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Patent Application Publication Oo) Pub. No.: US 2015/0322155 Al Zhao (43) Pub US 20150322155A1 US 20150322155A1 (19) United States (12) Patent Application Publication oo) Pub. No.: US 2015/0322155 Al Zhao (43) Pub. Date: Nov. 12,2015 (54) ACETYLENEDICARBOXYL LINKERS AND A61K47/48 (2006.01) THEIR USES IN SPECIFIC CONJUGATION C07C 237/52 (2006.01) OF A CELL-BINDING MOLECULE A61K45/06 (2006.01) A61K39/395 (2006.01) (71) Applicants:Dr. RobertYongxin Zhao, Lexington, C07D 207/46 (2006.01) MA (US); Suzhou M-conj Biotech Co., C07D 417/14 (2006.01) Ltd, Suzhou (CN) (52) U.S. Cl. CPC .......... C07K16/2863 (2013.01); C07D 207/46 (72) Inventor: Robert Yongxin Zhao, Lexington, MA (2013.01); C07C 59/76 (2013.01); C07D (US) 417/14 (2013.01); C07C237/52 (2013.01); A61K45/06 (2013.01); A61K39/3955 (73) Assignees: Sushou M-conj Biotech Co., Ltd, (2013.01); A61K 47/48561 (2013.01); A61K Suzhou City (CN); RobertYongxin 2039/505 (2013.01) Zhao, Lexington, MA (US) (57) ABSTRACT (21) Appl. No.: 14/799,666 The present invention relates to novel acetylenedicarboxyl (22) Filed: Jul. 15, 2015 linkers used for the specific conjugation of compounds/cyto- toxic agents to a cell-binding molecule, through bridge link­ Publication Classification ing pairs of thiols on the cell-binding molecule. The invention also relates to methods of making such linkers, and of using (51) Int. Cl. such linkers in making homogeneous conjugates, as well as of C07K16/28 (2006.01) application of the conjugates in treatment of cancers, infec­ C07C 59/76 (2006.01) tions and autoimmune disorders. PatentApplication Publication Nov. 12, 2015 Sheet I of 11 US 2015/0322155 Al υ MsCl HoN"OH)m =kO^ H0N^0-WVY- Na/THF m β ' 3 Pyr H2ZPdZC MsOt MeOH 20%HC1 OH H2N(^°t^/SV°Nf::~ H7N O ' Dioxanc VeW u 6 O NHS/EDC^ i—O O °<Νλ HO- JL -OH DMA V-O-11 ----- 1L-O-V 9 O OH pH 6-8.5 H O Drug-NH2 Drug"NY^/°vH‘N^1 -------- ^Ν"^Ν/,0')|^/ΛΥ SDrug EDC/DMA Antibody TC E I’ Druc'nYV0Vn-jlZ , O hSSh υ , ^inAb 1-20, m = 0-50 Figure I. PatentApplication Publication Nov. 12, 2015 Sheet 2 of 11 US 2015/0322155 Al O \ / I2 (5 mol%) %__ Λ Cl A^Yci + -Si ------- Si- / \ 0 0C-RT, DCM Vj 15 14 90% ο^ΌΗ HO O Cl 15 Drug-NlC antibod' EDC/DMA Dru§ TCEP H N. Drug^ Drug n 18 EDC/DMA antibod' Drug-O-NH- TCEP buffer Figure 2. PatentApplication Publication Nov. 12, 2015 Sheet 3 of 11 US 2015/0322155 Al o NHS/EDC ■° Q M HO JJ—OH DMA CNn —O- -O-NV1 8 O O^ 9 in A b OH?JO H u O I H O H2N-Tn-^0H —1 ~H 11 * -HO\Vs- hO^- ° w 28 NHBoc IBoc 29 N^NHBoc JO Si- Dr"s-N'\'%AN j[_ N>^AN'Drllg EDC/DMA H^oH -N T Τ' η Ho^h H Boc v^sNHBoc JO EtOAc —Hn VAT } N-11«- ° -N^Y"-rXN-Drug 1^NH2 H 1 e." ” = 1-20 Figure 3. Patent Application Publication Nov. 12, 2015 Sheet 4 of 11 US 2015/0322155 Al TsCl HoK-OH)j .=W hoK^VVV- Na/THF 3 Λ ' - NaN3 H2ZPdZC DMF MeOH ° 36 o ' + HNv. o u . 37 (74%) 20%HC1 38 (19%) Dioxane 20%HC1 I ίDioxane K0VV HN /N1Vj OOyoh ° 39 V-Ojrs-^OH 40 OHfJO η 9 NHSZED^ ηοΛΤνΥ^ν^-=- -N fW^OH r-* O H H O DMA IV\ NHBoc ^"NHBoc 29 Op O H JrWvUijjSΓ-*t nYS-O H Μ-ο-Φ l^NHBoe H ΰ ¢.NHBoc JO OHf W) O i"H ^ N OA/N/OH Dru§*NH2 g * J 3 ° edc/dma ° WnNHBoen111,... 42 VvNHBoc Dr"8'NW°^sVYssls2-K;v“/s^0^r”'Dr"s v I nNHBocniud— Vs- NHBoc 20%HC1 / Dioxane I v© H±1 o — - ',ni4 n O 3 HVV p-® OH WIL HVq VV2H ’Vv"'"'·=jO Ivn, V^NH1 Figure 4. PatentApplication Publication Nov. 12, 2015 Sheet 5 of 11 US 2015/0322155 Al 44 Ntcep I niAb JO II ; H O NH, \ / ^sNIl, I n nAb 45 n=l~20 ^0Wm Cf « H 4®0 pH 7.5 . if^ *^NHBoc Vs-NHBoc JO FkAJcjM} I^sNHBoc , Dmg-NH2 ED C/D MA I JO OHf η 9 V^0VKvihu8 Diii'j'(W0v4n Y^N-JL= -N .Nv-^n o O H O H 8 Drug Dn,8'N-^4(Ni j 'iNHBoc vnNHR,,. 3 H 20%TFA DCM \ H H JO N„ -N 0 H f o O η 9 V^0VK *Dru8 d^0W0A -N H Vbjl^x O J V0VaN^diu8 d^nM-oN^ ^sNH2 VNuxj -5 H TCEP 48 niAb H Q H N O O Λ Dmg7 (WiKV M JL ■Λ·"i^-Nϊ /^'0^O>DrUg W 11 Os?A t^NH2 7T vsNH. 3 H -VmAb1 49 n=l~20 Figure 5. PatentApplication Publication Nov. 12, 2015 Sheet 6 of 11 US 2015/0322155 Al .OH NHS "V8-N-N0W EDC/DMA NHBoc NHBoc , . S w. A <,! _ .AJWnN W 3 n s η ArW-0N N V Kjl^jlS T } ° ° O T 3Hd ° “ „ Whboc '''WHBoc 50 NHBoc NHBoc AcO V O H AcO X/ O H Figure 6. PatentApplication Publication Nov. 12, 2015 Sheet 7 of 11 US 2015/0322155 Al 53 I TCEP T mAh mAh OH H1N-U0-^V0" » - H°,yU0HrK-2^2'K'U°')Dr 54 o pH 7.5 55 (COCl)2 Cl DC M/D M F O N N O / mAh Figure 7. PatentApplication Publication Nov. 12, 2015 Sheet 8 of 11 US 2015/0322155 Al ^-NH _____________ \-t/ Maytansinol A J~~ CljCO^NtCCl, f ^ —------------► Ti M 4 O^N0H 0^f)>0 ZnTf2/DMF/Et3N 60 HiCCfH Q O HO. H H 'Ύ*^>-Τν'^ο I TCEP 63 S^iiiVirA) H3CC^H$ H f mAb H3CCf HO H mAb AA Met) ?£yu^ O O ^j'N A AA H3CCf HO H H3CCfHO H n = 1-20 29+ 62 \EDC/DMA Me' H3COho h TCEP mAb H3COhO H I Q__f O H H OMeqC1-'-0?^ BocHN--' Ψ 'λ T^^'^TVA) H3COhO H n= 1-20 PatentApplication Publication Nov. 12, 2015 Sheet 9 of 11 US 2015/0322155 Al H0^°^0Hl!£!^TS0-f0^OTs I 67 68 MeOH 8 -----MMAF ^ H7N NH7 EDC/DMA H EDC/DMA 70 TCEPl mAb OCH N pH 7.5-8 HX A IUhJ? >0.1 MMAF-I NHBoe NHBoc I). 20%HCI 2). TCEP in Dioxane W mAb OCH 75, n=l~20 Figure 9. Patent Application Publication Nov. 12, 2015 Sheet 10 of 11 US 2015/0322155 Al Figure 10. PatentApplication Publication Nov. 12, 2015 Sheet 11 of 11 US 2015/0322155 Al Tumor volume of BALB/c Nude Mice Bearing NCI-N87 Xenograft Tumor 1800 η 1700- 1600- 1500- 1400- 1300- 1200- 1100- 1000- -·- PBS T-DM 1(5 mg/kg) -Φ- Compound 91 (5 mg/kg) -+- Compound 93 (5 mg/kg) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Days (after Initiation of Treatment) Figure 11 US 2015/0322155 Al Nov. 12, 2015 I ACETYLENEDICARBOXYL LINKERS AND [0004] Therefore, biotechnology companies and academic THEIR USES IN SPECIFIC CONJUGATION institutions are highly focusing on establishing novel reliable OF A CELL-BINDING MOLECULE methods for site-specific ADC conjugation. So far, there are several approaches developed in recent years for site selective FIELD OF THE INVENTION ADC preparation (Panowski, S, 2014, mAbs 6, 34). They [0001] The present invention relates to the preparation of include incorporation of unpaired cysteines, e.g. engineered novel linkers used for the specific conjugation of compounds, reactive cysteine residues, called THIOMAB from Genen- in particular, cytotoxic agents to a biological molecule. The tech (Junutula, J. R., et al 2010 Clin. Cancer Res. 16, 4769; present invention also relates to methods of making cell­ Junutula, J. R., et al 2008 Nat Biotechnol. 26, 925-32; U.S. binding agent-drug (cytotoxic agent) conjugates in a specific Pat. Nos. 8,309,300; 7,855,275; 7,521,541; 7,723,485, manner comprising either modification of drugs with these W02008/141044), genetically introduced glutamine tag with linkers first, followed by reaction with prepared cell-binding Streptoverticillium mobaraense transglutaminase (mTG) agents; or modification of cell-binding agents with these link­ (Strop, P, Bioconjugate Chem., 2014, 25, 855-862; Strop, P, ers first, followed by reaction with drugs. et al, 2013, Chem. Biol. 20,161-167; U.S. Pat. No. 8,871,908 for Rinat-Pfizer) or with Microbial transglutaminase (MT- BACKGROUND OF THE INVENTION Gase) (Dennler, P, et al, 2014, Bioconjug. Chem. 25, 569- 578. US pat appl 20130189287 for Innate Pharma; U.S. Pat. [0002] Proteins, specifically antibodies have been exten­ No. 7,893,019 for Bio-Ker S.r.l. (IT)), incorporation of thiol- sively used in therapeutic applications, in vitro assays as fucose (Dennler, P, et al, 2014 Bioconjugate Chemistry 25, research reagents and in vivo as diagnostic tools or as thera­ 569; Okeley5N. M, etal2013 Bioconjugate Chem. 24,1650), peutic drugs (Gad, S. C. Drug discovery handbook, published incorporation of unnatural amino acids through mutagenesis by Wiley-Interscience, 2005). Formany applications the pro­ (Axup, J. Y, et al, 2012, Proc. Natl. Acad. Sci. 109, 16101- tein needs to be modified with an interesting group, such as a 16106; Zimmerman, E. S, et al, 2014, Bioconjug. Chem. 25, cytotoxic drug, a radio label element or a chromphore mol­ 351-361; Wu, P, et al, 2009 Proc. Natl. Acad. Sci. 106, 3000- ecule for use in therapy or a detection agent when used in 3005; Rabuka, D, et al, 2012 Nat.
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