Novel antibody-drug conjugates

Abstract

The present invention relates to a novel antibody-drug conjugate, in particular to an antibody-drug conjugate comprising polyethylene glycol, a solvate thereof, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the conjugate has excellent physical properties and stability.

Description

[Technical field]

[0001] The present invention relates to a novel antibody-drug conjugate, more particularly to an antibody-drug conjugate comprising a polyethylene glycol unit, a solvate thereof, a pharma-ceutically acceptable salt thereof, or a pharmaceutical composition comprising same. [Background technology]

[0002] Antibody-drug conjugates (ADCs) are compounds consisting of an antibody, a drug or payload, and a linker, and are prepared by covalently binding an antibody that binds to a specific target antigen with a drug that exhibits a pharmaceutical effect, such as an apoptotic effect. ADCs require targeting ability to selectively recognize antigens or receptors, ability to induce apoptosis of specific cells, and linker stabilization and dissociation ability, and antibody-drug conjugates that meet these requirements can selectively act only on specific cells through targeting, thereby reducing side reactions and increasing therapeutic effects. Research and development of antibody-drug conjugates has progressed in various ways and is developing rapidly, and drug conjugates such as Adcetris, Kadcyla, Besponsa, Mylotarg, Polivy, and Padcev have been approved by the FDA.

[0003] Polyethylene glycol (PEG) is a water-soluble, biocompatible, and non-toxic polymer with ethylene oxide monomer as a unit, and is used in the pharmaceutical field to extend plasma half-life, prevent enzymatic degradation, and provide sustained release through PEGylation. There are also attempts to use polyethylene glycol to provide beneficial effects in the field of antibody-drug conjugates. In this regard, U.S. Pat. No. 11,103,593 discloses conjugates containing PEG units and discloses PEGylation to increase antitumor activity and improve stability. However, although PEGylation is performed, the drug properties are not improved in all antibody-drug conjugates, and the effect of the conjugate may vary depending on the linker, drug, etc. Therefore, there is still a demand for antibody-drug conjugates with high stability and improved physical properties.

[0004] Prior art documents (Patent Document 1) U.S. Patent No. 1,110,359 (Non-Patent Document 1) Construction of paclitaxel-based antibody-drug conjugates with PEGylated linkers to achieve superior therapeutic index, Ting Shao et al., Signal Transduction and Targeted Therapy, 5, 2020 (Non-Patent Document 2) Optimization of PEGylated Glucuronide-Monomethyl Auristatin E Linkers for Antibody-Drug Conjugates, Patrick J Burke et al., Mol Cancer Ther, 2017 (Non-Patent Document 3) Optimal "click" formulation strategy for the synthesis of antibody-drug conjugates, Erol C Vtansever et al., Bioorg Med Chem, 2020 (Non-Patent Document 4) Click Chemistry Conjugation, Tak Ian Chio et al., Methods Mol Biol, 2020 Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides novel linkers that can exhibit superior properties and are directed to preventing precipitation of hydrophobic drugs.

[0006] The present invention also provides an antibody drug conjugate (ADC) or a pharma- ceutically acceptable salt thereof that comprises a linker.

[0007] The present invention also relates to providing pharmaceutical compositions comprising the novel ADCs. [Means for solving the problem]

[0008] The present invention will now be described in detail.

[0009] The present invention provides a conjugate represented by Formula 1 below: [Formula 1] [ka] Where: Ab is a ligand, Sp1, Sp2, Sp3, and Sp4 are each independently a spacer; L1 is the first linker unit, L2 is the second linker unit, L3, L3', and L3" are each an independently selected third linker unit; X1, X2 and X3 are each independently selected from an active agent or a polyethylene glycol unit; As used herein, at least one of X1, X2, and X3 is a polyethylene glycol unit; z is an integer from 1 to 20; n is an integer from 1 to 20; m is an integer from 1 to 20; wherein when both n and m are 2 or greater, L1, L2, L3, L3', Sp2, Sp3, X2, and X3 are each independently selected.

[0010] The present invention includes solvates of the conjugate or a pharma- ceutically acceptable salt thereof.

[0011] In one embodiment of the invention, Ab is an antibody, an antibody fragment, or an antigen-binding fragment thereof.

[0012] In the present invention, the antibody, antibody fragment, or antigen-binding fragment thereof is a monoclonal antibody, a polyclonal antibody, an antibody fragment, Fab, Fab', F(ab)2, Fv, scFv, a diabody, a linear antibody, a bispecific antibody, a multispecific antibody, a chimeric antibody, a humanized antibody, a fully human antibody, or an antigen-binding fragment thereof. In addition, in the present invention, the antibody, antibody fragment, or antigen-binding fragment thereof is a light chain region (V L region), heavy chain region (V H The invention may include a polypeptide having a specific affinity / avidity / specificity / selectivity (e.g., a polypeptide having a specific affinity for a particular polypeptide), a polypeptide having a specific polypeptide region, a constant domain thereof, or a variable domain thereof. In addition, the invention includes antibody variants that have one or more percentages of the affinity / avidity / specificity / selectivity of 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, or 97% or more.

[0013] In the present invention, non-limiting examples of antibodies include IgA, IgG, IgG1, IgG2, IgG3, IgG4, IgE and IgD.

[0014] Non-limiting examples of antibodies in the present invention include the following: anti-CD71 antibody, anti-EGFR antibody, anti-HER2 antibody, anti-CD20 antibody, anti-CA125 antibody, anti-CD19 antibody, anti-CD44 antibody, anti-CD22 antibody, anti-FAP antibody, anti-CD38 antibody, anti-CD56 antibody, anti-CEA antibody, anti-CD2 antibody, anti-CD3 antibody, anti-CD7 antibody, anti-CD10 antibody, anti-CD167 antibody, anti-CD140 antibody, anti-CD121 antibody, anti-CD145 antibody, anti-CD71 antibody, CCK2R, CLDN18 (claudin 18), CRIPTO, CSF2, CTLA4, DLL3, DLL4, interferon, interleukin (IL-1, IL-2, IL4, IL-9, etc.), IFN, NGF, cetuximab, panitumumab, nimotuzumab, brentuximab, rituximab, and ofatumumab. , tositumomab, ibritumab, trastuzumab, pertuzumab, ozogamicin, ozogamicin, ipilimumba, labetuzumab, lintuzumab, matuzumab, siplizumab, sontuzumab, mepolizumab, motavizumab, motavizumab, natalizumab, norobizumab, omalizumab, parvizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab , pexelizumab, ranibizumab, reslivizumab, reslizumab, resibizumab, rovelizumab, ruplizumab, sibrotuzumab, tacatuzumab, tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tuxituzumab, urtoxazumab, bislizumab, CNTO95, huC242, and huN901.

[0015] In one embodiment of the invention, the linkers represented as any combination of Sp1, Sp2, Sp3, Sp4, L1, L2, L3, L3', L3", X1, X2, and X3 are cleavable linkers or non-cleavable linkers.

[0016] In one embodiment of the invention, the linker is a cleavable linker.

[0017] In one embodiment of the invention, the cleavable linker may be protease-sensitive, pH-sensitive, or glutathione-sensitive.

[0018] In one embodiment of the invention, the linker may be an enzyme-cleavable linker. The linker may contain one or two or more sites that may be cleaved by an enzyme.

[0019] In an exemplary embodiment of the invention, the linkers represented by some combination of Sp1, Sp2, Sp3, Sp4, L1, L2, L3, L3', L3", X1, X2, and X3 are cleavable linkers that can be cleaved by glucuronidase. Additionally, the linkers are linkers that can be cleaved by β-glucuronidase.

[0020] Additionally, in exemplary embodiments of the invention, the linkers represented as some combination of Sp1, Sp2, Sp3, Sp4, L1, L2, L3, L3', L3", X1, X2, and X3 are cleavable linkers that can be cleaved by a cathepsin. For example, the linker can be valine-citrulline (val-cit), lysine-lysine (lys-lys), phenylalanine-lysine (phe-lys), valine-alanine (Val-Ala), or alanine- Alanine (Ala-Ala) linkers and the like may be included. In addition, the cleavable linker can be cleaved by cathepsin and remain stable in vivo. In addition, in certain examples, the cleavable linker can be cleaved by cathepsin B, cathepsin C, or cathepsin D and remain stable in vivo. Among these linkers, the valine-citrulline (Val-Cit) linker is a linker that can be cleaved by cathepsin B.

[0021] In addition, in the linkers represented as some combinations of Sp1, Sp2, Sp3, Sp4, L1, L2, L3, L3', L3", X1, X2, and X3 in the present invention, some of the spacer, the first linker, the second linker, and the third linker may be units that can be cleaved by cathepsin (e.g., cathepsin B, C, or D).

[0022] In one embodiment of the invention, the linker may include a pH sensitive linker that includes a group that induces hydrolysis of an acid labile group, such as a hydrazone.

[0023] In one embodiment of the present invention, a glutathione-sensitive linker may be included, such as a linker containing a disulfide bridge.

[0024] In the present invention, the antibody and the linker can be conjugated through a thiol of the antibody, particularly a cysteine ​​thiol. In addition, in the present invention, the antibody and the linker can be conjugated through an amine of the antibody, particularly a lysine amine.

[0025] In the present invention, when antibodies are conjugated to linker units, they may be conjugated via a structure containing a spacer.

[0026] In one embodiment of the present invention, the conjugate may include a structure conjugated by click chemistry. Specifically, the conjugate may include a structure conjugated through an oxime bond mediated by carbonyl-aminooxy or azide-alkyne-based click chemistry, or a structure conjugated by a previously known method (Bioorg Med Chem. 2020 Dec 15; 28(24), Methods Mol Biol, 2020; 2078: 83-97 or similar).

[0027] In one embodiment of the present invention, the spacer represents a direct bond or a chemical structure having 1-200 atoms.

[0028] In one embodiment of the present invention, the spacer is one or more selected from the group consisting of a first spacer, a second spacer, a third spacer and a fourth spacer.

[0029] In one embodiment of the invention, the spacer is two or more selected from the group consisting of a first spacer, a second spacer, a third spacer and a fourth spacer.

[0030] In one embodiment of the present invention, the spacers are a combination of two or more selected from the group consisting of a first spacer, a second spacer, a third spacer and a fourth spacer.

[0031] In one embodiment of the present invention, the spacer is a combination of a first spacer, a second spacer, a third spacer, and a fourth spacer.

[0032] In one embodiment of the present invention, the first spacer, the second spacer, the third spacer, or the fourth spacer is each a direct bond, a substituted or unsubstituted C 1-50 Alkylene, substituted or unsubstituted C 1-50 Heteroalkylene, substituted or unsubstituted C 2-50 Alkenylene, substituted or unsubstituted C 3-50 Cycloalkylene, substituted or unsubstituted C 6-50 Arylene, and substituted or unsubstituted C 6-50 heteroarylene.

[0033] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are unsubstituted C. 1-10 It is a heteroalkylene.

[0034] In one particular embodiment of the invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are unsubstituted C 1-10 It is heteroalkylene and contains an NH bonding site.

[0035] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are substituted C 1-20heteroalkylene, where the group is substituted, and the groups are halogen, =O, OH, NH2, SH, NO2, N3, CN, OR1, SR1, OC(O)R1, OC(O)NHR1, OC(O)OR1, CONHR1, CON(R1)2, NHC(O)R1, C(O)R1, NHR1, N(R1)2, C(O)R1, OS(O)2R1, -OP(O)(OR1)(OR1), OP(O)(NHR1)(NHR1), and C 1-3 alkyl, where R1 is H, OH, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 3-8 Aryl and C 3-8 Heteroaryl is selected from the group consisting of:

[0036] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are substituted C 6-50 Heteroarylene, where the groups can be substituted, includes halogen, =O, OH, NH2, SH, NO2, N3, CN, OR1, SR1, OC(O)R1, OC(O)NHR1, OC(O)OR1, CONHR1, CON(R1)2, NHC(O)R1, C(O)R1, NHR1, N(R1)2, C(O)R1, OS(O)2R1, -OP(O)(OR1)(OR1), OP(O)(NHR1)(NHR1), and C 1-3 alkylene, where R1 is H, OH, C 1-5 Alkyl, C 1-5 Heteroalkyl, C 3-8 Aryl and C 3-8 Heteroaryl is selected from the group consisting of:

[0037] In an exemplary embodiment of the invention, R1 is H, OH, or C 1-3 It is an alkyl.

[0038] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are C substituted with =O. 6-50 It is a heteroarylene.

[0039] In one embodiment of the invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are direct bonds.

[0040] In one embodiment of the invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer comprises a terminal C(O).

[0041] In one embodiment of the invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer comprises a terminal NH.

[0042] In one embodiment of the invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer comprises a terminal C(O)NH.

[0043] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are -C(O)(CH2) a -, -NH(CH2) a -, -C(O)(CH2) a C(O)-, -C(O)(CH2) a NH-, -NH(CH2) a NH-, -NHC(O)(CH2) a C(O)-, -NHC(O)(CH2) a NH-, -NHC(O)(CH2) a C(O)NH- and -NHC(O)(CH2) a O(CH2) b -, wherein a and b are each independently an integer from 1 to 10.

[0044] In an exemplary embodiment of the invention, a and b are each independently an integer from 1-7.

[0045] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are [ka] Includes.

[0046] Additionally, in one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are [ka] and where X is a substituted or unsubstituted C 1-10 Alkyl or substituted or unsubstituted C 1-10 Heteroalkyl, when substituted, is substituted with one or more selected from the group consisting of halogen, ═O, OH, NH 2 , and SH, and s 1 is an integer from 1 to 10.

[0047] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are [ka] and s1 is an integer from 1 to 10.

[0048] In one embodiment of the present invention, one or more of the first spacer, the second spacer, the third spacer, and the fourth spacer are [ka] It is.

[0049] In one embodiment of the present invention, the spacer is [ka] and Where X a and X b are each independently substituted or unsubstituted C 1-10 Alkyl or substituted or unsubstituted C 1-10When the group is heteroalkyl and substituted, the group is substituted with one or more selected from the group consisting of halo, ═O, OH, NH 2 , and SH, where s1 is an integer from 1 to 10.

[0050] In one embodiment of the present invention, X a and X b are each independently -C(O)(CH2) a -, -NH(CH2) a -, -C(O)(CH2) a C(O)-, -C(O)(CH2) a NH-, -NH(CH2) a NH-, -NHC(O)(CH2) a C(O)-, -NHC(O)(CH2) a NH-, -NHC(O)(CH2) a C(O)NH- and -NHC(O)(CH2) a O(CH2) b -, wherein a and b are each independently an integer from 1 to 10.

[0051] In one embodiment of the present invention, X a is -C(O)-.

[0052] In one embodiment of the present invention, X b is —CH2C(O)— or —(CH2)2OCH2C(O)—NH—.

[0053] In one embodiment of the invention, the spacer is -NH-(CH2) a and s is an integer of 1 to 5.

[0054] In one embodiment of the present invention, Sp1 is [ka] and X a of [ka] is attached to L1, and X bof [ka] is bound to Ab, X a , X b and s1 is defined as above.

[0055] In one embodiment of the invention, L1 and L2 are each independently selected from the group consisting of a direct bond, an amino acid, an unnatural amino acid, and a derivative thereof.

[0056] In one embodiment of the invention, L1 and L2 are each independently selected from the group consisting of a direct bond, alanine, β-alanine, γ-aminobutyric acid, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and derivatives thereof.

[0057] In one embodiment of the invention, L1 and L2 are each independently selected from the group consisting of a direct bond, arginine, asparagine, glutamic acid, glutamine, glycine, alanine, arginine, citrulline, isoleucine, leucine, lysine, phenylalanine, serine, tryptophan, valine, and derivatives thereof.

[0058] In one embodiment of the invention, L1 and L2 are each independently selected from the group consisting of a direct bond, arginine, asparagine, glutamic acid, glutamine, glycine, alanine, citrulline, lysine, phenylalanine, serine, and valine.

[0059] In one embodiment of the invention, L1 and L2 are each independently selected from the group consisting of a direct bond, arginine, asparagine, glutamine, citrulline, lysine, serine, and valine.

[0060] In one embodiment of the invention, L1 and L2 are each lysine.

[0061] In one embodiment of the present invention, L1 is [ka] where * and ** are sites that bind to another L1 or to Sp1 or Sp4, and *** is a site that binds to L2.

[0062] In one embodiment of the invention, one or more of L1 and L2 may be cleaved by an enzyme.

[0063] In one embodiment of the invention, one or more of L1 and L2 may be cleaved by a tumor-associated protease.

[0064] In one embodiment of the present invention, one or more of L1 and L2 can be cleaved by glucuronidase. Specifically, one or more of L1 and L2 can be cleaved by β-glucuronidase.

[0065] In an exemplary embodiment of the invention, one or more of L1 and L2 can be cleaved by a cathepsin.

[0066] In one embodiment of the present invention, when L2 in the conjugate is a direct bond, either -Sp2-L3-X2 or -Sp3-L3'-X3 is absent, and L1 is bonded to either Sp2-L3-X2 or -Sp3-L3'-X3.

[0067] In one embodiment of the present invention, when all L2 are direct bonds, the conjugate may be represented by Formula 2 below. [Formula 2] [ka] In the above formula, Ab is a ligand, Sp1, Sp2, and Sp4 are each independently a spacer; L1 is the first linker unit, L3 and L3″ are each an independently selected third linker unit; X1 and X2 are each independently selected activator or polyethylene glycol unit; wherein at least one of X1 and X2 is a polyethylene glycol unit; z is an integer from 1 to 20; n is an integer from 1 to 20; m is an integer from 1 to 20; wherein when n and m are 2 or greater, L1, L3, Sp2 and X2 are each independently selected.

[0068] Additionally, herein, each spacer, linker unit, active agent, and polyethylene glycol unit is defined as above.

[0069] In one embodiment of the invention, one or more of L3, L3', and L3" is a direct bond.

[0070] In one embodiment of the present invention, one or more of L3, L3', and L3" is represented by Formula A. [Formula A] [ka] In the above formula, G is glucuronic acid or a derivative thereof; A1 and A2 are direct bonds, substituted or unsubstituted C 1-50 Alkylene, substituted or unsubstituted C 1-50 Heteroalkylene, substituted or unsubstituted C 2-50 Alkenylene, substituted or unsubstituted C 3-50 Cycloalkylene, substituted or unsubstituted C 6-50 Arylene, and substituted or unsubstituted C 6-50 heteroarylene.

[0071] In one embodiment of the invention, G is beta-glucuronic acid.

[0072] In one embodiment of the present invention, A1 is attached to X2 or X3.

[0073] In one embodiment of the invention, A2 is bound to Sp2, Sp3, or Sp4.

[0074] In one embodiment of the present invention, A1 is -(CH2) a1 OC(O)-(CH2) b1 -, -(CH2) a1 C(O)-(CH2) b1 -, -(CH2) a1 NH-(CH2) b1 -, -(CH2) a1 C(O)NH-(CH2) b1 - and -(CH2) a1 OC(O)NH-(CH2) b1 -, wherein a1 and b1 are each independently an integer of 0 to 10.

[0075] In one embodiment of the present invention, A1 is -(CH2) a1 OC(O)-(CH2) b1 and a1 and b1 each independently represent an integer of 0 to 5.

[0076] In one embodiment of the present invention, A1 is -CH2OC(O)-.

[0077] In one embodiment of the present invention, A2 is represented by formula A-1. [Formula A-1] -A 21 -A 22 -A 23 -

[0078] A 21 and A 23 each independently represents -O-, -OCO-, -OCOO-, -OCONR a -, -NHR a -, -NR a CO-, -NRa CONR b -, -NR a COO-, -NR a COR b -, -NR a CO-R b -CO-, -NR a CO-R b -NH-, -S(O)-, Here, R a and R b are each independently H or C 1-5 is alkylene, A 22 is C 1-10 Alkylene or C 2-10 It is alkenylene.

[0079] In one embodiment of the invention, A2 is -NHC(O)-(CH2)2-NH-.

[0080] In the present invention, in a linker represented by some combination of Sp1, Sp2, Sp3, Sp4, L1, L2, L3, L3', L3", X1, X2 and X3, one or more of X1, X2 and X3 is a polyethylene glycol unit.

[0081] In the present invention, the polyethylene glycol units of the conjugate are linked in parallel form in the antibody-linker-drug combination. In addition, two or more polyethylene glycol units may be included in the present invention, and it does not mean herein that all polyethylene glycol units are linked in parallel form. However, the polyethylene glycol units of the present invention may be linked in parallel form.

[0082] In one embodiment of the invention, at least two or more of X1, X2, and X3 are polyethylene glycol repeat units.

[0083] In one embodiment of the present invention, the polyethylene glycol unit comprises -(CH2CH2O)- as a repeating unit.

[0084] In one embodiment of the invention, the polyethylene glycol unit is -(CH2CH2O) x - as a repeating unit, and x is an integer of 4 to 40.

[0085] In one embodiment of the invention, the polyethylene glycol unit comprises a -C(O)- linking moiety.

[0086] In one embodiment of the invention, the polyethylene glycol unit is 1-5 Contains an alkyl terminal portion.

[0087] In one embodiment of the present invention, the polyethylene glycol unit may be represented by the formula: [ka] In the above formula, x is an integer from 4 to 40.

[0088] In one embodiment of the invention, m is an integer equal to or less than n, and each repeat unit of m is independently selected, wherein the structural unit of m is bonded to the structural unit of n, and the structural unit of m corresponds to an integer less than or equal to the structural unit of n.

[0089] In one embodiment of the invention, both n and m are 1.

[0090] In one embodiment of the invention, both n and m are integers of 2 or more, where each structural unit can be independently selected from the other structural units. For example, when n is 3, three L1 are included, and the three L1 can each be independently selected from the group consisting of amino acids, non-natural amino acids, and derivatives thereof, representing each of the L1. In addition, when m is 3, L2, Sp2, Sp3, L3', L3", X2, and X3 each represent an independently selected unit, where L2 can each be independently selected from the group consisting of amino acids, non-natural amino acids, and derivatives thereof, representing three different L1, and each of the three X2 and X3 can independently be an active agent or a polyethylene glycol unit.

[0091] In one embodiment of the present invention, n is an integer of 2-6.

[0092] In one embodiment of the present invention, n is an integer of 2-4.

[0093] In one embodiment of the present invention, m is an integer of 2-6.

[0094] In one embodiment of the present invention, m is an integer of 2-4.

[0095] In one embodiment of the present invention, at least one of X1, X2 and X3 is an activator.

[0096] In the present invention, when L1 or L2 increases, the polyethylene glycol unit can be increased. More specifically, when L1 or L2 increases by 1, the polyethylene glycol unit can be increased by 1 or 2.

[0097] In one particular embodiment of the invention, the conjugate may be a conjugate represented by formula 1-2 below. [Formula 1-2] [ka] In the above formula, Ab, Sp1, X1 and z are the same as defined in Formula 1; L 11 , L 12 is the same as defined for L1 in Equation 1, L 21 , L 22 is the same as defined for L2 in Equation 1, L 31 , L 32 is the same as defined for L3 in Equation 1, Sp 21 , Sp 22 is the same as defined for Sp2 in formula 1, Sp 31 , Sp 32 is the same as defined for Sp3 in formula 1, X 21 , X 22 is the same as defined for X2 in formula 1, X 31 , X 32 is the same as that defined for X3 in formula 1.

[0098] In addition, in an exemplary embodiment of the invention, the conjugate may be a conjugate represented by Formula 1-3 below. [Formula 1-3] [ka] In the above formula, Ab, Sp1 and Sp4, L3", X1, and z are the same as defined in Formula 1; L 11 , L 12 is the same as defined for L1 in Equation 1, L 21 , L 22 is the same as defined for L2 in Equation 1, X 21 , X 22 is the same as defined for X2 in formula 1, X 31 , X 32is the same as that defined for X3 in formula 1.

[0099] In addition, in one particular embodiment of the invention, the conjugate may be a conjugate represented by formula 1-4 below. [Formula 1-4] [ka] In the above formula, Ab, Sp1, Sp4, L3", X1, and z are the same as defined in Formula 1; L 11 is the same as defined for L1 in Equation 1, L 21 is the same as defined for L2 in Equation 1, X 21 is the same as defined for X2 in formula 1, X 31 is the same as that defined for X3 in formula 1.

[0100] In one particular embodiment of the invention, the conjugate may be a conjugate represented by Formula 1-5 below. [Formula 1-5] [ka] In the above formula, Ab, Sp1, Sp4, L3", X1, and z are the same as defined in Formula 1; L 11 is the same as defined for L1 in Equation 1, Sp 21 is the same as defined for Sp2 in formula 1, X 21 is the same as that defined for X2 in formula 1.

[0101] In one particular embodiment of the invention, the conjugate may be a conjugate represented by formula 1-6. [Formula 1-6] [ka] In the above formula, Ab, Sp1, Sp4, L3", X1, and z are the same as defined in Formula 1; L 11 , L 12 is the same as defined for L1 in Equation 1, L 22 is the same as defined for L2 in Equation 1, L 32 is the same as defined for L3 in Equation 1, Sp 22 is the same as defined for Sp2 in formula 1, X 21 , X 22 is the same as defined for X2 in formula 1, X 32 is the same as that defined for X3 in formula 1.

[0102] Additionally, the present invention relates to a linker unit represented by formula 1a below: [Formula 1a] [ka] In the above formula, Sp1, Sp2, Sp3 and Sp4 are each independently a spacer; L1 is the first linker unit, L2 is the second linker unit, one or more of X1*, X2* and X3* is a polyethylene glycol unit; one or more of X1*, X2* and X3*, when not a polyethylene glycol unit, is an active agent binding moiety; n is an integer from 1 to 20; m is an integer from 1 to 20; wherein when n and m are 2 or greater, L1, L2, L3, L3', Sp2, Sp3, X2*, and X3* are each independently selected; Z is a ligand binding moiety.

[0103] In the present invention, L1, L2, Sp1, Sp2, Sp3 and Sp4 in formula 1a are the same as those defined in formula 1.

[0104] Additionally, in the present invention, when X1*, X2*, and X3* of formula 1a are not activator binding moieties, they are defined the same as X1, X2, and X3 of formula 1.

[0105] In one embodiment of the present invention, at least two of X1*, X2* and X3* are polyethylene glycol units.

[0106] In one embodiment of the invention, Z comprises an Fc binding protein.

[0107] In one embodiment of the invention, Z is [ka] and where X1 is CR, NR, S or O; where R is hydrogen, C 1-3 Alkyl, C 1-3 Heteroalkyl, or C 1-3 is an alkoxy; X2 is NH and Z1 is an Fc binding protein.

[0108] In one particular embodiment of the invention, Z1 is Ac-PEG8-DCAWH-(Dap)-GELVWCT-NH-(Ac: acetylated / Dap: diaminopropionic acid).

[0109] In one particular embodiment of the invention, Z1 is Ac-PEG8-DCAWH-(Dap)-GELVWCT-NH-, which contains a Cys-Cys disulfide bond (disulfide oxidation).

[0110] In one embodiment of the invention, the active agent binding moiety is absent or is -(CH2) z1OC(O)-(CH2) z2 -R z , -(CH2) z1 C(O)-(CH2) z2 -R z , -(CH2) z1 NH-(CH2) z2 -R z , -(CH2) z1 C(O)NH-(CH2) z2 -R z , -(CH2) z1 NHC(O)-(CH2) z2 -R z , and -(CH2) z1 OC(O)NH-(CH2) z2 -R z where R z COOH, NH2, C 2-5 Alkynyl, C 5-20 Cycloalkenyl, C 5-20 Cycloalkynyl, C 5-20 heterocyclic alkynyl, or N; z1 and z2 each independently represent an integer of 0 to 10.

[0111] In one embodiment of the invention, the active agent binding moiety [ka] and Here, X3 is -(CH2) z1 OC(O)-(CH2) z2 -R z , -(CH2) z1 C(O)-(CH2) z2 -R z , -(CH2) z1 NH-(CH2) z2 -R z , -(CH2) z1 C(O)NH-(CH2) z2 -R z , -(CH2) z1 NHC(O)-(CH2) z2 -R z , and -(CH2) z1 OC(O)NH-(CH2) z2-R z where R z COOH, NH2, C 2-5 Alkynyl, C 5-20 Cycloalkynyl, C 5-20 Heterocyclic alkynyl, or N3.

[0112] In one embodiment of the invention, the active agent binding moiety is -C(O)-CH2-N3.

[0113] In an exemplary embodiment of the present invention, the linker unit may be a linker unit represented by formula 1-2a below. [Formula 1-2a] [ka] In the above formula, Z and Sp1 are the same as in formula 1a; L 11 , L 12 is the same as L1 in formula 1a, L 21 , L 22 is the same as L2 in formula 1a, Sp 21 , Sp 22 is the same as Sp2 in formula 1a, X1*, X 21 *, X 22 *, X 31 * and X 32 Each * is independently a polyethylene glycol unit or an active agent binding moiety.

[0114] In one particular embodiment of the invention, the linker unit may be a linker unit of formula 1-3a. [Formula 1-3a] [ka] In the above formula, Z, Sp1 and Sp4 are the same as defined in formula 1a; L 11 , L 12 is the same as L1 in formula 1a, L 21, L 22 is the same as L2 in formula 1a, X1*, X 21 *, X 22 *, X 31 * and X 32 Each * is independently a polyethylene glycol unit or an active agent binding moiety.

[0115] In one particular embodiment of the invention, the linker unit may be a linker unit represented by formula 1-4a below: [Formula 1-4a] [ka] In the above formula, Z, Sp1 and Sp4 are the same as defined in formula 1a; L 11 is the same as L1 in formula 1a, L 21 is the same as L2 in formula 1a, X1*, X 21 * and X 31 Each * is independently a polyethylene glycol unit or an active agent binding moiety.

[0116] In one particular embodiment of the invention, the linker unit may be a linker unit represented by formula 1-5a below: [Formula 1-5a] [ka] In the above formula, Z, Sp1 and Sp4 are the same as defined in formula 1a; L 11 is the same as L1 in formula 1a, Sp 21 is the same as Sp2 in formula 1a, X1* and X 21 Each * is independently a polyethylene glycol unit or an active agent binding moiety.

[0117] In an exemplary embodiment of the present invention, the linker unit may be a linker unit represented by formula 1-6a below. [Formula 1-6a] [ka] In the above formula, Z, Sp1 and Sp4 are the same as defined in formula 1a; L 11 and L 12 is the same as L1 in formula 1a, L 22 is the same as L2 in formula 1a, Sp 22 is the same as Sp2 in formula 1a, X1*, X 21 *, X 22 * and X 32 Each * is independently a polyethylene glycol unit or an active agent binding moiety.

[0118] In one embodiment of the invention, the active agent is selected from the group consisting of a protein targeted agent, a cell targeted agent, a DNA targeted agent, and an RNA targeted agent.

[0119] In the present invention, each of "protein targeting drug", "cell targeting drug", "DNA targeting drug" and "RNA targeting drug" refers to an agent that alters or stops the function of any protein, cell, DNA, or RNA in a harmful or harmless manner. More specifically, each of protein targeting drug, cell targeting drug, DNA targeting drug, and RNA targeting drug can be a toxic drug. "Toxic drug" refers to an agent that alters the function of any protein, cell, DNA, or RNA in a harmful manner. For example, it can alter cell growth, cell proliferation, protein synthesis, and DNA synthesis in a harmful manner.

[0120] In the present invention, non-limiting examples of drugs include the following: antitubulin agents, antibiotics, antifolates, alkylating agents, anthracycline active agents, and camptothecin active agents, specifically, cyclophosphamide, mechlorethamine, chlorambucil, melphalan, carmustine (BCNU), lomustine (CCNU), ifofamine, procarbazine, dacarbazine, temesolomide, altretamine, cisplatin, carboplatin, taxol, taxotere, oxaliplatin ... Platinum, dolastatin 10, dolastatin 15, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), monomethyl auristatin D (MMAD), DM-1, DM-4, ​​anthracycline, tubulysin, daunorubicin, doxorubicin, epirubicin, idarubicin, epirubucin, glarbucin, daunorubicin, actinomycin, bleomycin, mitomycin, etoposide, valrubicin, mithramycin, mitoxin Introne, paclitaxel, vincristine, vinblastine, vinorelbine, estramustine, nemorubicin, neocarzinostatin, docetaxel, puromycin, camptothecin, camtothecin, 10-hydroxycamtothecin, cryptophycin, lurtotecan, gimatecan, topotecan, irinotecan, exatecan, oratecan, pirarbucin, ciratecan, cositecan, gimatecan, belotecan, rubitecan, SN-38, maytansinoids, benzodiaminetetraacetate, Azepines, pyrrolobenzodiazepines, pyrrolobenzodiazepine dimers, calicheamicins, duocarmycins, methotrexate, amanitin, deoxycoformycin, 6-mercaptopurine, 6-thioguanine, azathioprine, 2-chlorodeoxyadenosine, hydroxyurea, methotrexate, 5-fluorouracil, capecitabine, cytosine arabinoside, azacitidine, gemcitabine, fludarabine, asparaginase, FL118, afatinib. In one embodiment of the invention, the active agent is an auristatin.

[0121] In an exemplary embodiment of the invention, the active agent is a dolastatin, afatinib, a duocarmycin, FL118, MMAD, MMAE, or MMAF.

[0122] In one embodiment of the invention, the linker-active agent that binds to the antibody is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] or [ka] and where BG-MMAE [ka] and m-PEG8 [ka] It is.

[0123] In addition, the present invention relates to a pharmaceutical composition comprising the conjugate.

[0124] In addition, the present invention relates to a pharmaceutical composition for preventing or treating a proliferative disease, comprising the conjugate.

[0125] Additionally, the present invention relates to a method of treating a proliferative disease comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a conjugate.

[0126] In addition, the present invention relates to the use of the conjugate for preparing a medicament for treating a proliferative disease in a subject.

[0127] In one embodiment of the invention, the proliferative disease is cancer.

[0128] The administration route for the conjugate of the present invention can be, for example, oral or parenteral. In this specification, parenteral route means the route of administration in a broad sense, such as intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, intranasal, sublingual, intrathecal, inhalation, intraocular, intrarectal, intravaginal, intracerebroventricular administration and the like. When the composition is prepared, it is made using commonly used diluents or excipients, such as fillers, extenders, binders, humectants, disintegrants, and surfactants.

[0129] The solid preparation for oral administration includes tablets, pills, powders, granules, and capsules, and such solid preparations are prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin with the composition. In addition to simple excipients, lubricants such as magnesium stearate, talc, etc. are also used. The liquid preparation for oral administration includes suspensions, oral liquids, emulsions, and syrups, and may further include various types of excipients such as wetting agents, sweeteners, flavorings, and preservatives in addition to commonly used simple diluents such as water or liquid paraffin.

[0130] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. As non-aqueous solvents or suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate may be used. As suppository bases, witepsol, Tween® 61, cacao butter, lauric butter, glycerol, or gelatin may be used.

[0131] However, these are merely examples and are not limiting.

[0132] The composition of the present invention is administered in a pharmacologic effective amount. As used herein, "pharmacologic effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable for medical treatment, and the effective dose can be determined by parameters including the type of disease of the patient, severity, drug activity, drug sensitivity, administration time, administration route and excretion rate, duration of treatment, and drugs used simultaneously, and other parameters well known in the medical field. The composition of the present invention can be administered separately or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, or can be administered in a single or multiple doses. Considering all the above parameters, it is important to achieve maximum effect with minimum dosage without side effects, and such dosage can be easily determined by those skilled in the art. Effect of the Invention

[0133] Since the conjugate according to the present invention contains polyethylene glycol units, it has excellent physical properties and can prevent precipitation, resulting in increased drug delivery efficiency. [Brief description of the drawings]

[0134] [Figure 1] FIG. 1 illustrates a process for preparing a conjugate according to one embodiment of the present invention. [Diagram 2] FIG. 1 illustrates a process for preparing a conjugate according to one embodiment of the present invention. [Diagram 3] FIG. 1 illustrates a process for preparing a conjugate according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0135] In the present invention, each term is defined as follows.

[0136] In the present invention, "independently" means that each can be selected because the selection of one does not depend on or affect the selection of the other.

[0137] In the present invention, a "unit" refers to a divided or capable of being divided unit.

[0138] In the present invention, "analog" and "derivative" refer to compounds in which some moiety has been removed, modified, or added to the parent compound.

[0139] As used herein, a "linker" refers to the entire chemical moiety that connects a molecule or atom to another molecule, such as an antibody or an active agent. A linker can refer to a form in which multiple molecules or amino acids are linked together via chemical functional groups that can be covalently bonded.

[0140] As used herein, "cleavable" has the same chemical / biological meaning as known in the art, including cleavage under specific conditions, e.g., acidic, reducing, enzymatic, etc.

[0141] As used herein, "unsubstituted or substituted" means a parent group that may be unsubstituted or that may be substituted, "substituted" means a parent group that bears one or more substituents, and "substituent" refers to a chemical moiety that is covalently bonded or fused to a parent group.

[0142] In the present invention, "alkyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound; examples of saturated alkyls may include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl; examples of saturated linear alkyls may include methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-hexyl, and n-heptyl; examples of saturated branched alkyls may include isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.

[0143] In the present invention, "alkenyl" refers to an alkyl having one or more carbon-carbon double bonds, and examples of unsaturated alkenyl groups can include ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CHCH3), 2-propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.

[0144] In the present invention, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, and examples of unsaturated alkynyl groups may include ethynyl and 2-propynyl.

[0145] As used herein, "alkylene" refers to a divalent moiety obtained by further removing one hydrogen atom from a carbon atom in an alkyl.

[0146] As used herein, "alkenylene" refers to a divalent moiety obtained by further removing one hydrogen atom from a carbon atom in an alkenyl.

[0147] As used herein, "alkynylene" refers to a divalent moiety obtained by further removing one hydrogen atom from a carbon atom in an alkynyl.

[0148] As used herein, "halo" refers to fluorine, chlorine, bromine, or iodine.

[0149] In the present invention, an "aryl" is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, "C 5-7 "Aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having 5 to 7 ring atoms; 5-10 "Aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having from 5 to 10 ring atoms. 5-7 , C 5-10 or the like) refers to the number of ring atoms or range of numbers of ring atoms, whether carbon atoms or heteroatoms. For example, "C 5-6"Aryl" refers to an aryl group having 5 or 6 ring atoms. In this specification, the ring atoms can be all carbon atoms, as in "carboaryl groups". Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene, and pyrene. Examples of aryl groups containing fused rings, at least one of which is an aromatic ring, include, but are not limited to, those derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acephenanthrene, and aceanthrene. Alternatively, the ring atoms can include one or more heteroatoms, as in "heteroaryl groups". In the present invention, "heteroaryl" refers to an aryl containing one or more heteroatoms, and may include, for example, pyridine, pyrimidine, benzothiophene, furyl, dioxalanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, and pyrimidinyl, and more specifically, C9 having two fused rings derived from benzofuran, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodioxole, benzofuran, benzotriazole, benzothiofuran, benzothiazole, and benzothiadiazole; C10 having two fused rings derived from chromene, isochromene, chroman, isochroman, benzodioxane, quinoline, isoquinoline, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine. 10 ;C with two condensed rings derived from benzodiazepines 11 C with three fused rings derived from carbazole, dibenzofuran, dibenzothiophene, carboline, perimidine, and pyridoindole 13 ;Acridine, xanthene, thioxanthene, oxanthrene, phenoxathiin, phenazine, phenoxazine, phenothiazine, thianthrene, phenanthridine, phenanthroline, and C with three condensed rings derived from phenazine14 may include.

[0150] In the present invention, "cycloalkyl" refers to a cyclic alkyl group, which refers to a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include the following compounds and their derivatives, but the present invention is not limited thereto. "Cycloalkyl" can include unsaturated monocyclic hydrocarbon compounds such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, and methylcycloheptane; cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene, and methylcyclohexene; and saturated heterocyclic hydrocarbon compounds such as norcarane, norpinane, and norbornane.

[0151] As used herein, "arylene" refers to a divalent moiety obtained by further removing one hydrogen atom from a carbon atom in an aryl.

[0152] As used herein, "heteroarylene" refers to a divalent moiety obtained by further removing one hydrogen atom from a carbon atom in a heteroaryl.

[0153] In the present invention, the prefixes (e.g., C 1-12 , C 3-8 , or the like) refers to the number of ring atoms or range of numbers of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C 3-6 "Heterocyclyl" refers to a heterocyclyl group having 3 to 6 ring atoms, and the types of ring atoms are not limited thereto in this specification.

[0154] In the present invention, "solvate" refers to a molecular complex between a compound according to the present invention and a solvent molecule, and examples of solvates include compounds according to the present invention combined with water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine, or a mixture thereof, but the present invention is not limited thereto.

[0155] In the present invention, "pharmaceutically acceptable salt" refers to the salt form of the compound according to the present invention that has the desired pharmaceutical activity.Salt forms include, but are not limited to, inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid) and organic acids (acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, and benzoic acid).

[0156] In the present invention, a "pharmacologically effective amount" refers to an amount sufficient to prevent or treat a disease at a reasonable benefit / risk ratio applicable to medical prevention or treatment, and the effective dose may be determined by parameters including the severity of the disease, drug activity, the patient's weight, health, sex and drug sensitivity, the administration time, route and excretion rate of the compositions of the present application used herein, the duration of treatment, and drugs used in combination or simultaneously with the compositions of the present application used herein, and other parameters well known in the medical field.

[0157] The present invention may improve drug properties by placing specific units in juxtaposition with the antibody drug conjugate.

[0158] The present invention can be designed to enable efficient release of active compounds by binding to specific amino acid positions of the antibody Fc domain, and the linker and part of the active agent can be controlled to bind to the specific amino acid positions.

[0159] In order to control the orientation and binding position of the polyethylene glycol units, a suitable linker or functional group can be introduced, and thus the selectivity, pharmacokinetics, etc. of the antibody drug conjugate can be varied. Specifically, in order to control the parallel orientation and binding position of the polyethylene glycol units, a compound containing an amine functional group or an amino acid having an amine functional group can be used. The polyethylene glycol units can be increased or decreased depending on the number of amino acids having an amine functional group. In addition, the polyethylene glycol units can be increased or decreased depending on the position and structure of the amino acid having an amine functional group.

[0160] In the present invention, through the parallel orientation of polyethylene glycol units, the hydrophobic part of the drug can be shielded or masked, allowing the drug to be released efficiently in target cells.Therefore, it shows enhanced effects such as PK enhancement and improved in vivo efficacy.Polyethylene glycol units can be used in suitable positions or numbers for shielding or masking the hydrophobic part of the drug, which can vary depending on the type of drug.

[0161] In certain embodiments, a thioether functionality may be introduced to allow binding to the Fc domain 248 of an IgG1, 3 or 4 antibody. Additionally, compounds containing maleimide functionality or thiol-reactive additive compounds may be used to increase reactivity.

[0162] In certain embodiments, to eliminate interference factors such as hydrogen bonds that may occur when the cyclic peptide is bound to an antibody, a C6 spacer (e.g., a C6 alkyl structure) can be introduced and attached to lysine at amino acid position 248. In addition, a drug can be introduced after introducing a functional group by introducing a spacer at amino acid position 248, thus exhibiting a three-dimensional masking or shielding effect.

[0163] In certain embodiments, the amino acid having an amine functionality may be lysine, however this is merely an example that may be implemented and the invention is not so limited.

[0164] Hereinafter, the present invention will be described in detail with reference to examples and experimental examples.

[0165] However, the following examples and experimental examples are merely illustrative, and the contents of the present invention are not limited to the following examples and experimental examples. [example] <Example 1-1> Preparation of linker (branched PEGylated payload linker) [ka] Preparation of Compound 1 50 mL of dichloromethane was added to 2 g of 2-chlorotrityl chloride resin (1.4 mmol / g) and then stirred for 30 minutes. Then, ethylenediamine (5.6 mmol, 2 eq.) and N,N'-diisopropylethylamine (11.2 mmol, 4 eq.) were mixed with 40 mL of dichloromethane and then added to the resin. After the resulting mixture was stirred at room temperature for 2 hours, the reaction solution was removed. Then, 50 mL of dichloromethane and dimethylformamide were added three times to wash the remaining resin, thereby preparing compound 1.

[0166] Preparation of compound 2 N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine (5.6 mmol, 2 eq.), hydroxybenzotriazole (11.2 mmol, 4 eq.), and N,N'-diisopropylcarbodiimide (5.6 mmol, 2 eq.) were added to the resin containing compound 1, and the resulting mixture was stirred at room temperature for 2 hours by using 50 mL of dimethylformamide as the solvent, and then the reaction solution was removed. Subsequently, this process was repeated in the same manner as described above by successively adding the amino acids N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine and 4,7,10,13,16,19,22,25-octaoxahexacosanoic acid. After the reaction of 4,7,10,13,16,19,22,25-octaoxahexacosanoic acid, 50 mL each of dichloromethane and dimethylformamide were added three times to wash the resin, thereby preparing compound 2. [ka] Preparation of compound 3 50 mL of 5% (volume ratio) hydrazine-containing dimethylformamide was added to the resin, and the mixture was stirred at room temperature for 10 minutes, after which the reaction solution was removed. Then, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin, thereby preparing compound 3.

[0167] Preparation of compound 4 N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine (11.2 mmol, 4 eq.), hydroxybenzotriazole (22.4 mmol, 8 eq.), and N,N'-diisopropylcarbodiimide (11.2 mmol, 4 eq.) were added to the resin containing compound 3, and the resulting mixture was stirred at room temperature for 2 hours by using 50 mL of dimethylformamide as a solvent, and then the reaction solution was removed. After the reaction, 40 mL of 20% (volume ratio) piperidine-containing dimethylformamide solution was added to the resin, stirred at room temperature for 10 minutes, and then the solution was removed (repeated twice). Then, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin. For the next reaction, succinic anhydride (16.8mmol, 6eq) was added, diisopropylethylamine (16.8mmol, 6eq) was added to the resin, then 50mL of dimethylformamide was added as a solvent and stirred at room temperature for 1 hour, then the reaction solution was removed. After the reaction, 50mL of dichloromethane and dimethylformamide were added three times for washing. The subsequent process was carried out in the same manner as the process of preparing compound 3. Then, 2,5,8,11,14,17,20,23-octaoxahexacosane-26-position acid (28mmol, 2eq), hydroxybenzotriazole (56mmol, 4eq), and N,N'-diisopropylcarbodiimide (28mmol, 2eq) were added successively, 50mL of dimethylformamide was added as a solvent to carry out the reaction activation process for 10 minutes, then the resulting product was added to the resin. After stirring at room temperature for 2 hours, the reaction solution was removed. After the reaction was completed, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resulting product, and then the resin was dried to prepare compound 4. [ka] Preparation of compound 5 50mL of trifluoroacetic acid (TFA), triisopropylsilane (TIS) and deionized water (DW) mixed in a volume ratio of 95:2.5:2.5 (TFA:TIS:DW) were added to the treated resin to prepare compound 4, and then stirred at room temperature for 2 hours. After stirring, the solution and resin were separated, and 500mL of diethyl ether at 0°C was added to the separated solution, then mixed, and the resulting mixture was left at 0°C for 2 hours or more. After filtering the precipitated product, 50mL of diethyl ether at 0°C was added and filtered again (repeated twice). The resulting product was then dried to prepare compound 5 (2.24mmol, 80%).

[0168] Preparation of compound 6 Compound 5 (1 g, 0.511 mmol) and (2,5-dioxo-1-pyrrolidinyl 11,12-didehydro-ε-oxodibenzo[b,f]azocine-5(6H)-hexanoate (DBCO-C6-NHS; 0.613 mmol, 1.2 equiv.) were mixed in 10 mL of dimethylformamide, and then diisopropylethylamine (1.022 mmol, 2 equiv.) was added to the resulting mixture and stirred at room temperature for 1 h. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 5.0. The reaction solution was purified by prep-HPLC (C18), thereby obtaining compound 6 (0.434 mmol, 85%). [ka] Preparation of compound 7 Compound 6 (0.434 mmol) and tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (1.736 mmol, 4 equiv.) were mixed with 10 mL of dimethylformamide, diisopropylethylamine (1.736 mmol, 4 equiv.) was added, and the resulting mixture was stirred at room temperature for 0.5-2 h. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 5.0. The reaction solution was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 7.

[0169] Preparation of compound 8 The prepared H2N-BG-MMAE (0.26 mmol, 1.2 eq.) was mixed with the synthesized compound 7 (0.217 mmol) in 5 mL of dimethylformamide, and then diisopropylethylamine (0.434 mmol, 2 eq.) was added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 5.0. The reaction solution was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 8. Compound 8 was dried, sealed, and then stored at -80°C. <Example 1-2> Preparation of NH2-beta-glucuronide-monomethyl auristatin E (NH2-BG-MMAE) [ka] Preparation of compound 9 4-Hydroxy-3-nitrobenzaldehyde (4 g, 29.6 mmol) was dissolved in 120 mL of acetonitrile, and then molecular sieves (10 g) were added. Then, acetobromo-α-D-glucuronic acid methyl ether (10.3 g, 32.6 mmol) and silver(I) oxide (7 g, 30.2 mmol) were added, and the mixture was stirred for 18 hours under argon atmosphere. The reaction solution was filtered through Celite, concentrated under reduced pressure, and the organic layer was extracted with ethyl acetate and distilled water. The collected organic layer was dried over anhydrous magnesium sulfate. After filtration, concentration and purification by column chromatography were performed, thereby obtaining compound 9 (12.6 g, 88%).

[0170] Preparation of Compound 10 After dissolving compound 9 (12.6 g, 26.0 mmol) in isopropyl alcohol (50.6 mL) and chloroform (185 mL), sodium borohydride (1.67 g, 44.1 mmol) was slowly added under nitrogen atmosphere at 0° C., and then stirred for 2.5 hours. Deionized water was added to the reaction solution and stirred for 15 minutes. Ethyl acetate and deionized water were added to extract the organic layer. The collected organic layer was dried over anhydrous magnesium sulfate. After filtration, concentration and purification by column chromatography were carried out, thereby obtaining compound 10 (7.7 g, 61.1%).

[0171] Preparation of compound 11 Compound 10 (6.7 g, 14.2 mmol) was dissolved in ethyl acetate (90 mL), ethanol (190 mL), and methanol (44 mL), and then palladium (0.33 g) was added and stirred under hydrogen atmosphere for 3 h. The reaction solution was filtered through Celite, concentrated under reduced pressure, and then purified by column chromatography to obtain compound 11 (5.3 g, 76.9%).

[0172] Preparation of compound 12 Fluorenylmethyloxycarbonyl-beta-alanine (Fmoc-beta-alanine) (2.46 g, 7.9 mmol) was dissolved in dichloromethane (13 mL) and N,N-dimethylformamide (0.5 mL), oxalyl chloride (1.36 mL, 15.8 mmol) was added slowly under nitrogen atmosphere, and the resulting mixture was stirred for 2 hours. After concentrating the reaction solution under reduced pressure, the resulting concentrate was added slowly to compound 3 (3 g, 6.59 mmol) dissolved in dichloromethane (33 mL) at 0° C. Diisopropylethylamine (2.68 mL, 7.9 mmol) was added slowly to the dissolved compound at 0° C. The reaction solution was concentrated and then purified by column chromatography, thereby obtaining compound 12 (3.9 g, 79.1%).

[0173] Preparation of compound 13 Compound 12 (2.5 g, 3.34 mmol) was dissolved in dichloromethane (30 mL), and then bis(4-nitrophenyl) carbonate (1.73 g, 5.7 mmol) and N,N-diisopropylethylamine (0.99 mL, 5.68 mmol) were added and stirred for 2 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound 13 (2.3 g, 75.4%).

[0174] Preparation of compound 14 Compound 13 (1 g, 1.09 mmol) was dissolved in N,N-diisopropylethylamine (10.8 mL), followed by the addition of monomethylauristatin E (MMAE, 0.864 g, 1.2 mmol), N-hydroxybenzotriazole hydrate (HOBt.HO, 0.44 g, 3.27 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.64 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 14 (1.45 g, 89%).

[0175] Preparation of compound 15 Compound 14 (1.4 g, 9.37 mmol) was dissolved in methanol (15.2 mL), and then 0.4 N lithium hydroxide solution (1.5 mL) was added to the resulting mixture, which was then stirred for 6 hours. The reaction solution was purified by column chromatography, thereby obtaining compound 15 (0.62 g, 59%). <Example 2-1> Preparation of linker (C6PEG3 linker) [ka] Preparation of Compound 1 50mL of dichloromethane was added to 5g of 2-chlorotrityl chloride resin (1.4mmol / g) and then stirred for 30 minutes. After stirring, the solvent was removed, and for the next reaction, Fmoc-L-6-aminohexanoic acid (14mmol, 2eq) and N,N'-diisopropylethylamine (28mmol, 4eq) were mixed with 40mL of dichloromethane and then added to the resin. After stirring at room temperature for 2 hours, the reaction solution was removed. Then, 50mL of dichloromethane and dimethylformamide were added three times to wash the remaining resin, thereby preparing compound 1.

[0176] Preparation of compound 2 40 mL of 20% (volume ratio) piperidine in dimethylformamide solution was added to the resin and stirred at room temperature for 10 minutes, then the reaction solution was removed (repeated twice). The remaining resin was then washed by adding 20 mL of dichloromethane and dimethylformamide three times. N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine (14 mmol, 2 equiv.), hydroxybenzotriazole (28 mmol, 4 equiv.), and N,N'-diisopropylcarbodiimide (14 mmol, 2 equiv.) used in the subsequent reaction were added to the resin, and the resulting product was stirred at room temperature for 2 hours by using 50 mL of dimethylformamide as a solvent, then the reaction solution was removed. Then, the above process was repeated in the same manner as described above by successively adding N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine and 4,7,10,13,16,19,22,25-octaoxahexacosanoic acid. After the reaction of 4,7,10,13,16,19,22,25-octaoxahexacosanoic acid, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin, thereby preparing compound 2. [ka] Preparation of compound 3 50 mL of 5% (volume ratio) hydrazine in dimethylformamide was added to the resin, stirred at room temperature for 10 minutes, and then the reaction solution was removed. Then, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin, thereby preparing compound 3.

[0177] Preparation of compound 4 N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine (28 mmol, 4 eq.), hydroxybenzotriazole (56 mmol, 8 eq.), and N,N'-diisopropylcarbodiimide (28 mmol, 4 eq.) were added to the resin, 50 mL of dimethylformamide as a solvent was added, and the mixture was stirred at room temperature for 2 hours, and then the reaction solution was removed. After the reaction, 40 mL of 20% (volume ratio) piperidine-containing dimethylformamide solution was added to the resin, and the mixture was stirred at room temperature for 10 minutes, and then the reaction solution was removed (repeated twice). Then, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin. For the subsequent reaction, 2-azidoacetic acid (28 mmol, 2 eq.) was added, followed by hydroxybenzotriazole (56 mmol, 4 eq.) and N,N'-diisopropylcarbodiimide (28 mmol, 2 eq.) to the resin, and 50 mL of dimethylformamide was added as a solvent, stirred at room temperature for 2 hours, and the solution was removed. After the reaction, 50 mL of dichloromethane and dimethylformamide were added three times for washing. The following process was carried out in the same manner as the process for preparing compound 3 above. 2,5,8,11,14,17,20,23-Octaoxahexacosane-26 acid (28 mmol, 2 eq.), hydroxybenzotriazole (56 mmol, 4 eq.), and N,N'-diisopropylcarbodiimide (28 mmol, 2 eq.) were added successively, and 50 mL of dimethylformamide was added as a solvent, stirred at room temperature for 2 hours, and then the solution was removed. After the reaction was completed, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin, and the resulting resin was dried to prepare compound 4. [ka] Preparation of compound 5 50mL of trifluoroacetic acid (TFA), triisopropylsilane (TIS) and deionized water (DW) mixed in a volume ratio of 95:2.5:2.5 (TFA:TIS:DW) were added to the resin treated to prepare compound 4, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the solution and resin were separated. 500mL of diethyl ether at 0°C was added to the separated solution, mixed, and then left at 0°C for 2 hours or more. After filtering the precipitated product, 50mL of diethyl ether at 0°C was added and then filtered (repeated twice). The resulting product was then dried to prepare compound 5 (5.11mmol, 73%).

[0178] Preparation of compound 6 Compound 5 (0.996 g, 0.5 mmol) and tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (1 mmol, 2 eq.) were mixed with 5 mL of dimethylformamide, N,N'-diisopropylethylamine (1.5 mmol, 3 eq.) was added, and the resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 4.0. The reaction solution was purified by prep-HPLC (C18) to obtain compound 6 (0.375 mmol, 75%).

[0179] Preparation of compound 7 Compound 6 (0.375 mmol) and tert-butyl 2-mercaptoacetate (0.7 mmol, 2 eq.) were added to 5 mL of dimethylformamide and mixed, N,N'-diisopropylethylamine (1.1 mmol, 3 eq.) was added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 4.0. The reaction solution was purified by prep-HPLC (C18) and lyophilization to obtain compound 7 (0.3 mmol, 80%).

[0180] Preparation of compound 8 10 mL of trifluoroacetic acid and dichloromethane mixed in a 1:1 volume ratio was added to compound 7 (0.375 mmol) and then stirred at room temperature for 1 hour. After the reaction was completed, the solution was removed using a vacuum concentrator, and 10 mL of dichloromethane was added again and concentrated under reduced pressure (repeated three times), thereby obtaining compound 8. Compound 8 was dried and stored at -80°C (0.297 mmol, 99%).

[0181] Preparation of compound 9 10 mL of dimethylformamide solution was added to compound 8 (0.375 mmol), and N,N'-diisopropylethylamine was added to adjust the pH to 8-9. After the resulting mixture was stirred at room temperature for 10 min, tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (0.7 mmol, 2 equiv.) and N,N'-diisopropylethylamine (0.375 mmol, 1 equiv.) were added successively and stirred at room temperature for 2 h. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 4.0. The reaction solution was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 9 (0.173 mmol, 46%).

[0182] Preparation of Compound 10 5mL of dimethylformamide solution was added to compound 9 (0.173mmol), FcBP (sequence: Ac-PEG8-DCAWH-(Dap)-GELVWCT-NH2, Fc binding peptide, L-amino acid, disulfide bridge) (0.225mmol, 1.2 equivalents) peptide complex synthesized by solid phase peptide synthesis (SPPS) method was added, N,N'-diisopropylethylamine (0.26mmol, 1.5 equivalents) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the resulting product was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 10 (348mg, 0.087mmol, 50%). <Example 2-2> Preparation of linker (C6PEG4 linker) [ka] Preparation of compound 11 Compound 11 was synthesized by solid phase synthesis. 50mL of dichloromethane was added to 2g of 2-chlorotrityl chloride resin (1.4mmol / g) and stirred for 30 minutes. After stirring, the solvent was removed, and for the next reaction, Fmoc-L-6-aminohexanoic acid (5.6mmol, 2eq) and N,N'-diisopropylethylamine (11.2mmol, 4eq) were mixed with 40mL of dichloromethane and then added to the resin. After stirring for 2 hours at room temperature, the reaction solution was removed. Then, to wash the remaining resin, dichloromethane and dimethylformamide were added three times in 50mL portions, thereby preparing compound 11.

[0183] Preparation of compound 12 40 mL of 20% (volume ratio) piperidine in dimethylformamide solution was added to the resin, stirred at room temperature for 10 minutes, and then the reaction solution was removed (repeated twice). Then, 20 mL of dichloromethane and dimethylformamide were added three times to wash the remaining resin. N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine (5.6 mmol, 2 equiv.), hydroxybenzotriazole (11.2 mmol, 4 equiv.), and N,N'-diisopropylcarbodiimide (5.6 mmol, 2 equiv.) used in the next reaction were added to the resin, 50 mL of dimethylformamide was added as a solvent, stirred at room temperature for 2 hours, and then the reaction solution was removed. Then, this process was repeated in the same manner by successively adding N-alpha-Fmoc-N-epsilon-[1-(4,4-dimethyl-2,6-dioxycyclohex-1-ylidine)ethyl]-L-lysine and 2-azidoacetic acid. After the reaction of 2-azidoacetic acid, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin, thereby preparing compound 12. [ka] Preparation of compound 13 50 mL of 5% (volume ratio) hydrazine in dimethylformamide was added to the resin and stirred at room temperature for 10 minutes, then the reaction solution was removed, and then 50 mL each of dichloromethane and dimethylformamide was added three times to wash the resin, thereby preparing compound 13.

[0184] Preparation of compound 14 N-alpha-Fmoc-N-epsilon-Fmoc-L-lysine (11.2 mmol, 4 eq.), hydroxybenzotriazole (22.4 mmol, 8 eq.), and N,N'-diisopropylcarbodiimide (11.2 mmol, 4 eq.) were added to the resin, 50 mL of dimethylformamide as a solvent was added, and the mixture was stirred at room temperature for 2 hours, and then the reaction solution was removed. After the reaction, 40 mL of 20% (volume ratio) piperidine-containing dimethylformamide solution was added to the resin, and the mixture was stirred at room temperature for 10 minutes, and then the solution was removed (repeated twice). Then, 50 mL of dichloromethane and dimethylformamide were added three times to wash the resin. For the next process, 4,7,10,13,16,19,22,25-octaoxahexacosanoic acid (22.4mmol, 8eq) was added, then hydroxybenzotriazole (44.8mmol, 16eq) and N,N'-diisopropylcarbodiimide (22.4mmol, 8eq) were added to the resin in the same manner as the above process, 50mL of dimethylformamide was added as a solvent, stirred at room temperature for 2 hours, and then the reaction solution was removed. After the reaction, 50mL of dichloromethane and dimethylformamide were added three times to wash the remaining resin, and then the resulting resin was dried to prepare compound 14. [ka] Preparation of compound 15 50mL of trifluoroacetic acid (TFA), triisopropylsilane (TIS) and deionized water (DW) mixed in a volume ratio of 95:2.5:2.5 (TFA:TIS:DW) were added to the treated resin to prepare compound 14, and then stirred at room temperature for 2 hours. After stirring, the solution and resin were separated. 500mL of diethyl ether at 0°C was added to the separated solution, mixed, and then left for 2 hours or more. After filtering the precipitated product, 50mL of diethyl ether at 0°C was added, and then filtered again (repeated twice). The resulting product was then dried, thereby preparing compound 15 (2.13mmol, 76%).

[0185] Preparation of compound 16 Compound 15 (1 g, 0.433 mmol) and tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (1 mmol, 2 eq.) were added to 5 mL of dimethylformamide, then N,N'-diisopropylethylamine (1.3 mmol, 3 eq.) was added and stirred at room temperature for 1 h. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 4.0. The reaction solution was purified by prep-HPLC (C18) to obtain compound 16 (0.303 mmol, 70%).

[0186] Preparation of compound 17 Compound 16 (0.303 mmol) and tert-butyl 2-mercaptoacetate (0.606 mmol, 2 eq.) were added to 5 mL of dimethylformamide, then N,N'-diisopropylethylamine (0.909 mmol, 3 eq.) was added and stirred at room temperature for 1 hour. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 4.0. The reaction solution was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 17 (0.242 mmol, 80%).

[0187] Preparation of compound 18 10 mL of trifluoroacetic acid and dichloromethane mixed in a 1:1 volume ratio was added to compound 17 (0.242 mmol) and then stirred at room temperature for 1 hour. After the reaction was completed, the solution was removed using a vacuum concentrator, and 10 mL of dichloromethane was added again and concentrated under reduced pressure (repeated three times), thereby preparing compound 18. Compound 18 was dried and stored at -80°C.

[0188] Preparation of compound 19 10 mL of dimethylformamide solution was added to compound 18 (0.242 mmol), and N,N'-diisopropylethylamine was added to adjust the pH to 8-9. After the resulting mixture was stirred at room temperature for 10 min, tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (0.7 mmol, 2 equiv.) was added, and N,N'-diisopropylethylamine (0.375 mmol, 1 equiv.) was added and stirred at room temperature for 2 h. After the reaction was completed, trifluoroacetic acid was added until the pH of the solution reached 4.0. The reaction solution was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 19 (0.124 mmol, 51%).

[0189] Preparation of compound 20 5mL of dimethylformamide solution was added to compound 19 (0.173mmol), then FcBP (sequence: Ac-PEG8-DCAWH-(Dap)-GELVWCT-NH2, Fc binding peptide, L-amino acid, disulfide bridge) (0.225mmol, 1.2eq) peptide complex synthesized by solid phase peptide synthesis (SPPS) method was added, N,N'-diisopropylethylamine (0.26mmol, 1.5eq) was added, and reacted at room temperature for 1 hour. After the reaction was completed, the resulting product was purified by prep-HPLC (C18) and lyophilization, thereby obtaining compound 20 (283mg, 0.066mmol, 53%).

Claims

1. The following formula 1-2a: [Formula 1-2a] 【Chemistry 21】 a compound represented by where: Sp １ , Sp 21 and Sp 22 are each independently a spacer; L 11 and L 12 are each independently a first linker unit; L 21 and L 22 are each independently a second linker unit; X 1 *, X 21 *, X 22 *, X 31 * and X 32 * are each independently selected from polyethylene glycol units and active agent binding moieties; Z is a ligand-binding moiety; compound.

2. 2. The compound of claim 1, wherein each of the spacers is independently selected, wherein each of the spacers is any one or more selected from the group consisting of a first spacer, a second spacer, a third spacer, and a fourth spacer.

3. the first spacer, the second spacer, the third spacer, and the fourth spacer are independently selected from the group consisting of a direct bond, a substituted or unsubstituted C1-20 alkylene, and a substituted or unsubstituted C1-20 heteroalkylene; wherein when a group is substituted, said group is substituted with one selected from the group consisting of halo, ═O, OH, NH 2 , SH, NO 2 , N 3 , CN, OR 1 , SR 1 , OC(O)R 1 , OC(O)NHR 1 , OC(O)OR 1 , CONHR 1 , CON(R 1 ) 2 , NHC(O)R 1 , C(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)R 1 , OS(O) 2 R 1 , —OP(O)(OR 1 )(OR 1 ), OP(O)(NHR 1 )(NHR 1 ), and C 1-3 alkyl; 3. The compound of claim 2, wherein R 1 is selected from the group consisting of H, OH, C 1-5 alkyl, C 1-5 heteroalkyl, C 3-8 aryl, and C 3-8 heteroaryl.

4. The first spacer, the second spacer, the third spacer, and the fourth spacer are each independently a direct bond, —C(O)(CH ２ ) ａ -, -NH(CH ２ ) ａ -, -C(O)(CH ２ ) ａ C(O)-, -C(O)(CH ２ ) ａ NH-, -NH(CH ２ ) ａ NH-, -NHC(O)(CH ２ ) ａ C(O)-, -NHC(O)(CH ２ ) ａ NH-, -NHC(O)(CH ２ ) ａ C(O)NH-, and -NHC(O)(CH ２ ) ａ O (CH ２ ) ｂ is selected from the group consisting of wherein a and b are each independently an integer from 1 to 10. The compound of claim 2.

5. The compound of claim 1, wherein L 11 , L 12 , L 21 and L 22 are each independently selected from the group consisting of amino acids, unnatural amino acids, and derivatives thereof.

6. The compound of claim 1, wherein L 11 , L 12 , L 21 and L 22 are each independently selected from the group consisting of alanine, β-alanine, γ-aminobutyric acid, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

7. The compound of claim 1, wherein L 11 , L 12 , L 21 and L 22 are each independently lysine.

8. X 1 *, X 21 * and X 22 * ​​are each independently the polyethylene glycol unit; 2. The compound of claim 1, wherein X31* and X32* are each independently said activator binding moiety.

9. The polyethylene glycol units of claim 8, wherein each of the polyethylene glycol units is independently selected; 2. The compound of claim 1, wherein each of said polyethylene glycol units comprises --(CH 2 CH 2 O) x --, where x is an integer from 4 to 40.

10. Each of the polyethylene glycol units is 【Chemistry 12】 where x is an integer from 4 to 40; The compound of claim 1.

11. Each of the activator binding moieties is independently selected, wherein each of the activator binding moieties is absent or selected from —(CH 2 ) z1 OC(O)—(CH 2 ) z2 —R z , —(CH 2 ) z1 C(O)—(CH 2 ) z2 —R z , —(CH 2 ) z1 NH—(CH 2 ) z2 —R z , —(CH 2 ) z1 C(O)NH—(CH 2 ) z2 —R z , —(CH 2 ) z1 NHC(O)—(CH 2 ) z2 —R z , and —(CH 2 ) z1 OC(O)NH—(CH 2 ) z2 —R z , wherein R z is COOH, NH 2 , C 2-5 alkynyl, C 5-20 cycloalkenyl, C 5-20 cycloalkynyl, C 5-20 heterocycloalkynyl, N 3 or 【Transformation 62】 2. The compound of claim 1, wherein z1 and z2 are each independently an integer from 0 to 10.

12. The activator binding moiety of claim 1, wherein each of said activator binding moieties is —(CH 2 ) z1 C(O)—(CH 2 ) z2 —R z , where R z is COOH or 【Transformation 62】 2. The compound of claim 1, wherein z1 is 0 and z2 is an integer from 1 to 10.

13. Each of Sp 21 and Sp 22 is a direct bond; Sp 1 is —C(O)(CH 2 ) a C(O)—NH(CH 2 ) a NH— or —C(O)(CH 2 ) a NH—C(O)(CH 2 ) a NH—, where a is an integer from 0 to 10; L 11 , L 12 , L 21 and L 22 are each independently lysine; each of X 1 *, X 21 * and X 22 * ​​is said polyethylene glycol unit, wherein each of said polyethylene glycol units is independently selected, and wherein each of said polyethylene glycol units comprises -(CH 2 CH 2 O) x -, where x is an integer from 4 to 40; each of X 31 * and X 32 * is said activator binding moiety; wherein each of said activator binding moieties is independently selected, wherein each of said activator binding moieties is absent or selected from —(CH 2 ) z1 OC(O)—(CH 2 ) z2 —R z , —(CH 2 ) z1 C(O)—(CH 2 ) z2 —R z , —(CH 2 ) z1 NH—(CH 2 ) z2 —R z , —(CH 2 ) z1 C(O)NH—(CH 2 ) z2 —R z , —(CH 2 ) z1 NHC(O)—(CH 2 ) z2 —R z and —(CH 2 ) z1 OC(O)NH—(CH 2 ) z2 —R z , wherein R z is COOH, NH 2 , C 2-5 alkynyl, C 5-20 cycloalkenyl, C 5-20 cycloalkynyl, C 5-20 heterocycloalkynyl, N 3 or 【Transformation 62】 and 2. The compound of claim 1, wherein z1 and z2 are each independently an integer from 0 to 10.

14. A compound according to any one of claims 1 to 13, wherein the ligand binding moiety is an azide binding moiety.

15. The ligand-binding moiety, 【Transformation 63】 14. The compound of any one of claims 1 to 13, comprising:

16. The following formula: 【Chemistry 64】 a compound represented by where: Sp 1 is a spacer; X 1 *, X 21 *, X 22 *, X 31 * and X 32 * are each independently selected from polyethylene glycol units and active agent binding moieties; compound.

17. The compound described in claim 16, wherein the spacer is one or more selected from a first spacer, a second spacer, a third spacer and a fourth spacer.

18. The first spacer, the second spacer, the third spacer, and the fourth spacer are each independently selected from a direct bond, a substituted or unsubstituted C 1-20 alkylene, and a substituted or unsubstituted C 1-20 heteroalkylene; wherein when a group is substituted, said group is substituted with one or more selected from the group consisting of halo, ═O, OH, NH 2 , SH, NO 2 , N 3 , CN, OR 1 , SR 1 , OC(O)R 1 , OC(O)NHR 1 , OC(O)OR 1 , CONHR 1 , CON(R 1 ) 2 , NHC(O)R 1 , C(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)R 1 , OS(O) 2 R 1 , —OP(O)(OR 1 )(OR 1 ), OP(O)(NHR 1 )(NHR 1 ), and C 1-3 alkyl; wherein R 1 is selected from H, OH, C 1-5 alkyl, C 1-5 heteroalkyl, C 3-8 aryl and C 3-8 heteroaryl; 18. The compound of claim 17.

19. The first spacer, the second spacer, the third spacer and the fourth spacer are each independently selected from a direct bond, —C(O)(CH 2 ) a —, —NH(CH 2 ) a —, —C(O)(CH 2 ) a C(O)—, —C(O)(CH 2 ) a NH—, —NH(CH 2 ) a NH—, —NHC(O)(CH 2 ) a C(O)—, —NHC(O)(CH 2 ) a NH—, —NHC(O)(CH 2 ) a C(O)NH—, and —NHC(O)(CH 2 ) a O(CH 2 ) b —; 18. The compound of claim 17, wherein a and b are each independently an integer from 1 to 10.

20. The compound of claim 16, wherein the spacer is -C(O)(CH 2 ) a C(O)-NH(CH 2 ) a NH- or -C(O)(CH 2 ) a NH-C(O)(CH 2 ) a NH-, where a is an integer from 1 to 10.

21. X 1 *, X 21 * and X 22 * ​​are each independently the polyethylene glycol unit; 17. The compound of claim 16, wherein X31* and X32* are each independently said active agent binding moiety.

22. The compound of claim 16, wherein each of said polyethylene glycol units is independently selected, wherein each of said polyethylene glycol units comprises -(CH 2 CH 2 O) x -, where x is an integer from 4 to 40.

23. Each of said polyethylene glycol units is independently selected, wherein each of said polyethylene glycol units is 【Chemistry 12】 17. The compound of claim 16, wherein x is an integer from 4 to 40.

24. Each of the activator binding moieties is independently selected, wherein each of the activator binding moieties is absent or selected from —(CH 2 ) z1 OC(O)—(CH 2 ) z2 —R z , —(CH 2 ) z1 C(O)—(CH 2 ) z2 —R z , —(CH 2 ) z1 NH—(CH 2 ) z2 —R z , —(CH 2 ) z1 C(O)NH—(CH 2 ) z2 —R z , —(CH 2 ) z1 NHC(O)—(CH 2 ) z2 —R z , and —(CH 2 ) z1 OC(O)NH—(CH 2 ) z2 —R z , wherein R z is COOH, NH 2 , C 2-5 alkynyl, C 5-20 cycloalkenyl, C 5-20 cycloalkynyl, C 5-20 heterocycloalkynyl, N 3 or 【Transformation 62】 17. The compound of claim 16, wherein z1 and z2 are each independently an integer from 0 to 10.

25. The method of claim 25, wherein each of the activator binding moieties is independently selected and each of the activator binding moieties is —(CH 2 ) z1 C(O)—(CH 2 ) z2 —R z , where R z is COOH or 【Transformation 62】 17. The compound of claim 16, wherein z1 is 0 and z2 is an integer from 1 to 10.

26. The following formula: 【Transformation 65】 a compound represented by Here, each m-PEG8 is 【Chemistry 59】 That is, compound.

27. ​​The following formula: 【Chemical Formula 66】 a compound represented by Here, each m-PEG8 is 【Chemistry 59】 That is, compound.

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