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(12) Patent Application Publication (10) Pub. No.: US 2017/0143845 A1 Zhao (43) Pub US 20170143845A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0143845 A1 Zhao (43) Pub. Date: May 25, 2017 (54) ACETYLENEDCARBOXYL LINKERS AND Publication Classification THEIR USES IN SPECIFIC CONUGATION (51) Int. Cl. OFA CELL-BINDING MOLECULE A 6LX 9/27 (2006.01) A63L/337 (2006.01) (71) Applicant: SUZHOUM-CONJ BIOTECH CO., A 6LX 3/557 (2006.01) LTD., Suzhou (CN) GOIN 33/50 (2006.01) A 6LX 3/537 (2006.01) (72) Inventor: Robert Yongxin Zhao, Lexington, MA A63L/404 (2006.01) (US) (52) U.S. Cl. CPC. A61K 47/48569 (2013.01); A61K 47/48715 (73) Assignee: SUZHOUM-CONJ BIOTECH CO., (2013.01); A61K 47/4863 (2013.01); A61 K LTD, Suzhou (CN) 47/48615 (2013.01); A61K 47/48484 (2013.01); A61K 47/48407 (2013.01); A61 K (21) Appl. No.: 15/423,695 31/537 (2013.01); A61K3I/337 (2013.01); A61K 31/404 (2013.01); A61K 47/48438 (2013.01); A61 K3I/55.17 (2013.01); G0IN (22) Filed: Feb. 3, 2017 33/5014 (2013.01) (57) ABSTRACT Related U.S. Application Data Cell binding agent-drug conjugates comprising bridge link (62) Division of application No. 14/799,666, filed on Jul. ers, and methods of using Such linkers and conjugates are 15, 2015. provided. Patent Application Publication May 25, 2017. Sheet 1 of 11 US 2017/0143845 A1 O ch OH m =/a -k 2 Hoern-O }^ O 'e, -->MSC yohn')^ OYe- - G- N ^ On H/P/C> 4 5 H.Nhn- }^^e. 20%HCDioxane unkn- ^"O 6 O O NHS/EDC O - -O O HO-7-A-OH - > N- O 9 OsNs B Br O O O O 6 O. M. O. 17- O O to-yC Cl or13 ninter'? 97m H. C. h")/"< 14 O O Na Y'?- m1, h')." 2O,Dioxane HC 15 O O " } h')." EDC/DMADrug-NH 16 H O O H Antibodv Drug 1 N O N I kn O ^SN - 12 O H H O pH 7-8 17 a Figure 1. Patent Application Publication May 25, 2017. Sheet 2 of 11 US 2017/0143845 A1 O CI M M l, (5 mol%) 's E-4' c'Yn + -Si-E-Si- He O M V 0 °C-RT, DCM 15 13 14 90% O1 OH HO1 NO O O O cin1 C BrMg-E-MgBr - THFHol 13 O 16 O1 OH HOYSO 15 H 9 H EDC/DMADrug-N Drug N say = -R Drug antibodyTCEP O O 17 O O mAb H.N-(T)-RO 19 NH sayO = O- H 15 - EDC/DMAEo Q O --yoO 20 H 9 H antibody N N Drug-O-NH - E-oTCEP O S S O Co brillbuffer A4 J 21 mAb H R 9 H Drug-N N N M N zy Drug O W O S S O O AZ n = 1-20 mAb 22 Figure 2. Patent Application Publication May 25, 2017. Sheet 3 of 11 US 2017/0143845 A1 O O HO-IO = OTI-OH NHS/EDCyA Q-o-fiO = O -o- 8 O O 9 H O 23 O HO iry = - 1OH O -() 24 Drug-NH O O o O H O O NHS/EDCDMA C P O 1N I = Il N N-Drug H H O N) 26 o o H mAb- Drug N- N N-N-Drug TCEP 6 H ". \ H 5 NT) n=1-20 N Z mAb 27 O H E O H O N t O O NH HN N-OH-9-Ho O 1) = - O SOH 28 O 1-NHBoe NHBO 29 S^NHBoe Du N Drugs O N^H Null-N-DrugH EDC/DMA H - = is H NHBO S-rNHBoe 30 -T-2O/HC Drug- N^H O O NuO N-Drug EtOA H O H 31 NH \-rNu, O H O mAb Drug- N^ O O Nu-N-Drug TCEP H N a H H S S O C-a NH NH n-1-20 mAb Figure 3. Patent Application Publication May 25, 2017. Sheet 5 of 11 US 2017/0143845 A1 Figure 5. Patent Application Publication May 25, 2017. Sheet 7 of 11 US 2017/0143845 A1 HNI % SNYCCra N You 54 mAb O OH HO O --F-lO O H.Nf-')"54 O --pH 7.5 "re's)O 2 N = H (-O-)-OH2 SS COC C O O DCM/DMFa 'yr-Y)O 2 H = H (-o-)c2 56 H EtN Q's O N O DCM c S-WY OH 57 O C o Aco Y o H *a HO N \ is N O N Patent Application Publication May 25, 2017. Sheet 8 of 11 US 2017/0143845 A1 W NH O l, fancinal MeO Clco'OCC1,- Hos As HeMaytansinol Ono O1^NO ZnTr/DMF/EtN 60 61 O O HO - Ell COC)/DCM/DME rt'llH - It'),"H O Col.then 62/EtN 10 of M O O CI V 9 O re-it MeO N Figure 8. Patent Application Publication May 25, 2017. Sheet 9 of 11 US 2017/0143845 A1 Hor-Yoh Tscury Tsor-Yots NaN/DMF N^{-0-) N H/Pd(G 1 67 68 MeOH HN O NHL He->8 alsoMMAF 2 r n) EDC/DMA H.N(--) == r(s), NH, EDC/TDMA 70 H H P Ph Y RCN A N Ol H. O. H O N OHCO O O nN-N-NY Ol O OCH O HN Ö O H O s OCH CO O N rt-'), t = r(s), TCEP mAb 71 NHBOc in1). Dioxanesity 2).mAb TCEP NullH. O. (l H Ph N N 1Si N.\ OHCO O O Ph OCH Ph HO O H at O H Ph N N. N 6 H H O Ri OH,CO. O. O NH S S &^N. OCH 3 H O mAb 75, n=1-20 Patent Application Publication May 25, 2017. Sheet 10 of 11 US 2017/0143845 A1 O O O BL-L Li skif O O E O 76 77 HO 15 OH OH O H Qk O Ac O o O 51 D SCNS S y H O | EDC/DMA OH H O OA O N Q y N y N N Os S ? H O OH OH Q O OAC O f N N y OH TCEP N. Os- S H O Qf 4.O OA y O olN S S H O NHS O O Q O Q 28 15 - Aso N- Q-I =ll- Ny He EDC/DMA O O pH 7.5 O O 81 O O 51 HO 1NH HN 'OH EDC/TDMA NHBocO O O O a NHBoc 82 OH S) R. Q OAc O s O N - N y OH ? O N ON S-W O NHBOC 1) TFA/DCM OH (S) Ho Q O OAC O N-4' 2) TCEP/mAb 4. N H n1n O f W C S. O OH NHBO Yo 83 H OH H H 3) N O OA O N N O f al N 2N OH N ON ?/ N O O O S W S H O NH OH 2 S) mAb O YOAc O 9 H é S Na N Nn-S O N f O N J N OH O NYH W S H O NH In 85 2 Figure 10. Patent Application Publication May 25, 2017. Sheet 11 of 11 US 2017/0143845 A1 Tumor volume of BALB/C Nude Mice Bearing NCI-N87 Xenograft Tumor 1800 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 -O PBS 600 -- T-DM1(5 mg/kg) 500 -V Compound 91 (5 mg/kg) 400 -0 Compound 93 (5 mg/kg) 300 200 100 O 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Days (after Initiation of Treatment) Figure 11 US 2017/O 143845 A1 May 25, 2017 ACETYLENEDCARBOXYL LINKERS AND 7063). Thus some of the undesired ADC subpopulation THEIR USES IN SPECIFIC CONUGATION could lead to shorter circulation halflife, lower efficacy, OFA CELL-BINDING MOLECULE potentially increased off-target toxicity and a wide range of in vivo pharmacokinetic (PK) properties (Hamblett, K. J. et CROSS REFERENCE TO RELATED al, Clin. Cancer Res. 2004, 10, 7063-7070; Adem, Y.T. etal, APPLICATIONS Bioconjugate Chem. 2014, 25, 656-664: Boylan, N. J. 0001. This application is a division of U.S. application Bioconjugate Chem..., 2013, 24, 1008-1016; Strop, P., et Ser. No. 14/799,666, filed on Jul. 15, 2015, entitled al2013 Chem. Biol. 20, 161-167). In addition, with this ACETYLENEDICARBOXYL LINKERS AND THEIR classical conjugation, the batch-to-batch consistency in USES IN SPECIFIC CONJUGATION OF A CELL-BIND ADC production can be challenging and may require dili ING MOLECULE.” The content of the prior application is gent manufacturing capabilities (Wakankar, A. mAbs, 2011, hereby incorporated by reference in its entirety. 3, 161-172). 0005. Therefore, biotechnology companies and academic FIELD OF THE INVENTION institutions are highly focusing on establishing novel reli 0002 The present invention relates to the preparation of able methods for site-specific ADC conjugation. So far, there novel linkers used for the specific conjugation of com are several approaches developed in recent years for site pounds, in particular, cytotoxic agents to a biological mol selective ADC preparation (Panowski, S, 2014, mabs 6,34). ecule. The present invention also relates to methods of They include incorporation of unpaired cysteines, e.g. engi making cell-binding agent-drug (cytotoxic agent) conjugates neered reactive cysteine residues, called THIOMAB from in a specific manner comprising either modification of drugs Genentech (Junutula, J.
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