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(12) Patent Application Publication (10) Pub. No.: US 2016/0272711 A1 Sahin Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0272711 A1 Sahin Et Al US 20160272711A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0272711 A1 Sahin et al. (43) Pub. Date: Sep. 22, 2016 (54) AGENTS FORTREATMENT OF CLAUDIN (86). PCT No.: PCT/EP2013/003.399 EXPRESSING CANCER DISEASES S371 (c)(1), (2) Date: May 13, 2015 (71) Applicants: Biontech AG, Mainz (DE); Ganymed (30) Foreign Application Priority Data Pharmaceuticals AG, Mainz (DE); TRON-Translationale Onkologie an Nov. 13, 2012 (EP) ................... PCT/EP2012/004712 der Universitatsm edizin der Johannes Jul. 30, 2013 (EP) ................... PCT/EP2013/002270 Gutenberg-Universitat Mainz, Mainz Publication Classification (DE) (51) Int. Cl. C07K 6/28 (2006.01) (72) Inventors: Ugur Sahin, Mainz (DE); Ozlem C07K 6/30 (2006.01) Tureci, Mainz (DE); Christiane Stadler, (52) U.S. Cl. Bensheim (DE); Julia Holland, Mainz CPC ............. C07K 16/2809 (2013.01); C07K 16/28 (DE); Hayat Bahr-Mahmud, Wiesbaden (2013.01); C07K 16/30 (2013.01); C07K (DE); Tim Beissert, Gross-Gerau (DE); 2317/31 (2013.01); C07K 2317/622 (2013.01); Laura Plum, Mainz (DE); Fabrice Le A6 IK 2039/505 (2013.01) Gall, Mainz (DE), Arne Jendretzki, (57) ABSTRACT Matist (E. Markus Fiedler, The present invention provides binding agents that contain a alle an der Saale (DE) binding domain that is specific for CD3 allowing binding to T cells and a binding domain that is specific for a tumor-asso (21) Appl. No.: 14/442,445 ciated claudin molecule and methods of using these binding (22) PCT Filed: Nov.e -la?s12, 2013 agents or nucleic acids encoding therefor for treating cancer. Patent Application Publication Sep. 22, 2016 Sheet 1 of 54 US 2016/0272711 A1 Figure 1 A Bi-ScFw CLDN18.2x CD3 LL S. LL B Bi-scFW CD3X CLDN18.2 LL SL LL Patent Application Publication Sep. 22, 2016 Sheet 2 of 54 US 2016/0272711 A1 Figure 2 Cytolysis of NugC4 target cells (8h-24h Coincubation) 100 8h in 16h 90 24h 80 70 60 50 40 30 . 20 & 3 10 1BMAB no. 11 no.12 no, 13 no. 14 no.15 no.16 no.17 no. 18 no.19 no.20 no.35 Patent Application Publication Sep. 22, 2016 Sheet 3 of 54 US 2016/0272711 A1 Figure 3 A - - - - - - - - - - 9 160 110 80 60 - 1BIMAB (54 kD) 50 40 kD 80 60 -1BiMAB (54 kD) 50 40 30 20 WB: anti-His Patent Application Publication Sep. 22, 2016 Sheet 5 of 54 US 2016/0272711 A1 Figure 4 C Human TL g-a-m APC ctrl anti-His +g-a-m APC ctrl 20 15 H - -20 ng/ml 1BMAB 10 -20Ongirn? 1BMAB 5 2ug/ml 1BMAB O s S s 3. s So APC S 3 S & S 8 SS & S)S s S S D CLDN18.2 negative cell line (PA-1) : manti-His +g-a-m APC ctrl ---Onglm BMAB - -100ngm 1BMAB - - pg/ml BIMAB - - - g-a-h APC(mCLDN182ab) ctrl -10 uglimlmCLDN182ab Patent Application Publication Sep. 22, 2016 Sheet 6 of 54 US 2016/0272711 A1 Figure 5 Patent Application Publication Sep. 22, 2016 Sheet 7 of 54 US 2016/0272711 A1 Figure 6 Activation of TL. (24h coincubation) totalTL activation 100- is CD25+ O CD69+ ZZ CD25ICD69++ 8O S 60 - 92g 40 20 nglml BiMAB 0 1 10 100 1000 O 0.001 0.01 0. O 100 000 H- - hu TL NugC4+hu TL B Activation of TL. (48h coincubation) L total TL activation 100- is CD25 CD69-- CD25/CD69--- 80 - H S 60 " 92 S 40 s 2 20- s 2 OJs & an L .2 : . : 2 nglml 1 BiMAB 0 10 100 1000 O 0.001 0.01 0. 1 1 0 100 1000 hu T. NugC4 + huTL Patent Application Publication Sep. 22, 2016 Sheet 8 of 54 US 2016/0272711 A1 Figure 7 A C-values of CLDN18.2 expression. various tumor ceilines Cancer type | Activation of TL B (144h coincubation) 100 90 total TL activation 80 CD25+ FO O CD69+ o 50 CD25CD69++ S 50 40 2 s 30 s 20 3 10- % 2 0- 2 s's9 S sis'$9.8 sis's S g’s's es'ss sis& go y N sS. S$ SS S SS S& Patent Application Publication Sep. 22, 2016 Sheet 9 of 54 US 2016/0272711 A1 Figure 8 1500 TL + 1 ng/ml 1BiMAB 150 OOO 1000 3. {) 500 unstaired T 50 O 1 3. O-Hi O 10 10 10 1. FL1-h: Crse F-H: CFSE 25CO TL + NugG4 TL + 1 ng/ml 1BiMAB+ NugC4 SOO 2CO s 1500 s 400 O O 50 O-Hi 1 in 0-h 2 O 1. 10 10 O O 1. 1. F1-h; CFSE FL1-H CFSE GrB expression by human TL 2so s also g - TL+5ngmil BIMAB S s -Tl+NugC4 a HTL-NugG4+5ng/ml 1BIMAB 100 ------------- soo 1.we s s x t s as tss anti-Gr-PE a. Patent Application Publication Sep. 22, 2016 Sheet 10 of 54 US 2016/0272711 A1 Figure 9 1BiMAB dose response Curve 100 80 -- 1BIMAB (24h) -- 1BIMAB(48h) EC50=11.2 pg/ml 2 60 tes d 5 3. SS 40 20 O O 2 4. 6 log10(pg/ml) Patent Application Publication Sep. 22, 2016 Sheet 11 of 54 US 2016/0272711 A1 Figure 10 A Day 6 post tumor cellinoculation Day 21 post tumor cellinoculation Day Oct P treatment Day 15 of IP treatment six 800 K sacticed 5 450 400 1W s k 4) 30 d 20 -ee- O es so C ------era rt- -tat sy s s S s 8 Day 31 post tumor ceilinoculation Day 4 post tumor Celtinoculation Day 3 post P treatment Day 13 past IP treatment segrificed 4. X sacfied -H s-e- -ae O us ^ g ^ s s^ s & . S g RS fs e S S g * c s * cs ''' -- G3-PBMcIvehicle (n-13) -- G4-PBMCI BMAB (n=5) 100 900 800 700 600 500 400 300 200 100 6 8 9 10 1 2 13 415 1617 8 1920 224 25 26.27 2831 33 35 38 41 Daily IP treatment day 6-28 Time (days posthumor cellinoculation) Patent Application Publication Sep. 22, 2016 Sheet 12 of 54 US 2016/0272711 A1 Figure 10 Kaplan-Meier survival Curve 100 G1-PBSvehicle (n=4) 90 - - - G2-PBS1BIMAB (n=5) - G3-PBMCIvehicle (n=13) 80 - G4-PBMC 1BIMAB (n=15) p(0.0001 Daily IP treatment day 6-28 Time (days post tumor cellinoculation) 100 90 w 80 8 70 s 60 E 50 i-- SE 40- O 30 S s 20 10 O 1-- -- -T - & &S Ses SŠ S & SSs C 8 cy& cS8 * S$ Patent Application Publication Sep. 22, 2016 Sheet 13 of 54 US 2016/0272711 A1 Figure 11 A ) LL S. LL B Bi-scFv CD3x CLDN6 (6PHU3 ) LL SL LL Patent Application Publication Sep. 22, 2016 Sheet 14 of 54 US 2016/0272711 A1 Figure 12 Patent Application Publication Sep. 22, 2016 Sheet 15 of 54 US 2016/0272711 A1 Figure 13 Activation of human TL (44h coincubation) total activation CD25+ 100 CD69+ 90 CD25CD694+ 80 70 3 60 50 40 30 20 10 O kuku what nglml S is is s is 6PHU5 6PHU3 hu TL PA-1 +hu TL Patent Application Publication Sep. 22, 2016 Sheet 16 of 54 US 2016/0272711 A1 Figure 14 A kD 2 3 4 5 6 7 8 9 10 11 260 160 10 80 60 - 6PHU3 (53 kD) 50 40 30 2O kD 80 60 - 6PHU3 (53 kD) 50 40 30 20 WB anti-His Patent Application Publication Sep. 22, 2016 Sheet 17 of 54 US 2016/0272711 A1 Figure 15 A PA-1 Cells 1 gm BiMAR 10 ugm 18 MAE * -g-a-h AFC ctrl OugitimCLDN18.2ab APC APC 7000 5000 s 3000 9 1000 1000 800 3. 600 a. S 400 200 O SS SS SSSS is So So S. $$$$.S^^s &Y&Y&Y&SNV N N NV N . SSs s $ N $S$ & S’sSis N'SS Ss' s s WS Patent Application Publication Sep. 22, 2016 Sheet 18 of 54 US 2016/0272711 A1 Figure 15 A OV-90 Cells - " -g-a-m APC ctrl g-a-m APC ctrl 10 ng/ml 6PHU3 Tw-Ong/ml 1BIMAB 100 ng/ml 6PHU3 100 ng/ml 1BMAB 1 ugmlSPHU3 1 gm 1 BMAB 10 pg/ml&PHU3 g-a-h APC ctrl 10 ugmmCLDN6ab 1 10 10 O APC APC 2400 2000 234.56OOOOOO OOOOOOO --r- $$$$. SS S N NSN Patent Application Publication Sep. 22, 2016 Sheet 19 of 54 US 2016/0272711 A1 Figure 15 Human TL 30000 25000 s anti-is-g-a-m PE ctrl 15000 E. 10000 1 ugim SPHU3 5000 5uglint SPHU3 O s S. 10 ugimi SPHU3 S & S S S & S & S 8 s'S ' ' ' s Patent Application Publication Sep. 22, 2016 Sheet 20 of 54 US 2016/0272711 A1 Figure 15 C CLDN6 negative cell line (NugC4) g-a-m AFC ctr 1Ongirn BMAE 10Ongfml 1EMAE 1 g/ml 1BIMAB 10 uglrn 1 BMAB g-a-h APC ctrl 10 uglin mCLDN18.2ab APC APC 600 1400 era. 200 is 1000 Se 800 is 600 400 100 80 60 s Patent Application Publication Sep. 22, 2016 Sheet 21 of 54 US 2016/0272711 A1 Figure 16 Activation of TL (24h coincubation) 100 total TL activation st CD25+ O O CD69+ 8 CD25/CD69---- H + 60 s 92y 40 20 222 2 2 O : 2 2 nglml 6PHU3 O 1 1 0 100 1000 O 0.001 0.01 0.1 10 100 1000 H- H hu TL + 6PHU3 PA-1 + hu TL + 6PHU3 Activation of TL (48h coincubation) CD25CD69--- 100 total Tactivation CD25+ 80 CD69+ P 3 60 s 93 g 40 20 O 2 al A ng/ml 6PHU3 O 10 100 1000 0 0001 0.01 (0.1 1 10 100 1000 H- H hu T + 6PHU3 PA-1 + hu TL + 6PHU3 Patent Application Publication Sep.
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