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Patent Application Publication Oo) Pub. No.: US 2015/0284416 Al Zhao (43) Pub US 20150284416A1 US 20150284416A1 (19) United States (12) Patent Application Publication oo) Pub. No.: US 2015/0284416 Al Zhao (43) Pub. Date: Oct. 8,2015 (54) NOVEL LINKERS LOR CONJUGATION OL A61K47/48 (2006.01) CELL-BINDING MOLECULES C07K16/32 (2006.01) C07F 9/572 (2006.01) (71) Applicant: Robert Yongxin Zhao, Lexington, MA (US) A61K 31/537 (2006.01) (52) U.S. Cl. (72) Inventor: Robert Yongxin Zhao, Lexington, MA CPC ...........C07F 9/65583 (2013.01); C07F 9/5721 (US) (2013.01); A61K31/537 (2013.01); A61K (73) Assignee: SUZHOU M-CONJ BIOTECH CO., 47/48715 (2013.01); C07K16/32 (2013.01); LTD, Suzhou City (CN) A61K 47/48561 (2013.01 ),A61K 38/05 (2013.01) (21) Appl. No.: 14/740,403 (22) Filed: Jun. 16, 2015 (57) ABSTRACT Publication Classiflcation (51) Int. Cl. Cell binding agent-drug conjugates comprising hydrophilic C07F 9/6558 (2006.01) linkers, and methods of using such linkers and conjugates are A61K38/05 (2006.01) provided. PatentApplication Publication Oct. 8, 2015 Sheet I of 18 US 2015/0284416 Al FIGURES p 0 ° Λ O=PG3 H M /v. A N-VNH2 (Tjn-Vn-II-Ci ho^^nh, (f\-vΝ-Ρ-N ν^'ίOH -78°C, THF 1 H C' Cl --------2—W THO 4 O I Et3N η O O Q NllSZEDtC jf^N -P-NyVjlS0^ N^S I). Drug-SH DMA V HO “ . 2). mAb— (NH2)11 O OPCi3^ I n-vnh2 HO NH2 C' -78°C, THF I). Drug-SH 2). UiAb-(NH2)n 0. KJ kj ■Nj1^—1 Drug-NH2 (T\'VN'v^'"(LNn^-A>SzuV" Dri|8 dr & “V- P Figure I. The synthesis of phosphamide linkers containing maleimide groups and the application of these linkers in the conjugation of an antibody with drags. Patent Application Publication Oct. 8, 2015 Sheet 2 of 18 US 2015/0284416 Al OPCl O HO NH7 ^N S n M λ Li -Nv S IJ Wn-T-Na^ NHS/EDC HO DMA CCsA1~HO h ο"0 I). Drug-SH ^ H° ° \ 2). mAb—(NH2)n (Drugx XxX^N-P^nxXAjsj I mAb HO Hn H/q O ^N s OPCI3l Qf X^NH2 HO NH2 O0C, THF 13 0 O N § H x n -P-Nxs^OH NHS/EDC IXi^ J IV X «2^ 1 H DMA Cr'I T X^* nh I). Drug-SH /Drug'%^N^|LN/\-ANl mAb 2). mAb—(NH2)11 \ Drug"%-\^HH 2Q /q O O O O H /x-A Ii /N^A Drug 'P-N O Drug-NH2 'P-N V / H NH oP NHH h r H° ° TCEP * W--KsaN'""' mAb mAb 's-s^nhH H L 22 J q Figure 2. The synthesis of phosphamide linkers containing disulfide bonds and the application of these linkers in the conjugation of an antibody with drugs. Patent Application Publication Oct. 8,2015 Sheet 3 of 18 US 2015/0284416 Al H O OPCi3ZTHI^ H Ii H0VnJ) H2NxVn-?' NH7 -78°C then RT !IN. 'Nil, EDC/DMA τι ° Drng-COOH /Vn_?''h :^y H>N hA. h NH EDC/DMA O O U M Hit OIi Hu °M HOA/"Nj) N' NH2 /VN-P N H2NxVn-?' 25 .S' H2N I H HN> NH2 HN^/N H Qvv EDC/DMA NH 24 r~y O Q0 Drug-COOl^ HN— EDC/DMA^ X HNZvA__H O. o'^ TCEP or DTT OK NH >-iJ Drug mAh Figure 3. The synthesis of phosphamide linkers containing maleimide groups and the application of these linkers in the conjugation of an antibody with drags. Patent Application Publication Oct. 8, 2015 Sheet 4 of 18 US 2015/0284416 Al Drug-SH q= 1~30 EDC/DMA TCEP q = 1~20 O H Ii - NHNH H HN-^V X = Br or I EDC/DMA Drug-COOH TCEP EDC/DMA q= 1—20 Figure 4. The synthesis of phosphamide linkers containing maleimide, hydrazone, or lhioether groups and the application of these linkers in the conjugation of an antibody with drugs. Patent Application Publication Oct. 8, 2015 Sheet 5 of 18 US 2015/0284416 Al Q^°y.O .O I o O H O=PCl3 I-τΛ s M U. v-v / \ NH2________ ----------W Cn-v TcI HOa-^N 42 then HOAc c° -IO0C, THF O 44 * Ac2O, 90°C I O O In vs A NHS/EDC N-XvN-P-N'N-P-N v^OH ---------- > C' HO H I). Drug-SH 2). mAb-(NH2)„ J? I O I o O (ΓιΓ^° N-\,N Hn 'N O0C1THF Si Cl Vj 45 H O O O .O.Ο ΙΟΙ o -N- vs I). Drug-SH -------------------- ► 2). mAh—(NH2)11 ,rP v ..HSY- I __________ O____________________ .O I Ol οO ο o |°| ° “o °"N^l prMg-NH2 (f\ "VNI*-N N- • Drug ^N> "N^jJ O O 51 Figure 5. The synthesis of hinder phosphamide linkers containing maleimide groups and the application of these linkers in the conjugation of an antibody with drugs. Patent Application Publication Oct. 8, 2015 Sheet 6 of 18 US 2015/0284416 Al OSiMe3 Br^-Br ✓ν^,Βγ 9 HMDS Me3Si0.p^y^Br P-H --------► HP. <j-NH4+120uC, 2h OSiMc3 120 0C, 5h Mc3SiO' 35% from I O ° H2N-^V* HSAc,Kl Λ,, \ DIPEA OH EDC/HOBt/DIPEA O O AcS^^BAIl c IMNNaOHt 20%HC1 -s-O^ Nj -------------- pH 7 HN—'''''V \ Z>’ Dioxane, O0C 60 O PySSPy, 85% HN O Il Ow-N t-sOδ N- NHS/EDC ------------ ► Qw4-wS> HN.^011 DMA 62 O Drug-SH q= I ~ 20 -N VN/"-i>-"'\/ Drug-NH2 HNv^koh 62 O EDC HN^^N^Drug O TCEP Antibodies q = I ~ 30 B HO-QA 20%HCI ^ HN^/-Xf \ K|/D[PEA ΗΝ^-γ°7Γ· Dioxane, O0C Figure 6. The synthesis of phosphamide linkers containing disulfide or oxime groups and the application of these linkers in the conjugation of an antibody with drugs. PatentApplication Publication Oct. 8, 2015 Sheet 7 of 18 US 2015/0284416 Al HMDS ,OSiMe3 H-P-H ------------- mi_* Me3SiO. p Jv-O^ O-NHj+ 120 0C, 2h 'oSiMe, 120 0C, 5h Me3SiO' ' Imi m = 0~24 57b (COCl)2/DCM I -35% from 55 58b OH 'ET-V·, O Q 72 O K2C03/DMF 'NTV0N O O 73 HOSnBu3 NHS/EDC --------------) IOO0C DMA o >-vs °,. Hi1= 0~24, q = 1~20 ,Ν^/γ-ΟΗ ■NyV-N-Drug O O H In1= 0~24, q = 1~20 Figure 7. The synthesis of phosphamide linkers containing maleimide and polyethylene glycol groups and the application of these linkers in the conjugation of an antibody with drugs. Patent Application Publication Oct. 8, 2015 Sheet 8 of 18 US 2015/0284416 Al C^COOCH3 B>· Bry H ? H 2¾- [ηρ^8!Μ63 Mc3SiO ------------- Ul4--- (VnIIj IIO0C, 2h OSiMe3 50 0C, 2Ii Me3SiO'P^OMe 120 0C, 5h 56 79 55 m = 0~24 (COCl)2 then r/"|/0'Vvp'/svA()Mc NaN3 ' 'M| ΥOHλττ Q DMA nVn: N^NH 80 , . O O /vLO'Jh-p-^^'OMe Bu3SnOH NHS/EDC ' ' Ojv O V-fciV-°Zml1I O. H N-V-I ClCH2CH2Cl ^N-V- 85% Tol, 80~100°C P / . O O H ' an antibody Ν3^^°'4^ΡΧΝνΧ>17>"Ν'' ' V1 \ ^ cL 'mAb or a protein L ^ 85 <r In1 = 0 ~ 24 O 86 Drug]—SH "Drug2 'mi \ “iL· nV EDC 7nV P 88 P ivr / % O Oh Ν"%ψ>Α-ρ^·-^ηη,8ι TCEP or DTT _ Drug/ Jj Antibody 89 ml = 0~24, q = 1~30 Figure 8. The synthesis of phosphamide linkers containing maleimide, polyethylene glycol and azido groups and the application of these linkers in the conjugation of an antibody with two different compounds. Dragi and Drag2 here can be a cytotoxic agent for therapeutic application or a chromophore compound for monitoring the interaction with targeted cells. Patent Application Publication Oct. 8, 2015 Sheet 9 of 18 US 2015/0284416 Al r'''''^0''^ IVI c. «SAC ^ 'm< OH DIPEA/DMA / 80 93 / 1N^NC PySSPy, 86% 94 HN-J NHS/EDC an antibody ------------ ► 82% or a protein 95 111,=0-24 inAb drugf drugj— O-NH2 in 1 = 0~24, q = 1~20 \ ’mAb V. In1 = 0~24, q = I -20 . O O OO °-5NaOIL ,aLoJKII^Aoh DMA MeOH 3 ^ 'm' N-OQy 98 O 99 S . 0 0 iV-I NHS/EDC an antibody 82% * Κ,Ύ or a protein 100 O . ni| = 0~24, q = 1~20 Figure 9. The synthesis of phosphamide linkers containing disulfide, polyethylene glycol or ketone groups, and these linkers are used for conjugation of a protein with two different compounds. Drugi and Drug2 here can be a cytotoxic agent for therapeutic application or a chromophore compound for monitoring the interaction of the conjugates with targeted cells. PatentApplication Publication Oct. 8, 2015 Sheet 10 of 18 US 2015/0284416 Al O A Vvnh \ 0><^NH2 ' 105 ^ 103 ?w^° N 'I f U I/ Tol/DMA jP H « «ΛνγνΜ τϊΓ» όν^τν·ΛΑ ° 106 O0 107 20%Hg Al hnJiLii, S nhs/ld^ Dioxane \/\/ Il V OH DMA O ° 108 Drug-SH mAh q = I ~30 NH2 O -78°C, THF ► Tol/DMA 12 O0 C * i0"· 1V A\ HnJ-NH-S nhs/edc Dioxane \/\/ V'/'OH DMA Drug-SH I Jl H ο H O Drug VV1-N •mAb mAh q= 1~30 ' S ° 116 q Figure 10. The synthesis of the sulfonamide and the sulfinamide linkers containing a maleimide group and the application of these linkers in the conjugation of an antibody with a cytotoxic drug. 10 PatentApplication Publication Oct. 8, 2015 Sheet 11 of 18 US 2015/0284416 Al o 1).1N NaOH ^ § O ClSO3H 2). PySSPy, pH 7 N S' ^OH 80°C ^ 117 118 a Cl 119 s°3H EDC/DMA 122 NHS/EDC^ EDC/DIPEA DMA 123 protein ^ or in Ab Ovs^Y^n/v"©^ mAh P^gi-SH ^ Drugj-O^NH2 Figure 11.
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