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(12) Patent Application Publication (10) Pub. No.: US 2016/0177276 A1 L0 Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0177276 A1 L0 Et Al US 2016O177276A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0177276 A1 L0 et al. (43) Pub. Date: Jun. 23, 2016 (54) SIRP-ALPHA IMMUNOGLOBULINFUSION C07K 6/40 (2006.01) PROTEINS C07K 16/32 (2006.01) C07K 6/28 (2006.01) (71) Applicant: MERCK PATENT GMBH, Darmstadt C07K 6/30 (2006.01) (DE) (52) U.S. Cl. CPC .............. CI2N 9/16 (2013.01); C07K 16/2887 (72) Inventors: Kin-Ming Lo, Lexington, MA (US); (2013.01); C07K 16/30 (2013.01); C07K Nora Zizlsperger, Newton, MA (US); I6/2863 (2013.01); C07K 16/40 (2013.01); Aroop Sircar, Billerica, MA (US) C07K 16/32 (2013.01); C07K 16/18 (2013.01); 21) Appl. No.: 14/827,003 C07K 16/2827 (2013.01);s C07K 16/2803 (21) Appl. No 9 (2013.01); C12Y-301/03048 (2013.01); C07K (22) Filed: Aug. 14, 2015 2317/622 (2013.01); C07K 2319/74 (2013.01); A6 IK 2039/505 (2013.01) Related U.S. Application Data (60) Provisional application No. 62/038,196, filed on Aug. (57) ABSTRACT 15, 2014. Publication Classification The invention discloses immunoglobulin fusion proteins designed to bind both CD47 and a tumor cell antigen. The (51) Int. Cl. immunoglobulin fusion proteins include a SIRPC. moiety that CI2N 9/16 (2006.01) binds CD47 and an antigen binding site for a tumor cell C07K 6/8 (2006.01) antigen. Patent Application Publication Jun. 23, 2016 Sheet 1 of 36 US 2016/0177276 A1 2 EVE CL Patent Application Publication Jun. 23, 2016 Sheet 2 of 36 US 2016/0177276 A1 Patent Application Publication Jun. 23, 2016 Sheet 3 of 36 US 2016/0177276 A1 FG. K Patent Application Publication Jun. 23, 2016 Sheet 4 of 36 US 2016/0177276 A1 FG. Patent Application Publication Jun. 23, 2016 Sheet 5 of 36 US 2016/0177276 A1 2 3 4. 5 8 7 8 DAY'S OS.REAVENT FG. 2A 4 2 7 8 DAYS POS-TREAVEN F.G. 2B Patent Application Publication Jun. 23, 2016 Sheet 6 of 36 US 2016/0177276 A1 KDa N 183 98 62 49 38 FG. 3A 28 4. 8 3 900 80 70) 60 500 40 30 ... 1200 . O 100 90 80 70 60 50 40 30 20 5.465 5.966 O ( ; 2 3 4 5 & 7 8 & 10 1 2 3 4 5 TIME (min) G. 33 Patent Application Publication Jun. 23, 2016 Sheet 7 of 36 US 2016/0177276 A1 20 --Or Anti-CD20-hugG1-huSRPaV2 000 rty's F-SiRPW2 a: sis SRPW2-r f o:mo" : obo Anti-C20 pe 80 -- Anti-CD47 / oak 6 O 8 . RED BLOOD CELLS (CD235+) to E. LEUKOCYTES (CD45*) 5 t h Atop top. Antonio SRPCV2 SRPCV2. FC SRPCV2 FG. 4B Patent Application Publication Jun. 23, 2016 Sheet 8 of 36 US 2016/0177276 A1 400 so -o- Anti-CD20-hugG1-huSIRPaV2 : • 'A' FC-huSRPV2 A. g 300 oar- huSIRPav2-Fo A. i 250 -a-. Anti-CD47 f S 200 ti- s a 150 f 100 5 :e : 0. G. 4C 90 8) --Or Anti-CD20-huigG-huSRPaV2 : sexy. FC-SRPoV2 1. 70 -- Anti-CD20 1 i?S 60a - - Anti-CD47 s 50 is 40 2. is 30 e s' & 88 w st , 000 Patent Application Publication Jun. 23, 2016 Sheet 9 of 36 US 2016/0177276 A1 EDAs SURVIVA. DAYS wy w CONTRO. At mem. Anti-CD20 3S or Anti-CD47 143 {{ YYYYYYYYYYYYYYYY PPPPPPPPPPPPPPPPAwww.wa. A v. A was w8A wa &w A w w 8A wir aw Ove Anti-C2ianti-CD4F NO --- e k ?s 75 - 8 5 50 - y r - 25 1 a v g 20 40 80 8 OO 20 4 6 8 AYS POS iOR NOCAON F.G. 5A RA 8 mmm's iANSRWVA DAYS a - p SOTYPE CONTRO 3 80 on RXAN 8 w -" cooroo Anti-C47 37 6 (... as Os Anti-CD2O:Anti-C47 55 Patent Application Publication Jun. 23, 2016 Sheet 10 of 36 US 2016/0177276 A1 Ka 88 F.G. 6A Patent Application Publication Jun. 23, 2016 Sheet 11 of 36 US 2016/0177276 A1 anti-EGFR-huigG1-SRPow 5.561 6,025 (. 1 2 3 4 5 & 7 & 8 to 1 2 3 4 5 TIME (min) 380 6.8 i. 81 anti-EGFR-hulgG1-(G4S): SIRPoV2 2400 2200 2}} 1800 160040 20 000 8 6 4- 5,473 5.987 ; ; ; ; ; ; ; ; , , , , , , TIME (min) F.G. 6B Patent Application Publication Jun. 23, 2016 Sheet 12 of 36 US 2016/0177276 A1 (ii) anti-EGFR-hulgG1-(G4S4-SiRPoV2 :0 5.451 5985 2 3 4. " " " " . TIME (min) 2800 8.75- anti-EGFR-hulgG1-(G4S)5-SIRPoV2 is TIVE (min) FIG. 6B (CONT) Patent Application Publication Jun. 23, 2016 Sheet 13 of 36 US 2016/0177276 A1 1000 -k- Anti-EGFR-hugg1-h;SRPaw -- Anti-EGFR-hugg1-G4S)3-huSiRPaV2 & Anti-EGFR-hugG-G4S4-huSRPaV2 800 --- Anti-EGFR-hugg1-G4S5-huSiRPaV2 ...y. FC-SRPOW2 Mir SRPCW2-Fi 600 - - Anti-CED47 ... Atti-EGFR a a.s. 40 es 2 -: w 200 ->k x O.01 . 0.1 O OO 300 ni FG, 7A 90 . 80 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - RE BOOD CELS (CD235+) 70. E. EUKOCYTES (CD45+) 60 . g 50 - is 40-rrier to r as 30 - . : . :::::::::. 3. : . 20.... : ... ... : ... :... ... :. O . : . ::::::::. : . : . O+ hu Atop to of SRPW2 SRPx2-C hSRPOW G. 73 Patent Application Publication Jun. 23, 2016 Sheet 14 of 36 US 2016/0177276 A1 --C - Anti-EGFR-huigG-huSRPaV2 120 vyy FC-SRPCV2 wiro Sirf2-FC g O m:m Angpt mm. Anti-EGFR i. 3 80 it 60 s e 40 C O,000 O, OO 0000 Patent Application Publication Jun. 23, 2016 Sheet 15 of 36 US 2016/0177276 A1 2000000 - -o- Anti-EGFR-huigG-(G4S4-huSRPaV2 orro hSir POV2-r 1800000 ...A.. Fc-husiRPv2 ---O- - 800000 - obo Anti-EGFR o r 4000 200000 000000 800000 600000 400000 200000 O R 0.000 0.00 3.0 O. 10 00 Patent Application Publication Jun. 23, 2016 Sheet 16 of 36 US 2016/0177276 A1 00). -- Fe-SiRPo (20 ag) r^ - FC-SRPo (200 g) we anti-EGFR-Fe-SRPo (20 kg) ...O.. anti-EGFR-FC-SRPoi. (200 g) 0. t 50 100 50 200 250 TIME (h) G. 9A EDAN SRWWA DAYS O ope - SOTYPE CONTRO 28 oboe C225 3. 80 wim SRPa-FC 3. -- C225+ SRPa-Fo 4. 60 w C a C225iSR-a-F 40 40 20 to 2 3 4 so 70 DAYS OS.REAVEN START G. 9B Patent Application Publication Jun. 23, 2016 Sheet 17 of 36 US 2016/0177276 A1 FG. OA 2 3 4 5 6 7 & 8 to 12 13 14 15 TIME (min) FG. OB Patent Application Publication Jun. 23, 2016 Sheet 18 of 36 US 2016/0177276 A1 2000. --O- Anti-HER2-huigG4-h;SRPav2 180 - sexx as F-SRPo V2 .. othro h;SRPCV2-F2 e: 600 -- Anti-CD47 oboe Anti-ER2 4. O -: 4. 80 - / 2 800 - 30 200 - O ::::::: 3. O, . COO f FG. A 80. RED BLOOD CELLS (CD235t) 7 - . s' EUKOCYTES (CD45+) 8 O F. Anti-CD47 "Antier. Anti-ER SRC.V2 SRPCV2-C SR-V2 G. 13 Patent Application Publication Jun. 23, 2016 Sheet 19 of 36 US 2016/0177276 A1 400 - O - Anti-HER2-hulgG-huSRPaV2 ...yo. FC-hSRPOW2 20 on Anti-CD47 --- obo Anti-ER2 exo-boo" 800 800 400 200 F.G. 11C Patent Application Publication Jun. 23, 2016 Sheet 20 of 36 US 2016/0177276 A1 2200 2 200 30 800 47 8. 500 4. 30 25. 3. 800 700 8. 500 4. 3. 2 552 6,044 84.79,524 00 O 2 3 4 5 & 7 8 to 1 2 3 4 15 TIME (min) FG. 2B Patent Application Publication Jun. 23, 2016 Sheet 21 of 36 US 2016/0177276 A1 " -o- Anti-PDL1-hulgG1-muSIRPa. * -e-A. Anti-PDL4FC-muSIRPe. 10- -- huigG1 control i 0. ----------------------------------------- Gioboo oooo- O. 4 100 0000 Patent Application Publication Jun. 23, 2016 Sheet 22 of 36 US 2016/0177276 A1 Ka 88 98 62 49 38 FG. AA 28 280 260 2400 22 200 8 3. S. 4 2 {{0 800 60 400 2 5,486 5.984 ( ----------------------------------------------------------------------------------------------------------------------------------------------------; 2 3 4 5 & 7 & 8 to 12 3 4 5 TIME (min) FG. 4B Patent Application Publication Jun. 23, 2016 Sheet 23 of 36 US 2016/0177276 A1 900 wk- Anti-EGFR-huigG1-huSERPaV1 80 -x- Anti-EGFR-higG1-huSRPawt (N110C) OO c. Anti-EGFR-huggi-(G4S)4-huSRPaV2 A. Fo-SERPOV2 6 orro SRPoV2-Fe: -Do Anti-CD47 500 -- Anti-EGFR 4. 30 200 {{ O 8:: aaaa...: s 8 : 0.00 O.) O. O 00 000 Patent Application Publication Jun. 23, 2016 Sheet 24 of 36 US 2016/0177276 A1 FG. 6A 5,583 5.988 Y " --------------------------------------------------------------------------------------------------------------------------------------------------------" " " " " " " " " " " "," "is TIME (min) F.G. 18B Patent Application Publication Jun. 23, 2016 Sheet 25 of 36 US 2016/0177276 A1 --> huSRPoV2-FChuigG1}-anti-EGFR(Fab) ..o. Anti-EGFR-huggi-G4S4-huSRPaV2 war. SRPCV2-FC 700 A. Fo-huSRPoV2 600 - - - Anti-CR47 8 r"a oo::co. Anti-EGFr 300 g ...A is 400 - A A' g ... is 300 O ----------- (Bexel : -. 0.00 . O 100C f F.G. 17A w{v: huSRPoV2-FChuigG1}-anti-EGFR(Fab) 20000 - O - Anti-EGFR-huggi-G4S}4-huSRPaV2 3000 mew SRPCV2-C ---O- 600000 oyye FC-SRFCV2 O K1 wo-born Anti-EGFR 4000 2000 00000 8000 60 -4- 400000 - ? / 2000 geo OOOO . 0. 0. 00 f F.G. 17B Patent Application Publication Jun. 23, 2016 Sheet 26 of 36 US 2016/0177276 A1 EAN SRWWA DAYS wo wo orps SOTYPE CONTRO. 29.5 minor Ani-EGFR 35.5 m-go Ai-EGFr + SRParc 42 x X x Aiii-EGFRSRPa 43.
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