Trans-cyclooctene with improved t-linker

Abstract

Disclosed herein are trans-cyclooctenes (TCOs) that have an improved T-linker. In particular, the TCOs have improved in vitro and in vivo properties as compared to TCOs known from the prior art. The disclosure also pertains to in vivo and in vitro methods of using said trans-cyclooctenes, as well as medical uses thereof, and methods for making said TCOs.

Description

[0001] P136182PC00 Title: TRANS-CYCLOOCTENE WITH IMPROVED T-LINKER Field The disclosure disclosed herein relates to trans-cyclooctenes (TCOs) with improved properties. In particular, TCOs are provided that have a better clearance profile, a higher uptake at the target site, e.g. a tumor, a lower uptake off-target, and / or a cleaner metabolism profile as compared to known TCOs. Compositions and combinations comprising the TCOs of the disclosure, as well as methods for using same are provided as well. Background In the field of bioorthogonal chemistry the ligation between TCOs and dienes, in particular tetrazines, is well-studied. While the ligation works well both in vitro as in vivo, it is still a challenge to find optimal compounds for clinical use. Regarding TCOs, a strong candidate for clinical use is considered to be compound 1, disclosed in WO 2022 / 197182 as AVP0458-22-PEG24. Compound 1 is an AVP0458 diabody modified with four TCO- containing moieties, and has the following structure: However, the inventors have identified, for the first time, several hitherto unknown disadvantages of compound 1. First, it was found that while compound 1 has a good clearance from blood, further improvements are desired. Compound 1 has a half-life in the blood of healthy mice of 4.22 hours, and 48 hours after injection in healthy mice 1.14% ID / g of compound 1 in the blood of said mice was observed. Based on this newly found disadvantage of compound 1, it is desired that TCOs be provided that show faster clearance rates as compared to compound 1. Second, it was found that while compound 1 shows good tumor uptake of 18.42 %ID / g in LS174T xenograft bearing mice, further improvements are desired. It is therefore also desired that TCOs with a higher tumor uptake be provided. Third, it was observed that compound 1 shows uptake at off-target sites, e.g. non- tumour sites such as the heart, lung, etc. It is also desired that TCOs be provided with a lower off-target uptake. Fourth, it was observed that compound 1 shows a metabolism profile that can be improved. Thus, it is also desired that TCOs be provided showing a better metabolism profile. Finally, it is desired that TCOs be provided with overall good in vitro and in vivo properties, i.e. one or more of: good stability, good reactivity with tetrazines, and / or high payload release (especially in vivo). There is thus a need for TCOs that address one or more of the abovementioned problems and / or desires. Summary The disclosure relates to at least the following embodiments: Embodiment 1. A compound or a salt, hydrate, or solvate thereof; wherein said compound has a structure according to Formula (1): Formula (1); wherein R48 is –(Y1-C(=Y2))i-(SP)j-CA; CAis exatecan or an exatecan derivative; each of Y1and Y2are independently selected from O, and S; i is 0 or 1; j is 0 or 1; SPis a spacer; L1is selected from the group consisting of linear or branched C4-C12alkylene, C3-C8(hetero)cycloalkylene, C6-C12arylene, and C4-C11heteroarylene; L2a, L2b, and L2dare each independently a linker; L2cis selected from the group consisting of C1-C8 (hetero)alkanetriyl, C5-C6 (hetero)arenetriyl, C3-C7cycloalkanetriyl, and C2-C7heterocycloalkanetriyl; T1is selected from the group consisting of -OT1A, hydrogen, C2-C6alkyl, C6aryl, C4-C5heteroaryl, C3-C6 cycloalkyl, C5-C12 alkyl(hetero)aryl, C5-C12 (hetero)arylalkyl, C4-C12 alkylcycloalkyl, -N(T1A)2, -ST1A, -SO3H, -C(O)T1A, -C(O)OT1A, -O-C(O)T1A-C(O)N(T1A)2, -N(T1A)2-CO-T1A, and -Si(T1A)3; each T1Ais independently selected from the group consisting of hydrogen, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, and an amino acid residue; T2is a bioconjugation moiety or a group -L3-CB; wherein L3is a residue of a bioconjugation moiety, and CBis selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelating moieties, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof; and T3is a polymer; preferably the exatecan derivative is N-methyl-exatecan; preferably Y1and Y2are both O; preferably i is 1; preferably j is 0; preferably SPis a self-immolative linker; preferably L1is linear or branched C4-C12alkylene, more preferably L1is linear or branched C4-C10alkylene, and most preferably L1is linear C5-C6alkylene; preferably L2a, L2b, and L2dare each independently a linker containing at most twenty atoms; more preferably L2a, L2b, and L2dare each independently selected from the group consisting of -C(O)NL2T-, -NL2TC(O)-, -O-, -S-, - NL2T-, -N=N-, and -C(O)-; wherein L2Tis hydrogen or methyl, preferably L2Tis hydrogen; preferably L2cis C1-C8 (hetero)alkanetriyl, more preferably L2cis C1-C8 alkanetriyl, and most preferably L2cis C4-C6 alkanetriyl; preferably T1is -OT1A; and most preferably T1is -OH; preferably T1Ais hydrogen or methyl, more preferably T1Ais hydrogen; preferably T2is maleimidyl, N-hydroxysuccinimidyl, or -L3-CB; preferably L3is a residue of a maleimidyl moiety or a residue of an N-hydroxysuccinimidyl moiety; preferably CBis a protein, more preferably CBis an antibody or a diabody, even more preferably CBis a diabody, and most preferably CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; and preferably T3is a polymer comprising a polyethylene glycol moiety. Embodiment 2. The compound according to Embodiment 1, or a salt, hydrate, or solvate thereof; wherein said compound is according to Formula (2): Formula (2); wherein y is an integer in a range of from 1 to 50; preferably y is an integer in a range of from 2 to 45, more preferably 10 to 40, more preferably in a range of from 12 to 37, even more preferably in a range of from 15 to 35, more preferably still in a range of from 20 to 30, and most preferably in a range of from 23 to 25. Embodiment 3. The compound according to any one of the preceding Embodiments, or a salt, hydrate, or solvate thereof; wherein said compound is according to Formula (3): y is as defined in Embodiment 2; x is an integer in a range of from 4 to 12; preferably x is an integer in a range of from 4 to 8, more preferably x is an integer in a range of from 4 to 6. Embodiment 4. The compound according to any one of the preceding Embodiments, or a salt, hydrate, or solvate thereof; wherein R48is -O-CO-CA; preferably R48is: Embodiment 5. The compound according to any one of the preceding Embodiments, or a salt, hydrate, or solvate thereof; wherein T2is selected from the group consisting of CBis a protein; preferably CBis an antibody or a diabody, more preferably a diabody, and most preferably AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably CBis linked to the remainder of T2via S or N that is part of CB, more preferably S. Embodiment 6. The compound according to any one of the preceding Embodiments, or a salt, hydrate, or solvate thereof; wherein said compound is:

[0002] wherein E1is -H or -CH3. Embodiment 7. The compound according to any one of the preceding Embodiments, or a salt, hydrate, or solvate thereof; wherein said compound is

[0003] wherein E1is -H or -CH3. Embodiment 8. The compound according to any one of Embodiments 1 to 5, or a salt, hydrate, or solvate thereof; wherein said compound is: E1is -H or -CH3; wherein CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably CBis linked to the maleimidyl group via a sulfur atom that is part of CB, preferably the sulfur atom is part of a cysteine. Embodiment 9. The compound according to Embodiment 8, or a salt, hydrate, or solvate thereof; wherein said compound is: . Embodiment 10. A conjugate, or a salt, hydrate, or solvate thereof, wherein the conjugate comprises a protein conjugated to at least one compound according to Formula (1) as defined in any one of Embodiments 1 to 9, wherein L1, L2a, L2b, L2c, L2d, T1, T3, and R48are as defined in any one of Embodiments 1 to 9, and wherein T2is a residue of a bioconjugation moiety, and said protein and said compound are conjugated via T2; preferably the protein is a diabody or an antibody; more preferably the protein is a diabody; and most preferably the protein is AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably the protein is conjugated to at most 12 of said compounds; more preferably the protein is conjugated to at most 8 of said compounds, most preferably the protein is conjugated to at most 4 of said compounds; preferably said protein and said compound are conjugated via T2and a residue of a sulfhydryl of said protein, a residue of a hydroxyl of said protein, or a residue of an amine of said protein; more preferably said protein and said compound are conjugated via T2and a residue of a sulfhydryl of said protein; preferably T2is a residue of a maleimidyl moiety or a residue of an N-hydroxysuccinimidyl moiety; more preferably T2is a residue of a maleimidyl moiety. Embodiment 11. The conjugate according to Embodiment 10, or a salt, hydrate, or solvate thereof, wherein the conjugate is wherein E1is -H or -CH3; wherein CJ is in a range of from 1 to 12; wherein CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably CJ is of from 2 to 10, more preferably of from 2.5 to 8, even more preferably of from 3 to 6, even more preferably still of from 3.5 to 4, and most preferably about 4; preferably CBis linked to each maleimidyl group via a sulfur atom, preferably the sulfur atom is part of a cysteine. Embodiment 12. The conjugate according to Embodiment 11, or a salt, hydrate, or solvate thereof, wherein the conjugate is . Embodiment 13. A composition comprising: (a) a compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; and / or (b) the conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; preferably the composition is a pharmaceutical composition. Embodiment 14. A composition according to Embodiment 13, wherein said composition comprises: (a) a compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; and (b) the enantiomer of said compound, or the salt, hydrate, or solvate thereof; preferably said composition is a racemic mixture of (a) and (b). Embodiment 15. A combination of (A1) a compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; (A2) a conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; and / or (A3) a composition according to Embodiment 13 or 14: with (B) a diene or a salt, solvate, or hydrate thereof; preferably the diene is a tetrazine. Embodiment 16. The combination according to Embodiment 15, wherein the diene is selected from the group consisting of: salt, hydrate, and / or solvate thereof. Embodiment 17. The compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; the conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; the composition according to any one of Embodiments 13 to 14; or the combination according to any one of Embodiments 15 to 16; for use as a medicament. Embodiment 18. The compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; the conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; the composition according to any one of Embodiments 13 to 14; or the combination according to any one of Embodiments 15 to 16; for use in the treatment of a disease in a subject, preferably the subject is a human; preferably the disease is cancer. Embodiment 19. A method of treating a disease in a subject, wherein said method comprises the step of administering to said subject: (a) the compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; (b) the conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; (c) the composition according to any one of Embodiments 13 to 14; and / or (d) the combination according to any one of Embodiments 15 to 16; preferably the subject is a human; preferably the disease is cancer. Embodiment 20. A non-therapeutic method for reacting: (ia) the compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; (iia) the conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; and / or (iiia) the composition according to any one of Embodiments 13 to 14; with a diene or a salt, solvate, or hydrate thereof, wherein said method comprises the step of contacting (ia), (iia), or (iiia) with said diene or salt, solvate, or hydrate thereof, preferably said non-therapeutic method is an in vitro method; and preferably said diene is a tetrazine. Embodiment 21. A non-therapeutic use of: (a) the compound according to any one of Embodiments 1 to 9, or the salt, hydrate, or solvate thereof; (b) the conjugate according to any one of Embodiments 10 to 12, or the salt, hydrate, or solvate thereof; (c) the composition according to any one of Embodiments 13 to 14; and / or (d) the combination according to any one of Embodiments 15 to 16; in a click reaction. Embodiment 22. A method for synthesizing a compound according to any one of Embodiments 1 to 9, or a salt, hydrate, or solvate thereof; wherein said method comprises (A) coupling a compound of Formula (R) to a compound of Formula (S): Formula (R); wherein R48, T1, and y are as defined in any one of Embodiments 1 to 10; (S); wherein T2, and x, are as defined in any one of Embodiments 1 to 9, and S10is -COOH or an active ester, (B) coupling a compound of Formula (T) to a compound of Formula (U): Formula (T); wherein R48, and T1are as defined in any one of Embodiments 1 to 9; and S11is -COOH or an active ester; Formula (U); wherein T2, x, and y are as defined in any one of Embodiments 1 to 9; preferably S10is -COOH; preferably S11is an active ester. Embodiment 23. A method for synthesizing a conjugate according to any one of Embodiments 10 to 12, or a salt, hydrate, or solvate thereof; wherein said method comprises the step of coupling a protein to a compound according to any one of Embodiments 1 to 9, or a salt, hydrate, or solvate thereof; wherein in said compound T2is a bioconjugation moiety; preferably in said protein disulfide bonds have been reduced. Brief description of the Figures Figure 1 shows mass spectra of compounds 14a (panel A), 14b (panel B), 15a (panel C), and 15b (panel D) in the absence or presence of a bis-pyridyl tetrazine (Tz). The drug- antibody ratio (DAR) is 2 in all cases, as the AVP0458 monomers were measured. Quantitative release of exatecan or methyl-exatecan was observed upon reaction of the compounds with bis-pyridyl tetrazine in phosphate-buffered saline (PBS). Figure 2 depicts Scatchard plots of compound 14a (panel A), 15a (panel B), 14b (panel C), or 15b (panel D) binding to OV90 cells; see Example 7. Figure 3 shows the results of immunoreactivity analysis of compounds 14a (panel A) and 15a (panel B); see Example 8. Figure 4 depicts HEK293 cell proliferation in the presence of compound 14a (panel A), 15a (panel B), 14b (panel C), or 15b (panel D); each with or without tetrazine (TZ); see Example 9. Figure 5 shows the results of the in vivo stability tests of compounds 14a and 15a (panel A) and of compounds 14b and 15b (panel B); see Example 10. Detailed Description The claimed subject-matter, in a broad sense, is based on the judicious insight that TCOs of the disclosure meet one or more of the aforementioned desires. In particular, it was surprisingly found that replacing the PEG4 moiety of compound 1 resulted in a higher clearance rate, higher tumor uptake, lower off-target uptake, a better metabolism profile, and / or further improved in vitro and in vivo properties. Especially the combination of a faster clearance rate and a higher tumor uptake is surprising, since this means that the faster clearance from blood is not due to e.g. excretion from the body. Instead, the compounds of the disclosure are quickly taken up in the tumour. Even more advantageously the uptake of compounds of the disclosure in off-target tissues is much lower as compared to the uptake in the tumour. This means that a higher percentage of payload can be released at the desired target site, and that the trigger to activate this payload release (typically a diene, e.g. a tetrazine) can be administered at an earlier point in time, shortening the entire procedure. Thus, the compounds of the disclosure also result in a higher convenience for patients, as fewer and / or less severe side-effects are expected as well as a shorter treatment time. Preferred embodiments of the disclosure are further described below. All of these embodiments, regardless of whether said embodiments are disclosed in the general part of the description or as part of the Examples or claims, can be combined as long as said embodiments are not mutually exclusive. Compounds of the disclosure The compounds of the disclosure are according to according to Formula (1) as defined above. It is understood that any compounds as provided herein may be in a form, formulation or solution in which the compound is present as a salt, solvate or hydrate of the compound. Accordingly, whereever herein a compound or genus of compounds are provided, or reference is made to “compound of the disclosure” or “compounds of the disclosure”, it will be understood that also the salt, hydrate, or solvate of said compound(s) are included by such a statement even if the terms salt, hydrate or solvate are not specifically mentioned in each instance. In certain embodiments, a compound of the disclosure is purified or in a form or state in which it is not present as a salt, or as a hydrate, or as a solvate of the compound; however, unless specifically indicated as such it is intended to be assumed that any compound herein may be in the form of a salt, hydrate or solvate. Preferred embodiments of the compounds of the disclosure are further described below in relation to several Formulae and variables. Formulae Preferably, the compound of the disclosure is according to a Formula selected from the group consisting of Formula (1), Formula (2), Formula (3), Formula (D), Formula (E), Formula (F), Formula (G), Formula (H), Formula (I), Formula (J), Formula (K), Formula (L), Formula (M), Formula (N), Formula (O), Formula (P), and Formula (Q). Even more preferably, the compound of the disclosure is according to Formula (1). More preferably still, the compound of the disclosure is according to Formula (D). Even more preferably, the compound of the disclosure is according to Formula (E). Yet more preferably, the compound of the disclosure is according to Formula (F). Still more preferably, the compound of the disclosure is according to Formula (G). More preferably still, the compound of the disclosure is according to Formula (2). Even more preferably still, the compound of the disclosure is according to Formula (H). Yet more preferably still, the compound of the disclosure is according to Formula (I). Even more preferably, the compound of the disclosure is according to Formula (J). More preferably still, the compound of the disclosure is according to Formula (K). Even more preferably still, the compound of the disclosure is according to Formula (L). Yet more preferably, the compound of the disclosure is according to Formula (M). Even more preferably still, the compound of the disclosure is according to Formula (N). Still more preferably, the compound of the disclosure is according to Formula (O). Yet more preferably, the compound of the disclosure is according to Formula (3). Still more preferably, the compound of the disclosure is according to Formula (P). Even more preferably, the compound of the disclosure is according to Formula (Q). 5 Formula (K) is: . Formula (L) is: . Formula (M) is: . Formula (Q) is: . L1L1is a linker. Preferably, L1is according to Radical Group 2 as defined herein. Preferably, L1contains of from 1 to 100 atoms, preferably of from 2 to 75 atoms, more preferably of from 3 to 60 atoms, even more preferably of from 4 to 50 atoms, more preferably still of from 5 to 40 atoms, yet more preferably of from 6 to 35 atoms, even more preferably of from 7 to 30 atoms, more preferably still of from 8 to 25 atoms, even more preferably of from 9 to 22 atoms, and most preferably of from 10 to 20 atoms. Preferably, L1contains about 15 atoms. More preferably, L1is selected from the group consisting of linear or branched C1-C12 (hetero)alkylene, C3-C8 (hetero)cycloalkylene, C6-C12 arylene, and C4-C11 heteroarylene. More preferably than the foregoing, L1is selected from the group consisting of linear or branched C1-C12 alkylene, C3-C8 (hetero)cycloalkylene, C6-C12 arylene, and C4-C11 heteroarylene. More preferably than the foregoing, L1is selected from the group consisting of linear or branched C2-C12alkylene, C3-C8(hetero)cycloalkylene, C6-C12arylene, and C4-C11heteroarylene. More preferably than the foregoing, L1is selected from the group consisting of linear or branched C3-C12 alkylene, C3-C8 (hetero)cycloalkylene, C6-C12 arylene, and C4-C11 heteroarylene. More preferably than the foregoing, L1is selected from the group consisting of linear or branched C4-C12alkylene, C3-C8(hetero)cycloalkylene, C6-C12arylene, and C4-C11heteroarylene. More preferably than the foregoing, L1is a linear or branched C1-C12 alkylene. More preferably than the foregoing, L1is a linear or branched C2-C12 alkylene, viz. linear C2 alkylene, linear or branched C3alkylene, linear or branched C4alkylene, linear or branched C5alkylene, linear or branched C6 alkylene, linear or branched C7 alkylene, linear or branched C8 alkylene, linear or branched C9 alkylene, linear or branched C10 alkylene, linear or branched C11alkylene, or linear or branched C12alkylene. More preferably than the foregoing, L1is a linear or branched C3-C12alkylene. More preferably than the foregoing, L1is a linear or branched C4-C12 alkylene. More preferably than the foregoing, L1is a linear or branched C4- C11alkylene. More preferably than the foregoing, L1is a linear or branched C4-C10alkylene. More preferably than the foregoing, L1is a linear or branched C4-C9alkylene. More preferably than the foregoing, L1is a linear or branched C4-C8 alkylene. More preferably than the foregoing, L1is a linear or branched C4-C7 alkylene. More preferably than the foregoing, L1is a linear or branched C4-C6alkylene. More preferably than the foregoing, L1is a linear or branched C5 alkylene. More preferably than the foregoing, L1is a linear C1-C12 alkylene. More preferably than the foregoing, L1is a linear C2-C12 alkylene, viz. linear C2 alkylene, linear C3alkylene, linear C4alkylene, linear C5alkylene, linear C6alkylene, linear C7alkylene, linear C8alkylene, linear C9alkylene, linear C10alkylene, linear C11alkylene, or linear C12 alkylene. More preferably than the foregoing, L1is a linear C3-C12 alkylene. More preferably than the foregoing, L1is a linear C4-C12alkylene. More preferably than the foregoing, L1is a linear C4-C11alkylene. More preferably than the foregoing, L1is a linear C4-C10 alkylene. More preferably than the foregoing, L1is a linear C4-C9 alkylene. More preferably than the foregoing, L1is a linear C4-C8 alkylene. More preferably than the foregoing, L1is a linear C4-C7alkylene. More preferably than the foregoing, L1is a linear C4- C6 alkylene. Most preferably, L1is a linear C5 alkylene. L1can be substituted or unsubistuted. Preferably, L1is unsubstituted. Most preferably, L1is an unsubstituted, linear C5alkylene. Without wishing to be bound by theory, the inventors believe that the linker L1of compounds of Formula (1) of the present disclosure may provide a faster blood clearance rate, while maintaining a high uptake at the target site of the compound of Formula (1). Still without wishing to be bound by theory, an advantage of linkers L1having a length as defined in claim 1, in particular linear C4-C12 alkylene, may be that sufficient distance between the moiety CBand the trans-cyclooctene can be achieved, so that the double bond of the trans- cyclooctene may readily react with a diene. Still without wishing to be bound by theory, an advantage of linkers L1having a length as defined in claim 1, in particular linear C4-C12 alkylene, may be that they are not too long, so that they may still be shielded by moiety CBwhich may prevent e.g. deactivation. An advantage of relatively short alkylene linkers, such as C4-C6 alkylene, may be that their solubility is also higher than for relatively long alkylene linkers. L2a L2ais a linker. Preferably, L2ais according to Radical Group 2 as defined herein. More preferably, L2ais a linker containing at most twenty atoms. More preferably than the foregoing, L2ais a linker containing at most fifteen atoms. More preferably than the foregoing, L2ais a linker containing at most ten atoms. More preferably than the foregoing, L2ais a linker containing at most five atoms. More preferably than the foregoing, L2ais selected from the group consisting of -C(O)NL2T-, -NL2TC(O)-, -O-, -S-, -NL2T-, -N=N-, and -C(O)-; wherein L2Tis hydrogen or methyl. More preferably than the foregoing, L2ais selected from the group consisting of -C(O)NL2T-, and -NL2TC(O)-. More preferably than the foregoing, L2ais selected from the group consisting of -C(O)NH-, and -NHC(O)-. Most preferably, L2ais -NHC(O)-. L2bL2bis a linker. Preferably, L2bis according to Radical Group 2 as defined herein. More preferably, L2bis a linker containing at most twenty atoms. More preferably than the foregoing, L2bis a linker containing at most fifteen atoms. More preferably than the foregoing, L2bis a linker containing at most ten atoms. More preferably than the foregoing, L2bis a linker containing at most five atoms. More preferably than the foregoing, L2bis selected from the group consisting of -C(O)NL2T-, -NL2TC(O)-, -O-, -S-, -NL2T-, -N=N-, and -C(O)-; wherein L2Tis hydrogen or methyl. More preferably than the foregoing, L2bis selected from the group consisting of -C(O)NL2T-, and -NL2TC(O)-. More preferably than the foregoing, L2bis selected from the group consisting of -C(O)NH-, and -NHC(O)-. Most preferably, L2bis -NHC(O)-. L2cL2cis a linker. Preferably, L2cis according to Radical Group 2 as defined herein. More preferably than the foregoing, L2cis a linker comprising at most 50 atoms. More preferably than the foregoing, L2cis a linker comprising at most 40 atoms. More preferably than the foregoing, L2cis a linker comprising at most 30 atoms. More preferably than the foregoing, L2cis a linker comprising at most 20 atoms. More preferably than the foregoing, L2cis a linker comprising at most 15 atoms. More preferably than the foregoing, L2cis selected from the group consisting of C1-C8 (hetero)alkanetriyl, C5-C6 (hetero)arenetriyl. C3-C7 cycloalkanetriyl, and C2-C7 heterocycloalkanetriyl. More preferably than the foregoing, L2cis C1-C8(hetero)alkanetriyl. More preferably than the foregoing, L2cis C1-C8alkanetriyl. More preferably than the foregoing, L2cis C2-C7alkanetriyl. More preferably than the foregoing, L2cis C3-C6alkanetriyl. More preferably than the foregoing, L2cis C4-C5alkanetriyl. More preferably than the foregoing, L2cis C5 alkanetriyl. Most preferably, L2cis >CH-CH2-CH2- CH2-CH2-. L2dL2dis a linker. Preferably, L2dis according to Radical Group 2 as defined herein. More preferably than the foregoing, L2dis a linker containing at most twenty atoms. More preferably than the foregoing, L2dis a linker containing at most fifteen atoms. More preferably than the foregoing, L2dis a linker containing at most ten atoms. More preferably than the foregoing, L2dis a linker containing at most five atoms. More preferably than the foregoing, L2dis selected from the group consisting of -C(O)NL2T-, -NL2TC(O)-, -O-, -S-, -NL2T-, -N=N-, and -C(O)-; wherein L2Tis hydrogen or methyl. More preferably than the foregoing, L2dis selected from the group consisting of -C(O)NL2T-, and -NL2TC(O)-. More preferably than the foregoing, L2dis selected from the group consisting of -C(O)NH-, and -NHC(O)-. Most preferably, L2dis -C(O)NH-. T1T1is according to Radical Group 1, Radical Group 3, Radical Group 4, or Radical Group 5, as defined herein. Preferably, each T1is independently according to Radical Group 1 as defined herein. More preferably, each T1is independently selected from the group consisting of - OT1A, hydrogen, C1-C12 (hetero)alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 (hetero)cycloalkyl, C5- C12alkyl(hetero)aryl, C5-C12(hetero)arylalkyl, C4-C12alkylcycloalkyl, -N(T1A)2, -ST1A, - SO3H, -C(O)T1A, -C(O)OT1A, -O-C(O)T1A-C(O)N(T1A)2, -N(T1A)2-CO-T1A, and -Si(T1A)3. Even more preferably, each T1is independently selected from the group consisting of -OT1A, hydrogen, C2-C6 alkyl, C6 aryl, C4-C5 heteroaryl, C3-C6 cycloalkyl, C5-C12 alkyl(hetero)aryl, C5-C12(hetero)arylalkyl, C4-C12alkylcycloalkyl, -N(T1A)2, -ST1A, -SO3H, -C(O)T1A, - C(O)OT1A, -O-C(O)T1A-C(O)N(T1A)2, -N(T1A)2-CO-T1A, and -Si(T1A)3. Yet more preferably, each T1is independently selected from the group consisting of -OT1A, C2-C6 alkyl, C6 aryl, C4-C5heteroaryl, C3-C6cycloalkyl, C5-C12alkyl(hetero)aryl, C5-C12(hetero)arylalkyl, C4-C12alkylcycloalkyl, -N(T1A)2, -ST1A, -SO3H, -C(O)T1A, -C(O)OT1A, -O-C(O)T1A-C(O)N(T1A)2, - N(T1A)2-CO-T1A, and -Si(T1A)3. More preferably still, T1is -OT1A. Most preferably, T1is -OH. As used herein, each T1Ais independently selected from the group consisting of hydrogen, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, and an amino acid residue. More preferably, each T1Ais independently selected from the group consisting of hydrogen, C1-C6(hetero)alkyl, C1-C6(hetero)alkenyl, C1-C6(hetero)alkynyl, C2-C5heteroaryl, phenyl, and an amino acid residue. Even more preferably, each T1Ais independently selected from the group consisting of hydrogen, C1-C4 (hetero)alkyl, C1-C4 (hetero)alkenyl, C1-C4 (hetero)alkynyl, C3-C5 heteroaryl, phenyl, an aspartic acid residue, a glutamic acid residue, and a glycine residue. Even more preferably, each T1Ais independently selected from the group consisting of hydrogen, C1-C3 alkyl, an aspartic acid residue, a glutamic acid residue, and a glycine residue. Most preferably, T1Ais hydrogen. Preferably, T1is in an axial position. Without wishing to be bound by theory, the inventors believe that in that case and when R48is a releasable group, when the compound of the disclosure reacts with a diene, T1aids in releasing the payload. This results in optimal release yields and / or release kinetics. T2T2is an organic moiety. Preferably, T2is according to any one of Radical Group 1, Radical Group 3, or Radical Group 5, as defined herein, or wherein T2is a group -L3-CB. More preferably, T2is a bioconjugation moiety, a residue of a bioconjugation moiety, or a group -L3-CB. More preferably, T2is a bioconjugation moiety, or a group -L3-CB. In preferred embodiments, T2is a bioconjugation moiety. These embodiments typically relate to compounds that can be coupled to e.g. a protein. More preferably, T2is according to Radical Group 1f as defined herein. Residues of these bioconjugation moieties are known in the art. More preferably, T2is N-maleimidyl. In these embodiments, it is most preferred that T2is: . In other preferred embodiments, T2is a residue of a bioconjugation moiety. These embodiments typically relate to conjugates of the disclosure, wherein T2links to e.g. a protein. Such residues are well-known to the skilled person. In these embodiments, it is most preferred that T2is: wherein the asterisk indicates a bond to the protein, and the wiggly line denotes a bond to the rest of the compound of the disclosure. In other preferred embodiments, T2is a group -L3-CB. These embodiments relate to when T2itself comprises a Construct B (CB), which is usually a protein. CBis as defined herein. L3is according to Radical Group 2. Preferably, L3is a residue of a bioconjugation moiety. More preferably, L3is a residue of an N-maleimidyl moiety or a residue of an N- hydroxy-succinimidyl moiety. In these embodiments, it is preferred that T2is selected from the group consisting of For the moiety -L3-CB, it is preferred that L3and a sulfur atom, secondary nitrogen atom, or tertiary nitrogen atom, preferably a sulfur atom, of CBtogether form any one of the following structures -L3-CB: wherein CB1indicates S, secondary N, or tertiary N that is part of CB, preferably S; the wiggly line indicates a bond to moiety L1, and the asterisk indicates a bond to the remainder of CB, preferably AVP0458. CB CBis according to Radical Group 4 or Radical Group 5, as defined herein. Preferably, CBis a targeting agent as defined herein. Preferably, CBis selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelating moieties, fluorescent dyes, phosphorescent dyes, organic particles, gels, cells, and combinations thereof. More preferably, CBis a protein. Even more preferably, CBis an antibody or a diabody. More preferably still, CBis a diabody. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. While antibodies or immunoglobulins derived from IgG antibodies are particularly well-suited for use in this disclosure, immunoglobulins from any of the classes or subclasses may be selected, e.g. IgG, IgA, IgM, IgD and IgE. Suitably, the immunoglobulin is of the class IgG including but not limited to IgG subclasses (IgG1, 2, 3 and 4) or class IgM which is able to specifically bind to a specific epitope on an antigen. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, camelized single domain antibodies, recombinant antibodies, anti- idiotype antibodies, multispecific antibodies, antibody fragments, such as, Fv, VHH, Fab, F(ab)2, Fab', Fab'-SH, F(ab')2, single chain variable fragment antibodies (scFv), tandem / bis- scFv, Fc, pFc', scFv-Fc, disulfide Fv (dsFv), bispecific antibodies (bc-scFv) such as BiTE antibodies, trispecific antibody derivatives such as tribodies, camelid antibodies, minibodies, nanobodies, resurfaced antibodies, humanized antibodies, fully human antibodies, single domain antibodies (sdAb, also known as NanobodyTM), chimeric antibodies, chimeric antibodies comprising at least one human constant region, dual-affinity antibodies such as dual-affinity retargeting proteins (DARTTM), and multimers and derivatives thereof, such as divalent or multivalent single-chain variable fragments (e.g. di-scFvs, tri-scFvs) including but not limited to minibodies, diabodies, triabodies, tribodies, tetrabodies, and the like, and multivalent antibodies. Reference is made to [Trends in Biotechnology 2015, 33, 2, 65], [Trends Biotechnol.2012, 30, 575–582], and [Canc. Gen. Prot.201310, 1-18], and [BioDrugs 2014, 28, 331–343], the contents of which are hereby incorporated by reference. "Antibody fragment" refers to at least a portion of the variable region of the immunoglobulin that binds to its target, i.e. the antigen-binding region. Other embodiments use antibody mimetics as Drug DDor Targeting Agent TT, such as but not limited to Affimers, Anticalins, Avimers, Alphabodies, Affibodies, DARPins, and multimers and derivatives thereof; reference is made to [Trends in Biotechnology 2015, 33, 2, 65], the contents of which is hereby incorporated by reference. For the avoidance of doubt, in the context of this disclosure the term "antibody" is meant to encompass all of the antibody variations, fragments, derivatives, fusions, analogs and mimetics outlined in this paragraph, unless specified otherwise. Preferably, an antibody is selected from the group consisting of AVP0458, CC49, 3F8, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afasevikumab, afelimomab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, amivantamab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, ansuvimab, anrukinzumab, apolizumab, aprutumab ixadotin, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atidortoxumab, atinumab, atoltivimab, atoltivimab, maftivimab, odesivimab, atorolimumab, avelumab, azintuxizumab vedotin, bamlanivimab, bapineuzumab, basiliximab, bavituximab, BCD-100, bebtelovimab, bectumomab, bedinvetmab, begelomab, belantamab mafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, birtamimab, bivatuzumab, bleselumab, blinatumomab, blontuvetmab, blosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontictuzumab, burosumab, cabiralizumab, camidanlumab tesirine, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, casirivimab, capromab, carlumab, carotuximab, catumaxomab, cBR96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, cergutuzumab amunaleukin, certolizumab pegol, cetrelimab, cetuximab, cibisatamab, cilgavimab, cirmtuzumab, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab pelidotin, coltuximab ravtansine, conatumumab, concizumab, cosfroviximab, crenezumab, crizanlizumab, crotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrekumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, derlotuximab biotin, detumomab, dezamizumab, dinutuximab, dinutuximab beta, diridavumab, divozilimab, domagrozumab, donanemab, dorlimomab aritox, dostarlimab, drozitumab, DS-8201, duligotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elezanumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapotamab vedotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epcoritamab, epitumomab cituxetan, epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etesevimab, etigilimab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fibatuzumab, ficlatuzumab, figitumumab, firivumab, flanvotumab, fletikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, frovocimab, frunevetmab, fulranumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gedivumab, gemtuzumab ozogamicin, gevokizumab, gilvetmab, gimsilumab, girentuximab, glembatumumab vedotin, glofitamab, golimumab, gomiliximab, gosuranemab, guselkumab, ianalumab, ibalizumab, sintilimab, ibritumomab tiuxetan, icrucumab, idarucizumab, ifabotuzumab, igovomab, iladatuzumab vedotin, imalumab, imaprelimab, imciromab, imdevimab, imgatuzumab, inclacumab, indatuximab ravtansine, indusatumab vedotin, inebilizumab, infliximab, intetumumab, inolimomab, inotuzumab ozogamicin, ipilimumab, iomab-B, iratumumab, isatuximab, iscalimab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacnotuzumab, ladiratuzumab vedotin, lampalizumab, lanadelumab, landogrozumab, laprituximab emtansine, larcaviximab, lebrikizumab, lecanemab, lemalesomab, lendalizumab, lenvervimab, lenzilumab, lerdelimumab, leronlimab, lesofavumab, letolizumab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, loncastuximab tesirine, losatuxizumab vedotin, lilotomab satetraxetan, lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, lupartumab, lupartumab amadotin, lutikizumab, maftivimab, mapatumumab, margetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narnatumab, natalizumab, navicixizumab, navivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesvacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odesivimab, odulimomab, ofatumumab, olaratumab, oleclumab, olendalizumab, olokizumab, omalizumab, omburtamab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox, oregovomab, orticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pankomab, panobacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placulumab, pozelimab, prezalumab, plozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, porgaviximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO 140, quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranevetmab, ranibizumab, raxibacumab, ravagalimab, ravulizumab, refanezumab, regavirumab, regdanvimab, relatlimab, remtolumab, reslizumab, retifanlimab, rilotumumab, rinucumab, risankizumab, rituximab, rivabazumab pegol, robatumumab, Rmab, roledumab, romilkimab, romosozumab, rontalizumab, rosmantuzumab, rovalpituzumab tesirine, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samrotamab vedotin, sarilumab, satralizumab, satumomab pendetide, secukinumab, selicrelumab, seribantumab, setoxaximab, setrusumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, sirtratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, sotrovimab, spartalizumab, spesolimab, stamulumab, sulesomab, suptavumab, sutimlimab, suvizumab, suvratoxumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, tafasitamab, talacotuzumab, talizumab, talquetamab, tamtuvetmab, tanezumab, taplitumomab paptox, tarextumab, tavolimab, teclistamab, tefibazumab, telimomab aritox, telisotuzumab, telisotuzumab vedotin, tenatumomab, teneliximab, teplizumab, tepoditamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tibulizumab, tildrakizumab, tigatuzumab, timigutuzumab, timolumab, tiragol, umab, tiragotumab, tislelizumab, tisotumab vedotin, tixagevimab, TNX-650, tocilizumab, tomuzotuximab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, trastuzumab duocarmazine, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab talirine, vanalimab, vandortuzumab vedotin, vantictumab, vanucizumab, vapaliximab, varisacumab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, vilobelimab, visilizumab, vobarilizumab, volociximab, vonlerolizumab, vopratelimab, vorsetuzumab mafodotin, votumumab, vunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenocutuzumab, ziralimumab, zolbetuximab, and zolimomab aritox. Preferably, CBis selected from the group consisting of AVP0458, CC49, insulin, transferrin, fibrinogen-gamma fragment, thrombospondin, claudin, apolipoprotein E, Affibody molecules such as for example ABY-025, Ankyrin repeat proteins, ankyrin-like repeat proteins, interferons, e.g. alpha, beta, and gamma interferon, interleukins, lymphokines, colony stimulating factors and protein growth factor, such as tumor growth factor, e.g. alpha, beta tumor growth factor, platelet-derived growth factor (PDGF), uPAR targeting protein, apolipoprotein, LDL, annexin V, endostatin, and angiostatin. Examples of peptides as targeting agents include LHRH receptor targeting peptides, EC-1 peptide, RGD peptides, HER2-targeting peptides, PSMA targeting peptides, somatostatin-targeting peptides, bombesin. Other examples of targeting agents include lipocalins, such as anticalins. One particular embodiment uses AffibodiesTMand multimers and derivatives. More preferably, CBis AVP0458 or CC49. Most preferably, CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1. Preferably, CBis linked to the remainder of the compound of the disclosure or the conjugate of the disclosure via S or N that is part of CB. More preferably, CBis linked to the remainder of the compound of the disclosure or the conjugate of the disclosure via S that is part of CB. AVP0458 As used herein, AVP0458 refers to a TAG72-binding diabody derived from the CC49 antibody. AVP0458 is a diabody consisting of two monomers, each monomer having an amino acid sequence according to SEQ ID NO:1: SEQ ID NO:1 (amino acid sequence of AVP0458 diabody monomer): SVQLQQSDAELVKPGASVKISCKASGYTFTDHAIHWVKQNPEQGLEWIGYFSPGNDD FKYNERFKGKATLTADKSSSTAYLQLNSLTSEDSAVYFCTRSLNMAYWGQGTSVTV SSGGGGSDIVMTQSCSSCPVSVGEKVTLSCKSSQSLLYSGNQKNYLAWYQQKPGQSP KLLIYWASTRESGVPDRFTGSGSGTDFTLSISSVETEDLAVYYCQQYYSYPLTFGAGT KLVLKR Herein, the underlining indicates the cysteines that are preferably modified with or linked to a compound of the disclosure or the remainder thereof if AVP0458 is itself part of the compound of the disclosure. Thus, in SEQ ID NO: 1 it is preferred that at least one of the underligned cysteines, more preferably both underlined cysteines, is modified with or linked to a compound according to the disclosure. In other words: it is preferred that the sulfur atom of the underlined cysteines is coupled to a moiety T2as defined herein, preferably T2is the residue of an N-maleimidyl group. A Targeting Agent, TT, binds to a Primary Target. A "primary target" as used in the present disclosure can be any molecule, which is present in an organism, tissue or cell. Preferably, a “primary target” relates to a target for a targeting agent for therapy, imaging, theranostics, diagnostics, or in vitro studies. In order to allow specific targeting of the above-listed Primary Targets, the Targeting Agent TTcan comprise compounds including but not limited to antibodies, antibody derivatives, antibody fragments, antibody (fragment) fusions (e.g. bi-specific and tri-specific mAb fragments or derivatives), proteins, peptides, e.g. octreotide and derivatives, VIP, MSH, LHRH, chemotactic peptides, cell penetrating peptide, membrane translocation moiety, bombesin, elastin, peptide mimetics, organic compounds, inorganic compounds, carbohydrates, monosaccharides, oligosacharides, polysaccharides, oligonucleotides, aptamers, viruses, whole cells, phage, drugs, polymers, liposomes, chemotherapeutic agents, receptor agonists and antagonists, cytokines, hormones, steroids, toxins. Examples of organic compounds envisaged within the context of the present disclosure are, or are derived from, dyes, compounds targeting CAIX and PSMA, estrogens, e.g. estradiol, androgens, progestins, corticosteroids, methotrexate, folic acid, and cholesterol. Examples of Targeting Agents of protein nature include insulin, transferrin, fibrinogen-gamma fragment, thrombospondin, claudin, apolipoprotein E, Affibody molecules such as for example ABY-025, Ankyrin repeat proteins, ankyrin-like repeat proteins, interferons, e.g. alpha, beta, and gamma interferon, interleukins, lymphokines, colony stimulating factors and protein growth factor, such as tumor growth factor, e.g. alpha, beta tumor growth factor, platelet-derived growth factor (PDGF), uPAR targeting protein, apolipoprotein, LDL, annexin V, endostatin, and angiostatin. Examples of peptides as targeting agents include LHRH receptor targeting peptides, EC-1 peptide, RGD peptides, HER2-targeting peptides, PSMA targeting peptides, somatostatin-targeting peptides, bombesin. Other examples of targeting agents include lipocalins, such as anticalins. One particular embodiment uses AffibodiesTMand multimers and derivatives. In one embodiment antibodies are used as the TT. While antibodies or immunoglobulins derived from IgG antibodies are particularly well-suited for use in this disclosure, immunoglobulins from any of the classes or subclasses may be selected, e.g. IgG, IgA, IgM, IgD and IgE. Suitably, the immunoglobulin is of the class IgG including but not limited to IgG subclasses (IgG1, 2, 3 and 4) or class IgM which is able to specifically bind to a specific epitope on an antigen. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, camelized single domain antibodies, recombinant antibodies, anti-idiotype antibodies, multispecific antibodies, antibody fragments, such as, Fv, VHH, Fab, F(ab)2, Fab', Fab'-SH, F(ab')2, single chain variable fragment antibodies (scFv), tandem / bis-scFv, Fc, pFc', scFv-Fc, disulfide Fv (dsFv), bispecific antibodies (bc-scFv) such as BiTE antibodies, trispecific antibody derivatives such as tribodies, camelid antibodies, minibodies, nanobodies, resurfaced antibodies, humanized antibodies, fully human antibodies, single domain antibodies (sdAb, also known as NanobodyTM), chimeric antibodies, chimeric antibodies comprising at least one human constant region, dual-affinity antibodies such as dual-affinity retargeting proteins (DARTTM), and multimers and derivatives thereof, such as divalent or multivalent single-chain variable fragments (e.g. di-scFvs, tri-scFvs) including but not limited to minibodies, diabodies, triabodies, tribodies, tetrabodies, and the like, and multivalent antibodies. Reference is made to [Trends in Biotechnology 2015, 33, 2, 65], [Trends Biotechnol.2012, 30, 575–582], and [Canc. Gen. Prot.201310, 1-18], and [BioDrugs 2014, 28, 331–343], the contents of which are hereby incorporated by reference. "Antibody fragment" refers to at least a portion of the variable region of the immunoglobulin that binds to its target, i.e. the antigen-binding region. Other embodiments use antibody mimetics as TT, such as but not limited to Affimers, Anticalins, Avimers, Alphabodies, Affibodies, DARPins, and multimers and derivatives thereof; reference is made to [Trends in Biotechnology 2015, 33, 2, 65], the contents of which is hereby incorporated by reference. For the avoidance of doubt, in the context of this disclosure the term "antibody" is meant to encompass all of the antibody variations, fragments, derivatives, fusions, analogs and mimetics outlined in this paragraph, unless specified otherwise. Preferably the TTis selected from antibodies and antibody derivatives such as antibody fragments, fragment fusions, proteins, peptides, peptide mimetics, organic molecules, dyes, fluorescent molecules, enzyme substrates. Preferably the TTbeing an organic molecule has a molecular weight of less than 2000 Da, more preferably less than 1500 Da, more preferably less than 1000 Da, even more preferably less than 500 Da. In another preferred embodiment the TTis selected from antibody fragments, fragment fusions, and other antibody derivatives that do not contain a Fc domain. In another embodiment the TTis a polymer and accumulates at the Primary Target by virtue of the EPR effect. Typical polymers used in this embodiment include but are not limited to polyethyleneglycol (PEG), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-glycolic acid (PLGA), polyglutamic acid (PG), polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylene hydroxymethyl-formal (PHF). Other examples are copolymers of a polyacetal / polyketal and a hydrophilic polymer selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides and derivatives thereof. Other examples are oligopeptides, polypeptides, glycopolysaccharides, and polysaccharides such as dextran and hyaluronan. In addition reference is made to [G. Pasut, F.M. Veronese, Prog. Polym. Sci. 2007, 32, 933–961]. In some embodiments the TTcan be a cell penetrating moiety, such as cell penetrating peptide. In other embodiments, the TTis a polymer, particle, gel, biomolecule or another above listed TTmoiety and is locally injected to create a local depot of Prodrug, which can subsequently be activated by the Activator. In another embodiment the targeting agent TTis a solid material such as but not limited to polymer, metal, ceramic, wherein this solid material is or is comprised in a cartridge, reservoir, depot, wherein preferably said cartridge, reservoir, depot is used for drug release in vivo. In some embodiments, the targeting agent TTalso acts as a Drug, which may be denoted as DD. T3T3is an organic moiety. Preferably, T3is according to any one of Radical Group 1, Radical Group 3, or Radical Group 5, as defined herein. More preferably, T3is according to Radical Group 3, as defined herein. Even more preferably, T3is a polymer. More preferably still, T3is a polymer comprising a polyethylene glycol moiety. More preferably, T3comprises a moiety –(CH2CH2-O-)y-T4. Herein, y is an integer in a range of from 1 to 50, preferably y is an integer in a range of from 2 to 45, more preferably in a range of from 10 to 40, more preferably in a range of from 12 to 37, even more preferably in a range of from 15 to 35, more preferably still in a range of from 20 to 30, even more preferably in a range of from 23 to 25, and most preferably y is 24. This definition and these preferences for y also apply to compounds of Formula (2), Formula (3), Formula (G), Formula (O), Formula (P), and Formula (Q), wherein y is used as well. T4is according to Radical Group 1, Radical Group 3, Radical Group 4, or Radical Group 5 as defined herein. Preferably, T4is according to Radical Group 1. More preferably, T4is according to Radical Group 1a. More preferably, T4is according to Radical Group 1b. More preferably, T4is according to Radical Group 1c. More preferably, T4is according to Radical Group 1d. Even more preferably, T4is according to Radical Group 1e. Most preferably, T4is methyl. Even more preferably, T3is a moiety –(CH2CH2-O-)y-T4. Most preferably, T3is a moiety –(CH2CH2-O-)24-CH3. Variable x in Formulae (3), (O), (P), and (Q) In Formula (3), Formula (O), Formula (P), and Formula (Q), x is an integer in a range of from 4 to 12; preferably x is an integer in a range of from 4 to 8, more preferably x is an integer in a range of from 4 to 6, and most preferably x is 5. R48 R48 is –(Y1-C(=Y2))i-(SP)j-CA, wherein CAis exatecan or an exatecan derivative, and each of Y1and Y2are independently selected from O, and S; preferably Y1and Y2are both O. For R48, j is 0 or 1; preferably j is 0; and i is 0 or 1; preferably i is 1. Preferably, if j is 0, then i is 1. If i is 0, -(SP)j-CAis connected to the remainder of the compound via O or S, that is part of -(SP)j-CA. On the other hand, if i is 1, -(SP)j-CAis connected to -C(=Y2)- via O, S, a secondary N, or a tertiary N, that is part of -(SP)j-CA. Preferably, if i is 1, -(SP)j-CAis connected to -C(=Y2)- via a secondary N, or a tertiary N, that is part of -(SP)j-CA. More preferably, R48is –(O-C(=Y2))i-(SP)j-CA. More preferably, R48is –(Y1-C(=O))i- (SP)j-CA. More preferably, R48is –(O-C(=O))i-(SP)j-CA. More preferably, R48is –O-C(=O)- (SP)j-CA. Most preferably, R48 is -O-C(=O)-CA. Preferably, CAis linked to the moiety –(Y1-C(=Y2))i-, preferably -O-C(=O)-, via a secondary nitrogen atom that is part of CA, forming a carbamate. Preferably, R48 is a substituent on an allylic carbon of a compound of the disclosure. Preferably, R48 is in the axial position. Without wishing to be bound by theory, the inventors believe that having the releasable group in an axial position results in better release of the payload as compared to having the releasable group in an equatorial position. CAis exatecan or an exatecan derivative. Exatecan derivatives are known in the art. Preferably, exatecan and exatecan derivatives have the following structure: wherein E1is -H, or an optionally substituted C1-C4 alkyl group. It will be understood that when E1is -H, said structure is exatecan. Preferably, E1is -H, -CH3, or -C(O)- CH2-OH. If E1is – H or -CH3, then the exatecan or exatecan derivative is preferably linked to the remainder of R48 via the nitrogen atom to which E1is attached. If E1is C(O)-CH2-OH, then the exatecan derivative is preferably linked to the remainder of R48 via the oxygen atom that is part of the hydroxyl group of E1. More preferably, E1is -H or -CH3. Most preferably, E1is -H. Preferably R48 is: ; wherein E1is -H or an optionally substituted C1-C4alkyl group, more preferably E1is -H or -CH3. Most preferably, R48 is: . R48 is a releasable group, since the moiety -(SP)j-CAwill be released upon reaction of a compound of the disclosure with a diene. If SPis a self-immolative linker, then CAwill be released from -(SP)j-CA. SPis a spacer, of which preferred embodiments are defined below. Preferably, when SPis part of a releasable group, SPis a self-immolative linker, which is herein also referred to as LC. Such self-immolative linkers are well-known in the art, and preferred embodiments of self-immolative linkers are defined below. If the spacer in the releasable group is a self- immolative linker, upon reaction of a compound of the disclosure with a diene, initially a construct -LC-CAis released. Thereafter, the self-immolative linker self-immolates and releases the payload CA. Log P In preferred embodiments the Log P of compounds of Formula (1) have a value in a range of from 2.0 and -2.0, more preferably in a range of from 1.0 and -1.0. In embodiments where it is required that a compound as disclosed herein, in particular a diene, has an extracellular volume of distribution it is preferred that the Log P of said compound is at most 2, preferably at most 1, more preferably at most 0, even more preferably at most -1. In embodiments where it is required that a compound as disclosed herein, in particular a diene, has an intracellular volume of distribution it is preferred that the Log P of the Activator is at least -1, preferably at least 0, more preferably at least 1, even more preferably at least 2. For a compound of Formula (1) wherein T2is a bioconjugation moiety, it is preferred that the molecular weight of said compound is at most 5 kDa, more preferably at most 4 kDa, even more preferably at most 3.5 kDa, more preferably stil at most 3 kDa, and most preferably at most 2.5 kDa. For a compound of Formula (1) wherein T2is a group -L3-CB, it is preferred that the molecular weight of said compound is at most 100 kDa, more preferably at most 85 kDa, even more preferably at most 75 kDa, more preferably stil at most 65 kDa, and most preferably at most 62.5 kDa. All linkers as used herein may each independently be a spacer SP. As the skilled person is aware, the specific structure of a spacer used in either a dienophile or diene as described herein does not typically influence whether the payload is released. However, in some cases specific spacers are preferred. For example, if a payload is to be released, the spacer between e.g. the allylic carbon of the eight-membered non-aromatic cyclic mono-alkenylene moiety and the payload is preferably a self-immolative linker. Such a linker, which is typically referred to as LCherein, ensures that upon release of the end of the linker connected to said allylic carbon, a further rearrangement or reaction takes place, after which the payload is decoupled from the linker LC. Below, first spacers in general are discussed, and thereafter the more specific self-immolative linkers. In general, a spacer SPas used herein is a moiety according to radical group 2 (RG2), more preferably any one of the preferred and / or specific embodiments thereof. Preferably, a spacer SPconsists of one or multiple Spacer Units SUarranged linearly and / or branched and may be connected to one or more CBmoieties and / or one or more LCor TRmoieties. The Spacer may be used to connect CBto one TR(Example A below; with reference to Formula 5a and 5b: f, e, a = 1) or more TR(Example B and C below; with reference to Formula 5a and 5b: f, e = 1, a ≥ 1), but it can also be used to modulate the properties, e.g. pharmacokinetic properties, of the CB-TR-CAconjugate (Example D below; with reference to Formula 5a and 5b: one or more of c,e,g,h ≥ 1). Thus a Spacer unit does not necessarily connect two entities together, it may also be bound to only one component, e.g. the TRor LC. Alternatively, the Spacer may comprise a Spacer Unit linking CBto TRand in addition may comprise another Spacer Unit that is only bound to the Spacer and serves to modulate the properties of the conjugate (Example F below; with reference to Formula 5a and 5b: e ≥ 1). The Spacer may also consist of two different types of SUconstructs, e.g. a PEG linked to a peptide, or a PEG linked to an alkylene moiety (Example E below; with reference to Formula 5a and 5b: e ≥ 1). For the sake of clarity, Example B depicts a SUthat is branched by using a multivalent branched SU. Example C depicts a SUthat is branched by using a linear SUpolymer, such as a peptide, whose side chain residues serve as conjugation groups. The Spacer may be bound to the Activator in similar designs such as depicted in above examples A- F. Each individual spacer unit SUmay be independently selected from the group of radicals according to RG2. The Spacer Units include but are not limited to amino acids, nucleosides, nucleotides, and biopolymer fragments, such as oligo- or polypeptides, oligo- or polypeptoids, or oligo- or polylactides, or oligo- or poly-carbohydrates, varying from 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24 and more preferably 2 to 12 repeating units. Preferred biopolymer SUare peptides. Preferably each SUcomprises at most 50 carbon atoms, more preferably at most 25 carbon atoms, more preferably at most 10 carbon atoms. In some embodiments the SUis independently selected from the group consisting of (CH2)r, (C3-C8carbocyclo), O-(CH2)r, arylene, (CH2)r-arylene, arylene-(CH2)r, (CH2)r -(C3-C8 carbocyclo), (C3-C8 carbocyclo)-(CH2)r, (C3-C8 heterocyclo), (CH2)r -(C3-C8 heterocyclo), (C3-C8heterocyclo)-(CH2)r, -(CH2)rC(O)NR’(CH2)r, (CH2CH2O)r, (CH2CH2O)rCH2,(CH2)rC(O)NR’(CH2CH2O)r, (CH2)rC(O)NR’(CH2CH2O)rCH2,(CH2CH2O)rC(O)NR’(CH2CH2O)r, (CH2CH2O)r C(O)NR’(CH2CH2O)rCH2, (CH2CH2O)rC(O)NR’CH2; wherein r is independently an integer from 1 -10. As used herein, each R’is independently selected from the group consisting of radicals according to RG1. Preferably, R’is hydrogen. Other examples of Spacer Units SUare linear or branched polyalkylene glycols such as polyethylene glycol (PEG) or polypropylene glycol (PPG) chains varying from 2 to 200, particularly 2 to 113, preferably 2 to 50, more preferably 2 to 24 and more preferably 2 to 12 repeating units. It is preferred that when polyalkylene glycols such as PEG and PPG polymers are only bound via one end of the polymer chain, that the other end is terminated with -OCH3, -OCH2CH3, OCH2CH2CO2H. Other polymeric Spacer Units are polymers and copolymers such as poly-(2-oxazoline), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-glycolic acid (PLGA), polyglutamic acid (PG), dextran, polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylene hydroxymethyl-formal (PHF). Other exemplary polymers are polysaccharides, glycopolysaccharides, glycolipids, polyglycoside, polyacetals, polyketals, polyamides, polyethers, polyesters. Examples of naturally occurring polysaccharides that can be used as SUare cellulose, amylose, dextran, dextrin, levan, fucoidan, carrageenan, inulin, pectin, amylopectin, glycogen, lixenan, agarose, hyaluronan, chondroitinsulfate, dermatansulfate, keratansulfate, alginic acid and heparin. In yet other exemplary embodiments, the polymeric SUcomprises a copolymer of a polyacetal / polyketal and a hydrophilic polymer selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides and derivatives thereof. Preferred polymeric SUare PEG, HPMA, PLA, PLGA, PVP, PHF, dextran, oligopeptides, and polypeptides. In some embodiments, polymers used in a SUhave a molecular weight ranging from 2 to 200 kDa, from 2 to 100 kDa, from 2 to 80 kDa, from 2 to 60 kDa, from 2 to 40 kDa, from 2 to 20 kDa, from 3 to 15 kDa, from 5 to 10 kDa, from 500 dalton to 5 kDa. Other exemplary SUare dendrimers, such as poly(propylene imine) (PPI) dendrimers, PAMAM dendrimers, and glycol-based dendrimers. The SUof the disclosure expressly include but are not limited to conjugates prepared with commercially available cross-linker reagents such as BMPEO, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and SVSB, DTME, BMB, BMDB, BMH, BMOE, BM(PEO)3and BM(PEO)4. To construct a branching Spacer one may use a SUbased on one or several natural or non-natural amino acids, amino alcohol, aminoaldehyde, or polyamine residues or combinations thereof that collectively provide the required functionality for branching. For example serine has three functional groups, i.e. acid, amino and hydroxyl groups and may be viewed as a combined amino acid an aminoalcohol residue for purpose of acting as a branching SU. Other exemplary amino acids are lysine and tyrosine. In some embodiments, the Spacer consists of one Spacer Unit, therefore in those cases SPequals SU. Preferably the Spacer consists of two, three or four Spacer Units. In some embodiments, SPhas a molecular weight ranging from 2 to 200 kDa, from 2 to 100 kDa, from 2 to 80 kDa, from 2 to 60 kDa, from 2 to 40 kDa, from 2 to 20 kDa, from 3 to 15 kDa, from 5 to 10 kDa, or from 500 dalton to 5 kDa. In some embodiments, the SPhas a mass of no more than 5000 daltons, no more than 4000 daltons, no more than 3000 daltons, no more than 2000 daltons, no more than 1000 daltons, no more than 800 daltons, no more than 500 daltons, no more than 300 daltons, no more than 200 daltons. In some aspects the SPhas a mass from 100 daltons, from 200 daltons, from 300 daltons to 5000 daltons. In some aspects of the SPhas a mass from 30, 50, or 100 daltons to 1000 daltons, from about 30, 50, or 100 daltons to 500 daltons. Preferably, SPcomprises a moiety RG2a, RG2b, RG2c, or a residue of RG1f, as described herein. Preferably, said RG2a, RG2b, RG2c, or a residue of RG1f connects the SPto CB, LC, or TR. LCis an optional self-immolative linker, which may consist of multiple units arranged linearly and / or branched. The possible LCstructures, their use, position and ways of attachment of linkers LC, CAand the TR(the Trigger, i.e. the trans-cyclooctene moiety) are known to the skilled person, see for example [Papot et al., Anticancer Agents Med. Chem., 2008, 8, 618-637]. Nevertheless, preferred but non-limiting examples of self-immolative linkers LCare benzyl-derivatives, such as those drawn below. There are two main self- immolation mechanisms: electron cascade elimination and cyclization-mediated elimination. The preferred example below on the left functions by means of the cascade mechanism, wherein the bond between the allylic carbon of the Trigger and the -O- or -S- attached to said carbon is cleaved, and an electron pair of YC1, for example an electron pair of NR6, shifts into the benzyl moiety resulting in an electron cascade and the formation of 4-hydroxybenzyl alcohol, CO2and the liberated payload. The preferred example in the middle functions by means of the cyclization mechanism, wherein cleavage of the bond to the NR6on the side of the Trigger leads to nucleophilic attack of the amine on the carbonyl, forming a 5-ring 1,3- dimethylimidazolidin-2-one and liberating the payload. The preferred example on the right combines both mechanisms. This linker will degrade not only into CO2and one unit of 4- hydroxybenzyl alcohol (when YC1is O), but also into one 1,3-dimethylimidazolidin-2-one unit. wherein the wiggly line indicates a bond to -O- or -S- on the allylic position of the trans- cyclooctene, and the double dashed line indicates a bond to CA. By substituting the benzyl groups of aforementioned self-immolative linkers LC, it is possible to tune the rate of release of the payload, caused by either steric and / or electronic effects on the cyclization and / or cascade release. Synthetic procedures to prepare such substituted benzyl-derivatives are known to the skilled person (see for example [Greenwald et al, J. Med. Chem., 1999, 42, 3657-3667] and [Thornthwaite et al, Polym. Chem., 2011, 2, 773-790]. Some preferred substituted benzyl-derivatives with different release rates are drawn below. Self-immolative linkers that undergo cyclization include but are not limited to substituted and unsubstituted aminobutyric acid amide, appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring system, 2-aminophenylpropionic acid amides, and trimethyl lock-based linkers, see e.g. [Chem. Biol.1995, 2, 223], [J. Am. Chem. Soc.1972, 94, 5815], [J. Org. Chem.1990, 55, 5867], the contents of which are hereby incorporated by reference. Further preferred examples of LCcan be found in WO2009017394(A1), US7375078, WO2015038426A1, WO2004043493, Angew. Chem. Int. Ed.2015, 54, 7492 – 7509, the contents of which are hereby incorporated by reference. Preferably the LChas a mass of no more than 1000 daltons, no more than 500 daltons, no more than 400 daltons, no more than 300 daltons, or from 10, 50 or 100 to 1000 daltons, from 10, 50, 100 to 400 daltons, from 10, 50, 100 to 300 daltons, from 10, 50, 100 to 200 daltons, e.g., 10-1000 daltons, such as 50-500 daltons, such as 100 to 400 daltons. A person skilled in the art will know that one LCmay be connected to another LCthat is bound to CA, wherein upon reaction of the Activator with the Trigger TR, LC-LC-CAis released from the TR, leading to self-immolative release of both LCmoietes and the payload. With respect to the LCformulas disclosed herein, the LClinking the TRto the other LCthen does not release the payload but an LCthat is bound via YC1and further links to CA. The skilled person will acknowledge that this principle also holds for further linkers LClinked to LC, e.g. LC-LC-LC-LC-CA. Preferably, if the releasable group contains a self-immolative linker, the releasable group is according to any one of Group I, Group II, Group III, and Group IV as shown below. In the structures depicted for said Groups, only bonds to Construct A and an atom (typically oxygen) on the allylic position of the eight-membered non-aromatic cyclic mono-alkenylene moiety (preferably a trans-cyclooctene ring) are shown for reasons of clarity, but said Construct A and said atom are part of the releasable group. Releasable groups according to Group I are , wherein the wiggly line may also indicate a bond to -S- on the allylic position of the trans- cyclooctene, wherein U, V, W, Z are each independently selected from the group consisting of -CR7-, and -N-, wherein e is 0 or 1, wherein X is selected from the group consisting of -O-, -S- and -NR6-, wherein preferably each R8and R9are independently selected from the group consisting of hydrogen, C1-C4 (hetero)alkyl, C2-C4 (hetero)alkenyl, and C4-6 (hetero)aryl; wherein for R8and R9the (hetero)alkyl, (hetero)alkenyl, and (hetero)aryl are optionally substituted with a moiety selected from the group consisting of -Cl, -F, -Br, -I, -OH, -NH2,=O, -SH, -SO3H, -PO3H, -PO4H2 and -NO2 and preferably contain at most two heteroatomsselected from the group consisting of -O-, -S-, -NH-, -P-, and -Si-, wherein the N, S, and P atoms are optionally oxidized. Preferably, for releasable groups of Group I both R8and R9are hydrogen. The releasable group according to Group II is , wherein the wiggly line may also indicate a bond to -S- on the allylic position of the trans- cyclooctene, wherein m is an integer between 0 and 2, preferably m is 0, wherein e is 0 or 1. Preferably, for releasable groups of Group II both R8and R9are hydrogen. Preferably, for releasable groups of Group II R7is methyl or isopropyl. Optionally, R6, R7, R8, R9comprised in said Group I, and II, are -(SP)i-CB. For all releasable groups according to Group I and Group II YC1is selected from the group consisting of -O-, -S-, and -NR6-, preferably -NR6-. For all linkers according to Group I, and Group II, YC2is selected from the group consisting of O and S, preferably O. Releasable groups according to Group III are , wherein the wiggly line may also indicate a bond to -S- on the allylic position of the trans- cyclooctene. Releasable groups according to Group IV are

[0004] , wherein the wiggly line may also indicate a bond to -S- on the allylic position of the trans- cyclooctene. Preferably, R6, R7, R8, R9are according to RG1 or any preferred embodiment thereof. Preferably, R6, R7, R8, R9as used herein are not substituted. Most preferably, R6, R7, R8, R9as used herein are hydrogen. Conjugates of the disclosure The disclosure also relates to a conjugate, or a salt, hydrate, or solvate thereof, wherein the conjugate comprises a protein conjugated to at least one compound according to the disclosure wherein T2is a residue of a bioconjugation moiety, and said protein and said compound are conjugated via T2. Thus, the conjugate of the disclosure is to be understood as a compound of the disclosure (wherein T2was originally a bioconjugation moiety) linked to a protein via T2, wherein due to the coupling of said compound and said protein, T2in the conjugate of the disclosure is the residue of a bioconjugation moiety, preferably the residue of an N-maleimidyl group, viz.: wherein the asterisk indicates a bond to the protein, and the wiggly line denotes a bond to the rest of the compound of the disclosure. In the conjugate of the disclosure, the protein is preferably a diabody or an antibody, more preferably a diabody, and most preferably the protein is AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1. Preferably, in the conjugate of the disclosure the protein and the compound of the disclosure are conjugated via T2and a residue of a sulfhydryl of said protein, a residue of a hydroxyl of said protein, or a residue of an amine of said protein; more preferably via T2and a residue of a sulfhydryl of said protein. Preferably, the residue of the sulfhydryl group of said protein is part of a cysteine residue of said protein. Preferably, the conjugate of the disclosure is In relation to conjugates of the disclosure, CJ is in a range of from 1 to 12, preferably CJ is of from 2 to 10, more preferably of from 2.5 to 8, even more preferably of from 3 to 6, and most preferably of from 3.5 to 4. It will be understood that for individual conjugates, CJ is typically an integer, and is most preferably about 4. When measuring CJ for multiple conjugates, however, an average number may be obtained, which is not necessarily an integer. As CJ is commonly determined for multiple conjugates, CJ in relation to the disclosure typically refers to an average number. More preferably, the conjugate is: . . Compositions of the disclosure The disclosure also pertains to a composition comprising a compound according to the disclosure, or the salt, hydrate, or solvate thereof. Preferably, the composition is a pharmaceutical composition. Preferably, the composition of the disclosure further comprises a pharmaceutically acceptable carrier. It is also preferred that if a salt of a compound of the disclosure is included in the composition of the disclosure, a pharmaceutically acceptable salt is used. Combinations of the disclosure The disclosure also relates to a combination of (A1) a compound according to the disclosure, or the salt, hydrate, or solvate thereof; (A2) a conjugate according to the disclosure, or the salt, hydrate, or solvate thereof; and / or (A3) a composition according to the disclosure; with (B) a diene or a salt, solvate, or hydrate thereof. It will be understood that herein, a compound according to the disclosure is a dienophile and / or comprises a dienophile moiety, and may be called a “Trigger”. The diene may be referred to as an “Activator”. Preferably, the combination is of (A1) and (B). Preferably, the combination is of (A2) and (B). Preferably, the combination is of (A3) and (B). Preferably, the combination is of (A1), (A2), and (B). Preferably, the combination is of (A1), (A3), and (B). Preferably, the combination is of (A2), (A3), and (B). Preferably, the combination is of (A1), (A2), (A3), and (B). Preferably, the combination of the disclosure is a kit. More preferably, the combination of the disclosure is a kit wherein (A1), (A2), and / or (A3) is / are physically separated from (B). Preferably the diene is a tetrazine. More preferably, the diene is selected from the group consisting of: salt, hydrate, and / or solvate thereof. Preferably, the diene is (TZ1) or a salt, hydrate, and / or solvate thereof. More preferably, the diene is (TZ2) or a salt, hydrate, and / or solvate thereof. More preferably, the diene is (TZ3) or a salt, hydrate, and / or solvate thereof. More preferably, the diene is (TZ4) or a salt, hydrate, and / or solvate thereof. Most preferably, the diene is (TZ5) or a salt, hydrate, and / or solvate thereof. (TZ1) is the best-studied tetrazine for in vivo use in literature, and the most promising candidate for clinical use. Reference is made to, inter alia, Rossin et al., Angew. Chem. Int. Ed.2010, volume 49, pages 3375-3378; Rossin et al., J. Nucl. Med.2013, volume 54; pages 1989-1995; Rossin et al., Bioconjugate Chem.2013, volume 24, pages 1210-1217; Rossin et al., Mol. Pharm.2014, volume 11, pages 3090-3096; Van Duijnhoven et al., J. Nucl. Med. 2015, volume 56, pages 1422-1428; Edem et al. Molecules 2020, volume 25, page 463; Rossin et al., Bioconjugate Chem.2016, volume 27, pages 1697-1706; Rossin et al., Nature Commun.2018, volume 9, article 1484; WO 2020 / 256546 (in particular Example 5 at pages 294-296). However, the inventors have identified several hitherto unknown disadvantages of (TZ1). These problems mainly arise when using (TZ1) in vivo as an activator for the payload release from an eight-membered non-aromatic cyclic mono-alkenylene moiety (such as a trans-cyclooctene), which require higher doses than when using (TZ1) for radioimaging and / or radiotherapy. First, it was found that compound (TZ1) strongly inhibits the physiologically relevant enzymes cyclooxygenase (COX-1), acetyl cholinesterase (ACES), monoamine oxidase (MAO-B), and calcium channel L-type, dihydropyridine. Each of these proteins is important in maintaining health in a subject, and undesired inhibition of these enzymes and / or transporter may lead to side-effects. Second, it was found that (TZ1) has a relatively low maximum tolerated dose (MTD) in mice of about 39 µmol / kg. Furthermore, the synthesis of (TZ1) comprises many steps, while it is preferred that tetrazines are used that can be synthesized in fewer steps. Finally, it is desired that tetrazines with overall good in vitro and in vivo properties be provided, i.e. one or more of: good stability, good reactivity with and / or high payload release from trans-cyclooctenes (especially in vivo), low membrane permeability, low cell toxicity, and low genotoxicity. It was found that (TZ2), (TZ3), (TZ4), and in particular (TZ5) overcome one or more of these disadvantages of (TZ1). Therefore, combinations with at least one of (TZ2), (TZ3), (TZ4), and (TZ5) are preferred over combinations comprising (TZ1), and combinations with (TZ5) are most preferred. Non-therapeutic methods using and uses for using compounds of the disclosure The disclosure pertains to a non-therapeutic method and a non-therapeutic use. Preferably, the dienophile used therein is as described in relation to the combination of the disclosure. For the non-therapeutic method of the disclosure it is preferred that the compound of the disclosure (viz. (ia)), the conjugate of the disclosure (viz. (iia)), and / or the composition of the disclosure (viz. (iiia)), and the diene are further contacted with a solvent. The skilled person is aware of suitable solvents for a reaction between a trans-cyclooctene (TCO) and a tetrazine. Preferably, the solvent comprises water, and more preferably the solvent is water. For the non-therapeutic use, the click reaction is preferably a bioorthogonal click reaction. Preferably, the click reaction is performed in vitro, although non-therapeutic reactions in vivo can be carried out as well. Medical use The disclosure also relates to a compound of the disclosure, or the salt, hydrate, or solvate thereof; the conjugate of the disclosure, or the salt, hydrate, or solvate thereof; the composition of the disclosure; or the combination of the disclosure; for use in the treatment of a disease in a subject. The disclosure also pertains to a method of treating a disease in a subject, wherein said method comprises the step of administering to said subject: (a) the compound according to the disclosure, or the salt, hydrate, or solvate thereof; (b) the conjugate according to the disclosure, or the salt, hydrate, or solvate thereof; (c) the composition according to the disclosure; and / or (d) the combination according to the disclosure. Use of (a) a compound according to the disclosure, or the salt, hydrate, or solvate thereof; (b) a conjugate according to the disclosure, or the salt, hydrate, or solvate thereof; (c) a composition according to the disclosure; and / or (d) a combination according to the disclosure; for the manufacture of a medicament for the treatment of a disease in a subject. In relation to the medical use, preferably the subject is a human. Preferably, the disease is cancer. Methods of synthesizing compounds of the disclosure The disclosure also relates to a method for synthesizing a compound of the disclosure, wherein said method comprises coupling a compound of Formula (R) to a compound of Formula (S): or an active ester, preferably S10is -COOH. Preferably, in Formula (S) x is an integer of from 4 to 6, and most preferably x is 5. In the method for synthesizing a compound of the disclosure, when S10is -COOH, it is preferred that the compound of Formula (S) is contacted with at least one coupling reagent, preferably in the presence of a base, preferably a non-nucleophilic base. Preferred non- nucleophilic bases are N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN). Preferably, the the at least one coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), 4-(N,N-dimethylamino)pyridine (DMAP), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (7- azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TOTU), (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate (COMU), O-(N-Succinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TSTU), O-(5-Norbornene-2,3-dicarboximido)-N,N,N’,N’- tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-Dihydro-2-oxo-1-pyridyl-N,N,N’,N’- tetramethyluronium tetrafluoroborate (TPTU), N,N,N’,N’-Tetramethyl-O-(3,4-dihydro-4-oxo- 1,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU), 3-(Diethylphosphoryloxy)- 1,2,3-benzotriazin-4(3H)-one (DEPBT), carbonyldiimidazole (CDI), N,N,N’,N’- tetramethylchloroform-amidinium hexafluorophosphate (TCFH), thionyl chloride, oxalyl chloride, cyanuric chloride, cyanuric fluoride, phosphorous trichloride, phosphorous pentachloride, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, and combinations thereof. The skilled person is aware of suitable conditions to carry out a coupling reaction between a compound of Formula (R) and a compound of Formula (S). Preferably, the coupling is carried out at a temperature of from -20°C to 80°C, more preferably of from 0°C to 60°C, even more preferably of from 4°C to 50°C, more preferably still of from 10°C to 40°C, and most preferably of from 15°C to 30°C. Preferably, the coupling is carried out in the presence of a solvent, wherein preferably the solvent is an organic solvent. The disclosure also relates to an alternative method for synthesizing a compound of the disclosure, wherein said method comprises coupling a compound of Formula (T) to a compound of Formula (U): Formula (T); wherein T1and R48are as defined herein; and S11is -COOH or an active ester, preferably S11is an active ester, more preferably S11is selected from the group consisting of - C(O)O-N-succinimidyl, -C(O)O-pentafluorophenyl, -C(O)O-tetrafluorophenyl, -C(O)O-4- nitrophenyl, and -C(O)Cl; even more preferably, S11is -C(O)O-N-succinimidyl, or -C(O)O- pentafluorophenyl; and most preferably, S11is -C(O)O-pentafluorophenyl. Formula (U); wherein T2, x, and y, are as defined herein. Preferably, in Formula (U) x is an integer of from 4 to 6, and most preferably x is 5. In the alternative method for synthesizing a compound of the disclosure, when S11is - COOH, it is preferred that the compound of Formula (S) is contacted with at least one coupling reagent, preferably in the presence of a base, preferably a non-nucleophilic base. Preferred non-nucleophilic bases are N,N-diisopropylethylamine (DIPEA), 1,8- diazabicycloundec-7-ene (DBU), and 1,5-diazabicyclo(4.3.0)non-5-ene (DBN). Preferably, the at least one coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N’,N’- dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), 4- (N,N-dimethylamino)pyridine (DMAP), (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate, (7-azabenzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TOTU), (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate (COMU), O-(N-Succinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TSTU), O-(5-Norbornene-2,3-dicarboximido)-N,N,N’,N’- tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-Dihydro-2-oxo-1-pyridyl-N,N,N’,N’- tetramethyluronium tetrafluoroborate (TPTU), N,N,N’,N’-Tetramethyl-O-(3,4-dihydro-4-oxo- 1,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU), 3-(Diethylphosphoryloxy)- 1,2,3-benzotriazin-4(3H)-one (DEPBT), carbonyldiimidazole (CDI), N,N,N’,N’- tetramethylchloroform-amidinium hexafluorophosphate (TCFH), thionyl chloride, oxalyl chloride, cyanuric chloride, cyanuric fluoride, phosphorous trichloride, phosphorous pentachloride, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, and combinations thereof. The skilled person is aware of suitable conditions to carry out a coupling reaction between a compound of Formula (T) and a compound of Formula (U). Preferably, the coupling is carried out at a temperature of from -20°C to 80°C, more preferably of from 0°C to 60°C, even more preferably of from 4°C to 50°C, more preferably still of from 10°C to 40°C, and most preferably of from 15°C to 30°C. Preferably, the coupling is carried out in the presence of a solvent, wherein preferably the solvent is an organic solvent. Methods of synthesizing conjugates of the disclosure The disclosure also pertains to a method for synthesizing a conjugate of the disclosure, wherein said method comprises the step of coupling a protein to a compound of the disclosure, or a salt, hydrate, or solvate thereof; wherein in said compound T2is a bioconjugation moiety; wherein preferably in said protein disulfide bonds have been reduced. As T2in the compound of the disclosure is preferably a bioconjugation moiety that can react with a sulfhydryl group, such as an N-maleimidyl group, it is preferred that the protein contains free sulfhydryl groups. Typically, such sulfhydryl groups can be obtained by reducing disulfide bonds present in the protein. To that end, it is preferred that the protein has been contacted with a reducing agent prior to the coupling. Preferably, the reducing agent is selected from the group consisting of dithiothreitol (DTT), and tris-2-carboxyethylphosphine hydrochloride (TCEP). If the protein is contacted with a reducing agent prior to the coupling, the reducing agent is preferably DTT. Additionally or alternatively, the formation of free sulfhydryl groups on the protein can also be performed in situ. To that end, preferably the coupling is carried out in the presence of a reducing agent. In that case, it is preferred to use a reducing agent that does not contain free sulfhydryl groups itself. Thus, if the coupling is carried out in the presence of a reducing agent, it is preferred that the reducing agent is TCEP. The skilled person is aware of suitable conditions to carry out the method of synthesizing a conjugate of the disclosure. Prefeably, the coupling is carried out at a temperature of from 0°C to 40°C, more preferably of from 1°C to 30°C, more preferably still of from 2°C to 20°C, even more preferably of from 4°C to 10°C, and most preferably at about 4°C. Preferably, the coupling is carried out in an aqueous solution, preferably the aqueous solution is an aqueous buffer solution. Preferably the coupling is carried out at a pH of from 6.0 to 8.5, preferably of from 6.2 to 8.0, more preferably of from 6.4 to 7.8, even more preferably of from 6.5 to 7.4, more preferably still of from 6.6 to 7.0, and most preferably at a pH of about 6.8. The present disclosure is herein described with respect to particular embodiments, but the disclosure is not limited thereto but only by the claims. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated. The verb "to comprise", and its conjugations, as used in this description and in the claims is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there is one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one". Thus, the scope of the expression "a device comprising means A and B" should not be limited to devices consisting only of components A and B. It means that with respect to the present disclosure, the only relevant components of the device are A and B. The compounds herein may occur in different tautomeric forms. The compounds according to the disclosure are meant to include all tautomeric forms, unless stated otherwise. When the structure of a compound is depicted as a specific tautomer, it is to be understood that the disclosure of the present application is not limited to that specific tautomer, unless stated otherwise. The compounds herein may occur in different enantiomeric forms. The compounds according to the disclosure are meant to include all enantiomeric forms, unless stated otherwise. When the structure of a compound is depicted as a specific enantiomer, it is to be understood that the disclosure of the present application is not limited to that specific enantiomer, unless stated otherwise. Unless stated otherwise, the compounds of the disclosure and / or groups thereof may be protonated or deprotonated. It will be understood that it is possible that a compound may bear multiple charges which may be of opposite sign. For example, in a compound containing an amine and a carboxylic acid, the amine may be protonated while simultaneously the carboxylic acid is deprotonated. Unless stated otherwise, if in this disclosure reference is made to a molecular structure, such as “compound”, “diene”, “tetrazine”, and the like, it will be understood that such a molecular structure may also be in its salt, hydrate, and / or solvate form. In several formulae, groups or substituents are indicated with reference to letters such as “A”, “B”, “X”, “Y”, and various (numbered) “R” groups. In addition, the number of repeating units may be referred to with a letter, e.g. n in -(CH2)n-. The definitions of these letters are to be read with reference to each formula, i.e. in different formulae these letters, each independently, can have different meanings unless indicated otherwise. Herein, reference is made to "alkyl", and the like. The number of carbon atoms that these groups have, excluding the carbon atoms comprised in any optional substituents according to Radical Group 1, can be indicated by a designation preceding such terms (e.g. “C1-C8alkyl” means that said alkyl may have from 1 to 8 carbon atoms). For the avoidance of doubt, a butyl group substituted with a -OCH3 group is designated as a C4 alkyl, because the carbon atom in the substituent is not included in the carbon count. A cycloalkyl group is a cyclic alkyl group. Unsubstituted cycloalkyl groups comprise at least three carbon atoms and have the general formula CnH2n-1. Optionally, the cycloalkyl groups are substituted by one or more substituents further specified in this document. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. An alkenyl group comprises one or more carbon-carbon double bonds, and may be linear or branched. Unsubstituted alkenyl groups comprising one C-C double bond have the general formula CnH2n-1. Unsubstituted alkenyl groups comprising two C-C double bonds have the general formula CnH2n-3. An alkenyl group may comprise a terminal carbon-carbon double bond and / or an internal carbon-carbon double bond. A terminal alkenyl group is an alkenyl group wherein a carbon-carbon double bond is located at a terminal position of a carbon chain. An alkenyl group may also comprise two or more carbon-carbon double bonds. Examples of an alkenyl group include ethenyl, propenyl, isopropenyl, t-butenyl, 1,3- butadienyl, 1,3-pentadienyl, etc. Unless stated otherwise, an alkenyl group may optionally be substituted with one or more, independently selected, substituents according to Radical Group 1. A cycloalkenyl group is a cyclic alkenyl group. An unsubstituted cycloalkenyl group comprising one double bond has the general formula CnH2n-3. Optionally, a cycloalkenyl group is substituted by one or more substituents further specified in this document. An example of a cycloalkenyl group is cyclopentenyl. An alkynyl group comprises one or more carbon-carbon triple bonds, and may be linear or branched. Unsubstituted alkynyl groups comprising one C-C triple bond have the general formula CnH2n-3. An alkynyl group may comprise a terminal carbon-carbon triple bond and / or an internal carbon-carbon triple bond. A terminal alkynyl group is an alkynyl group wherein a carbon-carbon triple bond is located at a terminal position of a carbon chain. An alkynyl group may also comprise two or more carbon-carbon triple bonds. Unless stated otherwise, an alkynyl group may optionally be substituted with one or more, independently selected, substituents according to Radical Group 1. Examples of an alkynyl group include ethynyl, propynyl, isopropynyl, t-butynyl, etc. A cycloalkynyl group is a cyclic alkynyl group. An unsubstituted cycloalkynyl group comprising one triple bond has the general formula CnH2n-5. Optionally, a cycloalkynyl group is substituted by one or more substituents further specified in this document. An example of a cycloalkynyl group is cyclooctynyl. An aryl group refers to an aromatic hydrocarbon ring system that comprises six to twenty-four carbon atoms, more preferably six to twelve carbon atoms, and may include monocyclic and polycyclic structures. When the aryl group is a polycyclic structure, it is preferably a bicyclic structure. Optionally, the aryl group may be substituted by one or more substituents further specified in this document. Examples of aryl groups are phenyl and naphthyl. Preferably, an aryl group is phenyl. Arylalkyl groups and alkylaryl groups comprise at least seven carbon atoms and may include monocyclic and bicyclic structures. Optionally, the arylalkyl groups and alkylaryl may be substituted by one or more substituents further specified in this document. An arylalkyl group is for example benzyl. An alkylaryl group is for example 4-tert-butylphenyl. Preferably, heteroaryl groups comprise five to sixteen carbon atoms and contain between one to five heteroatoms. Heteroaryl groups comprise at least two carbon atoms (i.e. at least C2) and one or more heteroatoms N, O, P or S. A heteroaryl group may have a monocyclic or a bicyclic structure. Optionally, the heteroaryl group may be substituted by one or more substituents further specified in this document. Examples of suitable heteroaryl groups include pyridinyl, quinolinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, pyrrolyl, furanyl, triazolyl, benzofuranyl, indolyl, purinyl, benzoxazolyl, thienyl, phospholyl and oxazolyl. Heteroarylalkyl groups and alkylheteroaryl groups comprise at least three carbon atoms (i.e. at least C3) and may include monocyclic and bicyclic structures. Optionally, the heteroaryl groups may be substituted by one or more substituents further specified in this document. Where an aryl group is denoted as a (hetero)aryl group, the notation is meant to include an aryl group and a heteroaryl group. Similarly, an alkyl(hetero)aryl group is meant to include an alkylaryl group and an alkylheteroaryl group, and (hetero)arylalkyl is meant to include an arylalkyl group and a heteroarylalkyl group. A C2-C24 (hetero)aryl group is thus to be interpreted as including a C2-C24heteroaryl group and a C6-C24aryl group. Similarly, a C3- C24 alkyl(hetero)aryl group is meant to include a C7-C24 alkylaryl group and a C3-C24 alkylheteroaryl group, and a C3-C24 (hetero)arylalkyl is meant to include a C7-C24 arylalkyl group and a C3-C24heteroarylalkyl group. In general, when (hetero) is placed before a group, it refers to both the variant of the group without the prefix hetero- as well as the group with the prefix hetero-. Herein, the prefix hetero- denotes that the group contains one or more heteroatoms selected from the group consisting of O, N, S, P, and Si. Preferably, the one or more heteroatoms is selected from the group consisting of O, N, S, and P. It will be understood that for any compound containing a heteroatom, the N, S, and P atoms are optionally oxidized and the N atoms are optionally quaternized. Preferably, up to two heteroatoms are consecutive, such as in for example -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. More preferably, however, the heteroatoms are not directly bound to one another. Examples of heteroalkyls include -CH2CH2-O-CH3, -CH2CH2-NH-CH3, -CH2CH2- S(O)-CH3, -CH=CH-O-CH3, CH2CH2-NH2, CH2CH2-SH, -CH2CH2-OH, -CH2CH2-COOH, - CH2C(O)H, -C(O)HCH3, and -Si(CH3)3. Preferably, a C1-C4 heteroalkyl contains at most 2 heteroatoms. Herein, it will be understood that when the prefix hetero- is used for combinations of groups, the prefix hetero- only refers to the one group before it is directly placed. For example, heteroarylalkyl denotes the combination of a heteroaryl group and an alkyl group, not the combination of a heteroaryl and a heteroalkyl group. Herein, the prefix cyclo- denotes that groups are cyclic. It will be understood that when the prefix cyclo- is used for combinations of groups, the prefix cyclo- only refers to the one group before it is directly placed. For example, cycloalkylalkenylene denotes the combination of a cycloalkylene group (see the definition of the suffix -ene below) and an alkenylene group, not the combination of a cycloalkylene and a cycloalkenylene group. In general, when (cyclo) is placed before a group, it refers to both the variant of the group without the prefix cyclo- as well as the group with the prefix cyclo-. Herein, the suffix -ene denotes divalent groups, i.e. that the group is linked to at least two other moieties. An example of an alkylene is propylene (-CH2-CH2-CH2-), which is linked to another moiety at both termini. It is understood that if a group with the suffix -ene is substituted at one position with -H, then this group is identical to a group without the suffix. For example, an alkylene attached to an -H is identical to an alkyl group. I.e. propylene, - CH2-CH2-CH2-, attached to an -H at one terminus, -CH2-CH2-CH2-H, is logically identical to propyl, -CH2-CH2-CH3. Herein, when combinations of groups are listed with the suffix -ene, it refers to a divalent group, i.e. that the group is linked to at least two other moieties, wherein each group of the combination contains one linkage to one of these two moieties. As such, for example alkylarylene is understood as a combination of an arylene group and an alkylene group. An example of an alkylarylene group is -phenyl-CH2-, and an example of an arylalkylene group is -CH2-phenyl-. Herein, the suffix -triyl denotes trivalent groups, i.e. that the group is linked to at least three other moieties. An example of an arenetriyl is depicted below: , wherein the wiggly lines denote bonds to different groups of the main compound. It is understood that if a group with the suffix -triyl is substituted at one position with - H, then this group is identical to a divalent group with the suffix -ene. For example, an arenetriyl substituted with -H is identical to an arylene group. Similarly, it is understood that if a group with the suffix -triyl is substituted at two positions with -H, then this group is identical to a monovalent group. For example, an arenetriyl substituted with two -H is identical to an aryl group. Unless indicated otherwise, a hetero group may contain a heteroatom at non-terminal positions or at one or more terminal positions. In this case, “terminal” refers to the terminal position within the group, and not necessarily to the terminal position of the entire compound. For example, C2 heteroalkylene may refer to -NH-CH2-CH2-, -CH2-NH-CH2-, and -CH2-CH2- NH-. For example, C2 heteroalkyl may refer to -NH-CH2-CH3, -CH2-NH-CH3, and -CH2- CH2-NH2. Herein, it is understood that cyclic compounds (i.e. aryl, cycloalkyl, cycloalkenyl, etc.) are understood to be monocyclic, polycyclic or branched. It is understood that the number of carbon atoms for cyclic compounds not only refers to the number of carbon atoms in one ring, but that the carbon atoms may be comprised in multiple rings. These rings may be fused to the main ring or substituted onto the main ring. For example, C10 aryl optionally containing heteroatoms may refer to inter alia a naphthyl group (fused rings) or to e.g. a bipyridyl group (substituted rings, both containing an N atom). Unless stated otherwise, any group disclosed herein that is not cyclic is understood to be linear or branched. In particular, (hetero)alkyl groups, (hetero)alkenyl groups, (hetero)alkynyl groups, (hetero)alkylene groups, (hetero)alkenylene groups, (hetero)alkynylene groups, and the like are linear or branched, unless stated otherwise. As used herein, unless stated otherwise all of the following groups: (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)cycloalkyl, (hetero)cycloalkenyl, (hetero)cycloalkynyl, (hetero)aryl, (hetero)alkylene, (hetero)alkenylene, (hetero)alkynylene, (hetero)cycloalkylene, (hetero)cycloalkenylene, (hetero)cycloalkynylene, (hetero)arylene, (hetero)alkanetriyl, (hetero)cycloalkanetriyl, arenetriyl, heteroarenetriyl, combinations thereof, and the like, can be substituted or unsubstituted; preferably these groups are unsubstituted. If said groups are substituted, said groups preferably contain up to 4, more preferably up to 3, more preferably still up to 2, and most preferably 1 substituent according to Radical Group 1 as defined herein. The general term "sugar" is herein used to indicate a monosaccharide, for example glucose (Glc), galactose (Gal), mannose (Man) and fucose (Fuc). The term "sugar derivative" is herein used to indicate a derivative of a monosaccharide sugar, i.e. a monosaccharide sugar comprising substituents and / or functional groups. Examples of a sugar derivative include amino sugars and sugar acids, e.g. glucosamine (GlcNH2), galactosamine (GalNH2) N- acetylglucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), sialic acid (Sia) which is also referred to as N-acetylneuraminic acid (NeuNAc), and N-acetylmuramic acid (MurNAc), glucuronic acid (GlcA) and iduronic acid (ldoA). A sugar may be without further substitution, and then it is understood to be a monosaccharide. A sugar may be further substituted with at one or more of its hydroxyl groups, and then it is understood to be a disaccharide or an oligosaccharide. A disaccharide contains two monosaccharide moieties linked together. An oligosaccharide chain may be linear or branched, and may contain from 3 to 10 monosaccharide moieties. The term “amino acid” is used herein in its normal scientific meaning. In particular, amino acids in relation to the disclosure comprise both natural and unnatural amino acids. Preferably, amino acids as used herein are selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, azidolysine, beta-alanine (bAla), 4-aminomethyl phenylalanine (Amf), 4- guanidine phenylalanine (Gnf), 4-aminomethyl-N-isopropyl phenylalanine (Iaf), 3-pyridyl alanine (Pya), 4-piperidyl alanine (Ppa), 4-aminomethyl cyclohexyl alanine (Ama), 4- aminocyclohexyl alanine (Aca), ornithine (Orn), citrulline, hydroxylysine (Hyl), allo- hydroxylysine (aHyl), 6-N-methyllysine (MeLys), desmosine (Des), isodesmosine (Ide), 2- aminoadipic acid (Aad), 3-aminoadipic acid (bAad), 2-aminobutyric acid (Abu), 4- aminobutyric acid (4Abu), 6-aminohexonic acid (Acp), 2-aminoheptanoic acid (Ahe), 2- aminoisobutyric acid (Aib), 3-aminoisobutyric acid (bAib), 2-aminopimelic acid (Apm), 2,4- diaminobutyric acid (Dbu), 2,2’-diaminopimelic acid (Dpm), 2-3-diaminopropionic acid (Dpr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), 3-hydroxyproline (3Hyp), 4- hydroxyproline (4Hyp), allo-isoleucine (AIle), sarcosine (MeGly), N-methylisoleucine (MeIle), N-methylvaline (MeVal), norvaline (Nva), and norleucine (Nle). The term "protein" is herein used in its normal scientific meaning. Herein, polypeptides comprising about 10 or more amino acids are considered proteins. A protein may comprise natural, but also unnatural amino acids. The term “protein” herein is understood to comprise antibodies and antibody fragments. The term “peptide” is herein used in its normal scientific meaning. Herein, peptides are considered to comprise a number of amino acids in a range of from 2 to 9. The term “peptoid” is herein used in its normal scientific meaning. A spacer is herein defined as a moiety that connects two or more elements of a compound. The terms “spacer” and “linker” are used herein interchangeably. Typically, a spacer is herein denoted as SP, and the more specific self-immolative linkers as LC. It will be understood that when herein, it is stated that “each individual SPis linked at all ends to the remainder of the structure” this refers to the fact that the spacer SPconnects multiple moieties within a structure, and therefore the spacer has multiple ends by defintion. The spacer SPmay be linked to each individual moiety via different or identical moieties that may be each individually selected. Typically, these linking moieties are to be seen to be part of spacer SPitself. In case the spacer SPlinks two moieties within a structure, “all ends” should be interpreted as “both ends”. As an example, if the spacer connects a trans-cylooctene moiety to a Construct B, then “the remainder of the molecule” refers to the trans-cylooctene moiety and Construct B, while the connecting moieties between the spacer and the trans-cyclooctene moiety and Construct B (i.e. at both ends) may be individually selected. As used herein, an organic molecule is defined as a molecule comprising a C-H bond. Organic compound and organic molecule are used synonymously. As used herein, an inorganic molecule is defined as any molecule not being an organic molecule, i.e. not comprising a C-H bond. It will be understood that “inorganic molecule” typically also comprises hydrogen, -COOH, etc. As used herein, a “small molecule” is preferably a small organic molecule. In general, a small molecule has a molecular weight of at most 2 kDa, more preferably at most 1 kDa, more preferably at most 750 Da, more preferably at most 500 Da, and most preferably at most 300 Da. Preferably, a small molecule has a molecular weight of at least 15 Da, more preferably at least 50 Da, more preferably at least 75 Da, and most preferably at least 100 Da. As used herein, “particle” is preferably defined as a microparticle or a nanoparticle. The term "salt thereof” means a compound formed when an acidic proton, typically a proton of an acid, is replaced by a cation, such as a metal cation or an organic cation and the like. The term "salt thereof” also means a compound formed when an amine is protonated. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts that are not intended for administration to a patient. For example, in a salt of a compound the compound may be protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt. The term "pharmaceutically accepted salt” means a salt that is acceptable for administration to a patient, such as a mammal (salts with counter-ions having acceptable mammalian safety for a given dosage regime). Such salts may be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions known in the art and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc. As used herein, the term “solvate” refers to a compound that apart from a main molecule (e.g. a compound of the disclosure, a diene, and the like) further includes a stoichiometric or non-stoichiometric amount of solvent bound to said main molecule by non- covalent intermolecular forces. In particular, the term “solvate” may refer to a crystalline compound, the crystal lattice structure of which contains one or more molecules of the solvent. As used herein, the term “hydrate” refers to a compound that apart from a main molecule (e.g. a compound of the disclosure, a diene, and the like) further includes a stoichiometric or non-stoichiometric amount of water bound to said main molecule by non- covalent intermolecular forces. In particular, the term “hydrate” may refer to a crystalline compound, the crystal lattice structure of which contains one or more molecules of water. The logarithm of the partition-coefficient, i.e. Log P, is herein used as a measure of the hydrophobicity of a compound. Typically, the Log P is defined as ^^^^−^^^^^^^^^^^^^^ log The skilled person is aware of methods to determine the partition-coefficient of compounds without undue experimentation. Alternatively, the skilled person knows that software is available to reliably estimate the Log P value, for example as a function within ChemDraw® software or online available tools. The unified atomic mass unit or Dalton is herein abbreviated to Da. The skilled person is aware that Dalton is a regular unit for molecular weight and that 1 Da is equivalent to 1 g / mol (grams per mole). It will be understood that herein, the terms “moiety” and “group” are used interchangeably when referring to a part of a molecule. It will be understood that when a heteroatom is denoted as -X(R’)2-, wherein X is the heteroatom and R’ is a certain moiety, then this denotes that two moieties R’ are attached to the heteroatom. It will be understood that when a group is denoted as, for example, -((R51)2-R52)2- or a similar notation, in which R51 and R52 are certain moieties, then this denotes that first, it should be written as -R51-R51-R52-R51-R51-R52- before the individual R51and R52moieties are selected, rather than first selecting moieties R51and R52and then writing out the formula. As used herein, “activated carboxylic acid” and “active ester” may be used interchangeably. As the skilled person is aware, an “activated carboxylic acid” or an “active ester” is a derivative of a carboxylic acid (-C(O)OH) of which the -OH moiety has been exchanged for a better leaving group. Preferred activated carboxylic acids or active esters are selected from the group consisting of -C(O)O-N-succinimidyl, -C(O)O-pentafluorophenyl, - C(O)O-tetrafluorophenyl, -C(O)O-4-nitrophenyl, and -C(O)Cl. More preferably, the activated carboxylic acid or active ester is -C(O)O-N-succinimidyl, or -C(O)O-pentafluorophenyl. As the skilled person is aware, an “active carbonate” is a derivative of a carbonate (-O- C(O)-OH) of which the -OH moiety has been exchanged for a better leaving group. Preferred active carbonates are -OC(O)O-N-succinimidyl, -OC(O)O-pentafluorophenyl, -OC(O)O- tetrafluorophenyl, -OC(O)O-4-nitrophenyl, and -OC(O)Cl. More preferably, the active carbonate is -OC(O)O-N-succinimidyl, or -OC(O)O-pentafluorophenyl. As used herein, a “drug” refers to a pharmaceutical agent. As such, “drug”, “pharmaceutical agent”, “therapeutic agent”, and “medicine” can typically be used interchangeably. A preferred drug in relation to the disclosure is exatecan or an exatecan derivative, most preferably exatecan. Radical groups (RG) Radical Group 1: terminal groups For Radical Group 1 (RG1), the radical is selected from the group consisting of -H, - Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -CN, -N3, -NCS, -SCN, -SO3H, -PO3H, -PO4H2, -NO2, -CF3, -CF2H, -CFH2, =O, =NH, -SH, -SO2H, -(SP)i-CB, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)cycloalkyl, (hetero)cycloalkenyl, (hetero)cycloalkynyl, (hetero)aryl, and combinations thereof. Herein, SPis a spacer as defined herein, CBis Construct B as defined herein, and i is an integer in a range of from 0 to 4, preferably i is 0 or 1. For RG1, “combinations thereof” in particular refers to (hetero)alkylcycloalkyl, (hetero)alkylcycloalkenyl, (hetero)alkylcycloalkynyl, (hetero)cycloalkylalkyl, (hetero)cycloalkenylalkyl, (hetero)cycloalkynylalkyl, (hetero)alkenylcycloalkyl, (hetero)alkenylcycloalkenyl, (hetero)alkenylcycloalkynyl, (hetero)cycloalkylalkenyl, (hetero)cycloalkenylalkenyl, (hetero)cycloalkynylalkenyl, (hetero)alkynylcycloalkyl, (hetero)alkynylcycloalkenyl, (hetero)alkynylcycloalkynyl, (hetero)cycloalkylalkynyl, (hetero)cycloalkenylalkynyl, (hetero)cycloalkynylalkynyl, (hetero)arylalkyl, (hetero)arylalkenyl, (hetero)arylalkynyl, alkyl(hetero)aryl, alkenyl(hetero)aryl, alkynyl(hetero)aryl, cycloalkyl(hetero)aryl, cycloalkenyl(hetero)aryl, cycloalkynyl(hetero)aryl, (hetero)arylcycloalkyl, (hetero)arylcycloalkenyl, and (hetero)arylcycloalkynyl. In addition, “combinations thereof” in relation to RG1 also refers to e.g. an alkyl group substituted with one or more -Cl and / or -OH groups. As such, RG1 also comprises radicals such as -NH-CH2-COOH (a glycine residue), which is a combination of a heteroalkyl and -COOH. Preferably, for RG1 the radical is selected from the group RG1a consisting of -H, -Cl,-F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H, -PO4H2, -NO2, -CF3, =O, =NH, -SH,-(SP)i-CB, C1-C24(hetero)alkyl, C2-C24(hetero)alkenyl, C2-C24(hetero)alkynyl, C3-C24cycloalkyl, C2-C24heterocycloalkyl, C5-C24cycloalkenyl, C3-C24heterocycloalkenyl, C7-C24cycloalkynyl, C5-C24 (hetero)cycloalkynyl, C6-C24 aryl, C2-C24 heteroaryl, and combinations thereof. More preferably, for RG1 the radical is selected from the group RG1b consisting of -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H, -PO4H2, -NO2, -CF3, =O,=NH, -SH, -(SP)i-CB, C1-C12 (hetero)alkyl, C2-C12 (hetero)alkenyl, C2-C12 (hetero)alkynyl, C3- C12cycloalkyl, C2-C12heterocycloalkyl, C5-C12cycloalkenyl, C3-C12heterocycloalkenyl, C7- C12cycloalkynyl, C5-C12(hetero)cycloalkynyl, C6-C12aryl, C2-C12heteroaryl, and combinations thereof. Even more preferably, for RG1 the radical is selected from the group RG1c consistingof -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H, -PO4H2, -NO2, -CF3, =O,=NH, -SH, -(SP)i-CB, C1-C8 (hetero)alkyl, C2-C8 (hetero)alkenyl, C2-C8 (hetero)alkynyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C5-C8 cycloalkenyl, C3-C8 heterocycloalkenyl, C7-C8 cycloalkynyl, C5-C8(hetero)cycloalkynyl, C6-C8aryl, C2-C8heteroaryl, and combinations thereof. More preferably still, for RG1 the radical is selected from the group RG1d consistingof -H, -Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H, -PO4H2, -NO2, -CF3, =O,=NH, -SH, -(SP)i-CB, C1-C6 (hetero)alkyl, C2-C6 (hetero)alkenyl, C2-C6 (hetero)alkynyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, C5-C7 cycloalkenyl, C3-C5 heterocycloalkenyl, C8 cycloalkynyl, C6-C7(hetero)cycloalkynyl, phenyl, C3-C5heteroaryl, and combinations thereof. Most preferably, for RG1 the radical is selected from the group RG1e consisting of -H,-Cl, -F, -Br, -I, -OH, -NH2, -COOH, -CONH2, -SO3H, -PO3H, -PO4H2, -NO2, -CF3, =O, =NH,-SH, -(SP)i-CB, C1-C3(hetero)alkyl, C3-C6cycloalkyl, C2-C5heterocycloalkyl, phenyl, C4-C5heteroaryl, and combinations thereof. In some embodiments, for RG1 the radical is a conjugation moiety, which is a chemical group that can be used for binding, conjugation or coupling of a Construct, such as Construct-B, or a Spacer, or another molecule or construct of interest. The person skilled in the art is aware of the myriad of strategies that are available for the chemoselective or -unselective or enzymatic coupling or conjugation of one molecule or construct to another. In some embodiments, RG1 is a moiety that allows conjugation to a protein comprising natural and / or non-natural amino acids. Moieties suitable for conjugation are known to the skilled person. Conjugation strategies are for example found in [O. Boutureira, G.J.L. Bernardes, Chem. Rev., 2015, 115, 2174-2195]. If RG1 is a conjugation moiety, it is preferably selected from the group RG1f consisting of N-maleimidyl, halogenated N-alkylamido, sulfonyloxy N-alkylamido, vinyl sulfone, (activated) carboxylic acids, active ester, benzenesulfonyl halides, ester, carbonate, sulfonyl halide, thiol or derivatives thereof, C2-6alkenyl, C2-6alkynyl, C7-18cycloalkynyl, C5-18 heterocycloalkynyl, bicyclo[6.1.0]non-4-yn-9-yl], C3-12 cycloalkenyl, azido, phosphine, nitrile oxide, nitrone, nitrile imine, isonitrile, diazo, ketone, (O-alkyl)hydroxylamino, hydrazine, halogenated N-maleimidyl, aryloxymaleimides, dithiophenolmaleimides, bromo- and dibromopyridazinediones, 2,5-dibromohexanediamide, alkynone, 3-arylpropiolonitrile, 1,1-bis(sulfonylmethyl)-methylcarbonyl or elimination derivatives thereof, carbonyl halide, allenamide, 1,2-quinone, isothiocyanate, isocyanate, aldehyde, triazine, squaric acids, 2- imino-2-methoxyethyl, (oxa)norbornene, (oxa)norbornadiene, (imino)sydnones, methylsulfonyl phenyloxadiazole, aminooxy, 2-amino benzamidoxime, ethynylphosphonamidates, reactive in the Pictet−Spengler ligation and hydrazine- Pictet−Spengler (HIPS) ligation, DNA intercalators, tetrazine, trans-cyclooctene, and photocrosslinkers. More preferably, RG1f is N-maleimidyl. In other embodiments RG1f is selected from the group consisting of hydroxyl, amine, halogens, vinyl pyridine, disulfide, pyridyl disulfide, sulfonyloxy, mercaptoacetamide, anhydride, sulfonylated hydroxyacetamido, sulfonyl chlorides, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. In yet other embodiments RG1f is a group that can be connected to another group by means of an enzyme, for example sortase or Tubulin tyrosine ligase. Radical Group 2: connecting groups For Radical Group 2 (RG2), the radical is selected from the group consisting of (hetero)alkylene, (hetero)alkenylene, (hetero)alkynylene, (hetero)cycloalkylene, (hetero)cycloalkenylene, (hetero)cycloalkynylene, (hetero)arylene, amino acid, peptide, protein, polymer, oligonucleotide, nucleotide, carbohydrate, RG2a, RG2b, RG2c, and combinations thereof. The radicals from RG2 are optionally attached to one or more radicals according to RG1. Thus, RG2 also covers e.g. -NH-CH(CH2OH)-C(O)- (i.e. a serine residue), which is a heteroalkylene attached to -OH and =O. For RG2, “combinations thereof” in particular, but not exclusively, refers to alkyl(hetero)arylene, (hetero)arylalkylene, (hetero)arylalkenylene, (hetero)arylalkynylene, alkenyl(hetero)arylene, and alkynyl(hetero)arylene. Preferably, for RG2 the radical is selected from the group consisting of C1-C24(hetero)alkylene, C2-C24 (hetero)alkenylene, C2-C24 (hetero)alkynylene, C3-C24 cycloalkylene, C2-C24 heterocycloalkylene, C5-C24 cycloalkenylene, C3-C24 heterocycloalkenylene, C7-C24 cycloalkynylene, C5-C24(hetero)cycloalkynylene, C6-C24arylene, C2-C24heteroarylene, amino acid, peptide, protein, polymer, oligonucleotide, nucleotide, carbohydrate, RG2a, RG2b, RG2c, and combinations thereof. More preferably, for RG2 the radical is selected from the group consisting of C1-C12(hetero)alkylene, C2-C12(hetero)alkenylene, C2-C12(hetero)alkynylene, C3-C12cycloalkylene, C2-C12 heterocycloalkylene, C5-C12 cycloalkenylene, C3-C12 heterocycloalkenylene, C7-C12 cycloalkynylene, C5-C12(hetero)cycloalkynylene, C6-C12arylene, C2-C12heteroarylene, amino acid, peptide, protein, polymer, oligonucleotide, nucleotide, carbohydrate, RG2a, RG2b, RG2c, and combinations thereof. Even more preferably, for RG2 the radical is selected from the group consisting of C1- C8(hetero)alkylene, C2-C8(hetero)alkenylene, C2-C8(hetero)alkynylene, C3-C8cycloalkylene, C2-C8 heterocycloalkylene, C5-C8 cycloalkenylene, C3-C8 heterocycloalkenylene, C7-C8 cycloalkynylene, C5-C8 (hetero)cycloalkynylene, C6-C8 arylene, C2-C8heteroarylene, amino acid, peptide, protein, polymer, oligonucleotide, nucleotide, carbohydrate, RG2a, RG2b, RG2c, and combinations thereof. More preferably still, for RG2 the radical is selected from the group consisting of C1- C6(hetero)alkylene, C2-C6(hetero)alkenylene, C2-C6(hetero)alkynylene, C3-C6cycloalkylene, C2-C6heterocycloalkylene, C5-C7cycloalkenylene, C3-C5 heterocycloalkenylene, C8cycloalkynylene, C6-C7(hetero)cycloalkynylene, phenylene, C3-C5heteroarylene, amino acid, peptide, protein, polymer, oligonucleotide, nucleotide, carbohydrate, RG2a, RG2b, RG2c, and combinations thereof. Even more preferably still, for RG2 the radical is selected from the group consisting of C1-C3 (hetero)alkylene, C3-C6 cycloalkylene, C2-C5 heterocycloalkylene, phenylene, C4-C5 heteroarylene, amino acid, peptide, protein, polymer, oligonucleotide, nucleotide, carbohydrate, RG2a, RG2b, RG2c, and combinations thereof. RG2a is selected from the group consisting of -O-, -S-, -SS-, -NR4-, -N=N-, -C(O)-, - C(O)NR4-, -OC(O)-, -C(O)O-, -OC(O)O-, -OC(O)NR4-, -NR4C(O)-, -NR4C(O)O-, - NR4C(O)NR4-, -SC(O)-, -C(O)S-, -SC(O)O-, -OC(O)S-, -SC(O)NR4-, -NR4C(O)S-, -S(O)-, - S(O)2-, -OS(O)2-, -S(O2)O-, -OS(O)2O-, -OS(O)2NR4-, -NR4S(O)2O-, -C(O)NR4S(O)2NR4-, - OC(O)NR4S(O)2NR4-, -OS(O)-, -OS(O)O-, -OS(O)NR4-, -ONR4C(O)-, -ONR4C(O)O-, - ONR4C(O)NR4-, -NR4OC(O)-, -NR4OC(O)O-, -NR4OC(O)NR4-, -ONR4C(S)-, -ONR4C(S)O- , -ONR4C(S)NR4-, -NR4OC(S)-, -NR4OC(S)O-, -NR4OC(S)NR4-, -OC(S)-, -C(S)O-, - OC(S)O-, -OC(S)NR4-, -NR4C(S)-, -NR4C(S)O-, -SS(O)2-, -S(O)2S-, -OS(O2)S-, -SS(O)2O-, - NR4OS(O)-, -NR4OS(O)O-, -NR4OS(O)NR4-, -NR4OS(O)2-, -NR4OS(O)2O-, - NR4OS(O)2NR4-, -ONR4S(O)-, -ONR4S(O)O-, -ONR4S(O)NR4-, -ONR4S(O)2O-, - ONR4S(O)2NR4-, -ONR4S(O)2-, -OP(O)(R4)2-, -SP(O)(R4)2-, and -NR4P(O)(R4)2-. Herein, R4 is according to RG1, preferably R4 is hydrogen or methyl, more preferably R4 is hydrogen. Preferably, RG2a is selected from the group consisting of -O-, -S-, -SS-, -NR4-, -N=N- , -C(O)-, -C(O)NR4-, -OC(O)-, -C(O)O-, -OC(O)NR4-, -NR4C(O)-, -NR4C(O)O-, - NR4C(O)NR4-, -SC(O)-, -C(O)S-, -SC(O)O-, -OC(O)S-, -SC(O)NR4-, -NR4C(O)S-, -S(O)-, - S(O)2-, -C(O)NR4S(O)2NR4-, -OC(O)NR4S(O)2NR4-, -OC(S)-, -C(S)O-, -OC(S)O-, - OC(S)NR4-, -NR4C(S)-, -NR4C(S)O-, and -SS(O)2-. More preferably, for RG2 the radical is RG2b or RG2c, most preferably RG2b. RG2b is selected from the group consisting of Therein, R' is a radical according to RG1, preferably R’ is hydrogen or C1-3 alkyl. The dashed and wiggly lines denote bonds to the other parts of the molecule. RG2c is selected from the group consisting of Therein, R' is a radical according to RG1, preferably R’ is hydrogen or C1-3 alkyl. The dashed and wiggly lines denote bonds to the other parts of the molecule. Radical Group 3: organic molecule For Radical Group 3 (RG3) the radical is an organic molecule selected from the group consisting of a nucleic acid, a peptide, a protein, a carbohydrate, an aptamer, a hormone, a toxin, a steroid, a cytokine, a lipid, a small organic molecule as defined herein, a polymer, LNA, PNA, an amino acid, a peptoid, a chelating moiety, a molecule comprising a radionuclide, a fluorescent dye, a phosphorescent dye, a drug, a resin, a bead, an organic particle, a gel, an organic surface, an organometallic compound, a cell, and combinations thereof. Preferably, for RG3 the radical is a a nucleic acid, a peptide, a protein, a carbohydrate, a lipid, a polymer, an amino acid, a chelating moiety, a drug, or a gel. As used herein, a nucleic acid is preferably selected from the group consisting of an oligonucleotide, a polynucleotide, DNA, and RNA. As used herein, a protein is preferably an antibody or a diabody. A preferred antibody is CC49, and a preferred diabody is AVP0458. As used herein, a carbohydrate is preferably selected from the group consisting of a monosaccharide, an oligosaccharide, and a polysaccharide. As used herein, a polymer is typically selected from the group consisting of polyethyleneglycol (PEG), poly(N-(2-hydroxypropyl)methacrylamide) (HPMA), polylactic acid (PLA), polylactic-glycolic acid (PLGA), polyglutamic acid (PG), polyvinylpyrrolidone (PVP), poly(1-hydroxymethylethylene hydroxymethyl-formal (PHF), copolymers of a polyacetal / polyketal and a hydrophilic polymer selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, oligopeptides, polypeptides and derivatives thereof, oligopeptides, polypeptides, glycopolysaccharides, and polysaccharides such as dextran and hyaluronan. Preferably, a polymer as used herein is polyethylene glycol (PEG). As used herein, a resin is preferably a polystyrene resin or an agarose resin. As used herein, an organic particle is preferably a liposome or a polymersome. As used herein, a chelating moiety is preferably selected from the group consisting of DTPA (diethylenetriaminepentaacetic acid), DOTA (1,4,7,10- tetraazacyclododecane- N,N',N",N"-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N',N"­triacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N,N',N",N'-tetraacetic acid), OTTA (N1-(p- isothiocyanatobenzyl)-diethylenetriamine-N1,N2,N3,N3-tetraacetic acid), deferoxamine or DFA (N'­[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4- dioxobutyl]hydroxyamino]pentyl]-N-(5-aminopentyl)-N-hydroxybutanediamide) or HYNIC (hydrazinonicotinamide), EDTA (ethylenediaminetetraacetic acid), OTAM, TACN, sarcophagine, and 3,4-HOPO-based chelators. More preferably, herein a chelating moiety is selected from the group consisting of wherein the wiggly line denotes a bond to the remaining part of the molecule, optionally bound via -C(O)NH-, wherein the chelator moieties according to said group optionally chelate a metal, wherein the metal is preferably selected from the group consisting of44Sc,62Cu,64Cu,66Ga,67Ga,67Cu,68Ga,86Y,89Zr,90Y,99mTc,111In,166Ho,177Lu,186Re,188Re,211Bi,212Bi,212Pb,213Bi,214Bi, and225Ac. Radical Group 4: inorganic molecule For Radical Group 4 (RG4), the radical is an inorganic molecule selected from the group consisting of an inorganic surface, an inorganic particle, an allotrope of carbon, an inorganic drug, a radionuclide, and combinations thereof. As used herein, an inorganic surface is preferably selected from the group consisting of chips, wafers, metal such as gold, and silica-based surfaces such as glass. As used herein, an inorganic particle is preferably selected from the group consisting of beads, silica-based particles, polymer-based materials, and iron oxide particles. Preferably, a bead is a magnetic bead or a gold bead. As used herein, an allotrope of carbon is preferably selected from the group consisting of fullerenes such as Buckminsterfullerene; graphite, graphene, diamond, Lonsdaleite, Q- carbon, linearn acetylenic carbon, amorphous carbon, and carbon nanotubes. As used herein, an inorganic drug is preferably cisplatin. Radical group 5: further terminal groups For RG5 the radical is: wherein the dashed line indicates a bond to the remaining part of the dienophile or diene. For RG5, each R10is independently selected from RG2, preferably from RG2a. For RG5, each R11 is independently selected from RG2, preferably not being RG2a, RG2b, or RG2c. For RG5, R12is selected from RG1 or RG3, preferably RG3, more preferably a protein, polymer, or chelating moiety. Preferably, z is an integer in a range of from 0 to 12, preferably from 0 to 10, more preferably from 0 to 8, even more preferably from 1 to 6, most preferably from 2 to 4. Preferably, z is 0. In case the compound according to the disclosure comprises more than one moiety RG5, each z is independently selected. Preferably, h is 0 or 1. In case the compound according to the disclosure comprises more than one moiety RG5, each h, z, and n is independently selected. Preferably, each n belonging to RG5 is an integer independently selected from a range of from 0 to 24, preferably from 1 to 12, more preferably from 1 to 6, even more preferably from 1 to 3. Preferably, n is 1. In other preferred embodiments n is an integer in the range from 12 to 24. Preferably, z is 0, and n is 1. In other embodiments, z is 1, and n is 1. Preferably, the moiety RG5 has a molecular weight in a range of from 100 Da to 3000 Da, preferably, in a range of from 100 Da to 2000 Da, more preferably, in a range of from 100 Da to 1500 Da, even more preferably in a range of from 150 Da to 1500 Da. Even more preferably still, the moiety RG5 has a molecular weight in a range of from 150 Da to 1000 Da, most preferably in a range of from 200 Da to 1000 Da. Preferably, RG5 is selected from the group RG5a consisting of: , wherein the wiggly line denotes a bond to the remainder of the molecule. It is understood that when n is more than 1, -((R10)h-R11)n-(R10)h-R12 may be preceded by a group -(R10)h-R11- so as to form a group -(R10)h-R11-((R10)h-R11)n-(R10)h-R12. It is understood that this follows from the definition of how to write out the repeating units, i.e. -((R10)h-R11)2- would first be written as -(R10)h-R11-(R10)h-R11- before R10, h, and R11 are independently selected. Examples Example 1: synthesis of compounds 11a and 11b Compound 11a was prepared in several steps in situ. To a suspension of exatecan mesylate (7) (287 mg, 0.54 mmol, MedChemExpress) in 6 mL of anhydrous dimethylformamide (DMF) in a glass vial was added compound 8 (506 mg, 0.90 mmol) and diethylamine (DIEA; 313 µL, 1.80 mmol). The mixture was stirred at room temperature in the dark for 2 h, at which point LC-MS analysis indicated complete consumption of 7a and formation of intermediate 9a. The excess of compound 8 was quenched by addition of N- isopropylmethylamine (73 mg, 1.0 mmol) and stirring at room temperature in the dark for 2 h. To this reaction mixture was added a solution of compound 10 (trifluoroacetic acid salt, 1555 mg, 0.90 mmol) and DIEA (312 µL, 1.80 mmol) in 4 mL of anhydrous DMF. The reaction mixture was stirred at room temperature in the dark for 2 h. The mixture was purified by preparative RP-HPLC (HPLC conditions: solvent A (0.05% TFA in water), solvent B (acetonitrile), 10 to 65% of B over 30 min at a rate of 50 mL / min, elution time 24 min). The collected fractions were analyzed by HPLC / LC-MS. The pure fractions were lyophilized in the dark to give compound 11a (234 mg, 19 % yield from 7). LCMS m / z 1122.7 ((M+2H) / 2). Synthesis of 11b Compound 11b was prepared in several steps in situ. To N-methyl exatecan (7b, TFA salt, 240 mg, 0.43 mmol) in 6 mL of anhydrous dimethylformamide (DMF) in a glass vial was added compound 8 (1 eq, 288 mg, 0.51 mmol) and diethylamine (4 eq). The mixture was stirred at room temperature in the dark for 7 days. To this reaction mixture was added a solution of compound 10 (trifluoroacetic acid salt, 1 eq, (812 mg, 0.47 mmol) and DIEA ((174 µL, 1.00 mmol) in 2 mL of anhydrous DMF. The reaction mixture was stirred at room temperature in the dark for 3 h. The mixture was purified by preparative RP-HPLC (HPLC conditions: solvent A (0.05% TFA in water), solvent B (acetonitrile), 10 to 65% of B over 30 min at a rate of 50 mL / min; elution time 19 min). The collected fractions were analyzed by HPLC / LC-MS and pure fractions were lyophilized to give compound 11b (228 mg, 23 % yield)). LCMS m / z 1130.1 ((M+2H) / 2). Synthesis of 13a Compound 13a was prepared in several steps in situ. To a suspension of exatecan mesylate (7a) (287 mg, 0.54 mmol, MedChemExpress) in 6 mL of anhydrous DMF in a glass vial was added compound 8 (506 mg, 0.90 mmol) and DIEA (313 µL, 1.80 mmol). The mixture was stirred at room temperature in the dark for 2 h, at which point LC-MS analysis indicated complete consumption of 7a and formation of intermediate 9a. The excess of compound 8 was quenched by addition of N-isopropylmethylamine (73 mg, 1.0 mmol) and stirring at room temperature in the dark for 2 h. To this reaction mixture was added a solution of compound 12 (HCl salt, 1300 mg, 0.90 mmol, Biomatrik) and DIEA (156 µL, 0.90 mmol) in 4 mL of anhydrous DMF. The reaction mixture was stirred at room temperature in the dark for 2 h. The mixture was purified by preparative RP-HPLC (HPLC conditions: solvent A (0.05% TFA in water), solvent B (acetonitrile), 10 to 65% of B over 30 min at a rate of 50 mL / min, elution time 26 min). The collected fractions were analyzed by HPLC / LC-MS. The pure fractions were lyophilized in the dark to give compound 13a. (280 mg, 25 % yield from 7). LCMS m / z 1020.3 ((M+2H) / 2). Synthesis of 13b Compound 13b was prepared in several steps in situ. To N-methyl exatecan (7b, 1 eq, TFA salt, 240 mg, 0.43 mmol) in 6 mL of anhydrous dimethylformamide (DMF) in a glass vial is added compound 8 (288 mg, 0.51 mmol) and diethylamine ( 296 µL, 1.70 mmol). The mixture was stirred at room temperature in the dark for 7 days. To this reaction mixture was added a solution of compound 12 (HCl salt, 683 mg, 0.47 mmol,) and diethylamine (174 µL, 1.00 mmol ) in 2 mL of anhydrous DMF. The reaction mixture was stirred at room temperature in the dark for 3 h. The mixture was purified by preparative RP-HPLC (HPLC conditions: solvent A (0.05% TFA in water), solvent B (acetonitrile), 10 to 65% of B over 30 min at a rate of 50 mL / min. The collected fractions were analyzed by HPLC / LC-MS and pure fractions were lyophilized to give compound 13b (212 mg, 24 % yield). LCMS m / z 1027.6 ((M+2H) / 2). Example 3: synthesis of conjugates of AVP0458 and compound 11a, 11b, 13a, or 13b Compound 11a, 11b, 13a, or 13b was conjugated to diabody AVP0458 to afford compound14a, 14b, 15a, or 15b, respectively, following the optimized procedure by Rossin et al.,Nature Communications (2018)9:1484. Briefly, 2 mg AVP0458 was reacted with 6 mM DTT for 2 h at room temperature on a roller bench, followed by purification via PD-10 pre-equilibrated with 0.1 M phosphate buffer pH 6.8, containing 2 mM ETDA (PB-EDTA buffer). The purified diabody solution was then split in four aliquots which were then added with 24 eq of compound 11a, 11b, 13a, or 13b, respectively, dissolved in dry DMSO at 10 mM concentration. The four reaction mixtures were incubated for 1h at room temperature on a roller bench followed by overnight incubation at +4°C. The four resulting conjugates ADCs (compounds 14a, 14b, 15a, and 15b, conjugates of AVP0458 and compound 11a, 11b, 13a, or 13b, respectively) were then purified from the crude mixtures by SEC (Superdex7510 / 300 column eluted with PBS at 0.8 mL / min) followed by concentration via Amicon Ultra-4 (30 kDa MW cut-off). UV measurements on the final solutions showed 60-78% recovery of diabody. SDS-PAGE analysis of the two ADC solutions showed the presence of one species with the expected increase in MW with respect to that of the monomer in AVP0458. Further analysis using mass spectrometry showed a complete reaction between the four cysteine residues in AVP0458 with the respective TCOs, confirming the production of conjugates with a drug-to-antibody ratio (DAR) of 4 (Figure 1). Conjugates 14a, 14b, 15a, and 15b have the following structures 14a Example 4: in vivo blood clearance in mice Four groups of tumor-free mice (n = 3 or 4 per group) were injected125I-labeled compound 14a, 15a, 14b, or 15b in a dosage of 5 mg / kg (for compounds 14a, and 15a) or 1 mg / kg (for compounds 14b and 15b). Blood samples (ca 50 µL) were withdrawn from the vena saphena at various times up to 72h post injection. For experiments using compounds 14a, or 15a, after gamma-counting plasma isolated from blood was reacted ex vivo with an excess of tetrazine 6 for at least 1h at 37°C. Then, the samples were analyzed by SEC on a Superdex7510 / 300 column eluted with PBS at 0.8 mL / min. The eluates were collected in 1 ml fractions which were then measured by gamma-counting using a dual-isotope protocol with crossover correction. From the above exeperiments, the amount of compound 14a, 15a, 14b, or 15b in the blood of the mice 48 hours after injection could be determined, as well as the respective half-lives in blood for said compounds. The results are shown in Table 1. Table 1. Blood clearance in mice of compounds 14a, 15a, 14b, and 15b. Compound left in blood of Half-lives of compounds in mice 48h post-injection blood of mice (in %ID / g) (in hours) Compound 14a (reference) 1.36 ± 0.19 5.22 Compound 15a 0.92 ± 0.16 4.82 Compound 14b (reference) 1.02 ± 0.40 4.98 Compound 15b 0.85 ± 0.09 4.53Thus, compounds 15a and 15b advantageously and surprisingly have faster clearance rates than compounds 14a and 14b. Furthermore, it was observed that compounds 14a, 14b, 15a, and 15b showed high in vivo TCO stability (see Example 10). Example 5: in vivo tumor and off-target binding of in tumour-bearing mice Below, the in vivo tumor binding and off-target binding in tumor-bearing mice of compounds 14a, and 15a is described. Two groups of mice (n=4) bearing LS174T xenografts were injected compound 14a (reference) or compound 15a (2 mg / kg) The mice were euthanized 52 h post-ADC injection and blood, tumors and other tissues were harvested, weighed and counted together with standards. The125I counts were used to calculate the amounts of compounds 1 and 2 in the various tissues (as %ID / g). The results of Example 3 are shown in Tables 2 and 3. Table 2. Biodistribution of compounds in tumor-bearing mice. Amount of compound (in % ID / g) Compound 14a Compound 15a (reference) (claimed) Tumor 44.15 ± 2.02 55.34 ± 6.97 Blood 0.75 ± 0.14 0.87 ± 0.46aHeart 0.33 ± 0.06 0.33 ± 0.12 Lung 0.90 ± 0.17 1.03 ± 0.30 Liver 1.46 ± 0.73 1.69 ± 0.73 Spleen 0.71 ± 0.31 0.64 ± 0.20 Kidney 0.93 ± 0.25 0.64 ± 0.20 Muscle 0.10 ± 0.02 0.11 ± 0.04 Bone 0.19 ± 0.04 0.14 ± 0.10athe individual values are 0.45, 0.64, 0.87, and 1.51 (possible outlier). Without the possible outlier, the mean value is 0.66 ± 0.21 %ID / g.Table 3. Biodistribution of compounds in tumor-bearing mice.Amount of compound (in % ID / organ) Compound 14a Compound 15a (reference) (claimed) Stomach full 0.10 ± 0.04 0.07 ± 0.01 Small intestine full 0.42 ± 0.12 0.40 ± 0.14 Large intestine full 0.42 ± 0.08 0.33 ± 0.14Thyroid 1.12 ± 0.58 0.44 ± 0.20 From Tables 2 and 3 it is clear that compound 15a shows a higher uptake in tumour and a lower off-target uptake than reference compound 14a. These results are highly advantageous, since the higher the tumour / off target ratio, the lower the extent of unwanted side-effects are usually observed. Example 6: In vitro stability of compounds 14a and 15a The stability of compounds 14a and 15a in 20 mM citrate buffer pH 5.5 was tested at -80 °C, +4 °C, 37 °C, after repeated freeze-thaw cycles, or after 24h shaking (600 rpm) at room temperature followed by 3 weeks storage at +4 °C. At various times or after repeated freeze- thaw cycles, the samples were analyzed via size exclusion chromatography on a Superdex75 10 / 300 GL column (Cytiva) with UV detection at 280 and 370 nm to assess the % intact compound and the formation of high and small MW impurities. The results of the stability tests are summarized in Table 4 and show high stability in all tested conditions. Table 4: Intact compound 14a and 15a after storage in various conditions (based on absorbance measurements at 280 nm). 8 weeks at 8 weeks at 8 weeks at 5 freeze- shaking +4 °C -80 °C + 37 °C thaw cycles 14a (ref.) 99.3% 99.3% 95.6% 98.4% 98.6%15a (claimed) 99.4% 99.0% 95.4% 98.7% 99.4% OV-90 cells were maintained in advanced Dulbecco’s Modified Eagle Medium (DMEM) F12 supplemented with 2 mM glutamine, 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and 15% fetal calf serum (FCS) at 37°C in a humidified incubator with 5% CO2. One day prior to the assay, 70,000 cells were seeded per well in 48-well plates in 200 µL culture medium. Compounds 14a, 14b, 15a, and 15b were radiolabeled with125I using the Bolton-Hunter reagent and then purified using 0.5 mL zeba spin columns with a 40 KDa molecular-weight (MW) cut-off equilibrated with phosphate-buffered saline (PBS). The radiolabeled compounds were diluted with non-radioactive compound to obtain a final concentration of 1000 nM. These stock solutions were serially diluted with binding medium (0.5% bovine serum albumin (BSA) in advanced DMEM / F12 medium) to cover a concentration range between 0.005 and 1000 nM. 5x100 µL aliquots per concentration were used for the Scatchard assay, and 3x100 µL aliquots were used to prepare standards. The medium was aspirated and the cells were washed two times with PBS.50 µL binding buffer was added to three wells, and 50 µL binding buffer containing an excess of CC49 (3 µM) was added to two wells for non-specific binding measurements. The plates were incubated on ice for 3 hours, after which the medium was aspirated and the cells were washed with binding buffer. The cells were lysed with 0.1 M NaOH and the lysate were measured by gamma-counting using a protocol for125I. The percentages of bound and free 14a, 14b, 15a, and 15b were calculated using the CPM measured in the samples and in the standards (100%) and the values were corrected for non-specific binding. Scatchard plots were made by plotting the bound / free against bound ligand (Figure 2). Non-linear curve fitting was used to determine the values for the dissociation constant (Kd; see Table 5). Rather than a straight line, the Scatchard plots followed a concave-up curve. This behavior is typically found in the presence of cooperative binding to multiple epitopes on the antigen and can be caused by simultaneous binding to a higher and a lower affinity component (Wofsky et al., Mathematical Biosciences 1992). Table 5: The binding affinities of compounds 14a, 14b, 15a, and 15b for high affinity and low affinity sites on OV90 cells obtained by Scatchard analysis. Kd high Kd low 14a (ref.) 2.52 nM 24.56 nM 14b (ref.) 5.22 nM 525 nM 15a 4.90 nM 44.18 nM 15b 6.15 nM 875 nM Example 8: Immunoreactivity of125I-labeled 14a and 15a Compounds 14a and 15a were labeled with125I using the Bolton Hunter reagent and then were purified using Zeba desalting columns (0.5 mL, 40 kDa MW cut-off).1 µg of125I- labeled 14a and 15a was mixed with 0, 10, 60, 300, or 600 µg bovine submaxillary mucin (BSM) in 1% BSA in PBS (containing 3% dimethyl sulfoxide (DMSO)). The reaction mixtures were incubated at 37 °C for 1 hour and were then analyzed by size exclusion chromatography. The % bound compound was plotted against the inverse of the BSM amount (Figure 3). Linear regression of the data was used to calculate the immunoreactive fraction as 1 / intercept. With this method, 94.9% and 94.6% immunoreactivity were calculated for 14a and 15a, respectively. Example 9: Cytotoxicity evaluation of compounds 14a, 14b, 15a, and 15b HEK293 cells were maintained in DMEM high glucose medium supplemented with 10% FCS, GlutaMAX and pyruvate. The day of the experiment, serial dilutions of compounds 14a, 14b, 15a, and 15b were prepared in cell culture medium and were added to the wells of a 48- well plate, with or without the addition of 2.5 eq TZ3 (see the structure of TZ3 on page 46) with respect to diabody. Free exatecan mesylate and methyl-exatecan were used as controls. 200 µL of cell suspension containing 10,000 cells was then added to the wells and the plates were incubated at 37 °C in the presence of 5% CO2. Three wells were used per condition. After 5 days incubation, cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. Curve fitting (Figure 4) and IC50 calculations (Table 6) were performed using GraphPad Prism (v.10.4.1). Table 6: IC50 values for compounds 14a, 14b, 15a, and 15b with or without tetrazine 16 (TZ), and free payloads (exatecan mesylate or methyl-exatecan) in HEK293 cells. IC50 (nM) IC50 (nM) 14a 669 14b 348 14a + TZ 2.02 14b + TZ 15.32 15a 647 15b 456 15a + TZ 1.64 15b + TZ 12.13 Exatecan mesylate 1.93 Methyl-exatecan 10.88 Example 10: In vivo stability of compounds 14a, 14b, 15a, and 15b Tumor-free mice (n=3) were injected125I-labeled compounds 14a, 14b, 15a, or 15b (100 µg per mouse). At selected times, approx.50 µL blood was withdrawn via the vena saphena, collected in heparinized vials, weighed and added with 100 µL PBS. Blood cells were then separated from the plasma by centrifugation and the supernatant was added with an excess of111In-labeled tetrazine 6 (see the structure of tetrazine 6 in Example 4) The same111In-6 solution, stored at -20 °C in aliquots, was used for all blood samples from one group of mice. After 1h incubation at 37 °C the reaction mixtures were analyzed by size exclusion chromatography on a Superdex200 column eluted with PBS.1 mL fractions were collected and measured in a gamma-counter with a dual isotope protocol with cross-contamination correction. The125I and111In counts in the peak corresponding to the diabody were corrected for decay to the time of mouse injection and the I-125 / In-111 ratio plotted against time was used to evaluate the in vivo trans-to-cis isomerization of the trans-cyclooctene (TCO) moiety, as previously published (Rossin et al., Bioconjug Chem 2013, 24, 1210-1217). For all compounds, a slight increase of I-125 / In-111 was observed over time (Figure 5), which suggests that the TCO linkers in 14a, 14b, 15a, and 15b do not isomerize in vivo in mice, but that some compound dehalogenation may occur.

Claims

Claims 1. A compound having a structure according to Formula (1):Formula (1); wherein R48 is –(Y1-C(=Y2))i-(SP)j-CA; CAis exatecan or an exatecan derivative; each of Y1and Y2are independently selected from O, and S; i is 0 or 1; j is 0 or 1; SPis a spacer; L1is selected from the group consisting of linear or branched C4-C12 alkylene, C3-C8 (hetero)cycloalkylene, C6-C12 arylene, and C4-C11 heteroarylene; L2a, L2b, and L2dare each independently a linker; L2cis selected from the group consisting of C1-C8 (hetero)alkanetriyl, C5-C6 (hetero)arenetriyl, C3-C7 cycloalkanetriyl, and C2-C7 heterocycloalkanetriyl; T1is selected from the group consisting of -OT1A, hydrogen, C2-C6alkyl, C6aryl, C4-C5heteroaryl, C3-C6cycloalkyl, C5-C12alkyl(hetero)aryl, C5-C12(hetero)arylalkyl, C4-C12alkylcycloalkyl, -N(T1A)2, -ST1A, -SO3H, -C(O)T1A, -C(O)OT1A, -O-C(O)T1A-C(O)N(T1A)2, -N(T1A)2-CO-T1A, and -Si(T1A)3; each T1Ais independently selected from the group consisting of hydrogen, (hetero)alkyl, (hetero)alkenyl, (hetero)alkynyl, (hetero)aryl, and an amino acid residue; T2is a bioconjugation moiety or a group -L3-CB; wherein L3is a residue of a bioconjugation moiety, and CBis selected from the group consisting of proteins, nucleic acids, peptides, carbohydrates, aptamers, lipids, small organic molecules, polymers, LNA, PNA, amino acids, peptoids, chelating moieties, fluorescent dyes, phosphorescent dyes,organic particles, gels, cells, and combinations thereof; and T3is a polymer; preferably the exatecan derivative is N-methyl-exatecan; preferably Y1and Y2are both O; preferably i is 1; preferably j is 0; preferably SPis a self-immolative linker; preferably L1is linear or branched C4-C12 alkylene, more preferably L1is linear or branched C4-C10 alkylene, and most preferably L1is linear C5-C6 alkylene; preferably L2a, L2b, and L2dare each independently a linker containing at most twenty atoms; more preferably L2a, L2b, and L2dare each independently selected from the group consisting of -C(O)NL2T-, -NL2TC(O)-, -O-, -S-, -NL2T-, -N=N-, and -C(O)-; wherein L2Tis hydrogen or methyl, preferably L2Tis hydrogen; preferably L2cis C1-C8 (hetero)alkanetriyl, more preferably L2cis C1-C8 alkanetriyl, and most preferably L2cis C4-C6alkanetriyl; preferably T1is -OT1A; and most preferably T1is -OH; preferably T1Ais hydrogen or methyl, more preferably T1Ais hydrogen; preferably T2is maleimidyl, N-hydroxysuccinimidyl, or -L3-CB; preferably L3is a residue of a maleimidyl moiety or a residue of an N- hydroxysuccinimidyl moiety; preferably CBis a protein, more preferably CBis an antibody or a diabody, even more preferably CBis a diabody, and most preferably CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; and preferably T3is a polymer comprising a polyethylene glycol moiety.

2. The compound according to claim 1, wherein said compound is according to Formula (2):Formula (2); wherein y is an integer in a range of from 1 to 50; preferably y is an integer in a range of from 2 to 45, more preferably 10 to 40, more preferably in a range of from 12 to 37, even more preferably in a range of from 15 to 35, more preferably still in a range of from 20 to 30, and most preferably in a range of from 23 to 25.

3. The compound according to any one of the preceding claims, wherein said compound is according to Formula (3):y is as defined in claim 2; x is an integer in a range of from 4 to 12; preferably x is an integer in a range of from 4 to 8, more preferably x is an integer in a range of from 4 to 6.

4. The compound according to any one of the preceding claims, wherein R48is -O-CO-CA; preferably R48is:E1is -H or -CH3.

5. The compound according to any one of the preceding claims, wherein T2is selected from the group consisting ofCBis a protein; preferably CBis an antibody or a diabody, more preferably a diabody, and most preferably AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably CBis linked to the remainder of T2via S or N that is part of CB, more preferably S.

6. The compound according to any one of the preceding claims, wherein said compound is:E1is -H or -CH3.

7. The compound according to any one of the preceding claims, wherein said compoundE1is -H or -CH3.

8. The compound according to any one of claims 1 to 5, wherein said compound is:; wherein E1is -H or -CH3; wherein CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably CBis linked to the maleimidyl group via a sulfur atom that is part of CB, preferably the sulfur atom is part of a cysteine.

9. The compound according to claim 8, wherein said compound is:or.

10. A conjugate comprising a protein conjugated to at least one compound according to Formula (1) as defined in any one of claims 1 to 9, wherein L1, L2a, L2b, L2c, L2d, T1, T3, and R48are as defined in any one of claims 1 to 9, and wherein T2is a residue of a bioconjugation moiety, and said protein and said compound are conjugated via T2; preferably the protein is a diabody or an antibody; more preferably the protein is a diabody; and most preferably the protein is AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably the protein is conjugated to at most 12 of said compounds; more preferably the protein is conjugated to at most 8 of said compounds, most preferably the protein is conjugated to at most 4 of said compounds; preferably said protein and said compound are conjugated via T2and a residue of a sulfhydryl of said protein, a residue of a hydroxyl of said protein, or a residue of an amine of said protein; more preferably said protein and said compound are conjugated via T2and a residue of a sulfhydryl of said protein; preferably T2is a residue of a maleimidyl moiety or a residue of an N- hydroxysuccinimidyl moiety; more preferably T2is a residue of a maleimidyl moiety.

11. The conjugate according to claim 10, wherein the conjugate iswherein E1is -H or -CH3; wherein CJ is in a range of from 1 to 12; wherein CBis AVP0458 consisting of two monomers, wherein each of the two monomers has an amino acid sequence according to SEQ ID NO: 1; preferably CJ is of from 2 to 10, more preferably of from 2.5 to 8, even more preferably of from 3 to 6, even more preferably still of from 3.5 to 4, and most preferably about 4; preferably CBis linked to each maleimidyl group via a sulfur atom, preferably the sulfur atom is part of a cysteine.

12. The conjugate according to claim 11, wherein the conjugate is.

13. A composition comprising: (a) a compound according to any one of claims 1 to 9; and / or (b) the conjugate according to any one of claims 10 to 12; preferably the composition is a pharmaceutical composition.

14. A composition according to claim 13, wherein said composition comprises:(a) a compound according to any one of claims 1 to 9; and (b) the enantiomer of said compound; preferably said composition is a racemic mixture of (a) and (b).

15. A combination of (A1) a compound according to any one of claims 1 to 9; (A2) a conjugate according to any one of claims 10 to 12; and / or (A3) a composition according to claim 13 or 14: with (B) a diene; preferably the diene is a tetrazine.

16. The combination according to claim 15, wherein the diene is selected from the group consisting of:

17. The compound according to any one of claims 1 to 9, the conjugate according to any one of claims 10 to 12, the composition according to any one of claims 13 to 14; or the combination according to any one of claims 15 to 16; for use as a medicament.

18. The compound according to any one of claims 1 to 9, the conjugate according to any one of claims 10 to 12, the composition according to any one of claims 13 to 14; or the combination according to any one of claims 15 to 16; for use in the treatment of a disease in a subject, preferably the subject is a human; preferably the disease is cancer.

19. A method of treating a disease in a subject, wherein said method comprises the step of administering to said subject: (a) the compound according to any one of claims 1 to 9; (b) the conjugate according to any one of claims 10 to 12; (c) the composition according to any one of claims 13 to 14; and / or (d) the combination according to any one of claims 15 to 16; preferably the subject is a human; preferably the disease is cancer.

20. A non-therapeutic method for reacting: (ia) the compound according to any one of claims 1 to 9; (iia) the conjugate according to any one of claims 10 to 12; and / or (iiia) the composition according to any one of claims 13 to 14; with a diene, wherein said method comprises the step of contacting (ia), (iia), or (iiia) with said diene, preferably said non-therapeutic method is an in vitro method; and preferably said diene is a tetrazine.

21. A non-therapeutic use of: (a) the compound according to any one of claims 1 to 9; (b) the conjugate according to any one of claims 10 to 12; (c) the composition according to any one of claims 13 to 14; and / or(d) the combination according to any one of claims 15 to 16; in a click reaction.

22. A method for synthesizing a compound according to any one of claims 1 to 9, wherein said method comprises (A) coupling a compound of Formula (R) to a compound of Formula (S):is -COOH or an active ester, or (B) coupling a compound of Formula (T) to a compound of Formula (U):Formula (T); wherein R48, and T1are as defined in any one of claims 1 to 9; and S11is -COOH or an active ester;Formula (U); wherein T2, x, and y are as defined in any one of claims 1 to 9;preferably S10is -COOH; preferably S11is an active ester.

23. A method for synthesizing a conjugate according to any one of claims 10 to 12, wherein said method comprises the step of coupling a protein to a compound according to any one of claims 1 to 9; wherein in said compound T2is a bioconjugation moiety; preferably in said protein disulfide bonds have been reduced.

Images