JP-2022516032-A5 -

Dates

Publication Date

20221227

Application Date

20191219

Description

The MMAE polyamide trastuzumab ADC is active against SKBR3 cells, with an estimated protein concentration IC50 of 158.5 pM. The present invention provides the following: [1] Antibody-drug conjugates including the following: (i) an antibody or its antigen-binding fragment; (ii) Polymers containing repeating units of formula (I'): (In the formula, Each n and each p are independently integers from 0 to 6; Each m is independently 0 or an integer between 1 and 4, preferably at least one m is 1; V is And; -------- is a conjunction, and may or may not exist; Each D1 is independently O or L1 - B1 ; Each D2 is independently O or L2 - B2 ; Each D3 is independently O or L3 - B3 ; Here, L1 is a linker group or bond, L2 is a linker group or bond, L3 is a linker group or bond, and B1 , B2 and B3 are each bioactive moieties; However, if at least one D1, D2, or D3 group in the polymer is not O , and furthermore, if D1 , D2 , or D3 is O, there is a double bond between the O atom and the carbon atom to which it is bonded; Each q is an integer between 1 and 8; X and Y are selected independently from O, NH, NR', and S; R' is C1-20 hydrocarbyl ; Q is selected from -CH₂ (NMe(C=O)CH₂ ) o- , -T₁O ( CH₂CH₂O ) sT₂- , and -T₁O ( CH₂CH₂CH₂O ) sT₂- , where T₁ is selected from a divalent methylene, ethylene, propylene, or butylene group, and T₂ is selected from a divalent methylene , ethylene , propylene , or butylene group ; o is an integer between 0 and 100; s is an integer between 0 and 150); and (iii) A polymer-antibody linker covalently bonded to both the antibody and the polymer. [2] The antibody-drug conjugate described in [1], wherein the polymer comprises repeating units of formula (I): (In the formula, X, Y, D1 , D2 , D3 , n , m , and p are as described above, and Q is selected from -T1O ( CH2CH2O ) sT2- and -T1O ( CH2CH2CH2O ) sT2- ) . [3] The antibody-drug conjugate according to [1] or [2], wherein the polymer-antibody linker is covalently bonded to the polymer via the carbon atoms of the -CD1- portion in formula (I') or the Y group in formula (I'). [4] An antibody-drug conjugate according to any one of items [1] to [3], wherein each D1 and each D3 is O. [5] An antibody-drug conjugate according to any one of items [1] to [4], wherein each q is 1. [6] An antibody-drug conjugate according to any one of items [1] to [5], wherein each m is 1 or 2. [7] An antibody-drug conjugate according to any one of items [1] to [6], wherein each n is 1, 2, or 3. [8] An antibody-drug conjugate according to any one of items [1] to [7], wherein each p is 0, 1, or 2. [9] The repeating unit of equation (I') is and An antibody-drug conjugate according to any one of [1] to [8], having a structure selected from the above. [10] An antibody-drug conjugate according to any one of [1] to [9], wherein the polymer-antibody linker is derived from maleimide, monobromomaleimide, vinyl sulfone, bis(sulfone), allenamide, dehydroalanine, alkene, perfluoroaromatic species, sulfone reagents such as Julia-Kosienski reagent, N-hydroxysuccinamide-ester activated carboxylate species, and ketones. [11] An antibody-drug conjugate according to any one of items [1] to [9], having formula (III) or (IV): (In the formula, (I') is a repeating unit of expression (I') as defined in any of the above terms; Ab is an antibody or its antigen-binding fragment; L is a polymer-antibody linker as defined in [1] or [9]; R 1 is selected from OH, OR', SH, SR', NH 2 , NHR', and NR' 2 ; E is selected from H and R'; R' is defined as in [1]; z is an integer between 2 and 50. [12] X is O or NH, and Y is O or NH, preferably both X and Y are O. Alternatively, an antibody-drug conjugate according to any one of items [1] to [11], wherein both X and Y are NH. [13] The antibody - drug conjugate according to any one of [1 ] to [ 12 ] , wherein Q is -CH2CH2O ( CH2CH2O ) sCH2CH2- or -CH2CH2CH2O ( CH2CH2O ) sCH2CH2CH2- , preferably where s is 1 to 100 . [14] An antibody-drug conjugate according to any one of items [1] to [13], wherein XQY is derived from PEG 400, PEG 500, PEG 600, PEG 1000, PEG 1500, PEG 2000 or (poly(ethylene glycol) bis(3-aminopropyl) terminus) 1500. [15] The antibody-drug conjugate according to [1], wherein V is -X-(C=O)-, Q is -CH2 ( NMe(C=O)CH2 ) o- , and Y is -NMe-, where the portion Q is directly bound to the carbonyl group of the portion V, preferably where o is 5 to 25. [16] Each biologically active portion is identical or different, comprising portions B1 , B2 and/or B3 , wherein HB1 , HB2 and /or HB3 are independently selected from small molecule drugs, peptides, proteins, peptide mimes, antibodies, antigens, DNA, mRNA, small interfering RNA, small hairpin RNA, microRNA, PNA, foldomers, carbohydrates, carbohydrate derivatives, non-lipinski molecules, synthetic peptides and synthetic oligonucleotides, preferably small molecule drugs, and preferably HB1, HB2 and/or HB3 comprises at least one hydrazine group , at least one hydrazide group, at least one amine group, at leas