-diyl)-* wherein * represents the attachment point of Rz to the remainder of the compound under (ii); and#represents the attachment point of Rz to the remainder of the STING agonist moiety.

[0046] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-73'b) as disclosed herein, wherein Rr is a bond, -C(O)-,#-C(O)NH- *, or#-C(O)NHNH-*, preferably Rr is#-C(O)NHNH-*, wherein * represents the attachment point of Rr to the remainder of the compound under (ii); and#represents the attachment point of Rr to the remainder of the STING agonist moiety.

[0047] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-6') as disclosed herein, wherein Rr is a bond, -C(O)-,#-C(O)NH-*, or#-C(O)NHNH-*, preferably Rr is#-C(O)NHNH-*, wherein * represents the attachment point of Rr to the remainder of the compound under (ii); and#represents the attachment point of Rr to the remainder of the STING agonist moiety.

[0048] In some particualry preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-53') as disclosed herein, wherein Rz is a bond, -(CH2)3-, (CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-*, preferably Rz is#-(CH2)3N(CH3)NH-*, wherein * represents the attachment point of R2- to the remainder of the compound under (ii); and#represents the attachment point of R2' to the remainder of the STING agonist moiety.

[0049] In some embodiments, the compound under (ii) comprises one or more than one tag to which the binding moiety for a tag binds.

[0050] In some embodiments, the tag is a peptide tag.

[0051] In some embodiments, the compound under (ii) comprises a moiety comprising a polymer. In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising a polymer.

[0052] In some embodiments, the polymer is not a polymer of proteinogenic amino acids or their D- isomers.

[0053] In some embodiments, the polymer is selected from the group consisting of polyethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

[0054] In some embodiments, the polymer comprises poly(ethylene glycol) (PEG), or poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

[0055] In some embodiments, the polymer comprises at least one poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0056] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of polyethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof. In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of poly(ethylene glycol) (PEG), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

[0057] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising at least one poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the nucleic acid is RNA.

[0058] In some embodiments, the compound under (ii) comprises one tag.

[0059] In some embodiments, the total number of tags in the compound under (ii) is one.

[0060] In some embodiments, the compound under (ii) comprises one or more payload moieties.

[0061] In some embodiments, the compound under (ii) comprises one payload moiety.

[0062] In some embodiments, the total number of payload moieties in the compound under (ii) is one.

[0063] In some embodiments, the compound under (ii) comprises one tag and one payload moiety.

[0064] In some embodiments, the total number of tags in the compound under (ii) is one and the total number of payload moieties in the compound under (ii) is one.

[0065] In some embodiments, the compound under (ii) comprises one tag and two payload moieties. In some embodiments, the total number of tags in the compound under (ii) is one and the total number of payload moieties in the compound under (ii) is two.

[0066] In some embodiments, the compound under (ii) is SD18317 (PIC8) as disclosed herein.

[0067] In some embodiments, the compound under (ii) is SD17248 as disclosed herein.

[0068] In some embodiments, the compound under (ii) is PIC12 as disclosed herein.

[0069] In some embodiments, the compound under (ii) is PIC13 as disclosed herein.

[0070] In some embodiments, the compound under (ii) is PIC14 as disclosed herein.

[0071] In some embodiments, the compound under (ii) is EX-M74 (PIC15) as disclosed herein.

[0072] In some embodiments, the compound under (ii) is EX-M69 (PIC16) as disclosed herein.

[0073] In some embodiments, the compound under (ii) is EX-M71 (PIC17) as disclosed herein.

[0074] In some embodiments, the compound under (ii) comprises two payload moieties.

[0075] In some embodiments, the total number of payload moieties in the compound under (ii) is two.

[0076] In some embodiments, the compound under (ii) comprises three payload moieties.

[0077] In some embodiments, the total number of payload moieties in the compound under (ii) is three.

[0078] In some embodiments, the compound under (ii) comprises four payload moieties.

[0079] In some embodiments, the total number of payload moieties in the compound under (ii) is four. In some embodiments, the compound under (ii) comprises one tag and three payload moieties.

[0080] In some embodiments, the total number of tags in the compound under (ii) is one and the total number of payload moieties in the compound under (ii) is three.

[0081] In some embodiments, the compound under (ii) comprises one tag and four payload moieties. In some embodiments, the total number of tags in the compound under (ii) is one and the total number of payload moieties in the compound under (ii) is four.

[0082] In some embodiments, the compound under (ii) comprises two tags and two payload moieties. In some embodiments, the total number of tags in the compound under (ii) is two and the total number of payload moieties in the compound under (ii) is two.

[0083] In some embodiments, the compound under (ii) is SD18321 (PIC7) as disclosed herein.

[0084] In some embodiments, the compound under (ii) is EX-B122 (PIC 18) as disclosed herein.

[0085] In some embodiments, the compound under (ii) is EX-B133 (PIC19) as disclosed herein.

[0086] In some embodiments, the compound under (ii) comprises two tags and three payload moieties.

[0087] In some embodiments, the total number of tags in the compound under (ii) is two and the total number of payload moieties in the compound under (ii) is three.

[0088] In some embodiments, the compound under (ii) comprises two tags and four payload moieties.

[0089] In some embodiments, the total number of tags in the compound under (ii) is two and the total number of payload moieties in the compound under (ii) is four.

[0090] In some embodiments, the compound under (ii) comprises a linking moiety connecting a tag and a payload moiety.

[0091] In some embodiments, the linking moiety is a branched or an unbranched linking moiety.

[0092] In some embodiments, the linking moiety comprises a continuous or non-continuous poly-2- (2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0093] In some embodiments, the compound under (ii) comprises the formula:

[0094] P-L-T wherein P comprises a payload moiety as specified herein;

[0095] T comprises a tag; and

[0096] L comprises a linking moiety.

[0097] In some embodiments, L comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0098] In some embodiments, L comprises the formula [AEEA]U-[L'-[AEEA]V]W, wherein

[0099] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0100] L' comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [L'-[AEEA]V] may be identical or different.

[0101] In some embodiments, u and v are each integers from 2 to 10.

[0102] In some embodiments, u and v are each integers from 2 to 8.

[0103] In some embodiments, u and v are each integers of 2, 4 or 6.

[0104] In some embodiments, L or L' comprises an amino acid.

[0105] In some embodiments, Lor L' comprises the D-isomer of an amino acid.

[0106] In some embodiments, Lor L' comprises cysteine or lysine.

[0107] In some embodiments, L or L' is connected to a side chain.

[0108] In some embodiments, a side chain comprises a functional moiety.

[0109] In some embodiments, a functional moiety comprises a solubilizing functional group.

[0110] In some embodiments, a functional moiety comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0111] In some embodiments, the compound under (ii) comprises at least two of said tags.

[0112] In some embodiments, the total number of tags in the compound under (ii) is two.

[0113] In some embodiments, the compound under (ii) comprises one or more payload moieties.

[0114] In some embodiments, the total number of payload moieties in the compound under (ii) is one. In some embodiments, the compound under (ii) comprises two or more payload moieties.

[0115] In some embodiments, the total number of payload moieties in the compound under (ii) is two.

[0116] In some embodiments, the compound under (ii) comprises payload moieties and tags in an unbranched (linear) configuration.

[0117] In some embodiments, the compound under (ii) comprises at least two tags and at least one payload moiety in an unbranched (linear) configuration.

[0118] In some embodiments, the compound under (ii) comprises at least two tags and at least two payload moieties in an unbranched (linear) configuration.

[0119] In some embodiments, the compound under (ii) comprises two tags and one or two payload moieties in an unbranched (linear) configuration.

[0120] In some embodiments, the compound under (ii) comprises one or more linking moieties connecting tags and payload moieties in an unbranched (linear) configuration.

[0121] In some embodiments, a linking moiety is a branched or unbranched linking moiety.

[0122] In some embodiments, at least one linking moiety comprises a continuous or non-continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0123] In some embodiments, the compound under (ii) comprises two tags which are connected by a linking moiety

[0124] In some embodiments, the linking moiety connecting the tags comprises a continuous or non- continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0125] In some embodiments, a payload moiety is connected to at least one of the tags.

[0126] In some embodiments, a payload moiety is connected to a tag by a linking moiety.

[0127] In some embodiments, the linking moiety connecting a payload moiety and a tag comprises a continuous or non-continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0128] In some embodiments, the linking moiety connecting a payload moiety and a tag comprises an enzymatic cleavage site.

[0129] In some embodiments, the compound under (ii) comprises the formula:

[0130] P-LA-T-LB-T or

[0131] P-LA-T-LB-T-LC-P wherein

[0132] P comprises a payload moiety as specified herein;

[0133] T comprises a tag;

[0134] LA comprises a linking moiety;

[0135] LB comprises a linking moiety; and

[0136] Lc comprises a linking moiety.

[0137] In some embodiments, one or more of LA, LB, and Lc comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0138] In some embodiments, LB comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0139] In some embodiments, LA and / or Lc comprise a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0140] In some embodiments, LA and / or Ledo not comprise a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0141] In some embodiments, LA and / or Lc comprise an enzymatic cleavage site.

[0142] In some embodiments, one or more of LA, LB, and Lc comprises the formula [AEEA]U-[LD- [AEEA]v]w, wherein

[0143] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0144] LD comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [LD-[AEEA]V] may be identical or different.

[0145] In some embodiments, LB comprises the formula [AEEA]U-[LD-[AEEA]V]W, wherein

[0146] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof; LD comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [LD-[AEEA]V] may be identical or different.

[0147] In some embodiments, u and v are each integers from 2 to 10.

[0148] In some embodiments, u and v are each integers from 2 to 8.

[0149] In some embodiments, u and v are each integers of 2, 4 or 6.

[0150] In some embodiments, LD comprises an amino acid.

[0151] In some embodiments, LD comprises the D-isomer of an amino acid.

[0152] In some embodiments, LD comprises cysteine or lysine.

[0153] In some embodiments, Lois connected to a side chain.

[0154] In some embodiments, a side chain comprises a functional moiety.

[0155] In some embodiments, a functional moiety comprises a solubilizing functional group.

[0156] In some embodiments, the compound under (ii) comprises payload moieties and tags in a branched (non-linear) configuration.

[0157] In some embodiments, the compound under (ii) comprises one tag and at least two payload moieties in a branched (non-linear) configuration.

[0158] In some embodiments, the compound under (ii) comprises at least two tags and at least one payload moiety in a branched (non-linear) configuration.

[0159] In some embodiments, the compound under (ii) comprises at least two tags and at least two payload moieties in a branched (non-linear) configuration.

[0160] In some embodiments, the compound under (ii) comprises two tags and one or two payload moieties in a branched (non-linear) configuration.

[0161] In some embodiments, the compound under (ii) comprises one or more linking moieties connecting tags and payload moieties in a branched (non-linear) configuration.

[0162] In some embodiments, at least one linking moiety is a branched linking moiety.

[0163] In some embodiments, at least one linking moiety comprises a continuous or non-continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the compound under (ii) comprises two tags which are connected by a linking moiety

[0164] In some embodiments, the linking moiety connecting the tags comprises a continuous or non- continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0165] In some embodiments, a payload moiety is connected to the linking moiety connecting the tags.

[0166] In some embodiments, a payload moiety is connected to the linking moiety connecting the tags by a linking moiety.

[0167] In some embodiments, the linking moiety connecting a payload moiety and a linking moiety connecting the tags comprises a continuous or non-continuous poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0168] In some embodiments, the compound under (ii) comprises a main chain connecting two tags and one or more side chains branching from the main chain and connecting one or more payload moieties to the main chain.

[0169] In some embodiments, one or more payload moieties are connected to the main chain through a moiety comprising a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0170] In some embodiments, a side chain is connected to the main chain through a branching moiety in the main chain.

[0171] In some embodiments, the main chain comprises a continuous or non-continuous poly-2-(2- (2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0172] In some embodiments, the main chain comprises two or more poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moieties or derivatives thereof.

[0173] In some embodiments, poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moieties or derivatives thereof of the main chain are connected through a moiety comprising a branching moiety.

[0174] In some embodiments, the compound under (ii) comprises the formula:

[0175] [P-La]2-B-LrT wherein P comprises a payload moiety s specified herein;

[0176] B comprises a branching moiety;

[0177] T comprises a tag;

[0178] Lacomprises a linking moiety; and

[0179] Ltcomprises a linking moiety; wherein the different groups [P-La] may be identical or different, and the different groups P may be identical or different.

[0180] In some embodiments, the valency of B corresponds to or is greater than 3.

[0181] In some embodiments, B comprises an amino acid or bis-amino acid.

[0182] In some embodiments, B comprises the D-isomer of an amino acid.

[0183] In some embodiments, B comprises cysteine or lysine.

[0184] In some embodiments, Lacomprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, cysteine, or a combination thereof.

[0185] In some embodiments, Lacomprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0186] In some embodiments, Lacomprises an enzymatic cleavage site.

[0187] In some embodiments, Lacomprises a moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the moiety which is substituted by a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is an amino acid. In some embodiments, the amino acid which is substituted by a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is cysteine.

[0188] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais between 2 and 30.

[0189] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais between 2 and 10. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais 2, 4 or 6.

[0190] In some embodiments, Lais substituted with a solubilizing functional group. In some embodiments, Lacomprises an amino acid which is substituted with a solubilizing functional group. In some embodiments, the amino acid which is substituted with a solubilizing functional group is lysine or cysteine.

[0191] In some embodiments, Ltcomprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0192] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

[0193] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

[0194] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6.

[0195] In some embodiments, Lt comprises one or more selected from the group consisting of a moiety constraining conformation, a moiety for albumin binding, a moiety which increases circulation time, a moiety which reduces renal retention or uptake and an enzymatic cleavage site.

[0196] In some embodiments, the compound under (ii) comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, and EX-M60 to EX-M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)). In some preferred embodiments, the compound under (ii) comprises a structure of a compound shown herein as SD18317 (PIC8).

[0197] In some embodiments, the compound under (ii) comprises the formula:

[0198] [[Pk-Ldn-BHLz-TJo wherein P comprises a payload moiety as specified herein;

[0199] Bi comprises a branching moiety;

[0200] T comprises a tag;

[0201] Li comprises a linking moiety;

[0202] L2 comprises a linking moiety; m is an integer from 1 to 4; n is an integer from 1 to 4; and o is an integer from 2 to 4; wherein the different groups [L2-T] may be identical or different, the different groups P may be identical or different, and the different groups [[P]m-Li] may be identical or different.

[0203] In some embodiments, the valency of Bi corresponds to or is greater than the sum of n and o.

[0204] In some embodiments, Bicomprises an amino acid or bis-amino acid.

[0205] In some embodiments, Bi comprises the D-isomer of an amino acid.

[0206] In some embodiments, Bi comprises cysteine or lysine.

[0207] In some embodiments, Li comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0208] In some embodiments, Li comprises an enzymatic cleavage site.

[0209] In some embodiments, L2 comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0210] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

[0211] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

[0212] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6. In some embodiments, L2 comprises one or more selected from the group consisting of a moiety constraining conformation, a moiety for albumin binding, a moiety which increases circulation time, a moiety which reduces renal retention or uptake and an enzymatic cleavage site.

[0213] In some embodiments, L2 comprises (i) a moiety comprising cysteine and (ii) a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, wherein the poly-2- (2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or derivative thereof and T are linked by the moiety comprising cysteine.

[0214] In some embodiments, [[P] m-Li] comprises the formula [[P-Lr]m-B2-Lr], wherein

[0215] B2 comprises a branching moiety;

[0216] Lr comprises a linking moiety;

[0217] Lr comprises a linking moiety; and m is an integer from 1 to 4; wherein the different groups [[P-Lr]m-B2-Lr] may be identical or different, and wherein in a group [[P- Li']m-B2-Li"] the different groups [P-Li ] may be identical or different.

[0218] In some embodiments, the valency of B2 corresponds to or is greater than the value of m plus 1.

[0219] In some embodiments, B2 comprises an amino acid.

[0220] In some embodiments, B2 comprises the D-isomer of an amino acid.

[0221] In some embodiments, B2 comprises cysteine or lysine.

[0222] In some embodiments, Lr comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, cysteine, or a combination thereof.

[0223] In some embodiments, Lr comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0224] In some embodiments, Lr comprises a moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0225] In some embodiments, the moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is an amino acid. In some embodiments, the amino acid which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is lysine.

[0226] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lr is between 2 and 30.

[0227] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lr is between 2 and 10.

[0228] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Li •• is 2, 4 or 6.

[0229] In some embodiments, Li- and / or Lr is substituted with a solubilizing functional group.

[0230] In some embodiments, Lr and / or Lr comprises an amino acid which is substituted with a solubilizing functional group.

[0231] In some embodiments, the amino acid which is substituted with a solubilizing functional group is lysine or cysteine.

[0232] In some embodiments, m is an integer from 1 to 3, n is an integer from 1 to 3, and o is 2 or 3.

[0233] In some embodiments, o is 2.

[0234] In some embodiments, n is 1 or 2.

[0235] In some embodiments, m is 1 or 2.

[0236] In some embodiments, o is 2, n is 1 and m is 1.

[0237] In some embodiments, o is 2, n is 2 and m is 2.

[0238] In some embodiments, the compound under (ii) comprises 1, 2, 3, 4, 5, or 6 molecules of a payload as specified herein, which molecules of a a payload are preferably covalently attached to the compound under (ii). In some embodiments, the compound under (ii) comprises 4 molecules of a payload as specified herein. In some embodiments, the compound under (ii) comprises 2 molecules of a payload as specified herein.

[0239] In some embodiments, the compound under (i) comprises one or more binding moieties for the tag. In some embodiments, the compound under (i) comprises a single binding moiety for the tag or at least two, e.g., two, binding moieties for the tag.

[0240] In some embodiments, the compound under (ii) comprises the formula:

[0241] P-LI-B1-[L2-T]2 wherein

[0242] P comprises a payload moiety as specified herein;

[0243] Bi comprises a branching moiety;

[0244] T comprises a tag;

[0245] Li comprises a linking moiety; and

[0246] 1.2 comprises a linking moiety; wherein the different groups [L2-T] may be identical or different.

[0247] In some embodiments, the compound under (ii) comprises the formula:

[0248] P-[AEEA]p-Bi-[[AEEA]q-R-[AEEA]r-C-T]2 wherein

[0249] P comprises a payload moiety as specified herein;

[0250] Bi comprises a branching moiety;

[0251] R is optional and comprises a moiety constraining conformation;

[0252] C is optional and comprises a connecting moiety;

[0253] T comprises a tag; p is an integer from 0 to 6; q is an integer from 1 to 4; and r is an integer from 1 to 4; wherein the different groups [[AEEA]q-R-[AEEA]rC-T] may be identical or different.

[0254] In some embodiments, the compound under (ii) comprises the formula:

[0255] [[P-L1']2-B2-L1"]2-B1-[L2-T]2 wherein

[0256] P comprises a payload moiety as specified herein;

[0257] Bi comprises a branching moiety;

[0258] B2 comprises a branching moiety;

[0259] T comprises a tag; Li' comprises a linking moiety;

[0260] Li" comprises a linking moiety; and

[0261] L2 comprises a linking moiety; wherein the different groups [ [P-L1J2-B2-L1-] may be identical or different, wherein in a group [[P-L1J2- B2-L1"] the different groups [P-Li] may be identical or different, and the different groups [L2- T] may be identical or different.

[0262] In some embodiments, the compound under (ii) comprises the formula:

[0263] [[P-Lij2-B2-[AEEA]5]2-Bi-[[AEEA]t-T]2 wherein

[0264] P comprises a payload moiety as specified herein;

[0265] Bi comprises a branching moiety;

[0266] B2 comprises a branching moiety;

[0267] T comprises a tag;

[0268] Li' comprises a linking moiety; s is an integer from 2 to 8; and t is an integer from 2 to 8; wherein the different groups [[P-LI ]2-B2-[AEEA]S] may be identical or different, wherein in a group [[P- Lr]2-B2-[AEEA]s] the different groups [P-Li ] may be identical or different, and the different groups [[AEEA]t-T] may be identical or different.

[0269] In some embodiments, the tag is an ALFA-tag.

[0270] In some embodiments, the tag is a cyclic ALFA-tag.

[0271] In some embodiments, [AEEA] is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof.

[0272] In some embodiments, the compound under (ii) comprises the formula:

[0273] P-[AEEA]-Bi-[[AEEA]2-C-T]2 wherein

[0274] P comprises a payload moiety as specified herein;

[0275] Bi comprises a branching moiety;

[0276] C is optional and comprises a connecting moiety; and T comprises an ALFA-tag; wherein the different groups [[AEEA]2-C-T] may be identical or different.

[0277] In some embodiments, Bi comprises an amino acid. In some embodiments, C comprises an amino acid.

[0278] In some embodiments, the compound under (ii) comprises the formula:

[0279] P-[AEEA]-BI-[[AEEA]2-C-T]2wherein

[0280] P comprises a payload moiety as specified herein ;

[0281] Bi comprises an amino acid, preferably lysine;

[0282] C comprises a cysteine moiety; and

[0283] T comprises an ALFA-tag; wherein the different groups [[AEEA]2-C-T] may be identical or different.

[0284] In some embodiments, T comprises an ALFA-tag of the formula -Ser-Arg-Leu-Glu-cyclo(Asp- Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-. In some embodiments, T comprises an ALFA-tag of the formula -Pro-Ser-Arg-Leu-cyclo(Glu-Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-.

[0285] In some embodiments, the compound under (ii) comprises a structure of a compound shown herein as any one of SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), and EX-B122 to EX-B132 (in particular, EX-B122 (PIC18), EX-B133 (PIC19)). In some preferred embodiments, the compound under (ii) comprises a structure of a compound shown herein as SD18321 (PIC7).

[0286] In some embodiments, the compound under (ii) comprises at least two chains, wherein each of said chains comprises a tag, and wherein the at least two chains are covalently connected. In some embodiments, the compound under (ii) comprises two chains, wherein each of said chains comprises a tag, and wherein the two chains are covalently connected. In some embodiments, at least one of the chains comprises at least one payload moiety. In some embodiments, each of the chains comprises at least one payload moiety. In some embodiments, the compound under (ii) comprises two chains, wherein each of said chains comprises a tag and a payload moiety, and wherein the two chains are covalently connected. In some embodiments, the compound under (ii) comprises two chains, wherein each of said chains comprises a tag and two payload moieties, and wherein the two chains are covalently connected.

[0287] In some embodiments, the tag comprises an ALFA-tag.

[0288] In some embodiments, the compound under (ii) comprises two chains, wherein each of said chains comprises an ALFA-tag and two payload moieties, and wherein the two chains are covalently connected.

[0289] In some embodiments, the covalent connection comprises a triazole. In some embodiments, the covalent connection comprises a 1,2,3-triazole. In some embodiments, the covalent connection is formed through an intermolecular cycloaddition ("click") reaction between azides and alkynes comprised in the chains to be connected.

[0290] In some embodiments, the compound under (ii) comprises two chains, wherein each of said chains comprises an ALFA-tag and two payload moieties, and wherein the two chains are covalently connected through a moiety comprising a 1,2,3-triazole.

[0291] In some embodiments, each chain comprises a moiety of the formula:

[0292] *-[[AEEA]2-C-T] wherein

[0293] C is optional and comprises a connecting moiety;

[0294] T comprises a tag; and

[0295] * is the attachment point to a moiety that forms a covalent connection to another of the chains.

[0296] In some embodiments, the compound under (ii) comprises two chains wherein each chain comprises a moiety of the formula:

[0297] *-[[AEEA]2-C-T] wherein

[0298] C is optional and comprises a connecting moiety;

[0299] T comprises a tag; and

[0300] * is the attachment point to a moiety that forms a covalent connection to the other chain.

[0301] In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises one or more payload moieties. In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises two payload moieties.

[0302] In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises a 2-(2-(2- aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10 such as 2, 4 or 6, in particular 2.

[0303] In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises a main chain extending from the attachment point * and comprising two amino acids, wherein the two amino acids are connected through a moiety comprising a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, and wherein the two amino acids are each connected to a payload moiety through their side chains. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2- (2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10 such as 2, 4 or 6, in particular 2. In some embodiments, the amino acid comprises cysteine. In some embodiments, the compound under (ii) comprises two chains wherein each chain comprises a moiety of the formula:

[0304] Cys-[AEEA]u-Cys-A-[AEEA]2-C-T wherein

[0305] A is optional and comprises a moiety attaching the moiety Cys-[AEEA]U-Cys to the moiety [AEEAh-C-T;

[0306] C is optional and comprises a connecting moiety;

[0307] T comprises a tag;

[0308] Cys is cysteine connected to a payload moiety through its side chain; and u is 1 or 2. In some embodiments, the compound under (ii) comprises two chains wherein each chain comprises a moiety of the formula:

[0309] Cys-[AEEA]U-Cys-A-[AEEA]2-C-T wherein

[0310] A is optional and comprises a moiety attaching the moiety Cys-[AEEA]U-Cys to the moiety [AEEAh-C-T;

[0311] C is optional and comprises a connecting moiety;

[0312] T comprises an ALFA-tag;

[0313] Cys is cysteine connected to a payload moiety through its side chain; and u is 1 or 2.

[0314] In some embodiments, the compound under (ii) comprises two chains wherein each chain comprises a moiety of the formula:

[0315] Cys-[AEEA]U-Cys-A-[AEEA]2-C-T wherein

[0316] A is optional and comprises a moiety attaching the moiety Cys-[AEEA]U-Cys to the moiety [AEEAh-C-T;

[0317] C is optional and comprises a connecting moiety;

[0318] T comprises an ALFA-tag;

[0319] Cys is cysteine connected to a payload through its side chain; and u is 1 or 2.

[0320] In some embodiments, C comprises an amino acid.

[0321] In some embodiments, A comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the number of repeating units of 2-(2-(2- aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10 such as 2, 4 or 6, in particular 2. In some embodiments, A forms a covalent connection to the other chain. In some embodiments, the covalent connection comprises a triazole. In some embodiments, the covalent connection comprises a 1,2,3-triazole. In some embodiments, the covalent connection is formed through an intermolecular cycloaddition ("click") reaction between azides and alkynes comprised in the chains to be connected.

[0322] In some embodiments, T comprises an ALFA-tag of the formula -Ser-Arg-Leu-Glu-cyclo(Glu- Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-. In some embodiments, T comprises an ALFA-tag of the formula -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-Arg-Leu-Thr-Glu-.

[0323] In some embodiments, the compound under (ii) comprises a structure of a compound shown herein as EX-053, EX-054, SD18321 (PIC7), EX-B122 (PIC18), or EX-B133 (PIC19).

[0324] In some embodiments, the compound under (ii) comprises a structure of a compound shown herein, in particular of a compound shown in the Examples. In some embodiments, the compound under (ii) comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), EX-M60 to EX-M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)), and EX-B122 to EX-B132 (in particular, EX-B122 (PIC18)), EX-B133 (PIC19)), EX-024 to EX-035, EX-032 to EX-035, and EX-047 to EX-054. In some embodiments, the compound under (ii) comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD1832O (PIC10), SD18321 (PIC7), SD18322 (PICll), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19). In some preferred embodiments, the compound under (ii) comprises a structure of a compound shown herein as any one of SD18321 (PIC7) and SD18317 (PIC8). In some particularly preferred embodiments, the compound under (ii) comprises a structure of a compound shown herein as SD18321 (PIC7). It should be understood that those structures containing a STING agonist as payload may also contain any other STING agonist (in particular any other STING agonist as specified herein, such as any other STING agonist of Formula (XX)) instead of the specific STING agonist shown in these structures. It should further be understood that those structures containing a placeholder reference to a to a toxin or immunomodulator may also contain a STING agonist (in particular a STING agonist as specified herein, such as a STING agonist of Formula (XX)) instead of the placeholder reference shown in these structures. It should further be understood that those structures containing a group other than a STING agonist as payload (e.g., which contain a toxin or a chelator (with or without a radioisotope)) may also contain a STING agonist (in particular a STING agonist as specified herein, such as a STING agonist of Formula (XX)) as payload instead of the group other than a STING agonist. It should further be understood that those structures containing a STING agonist as payload may also contain any other STING agonist instead of the specific STING agonist shown in these structures.

[0325] In some embodiments of all aspects and embodiments of the kit described herein, the payload comprises the STING agonist of Formula (XX).

[0326] In some embodiments of all aspects and embodiments of the kit described herein, the payload comprises the STING agonist of Formula (XXH) or (XXK).

[0327] In some embodiments of all aspects and embodiments of the kit described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX).

[0328] In some embodiments of all aspects and embodiments of the kit described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK).

[0329] In some embodiments of all aspects and embodiments of the kit described herein, the payload moiety comprises a STING agonist moiety having the Formula (XX-181), (XX-61), (XX-51'), (XX- 53'), (XX-73'a), or (XX-73'b).

[0330] In some embodiments of all aspects and embodiments of the kit described herein, the tag is an ALFA-tag.

[0331] In some embodiments of all aspects and embodiments of the kit described herein, the tag is a cyclic ALFA-tag.

[0332] In some embodiments of all aspects and embodiments of the kit described herein, the payload comprises the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0333] In some embodiments of all aspects and embodiments of the kit described herein, the payload comprises the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag. In some embodiments of all aspects and embodiments of the kit described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0334] In some embodiments of all aspects and embodiments of the kit described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0335] In some embodiments of all aspects and embodiments of the kit described herein, the payload moiety comprises a STING agonist moiety having the Formula (XX-18'), (XX-61), (XX-511), (XX- 53'), (XX-73'a), or (XX-73'b), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0336] In some embodiments of all aspects and embodiments of the kit described herein, the compound under (ii) comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICH), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19), or the compound under (ii) is selected from the group consisting of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICll), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19). In some preferred embodiments of the kit described herein, the compound under (ii) comprises a structure of a compound shown herein as any one of SD18321 (PIC7) and SD18317 (PIC8), or the compound under (ii) is selected from the group consisting of SD18321 (PIC7) and SD18317 (PIC8). In some particularly preferred embodiments of the kit described herein, the compound under (ii) comprises a structure of a compound shown herein as SD18321 (PIC7), or the compound under (ii) is SD18321 (PIC7).

[0337] In one aspect, the invention relates to the compound under (ii) described above.

[0338] In one aspect, the invention relates to a compound comprising a payload moiety and a tag, wherein the payload comprises a STING agonist.

[0339] In some embodiments, the STING agonist has the following Formula (XX):

[0340] wherein:

[0341] Ring A is selected from the group consisting of

[0342] G and Gi are independently N, CH, or C-Xi-Rz; or when G and Gi are each C-X1-R2, the Rz groups are optionally linked to form L2;

[0343] G' and Gz are independently N or CH;

[0344] X is N-R, O, or S;

[0345] X' is N or CH;

[0346] Xi is CH2, 0 or S;

[0347] R is hydrogen or C1-4 alkyl;

[0348] L1and L2are each independently C2-4 alkylene or C2-4 alkenylene;

[0349] Rz is selected from the group consisting of hydrogen, C2-4 cyclic ether, C1-4 alkylene-(C2-4 cyclic o o

[0350] Ri and R3 are independently selected from the group consisting of

[0351] Ring B is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 2 heteroatoms independently selected from N, O, and S;

[0352] Rs is -OH or -NR9R10;

[0353] R9 and Rio are independently selected from hydrogen and C1-6 alkyl;

[0354] X2 and X3 are independently NH or S;

[0355] Yi and Y2 are independently a 5-membered heteroaryl or heterocyclic ring, wherein the 5- membered heteroaryl or heterocyclic ring (i) has 1 to 4 heteroatoms independently selected from N, O, and S, (ii) is attached to the remainder of the STING agonist via a C ring atom of the

[0356] 5-membered heteroaryl or heterocyclic ring, and (iii) is optionally substituted with 1 to 4 R21, wherein each R21 is independently C1-4 alkyl (such as methyl, ethyl, propyl, or butyl);

[0357] Rs, Re, and R7 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, , or Rs and Re are optionally connected to form a 5- or 6- membered heterocyclic ring;

[0358] Ris is -OH or -NR9R10;

[0359] Ring C is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 ring heteroatoms independently selected from N, 0, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 4 ring heteroatoms independently selected from N, O, and S; n, p, q, q', t, and v are independently an integer from 2 to 6 (i.e., 2, 3, 4, 5, or 6, such as 2, 3,

[0360] 4, or 5, e.g., 2, 3, or 4); and k, I, m, o, u, and w are independently an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6, such as 1, 2, 3, 4, or 5, e.g., 1, 2, 3, or 4).

[0361] In some preferred embodiments, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX). In some preferred embodiments, the payload moiety comprises a STING agonist moiety of Formula (XX') as disclosed herein.

[0362] Preferred embodiments of the STING agonist of Formula (XX) and / or of the STING agonist moiety of Formula (XX') are disclosed herein and include: (1) any one of Formulas (XXA), (XXB), (XXC), (XXD), (XXE), (XXF), (XXG), (XXH), (XXJ), (XXK), (XX-I) to (XX-LXII), (XX-1) to (XX-73), (XX- 6'), (XX-18'), (XX-511), (XX-53'), (XX-73'a), and (XX-73'b); (2) the embodiments of substituents specified herein with respect to any one of Formulas (XX), (XXA), (XXB), (XXC), (XXD), (XXE), (XXF), (XXG), (XXH), (XXJ), (XXK), and (XX-I) to (XX-LXII) (e.g., that in some embodiments of Formula (XX), G2 is CH); and (iii) the embodiments of substituents specified herein with respect to any one of Formulas (XX'), (XXA1), (XXB'), (XXC), (XXD1), (XXE'), (XXF'), (XXG'), (XXH1), (XXJ'), (XXK1), (XX-61), (XX-18'), (XX-51'), (XX-531), (XX-73'a), and (XX-73'b) (e.g., that in some embodiments of Formula (XX1), one of the monovalent substituents present in the STING agonist of Formula (XX) (e.g., R2 being hydrogen or C1-4 alkyl; or Ri being N(R6)(R?)N(Rs)C(O)-) has been replaced by a corresponding divalent substituent (e.g., R? has been replaced by R2', wherein Rz1is a bond (if R2 was hydrogen) or C1-4 alkylene (if R2 was a C1-4 alkyl); or Ri has been replaced by Rr, wherein Rr is selected from the group consisting of *-N(Re)N(Rs)C(O)-#, *- N(Rs)C(O)-#, and -C(O)-, wherein * represents the attachment point of R2' and Rr, respectively, to the remainder of the compound under (ii); and#represents the attachment point of R21and Ri', respectively, to the remainder of the STING agonist moiety of Formula (XX')).

[0363] In some embodiments, the STING agonist of Formula (XX) has Formula (XXA) as disclosed herein, wherein G is CH, C-SCH3, C-OCH3, or N. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXA), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXA').

[0364] In some embodiments, the STING agonist of Formula (XX) has Formula (XXB) as disclosed herein, wherein G is CH, C-SCHs, C-OCH3, or N; Rs is -OH or -NH2; Yi and Y2 are independently oxazolyl, pyrazolyl, thiazolyl, or imidazolyl, each of which is optionally substituted with 1 or 2 R21. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXB), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXB').

[0365] In some embodiments, the STING agonist of Formula (XX) has Formula (XXC) as disclosed herein, wherein Yi and Y2 are independently oxazolyl, pyrazolyl, thiazolyl, or imidazolyl, each of which is optionally substituted with 1 or 2 R21. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXC), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXC).

[0366] In some embodiments, the STING agonist of Formula (XX) has Formula (XXD) as disclosed herein, wherein R21' is hydrogen or C1-4 alkyl. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXD), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXD1).

[0367] In some embodiments, the STING agonist of Formula (XX) has Formula (XXE) as disclosed herein, wherein X is S or O. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXE), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXE').

[0368] In some embodiments, the STING agonist of Formula (XX) has Formula (XXF) as disclosed herein, wherein G is CH, C-SCH3, C-OCH3, or N. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXF), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXF1).

[0369] In some embodiments, the STING agonist of Formula (XX) has Formula (XXG) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXG), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXG1). In some embodiments, the STING agonist of Formula (XX) has Formula (XXH) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXH), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXH1).

[0370] In some embodiments, the STING agonist of Formula (XX) has Formula (XXJ) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXJ), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXJ1).

[0371] In some embodiments, the STING agonist of Formula (XX) has Formula (XXK) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXK), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXK1).

[0372] In some preferred embodiments, the STING agonist of Formula (XX) has Formula (XXH) or (XXK) as disclosed herein. In some preferred embodiments, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK), more preferably, the payload moiety comprised in the compound under (ii) comprises a STING agonist moiety of Formula (XXH') or (XXK1).

[0373] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-181) as disclosed herein, wherein Rz1is a bond, -(CH2)3-,#- (CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-*, preferably R2' is -(CH2)3-,#-(CH2)3N(CH3)-*, or#- (CH2)3N(CH3)NH-*, more preferably R2' is#-(CH2)3N(CH3)NH-*, wherein * represents the attachment point of Rz to the remainder of the compound under (ii); and#represents the attachment point of Rz to the remainder of the STING agonist moiety.

[0374] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-511) as disclosed herein, wherein Rr is a bond, -C(O)-,#-C(O)NH-*, or#-C(O)NHNH-*, preferably Rr is#-C(O)NHNH-*, wherein * represents the attachment point of Rr to the remainder of the compound under (ii); and#represents the attachment point of Ri' to the remainder of the STING agonist moiety.

[0375] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-73'a), wherein R21is a bond, -(CH 2)3-, or *-(CH2)3(piperazin-l,4-diyl)- *, preferably R2' is#-(CH2)3(piperazin-l,4-diyl)-* wherein * represents the attachment point of R2' to the remainder of the compound under (ii); and#represents the attachment point of R2' to the remainder of the STING agonist moiety.

[0376] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-73'b) as disclosed herein, wherein Rr is a bond, -C(O)-,#-C(O)NH- *, or#-C(O)NHNH-*, preferably Rr is#-C(O)NHNH-*, wherein * represents the attachment point of Rr to the remainder of the compound under (ii); and#represents the attachment point of Rr to the remainder of the STING agonist moiety.

[0377] In some particularly preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-61) as disclosed herein, wherein Rr is a bond, -C(O)-,#-C(O)NH-*, or#-C(O)NHNH-*, preferably Rr is#-C(O)NHNH-*, wherein * represents the attachment point of Rr to the remainder of the compound under (ii); and#represents the attachment point of Rr to the remainder of the STING agonist moiety.

[0378] In some particualry preferred embodiments, the payload moiety comprises a STING agonist moiety having Formula (XX-531) as disclosed herein, wherein R2' is a bond, -(CFhh-,#- (CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-*, preferably Rr is MCH2)3N(CH3)NH-*, wherein * represents the attachment point of R2' to the remainder of the compound under (ii); and#represents the attachment point of R?' to the remainder of the STING agonist moiety.

[0379] In some embodiments, the compound comprises one or more than one tag to which the binding moiety for a tag binds.

[0380] In some embodiments, the tag is a peptide tag.

[0381] In some embodiments, the compound comprises a moiety comprising a polymer.

[0382] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising a polymer. In some embodiments, the polymer is not a polymer of proteinogenic amino acids or their D- isomers.

[0383] In some embodiments, the polymer is selected from the group consisting of poly(ethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

[0384] In some embodiments, the polymer comprises polyethylene glycol) (PEG), or poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

[0385] In some embodiments, the polymer comprises at least one poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0386] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of polyethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

[0387] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of poly(ethylene glycol) (PEG), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

[0388] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising at least one poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0389] In some embodiments, the payload moiety and the tag or tags are coupled through a moiety comprising at least one poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety.

[0390] In some embodiments, the compound comprises one tag.

[0391] In some embodiments, the total number of tags in the compound is one.

[0392] In some embodiments, the compound comprises one or more payload moieties.

[0393] In some embodiments, the compound comprises one payload moiety.

[0394] In some embodiments, the total number of payload moieties in the compound is one.

[0395] In some embodiments, the compound comprises one tag and one payload moiety.

[0396] In some embodiments, the total number of tags in the compound is one and the total number of payload moieties in the compound is one. In some embodiments, the compound comprises one tag and two payload moieties.

[0397] In some embodiments, the total number of tags in the compound is one and the total number of payload moieties in the compound is two.

[0398] In some embodiments, the compound is SD18317 (PIC8) as disclosed herein.

[0399] In some embodiments, the compound is SD17248 as disclosed herein.

[0400] In some embodiments, the compound is PIC12 as disclosed herein.

[0401] In some embodiments, the compound is PIC13 as disclosed herein.

[0402] In some embodiments, the compound is PIC14 as disclosed herein.

[0403] In some embodiments, the compound is EX-M69 (PIC16) as disclosed herein.

[0404] In some embodiments, the compound is EX-M71 (PIC17) as disclosed herein.

[0405] In some embodiments, the compound is EX-M74 (PIC15) as disclosed herein.

[0406] In some embodiments, the compound comprises two payload moieties.

[0407] In some embodiments, the total number of payload moieties in the compound is two.

[0408] In some embodiments, the compound comprises three payload moieties.

[0409] In some embodiments, the total number of payload moieties in the compound is three.

[0410] In some embodiments, the compound comprises four payload moieties.

[0411] In some embodiments, the total number of payload moieties in the compound is four.

[0412] In some embodiments, the compound comprises one tag and three payload moieties.

[0413] In some embodiments, the total number of tags in the compound is one and the total number of payload moieties in the compound is three.

[0414] In some embodiments, the compound comprises one tag and four payload moieties.

[0415] In some embodiments, the total number of tags in the compound is one and the total number of payload moieties in the compound is four.

[0416] In some embodiments, the compound comprises two tags and two payload moieties.

[0417] In some embodiments, the total number of tags in the compound) is two and the total number of payload moieties in the compound is two.

[0418] In some embodiments, the compound comprises two tags and three payload moieties.

[0419] In some embodiments, the total number of tags in the compound is two and the total number of payload moieties in the compound is three.

[0420] In some embodiments, the compound comprises two tags and four payload moieties. In some embodiments, the total number of tags in the compound is two and the total number of payload moieties in the compound is four.

[0421] In some embodiments, the compound comprises a linking moiety connecting a tag and a payload moiety.

[0422] In some embodiments, the linking moiety is a branched or an unbranched linking moiety.

[0423] In some embodiments, the linking moiety comprises a continuous or non-continuous poly-2- (2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0424] In some embodiments, the compound comprises the formula:

[0425] P-L-T wherein

[0426] P comprises a payload moiety as specified herein;

[0427] T comprises a tag; and

[0428] L comprises a linking moiety.

[0429] In some embodiments, L comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0430] In some embodiments, Lcomprises the formula [AEEA]u-[L'-[AEEA]v]w, wherein

[0431] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0432] L' comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [L'-[AEEA]V] may be identical or different.

[0433] In some embodiments, u and v are each integers from 2 to 10.

[0434] In some embodiments, u and v are each integers from 2 to 8.

[0435] In some embodiments, u and v are each integers of 2, 4 or 6.

[0436] In some embodiments, L or L' comprises an amino acid.

[0437] In some embodiments, Lor L' comprises the D-isomer of an amino acid. In some embodiments, Lor L' comprises cysteine or lysine.

[0438] In some embodiments, L or L' is connected to a side chain.

[0439] In some embodiments, a side chain comprises a functional moiety.

[0440] In some embodiments, a functional moiety comprises a solubilizing functional group.

[0441] In some embodiments, the compound comprises at least two of said tags.

[0442] In some embodiments, the total number of tags in the compound is two.

[0443] In some embodiments, the compound comprises one or more payload moieties.

[0444] In some embodiments, the total number of payload moieties in the compound is one.

[0445] In some embodiments, the compound comprises two or more payload moieties.

[0446] In some embodiments, the total number of payload moieties in the compound is two.

[0447] In some embodiments, the compound comprises payload moieties and tags in an unbranched (linear) configuration.

[0448] In some embodiments, the compound comprises at least two tags and at least one payload moiety in an unbranched (linear) configuration.

[0449] In some embodiments, the compound comprises at least two tags and at least two payload moieties in an unbranched (linear) configuration.

[0450] In some embodiments, the compound comprises two tags and one or two payload moieties in an unbranched (linear) configuration.

[0451] In some embodiments, the compound comprises one or more linking moieties connecting tags and payload moieties in an unbranched (linear) configuration.

[0452] In some embodiments, a linking moiety is a branched or unbranched linking moiety.

[0453] In some embodiments, at least one linking moiety comprises a continuous or non-continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0454] In some embodiments, the compound comprises two tags which are connected by a linking moiety

[0455] In some embodiments, the linking moiety connecting the tags comprises a continuous or non- continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0456] In some embodiments, a payload moiety is connected to at least one of the tags.

[0457] In some embodiments, a payload moiety is connected to a tag by a linking moiety. In some embodiments, the linking moiety connecting a payload moiety and a tag comprises a continuous or non-continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0458] In some embodiments, the linking moiety connecting a payload moiety and a tag comprises an enzymatic cleavage site.

[0459] In some embodiments, the compound comprises the formula:

[0460] P-LA-T-LB-T or

[0461] P-LA-T-LB-T-LC-P wherein

[0462] P comprises a payload moiety as specified herein;

[0463] T comprises a tag;

[0464] LA comprises a linking moiety;

[0465] LB comprises a linking moiety; and

[0466] Lc comprises a linking moiety.

[0467] In some embodiments, one or more of LA, LB, and Lc comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0468] In some embodiments, LB comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0469] In some embodiments, LA and / or Lc comprise a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0470] In some embodiments, LA and / or Ledo not comprise a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0471] In some embodiments, LA and / or Lc comprise an enzymatic cleavage site.

[0472] In some embodiments, one or more of LA, LB, and Lc comprises the formula [AEEA]U-[LD- [AEEA]v]w, wherein

[0473] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0474] LD comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [LD-[AEEA]V] may be identical or different.

[0475] In some embodiments, LB comprises the formula [AEEA]U-[LD-[AEEA]V]W, wherein

[0476] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0477] LD comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [LD-[AEEA]V] may be identical or different.

[0478] In some embodiments, u and v are each integers from 2 to 10.

[0479] In some embodiments, u and v are each integers from 2 to 8.

[0480] In some embodiments, u and v are each integers of 2, 4 or 6.

[0481] In some embodiments, LD comprises an amino acid.

[0482] In some embodiments, LD comprises the D-isomer of an amino acid.

[0483] In some embodiments, LD comprises cysteine or lysine.

[0484] In some embodiments, LD is connected to a side chain.

[0485] In some embodiments, a side chain comprises a functional moiety.

[0486] In some embodiments, a functional moiety comprises a solubilizing functional group.

[0487] In some embodiments, the compound comprises payload moieties and tags in a branched (non-linear) configuration.

[0488] In some embodiments, the compound under (ii) comprises one tag and at least two payload moieties in a branched (non-linear) configuration.

[0489] In some embodiments, the compound comprises at least two tags and at least one payload moiety in a branched (non-linear) configuration.

[0490] In some embodiments, the compound comprises at least two tags and at least two payload moieties in a branched (non-linear) configuration. In some embodiments, the compound comprises two tags and one or two payload moieties in a branched (non-linear) configuration.

[0491] In some embodiments, the compound comprises one or more linking moieties connecting tags and payload moieties in a branched (non-linear) configuration.

[0492] In some embodiments, at least one linking moiety is a branched linking moiety.

[0493] In some embodiments, at least one linking moiety comprises a continuous or non-continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0494] In some embodiments, the compound comprises two tags which are connected by a linking moiety

[0495] In some embodiments, the linking moiety connecting the tags comprises a continuous or non- continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0496] In some embodiments, a payload moiety is connected to the linking moiety connecting the tags.

[0497] In some embodiments, a payload moiety is connected to the linking moiety connecting the tags by a linking moiety.

[0498] In some embodiments, the linking moiety connecting a payload moiety and a linking moiety connecting the tags comprises a continuous or non-continuous poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0499] In some embodiments, the compound comprises a main chain connecting two tags and one or more side chains branching from the main chain and connecting one or more payload moieties to the main chain.

[0500] In some embodiments, one or more payload moieties are connected to the main chain through a moiety comprising a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0501] In some embodiments, a side chain is connected to the main chain through a branching moiety in the main chain.

[0502] In some embodiments, the main chain comprises a continuous or non-continuous poly-2-(2- (2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the main chain comprises two or more poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moieties or derivatives thereof.

[0503] In some embodiments, poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moieties or derivatives thereof of the main chain are connected through a moiety comprising a branching moiety.

[0504] In some embodiments, the compound comprises the formula:

[0505] [P-Lah-B-Lt-T wherein

[0506] P comprises a payload moiety s specified herein;

[0507] B comprises a branching moiety;

[0508] T comprises a tag;

[0509] Lacomprises a linking moiety; and

[0510] Ltcomprises a linking moiety; wherein the different groups [P-La] may be identical or different, and the different groups P may be identical or different.

[0511] In some embodiments, the valency of B corresponds to or is greater than 3.

[0512] In some embodiments, B comprises an amino acid or bis-amino acid.

[0513] In some embodiments, B comprises the D-isomer of an amino acid.

[0514] In some embodiments, B comprises cysteine or lysine.

[0515] In some embodiments, Lacomprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, cysteine, or a combination thereof.

[0516] In some embodiments, Lacomprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0517] In some embodiments, Lacomprises an enzymatic cleavage site.

[0518] In some embodiments, Lacomprises a moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the moiety which is substituted by a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is an amino acid. In some embodiments, the amino acid which is substituted by a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is cysteine.

[0519] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais between 2 and 30.

[0520] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais between 2 and 10.

[0521] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais 2, 4 or 6.

[0522] In some embodiments, Lais substituted with a solubilizing functional group. In some embodiments, Lacomprises an amino acid which is substituted with a solubilizing functional group. In some embodiments, the amino acid which is substituted with a solubilizing functional group is lysine or cysteine.

[0523] In some embodiments, Ltcomprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0524] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

[0525] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

[0526] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6.

[0527] In some embodiments, Ltcomprises one or more selected from the group consisting of a moiety constraining conformation, a moiety for albumin binding, a moiety which increases circulation time, a moiety which reduces renal retention or uptake and an enzymatic cleavage site. In some embodiments, the compound comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, and EX-M60 to EX-M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)). In some preferred embodiments, the compound comprises a structure of a compound shown herein as SD18317 (PIC8).

[0528] In some embodiments, the compound comprises the formula:

[0529] [[P]m-Ll]n-Bl-[L2-T]o wherein

[0530] P comprises a payload moiety as specified herein;

[0531] Bi comprises a branching moiety;

[0532] T comprises a tag;

[0533] Li comprises a linking moiety;

[0534] Lz comprises a linking moiety; m is an integer from 1 to 4; n is an integer from 1 to 4; and o is an integer from 2 to 4; wherein the different groups [Ls-T] may be identical or different, the different groups P may be identical or different, and the different groups [[P]m-Li] may be identical or different.

[0535] In some embodiments, the valency of Bi corresponds to or is greater than the sum of n and o. In some embodiments, Bi comprises an amino acid or bis-amino acid.

[0536] In some embodiments, Bi comprises the D-isomer of an amino acid.

[0537] In some embodiments, Bi comprises cysteine or lysine.

[0538] In some embodiments, Li comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0539] In some embodiments, Li comprises an enzymatic cleavage site.

[0540] In some embodiments, L2 comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

[0541] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

[0542] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6.

[0543] In some embodiments, L2 comprises one or more selected from the group consisting of a moiety constraining conformation, a moiety for albumin binding, a moiety which increases circulation time, a moiety which reduces renal retention or uptake and an enzymatic cleavage site.

[0544] In some embodiments, L2 comprises (i) a moiety comprising cysteine and (ii) a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, wherein the poly-2- (2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or derivative thereof and T are linked by the moiety comprising cysteine.

[0545] In some embodiments, [[P]m-Li] comprises the formula [[P-Lijm-Bz-Lr], wherein

[0546] B2 comprises a branching moiety;

[0547] Li- comprises a linking moiety;

[0548] Lr comprises a linking moiety; and m is an integer from 1 to 4; wherein the different groups [[P-Lr]m-B2-Lr] may be identical or different, and wherein in a group [[P- Lr]m-B2-Li"] the different groups [P-Lr] may be identical or different.

[0549] In some embodiments, the valency of B2 corresponds to or is greater than the value of m plus 1.

[0550] In some embodiments, B2 comprises an amino acid.

[0551] In some embodiments, B2 comprises the D-isomer of an amino acid.

[0552] In some embodiments, B2 comprises cysteine or lysine. In some embodiments, Lr comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, cysteine, or a combination thereof.

[0553] In some embodiments, Lr comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0554] In some embodiments, Lr comprises a moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0555] In some embodiments, the moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is an amino acid.

[0556] In some embodiments, the amino acid which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is lysine.

[0557] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lr is between 2 and 30.

[0558] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lr is between 2 and 10.

[0559] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lr is 2, 4 or 6.

[0560] In some embodiments, Lr and / or Lr is substituted with a solubilizing functional group.

[0561] In some embodiments, Lr and / or Lr1comprises an amino acid which is substituted with a solubilizing functional group.

[0562] In some embodiments, the amino acid which is substituted with a solubilizing functional group is lysine or cysteine.

[0563] In some embodiments, m is an integer from 1 to 3, n is an integer from 1 to 3, and o is 2 or 3.

[0564] In some embodiments, o is 2.

[0565] In some embodiments, n is 1 or 2.

[0566] In some embodiments, m is 1 or 2.

[0567] In some embodiments, o is 2, n is 1 and m is 1. In some embodiments, o is 2, n is 2 and m is 2.

[0568] In some embodiments, the payload moiety comprises 1, 2, 3, 4, 5, or 6 molecules of a payload as specified herein, which molecules of a payload are preferably covalently attached to the compound. In some embodiments, the compound comprises 4 molecules of a payload as specified herein. In some embodiments, the compound comprises 2 molecules of a payload as specified herein.

[0569] In some embodiments, the compound comprises the formula:

[0570] P-LI-BI-[L2-T]2wherein

[0571] P comprises a payload moiety as specified herein;

[0572] Bi comprises a branching moiety;

[0573] T comprises a tag;

[0574] Li comprises a linking moiety; and

[0575] L2comprises a linking moiety; wherein the different groups [L2-T] may be identical or different.

[0576] In some embodiments, the compound comprises the formula:

[0577] P-[AEEA]p-Bi-[[AEEA]q-R-[AEEA]r-C-T]2wherein

[0578] P comprises a payload moiety as specified herein;

[0579] Bi comprises a branching moiety;

[0580] R is optional and comprises a moiety constraining conformation;

[0581] C is optional and comprises a connecting moiety;

[0582] T comprises a tag; p is an integer from 0 to 6; q is an integer from 1 to 4; and r is an integer from 1 to 4; wherein the different groups [[AEEA]q-R-[AEEA]r-C-T] may be identical or different.

[0583] In some embodiments, the compound comprises the formula: [[P-Li-]2-B2-Lr]2-Bi-[L2-T]2wherein P comprises a payload moiety as specified herein;

[0584] Bi comprises a branching moiety;

[0585] B2 comprises a branching moiety;

[0586] T comprises a tag;

[0587] Lr comprises a linking moiety;

[0588] Li " comprises a linking moiety; and

[0589] L2 comprises a linking moiety; wherein the different groups [[P-Lr]2-B2-Lr] may be identical or different, wherein in a group [[P-L1J2- B2-L1 '] the different groups [P-Lr] may be identical or different, and the different groups [L2- T] may be identical or different.

[0590] In some embodiments, the compound comprises the formula:

[0591] [[P-Li']2-B2-[AEEA]s]2-Bi-[[AEEA]t-T]2 wherein

[0592] P comprises a payload moiety as specified herein;

[0593] Bi comprises a branching moiety;

[0594] B2 comprises a branching moiety;

[0595] T comprises a tag;

[0596] Lr comprises a linking moiety; s is an integer from 2 to 8; and t is an integer from 2 to 8; wherein the different groups [[P-Lr]2-B2-[AEEA]S] may be identical or different, wherein in a group [[P- Lr]2-B2-[AEEA]S] the different groups [P-Lr] may be identical or different, and the different groups [[AEEA]t-T] may be identical or different.

[0597] In some embodiments, the tag is an ALFA-tag.

[0598] In some embodiments, the tag is a cyclic ALFA-tag.

[0599] In some embodiments, [AEEA] is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof.

[0600] In some embodiments, the compound comprises the formula:

[0601] P-[AEEA]-BI-[[AEEA]2-C-T]2 wherein

[0602] P comprises a payload moiety as specified herein;

[0603] Bi comprises a branching moiety;

[0604] C is optional and comprises a connecting moiety; and

[0605] T comprises an ALFA-tag; wherein the different groups [[AEEA]2-C-T] may be identical or different.

[0606] In some embodiments, Bi comprises an amino acid. In some embodiments, C comprises an amino acid.

[0607] In some embodiments, the compound comprises the formula:

[0608] P-[AEEA]-BI-[[AEEA]2-C-T]2wherein

[0609] P comprises a payload moiety as specified herein;

[0610] Bi comprises an amino acid, preferably lysine;

[0611] C comprises a cysteine moiety; and

[0612] T comprises an ALFA-tag; wherein the different groups [[AEEA]2-C-T] may be identical or different.

[0613] In some embodiments, T comprises an ALFA-tag of the formula -Ser-Arg-Leu-Glu-cyclo(Asp- Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-. In some embodiments, T comprises an ALFA-tag of the formula -Pro-Ser-Arg-Leu-cyclo(Glu-Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-.

[0614] In some embodiments, the compound comprises a structure of a compound shown herein as any one of SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), EX-B122 to EX-B132 (in particular, EX-B122 (PIC18)), and EX-B133 (PIC19)). In some preferred embodiments, the compound comprises a structure of a compound shown herein as SD18321 (PIC7).

[0615] In some embodiments, the compound comprises at least two chains, wherein each of said chains comprises a tag, and wherein the at least two chains are covalently connected. In some embodiments, the compound comprises two chains, wherein each of said chains comprises a tag, and wherein the two chains are covalently connected. In some embodiments, at least one of the chains comprises at least one payload moiety. In some embodiments, each of the chains comprises at least one payload moiety. In some embodiments, the compound comprises two chains, wherein each of said chains comprises a tag and a payload moiety, and wherein the two chains are covalently connected. In some embodiments, the compound comprises two chains, wherein each of said chains comprises a tag and two payload moieties, and wherein the two chains are covalently connected.

[0616] In some embodiments, the tag comprises an ALFA-tag.

[0617] In some embodiments, the compound comprises two chains, wherein each of said chains comprises an ALFA-tag and two payload moieties, and wherein the two chains are covalently connected.

[0618] In some embodiments, the covalent connection comprises a triazole. In some embodiments, the covalent connection comprises a 1,2,3-triazole. In some embodiments, the covalent connection is formed through an intermolecular cycloaddition ("click") reaction between azides and alkynes comprised in the chains to be connected.

[0619] In some embodiments, the compound comprises two chains, wherein each of said chains comprises an ALFA-tag and two payload moieties, and wherein the two chains are covalently connected through a moiety comprising a 1,2,3-triazole.

[0620] In some embodiments, each chain comprises a moiety of the formula:

[0621] *-[[AEEA]2-C-T] wherein

[0622] C is optional and comprises a connecting moiety;

[0623] T comprises a tag; and

[0624] * is the attachment point to a moiety that forms a covalent connection to another of the chains.

[0625] In some embodiments, the compound comprises two chains wherein each chain comprises a moiety of the formula:

[0626] *-[[AEEAh-C-T] wherein

[0627] C is optional and comprises a connecting moiety;

[0628] T comprises a tag; and

[0629] * is the attachment point to a moiety that forms a covalent connection to the other chain. In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises one or more payload moieties. In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises two payload moieties.

[0630] In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises a 2-(2-(2- aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10 such as 2, 4 or 6, in particular 2.

[0631] In some embodiments, the moiety that forms a covalent connection to another of the chains or the moiety that forms a covalent connection to the other chain comprises a main chain extending from the attachment point * and comprising two amino acids, wherein the two amino acids are connected through a moiety comprising a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, and wherein the two amino acids are each connected to a payload moiety through their side chains. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2- (2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10 such as 2, 4 or 6, in particular 2. In some embodiments, the amino acid comprises cysteine. In some embodiments, the compound comprises two chains wherein each chain comprises a moiety of the formula:

[0632] Cys-[AEEA]U-Cys-A-[AEEA]2-C-T wherein

[0633] A is optional and comprises a moiety attaching the moiety Cys-[AEEA]U-Cys to the moiety [AEEA]2-C-T;

[0634] C is optional and comprises a connecting moiety;

[0635] T comprises a tag; Cys is cysteine connected to a payload moiety through its side chain; and u is 1 or 2.

[0636] In some embodiments, the compound comprises two chains wherein each chain comprises a moiety of the formula:

[0637] Cys-[AEEA]U-Cys-A-[AEEA]2-C-T wherein

[0638] A is optional and comprises a moiety attaching the moiety Cys-[AEEA]U-Cys to the moiety [AEEA]2-C-T;

[0639] C is optional and comprises a connecting moiety;

[0640] T comprises an ALFA-tag;

[0641] Cys is cysteine connected to a payload moiety through its side chain; and u is 1 or 2.

[0642] In some embodiments, the compound comprises two chains wherein each chain comprises a moiety of the formula:

[0643] Cys-[AEEA]U-Cys-A-[AEEA]2-C-T wherein

[0644] A is optional and comprises a moiety attaching the moiety Cys-[AEEA]U-Cys to the moiety [AEEA]2-C-T;

[0645] C is optional and comprises a connecting moiety;

[0646] T comprises an ALFA-tag;

[0647] Cys is cysteine connected to a payload through its side chain; and u is 1 or 2.

[0648] In some embodiments, C comprises an amino acid.

[0649] In some embodiments, A comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the number of repeating units of 2-(2-(2- aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10 such as 2, 4 or 6, in particular 2. In some embodiments, A forms a covalent connection to the other chain. In some embodiments, the covalent connection comprises a triazole. In some embodiments, the covalent connection comprises a 1,2,3-triazole. In some embodiments, the covalent connection is formed through an intermolecular cycloaddition ("click") reaction between azides and alkynes comprised in the chains to be connected.

[0650] In some embodiments, T comprises an ALFA-tag of the formula -Ser-Arg-Leu-Glu-cyclo(Glu- Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-. In some embodiments, T comprises an ALFA-tag of the formula -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-Arg-Leu-Thr-Glu-.

[0651] In some embodiments, the compound comprises a structure of a compound shown herein as EX-053, EX-054, SD18321 (PIC7), EX-B122 (PIC18), or EX-B133 (PIC19). In some preferred embodiments, the compound comprises a structure of a compound shown herein as SD18321 (PIC7).

[0652] In some embodiments, the compound comprises a structure of a compound shown herein, in particular of a compound shown in the Examples. In some embodiments, the compound comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), EX-M60 to EX- M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)), EX-B122 to EX-B132 (in particular, EX-B122 (PIC18)), EX-B133 (PIC19), EX-024 to EX-035, EX-032 to EX-035, and EX- 047 to EX-054. In some preferred embodiments, the compound comprises a structure of a compound shown herein as any one of SD18321 (PIC7) and SD18317 (PIC8). In some particularly preferred embodiments, the compound comprises a structure of a compound shown herein as SD18321 (PIC7). It should be understood that those structures containing a STING agonist as payload may also contain any other STING agonist (in particular a STING agonist as specified herein, such as a STING agonist of Formula (XX)) instead of the specific STING agonist shown in these structures. It should further be understood that those structures containing a placeholder reference to a to a toxin or immunomodulator may also contain a STING agonist (in particular a STING agonist as specified herein, such as a STING agonist of Formula (XX)) instead of the placeholder reference shown in these structures. It should further be understood that those structures containing a group other than a STING agonist as payload (e.g., which contain a toxin or a chelator (with or without a radioisotope)) may also contain a STING agonist (in particular a STING agonist as specified herein, such as a STING agonist of Formula (XX)) as payload instead of the group other than a STING agonist. It should further be understood that those structures containing a STING agonist as payload may also contain any other STING agonist instead of the specific STING agonist shown in these structures.

[0653] In some embodiments of all aspects and embodiments of the compound described herein, the payload comprises the STING agonist of Formula (XX).

[0654] In some embodiments of all aspects and embodiments of the compound described herein, the payload comprises the STING agonist of Formula (XXH) or (XXK).

[0655] In some embodiments of all aspects and embodiments of the compound described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX).

[0656] In some embodiments of all aspects and embodiments of the compound described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK).

[0657] In some embodiments of all aspects and embodiments of the compound described herein, the payload moiety comprises a STING agonist moiety having the Formula (XX-181), (XX-6'), (XX- 51'), (XX-531), (XX-73'a), or (XX-73'b).

[0658] In some embodiments of all aspects and embodiments of the compound described herein, the tag is an ALFA-tag.

[0659] In some embodiments of all aspects and embodiments of the compound described herein, the tag is a cyclic ALFA-tag.

[0660] In some embodiments of all aspects and embodiments of the compound described herein, the payload comprises the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0661] In some embodiments of all aspects and embodiments of the compound described herein, the payload comprises the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag. In some embodiments of all aspects and embodiments of the compound described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0662] In some embodiments of all aspects and embodiments of the compound described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0663] In some embodiments of all aspects and embodiments of the compound described herein, the payload moiety comprises a STING agonist moiety having the Formula (XX-181), (XX-6'), (XX- 51'), (XX-53'), (XX-73'a), or (XX-73'b), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag. In some embodiments of all aspects and embodiments of the compound described herein, the compound described herein comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19), or the compound described herein is selected from the group consisting of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD1832O (PIC1O), SD18321 (PIC7), SD18322 (PICll), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19). In some preferred embodiments of the compound described herein, the compound described herein comprises a structure of a compound shown herein as any one of SD18321 (PIC7) and SD18317 (PIC8), or the compound described herein is selected from the group consisting of SD18321 (PIC7) and SD18317 (PIC8). In some particularly preferred embodiments, the compound described herein comprises a structure of a compound shown herein as SD18321 (PIC7), or the compound described herein is SD18321 (PIC7).

[0664] In one aspect, the invention relates to a method for treating a subject having a disease, disorder or condition characterized by cells expressing a target antigen, comprising:

[0665] (i) providing to the subject a compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag; (ii) allowing the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag to become associated with cells expressing the target antigen; and

[0666] (iii) administering to the subject a compound described above, e.g., the compound under (ii) described above for the kit of the present invention, comprising one or more tags to which the binding moiety for a tag binds.

[0667] In some embodiments, the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag is provided to the subject by administering to the subject RNA encoding a polypeptide comprising a binding moiety binding to the target antigen and a binding moiety for a tag; and allowing expression of the polypeptide by cells in the subject.

[0668] In some embodiments, the cells expressing the polypeptide are transfected with the RNA.

[0669] In some embodiments, the RNA is administered as particulate formulation such as formulated as lipid nanoparticles.

[0670] In some embodiments, the cells expressing the polypeptide secrete the polypeptide.

[0671] In some embodiments, the cells expressing the polypeptide express the polypeptide such that it is released into the bloodstream.

[0672] In some embodiments, the target antigen is a cell surface antigen.

[0673] In some embodiments, the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag is a fusion polypeptide comprising the binding moiety binding to the target antigen and the binding moiety for a tag.

[0674] In some embodiments, the binding moiety binding to the target antigen comprises an antibody or an antibody derivative.

[0675] In some embodiments, the binding moiety for a tag comprises an antibody or an antibody derivative.

[0676] In some embodiments, the antibody derivative is an antibody fragment.

[0677] In some embodiments, the disease, disorder or condition is cancer.

[0678] In some embodiments, the cells expressing a target antigen are diseased cells.

[0679] In some embodiments, the cells expressing a target antigen are cancer cells.

[0680] In some embodiments, the target antigen is a tumor antigen. In some embodiments, the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag comprises a single binding moiety for the tag or at least two, e.g., two, binding moieties for the tag.

[0681] In some embodiments of all aspects and embodiments of the method described herein, the payload comprises the STING agonist of Formula (XX).

[0682] In some embodiments of all aspects and embodiments of the method described herein, the payload comprises the STING agonist of Formula (XXH) or (XXK).

[0683] In some embodiments of all aspects and embodiments of the method described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX).

[0684] In some embodiments of all aspects and embodiments of the method described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK).

[0685] In some embodiments of all aspects and embodiments of the method described herein, the payload moiety comprises a STING agonist moiety having the Formula (XX-18'), (XX-6'), (XX- 51'), (XX-53'), (XX-73'a), or (XX-73'b).

[0686] In some embodiments of all aspects and embodiments of the method described herein, the tag is an ALFA-tag.

[0687] In some embodiments of all aspects and embodiments of the method described herein, the tag is a cyclic ALFA-tag.

[0688] In some embodiments of all aspects and embodiments of the method described herein, the payload comprises the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0689] In some embodiments of all aspects and embodiments of the method described herein, the payload comprises the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0690] In some embodiments of all aspects and embodiments of the method described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag. In some embodiments of all aspects and embodiments of the method described herein, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[0691] In some embodiments of all aspects and embodiments of the method described herein, the payload moiety comprises a STING agonist moiety having the Formula (XX-18'), (XX-6'), (XX- 51'), (XX-531), (XX-73'a), or (XX-73'b), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag. In some embodiments of all aspects and embodiments of the method described herein, the compound comprising one or more tags to which the binding moiety for a tag binds (i.e., the compound to be administered under (iii) in the method described herein) comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), EX-M60 to EX-M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)), EX-B122 to EX-B132 (in particular, EX-B122 (PIC18)), EX-B133 (PIC19), EX-024 to EX-035, EX-032 to EX-035, and EX-047 to EX-054. In some embodiments of the method described herein, the compound to be administered under (iii) comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICll), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19), or the compound to be administered under (iii) is selected from the group consisting of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICH), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19). In some preferred embodiments of the method described herein, the compound to be administered under (iii) comprises a structure of a compound shown herein as anyone of SD18321 (PIC7) and SD18317 (PIC8), or the compound to be administered under (iii) is selected from the group consisting of SD18321 (PIC7) and SD18317 (PIC8). In some particularly preferred embodiments of the method described herein, the compound to be administered under (iii) comprises a structure of a compound shown herein as SD18321 (PIC7), or the compound to be administered under (iii) is SD18321 (PIC7). Brief description of the drawings

[0692] Figure 1: Plasma stability results of (a) EX-004, and (b) EX-007. All tested compounds were more stable in human plasma.

[0693] Figure 2: Association and dissociation curves of BisALFA conjugates in affinity and avidity measurements. Time was plotted on the X-axis while the response of the affinity measurement was plotted on the left Y-axis, the response in the avidity setup was plotted on the right Y-axis. Affinity curves are depicted as dotted lines while avidity binding curves are shown as a plain line. The pairs correspond to Table 2.

[0694] Figure 3: Association and dissociation curves of BisALFA conjugates in affinity and avidity measurements. Time was plotted on the X-axis while the response of the affinity measurement was plotted on the left Y-axis, the response in the avidity setup was plotted on the right Y-axis. Affinity curves are depicted as dotted lines while avidity binding curves are shown as a plain line. The pairs correspond to Table 3. For the high affinity pair, affinity measurements on linear NbALFA was included as reference, with the response plotted on a second left Y axis.

[0695] Figure 4: Denaturation curve of the bivalent ProteinDocker in the presence of different concentrations of the BisALFA conjugate EX-036. The first derivative of the ratio of the fluorescence signal at 350 nm and 330 nm was plotted against the temperature. Minima and maxima reflect TM values. While the plots in the top row show a clear minimum at ~54°C, which reflects the TM value of NbALFA, no such minima were observed in the lower two plots where at least equimolar concentrations of BisALFA were applied to the ProteinDocker.

[0696] Figure 5: Size exclusion analysis of bivalent ProteinDocker with different concentrations of the BisALFA conjugate EX-036. The top graph represents a 10-fold molecular excess of the BisALFA conjugate, while the middle one shows an equimolar BisALFA concentration to the ProteinDocker. In the lower plot, BisALFA was added to a 10-fold lower molecular concentration compared to the ProteinDocker. As a dotted line, uncomplexed Protein Docker was always overlayed as a comparison.

[0697] Figure 6: Peptide 29 Cold unlabelled Chemical Purity by HPLC.

[0698] Figure 7: Radio-HPLC chromatogram of Ga-68-DOTA-peptide 29.

[0699] Figure 8: Radio TLC Peptide 29 Ga-68 labelled.

[0700] Figure 9: Peptide 31 Cold unlabelled Chemical Purity by HPLC.

[0701] Figure 10: Radio-HPLC chromatogram of Ga-68-DOTA-peptide 31.

[0702] Figure 11: Peptide 31 Ga-68 labelled Radio TLC.

[0703] Figure 12: Stability of Peptide 29 Ga-68 labelled over 7hrs.

[0704] Figure 13: Stability of Peptide 31 Ga-68 labelled over 7 hrs.

[0705] Figure 14: Radio-HPLC chromatogram of ln-111-DOTA-peptide 29.

[0706] Figure 15: Peptide 29 In-111 labelled Radio TLC

[0707] Figure 16: Radio-HPLC chromatogram of ln-111-DOTA-peptide 31

[0708] Figure 17: Peptide 31 In-111 labelled Radio TLC.

[0709] Figure 18: Peptide 29 In-111 labelled Stability over 24 hrs.

[0710] Figure 19: Peptide 31 In-111 labelled Stability over 24 hrs. Figure 20: Dose response curve for cytotox readout 73 hours after treatment is shown for antigen negative ES-2 and antigen positive ES-2-antigen+ cells. Bivalent ProteinDocker only and ProteinDocker + EX-036 serve as controls for ProteinDocker-mediated effects. Specificity of the ProteinDocker + BisALFA complex is evaluated using antigen-negative cells or a ProteinDocker with irrelevant target. EC50 values are calculated and shown in the legend table.

[0711] Figure 21: Components of RiboDocker immunomodulators.

[0712] Figure 22: Co-culture assay for analysing Fc-mediated activity.

[0713] Figure 23: Biolayer interferometric avidity measurements of BisALFA-STING agonists to NbALFA. Sensorgrams of the avidity-driven interaction of SD17453 (A) or SD17516 (B) to NbALFA are shown. A 1:1 serial dilution of the BisALFA-STING agonists, starting at 2.5 nM down to 39.0625 pM were applied to immobilized NbALFA for 900 sec. The shift in wavelength based on the NbALFA-ALFA binding is depicted on the Y axis. After 900 sec (vertical line) dissociation was initiated and measured for the remaining 1500 sec. The acquired datapoints are depicted as a continuous line while the global fitting, based on a the global 1:1 Langmuir binding model, is depicted as a dotted line. Kinetic interaction parameters derived from this fitting are depicted in C.

[0714] Figure 24: Complex formation assessment using Dynamic light scattering. ProteinDocker comprising two NbALFA VHH moieties were incubated without a BisALFA STING agonist peptide (no peptide) or with 10-fold excess of SD17516 or SD17453. Intensities observed at higher radii indicate the formation of larger molecular complexes.

[0715] Figure 25: Biodistribution of Ga68-DOTA-bisALFA with and without RiboDocker

[0716] Figure 26: Biodistribution of Cu64-DOTA-bisALFA with RiboDocker Figure 27: Pretargeting approach using monovalent RiboDocker and fluorophore-labeled monovalent ALFA (monoALFA) conjugate

[0717] Figure 28: In vitro activity of pre-complexes using a co-culture of an antigen+ tumor cell line, which was transfected to express the antigen, and THP-1 Dual reporter cells indicating IRF and NFB induction as described in the THP-1 co-culture assay protocol.

[0718] Figure 29: In vitro activity of pre-complexes using a co-culture of a second antigen+ tumor cell line, which endogenously expresses the antigen, and THP-1 Dual reporter cells indicating IRF and NFB induction as described in the THP-1 co-culture assay protocol.

[0719] Figure 30: In vitro activity of two STING-targeting small molecule payloads in THP-1 Dual reporter cells.

[0720] Figure 31: In vitro activity of pre-complexes using a co-culture of two antigen+ tumor cell lines and THP-1 Dual reporter cells indicating IRF and NFB induction as described in the THP-1 coculture assay protocol. A) The antigen+ tumor cell line used was transfected with the antigen. B) The antigen+ tumor cell line used endogenously expresses the antigen. C) The antigen+ tumor cell line used was transfected to express the antigen.

[0721] Figure 32: Anti-tumoral efficacy of pre-complexes consisting of the tumor-antigen targeted ProteinDocker and either SD17453 (A) or SD17516 (B) compared to complexes with a nonbinding ProteinDocker. A+B) Tumor growth depicted as Mean + SEM. C) Growth of single tumors.

[0722] Figure 33: Anti-tumoral efficacy of pre-complexes consisting of the tumor-antigen targeted ProteinDocker and either PIC7 or PIC8 compared to complexes with a non-binding ProteinDocker. A) Tumor growth depicted as Mean + SEM. B) Growth of single tumors. Figure 34: In vivo tolerability of the pre-complexes of ProteinDocker and immune-conjugate in the murine B16F10 melanoma model stably transfected to overexpress the model antigen. C57BI / 6JRjx mice were injected subcutaneously with B16F10 cells. Different pre-complexes with antigen binding ProteinDocker and one pre-complex with a non-binder were injected intravenously on day 16 after tumor inoculations. Plasma was taken 4 and 24 hours after i.v. injection to analyze systemic cytokine induction (IFNa, IFN P, IL-6 and IP-10).

[0723] Figure 35: In vivo tolerability of the pre-complexes of ProteinDocker and immune-conjugate in the murine B16F10 melanoma model stably transfected to overexpress the model antigen. C57BI / 6JRjx mice were injected subcutaneously with B16F10 cells. Different pre-complexes with antigen binding ProteinDocker and one pre-complex with a non-binder were injected intravenously on day 16 after tumor inoculations. Plasma was taken 4 and 24 hours after i.v. injection to analyze systemic cytokine induction (IFNa, IFN P, IL-6 and IP-10).

[0724] Figure 36: Anti-tumoral efficacy of the RiboDocker mRNA LNP and immune-conjugate in the human ovarian cancer model OV90 which inherently expresses the target antigen. Athymic Nude-Foxnlnu mice were injected subcutaneously with the tumor cell line. RiboDocker mRNA LNPs were injected intraveneously on days 11, 18, and 25 after tumor inoculation. PIC7 was administered intraveneously 24 hours after injection of the mRNA LNP. Tumor size was monitored using caliper measurement until mice reached exclusion criteria. A) Tumor growth depicted as Mean + SEM. B) Growth of single tumors.

[0725] Figure 37: Anti-tumoral efficacy of the RiboDocker mRNA LNP and immune-conjugate in the teratocarcinoma model PA-1 which inherently expresses the target antigen. Athymic Nude- Foxnlnu mice were injected subcutaneously with the tumor cell line. RiboDocker mRNA LNPs were injected intraveneously on days 16, 23, and 30 after tumor inoculation. PIC7 was administered intraveneously 24 hours after injection of the mRNA LNP. Tumor size was monitored using caliper measurement until mice reached exclusion criteria. A) Tumor growth depicted as Mean + SEM. B) Growth of single tumors. Detailed description

[0726] Although the present disclosure is further described in more detail below, it is to be understood that this disclosure is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0727] In the following, the elements of the present disclosure will be described in more detail. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present disclosure to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0728] The practice of the present disclosure will employ, unless otherwise indicated, conventional chemistry, biochemistry, pharmaceutical, cell biology, immunology, and recombinant DNA techniques which are explained in the literature in the field.

[0729] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated feature, element, member, integer or step or group of features, elements, members, integers or steps but not the exclusion of any other feature, element, member, integer or step or group of features, elements, members, integers or steps. The term "consisting essentially of" limits the scope of a claim or disclosure to the specified features, elements, members, integers, or steps and those that do not materially affect the basic and novel characteristic(s) of the claim or disclosure. The term "consisting of" limits the scope of a claim or disclosure to the specified features, elements, members, integers, or steps. The term "comprising" encompasses the term "consisting essentially of" which, in turn, encompasses the term "consisting of". Thus, at each occurrence in the present application, the term "comprising" may be replaced with the term "consisting essentially of" or "consisting of". Likewise, at each occurrence in the present application, the term "consisting essentially of" may be replaced with the term "consisting of".

[0730] The terms "a", "an" and "the" and similar references used in the context of describing the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0731] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0732] The use of any and all examples, or exemplary language (e.g., "such as"), provided herein is intended merely to better illustrate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0733] The term "optional" or "optionally" as used herein means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances where said event, circumstance, or condition occurs and instances in which it does not occur.

[0734] Where used herein, "and / or" is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, "X and / or Y" is to be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, just as if each is set out individually herein.

[0735] In the context of the present disclosure, the term "about" denotes an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±10%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±5%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±4%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±3%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±2%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±1%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.9%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.8%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.7%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.6%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.5%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.4%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.3%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.2%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.1%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.05%. In some embodiments, "about" indicates deviation from the indicated numerical value by ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect.

[0736] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0737] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0738] In the following, definitions and embodiments will be provided which apply to all aspects of the present disclosure. Terms which are defined in the following have the meanings as defined unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0739] Terms such as "reduce" or "inhibit" as used herein means the ability to cause an overall decrease, for example, of about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, or about 75% or greater, in the level. The term "inhibit" or similar phrases includes a complete or essentially complete inhibition, i.e., a reduction to zero or essentially to zero.

[0740] Terms such as "enhance" as used herein means the ability to cause an overall increase, or enhancement, for example, by at least about 5% or greater, about 10% or greater, about 15% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 75% or greater, or about 100% or greater in the level. "Physiological pH" as used herein refers to a pH of about 7.4. In some embodiments, physiological pH is from 7.3 to 7.5. In some embodiments, physiological pH is from 7.35 to 7.45. In some embodiments, physiological pH is 7.3, 7.35, 7.4, 7.45, or 7.5.

[0741] As used in the present disclosure, "% w / v" refers to weight by volume percent, which is a unit of concentration measuring the amount of solute in grams (g) expressed as a percent of the total volume of solution in milliliters (mL).

[0742] As used in the present disclosure, "% by weight" refers to weight percent, which is a unit of concentration measuring the amount of a substance in grams (g) expressed as a percent of the total weight of the total composition in grams (g).

[0743] As used in the present disclosure, "mol %" is defined as the ratio of the number of moles of one component to the total number of moles of all components, multiplied by 100.

[0744] As used in the present disclosure, "mol % of the total lipid" is defined as the ratio of the number of moles of one lipid component to the total number of moles of all lipids, multiplied by 100. In this context, in some embodiments, the term "total lipid" includes lipids and lipid- like material.

[0745] The term "ionic strength" refers to the mathematical relationship between the number of different kinds of ionic species in a particular solution and their respective charges. Thus, ionic strength I is represented mathematically by the formula: in which c is the molar concentration of a particular ionic species and z the absolute value of its charge. The sum 1 is taken over all the different kinds of ions (i) in solution.

[0746] According to the disclosure, the term "ionic strength" in some embodiments relates to the presence of monovalent ions. Regarding the presence of divalent ions, in particular divalent cations, their concentration or effective concentration (presence of free ions) due to the presence of chelating agents is, in some embodiments, sufficiently low so as to prevent degradation of a nucleic acid. In some embodiments, the concentration or effective concentration of divalent ions is below the catalytic level for hydrolysis of the phosphodiester bonds between nucleotides such as RNA nucleotides. In some embodiments, the concentration of free divalent ions is 20 pM or less. In some embodiments, there are no or essentially no free divalent ions.

[0747] "Osmolality" refers to the concentration of a particular solute expressed as the number of osmoles of solute per kilogram of solvent.

[0748] The term "lyophilizing" or "lyophilization" refers to the freeze-drying of a substance by freezing it and then reducing the surrounding pressure (e.g., below 15 Pa, such as below 10 Pa, below 5 Pa, or 1 Pa or less) to allow the frozen medium in the substance to sublimate directly from the solid phase to the gas phase. Thus, the terms "lyophilizing" and "freeze- drying" are used herein interchangeably.

[0749] The term "spray-drying" refers to spray-drying a substance by mixing (heated) gas with a fluid that is atomized (sprayed) within a vessel (spray dryer), where the solvent from the formed droplets evaporates, leading to a dry powder.

[0750] The term "reconstitute" relates to adding a solvent such as water to a dried product to return it to a liquid state such as its original liquid state.

[0751] The term "recombinant" in the context of the present disclosure means "made through genetic engineering". In some embodiments, a "recombinant object" in the context of the present disclosure is not occurring naturally.

[0752] The term "naturally occurring" as used herein refers to the fact that an object can be found in nature. For example, a peptide or nucleic acid that is present in an organism (including viruses) and can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring. The term "found in nature" means "present in nature" and includes known objects as well as objects that have not yet been discovered and / or isolated from nature, but that may be discovered and / or isolated in the future from a natural source.

[0753] As used herein, the terms "room temperature" and "ambient temperature" are used interchangeably herein and refer to temperatures from at least about 15°C, e.g., from about 15°C to about 35°C, from about 15°C to about 30°C, from about 15°C to about 25°C, or from about 17°C to about 22°C. Such temperatures will include 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C and 22°C.

[0754] The term "EDTA" refers to ethylenediaminetetraacetic acid disodium salt. All concentrations are given with respect to the EDTA disodium salt.

[0755] The term "cryoprotectant" relates to a substance that is added to a formulation in order to protect the active ingredients during the freezing stages.

[0756] The term "lyoprotectant" relates to a substance that is added to a formulation in order to protect the active ingredients during the drying stages.

[0757] According to the present disclosure, the term "peptide" refers to substances which comprise about two or more, about 3 or more, about 4 or more, about 6 or more, about 8 or more, about 10 or more, about 13 or more, about 16 or more, about 20 or more, and up to about 50, about 100 or about 150, consecutive amino acids linked to one another via peptide bonds. The term "polypeptide" refers to large peptides, in particular peptides having at least about 151 amino acids. "Peptides" and "polypeptides" are both protein molecules. Thus, the terms "peptide", "protein" and "polypeptide" are used herein usually as synonyms.

[0758] Peptides and polypeptides disclosed herein may comprise a linear or a cyclized peptide sequence.

[0759] In some embodiments, the peptides disclosed herein comprises at least one cyclic portion, i.e., a polypeptide chain that contains a circular sequence of bonds that is referred to herein as a "cyclic peptide." The circular sequence can occur through a connection between the amino and carboxyl ends of the peptide; a connection between the amino end and a side chain; a connection between the carboxyl end and a side chain; or a connection between two side chains including sulfur groups of two cysteine amino acids by forming a disulfide bond, or more complicated arrangements.

[0760] In some embodiments, the peptides and polypeptides disclosed herein are composed of naturally occurring amino acids, non-naturally occurring amino acids, amino acid derivatives and non-amino acid components, or a mixture thereof. In some embodiments, the peptides and polypeptides disclosed herein comprise amino acid mimetics and amino acid analogs. In some embodiments, the peptides and polypeptides disclosed herein comprise non-naturally occurring amino acid sequences that are resistant to enzymatic cleavage.

[0761] In some embodiments, one or more positions of a peptide or polypeptide disclosed herein are substituted with a non-naturally occurring amino acid. In some embodiments, the substituted amino acid is chemically related to the original residue (e.g., aliphatic, charged, basic, acidic, aromatic, hydrophilic) or an isostere of the original residue.

[0762] In its broadest sense, as used herein, the term "amino acid" refers to a compound and / or substance that can be, is, or has been incorporated into a peptide, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally-occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid. In some embodiments, an amino acid is a D-amino acid. In some embodiments, an amino acid is an L-amino acid. "Standard amino acid" or "proteinogenic amino acid" refers to any of the twenty standard L- amino acids commonly found in naturally occurring peptides and polypeptides. "Nonstandard amino acid" refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a peptide or polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a peptide or polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a peptide or polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from 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 peptide or polypeptide.

[0763] The following table lists the 20 natural amino acids and their abbreviations:

[0764] Generally, amino acids are L-amino acids while D-amino acids are denoted by the prefix "D". The prefix "homo" or "h" designates an a-amino acid that is otherwise similar to one of the common ones, but that contains one more methylene group in the carbon chain.

[0765] As used herein, "Orn" means ornithine or 2,5-diaminopentanoic acid, "Dab" means 2,4- diaminobutanoic acid, "Dap" means 2,3-diaminopropanoic acid, "hLys" means 2,7- diaminoheptanoic acid, "hCys" means 2-amino-4-mercaptobutanoic acid, and "Pen" means penicillamine or 2-amino-3-methyl-3-sulfanylbutanoic acid.

[0766] It may also be possible to include non-peptide linkages and other chemical modification. For example, part or all of the peptide or polypeptide may be synthesized as a peptidomimetic, e.g., a peptoid (see, e.g., Simon et al. (1992) Proc. Natl. Acad. Sci. USA 89:9367-71 and Horwell (1995) Trends BiotechnoLI3:132-4). A peptide or polypeptide may include one or more (e.g., all) non-hydrolyzable bonds. Many non-hydrolyzable peptide bonds are known in the art, along with procedures for synthesis of peptides containing such bonds. Exemplary non- hydrolyzable bonds include -[CHzNHj- reduced amide peptide bonds, -[COCH2]- ketomethylene peptide bonds, -(CH(CN)NH]- (cyanomethylene)amino peptide bonds, - [CH2CH(OH)]- hydroxyethylene peptide bonds, -[CH2O]- oxymethylene peptide bonds, and - [CH2S]- thiomethylene peptide bonds (see e.g., U.S. Pat. No. 6,172,043). The term "amide" as used herein, represents a group of formula "-NHC(O)-".

[0767] The term "thioamide" represents a group of formula "-NHC(S)-".

[0768] As used herein the term "disulfide bond", "disulfide bridge" or "disulfide" includes the covalent bond formed between two sulfur atoms. The amino acid cysteine comprises a thiol group that can form a disulfide bond or bridge with a second thiol group.

[0769] The term "ether" refers to a group or compound having an oxygen between two carbon atoms. The term "cyclic ether" refers to a hetercyclic ring which contains only oxygen atoms as ring heteroatoms. Depending on the size of the heterocyclic ring, a cyclic ether may contain 1, 2, or 3 oxygen atoms as ring heteroatoms (e.g., 3-membered and higher rings may contain 1 oxygen atom; 5-membered and higher rings may contain 2 oxygen atoms; and 7-membered and higher rings may contain 3 oxygen atoms, wherein optionally every two oxygen ring atoms are spaced by at least one carbon ring atoms). Examples of cyclic ethers include oxirane, oxirene, furan, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxole, pyran, tetrahydropyran, 1,3- dioxane, and 1,4-dioxane.

[0770] The term "amino" refers to to the the moiety -NHz.

[0771] The term "thioether" refers to a group or compound having a sulfur between two carbon atoms.

[0772] The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0773] The term "ester" refers a compound derived from an carboxylic acid and an alcohol by linking with formal loss of water the hydroxyl group of the -C(=O)OH group in the former and a hydroxy group of the latter. Thus, the term refers to the group -C(O)O-.

[0774] The term "thioester" refers to the group -C(O)S- or -C(S)O-.

[0775] The term "triazole" refers to chemical compounds that incorporate in their structure any heterocyclic structure having a five-membered ring of two carbon atoms and three nitrogen atoms (e.g., 1,2,3-triazole).

[0776] The term "portion" refers to a fraction. With respect to a particular structure such as an amino acid sequence or protein the term "portion" thereof may designate a continuous or a discontinuous fraction of said structure.

[0777] The terms "part" and "fragment" are used interchangeably herein and refer to a continuous element. For example, a part of a structure such as an amino acid sequence or protein refers to a continuous element of said structure. When used in context of a composition, the term "part" means a portion of the composition. For example, a part of a composition may be any portion from 0.1% to 99.9% (such as 0.1%, 0.5%, 1%, 5%, 10%, 50%, 90%, or 99%) of said composition.

[0778] "Fragment", with reference to an amino acid sequence (peptide or polypeptide), relates to a part of an amino acid sequence, i.e., a sequence which represents the amino acid sequence shortened at the N-terminus and / or C-terminus. A fragment shortened at the C-terminus (N- terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 3'-end of the open reading frame. A fragment shortened at the N-terminus (C- terminal fragment) is obtainable, e.g., by translation of a truncated open reading frame that lacks the 5'-end of the open reading frame, as long as the truncated open reading frame comprises a start codon that serves to initiate translation. A fragment of an amino acid sequence comprises, e.g., at least 50 %, at least 60 %, at least 70 %, at least 80%, at least 90% of the amino acid residues from an amino acid sequence. A fragment of an amino acid sequence comprises, e.g., at least 6, in particular at least 8, at least 10, at least 12, at least 15, at least 20, at least 30, at least 50, or at least 100 consecutive amino acids from an amino acid sequence. A fragment of an amino acid sequence comprises, e.g., a sequence of up to 8, in particular up to 10, up to 12, up to 15, up to 20, up to 30 or up to 55, consecutive amino acids of the amino acid sequence.

[0779] "Variant," as used herein and with reference to an amino acid sequence (peptide or polypeptide), is meant an amino acid sequence that differs from a parent amino acid sequence by virtue of at least one amino acid (e.g., a different amino acid, or a modification of the same amino acid). The parent amino acid sequence may be a naturally occurring or wild type (WT) amino acid sequence, or may be a modified version of a wild type amino acid sequence. In some embodiments, the variant amino acid sequence has at least one amino acid difference as compared to the parent amino acid sequence, e.g., from 1 to about 20 amino acid differences, such as from 1 to about 10 or from 1 to about 5 amino acid differences compared to the parent.

[0780] By "wild type" or "WT" or "native" as used herein and with reference to an amino acid sequence (peptide or polypeptide) is meant an amino acid sequence that is found in nature, including allelic variations. A wild type amino acid sequence, peptide or polypeptide has an amino acid sequence that has not been intentionally modified.

[0781] For the purposes of the present disclosure, "variants" of an amino acid sequence (peptide or polypeptide) may comprise amino acid insertion variants, amino acid addition variants, amino acid deletion variants and / or amino acid substitution variants. The term "variant" includes all mutants, splice variants, post-translationally modified variants, conformations, isoforms, allelic variants, species variants, and species homologs, in particular those which are naturally occurring. The term "variant" includes, in particular, fragments of an amino acid sequence. Amino acid insertion variants comprise insertions of single or two or more amino acids in a particular amino acid sequence. In the case of amino acid sequence variants having an insertion, one or more amino acid residues are inserted into a particular site in an amino acid sequence, although random insertion with appropriate screening of the resulting product is also possible. Amino acid addition variants comprise amino- and / or carboxy-terminal fusions of one or more amino acids, such as 1, 2, 3, 5, 10, 20, 30, 50, or more amino acids. Amino acid deletion variants are characterized by the removal of one or more amino acids from the sequence, such as by removal of 1, 2, 3, 5, 10, 20, 30, 50, or more amino acids. The deletions may be in any position of the protein. Amino acid deletion variants that comprise the deletion at the N-terminal and / or C-terminal end of the protein are also called N-terminal and / or C- terminal truncation variants. Amino acid substitution variants are characterized by at least one residue in the sequence being removed and another residue being inserted in its place. Preference is given to the modifications being in positions in the amino acid sequence which are not conserved between homologous peptides or polypeptides and / or to replacing amino acids with other ones having similar properties. In some embodiments, amino acid changes in peptide and polypeptide variants are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In some embodiments, conservative amino acid substitutions include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.

[0782] In some embodiments, the degree of similarity, such as identity between a given amino acid sequence and an amino acid sequence which is a variant of said given amino acid sequence will be at least about 60%, 70%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the degree of similarity or identity is given for an amino acid region which is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference amino acid sequence. For example, if the reference amino acid sequence consists of 200 amino acids, the degree of similarity or identity is given, e.g., for at least about 20, at least about 40, at least about 60, at least about 80, at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 amino acids, in some embodiments continuous amino acids. In some embodiments, the degree of similarity or identity is given for the entire length of the reference amino acid sequence. The alignment for determining sequence similarity, such as sequence identity can be done with art known tools, such as using the best sequence alignment, for example, using Align, using standard settings, preferably EMBOSS::needle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5.

[0783] "Sequence similarity" indicates the percentage of amino acids that either are identical or that represent conservative amino acid substitutions. "Sequence identity" between two amino acid sequences indicates the percentage of amino acids that are identical between the sequences. "Sequence identity" between two nucleic acid sequences indicates the percentage of nucleotides that are identical between the sequences.

[0784] The terms "% identical" and "% identity" or similar terms are intended to refer, in particular, to the percentage of nucleotides or amino acids which are identical in an optimal alignment between the sequences to be compared. Said percentage is purely statistical, and the differences between the two sequences may be but are not necessarily randomly distributed over the entire length of the sequences to be compared. Comparisons of two sequences are usually carried out by comparing the sequences, after optimal alignment, with respect to a segment or "window of comparison", in order to identify local regions of corresponding sequences. The optimal alignment for a comparison may be carried out manually or with the aid of algorithms, e.g., the local homology algorithm by Smith and Waterman, 1981, Ads App. Math. 2, 482, the local homology algorithm by Neddleman and Wunsch, 1970, J. Mol. Biol. 48, 443, the similarity search algorithm by Pearson and Lipman, 1988, Proc. Natl Acad. Sci. USA 88, 2444, or with the aid of computer programs using said algorithms (GAP, BESTFIT, FASTA, BLAST P, BLAST N and TFASTA in Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.). In some embodiments, percent identity of two sequences is determined using the BLASTN or BLASTP algorithm, as available on the United States National Center for Biotechnology Information (NCBI) website (e.g., at blast. ncbi.nlm. nih.gov / Blast. cgi?PAGE_TYPE=BlastSearch&BLAST_SPEC=blast2seq&LINK_LOC =align2seq). In some embodiments, the algorithm parameters used for BLASTN algorithm on the NCBI website include: (i) Expect Threshold set to 10; (ii) Word Size set to 28; (iii) Max matches in a query range set to 0; (iv) Match / Mismatch Scores set to 1, -2; (v) Gap Costs set to Linear; and (vi) the filter for low complexity regions being used. In some embodiments, the algorithm parameters used for BLASTP algorithm on the NCBI website include: (i) Expect Threshold set to 10; (ii) Word Size set to 3; (iii) Max matches in a query range set to 0; (iv) Matrix set to BLOSUM62; (v) Gap Costs set to Existence: 11 Extension: 1; and (vi) conditional compositional score matrix adjustment.

[0785] Percentage identity is obtained by determining the number of identical positions at which the sequences to be compared correspond, dividing this number by the number of positions compared (e.g., the number of positions in the reference sequence) and multiplying this result by 100.

[0786] In some embodiments, the degree of similarity or identity is given for a region which is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference sequence. For example, if the reference nucleic acid sequence consists of 200 nucleotides, the degree of identity is given for at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 nucleotides, in some embodiments continuous nucleotides. In some embodiments, the degree of similarity or identity is given for the entire length of the reference sequence. Homologous amino acid sequences exhibit according to the disclosure at least 40%, in particular at least 50%, at least 60%, at least 70%, at least 80%, at least 90% and, e.g., at least 95%, at least 98 or at least 99% identity of the amino acid residues. The amino acid sequence variants described herein may readily be prepared by the skilled person, for example, by recombinant DNA manipulation. The manipulation of DNA sequences for preparing peptides or polypeptides having substitutions, additions, insertions or deletions, is described in detail in Molecular Cloning: A Laboratory Manual, 4th Edition, M.R. Green and J. Sambrook et al. (1989), eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2012, for example. Furthermore, the peptides, polypeptides and amino acid variants described herein may be readily prepared with the aid of known peptide synthesis techniques such as, for example, by solid phase synthesis and similar methods.

[0787] In some embodiments, a fragment or variant of an amino acid sequence (peptide or polypeptide) is a "functional fragment" or "functional variant". The term "functional fragment" or "functional variant" of an amino acid sequence relates to any fragment or variant exhibiting one or more functional properties identical or similar to those of the amino acid sequence from which it is derived, i.e., it is functionally equivalent. With respect to sequences of binding agents such as antibodies, one particular function is one or more binding activities displayed by the amino acid sequence from which the fragment or variant is derived. The term "functional fragment" or "functional variant", as used herein, in particular refers to a variant molecule or sequence that comprises an amino acid sequence that is altered by one or more amino acids compared to the amino acid sequence of the parent molecule or sequence and that is still capable of fulfilling one or more of the functions of the parent molecule or sequence, e.g., binding to a target molecule. In some embodiments, the modifications in the amino acid sequence of the parent molecule or sequence do not significantly affect or alter the characteristics of the molecule or sequence. In different embodiments, the function of the functional fragment or functional variant may be reduced but still significantly present, e.g., function of the functional fragment or functional variant may be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the parent molecule or sequence. However, in other embodiments, function of the functional fragment or functional variant may be enhanced compared to the parent molecule or sequence.

[0788] An amino acid sequence (peptide or polypeptide) "derived from" a designated amino acid sequence (peptide or polypeptide) refers to the origin of the first amino acid sequence. In some embodiments, the amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentially identical or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a particular amino acid sequence may be variants of that particular sequence or a fragment thereof. For example, it will be understood by one of ordinary skill in the art that the sequences suitable for use herein may be altered such that they vary in sequence from the naturally occurring or native sequences from which they were derived, while retaining the desirable activity of the native sequences.

[0789] In some embodiments, "isolated" means removed (e.g., purified) from the natural state or from an artificial composition, such as a composition from a production process. For example, a nucleic acid, peptide or polypeptide naturally present in a living animal is not "isolated", but the same nucleic acid, peptide or polypeptide partially or completely separated from the coexisting materials of its natural state is "isolated". An isolated nucleic acid, peptide or polypeptide can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0790] The term "bind" or "binding" relates to the non-covalent interaction with a target. In some embodiments, the term "bind" or "binding" relates to a specific binding. By the term "specific binding" or "specifically binds", as used herein, is meant a molecule such as an antibody which recognizes a specific target molecule, but does not substantially recognize or bind other molecules in a sample or in a subject. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more other species. But, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific.

[0791] In some instances, the terms "specific binding" or "specifically binds", can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A" and the antibody, will reduce the amount of labeled A bound to the antibody.

[0792] As used herein, the terms "binding" or "capable of binding" typically is a binding with an affinity corresponding to a KD of about 10~7M or less, such as about 10'8M or less, such as about 10~9M or less, about IO10M or less, or about 1011M or even less, when determined using Bio-Layer Interferometry (BLI), or, for instance, when determined using surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument. In some embodiments, a binding moiety or agent binds to a predetermined target with an affinity corresponding to a KD that is at least ten-fold lower, such as at least 100-fold lower, for instance at least 1,000-fold lower, such as at least 10,000-fold lower, for instance at least 100,000-fold lower than its affinity for binding to a non-specific target (e.g., BSA, casein).

[0793] The term "kd" (sec-1), as used herein, refers to the dissociation rate constant of a particular interaction, e.g., antibody-antigen interaction. Said value is also referred to as the kotf value.

[0794] The term "KD" (M), as used herein, refers to the dissociation equilibrium constant of a particular interaction, e.g., antibody-antigen interaction.

[0795] Generally, the terms "bind" or "binding" and "target" or "targeting" are used interchangeably herein.

[0796] The term "genetic modification" or simply "modification" includes the transfection of cells with nucleic acid. The term "transfection" relates to the introduction of nucleic acids, e.g., DNA and / or RNA, into a cell. For purposes of the present disclosure, the term "transfection" also includes the introduction of a nucleic acid into a cell or the uptake of a nucleic acid by such cell, wherein the cell may be present in a subject, e.g., a patient, or the cell may be in vitro, e.g., outside of a patient. Thus, according to the present disclosure, a cell for transfection of a nucleic acid described herein can be present in vitro or in vivo, e.g. the cell can form part of an organ, a tissue and / or the body of a patient. According to the disclosure, transfection can be transient or stable. For some applications of transfection, it is sufficient if the transfected genetic material is only transiently expressed. RNA can be transfected into cells to transiently express its coded protein. Since the nucleic acid introduced in the transfection process is usually not integrated into the nuclear genome, the foreign nucleic acid will be diluted through mitosis or degraded. Cells allowing episomal amplification of nucleic acids greatly reduce the rate of dilution. If it is desired that the transfected nucleic acid actually remains in the genome of the cell and its daughter cells, a stable transfection must occur. Such stable transfection can be achieved by using virus-based systems or transposon-based systems for transfection, for example. Generally, cells that are transfected with nucleic acid encoding a docking compound are transiently transfected with nucleic acid encoding the docking compound. RNA can be transfected into cells to transiently express its coded protein. As used herein, the terms "linked", "fused", or "fusion" are used interchangeably. These terms refer to the joining together of two or more elements or components or domains.

[0797] The term "fusion protein" as used herein refers to a polypeptide or protein comprising two or more subunits. Preferably, the fusion protein is a translational fusion between the two or more subunits. The translational fusion may be generated by genetically engineering the coding nucleotide sequence for one subunit in a reading frame with the coding nucleotide sequence of a further subunit. Subunits may be interspersed by a linker.

[0798] As used herein "endogenous" refers to any material from or produced inside an organism, cell, tissue or system.

[0799] As used herein, the term "exogenous" refers to any material introduced from or produced outside an organism, cell, tissue or system.

[0800] The term "autologous" is used to describe anything that is derived from the same subject. For example, "autologous transplant" refers to a transplant of tissue or organs derived from the same subject. Such procedures are advantageous because they overcome the immunological barrier which otherwise results in rejection.

[0801] The term "allogeneic" is used to describe anything that is derived from different individuals of the same species. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical.

[0802] The term "syngeneic" is used to describe anything that is derived from individuals or tissues having identical genotypes, i.e., identical twins or animals of the same inbred strain, or their tissues.

[0803] The term "heterologous" is used to describe something consisting of multiple different elements. As an example, the transfer of one individual's bone marrow into a different individual constitutes a heterologous transplant. A heterologous gene is a gene derived from a source other than the subject.

[0804] According to various embodiments of the present disclosure, a nucleic acid encoding a peptide or polypeptide is taken up by or introduced, i.e. transfected or transduced, into a cell which cell may be present in vitro or in a subject, resulting in expression of said peptide or polypeptide. The cell may, e.g., express the encoded peptide or polypeptide intracellularly (e.g. in the cytoplasm and / or in the nucleus), may secrete the encoded peptide or polypeptide, and / or may express it on the surface. In some embodiments, if the encoded peptide or polypeptide is a docking compound, the cell secretes the encoded peptide or polypeptide. According to the present disclosure, terms such as "nucleic acid expressing" and "nucleic acid encoding" or similar terms are used interchangeably herein and with respect to a particular peptide or polypeptide mean that the nucleic acid, if present in the appropriate environment, e.g. within a cell, can be expressed to produce said peptide or polypeptide.

[0805] The term "expression" as used herein includes the transcription and / or translation of a particular nucleotide sequence.

[0806] In the context of the present disclosure, the term "transcription" relates to a process, wherein the genetic code in a DNA sequence is transcribed into RNA (especially mRNA). Subsequently, the RNA may be translated into peptide or polypeptide.

[0807] With respect to RNA, the term "expression" or "translation" relates to the process in the ribosomes of a cell by which a strand of mRNA directs the assembly of a sequence of amino acids to make a peptide or polypeptide.

[0808] A medical preparation, in particular kit, described herein may comprise instructional material or instructions. As used herein, "instructional material" or "instructions" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the compositions and methods of the present disclosure. The instructional material of the kit of the present disclosure may, for example, be affixed to a container which contains the compositions / formulations of the present disclosure or be shipped together with a container which contains the compositions / formulations. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compositions be used cooperatively by the recipient.

[0809] The term "average diameter" refers to the mean hydrodynamic diameter of particles as measured by dynamic light scattering (DLS) with data analysis using the so-called cumulant algorithm, which provides as results the so-called Zaverage with the dimension of a length, and the polydispersity index (PDI), which is dimensionless (Koppel, D., J. Chem. Phys. 57, 1972, pp 4814-4820, ISO 13321). Here "average diameter", "diameter" or "size" for particles is used synonymously with this value of the Zaverage-

[0810] In some embodiments, the "polydispersity index" is calculated based on dynamic light scattering measurements by the so-called cumulant analysis as mentioned in the definition of the "average diameter". Under certain prerequisites, it can be taken as a measure of the size distribution of an ensemble of nanoparticles. The term "alkyl" refers to a monovalent radical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 12 (such as 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, abbreviated as C1-12 alkyl, (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, abbreviated as Cuo alkyl), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl (also called 2-propyl or 1-methylethyl), butyl, iso-butyl, tert-butyl, n- pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. A "substituted alkyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0811] The term "alkylene" refers to a divalent radical of a saturated straight or branched hydrocarbon. Preferably, the alkylene comprises from 1 to 12 (such as 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylene groups include methylene, ethylene (i.e., 1,1-ethylene, 1,2-ethylene), propylene (i.e., 1,1-propylene, 1,2-propylene (-CH(CHs)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), the butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene, 1,3- butylene, 2,3-butylene (cis or trans or a mixture thereof), 1,4-butylene, 1,1-iso-butylene, 1,2- iso-butylene, and 1,3-iso-butylene), the pentylene isomers (e.g., 1,1-pentylene, 1,2- pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-iso-pentylene, 1,1-sec-pentyl, 1,1-neo-pentyl), the hexylene isomers (e.g., 1,1-hexylene, 1,2-hexylene, 1,3-hexylene, 1,4- hexylene, 1,5-hexylene, 1,6-hexylene, and 1,1-isohexylene), the heptylene isomers (e.g., 1,1- heptylene, 1,2-heptylene, 1,3-heptylene, 1,4-heptylene, 1,5-heptylene, 1,6-heptylene, 1,7- heptylene, and 1,1-isoheptylene), the octylene isomers (e.g., 1,1-octylene, 1,2-octylene, 1,3- octylene, 1,4-octylene, 1,5-octylene, 1,6-octylene, 1,7-octylene, 1,8-octylene, and 1,1- isooctylene), and the like. The straight alkylene moieties having at least 3 carbon atoms and a free valence at each end can also be designated as a multiple of methylene (e.g., 1,4-butylene can also be called tetramethylene). Generally, instead of using the ending "ylene" for alkylene moieties as specified above, one can also use the ending "diyl" (e.g., 1,2-butylene can also be called butan-l,2-diyl). A "substituted alkylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0812] The term "alkenyl" refers to a monovalent radical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenyl group can be equal to the integer which is calculated by dividingthe number of carbon atoms in the alkenyl group by 2 and, if the number of carbon atoms in the alkenyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, carbon-carbon double bonds. Preferably, the alkenyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms, 2 to 4 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 or 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises from 2 to 12, abbreviated as C2-12 alkenyl, (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1- butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5- octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6- nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6- decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4- undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7- dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, and the like. If an alkenyl group is attached to a nitrogen atom, it is preferred that the double bond is not alpha to the nitrogen atom. A "substituted alkenyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkenyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkenyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0813] The term "alkenylene" refers to a divalent radical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenylene group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenylene group by 2 and, if the number of carbon atoms in the alkenylene group is uneven, rounding the result of the division down to the next integer. For example, for an alkenylene group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenylene group has

[0814] 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, carbon-carbon double bonds. Preferably, the alkenylene group comprises from 2 to 12 (such as 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably

[0815] 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenylene group comprises from 2 to 12 (such as 2 to 10 carbon) atoms and 1, 2, 3, 4, 5, or 6 (such as 1, 2, 3, 4, or 5) carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenylene groups include ethen-l,2-diyl, vinylidene (also called ethenylidene), l-propen-l,2-diyl, l-propen-l,3-diyl, l-propen-2,3-diyl, allylidene, 1-buten- 1,2-diyl, l-buten-l,3-diyl, l-buten-l,4-diyl, l-buten-2,3-diyl, l-buten-2,4-diyl, l-buten-3,4- diyl, 2-buten-l,2-diyl, 2-buten-l,3-diyl, 2-buten-l,4-diyl, 2-buten-2,3-diyl, 2-buten-2,4-diyl, 2- buten-3,4-diyl, and the like. If an alkenylene group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom. A "substituted alkenylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkenylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkenylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0816] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon moiety having at least one carbon-carbon triple bond in which the total carbon atoms may be 2 to 20, typically six to twenty, often 2 to 10, such as 2 to 8, 2 to 6, or 2 to 4. Alkynyl groups can optionally have one or more carbon carbon double bonds. Generally, the maximal number of carbon-carbon triple bonds in the alkynyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkynyl group by 2 and, if the number of carbon atoms in the alkynyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, more preferably 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 3- heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5- octynyl, 6-octynyl, 7-octynyl, 1-nonylyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6- nonynyl, 7-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6- decynyl, 7-decynyl, 8-decynyl, 9-decynyl, and the like. If an alkynyl group is attached to a nitrogen atom, it is preferred that the triple bond is not alpha to the nitrogen atom. A "substituted alkynyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkynyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0817] The term "cycloalkyl" or "cyclic alkyl" represents cyclic non-aromatic versions of "alkyl", "alkenyl", and "alkynyl" with preferably 3 to 20 ring-forming carbon atoms, such as 3 to 15, 3 to 10, 3 to 8 , 3 to 6, 3 to 5, 4 to 6, or 5 or 6 ring-forming carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring-forming carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms), more preferably 3 to 7 ring-forming carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, norbornyl, norpinyl, norcarnyl, oradamantly. The cycloalkyl group may consist of one ring (monocyclic), two rings (bicyclic), or more than two rings (polycyclic). A "substituted cycloalkyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the cycloalkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein or an oxo (i.e., =0) or sulfido (i.e., =S) group.

[0818] The term "cycloalkylene" represents cyclic non-aromatic versions of "alkylene" and may be saturated or unsaturated. A cycloalkylene is a geminal, vicinal or isolated divalent radical. In certain embodiments, the cycloalkylene (i) is monocyclic or polycyclic (such as bi- or tricyclic) and / or (ii) is 3- to 14-membered {i.e., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered, such as 3- to 12-membered or 3- to 10-membered). In one embodiment the cycloalkylene is a mono-, bi- or tricyclic 3- to 14-membered {i.e., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14- membered, such as 3- to 12-membered or 3- to 10-membered) cycloalkylene. Generally, instead of using the ending "ylene" for cycloalkylene moieties as specified above, one can also use the ending "diyl" {e.g., 1,2-cyclopropylene can also be called cyclopropan-l,2-diyl). Exemplary cycloalkylene groups include cyclohexylene, cycloheptylene, cyclopropylene, cyclobutylene, cyclobutenylene, cyclopentylene, cyclooctylene, bicyclo[3.2.1]octylene, bicyclo[3.2.2]nonylene, and adamantanylene {e.g., tricyclo[3.3.1.13'7]decan-2,2-diyl). A "substituted cycloalkylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an cycloalkylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the cycloalkylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0819] The term "aryl" refers to a monovalent radical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, such as 5, 6, or 10) carbon atoms which can be arranged in one ring (e.g., pheny!) or two or more condensed rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenylium, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl. Preferably, "aryl" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. Aryl does not encompass fullerenes. A "substituted aryl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an aryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the aryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0820] The term "arylene" refers to a divalent radical of an aryl as specified above. Preferably, the arylene group contains 3 to 20 carbon atoms which can be arranged in one ring (e.g., phenylene), or two or more condensed rings (e.g., naphthylene). Exemplary arylene groups are derived from cyclopropenylium, cyclopentadienyl, benzene, indene, naphthalene, azulene, fluorene, anthracene, or phenanthracene by removing two hydrogen atoms. Preferably, "arylene" refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenylene and naphthylene. A "substituted arylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an arylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the arylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0821] The term "heteroaryl" or "heteroaromatic ring" means an aryl group as defined above in which one or more carbon atoms in the aryl group are replaced by heteroatoms of O, S, or N. Preferably, heteroaryl refers to a five or six-membered aromatic monocyclic ring wherein 1, 2, or 3 carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Alternatively, it means an aromatic bicyclic or tricyclic ring system wherein 1, 2, 3, 4, or 5 carbon atoms are replaced with the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. Exemplary heteroaryl groups include furanyl (= furyl), thienyl, oxazolyl, isoxazolyl, oxadiazolyl (such as 1,2,5-oxadiazolyl (= furazanyl)), pyrrolyl (= pyrryl), imidazolyl, pyrazolyl, triazolyl (including 1,2,4-triazolyl and 1,2,3-triazolyl), tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (= pyridyl), pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, 1H- indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl (= quinolyl), isoquinolinyl (= isoquinolyl), benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, pyridazinyl, phenoxazinyl, thiazolopyridinyl, pyrrolothiazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, and phenazinyl. Exemplary 5- or 6-memered heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl (e.g., 2-imidazolyl), pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl (e.g., 4-pyridyl), pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl. A "substituted heteroaryl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heteroaryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heteroaryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0822] The term "heteroarylene" refers to a divalent radical of a heteroaryl as specified above, a heteroaryl group as defined above in which one hydrogen atom has been removed resulting in a diradical. Exemplary heteroarylene groups include furanylene, thienylene, oxazolylene, isoxazolylene, oxadiazolylene (1,2,5- and 1,2,3-), pyrrolylene, imidazolylene, pyrazolylene, triazolylene (1,2,3- and 1,2,4-), thiazolylene, isothiazolylene, thiadiazolylene (1,2,3- and 1,2,5- ), pyridinylene, pyrimidinylene, pyrazinylene, triazinylene (1,2,3-, 1,2,4-, and 1,3,5-), benzofuranylene (1- and 2-), indolylene, isoindolylene, benzothienylene (1- and 2), 1H- indazolylene, benzimidazolylene, benzoxazolylene, indoxazinylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, quinolinylene, isoquinolinylene, benzodiazinylene, quinoxalinylene, quinazolinylene, benzotriazinylene (1,2,3- and 1,2,4- benzotriazinyl), pyridazinylene, phenoxazinylene, thiazolopyridinylene, pyrrolothiazolylene, phenothiazinylene, isobenzofuranylene, chromenylene, xanthenylene, phenoxathiinylene, pyrrolizinylene, indolizinylene, indazolylene, purinylene, quinolizinylene, phthalazinylene, napht hyridinylene (1,5-, 1,6-, 1,7-, 1,8-, and 2,6-), cinnolinylene, pteridinylene, carbazolylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene (1,7-, 1,8-, 1,10-, 3,8-, and 4,7-), phenazinylene, oxazolopyridinylene, isoxazolopyridinylene, pyrrolooxazolylene, and pyrrolopyrrolyl. Exemplary 5- or 6-memered heteroarylene groups include furanylene, thienylene, oxazolylene, isoxazolylene, oxadiazolylene (1,2,5- and 1,2,3-), pyrrolylene, imidazolylene, pyrazolylene, triazolylene (1,2,3- and 1,2,4-), thiazolylene, isothiazolylene, thiadiazolylene (1,2,3- and 1,2,5-), pyridylene, pyrimidinylene, pyrazinylene, triazinylene (1,2,3-, 1,2,4-, and 1,3,5-), and pyridazinylene. A "substituted heteroarylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heteroarylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heteroarylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein.

[0823] The term "heterocyclyl" or "heterocyclic ring" means a cycloalkyl group as defined above in which from 1, 2, 3, or 4 carbon atoms in the cycloalkyl group are replaced by heteroatoms of oxygen, nitrogen, silicon, selenium, phosphorous, or sulfur, preferably O, S, or N. A heterocyclyl group has preferably 1 or 2 rings containing from 3 to 10, such as 3, 4, 5, 6, or 7, ring atoms; e.g., a monocyclic heterocyclyl group may contain 3, 4, 5, 6, or 7 (preferably 5, 6, or 7) ring atoms, whereas a bicyclic heterocyclyl group may contain 7 to 10 (such as 8, 9, or 10) ring atoms. Preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. The term "heterocyclyl" is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro or perhydro forms) of the above-mentioned heteroaryl groups. Exemplary heterocyclyl groups include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl (also called piperidyl), piperazinyl, di- and tetrahydrofuranyl, di- and tetrahydrothienyl, di- and tetrahydropyranyl, urotropinyl, lactones, lactams, cyclic imides, and cyclic anhydrides. A "substituted heterocyclyl" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heterocyclyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein or an oxo or sulfido group.

[0824] The term "heterocycloalkylene" or "divalent heterocyclic ring" as used herein means a heterocyclyl group as defined above which contains at least one ring heteroatom (such as those selected from the group consisting of O, S, N, B, Si, and P) and in which one hydrogen atom has been removed resulting in a geminal, vicinal or isolated divalent radical. In some embodiments, the heteroatoms of the heterocycloalkylene group are selected from the group consisting of O, S, and N. For example, the heterocycloalkylene may be O / S- heterocycloalkylene, such as O-heterocycloalkylene. In some embodiments, in each ring of the heterocycloalkylene group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. The heterocycloalkylene may be monocyclic or polycyclic (such as bi- or tricyclic). In some embodiments, the heterocycloalkylene is a mono-, bi- or tricyclic 4- to 14-membered (i.e., 4-, 5-, 6-, 7-, 8-, 9-, 10- , 11-, 12-, 13-, or 14-membered, such as 4- to 12-membered or 4- to 10-membered) heterocycloalkylene. The term "heterocycloalkylene" is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro or perhydro forms) of the above- mentioned heteroaryl groups (preferably partially or completely hydrogenated forms of the above-mentioned mono-, bi-, or tricyclic heteroaryl groups) in which one hydrogen atom has been removed from the same carbon atom resulting in a geminal divalent radical. Thus, in some embodiments, a heterocycloalkylene is saturated or unsaturated (i.e., it contains one or more double bonds within the ring) but cannot be aromatic. Exemplary heterocycloalkylene groups include pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene (such as 1,4-piperazinylen which is also designated as piperazin-1, 4-diyl), indolinylene, isoindolinylene, etc. A "substituted heterocycloalkylene" means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heterocycloalkylene group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heterocycloalkylene group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1stlevel substituent as specified herein or an oxo or sulfido group.

[0825] The expression "partially hydrogenated form" of an unsaturated compound or group as used herein means that part of the unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group without removing all unsaturated moieties. The phrase "completely hydrogenated form" of an unsaturated compound or group is used herein interchangeably with the term "perhydro" and means that all unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group. For example, partially hydrogenated forms of a 5-membered heteroaryl group (containing 2 double bonds in the ring, such as furan) include dihydro forms of said 5-membered heteroaryl group (such as 2,3-dihydrofuran or 2,5-dihydrofuran), whereas the tetrahydro form of said 5-membered heteroaryl group (e.g., tetrahydrofuran, i.e., THF) is a completely hydrogenated (or perhydro) form of said 5-membered heteroaryl group. Likewise, for a 6-membered heteroaryl group having 3 double bonds in the ring (such as pyridyl), partially hydrogenated forms include di- and tetrahydro forms (such as di- and tetrahydropyridyl), whereas the hexahydro form (such as piperidinyl in case of the heteroaryl pyridyl) is the completely hydrogenated (or perhydro) derivative of said 6-membered heteroaryl group. Consequently, a hexahydro form of an aryl or heteroaryl can only be considered a partially hydrogenated form according to the present disclosure if the aryl or heteroaryl contains at least 4 unsaturated moieties consisting of double and triple bonds between ring atoms.

[0826] The term "aromatic" as used in the context of hydrocarbons means that the whole molecule has to be aromatic. For example, if a monocyclic aryl is hydrogenated (either partially or completely) the resulting hydrogenated cyclic structure is classified as cycloalkyl for the purposes of the present disclosure. Likewise, if a bi- or polycyclic aryl (such as naphthyl) is hydrogenated the resulting hydrogenated bi- or polycyclic structure (such as 1,2- dihydronaphthyl) is classified as cycloalkyl for the purposes of the present disclosure (even if one ring, such as in 1,2-dihydronaphthyl, is still aromatic). A similar distinction is made within the present application between heteroaryl and heterocyclyl. For example, indolinyl, i.e., a dihydro variant of indolyl, is classified as heterocyclyl for the purposes of the present disclosure, since only one ring of the bicyclic structure is aromatic and one of the ring atoms is a heteroatom.

[0827] Typical 1stlevel substituents are preferably selected from the group consisting of C1-3 alkyl, phenyl, halogen, -CF3, -OH, -OCH3, -SCH3, -NH2-Z(CH3)Z, -C(=O)OH, and -C(=O)OCH3, wherein z is 0, 1, or 2 and C1.3 alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred 1stlevel substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), and -CF3, such as halogen (e.g., F, Cl, or Br), and -CF3. Additional typical 1stlevel substituents of non-aromatic ring moieties (such as cycloalkyl or heterocyclyl moieties) are oxo or sulfido.

[0828] It is intended that all compounds shown herein (e.g., tag conjugates and docking compounds) and all formulas shown herein (in particular, any of Formulas (XXA), (XXB), (XXC), (XXD), (XXE), (XXF), (XXG), (XXH), (XXJ), (XXK), (XX-I) to (XX-LXII), (XX-1) to (XX-73), (XX'), (XXA'), (XXB'), (XXC), (XXD'), (XXE1), (XXF'), (XXG'), (XXH'), (XXJ'), (XXK'), (XX-61), (XX-18'), (XX-51'), (XX-531), (XX-73'a), (XX-73'b), SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC1O), SD18321 (PIC7), SD18322 (PICH), EX-M60 to EX-M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)), EX-B122 to EX-B132 (in particular, EX-B122 (PIC18)), EX-B133 (PIC19)), EX-024 to EX- 035, EX-032 to EX-035, and EX-047 to EX-054) encompass not only the compounds / formulas as depicted but also their tautomers, solvates (e.g., hydrates), salts (in particular, pharmaceutically acceptable salts), crystalline forms, non-crystalline, unlabeled forms, isotopically labeled forms, diastereomers, enantiomers, and any combinations thereof (unless this is clearly contracdicted by the specific compound / formula).

[0829] "Isomers" are compounds having the same molecular formula but differ in structure ("structural isomers") or in the geometrical (spatial) positioning of the functional groups and / or atoms ("stereoisomers"). "Enantiomers" are a pair of stereoisomers which are non- superimposable mirror-images of each other. A "racemic mixture" or "racemate" contains a pair of enantiomers in equal amounts and is denoted by the prefix (±). "Diastereomers" are stereoisomers which are non-superimposable and which are not mirror-images of each other. "Tautomers" are structural isomers of the same chemical substance that spontaneously and reversibly interconvert into each other, even when pure, due to the migration of individual atoms or groups of atoms; i.e., the tautomers are in a dynamic chemical equilibrium with each other. An example of tautomers are the isomers of the keto-enol-tautomerism. "Conformers" are stereoisomers that can be interconverted just by rotations about formally single bonds, and include, in particular, those leading to different 3-dimentional forms of (hetero)cyclic rings, such as chair, half-chair, boat, and twist-boat forms of cyclohexane.

[0830] The term "solvate" as used herein refers to an addition complex of a dissolved material in a solvent (such as an organic solvent (e.g., an aliphatic alcohol (such as methanol, ethanol, n- propanol, isopropanol), acetone, acetonitrile, ether, and the like), water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A "hydrate" is a solvate, wherein the solvent is water.

[0831] Docking compound

[0832] According to the disclosure, a payload is delivered specifically to a target cell by providing a docking compound with a moiety that binds to a target on target cells, e.g., an antigen on target cells, and a moiety that binds to a compound which carries the payload (tag conjugate). The target on target cells is also referred to herein as "primary target".

[0833] A "docking compound" is used to form a connection, such as a non-covalent connection, between a primary target, e.g., a target cell or an antigen on target cells, and the docking compound. The docking compound may form a connection, such as a non-covalent or covalent connection, to a compound comprising a payload to be delivered to a target cell (tag conjugate). The tag conjugate comprises one or more tags for binding by the docking compound which are covalently attached to the payload.

[0834] In some embodiments, a docking compound comprises a "primary targeting moiety", e.g., a moiety targeting a cell surface antigen on target cells, that is capable of binding to the primary target of interest, e.g., a cell surface antigen on target cells. A "primary targeting moiety" as used herein relates to the part of the docking compound which binds to a primary target. Such targeting moieties are typically moieties that have affinity for cell surface targets. These moieties can be any peptide or protein (e.g. antibodies or antibody fragments) binding to the primary target. Particular embodiments of suitable primary targeting moieties for use herein include cell surface antigen binding moieties, such as antibodies, antibody fragments and DARPins. Other examples of primary targeting moieties are peptides or proteins which bind to a receptor.

[0835] A primary targeting moiety preferably binds with high specificity and / or high affinity and the bond with the primary target is preferably stable within the body.

[0836] In order to allow specific targeting of primary targets, the primary targeting moiety of the docking compound can comprise compounds including but not limited to antibodies, antibody fragments, e.g. F(ab')2, Fab, scFV, VHH domains, and other proteins or peptides.

[0837] According to some embodiments, the primary target is a cell surface antigen such as a cancer antigen, and suitable primary targeting moieties include but are not limited to, peptides and polypeptides targeting the cell surface antigen, e.g., antibodies, antibody fragments and DARPins.

[0838] According to some embodiments, the primary target is a receptor and suitable primary targeting moieties include but are not limited to, the ligand of such a receptor or a part thereof which still binds to the receptor, e.g., a receptor binding peptide in the case of receptor binding protein ligands.

[0839] According to some embodiments, the primary target and primary targeting moiety are selected so as to result in the specific or increased targeting of certain cells, e.g., diseased cells, such as cells involved in and characteristic for a disease such as cancer, an inflammation, an infection, a cardiovascular disease, e.g. thrombus, atherosclerotic lesion, hypoxic site, e.g. stroke, tumor, cardiovascular disorder, brain disorder, apoptosis, and angiogenesis. This can be achieved by selecting primary targets with cell-specific expression. For example, cancer antigens, e.g., those described herein, may be expressed in cancer cells while they are not expressed or expressed in a lower amount in normal non-cancerous cells.

[0840] The docking compound further comprises a group which serves as a binding moiety for a respective tag of a tag conjugate. The moiety of the docking compound binding to the tag conjugate and the primary targeting moiety are linked to each other, preferably by a covalent linkage.

[0841] According to some embodiments, the docking compound comprises a bispecific molecule, such as a bispecific polypeptide, e.g., a bispecific antibody. In some embodiments, the docking compound comprises a binding domain binding to a primary target and a binding domain binding to a tag conjugate. In some embodiments, the docking compound comprises an antibody or antibody fragment binding to a primary target and an antibody or antibody fragment binding to a tag conjugate. In some embodiments, at least one binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody. In some embodiments, each binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody. In some embodiments, at least one binding domain comprises a single-domain antibody such as a VHH. In some embodiments, each binding domain comprises a single-domain antibody such as a VHH. In some embodiments, one binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody and the other binding domain comprises a single-domain antibody such as a VHH. In some embodiments, the binding domain binding to a primary target comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody. In some embodiments, the binding domain binding to a primary target comprises a single-domain antibody such as a VHH. In some embodiments, the binding domain binding to a tag conjugate comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody. In some embodiments, the binding domain binding to a tag conjugate comprises a single-domain antibody such as a VHH. In some embodiments, the binding domain binding to a primary target comprises a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody and the binding domain binding to a tag conjugate comprises a single-domain antibody such as a VHH.

[0842] In some embodiments, the docking compound comprises one binding domain binding to a primary target and one binding domains binding to a tag conjugate. In some embodiments, the docking compound comprises one binding domain binding to a primary target and two binding domains binding to a tag conjugate. In some embodiments, the docking compound comprises two binding domains binding to a primary target and two binding domains binding to a tag conjugate.

[0843] In some embodiments, the docking compound comprises an antibody wherein the Fab fragments of the antibody are replaced by VHHs binding to a primary target and being N- terminally linked to the remaining part of the heavy chains. In some embodiments, the heavy chains are C-terminally linked to VHHs binding to a tag on a tag conjugate.

[0844] In some embodiments, the docking compound comprises a full-length antibody binding to a primary target. In some embodiments, the heavy chains of the full-length antibody are C- terminally linked to VHHs binding to a tag on a tag conjugate.

[0845] In some embodiments, the docking compound comprises a fusion protein which comprises a binding domain binding to a primary target and a binding domain binding to a tag conjugate. In some embodiments, the docking compound comprises a single peptide chain. In some embodiments, the single peptide chain comprises a portion, e.g., antibody, antibody fragment or DARPin, binding to a primary target and a portion, e.g., antibody or antibody fragment, binding to a tag conjugate. In some embodiments, the docking compound comprises two peptide chains which may be covalenty linked, e.g., by one or more disulfide bonds, wherein each peptide chain comprises a portion, e.g., antibody, antibody fragment or DARPin, binding to a primary target and a portion, e.g., antibody or antibody fragment, binding to a tag conjugate. In some embodiments, the antibody fragments are VHH, scFv, or a mixture thereof. In different embodiments, the docking compound or a peptide chain of a docking compound comprises one of the following structures (from N- to C-terminus):

[0846] VHH (a tag conjugate)-optional linker-VHH (a primary target) VHH (a primary targetj-optional linker-VHH (a tag conjugate) VHH (a tag conjugatej-optional linker-scFv (a primary target) scFv (a primary targetj-optional linker-VHH (a tag conjugate) VHH (a primary targetj-optional linker-scFv (a tag conjugate) scFv (a tag conjugatej-optional linker-VHH (a primary target) scFv (a tag conjugatej-optional linker-scFv (a primary target) scFv (a primary target)-optional linker-scFv (a tag conjugate)

[0847] The present disclosure provides in one aspect, a docking compound as described herein. In some embodiments, the docking compound comprises a bispecific molecule, such as a bispecific polypeptide, e.g., a bispecific antibody, wherein one specificity binds (monovalently, bivalenty or with even more valency) to an epitope tag, e.g., an ALFA-tag and the other specificity binds (monovalently, bivalenty or with even more valency) to a primary target, e.g., a cell surface antigen on target cells. In some embodiments, the specificity which binds to an epitope tag is an antibody or antibody fragment such as an NbALFA-nanobody (NbALFA). In some embodiments, the specificity which binds to a primary target is an antibody, antibody fragment or DARPin. In some embodiments, the moiety targeting a primary target of the docking compound is selected from the group consisting of an anti-primary target DARPin, an anti-primary target VHH and an anti-primary target scFv and / or the moiety binding to a tag conjugate of the docking compound is an NbALFA-nanobody (NbALFA). In some embodiments, the docking compound has a structure selected from the group consisting of NbALFA x antiprimary target DARPin, NbALFA x anti-primary target VHH and NbALFA x anti-primary target scFv. In some embodiments, the primary target is a cancer antigen. In some embodiments, the docking compound comprises a bispecific antibody comprising a nanobody which binds to an epitope tag, e.g., an ALFA-tag, and an anti-cancer antigen VHH. In some embodiments, the docking compound comprises a bispecific antibody comprising a nanobody which binds to an epitope tag, e.g., an ALFA-tag, and an anti-cancer antigen scFv. In some embodiments, the docking compound comprises a bispecific molecule comprising a nanobody which binds to an epitope tag, e.g., an ALFA-tag, and an anti-cancer antigen DARPin. In some embodiments, a docking compound may be provided by administering to a subject nucleic acid encoding the docking compound and allowing expression of the docking compound by cells of the subject. Delivery of nucleic acid encoding a docking compound to target cells for expression may be effected by using particles comprising the nucleic acid. The particles may comprise a targeting molecule that binds to a target, e.g., an antigen on target cells, for expression. In some embodiments, the docking compound is secreted from the cells expressing the nucleic acid. In some embodiments, the docking compound comprises a signal peptide, e.g., an N-terminal signal peptide, which allows secretion of the docking compound from the cell expressing the nucleic acid. In some embodiments, the cells expressing the nucleic acid are the same cells as those to which a payload is to be delivered herein. In some embodiments, the cells expressing the nucleic acid are different to the cells to which a payload is to be delivered herein. In some embodiments, the cells expressing the nucleic acid are liver cells. In some embodiments, the cells expressing the nucleic acid secrete the docking compound into the bloodstream. In some preferred embodiments, the nucleic acid encoding the docking compound is RNA. The RNA-encoded docketing compound is also called "RiboDocker" herein.

[0848] Tag conjugate

[0849] The tag conjugate described herein comprises a payload to be delivered and one or more tags for binding by the docking compound. The one or more tags of the tag conjugate thus are the part of the tag conjugate that forms the binding partner for the docking compound. Generally, the one or more tags of the tag conjugate are covalently attached to the payload moiety in a manner such that they are available for binding to the docking compound.

[0850] A tag conjugate described herein comprises at least one tag, e.g., at least two tags.

[0851] In some embodiments, a tag conjugate described herein comprises a single tag, preferably a single ALFA-tag and preferably comprises a single payload moiety as specified herein. In some embodiments, a tag conjugate described herein comprises a single tag, preferably a single ALFA-tag and comprises two payload moieties as specified herein.

[0852] In some embodiments, a tag conjugate described herein comprises 2, 3, 4, 5, 6, 7, 8 or even more tags, which tags may be identical or different. In some embodiments, the tags of a tag conjugate described herein are identical. In some embodiments, a tag conjugate described herein comprises partially or completely different tags, but the one or more binding moieties for a tag of a docking compound bind to the different tags. In some embodiments, each of the tags of a tag conjugate described herein comprises an ALFA-tag. In some embodiments, a tag conjugate described herein comprises one tag, preferably one ALFA-tag. In some embodiments, a tag conjugate described herein comprises two tags, preferably two ALFA- tags. In some embodiments, a tag conjugate described herein comprises two identical tags, preferably two identical ALFA-tags.

[0853] In some embodiments, the one or more tags of the tag conjugate comprise a peptide or protein (e.g., peptide tags).

[0854] In some embodiments, the one or more tags of the tag conjugate comprise a peptide or protein (e.g., peptide tags) and are chemically linked, e.g., through a linker, to the payload moiety.

[0855] A tag conjugate further comprises a moiety, termed "payload moiety" or "payload" herein, that is capable of attracting, providing or bringing about the desired effect, e.g., therapeutic effect. The tags and the payload moiety may be covalently or non-covalently linked.

[0856] In some embodiments, the tag conjugate comprises a polymer. In some embodiments, the payload moiety of the tag conjugate and the one or more tags of the tag conjugate are connected through a linker comprising the polymer.

[0857] In some embodiments, the polymer is not a polymer of proteinogenic amino acids or their D- isomers. In some embodiments, the polymer is a hydrophilic polymer. In some embodiments, the polymer portion of the tag conjugate contributes to conferring stealth properties on the tag conjugate. In some embodiments, the plasmatic half-life of the tag conjugate described herein is greater than 2 hours, e.g., between 3 and 10 hours. This characteristic advantageously allows the tag conjugate to accumulate at the target cells and to liberate therein their contents (payload) within reasonable amounts of time. The effectiveness of the targeted delivery described herein therefore increases as a result.

[0858] The term "stealth" is used herein to describe the ability of the particles described herein not to be detected and then sequestered and / or degraded, or to be hardly detected and then sequestered and / or degraded, and / or to be detected and then sequestered and / or degraded late, by the immune system of the host to which they are administered.

[0859] Macrophages constitute one of the most important components of the immune system and play a predominant role in eliminating foreign particles, including liposomes and other colloidal particles, from the blood circulation. At the molecular level, the clearance of particles takes place in two steps: opsonization by the depositing of serum proteins (or "opsonins") at the surface of the particles followed by recognition and capture of the opsonized particles by macrophages.

[0860] Modification of the surface of particles with chains of hydrophilic and flexible polymers, e.g., polymers of the polyethylene glycol) type, confers them a steric protection by preventing the opsonins reaching the surface of the particles.

[0861] In some embodiments, the polymer for use herein is selected from the group consisting of polyethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) (including derivatives thereof).

[0862] In some embodiments, a polymer is designed to sterically stabilize a tag conjugate by forming a protective hydrophilic layer. In some embodiments, a polymer can reduce association of a tag conjugate with serum proteins and / or the resulting uptake by the reticuloendothelial system when such tag conjugates are administered in vivo.

[0863] In some embodiments, the PEG is an optionally substituted linear or branched polymer of ethylene glycol or ethylene oxide. In some embodiments, the PEG is unsubstituted. In some embodiments, the PEG is substituted, e.g., by one or more alkyl, alkoxy, acyl, hydroxy or aryl groups. In some embodiments, the PEG has a molecular weight of from about 130 to about 50,000, in another embodiment about 150 to about 30,000, in another embodiment about 150 to about 20,000, in another embodiment about 150 to about 15,000, in another embodiment about 150 to about 10,000, in another embodiment about 150 to about 6000, in another embodiment about 150 to about 5000, in another embodiment about 150 to about 4000, in another embodiment about 150 to about 3000, in another embodiment about 300 to about 3000, in another embodiment about 1000 to about 3000, and in still another embodiment about 1500 to about 2500.

[0864] In some embodiments, the PEG moiety has a molecular weight of 1000 or more. In some embodiments, the PEG moiety comprises 10 units or more of formula (O-CH2-CH2)n. In some embodiments, the PEG comprises from 20 to 200 ethylene oxide units, such as about 45 ethylene oxide units.

[0865] In some embodiments, the PEG comprises "PEG2k", also termed "PEG 2000", which has an average molecular weight of about 2000 Daltons.

[0866] In some embodiments, PEG2000, PEG3000 and PEG5000 are used as the polymer. In some embodiments, a pSar comprises between 2 and 200 sarcosine units, such as between 5 and 100 sarcosine units, between 10 and 50 sarcosine units, between 15 and 40 sarcosine units, e.g., about 23 sarcosine units.

[0867] In some embodiments, a pSar comprises the structure of the following general formula: wherein s is the number of sarcosine units.

[0868] In some embodiments, the POX and / or POZ polymer comprises between 2 and 200, between 2 and 190, between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70 POX and / or POZ repeating units.

[0869] In some embodiments, the POX and / or POZ polymer comprises the following general formula: wherein a is an integer between 1 and 2; Rn is alkyl, in particular C1-3 alkyl, such as methyl, ethyl, iso-propyl, or n-propyl, and is independently selected for each repeating unit; and m refers to the number of POX and / or POZ repeating units.

[0870] In some embodiments, the POX and / or POZ polymer is a polymer of POX and comprises repeating units of the following general formula: In some embodiments, the POX and / or POZ polymer is a polymer of POZ and comprises repeating units of the following general formula:

[0871] In any of the above embodiments of formulas, m (i.e., the number of repeating units in the polymer) preferably is between 2 and 190, such as between 2 and 180, between 2 and 170, between 2 and 160, between 2 and 150, between 2 and 140, between 2 and 130, between 2 and 120, between 2 and 110, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 5 and 200, between 5 and 190, between 5 and 180, between 5 and 170, between 5 and 160, between 5 and 150, between 5 and 140, between 5 and 130, between 5 and 120, between 5 and 110, between 5 and 100, between 5 and 90, between 5 and 80, between 5 and 70, between 10 and 200, between 10 and 190, between 10 and 180, between 10 and 170, between 10 and 160, between 10 and 150, between 10 and 140, between 10 and 130, between 10 and 120, between 10 and 110, between 10 and 100, between 10 and 90, between 10 and 80, or between 10 and 70. In certain embodiments, m is

[0872] 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50.

[0873] In some embodiments, the POX and / or POZ polymer is a copolymer comprising repeating units of the following general formulas: wherein the number of repeating units shown on the left in the copolymer is 1 to 199; the number of repeating units of formula on the right in the copolymer is 1 to 199; and the sum of the number of repeating units of formula on the left and the number of repeating units of formula on the right in the copolymer is 2 to 200.

[0874] In some embodiments, the number of repeating units of formula on the left in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; the number of repeating units of formula on the right in the copolymer is 1 to 179, such as 1 to 159, 1 to 139, 1 to 119 or 1 to 99; and the sum of the number of repeating units of formula on the left and the number of repeating units of formula on the right in the copolymer is 2 to 180, such as 4 to 160, 6 to 140, 8 to 120 or 10 to 100, e.g., 20 to 80, 30 to 70, or 40 to 50. In some of the above embodiments, Rn at each occurrence (i.e., in each repeating unit) may be the same alkyl group (e.g., Rn may be methyl in each repeating unit). In some alternative embodiments, Rn in at least one repeating unit differs from Rn in another repeating unit (e.g., for at least one repeating unit Rn is one specific alkyl (such as ethyl), and for at least one different repeating unit Rn is a different specific alkyl (such as methyl)). For example, each Rn may be selected from two different alkyl groups (such as methyl and ethyl) and not all Rn are the same alkyl.

[0875] In any of the above embodiments, Rn preferably is methyl or ethyl, more preferably methyl. Thus, in some embodiments, each Rn is methyl or each Rn is ethyl. In some alternative embodiments, Rn is independently selected from methyl and ethyl for each repeating unit, wherein in at least one repeating unit Rn is methyl, and in at least one repeating unit Rn is ethyl.

[0876] In some embodiments, the polymer comprises poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or poly-2-(2-(2-methylaminoethoxy)ethoxy)acetic acid (pMAEEA), or a derivative thereof.

[0877] In some embodiments, the polymer comprises the following general formula: wherein

[0878] X2and X1taken together are optionally substituted amide, optionally substituted thioamide ester, or thioester;

[0879] Y is -CH2-, -(CH2)2-, or -(CH2)3-; z is 2 to 24; and n is the number of repeating units, e.g., 1 to 100.

[0880] In some embodiments,

[0881] (i) when X1is -C(O)- then X2is -NR1-;

[0882] (ii) when X1is -NR1- then X2is -C(O)-;

[0883] (iii) when X1is -C(S)- then X2is -NR1-;

[0884] (iv) when X1is -NR1- then X2is -C(S)-;

[0885] (v) when X1is -C(O)- then X2is -O-;

[0886] (vi) when X1is -O- then X2is -C(O)-; (vii) when X1is -C(S)- then X2is -0-;

[0887] (viii) when X1is -0- then X2is -C(S)-;

[0888] (ix) when X1is -C(0)- then X2is -S-; or

[0889] (x) when X1is -S- then X2is -C(0)-; wherein R1is hydrogen or Ci-8 alkyl; preferably

[0890] (i) when X1is -C(0)- then X2is -NR1-;

[0891] (ii) when X1is -NR1- then X2is -C(0)-;

[0892] (iii) when X1is -C(S)- then X2is -NR1-;

[0893] (iv) when X1is -NR1- then X2is -C(S)-;

[0894] (v) when X1is -C(0)- then X2is -0-; or

[0895] (vi) when X1is -0- then X2is -C(0)-; wherein R1is hydrogen or Ci-8 alkyl.

[0896] In some embodiments, X1is -C(0)- and X2is -NR1-, wherein R1is hydrogen or Ci-8 alkyl. In some embodiments, X1is -C(0)- and X2is -NR1-, wherein R1is hydrogen or methyl. In some embodiments, X1is -C(0)- and X2is -NR1-, wherein R1is hydrogen.

[0897] In some embodiments, Y is -CH2- or -(CHih-- In some embodiments, Y is -CH?-.

[0898] In some embodiments, the polymer comprises the following general formula: wherein

[0899] R1is hydrogen or C1-8 alkyl; z is 2 to 24; and n is the number of repeating units, e.g., 1 to 100.

[0900] In some embodiments of the above formulas, z is 2 to 10. In some embodiments, z is 2 to 7. In some embodiments, z is 2 to 5. In some embodiments, z is 2 or 3. In some embodiments, z is 2.

[0901] In some embodiments, the polymer comprises the following general formula: R1is hydrogen or Ci-s alkyl; and n is the number of repeating units, e.g., 1 to 100.

[0902] In some embodiments of the above formulas, R1is hydrogen or methyl. In some embodiments, R1is hydrogen.

[0903] In some embodiments, the polymer comprises the following general formula: wherein n is the number of repeating units, e.g., 1 to 100.

[0904] In some embodiments of the above formulas, n is 2 to 50. In some embodiments, n is 4 to 25. In some embodiments, n is 6 to 20. In some embodiments, n is 8 to 16. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, n is

[0905] 2, 4, 6, 8, 10, or 12. In some embodiments, n is 2, 4, or 6.

[0906] In some embodiments, a tag conjugate comprises one or more tags and one or more payload moieties in an unbranched arrangement.

[0907] In some embodiments, a tag conjugate comprises the formula:

[0908] P-L-T wherein

[0909] P comprises a payload moiety as specified herein;

[0910] T comprises a tag; and

[0911] L comprises a linking moiety.

[0912] In some embodiments, L comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0913] In some embodiments, a tag conjugate comprises the formula:

[0914] P-LA-T-LB-T or

[0915] P-LA-T-LB-T-LC-P wherein

[0916] P comprises a payload moiety as specified herein;

[0917] T comprises a tag;

[0918] LA comprises a linking moiety; LB comprises a linking moiety; and

[0919] Lc comprises a linking moiety.

[0920] In some embodiments, one or more of LA, LB, and Lc comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0921] In some embodiments, LB comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0922] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30, e.g., between 2 and 10, such as 2, 4 or 6. In some embodiments, the poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof comprises poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or poly-2- (2-(2-methylaminoethoxy)ethoxy)acetic acid (pMAEEA), or a derivative thereof. In some embodiments, the poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof comprises the following general formula: wherein n is between 2 and 30, e.g., between 2 and 10, such as 2, 4 or 6.

[0923] In some embodiments, a tag conjugate comprises the formula:

[0924] P-LA-T-LB-T or

[0925] P-LA-T-LB-T-LC-P wherein

[0926] P comprises a payload moiety as specified herein;

[0927] T comprises a tag;

[0928] LA comprises a linking moiety;

[0929] LB comprises a linking moiety; and

[0930] Lc comprises a linking moiety.

[0931] In some embodiments, one or more of LA, LB, and Lc comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0932] In some embodiments, LB comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, LA and / or Lc comprise a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0933] In some embodiments, LA and / or Ledo not comprise a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0934] In some embodiments, LA and / or Lc comprise an enzymatic cleavage site.

[0935] In some embodiments, one or more of LA, LB, and Lc comprises the formula [AEEA]U-[LD- [AEEA]V]W, wherein

[0936] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0937] LD comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [LD-[AEEA]V] may be identical or different.

[0938] In some embodiments, LB comprises the formula [AEEA]U-[LD-[AEEA]V]W, wherein

[0939] AEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;

[0940] LD comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [LD-[AEEA]V] may be identical or different.

[0941] In some embodiments, u and v are each integers from 2 to 10.

[0942] In some embodiments, u and v are each integers from 2 to 8.

[0943] In some embodiments, u and v are each integers of 2, 4 or 6.

[0944] In some embodiments, LD comprises an amino acid.

[0945] In some embodiments, LD comprises the D-isomer of an amino acid.

[0946] In some embodiments, LD comprises cysteine or lysine.

[0947] In some embodiments, Lois connected to a side chain.

[0948] In some embodiments, a side chain comprises a functional moiety. In some embodiments, a functional moiety comprises a solubilizing functional group.

[0949] In some embodiments, a tag conjugate comprises a branching moiety to which the tags and the payload moieties are connected through a linking moiety.

[0950] The term "branching moiety" refers to a chemical moiety, e.g., an amino acid or polymer such as a peptide, that provides the functional groups for linking to the tags, e.g., via a linking moiety comprising a polymer as described herein, and provides the functional group(s) for linking to the payload moiety / moieties, e.g., via a linking moiety which may comprise a polymer as described herein. Thus, a tag conjugate described herein may comprise several arms which are connected by a branching moiety. In some embodiments, a tag conjugate described herein comprises two arms ending in a tag, and one or more arms ending in a payload moiety.

[0951] In some embodiments, the term "branching moiety" refers to a chemical moiety in an arm ending in a payload moiety which provides the functional groups for linking, e.g., via a linking moiety, more than one payload moiety and / or further functional groups to the arm.

[0952] In some embodiments, at least one of the linking moieties connecting a tag to the branching moiety comprises a polymer as described above. In some embodiments, each of the linking moieties connecting a tag to the branching moiety comprises a polymer as described above. In some embodiments, at least one of the linking moieties connecting a payload moiety to the branching moiety comprises a polymer as described above. In some embodiments, each of the linking moieties connecting a payload moiety to the branching moiety comprises a polymer as described above.

[0953] In some embodiments, a tag conjugate comprises the formula:

[0954] [P-La]2-B-Lt-T wherein

[0955] P comprises a payload moiety as specified herein;

[0956] B comprises a branching moiety;

[0957] T comprises a tag;

[0958] La comprises a linking moiety; and

[0959] Lt comprises a linking moiety; wherein the different groups [P-La] may be identical or different, and the different groups P may be identical or different.

[0960] In some embodiments, the valency of B corresponds to or is greater than 3. In some embodiments, B comprises an amino acid or bis-amino acid.

[0961] In some embodiments, B comprises the D-isomer of an amino acid.

[0962] In some embodiments, B comprises cysteine or lysine.

[0963] In some embodiments, Lacomprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, cysteine, or a combination thereof.

[0964] In some embodiments, Lacomprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0965] In some embodiments, Lacomprises an enzymatic cleavage site.

[0966] In some embodiments, Lacomprises a moiety which is substituted by a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the moiety which is substituted by a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is an amino acid. In some embodiments, the amino acid which is substituted by a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is cysteine.

[0967] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais between 2 and 30.

[0968] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais between 2 and 10.

[0969] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Lais 2, 4 or 6.

[0970] In some embodiments, Lais substituted with a solubilizing functional group. In some embodiments, Lacomprises an amino acid which is substituted with a solubilizing functional group. In some embodiments, the amino acid which is substituted with a solubilizing functional group is lysine or cysteine.

[0971] In some embodiments, Lt comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof. In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

[0972] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

[0973] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6.

[0974] In some embodiments, Ltcomprises one or more selected from the group consisting of a moiety constraining conformation, a moiety for albumin binding, a moiety which increases circulation time, a moiety which reduces renal retention or uptake and an enzymatic cleavage site.

[0975] In some embodiments, a tag conjugate comprises the formula:

[0976] [[P]m-Li]n-Bi-[L2-T]0wherein

[0977] P comprises a payload moiety as specified herein;

[0978] Bi comprises a branching moiety;

[0979] T comprises a tag;

[0980] Li comprises a linking moiety;

[0981] L2 comprises a linking moiety; m is an integer from 1 to 4; n is an integer from 1 to 4; and o is an integer from 2 to 4; wherein the different groups [L2-T] may be identical or different, the different groups P may be identical or different, and the different groups [[P]m-Li] may be identical or different. in some embodiments, the valency of Bi corresponds to or is greater than the sum of n and o. In some embodiments, Bi comprises an amino acid or bis-amino acid. In some embodiments, bivalent amino acid conjugates are obtainable via an intermolecular cycloaddition ("click") reaction using amino acid derived azides and alkynes as building blocks.

[0982] In some embodiments, Bi comprises the D-isomer of an amino acid.

[0983] In some embodiments, Bi comprises cysteine or lysine. In some embodiments, Li comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0984] In some embodiments, L? comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0985] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30, e.g., between 2 and 10, such as 2, 4 or 6. In some embodiments, the poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof comprises poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or poly-2- (2-(2-methylaminoethoxy)ethoxy)acetic acid (pMAEEA), or a derivative thereof. In some embodiments, the poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof comprises the following general formula: wherein n is between 2 and 30, e.g., between 2 and 10, such as 2, 4 or 6.

[0986] In some embodiments, L2 comprises (i) a moiety comprising cysteine and (ii) a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, wherein the poly-2- (2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or derivative thereof and T are linked by the moiety comprising cysteine.

[0987] In some embodiments, [[P]m-Li] comprises the formula [[P-Li']m-B2-Lr], wherein

[0988] B2 comprises a branching moiety;

[0989] Lr comprises a linking moiety;

[0990] Lr comprises a linking moiety; and m is an integer from 1 to 4; wherein the different groups [[P-Li ]m-B2-Lr ] may be identical or different, and wherein in a group [[P- Li ]m-B2-Li") the different groups [P-Lr] may be identical or different.

[0991] In some embodiments, the valency of B2 corresponds to or is greater than the value of m plus 1.

[0992] In some embodiments, B2 comprises an amino acid. In some embodiments, B2 comprises the D-isomer of an amino acid.

[0993] In some embodiments, B2 comprises cysteine or lysine.

[0994] In some embodiments, Li- comprises a 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof, cysteine, or a combination thereof.

[0995] In some embodiments, Lr comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

[0996] In some embodiments, the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof in Li " is between 2 and 30, e.g., between 2 and 10, such as 2, 4 or 6. in some embodiments, the poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof comprises poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or poly-2- (2-(2-methylaminoethoxy)ethoxy)acetic acid (pMAEEA), or a derivative thereof. In some embodiments, the poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof comprises the following general formula: wherein n is between 2 and 30, e.g., between 2 and 10, such as 2, 4 or 6.

[0997] In some embodiments of the formula [[P]m-Li]n-Bi-[L2-T]0, or [[P-Li’]m-B2-Li"]n-Bi-[L2-T]0, m is an integer from 1 to 3, n is an integer from 1 to 3, and o is 2 or 3.

[0998] In some embodiments, o is 2.

[0999] In some embodiments, n is 1 or 2.

[1000] In some embodiments, m is 1 or 2.

[1001] In some embodiments, o is 2, n is 1 and m is 1. In these embodiments, the docking compound may comprise a single binding moiety for the tag.

[1002] In some embodiments, the tag conjugate comprises the formula:

[1003] P-LI-BI-[L2-T]2wherein

[1004] P comprises a payload moiety as specified herein;

[1005] Bi comprises a branching moiety; T comprises a tag;

[1006] Li comprises a linking moiety; and

[1007] L? comprises a linking moiety; wherein the different groups [L2-T] may be identical or different.

[1008] In some embodiments, the tag conjugate comprises the formula:

[1009] P-[AEEA]p-Bi-[[AEEA]q-R-[AEEA]r-C-T]2 wherein

[1010] P comprises a payload moiety as specified herein;

[1011] Bi comprises a branching moiety;

[1012] R is optional and comprises a moiety constraining conformation;

[1013] C is optional and comprises a connecting moiety;

[1014] T comprises a tag; p is an integer from 0 to 6; q is an integer from 1 to 4; and r is an integer from 1 to 4; wherein the different groups [[AEEA]q-R-[AEEA]r-C-T] may be identical or different.

[1015] In some embodiments, o is 2, n is 2 and m is 2. In these embodiments, the docking compound may comprise at least two binding moieties for the tag, e.g., two binding moieties for the tag. In some embodiments, the tag conjugate comprises the formula: [[P-L1']2-B2-L1"]2-B1-[L2-T]2 wherein

[1016] P comprises a payload moiety as specified herein;

[1017] Bi comprises a branching moiety;

[1018] B2 comprises a branching moiety;

[1019] T comprises a tag;

[1020] Lr comprises a linking moiety;

[1021] Li" comprises a linking moiety; and

[1022] L2 comprises a linking moiety; wherein the different groups [[P-L1J2-B2-L1"] may be identical or different, wherein in a group [[P-LI ]2- B2-L1 "] the different groups [P-Li ] may be identical or different, and the different groups [L2- T] may be identical or different.

[1023] In some embodiments, the tag conjugate comprises the formula: [[P-Lr]2-B2-[AEEA]5]2-B1-[[AEEA]t-T]2wherein

[1024] P comprises a payload moiety as specified herein;

[1025] Bi comprises a branching moiety;

[1026] B2comprises a branching moiety;

[1027] T comprises a tag;

[1028] Li- comprises a linking moiety; s is an integer from 2 to 8; and t is an integer from 2 to 8; wherein the different groups [(P-Lr]2-B2-[AEEA]S] may be identical or different, wherein in a group [[P- LI']2-B2-[AEEA]S] the different groups [P-Li ] may be identical or different, and the different groups [[AEEA]t-T] may be identical or different.

[1029] In some embodiments of all tag conjugates described above, the payload comprises the STING agonist of Formula (XX).

[1030] In some embodiments of all tag conjugates described above, the payload comprises the STING agonist of Formula (XXH) or (XXK).

[1031] In some embodiments of all tag conjugates described above, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX).

[1032] In some embodiments of all tag conjugates described above, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK).

[1033] In some embodiments of all tag conjugates described above, the payload moiety comprises a STING agonist moiety having the Formula (XX- 18’), (XX-6'), (XX-511), (XX-531), (XX-73'a), or (XX- 73'b).

[1034] In some embodiments of all tag conjugates described above, the tag is an ALFA-tag, e.g., a cyclic ALFA-tag.

[1035] In some embodiments of all tag conjugates described above, the payload comprises the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[1036] In some embodiments of all tag conjugates described above, the payload comprises the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag. In some embodiments of all tag conjugates described above, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[1037] In some embodiments of all tag conjugates described above, the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH) or (XXK), and the tag is an ALFA- tag, preferably a cyclic ALFA-tag.

[1038] In some embodiments of all tag conjugates described above, the payload moiety comprises a STING agonist moiety having the Formula (XX-181), (XX-6'), (XX-51'), (XX-53’), (XX-73'a), or (XX- 73'b), and the tag is an ALFA-tag, preferably a cyclic ALFA-tag.

[1039] In some embodiments of all tag conjugates described above, the tag conjugate comprises a structure of a compound shown herein as any one of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICH), EX-M60 to EX-M121 (in particular, EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15)), EX-B122 to EX-B132 (in particular, EX-B122 (PIC18)), EX-B133 (PIC19), EX-024 to EX-035, EX-032 to EX-035, and EX-047 to EX-054. In some embodiments, the tag conjugate comprises a structure of a compound shown herein as any one of SD18317 (PICS), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICll), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX- 6133 (PIC19), or the tag conjugate is selected from the group consisting of SD18317 (PIC8), SD17248, PIC12, PIC13, PIC14, SD17247 (PIC6), SD17553, SD17453 (PIC2), SD17516 (PIC1), SD17537 (PIC3), SD18319 (PIC9), SD18320 (PIC10), SD18321 (PIC7), SD18322 (PICH), EX-M69 (PIC16), EX-M71 (PIC17), EX-M74 (PIC15), EX-B122 (PIC18), and EX-B133 (PIC19). In some preferred embodiments, the tag conjugate comprises a structure of a compound shown herein as any one of SD18321 (PIC7) and SD18317 (PIC8), or the tag conjugate is selected from the group consisting of SD18321 (PIC7) and SD18317 (PIC8). In some particularly preferred embodiments, the tag conjugate comprises a structure of a compound shown herein as SD18321 (PIC7), or the tag conjugate is SD18321 (PIC7).

[1040] The present disclosure provides in one aspect, a tag conjugate as described above. Interacting moieties on the tag conjugate and on the docking compound

[1041] In some embodiments, the moiety on the tag conjugate, i.e., the one or more tags, and the moiety on the docking compound interacting with each other non-covalently bind to each other.

[1042] In some embodiments, the moieties on the tag conjugate and on the docking compound interacting with each other bind to each other under physiological conditions.

[1043] In some embodiments, the moieties on the tag conjugate and on the docking compound interacting with each other are antigen / antibody systems.

[1044] In some embodiments, the moiety of the tag conjugate binding to the docking compound comprises a peptide or protein, e.g., a peptide tag, and the moiety of the docking compound binding to the tag conjugate comprises a binder, e.g., an antibody or antibody fragment, binding to the peptide or protein.

[1045] In some embodiments, the moieties on the tag conjugate and on the docking compound interacting which each other comprise an epitope tag / binder system.

[1046] As used herein, an "epitope tag" refers to a stretch of amino acids to which an antibody or proteinaceous molecule with antibody-like function can bind.

[1047] In some embodiments, the epitope tag comprises an ALFA-tag. In some embodiments, the epitope tag / binder system comprises an ALFA-tag and an ALFA-specific single-domain antibody (sdAb), NbALFA-nanobody.

[1048] The use of an ALFA-tag / ALFA-specific sdAb system is particularly advantageous in the context of the present disclosure. It will be possible to select an ALFA-tag with a suitable affinity to the sdAb for the respective application.

[1049] In embodiments where the tag conjugate comprises a total number of one tag, it is preferred that the tag is a high affinity tag, such as a high affinity ALFA-tag. For example, in applications which profit from a tight binding between the docking compound and the tag conjugate, a high affinity tag, such as a high affinity ALFA-tag, can be selected. In such embodiments, it can also be preferred to use a tag conjugate that has at least two tags and a docking compound that has at least two binding moieties for a tag, wherein the tag is preferably a high affinity tag. The effect of two tags in one compound binding to two binding moieties for a tag in another compound may lead to even tighter binding. This "two-on-two" binding between a docking compound and a tag conjugate can be particularly advantageous in applications, where circulation of free tag-conjugates should be minimized, for example to avoid off-target effects of the free tag-conjugate or to increase the half-live of the tag-conjugate in circulation. Epitope tag / binder systems with suitable affinities are described herein.

[1050] In other applications that leverage the avidity effect of the tag conjugates described herein only at the target side, a comparably lower affinity tag (a medium / low affinity tag), such as a medium / low affinity ALFA-tag, may be preferred to increase the avidity effect at the target site, for example at a tumor cell. In such embodiments, it can also be preferred to use a tag conjugate that has at least two tags and a docking compound that has a single binding moiety for a tag, wherein the tag is preferably a medium / low affinity tag. In such embodiments, a target site (e.g., target cells) with a high density of target antigen will lead to binding of docking compounds (e.g., with one tag-binding moiety) in close proximity to each other. Due to this proximity, the tag conjugates comprising two tags will preferably bind to the docking compounds at the target site, due to an avidity effect resulting from the proximity of two tagbinding moieties of two docking compounds at the target site or on the target cells. Binding to single docking compounds at sides of lower docking compound proximity (e.g. in circulation or at sides of target-unspecific docking compound deposition) is less likely. Epitope tag / binder systems that can be used in the context of the present invention taking advantage of the avidity effect are disclosed herein.

[1051] One main advantage of this avidity effect is that off-target binding of free tag-conjugates comprising two tags can be minimized while a target-sepcific accumulation of the tagconjugates occurs on target cells with a high density of bound docking compounds comprising one tag-binding moiety.

[1052] In some embodiments, the affinity of WT ALFA (Ac-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-Arg- Leu-Thr-Glu-NHz) to NbALFA is used as a reference point. In some embodiments, a high affinity tag (e.g., high affinity Alfa-tag) is characterized by having a value of dissociation from a particular binding partner (e.g., NbAlfa), such as measured by kdis, that, relative to the corresponding value of the corresponding wild-type tag (e.g., Alfa-tag), is 5 or less, e.g., 4 or less, 3 or less, 2 or less, or 1 or less. In other words, in some embodiments, the ratio kdis (high affinity tag) / kdis (wild-type tag) is 5 or less, e.g., 4 or less, 3 or less, 2 or less, or 1 or less. In some embodiments, a medium / low affinity tag (e.g., medium / low affinity Alfa-tag) is characterized by having a value of dissociation from a particular binding partner (e.g., NbAlfa), such as measured by kdis, that, relative to the corresponding value of the corresponding wildtype tag (e.g., Alfa-tag), is more than 5, e.g., more than 6, more than 7, or more than 8. In other words, in some embodiments, the ratio kdis (medium / low affinity tag) / kdiS(wild-type tag) is more than 5, e.g., more than 6, more than 7, or more than 8. In some embodiments, affinities are determined by biolayer interferometry (BLI).

[1053] In some embodiments it is also possible to select a tag / binder system with suitable binding properties, such as suitable kdis, that is different from the ALFA-tag / ALFA-specific sdAb system by using WT ALFA as a reference.

[1054] Examples of high affinity tags are

[1055] - Ac-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-Arg-Leu-Thr-Glu-NH2,

[1056] Ac-Ser-Arg-Leu-Glu-(cyclo5)Glu-Glu-Leu-(cyclo8)Lys-Arg-Arg-Leu-Thr-Glu-NH2,

[1057] - Ac-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-(cyclo9)Lys-Arg-Leu-Thr-(cyclol3)Glu-NH2, Ac-Ser-Arg-Leu-Glu-(cyclo5)Glu-Glu-Leu-Arg-(cyclo9)Lys-Arg-Leu-Thr-Glu-NH2,

[1058] - Ac-Pro-Ser-Arg-Leu-Glu-(cyclo6)Glu-Glu-Leu-Arg-(cyclolO)Lys-Arg-Leu-Thr-Glu-NH2.

[1059] Examples of medium / low affinity tags are

[1060] - Ac-Ser-Arg-Leu-Glu-(cyclo5)Asp-Glu-Leu-Arg-(cyclo9)Lys-Arg-Leu-Thr-Glu-NH2,

[1061] - Ac-Pro-Ser-Arg-Leu-Glu-(cyclo6)Lys-Glu-Leu-Arg-(cyclolO)Glu-Arg-Leu-Thr-Glu-NH2,

[1062] - Ac-Pro-Ser-Arg-Leu-(cyclo5)Glu-Glu-Glu-Leu-(cyclo9)Lys-Arg-Arg-Leu-Thr-Glu-NH2.

[1063] Based on the provided examples of high and medium / low affinity tags and the provided method of determining the suitability of an epitope tag / binder system for the respective application a skilled person can select a suitable system.

[1064] In some embodiments, an ALFA-tag comprises the amino acid sequence

[1065] -AA0-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-AA10-AA11-AA12-AA13-AA14-, wherein the amino acids of AAO, AA1, AA2, AA3, AA4, AA5, AA6, AA7, AA8, AA9, AA10, AA11, AA12, AA13 and AA14 are:

[1066] AAO is Pro or deleted;

[1067] AA1 is Ser, Gly, Thr, or Pro;

[1068] AA2 is Arg, Gly, Ala, Glu, or Pro;

[1069] AA3 is Leu, He, or Vai;

[1070] AA4 is Glu or Gin;

[1071] AA5 is Glu or Gin;

[1072] AA6 is Glu or Gin;

[1073] AA7 is Leu, He, or Vai;

[1074] AA8 is Arg, Ala, Gin, or Glu; AA9 is Arg, Ala, Gin, or Glu;

[1075] AA10 is Arg;

[1076] AA11 is Leu;

[1077] AA12 is Thr, Ser, Asp, Glu, Pro, Ala, or deleted;

[1078] AA13 is Glu, Lys, Pro, Ser, Ala, Asp, or deleted; and

[1079] AA14 is Pro or deleted.

[1080] In some embodiments, an ALFA-tag comprises a sequence selected from the group consisting of SRLEEELRRRLTE, PSRLEEELRRRLTE, SRLEEELRRRLTEP, and PSRLEEELRRRLTEP.

[1081] In some embodiments, an ALFA-tag comprises the cyclized amino acid sequence -AA0-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-AA10-AA11-AA12-AA13-AA14-, wherein the side-chains of any two of the amino acids of AAO, AA1, AA2, AA3, AA4, AA5, AA6, AA7, AA8, AA9, AA10, AA11, AA12, AA13 and AA14 (XI, X2) are connected covalently; and wherein the amino acids of AAO, AA1, AA2, AA3, AA4, AA5, AA6, AA7, AA8, AA9, AA10, AA11, AA12, AA13 and AA14 which are not XI and X2 are: AAO is Pro or deleted;

[1082] AA1 is Ser, Gly, Thr, or Pro;

[1083] AA2 is Arg, Gly, Ala, Glu, or Pro;

[1084] AA3 is Leu, lie, or Vai;

[1085] AA4 is Glu or Gin;

[1086] AA5 is Glu or Gin;

[1087] AA6 is Glu or Gin;

[1088] AA7 is Leu, lie, or Vai;

[1089] AA8 is Arg, Ala, Gin, or Glu;

[1090] AA9 is Arg, Ala, Gin, or Glu;

[1091] AA10 is Arg;

[1092] AA11 is Leu;

[1093] AA12 is Thr, Ser, Asp, Glu, Pro, Ala, or deleted;

[1094] AA13 is Glu, Lys, Pro, Ser, Ala, Asp, or deleted; and AA14 is Pro or deleted.

[1095] In some embodiments, XI and X2 are separated by 2 or 3 amino acids. In some embodiments, AA5 is XI and AA9 is X2, AA5 is XI and AA8 is X2, AA9 is XI and AA13 is X2, AA6 is XI and AA9 is X2, AA9 is XI and AA12 is X2, AA10 is XI and AA13 is X2, AA6 is XI and AA1O is X2 or AA4 is XI and AA8 is X2.

[1096] In some embodiments, an ALFA-tag comprises a cyclized amino acid sequence selected from the group consisting of a. -AA0-AAl-AA2-AA3-AA4-cyclo(Xl-AA6-AA7-AA8-X2)-Arg-Leu-AA12-AA13-AA14-, b. -AA0-AAl-AA2-AA3-AA4-cyclo(Xl-AA6-AA7-X2)-AA9-Arg-Leu-AA12-AA13-AA14-, c. -AA0-AAl-AA2-AA3-AA4-AA5-AA6-AA7-AA8-cyclo(Xl-Arg-Leu-AA12-X2)-AA14-, d. -AA0-AAl-AA2-AA3-AA4-AA5-cyclo(Xl-AA7-AA8-X2)-Arg-Leu-AA12-AA13-AA14-, e. -AA0-AAl-AA2-AA3-AA4-AA5-AA6-AA7-AA8-cyclo(Xl-Arg-Leu-X2)-AA13-AA14-, f. -AA0-AAl-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-cyclo(Xl-Leu-AA12-X2)-AA14-, g. -AA0-AAl-AA2-AA3-AA4-AA5-cyclo(Xl-AA7-AA8-AA9-X2)-Leu-AA12-AA13-AA14-, and h. -AA0-AAl-AA2-AA3-cyclo(Xl-AA5-AA6-AA7-X2)-AA9-Arg-Leu-AA12-AA13-AA14-, wherein the side-chains of Xi and X2 amino acid residues are connected covalently;

[1097] AAO is Pro or deleted;

[1098] AA1 is Ser, Gly, Thr, or Pro;

[1099] AA2 is Arg, Gly, Ala, Glu, or Pro;

[1100] AA3 is Leu, lie, or Vai;

[1101] AA4 is Glu or Gin;

[1102] AA5 is Glu or Gin;

[1103] AA6 is Glu or Gin;

[1104] AA7 is Leu, He, or Vai;

[1105] AA8 is Arg, Ala, Gin, or Glu;

[1106] AA9 is Arg, Ala, Gin, or Glu;

[1107] AA12 is Thr, Ser, Asp, Glu, Pro, Ala, or deleted;

[1108] AA13 is Glu, Lys, Pro, Ser, Ala, Asp, or deleted; and

[1109] AA14 is Pro or deleted.

[1110] In some embodiments, Xi and X? in the peptides disclosed herein are connected covalently via an amide, disulfide, thioether, ether, ester, thioester, thioamide, alkylene, alkenylene, alkynylene, and / or 1,2,3-triazole.

[1111] In some embodiments, a cyclized amino acid sequence described herein is generated by linking an amino group of a side-chain of one of Xi and X2 to the carboxyl group of a side-chain of the other of Xi and X2 via an amide bond. The amino group of the side chain of an amino acid that possesses a pendant amine group, e.g., lysine or a lysine derivative, and the carboxyl group of the side chain of an acidic amino acid, e.g., aspartic acid, glutamic acid or a derivative thereof, can be used to generate a cyclized amino acid sequence via an amide bond.

[1112] In some embodiments, a cyclized amino acid sequence described herein is generated by linking a sulfhydryl group of a side-chain of one of Xi and X2 to the sulfhydryl group of a sidechain of the other of Xi and X2 via a disulfide bond. Sulfhydryl group-containing amino acids include cysteine and other sulfhydryl-containing amino acids as Pen.

[1113] In some embodiments, Xi and X2 are, independently, selected from the group consisting of Glu, DGIu, Asp, DAsp, Lys, DLys, hLys, DhLys, Orn, DOrn, Dab, DDab, Dap, DDap, Cys, DCys, hCys, DhCys, Pen, and DPen, with the proviso that when Xi is Glu, DGIu, Asp, or DAsp, X2 is Lys, DLys, hLys, DhLys, Orn, DOrn, Dab, DDab, Dap, or DDap; when XI is Lys, DLys, hLys, DhLys, Orn, DOrn, Dab, DDab, Dap, or DDap, X2 is Glu, DGIu, Asp, or DAsp; and when XI is Cys, DCys, hCys, DhCys, Pen, or DPen, X2 is Cys, DCys, hCys, DhCys, Pen, or DPen.

[1114] In some embodiments, Xi is Glu and X2 is Lys. In some embodiments, -cyclo(Glu - Lys)-, - c(Glu - Lys)-, -cyclo(E - K)-, -c(E - K)-, -E K- cyclo, or -cycloE— -cycloK- comprises the following structure:

[1115] In some embodiments, Xi is Lys and X2 is Glu. In some embodiments, -cyclo(Lys - Glu)-, - c(Lys - Glu)-, -cyclo(K - E)-, -c(K - E)-, -K - E- cyclo, or cycloK - cycloE- comprises the following structure:

[1116] In some embodiments, Xi is Cys and X2 is Cys. In some embodiments, -cyclo(Cys - Cys)-, -cyclo(C C)-, -c(C - C)-, -C — C- cyclo, or -cycloC cycloC- comprises the following structure:

[1117] Particular cyclized amino acid sequences of the above-identified generic formulas include, for example,

[1118] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1119] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1120] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1121] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Thr-Glu)-,

[1122] -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-,

[1123] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1124] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Thr-Asp)-,

[1125] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1126] -Pro-Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1127] -Pro-Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1128] -Pro-Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1129] -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-,

[1130] -Pro-Ser-Arg-Leu-cyclo(Glu-Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1131] -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-,

[1132] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Thr-Cys)-,

[1133] -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-,

[1134] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-,

[1135] -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Arg-Cys)-Leu-Thr-Glu-,

[1136] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Thr-Cys)-,

[1137] -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-,

[1138] -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-,

[1139] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-,

[1140] -Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Arg-Cys)-Leu-Thr-Glu-,

[1141] -Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1142] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-,

[1143] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DGIu)-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DGIu)-Arg-Leu-Thr-Glu-,

[1144] -Pro-Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1145] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-,

[1146] -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DGlu)-Arg-Leu-Thr-Glu-,

[1147] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DGIu)-Arg-Leu-Thr-Glu-,

[1148] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-,

[1149] -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1150] -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1151] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1152] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DAsp)-Arg-Leii-Thr-Glu-,

[1153] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-,

[1154] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-,

[1155] -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1156] -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1157] -Pro-Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-,

[1158] -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-,

[1159] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-,

[1160] -Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1161] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-,

[1162] -Ser-Ar -Leu-Glu-cyclo(DGIu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-z

[1163] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Glu)-Arg-Arg-Leu-Thr-Glu-,

[1164] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-,

[1165] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-,

[1166] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1167] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-,

[1168] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-,

[1169] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-z

[1170] -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1171] -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-,

[1172] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-z

[1173] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-,

[1174] -Pro-Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu- -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Glu)-Arg-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-z-Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-z-Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-z-Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-;

[1175] -Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-z-Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-z-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-z-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-z-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Cys)-Glu-z-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-z -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Cys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-;

[1176] -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-,

[1177] -Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-z-Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-,

[1178] -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-Cys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclothCys-Leu-Thr-Cys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-DCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-hCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-hCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-,

[1179] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-Cys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-DCys)-,

[1180] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-hCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DhCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-Pen)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-DPen)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-Pen)-,

[1181] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-DPen)-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-Cys)-Glii-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-DCys)-Glu-, -Ser-Arg-Leu-Glii-Glu-Glu-Leii-Arg-cyclo(Cys-Arg-Leu-DCys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-Cys)-Glu-;

[1182] -Ser-Arg-Leu-Glu-Glu-Glu-Leii-Arg-cyclo(hCys-Arg-Leu-DCys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-hCys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-hCys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DhCys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DhCys-Arg-Leu-hCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-Cys)-,

[1183] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-Cys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-DCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-hCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-hCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-Cys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-DCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-hCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DhCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-Pen)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-DPen)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-Pen)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-DPen)-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-Cys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-DCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-DCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-Cys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-hCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-hCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DhCys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DhCys-Arg-Leu-hCys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Asp)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Asp-Arg-Leu-Lys)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Glu)-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Glu-Arg-Leu-Lys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Asp)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Asp-Arg-Leu-Lys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Glu)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Glu-Arg-Leu-Lys)-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclofCys-Arg-Leu-Thr-Cys)-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-;

[1184] -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Arg-Cys)-Leu-Thr-Glu-,

[1185] -Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-,

[1186] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-Pro-,

[1187] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DGIu)-Arg-Leu-Thr-Glu-Pro-,

[1188] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DGlu)-Arg-Leu-Thr-Glu-Pro-,

[1189] -Pro-Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-,

[1190] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-Pro-;

[1191] -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DGIu)-Arg-Leu-Thr-Glu-Pro-;

[1192] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DGIu)-Arg-Leu-Thr-Glu-Pro-,

[1193] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-Pro-,

[1194] -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-,

[1195] -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-Pro-,

[1196] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-,

[1197] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-,

[1198] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-,

[1199] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-Pro-,

[1200] -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-,

[1201] -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-Pro-,

[1202] -Pro-Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-,

[1203] -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-,

[1204] -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-,

[1205] -Ser-Ar -Leu-Glu-cyclo(DGIu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1206] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1207] -Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1208] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Glu)-Arg-Arg-Leu-Thr-Glu-Pro-;

[1209] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1210] -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1211] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1212] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-;

[1213] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-Pro-,

[1214] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Glu)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DGIu)-Arg-Arg-Leu-Thr-Glu-Pro-;-Pro-Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DAsp-Glu-Leu-DLys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-DAsp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DLys-Glu-Leu-Asp)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Ar -Lys)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Lys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Asp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-Asp)-Arg-Leu-Thr-Glu-Pro-,

[1215] -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DLys-Leu-Arg-DAsp)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(DAsp-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Cys)-Glu-Pro-, -Ser-Ar -Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Cys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-z-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-Pro-z-Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-;-Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-hCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(hCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-; -Pro-Ser-Arg-Leu-Glu-cyclo(DCys-Glu-Leu-DhCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu yclo(DhCys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-cyclo(DhCys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-Cys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-Cys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-DCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-hCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-hCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-Cys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-DCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-hCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DhCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-Pen)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-DPen)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-Pen)-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-DPen)-Pro-;-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-Cys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-DCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-DCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-Cys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-hCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-hCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DhCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DhCys-Arg-Leu-hCys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg<yclo(Cys-Leu-Thr-DCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-Cys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-Cys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-DCys)-Pro-;-Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(hCys-Leu-Thr-hCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-hCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-hCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-Cys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-DCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DhCys-Leu-Thr-hCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DCys-Leu-Thr-DhCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-DhCys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-Pen)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Pen-Leu-Thr-DPen)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-Pen)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(DPen-Leu-Thr-DPen)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-Cys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DCys-Arg-Leu-DCys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-DCys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-Cys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DCys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-hCys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-hCys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(hCys-Arg-Leu-DhCys)-Glu-Pro-;-Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(DhCys-Arg-Leu-hCys)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Asp)-Glu-Pro-;-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Asp-Arg-Leu-Lys)-Glu-Pro-;-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Glu)-Glu-Pro-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Glu-Arg-Leu-Lys)-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclofLys-Arg-Leu-AspJ-Glu-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Asp-Arg-Leu-Lys)-Glu-Pro-,

[1216] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Glu)-Glu-Pro-,

[1217] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Glu-Arg-Leu-Lys)-Glu-Pro-,

[1218] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Thr-Cys)-Pro-,

[1219] -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-Pro-,

[1220] -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-Pro-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Arg-Cys)-Leu-Thr-Glu-Pro-, -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-, and -Ser-Arg-Leu-cyclo(Glu-Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-.

[1221] In some embodiments, the cyclic peptide is attached to a 3-mercaptopropionyl moiety through an a-amine moiety of the leftmost amino acid in the cyclic peptide. In some embodiments, the rightmost amino acid in the cyclic peptide comprises an amide.

[1222] In some embodiments, the cyclized amino acid sequence is one selected from the group consisting of

[1223] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1224] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1225] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1226] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Thr-Glu)-,

[1227] -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-,

[1228] -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-,

[1229] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Thr-Asp)-,

[1230] -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-

[1231] -Pro-Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-,

[1232] -Pro-Ser-Arg-Leu-Glu-cyclo(DGIu-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-

[1233] -Pro-Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Arg-DLys)-Arg-Leu-Thr-Glu-

[1234] -Pro-Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-

[1235] -Pro-Ser-Arg-Leu-cyclo(Glu-Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-DCys)-Arg-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Thr-Cys)-, -Pro-Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-, -Pro-Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-, -Pro-Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Arg-Cys)-Leu-Thr-Glu-, -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Cys-Arg-Leu-Thr-Cys)-,

[1236] -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Arg-Cys)-Arg-Leu-Thr-Glu-,

[1237] -Ser-Arg-Leu-Glu-cyclo(Cys-Glu-Leu-Cys)-Arg-Arg-Leu-Thr-Glu-,

[1238] -Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-Arg-cyclo(Cys-Leu-Thr-Cys)-,

[1239] -Ser-Arg-Leu-Glu-Glu-cyclo(Cys-Leu-Arg-Arg-Cys)-Leu-Thr-Glu-,

[1240] -Ser-Arg-Leu-Glu-cyclo(Lys-Glu-Leu-Arg-Glu)-Arg-Leu-Thr-Glu-, and -Ser-Arg-Leu-cyclo(Glu-Glu-Glu-Leu-Lys)-Arg-Arg-Leu-Thr-Glu-.

[1241] In some embodiments, the cyclized amino acid sequence is -Ser-Arg-Leu-Glu-cyclo(Glu-Glu- Leu-Arg-Lys)-Arg-Leu-Thr-Glu-. In some other embodiments, the cyclized amino acid sequence is -Ser-Arg-Leu-Glu-cyclo(Asp-Glu-Leu-Arg-Lys)-Arg-Leu-Thr-Glu-. In yet some other embodiments, the cyclized amino acid sequence is -Ser-Arg-Leu-Glu-cyclo(Glu-Glu-Leu-Lys)- Arg-Arg-Leu-Thr-Glu-. In still some other embodiments, the cyclized amino acid sequence is - Ser-Arg-Leu-Glu-Glu-Glu-Leu-Arg-cyclo(Lys-Arg-Leu-Thr-Glu)-.

[1242] The cyclic peptides may have different cyclic bridging moieties forming the ring structure. Preferably, chemically stable bridging moieties are included in the ring structure such as, for example, an amide group, a lactone group, an ether group, a thioether group, a disulfide group, an alkylene group, an alkenyl group, or a 1,2,3-triazole. The following are examples illustrating the variability of bridging moieties in a peptide:

[1243] In some embodiments, an ALFA-tag binding moiety comprises an antibody or antibody fragment, e.g., a camelid VHH domain. In some embodiments, an ALFA-tag binding moiety comprises a single-domain antibody (sdAb), NbALFA-nanobody.

[1244] In some embodiments, an ALFA-tag binding moiety comprises a single domain antibody, e.g., a camelid VHH domain comprising the CDR1 sequence VTXiSALNAMAMG, wherein Xi is I or V, the CDR2 sequence AVSX2RGNAM, wherein X2 is E, H, N, D, or S, and the CDR3 sequence LEDRVDSFHDY.

[1245] In some embodiments, an ALFA-tag binding moiety comprises a single domain antibody, e.g., a camelid VHH domain comprising the CDR1 sequence GVTXiSALNAMAMG, wherein Xi is I or V, the CDR2 sequence AVSX2RGNAM, wherein X2 is E, H, N, D, or S, and the CDR3 sequence LEDRVDSFHDY.

[1246] In some embodiments, an ALFA-tag binding moiety comprises a single domain antibody, e.g., a camelid VHH domain comprising the CDR1 sequence VTISALNAMAMG, the CDR2 sequence AVSERGNAM, and the CDR3 sequence LEDRVDSFHDY.

[1247] In some embodiments, an ALFA-tag binding moiety comprises a single domain antibody, e.g., a camelid VHH domain comprising the CDR1 sequence GVTISALNAMAMG, the CDR2 sequence AVSERGNAM, and the CDR3 sequence LEDRVDSFHDY.

[1248] In some embodiments, an ALFA-tag binding moiety comprises a single domain antibody, e.g., a camelid VHH domain comprising the amino acid sequence EVQLQESGGGLVQPGGSLRLSCTASGVTISALNAMAMGWYRQAPGERRVMVAAVSERGNAMYRESV Q.GRFTVTRDFTNKMVSLQ.MDNLKPEDTAVYYCHVLEDRVDSFHDYWGQ.GTQ.VTVSS, an amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to said amino acid sequence, or a fragment of said amino acid sequence or the amino acid sequence having at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identity to said amino acid sequence. In some embodiments, the amino acid sequence comprises CDR1, CDR2 and CDR3 sequences as described above.

[1249] In some embodiments, the epitope tag / binder system comprises an epitope tag comprising the sequence PDRVRAVSHWSS (Spot-tag) and the binder comprises a single-domain antibody (sdAb, or nanobody) (Spot-nanobody (14.7 kD)) that specifically binds to the Spot-tag. In some embodiments, following binding of the moieties on the tag conjugate and on the docking compound interacting which each other, a covalent connection is formed. In these embodiments, the system used herein may comprise a Tag / Catcher system forming a covalent bond, e.g., SpyTag / SpyCatcher forming an isopeptide bond.

[1250] The SpyTag / SpyCatcher system is a technology for irreversible conjugation of recombinant proteins. The peptide SpyTag spontaneously reacts with the protein SpyCatcher to form an intermolecular isopeptide bond between the pair. Using the Tag / Catcher pair, bioconjugation can be achieved between two recombinant proteins.

[1251] In some embodiments, the interacting moieties on the tag conjugate and on the docking compound comprise Digoxigenin and an antibody, antibody fragment or derivative, e.g., scFv, or any protein binding to Digoxigenin.

[1252] In some embodiments, the interacting moieties on the tag conjugate and on the docking compound comprise caffeine and an antibody, antibody fragment or derivative, e.g., nanobody, binding to caffeine.

[1253] In some embodiments, the interacting moieties on the tag conjugate and on the docking compound comprise GFP and an antibody, antibody fragment or derivative, e.g., nanobody, binding to GFP.

[1254] In some embodiments, the interacting moieties on the tag conjugate and on the docking compound comprise biotin and an antibody, antibody fragment or derivative binding to biotin. The present disclosure provides in one aspect, a complex wherein a tag conjugate is bound to a docking compound. Thus, the tag conjugate and the docking compound comprise moieties interacting which each other.

[1255] Accordingly, the present disclosure provides in one aspect, a complex comprising:

[1256] (i) a compound comprising a binding moiety binding to a target antigen and a binding moiety for a tag (docking compound), and

[1257] (ii) a compound comprising a payload moiety and at least one tag, e.g., at least two tags, to which the binding moiety for a tag binds (tag conjugate).

[1258] Different embodiments of the tag conjugate and the docking compound which are complexed are described herein.

[1259] In some embodiments, the tag conjugate comprises at least one ALFA-tag, e.g., at least two ALFA-tags. In some embodiments, the at least two ALFA-tags may be identical or different. In some embodiments, the tag conjugate comprises at least two identical ALFA-tags. In these embodiments, the moiety binding to a tag conjugate of the docking compound may be a NbALFA-nanobody (NbALFA). In some embodiments, the docking compound comprises at least two moieties binding to a tag of a tag conjugate, e.g., at least two NbALFA-nanobodies (NbALFA). In some embodiments, the docking compound may have a structure selected from the group consisting of NbALFA x anti-primary target DARPin, NbALFA x anti-primary target VHH and NbALFA x anti-primary target scFv. In some embodiments, the docking compound comprises a full-length anti-primary target antibody comprising two heavy chains and two light chains, wherein NbALFA is linked to the C-terminus of each of the heavy chains.

[1260] Payload

[1261] In the present disclosure, a payload comprises a Stimulator of Interferon Genes (STING) agonist (i.e., an immunomodulator).

[1262] STING is expressed broadly in numerous tissue types, of both immune and non-immune origin, and is required for the type 1 interferon response in both immune and non-immune cells. STING has been shown to directly bind to a variety of different cyclic-di-nucleotides. The substantial pre-clinical anti-tumor activity of STING agonists has led to the development of multiple pharmacologic classes of agents at various stages of being translated into the clinic. The term "STING agonist" as used herein refers to a compound, e.g., a small molecule, which agonizes STING.

[1263] In some embodiments, the STING agonist is a compound having the following Formula (XX): wherein:

[1264] Ring A is selected from the group consisting of G and Gi are independently N, CH, or C-X1-R2; or when G and Gi are each C-X1-R2, the R2 groups are optionally linked to form L2;

[1265] G' and G2 are independently N or CH;

[1266] X is N-R, 0, or S;

[1267] X' is N or CH;

[1268] Xi is CH2, 0 or S;

[1269] R is hydrogen or C1-4 alkyl;

[1270] L1and L2are each independently C2-4 alkylene or C2-4 alkenylene;

[1271] R2 is selected from the group consisting of hydrogen, C2-4 cyclic ether, C1-4 alkylene-(C24 cyclic ether), C3-4 cycloalkyl, C1-4 alkylene-(C3-4 cycloalkyl), C1-4 alkyl,

[1272] O O

[1273] Ri and R3 are independently selected from the group consisting of

[1274] Ring B is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 2 heteroatoms independently selected from N, O, and S;

[1275] Rs is -OH or -NR9R10;

[1276] R9 and Rio are independently selected from hydrogen and Ci-e alkyl (preferably, selected from hydrogen and C1-4 alkyl (such as methyl, ethyl, propyl, or butyl));

[1277] X2 and X3 are independently NH or S; Yi and Y2 are independently a 5-membered heteroaryl or heterocyclic ring, wherein the 5- membered heteroaryl or heterocyclic ring (i) has 1 to 4 heteroatoms independently selected from N, O, and S, (ii) is attached to the remainder of the STING agonist via a C ring atom of the

[1278] 5-membered heteroaryl or heterocyclic ring, and (iii) is optionally substituted with 1 to 4 R21, wherein each R21 is independently C1-4 alkyl (such as methyl, ethyl, propyl, or butyl);

[1279] Rs, Re, and R7 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, , or Rs and Re are optionally connected to form a 5- or 6- membered heterocyclic ring;

[1280] Ris is -OH or -NR9R10;

[1281] Ring C is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 ring heteroatoms independently selected from N, 0, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 4 ring heteroatoms independently selected from N, O, and S; n, p, q, q', t, and v are independently an integer from 2 to 6 (i.e., 2, 3, 4, 5, or 6, such as 2, 3, 4, or 5, e.g., 2, 3, or 4); and k, I, m, o, u, and w are independently an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6, such as 1, 2, 3, 4, or 5, e.g., 1, 2, 3, or 4).

[1282] In some embodiments of Formula (XX), G2 is CH.

[1283] In those embodiments of Formula (XX), where Ring A is , preferably G' is CH, more preferably both of G' and G? are CH.

[1284] In some embodiments of Formula (XX), Ring A is selected from the group consisting of wherein R preferably is hydrogen, methyl, ethyl, propyl, or butyl, such as hydrogen. In some preferred embodiments, Ring A is selected from the group consisting of

[1285] In some embodiments of Formula (XX), G and Gi are independently N or C-X1-R2. In some preferred embodiments of Formula (XX), each of G and Gi is C-X1-R2, or one of G and Gi is C- X1-R2 and the other of G and Gi is N.

[1286] In those embodiments of Formula (XX), where G and / or Gi is C-X1-R2, it is preferred that R2is selected from the group consisting of hydrogen, C1-4 alkylene-(Ca-4 cycloalkyl), C1-4 alkyl,

[1287] In some embodiments of Formula (XX), L2is ethylene, propylene, butylene, ethenylene, propenylene, or butenylene, preferably propylene; and / or that each Xi is O. In some preferred embodiments of Formula (XX), L2is ethylene, propylene, butylene, ethenylene, propenylene, or butenylene (preferably propylene), and each Xi is O.

[1288] In some embodiments of Formula (XX), one of X2 and X3 is S and the other is NH. In some preferred embodiments of Formula (XX), each of X2 and X3 is NH. In some embodiments of Formula (XX), L1is ethenylene, propenylene, butenylene, ethylene, propylene, or butylene, preferably ethenylene.

[1289] In some embodiments of Formula (XX), L1is ethenylene, propenylene, butenylene, ethylene, propylene, or butylene, preferably ethenylene; and each of X2 and X3 is ...

Claims

Claims1. A kit comprising:(i) a compound comprising a binding moiety binding to a target antigen and a binding moiety for a tag, or a nucleic acid encoding said compound; and(ii) a compound comprising a payload moiety and a tag to which the binding moiety for a tag binds, wherein the payload comprises a STING agonist.

2. The kit of claim 1, wherein the STING agonist has the following Formula (XX):wherein:Ring A is selected from the group consisting ofG and Gi are independently N, CH, or C-X1-R2; or when G and Gi are each C-X1-R2, the R2groups are optionally linked to form L2;G' and G2are independently N or CH;X is N-R, O, or S;X' is N or CH;Xi is CH2, 0 or S;R is hydrogen or C1-4 alkyl;L1and L2are each independently C2-4 alkylene or C2-4 alkenylene;Rz is selected from the group consisting of hydrogen, C24 cyclic ether, Ci-4 alkylene-(C2-4 cyclic ether), C3-4 cycloalkyl. CM alkylene-(C3-4 cycloalkyl), C1-4 alkyl,o oRi and R3 are independently selected from the group consisting ofH2NRing B is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 2 heteroatoms independently selected from N, O, and S; Rs is -OH or -NR9R10;R9 and Rio are independently selected from hydrogen and C1-6 alkyl;X2 and X3 are independently NH or S;Yi and Y2 are independently a 5-membered heteroaryl or heterocyclic ring, wherein the 5- membered heteroaryl or heterocyclic ring (i) has 1 to 4 heteroatoms independently selected from N, O, and S, (ii) is attached to the remainder of the STING agonist via a C ring atom of the 5-membered heteroaryl or heterocyclic ring, and (iii) is optionally substituted with 1 to 4R21, wherein each R21 is independently C1-4 alkyl (such as methyl, ethyl, propyl, or butyl);R15< ARs, Rs, and R7are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, \ / w, or R5 and Rs are optionally connected to form a 5- or 6- membered heterocyclic ring;Ris is -OH or -NR9R10;Ring C is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 ring heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 4 ring heteroatoms independently selected from N, O, and S; n, p, q, q t, and v are independently an integer from 2 to 6; and k, I, m, o, u, and w are independently an integer from 1 to 6, preferably the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX).

3. The kit of claim 2, wherein the STING agonist has the following formula (XXH):preferably the payload moiety comprises a STING agonist moiety of the STING agonist ofFormula (XXH).

4. The kit of any one of claims 1 to 3, wherein the payload moiety comprises a STING agonist moiety having the following Formula (XX-18'):wherein R2' is a bond, -(CFhh-,#-(CH2)3N(CH3)-*, or#-(CH2)sN(CH3)NH-*, preferably R2' is - (CH2)3-,#-(CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-*, more preferably R2' is#-(CH2)3N(CH3)NH-*,wherein * represents the attachment point of R2' to the remainder of the compound under (ii); and#represents the attachment point of R2' to the remainder of the STING agonist moiety.

5. The kit of any one of claims 1 to 4, wherein the compound under (ii) comprises one or more than one tag to which the binding moiety for a tag binds.

6. The kit of any one of claims 1 to 5, wherein the tag is a peptide tag.

7. The kit of any one of claims 1 to 6, wherein the compound under (ii) comprises a moiety comprising a polymer.

8. The kit of any one of claims 1 to 7 , wherein the payload moiety and the tag or tags are coupled through a moiety comprising a polymer.

9. The kit of claim 7 or 8, wherein the polymer is not a polymer of proteinogenic amino acids or their D-isomers.

10. The kit of any one of claims 7 to 9, wherein the polymer is selected from the group consisting of polyethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

11. The kit of any one of claims 7 to 8, wherein the polymer comprises polyethylene glycol) (PEG), or poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

12. The kit of any one of claims 7 to 9, wherein the polymer comprises at least one poly- 2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

13. The kit of any one of claims 1 to 12, wherein the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting ofpolyethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

14. The kit of any one of claims 1 to 13, wherein the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of polyethylene glyco!) (PEG), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

15. The kit of any one of claims 1 to 14, wherein the payload moiety and the tag or tags are coupled through a moiety comprising at least one poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

16. The kit of any one of claims 1 to 15, wherein the nucleic acid is RNA.

17. The kit of any one of claims 1 to 16, wherein the compound under (ii) comprises one tag.

18. The kit of any one of claims 1 to 17, wherein the total number of tags in the compound under (ii) is one.

19. The kit of any one of claims 1 to 18, wherein the compound under (ii) comprises one payload moiety.

20. The kit of any one claims 1 to 19, wherein the total number of payload moieties in the compound under (ii) is one.

21. The kit of any one of claims 1 to 20, wherein the compound under (ii) comprises a linking moiety connecting a tag and a payload moiety.

22. The kit of claim 21, wherein the linking moiety comprises a continuous or non- continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

23. The kit of any one of claims 1 to 19, wherein the compound under (ii) comprises the formula:P-L-T whereinP comprises a payload moiety, wherein the payload comprises a STING agonist, wherein preferably: the payload comprises the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety having the Formula (XX- 18'), (XX-6'), (XX-511), (XX-53'), (XX-73'a), or (XX-73'b);T comprises a tag; andL comprises a linking moiety.

24. The kit of claim 23, wherein L comprises a poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

25. The kit of claim 23 or 24, wherein L comprises the formula [AEEA]u-[L'-[AEEA]v]w, whereinAEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;L' comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [L'-[AEEA]V] may be identical or different.

26. The kit of any one of claims 23 to 25, wherein L or L' comprises an amino acid.

27. The kit of any one of claims 23 to 26, wherein L or L' comprises the D-isomer of an amino acid.

28. The kit of any one of claims 23 to 27, wherein L or L' comprises cysteine or lysine.

29. The kit of any one of claims 23 to 28, wherein L or L' is connected to a side chain.

30. The kit of any one of claims 1 to 16, wherein the compound under (ii) comprises at least two of said tags.

31. The kit of any one of claims 1 to 16 and 30, wherein the total number of tags in the compound under (ii) is two.

32. The kit of any one of claims 1 to 16, 30 and 31, wherein the compound under (ii) comprises one or more payload moieties.

33. The kit of any one of claims 1 to 16, and 30 to 32, wherein the total number of payload moieties in the compound under (ii) is one.

34. The kit of any one of claims 1 to 16, and 30 to 32, wherein the compound under (ii) comprises two or more payload moieties.

35. The kit of any one of claims 1 to 16, 30 to 32 and 34, wherein the total number of payload moieties in the compound under (ii) is two.

36. The kit of any one of claims 1 to 16, and 30 to 35, wherein the compound under (ii) comprises payload moieties and tags in an unbranched (linear) configuration.

37. The kit of any one of claims 1 to 16, and 30 to 36, wherein the compound under (ii) comprises the formula:P-LA-T-LB-T orP-LA-T-LB-T-LC-P whereinP comprises a payload moiety, wherein the payload comprises a STING agonist, wherein preferably: the payload comprises the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety having the Formula (XX- 18' j, (XX-6'), (XX-51’), (XX-53'), (XX-73'a), or (XX-73'b);T comprises a tag;LA comprises a linking moiety;LB comprises a linking moiety; andLc comprises a linking moiety.

38. The kit of claim 37, wherein one or more of LA, LB, and Lc comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

39. The kit of claim 37 or 38, wherein LB comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

40. The kit of any one of claims 1 to 16, and 30 to 35, wherein the compound under (ii) comprises payload moieties and tags in a branched (non-linear) configuration.

41. The kit of any one of claims 1 to 16, 30 to 35 and 40, wherein the compound under (ii) comprises the formula:[[P]m-Li]n-Bi-[L2-T]o whereinP comprises a payload moiety, wherein the payload comprises a STING agonist, wherein preferably: the payload comprises the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety having the Formula (XX- 18'), (XX-6'), (XX-51'), (XX-53'), (XX-73'a), or (XX-73'b);Bi comprises a branching moiety;T comprises a tag;Li comprises a linking moiety;L2 comprises a linking moiety; m is an integer from 1 to 4; n is an integer from 1 to 4; and o is an integer from 2 to 4; wherein the different groups [L2-T] may be identical or different, the different groups P may be identical or different, and the different groups [[P]m-Li] may be identical or different.

42. The kit of claim 41, wherein Bi comprises an amino acid or bis-amino acid.

43. The kit of claim 41 or 42, wherein Bi comprises the D-isomer of an amino acid.

44. The kit of any one of claims 41 to 43, wherein Bi comprises cysteine or lysine.

45. The kit of any one of claims 41 to 44, wherein Li comprises a 2-(2-(2- aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

46. The kit of any one of claims 41 to 45, wherein L2 comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

47. The kit of any one of claims 10 to 46, wherein the number of repeating units of 2-(2- (2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

48. The kit of any one of claims 10 to 47, wherein the number of repeating units of 2-(2- (2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

49. The kit of any one of claims 10 to 48, wherein the number of repeating units of 2-(2- (2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6.

50. The kit of any one of claims 41 to 49, wherein in formula [[P]m-Li]n-Bi-[L2-T]0m is an integer from 1 to 3, n is an integer from 1 to 3, and o is 2 or 3.

51. The kit of any one of claims 41 to 50, wherein in formula [[P]m-Li]n-Bi-[L2-T]0o is 2.

52. The kit of any one of claims 41 to 51, wherein in formula [[P]m-Li]n-Bi-[L2-T]0o is 2, n is1 and m is 1.

53. The kit of any one of claims 41 to 51, wherein in formula [[P]m-Li]n-Bi-[L2-T]0o is 2, n is2 and m is 2.

54. The kit of any one of claims 1 to 53, wherein the compound under (i) comprises one or more binding moieties for the tag.

55. The kit of any one of claims 1 to 54, wherein the compound under (i) comprises at least two binding moieties for the tag.

56. The kit of any one of claims 1 to 55, wherein the compound under (i) comprises two binding moieties for the tag.

57. The kit of any one of claims 1 to 56, wherein the tag is an ALFA-tag.

58. The kit of any one of claims 1 to 57, wherein the tag is a cyclic ALFA-tag.

59. A compound comprising a payload moiety and a tag, wherein the payload comprises a STING agonist.

60. The compound of claim 59, wherein the STING agonist has the following Formula (XX):wherein:Ring A is selected from the group consisting ofG and Gi are independently N, CH, or C-X1-R2; or when G and Gi are each C-X1-R2, the R2 groups are optionally linked to form L2;G' and G2 are independently N or CH;X is N-R, O, or S;X' is N or CH;Xi is CH2, O or S;R is hydrogen or C1-4 alkyl;L1and L2are each independently C2-4 alkylene or C2-4 alkenylene;R2 is selected from the group consisting of hydrogen, C2-4 cyclic ether, C1-4 alkylene-(C2-4 cyclic ether), C3-4 cycloalkyl, CM alkylene-(C34 cycloalkyl), C1-4 alkyl.o oRi and R3 are independently selected from the group consisting ofRing B is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 2 heteroatoms independently selected from N, O, and S;Rs is -OH or -NR9R10;Rg and Rio are independently selected from hydrogen and Ci-6 alkyl;X2 and X3 are independently NH or S;Yi and Y2 are independently a 5-membered heteroaryl or heterocyclic ring, wherein the 5- membered heteroaryl or heterocyclic ring (i) has 1 to 4 heteroatoms independently selected from N, O, and S, (ii) is attached to the remainder of the STING agonist via a C ring atom of the 5-membered heteroaryl or heterocyclic ring, and (iii) is optionally substituted with 1 to 4R21, wherein each R21 is independently C1-4 alkyl (such as methyl, ethyl, propyl, or butyl);Rs, Re, and R7are independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl,, , or Rs and Re are optionally connected to form a 5- or 6- membered heterocyclic ring;Ris is -OH or -NR9R10;Ring C is 6-membered arylene, 5- or 6-membered heteroarylene comprising 1 to 2 ring heteroatoms independently selected from N, O, and S, or 5- or 6-membered divalent heterocyclic ring comprising 1 to 4 ring heteroatoms independently selected from N, O, andS; n, p, q, q', t, and v are independently an integer from 2 to 6 (i.e., 2, 3, 4, 5, or 6, such as 2, 3,4, or 5, e.g., 2, 3, or 4); and k, I, m, o, u, and w are independently an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6, such as 1,2, 3, 4, or 5, e.g., 1, 2, 3, or 4),preferably the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX).

61. The compound of claim 60, wherein the STING agonist has the following formula(XXH):preferably the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XXH).

62. The compound of any one of claims 59 to 61, wherein the payload moiety comprises a STING agonist moiety having the following Formula (XX-18'):wherein Rzis a bond, -(CH2)3-,#-(CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-\ preferably R2' is - (CH2)3-, *-(CH2)3N(CH3)-*, or#-(CH2)3N(CH3)NH-*, more preferably Rz is#-(CH2)3N(CH3)NH-*, wherein * represents the attachment point of R2' to the remainder of the compound comprising a payload moiety and a tag, wherein the payload comprises a STING agonist; and * represents the attachment point of R2' to the remainder of the STING agonist moiety.

63. The compound of any one of claims 59 to 62, which comprises one or more than one tag-64. The compound of any one of claims 59 to 63, wherein the tag is a peptide tag.

65. The compound of any one of claims 59 to 64, which comprises a moiety comprising a polymer.

66. The compound of any one of claims 59 to 65, wherein the payload moiety and the tag or tags are coupled through a moiety comprising a polymer.

67. The compound of claim 65 or 66, wherein the polymer is not a polymer of proteinogenic amino acids or their D-isomers.

68. The compound of any one of claims 65 to 67, wherein the polymer is selected from the group consisting of polyethylene glycol) (PEG), polysarcosine (pSar) (poly(N- methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

69. The compound of any one of claims 65 to 68, wherein the polymer comprises poly(ethylene glycol) (PEG), or poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

70. The compound of any one of claims 65 to 69, wherein the polymer comprises at least one poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

71. The compound of any one of claims 59 to 70, wherein the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of poly(ethylene glycol) (PEG), polysarcosine (pSar) (poly(N-methylglycine)), polyoxazoline (POX), polyoxazine (POZ), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA), derivatives and combinations thereof.

72. The compound of any one of claims 59 to 71, wherein the payload moiety and the tag or tags are coupled through a moiety comprising a polymer selected from the group consisting of polyethylene glycol) (PEG), and poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) or a derivative thereof.

73. The compound of any one of claims 59 to 72, wherein the payload moiety and the tag or tags are coupled through a moiety comprising at least one poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

74. The compound of any one of claims 59 to 73, which comprises one tag.

75. The compound of any one of claims 59 to 74, wherein the total number of tags in the compound is one.

76. The compound of any one of claims 659to 75, which comprises one payload moiety.

77. The compound of any one of claims 59 to 76, wherein the total number of payload moieties in the compound is one.

78. The compound of any one of claims 59 to 77, which comprises a linking moiety connecting a tag and a payload moiety.

79. The compound of claim 78, wherein the linking moiety comprises a continuous or non- continuous poly-2-(2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

80. The compound of any one of claims 62 to 79, which comprises the formula:P-L-T whereinP comprises a payload moiety, wherein the payload comprises a STING agonist, wherein preferably: the payload comprises the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), (XXH),or (XXK), or the payload moiety comprises a STING agonist moiety having the Formula (XX- 18'), (XX-6'), (XX-51'), (XX-531), (XX-73'a), or (XX-73'b);T comprises a tag; andL comprises a linking moiety.

81. The compound of claim 80, wherein L comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

82. The compound of claim 80 or 81, wherein L comprises the formula [AEEA]U-[L'- [AEEA]v]w, whereinAEEA is 2-(2-(2-aminoethoxy)ethoxy)acetic acid or a derivative thereof;L' comprises a linking moiety; u is an integer of 2 or more; each v is an integer of 2 or more; and w is an integer from 1 to 4; wherein the different groups [L'-[AEEA]V] may be identical or different.

83. The compound of any one of claims 80 to 82, wherein L or L' comprises an amino acid.

84. The compound of any one of claims 80 to 83, wherein L or L' comprises the D-isomer of an amino acid.

85. The compound of any one of claims 80 to 84, wherein L or L' comprises cysteine or lysine.

86. The compound of any one of claims 80 to 85, wherein L or L' is connected to a side chain.

87. The compound of any one of claims 59 to 73, which comprises at least two of said tags.

88. The compound of any one of claims 59 to 73 and 87, wherein the total number of tags in the compound is two.

89. The compound of any one of claims 62 to 73, 87 and 88, which comprises one or more payload moieties.

90. The compound of any one of claims 59 to 73 and 87 to 89, wherein the total number of payload moieties in the compound is one.

91. The compound of any one of claims 59 to 73 and 87 to 89, which comprises two or more payload moieties.

92. The compound of any one of claims 59 to 73, 87 to 89 and 91, wherein the total number of payload moieties in the compound is two.

93. The compound of any one of claims 59 to 73, and 87 to 92, which comprises payload moieties and tags in an unbranched (linear) configuration.

94. The compound of any one of claims 59 to 73, and 87 to 93, which comprises the formula:P-LA-T-LB-T orP-LA-T-LB-T-LC-P whereinP comprises a payload moiety, wherein the payload comprises a STING agonist, wherein preferably: the payload comprises the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety having the Formula (XX- 18'), (XX-61), (XX-511), (XX-531), (XX-73'a), or (XX-73'b);T comprises a tag;LA comprises a linking moiety;LB comprises a linking moiety; andLc comprises a linking moiety.

95. The compound of claim 94, wherein one or more of LA, LB, and Lc comprises a poly-2- (2-(2-aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

96. The compound of claim 94 or 95, wherein LB comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

97. The compound of any one of claims 59 to 73, and 87 to 92, which comprises payload moieties and tags in a branched (non-linear) configuration.

98. The compound of any one of claims 59 to 73, 87 to 92 and 97, which comprises the formula:[[P]m-Li]n-Br[L2-T]0whereinP comprises a payload moiety, wherein the payload comprises a STING agonist, wherein preferably: the payload comprises the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety of the STING agonist of Formula (XX), (XXH), or (XXK), or the payload moiety comprises a STING agonist moiety having the Formula (XX- 18'), (XX-6'), (XX-511), (XX-531), (XX-73'a), or (XX-73'b);Bi comprises a branching moiety;T comprises a tag;Li comprises a linking moiety;L2comprises a linking moiety; m is an integer from 1 to 4; n is an integer from 1 to 4; and o is an integer from 2 to 4; wherein the different groups [L2-T] may be identical or different, the different groups P may be identical or different, and the different groups [[P]m-Li] may be identical or different.

99. The compound of claim 98, wherein Bi comprises an amino acid or bis-amino acid.

100. The compound of claim 98 or 99, wherein Bi comprises the D-isomer of an amino acid.

101. The compound of any one of claims 98 to 100, wherein Bi comprises cysteine or lysine.

102. The compound of any one of claims 98 to 101, wherein Li comprises a 2-(2-(2- aminoethoxy)ethoxy)acetic acid (AEEA) moiety or a derivative thereof, or a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

103. The compound of any one of claims 98 to 102, wherein Lz comprises a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof.

103. The compound of any one of claims 68 to 103, wherein the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 30.

105. The compound of any one of claims 68 to 104, wherein the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is between 2 and 10.

106. The compound of any one of claims 68 to 105, wherein the number of repeating units of 2-(2-(2-aminoethoxy)ethoxy)acetic acid (AEEA) or a derivative thereof of a poly-2-(2-(2- aminoethoxy)ethoxy)acetic acid (pAEEA) moiety or a derivative thereof is 2, 4 or 6.

107. The compound of any one of claims 98 to 106, wherein in formula [[P]m-Li]n-Bi-[L2-T]0m is an integer from 1 to 3, n is an integer from 1 to 3, and o is 2 or 3.

108. The compound of any one of claims 98 to 107, wherein in formula [[P]m-Li]n-Bi-[l-2-T]0o is 2.

109. The compound of any one of claims 98 to 108, wherein in formula [[P]m-Li]n-Bi-[L2-T]0o is 2, n is 1 and m is 1.

110. The compound of any one of claims 98 to 108, wherein in formula [[P]m-Li]n-Bi-[L.2-T]0o is 2, n is 2 and m is 2.

111. The compound of any one of claims 59 to 110, wherein the tag is an ALFA-tag.

112. The compound of any one of claims 59 to 111, wherein the tag is a cyclic ALFA-tag.

113. A method for treating a subject having a disease, disorder or condition characterized by cells expressing a target antigen, comprising:(i) providing to the subject a compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag;(ii) allowing the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag to become associated with cells expressing the target antigen; and(iii) administering to the subject a compound of any one of claims 59 to 112 comprising one or more tags to which the binding moiety for a tag binds.

114. The method of claim 113, wherein the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag is provided to the subject by administering to the subject RNA encoding a polypeptide comprising a binding moiety binding to the target antigen and a binding moiety for a tag; and allowing expression of the polypeptide by cells in the subject.

115. The method of claim 114, wherein the cells expressing the polypeptide are transfected with the RNA.

116. The method of claim 114 or 115, wherein the RNA is administered as particulate formulation such as formulated as lipid nanoparticles or lipoplex particles.

117. The method of any one of claims 114 to 116, wherein the cells expressing the polypeptide secrete the polypeptide.

118. The method of any one of claims 114 to 117, wherein the cells expressing the polypeptide express the polypeptide such that it is released into the bloodstream.

119. The method of any one of claims 113 to 118, wherein the target antigen is a cell surface antigen.

120. The method of any one of claims 113 to 119, wherein the compound comprising a binding moiety binding to the target antigen and a binding moiety for a tag is a fusion polypeptide comprising the binding moiety binding to the target antigen and the binding moiety for a tag.

121. The method of any one of 113 to 120, wherein the binding moiety binding to the target antigen comprises an antibody or an antibody derivative.

122. The method of any one of claims 113 to 121, wherein the binding moiety for a tag comprises an antibody or an antibody derivative.

123. The method of claim 121 or 122, wherein the antibody derivative is an antibody fragment.

124. The method of any one of claims 113 to 123, wherein the disease, disorder or condition is cancer.

125. The method of any one of claims 113 to 124, wherein the cells expressing a target antigen are diseased cells.

126. The method of any one of claims 113 to 125, wherein the cells expressing a target antigen are cancer cells.

127. The method of any one of 113 to 126, wherein the target antigen is a tumor antigen.

128. The method of any one of claims 113 to 127, wherein the compound under (i) comprises a single binding moiety for the tag.

129. The method of any one of claims 113 to 127, wherein the compound under (i) comprises at least two binding moieties for the tag.

130. The method of any one of claims 113 to 129, wherein the compound under (i) comprises two binding moieties for the tag.

131. The method of any one of claims 113 to 130, wherein the tag is an ALFA-tag.

132. The method of any one of claims 113 to 131, wherein the tag is a cyclic ALFA-tag.

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