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(12) Patent Application Publication (10) Pub. No.: US 2012/0177568 A1 WILLIAMS Et Al US 20120177568A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0177568 A1 WILLIAMS et al. (43) Pub. Date: Jul. 12, 2012 (54) NOVEL MEDITOPES AND RELATED C07K 7/06 (2006.01) MEDITOPE-MONOCLONAL ANTIBODY A6IP37/02 (2006.01) DELIVERY SYSTEMS, SYNTHESIS AND A6IP39/04 (2006.01) THERAPEUTIC USES THEREOF C07K 4/00 (2006.01) C07K L/4 (2006.01) (76) Inventors: John C. WILLIAMS, Monrovia, B82Y5/00 (2011.01) CA (US); David A. Horne, Duarte, CA (US); Yuelong Ma, Duarte, CA (52) U.S. C. ... 424/1.49; 530/300: 530/327: 530/387.3; (US); Heng Wei Chen, Foster City, 530/408; 530/322; 435/188: 530/387.1:530/387.9; CA (US) 424/133.1; 424/9.1; 424/9.6; 435/375; 530/326; 977/773; 977/915;977/927 (21) Appl. No.: 13/270,207 (57) ABSTRACT (22) Filed: Oct. 10, 2011 Meditope variants and methods for their use are provided Related U.S. Application Data herein. A meditope variant as described herein comprises a peptide having a sequence CQFDLSTRRLKC (SEQ ID (60) Provisional application No. 61/391,558, filed on Oct. NO: 1) or CQYNLSSRALKC (SEQID NO:2) that has one or 8, 2010. more modifications at of least one amino acid residue of the sequence. Multivalent meditope variant tethering entities are Publication Classification also provided. Such entities may include two or more medi (51) Int. Cl. topes coupled via a long linker, multivalent scaffold, biotin A6 IK 5L/It (2006.01) streptavidin, or IgGFc domain. Further, methods of treating, C07K 7/08 (2006.01) imaging or diagnosing a disease or condition are provided. C07K 9/00 (2006.01) Such methods may include administering a therapeutically CI2N 9/96 (2006.01) effective amount of a pharmaceutical composition to a Sub C07K I6/44 (2006.01) ject, the pharmaceutical compound comprising an antibody A 6LX 39/395 (2006.01) meditope complex; a multivalent tethering agent in combina A6R 49/00 (2006.01) tion with a monoclonal antibody or functional fragment CI2N 5/09 (2010.01) thereof, or a combination thereof. Patent Application Publication Jul. 12, 2012 Sheet 1 of 44 US 2012/0177568 A1 fight: ; A. ^.i.deg Patent Application Publication Jul. 12, 2012 Sheet 2 of 44 US 2012/0177568 A1 figure 2 A: light Cai 8. O85 Patent Application Publication Jul. 12, 2012 Sheet 3 of 44 US 2012/0177568 A1 figure 3 Patent Application Publication Jul. 12, 2012 Sheet 4 of 44 US 2012/0177568 A1 Figare 3 A &:x:::::: ... 8:8 883. 88:8 s Patent Application Publication Jul. 12, 2012 Sheet 5 of 44 US 2012/0177568 A1 figure is imotope 40 cc 88 to Erik iii. Patent Application Publication Jul. 12, 2012 Sheet 6 of 44 US 2012/0177568 A1 Figure : isotype Control Patent Application Publication Jul. 12, 2012 Sheet 7 of 44 US 2012/0177568 A1 Figure 8 Patent Application Publication Jul. 12, 2012 Sheet 8 of 44 US 2012/0177568 A1 -editope Fab Patent Application Publication Jul. 12, 2012 Sheet 9 of 44 US 2012/0177568 A1 Figares 8 Patent Application Publication Jul. 12, 2012 Sheet 10 of 44 US 2012/0177568 A1 figure 8 Fab variabieight chain a variate heavy chain Patent Application Publication Jul. 12, 2012 Sheet 11 of 44 US 2012/0177568 A1 Patent Application Publication Jul. 12, 2012 Sheet 12 of 44 US 2012/0177568 A1 figure is into Association rease Site N-territ is Patent Application Publication Jul. 12, 2012 Sheet 13 of 44 US 2012/0177568 A1 Figtire 33 isionawatent editope tetra water tecitope 3. 8 8. 338 ::::::: 838 &: Patent Application Publication Jul. 12, 2012 Sheet 14 of 44 US 2012/0177568 A1 Figure 13A 60 - 40 - 4 -ao - Ssssssswww. 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Cleavege from resin 1 and deprotection 2 = SEQID NO:21,31) Patent Application Publication Jul. 12, 2012 Sheet 20 of 44 US 2012/0177568 A1 figrate 8 figure is RHN1 N-1N1 N1R NR" Modified Arg8 Realkyl Patent Application Publication Jul. 12, 2012 Sheet 21 of 44 US 2012/0177568 A1 Patent Application Publication Jul. 12, 2012 Sheet 22 of 44 US 2012/0177568 A1 Patent Application Publication Jul. 12, 2012 Sheet 23 of 44 US 2012/0177568 A1 its 38 * *- : 88.38& 8388 3: 3. 8::::::::::::::::::: :::::::: . ::::: 3 & x * s&f 8irt:8:388 3 : 8 x *:::f :::::::::::::::: 38. 3:38: 8.-------------------------------- : & : :::::8: 8xxx &::::::::::::::::::::::::::::: Patent Application Publication Jul. 12, 2012 Sheet 24 of 44 US 2012/0177568 A1 Figure 21 K s Patent Application Publication Jul. 12, 2012 Sheet 25 of 44 US 2012/0177568 A1 Figare: 22 &: Si: 3 x 333 ::::::::::::: Patent Application Publication Jul. 12, 2012 Sheet 26 of 44 US 2012/0177568 A1 figure 23 Patent Application Publication Jul. 12, 2012 Sheet 27 of 44 US 2012/0177568 A1 Figure 28 Patent Application Publication Jul. 12, 2012 Sheet 28 of 44 US 2012/0177568 A1 figure 28 wiecitage Patent Application Publication Jul. 12, 2012 Sheet 29 of 44 US 2012/0177568 A1 figure 28 Dose Depencient inhibition of Cetuximah interaction with its rescein-liaixietieptide by triataeieri reptide 888 ex88: x: {{xia:ex: 8::::::::: Patent Application Publication Jul. 12, 2012 Sheet 30 of 44 US 2012/0177568 A1 figure 27 Patent Application Publication Jul. 12, 2012 Sheet 31 of 44 US 2012/0177568 A1 figure 38 : :: * : x xxx 8xxx xx {{x: {x : x xxx ::: * x Patent Application Publication Jul. 12, 2012 Sheet 32 of 44 US 2012/0177568A1 figure 28 *x:{x : x: 8:8 ... Patent Application Publication Jul. 12, 2012 Sheet 33 of 44 US 2012/0177568 A1 Figure 30 A B 1222 1323) Patent Application Publication Jul. 12, 2012 Sheet 34 of 44 US 2012/0177568 A1 Figure 30 (cont.) 2131) 2232) K L & & y Y. S. S Y s & S. Š Š Š a tre.&S& AS S. 2333 2434) Patent Application Publication Jul. 12, 2012 Sheet 35 of 44 US 2012/0177568 A1 Figure 30 (cont.) M N s & S. & s Šas & s SS SS S Š SS Sees S at Š S vs. S S S S S & s *& s 2939) 3040 Patent Application Publication Jul. 12, 2012 Sheet 36 of 44 US 2012/0177568 A1 Figure 31 SEC ID NO: 515) 616) 717 818) Data Collection Space group P222 P222 P222 P222 Cell dimensions a, b, c (A) 64.33, 82.84, 64.20, 82.50, 64.02, 82.83, 64.28, 83.25, 212.32 212.49 212.10 212.30 o, 3, Y () 90.0, 90.0, 90.0 90.0, 90.0, 90.0 90.0, 90.0, 90.0 90.0, 90.0, 90.0 Resolution (A)8 30.00-2.24 (2.45 32.99-2.53 34.36-2.48 (2.54- 33.19-248 2.24) (2.60-2.53) 2.48) (2.54-2.48) 0.070 (0.281) 0.066 (0.334) 0.065 (0.312) 0.072 (0.331) I/o(I) 1905 (5.92) 24.74 (5.21) 24,88 (4.97) 23.52 (4.68) Completeness (%) 99.1 (99.1) 97.6 (91.3) 99.4 (92.6) 99.1 (90.3) Redundancy 5.2 (5.4) 4.9 (4.5) 6.19 (4.27) 4.61 (3.16) Refinement Resolution (A) 2.24 2.53 2.48 2.48 NO. reflections 55,026 37,650 40,641 41,098 Rwork/Rfree 18.0/22.6 17.2/23.6 17.6/22.O 17.4/22.9 NO. atoms Protein 6526 6514 6551 6541 Meditope 174 291 (198)" 212 218 Water 507 392 511 469 B-factors Protein Fab 38.16 27.79 25.74 25.23 Meditope 49.08 43.40 (27.51)* 31.78 31.52 Water 41.78 28.05 28.32 29.65 r.m.S.C. Bond lengths (A) OOO7 O.OO7 OOO8 Bond angles () 1093 1091 1106 Ramachandran favored/allowed/disallowed 96.9/3.1/O.O 96.8/3.2/O.O 97.6/2.4/O.O 97.2/2.7/0.1 *3 meditopes in asymmetric unit. Data in parenthesis refer to the meditopes in the meditope binding pocket characteristic for the WT meditope Patent Application Publication Jul. 12, 2012 Sheet 37 of 44 US 2012/0177568 A1 Figure 31 (cont.) SEQID NO: 1222 1323 1424) 1525) Data Collection Space group P2212 P222 P2212 P222 Cell dimensions 64.24, 83.14, 64.30,83.39, 64.46, 83.21, 64.10, 83.16, a, b, c (A) 21194 212.73 212.44 212.32 o, 3, Y () 90.0, 90.0, 90.0 90.0, 90.0, 90.0 90.0, 90.0, 90.0 90.0, 90.0, 90.0 s 33.15-2.48 33.23-2.49 34.96-2.62 33.14-2.55 Resolution (A) (2.55-2.48) (2.55-2.49) (2.69-2.62) (2.62-2.55) Rmrgd-F 0.044 (0.153) 0.056 (0.219) 0.125 (0.470) 0.094 (0.374) I/o(I) 25.24 (9.23) 19.83 (6.03) 15.21 (3.87) 19.13 (4.60) Completeness (%) 95.1 (72.3) 99.6 (95.4) 98.6 (97.7) 99.4 (94.1) Redundancy 5.2 (4.6) 5.0 (3.66) 4.95 (5.05) 4.33 (3.96) Refinement Resolution (A) 2.48 2.49 2.62 2.55 NO.
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