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(12) Patent Application Publication (10) Pub. No.: US 2016/0367695A1 Wilson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0367695A1 Wilson Et Al US 20160367695A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0367695A1 Wilson et al. (43) Pub. Date: Dec. 22, 2016 (54) POLYPEPTIDE CONSTRUCTS AND USES (30) Foreign Application Priority Data THEREOF Oct. 28, 2011 (AU) ................................ 2011 9045O2 (71) Applicant: Teva Pharmaceuticals Australia Pty Ltd, Macquarie Park (AU) Publication Classification (72) Inventors: David S. Wilson, Freemont, CA (US); Sarah L. Pogue, Freemont, CA (US); (51) Int. Cl. Glen E. Mikesell, Pacifica, CA (US); A6II 47/48 (2006.01) Tetsuya Taura, Palo Alto, CA (US); C07K 6/28 (2006.01) Wouter Korver, Mountain View, CA (52) U.S. Cl. (US); Anthony G. Doyle, Drummoyne CPC ..... A61K 47/48269 (2013.01); C07K 16/2896 (AU); Adam Clarke, Five Dock (AU); (2013.01); C07K 231 7/565 (2013.01); C07K Matthew Pollard, Dural (AU): 2317/55 (2013.01); C07K 2317/92 (2013.01) Stephen Tran, Strathfield South (AU); Jack Tzu Chiao Lin, Redwood City, (57) ABSTRACT CA (US) (21) Appl. No.: 15/194,926 The present invention provides a polypeptide construct (22) Filed: Jun. 28, 2016 comprising a peptide or polypeptide signaling ligand linked to an antibody or antigen binding portion thereof which Related U.S. Application Data binds to a cell Surface-associated antigen, wherein the ligand (63) Continuation of application No. 14/262,841, filed on comprises at least one amino acid Substitution or deletion Apr. 28, 2014, which is a continuation of application which reduces its potency on cells lacking expression of said No. PCT/AU2012/001323, filed on Oct. 29, 2012. antigen. Patent Application Publication Dec. 22, 2016 Sheet 1 of 62 US 2016/0367695 A1 FIGURE 1: EGENO EABOVES Antibody heavy chain IgG Antibody light chair IgG Attenuated (Polypeptide Ligand Peptide linker (0-50 a mino acids if length) Patent Application Publication Dec. 22, 2016 Sheet 2 of 62 US 2016/0367695 A1 FIGURE 2: LEGEND EMBODEMENT Antibody to cell surface protein attached to Attenuated Ligand (AL) Receptor for ligand Viv Cell Surface Antigen Patent Application Publication Dec. 22, 2016 Sheet 3 of 62 US 2016/0367695 A1 FIGURE 3: Human CD38 (SEQ ID NO: 131) : 1 MANCEFSPVSGDKPCCRLSRRAOLCLGVSILVLILVVVLAVVVPRWRQOWSGPGTTKRFP 60 61. ETVLARCVKYTEIHPEMRHVDCOSWWDAFKGAFISKHPCNITEEDYOPLMKLGTOTV PCN 120 121. KILLWSRIKDLAHQFTQVORDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDC 180 181 SNNPVSV FWKTVSRREAEAACDVVHVMLNGSRSKIF DKNSTFGSVEVHNL QPEKVOTLEA 240 241 WVIHGGREDSRDLCQDPTIKELESTISKRNT OFSCKNTYRPDKET, OCVKNPEDSSCTSET 3 OO underlined: extra Callular domain italic: trans IIleinbrane do Ilain Patent Application Publication Dec. 22, 2016 Sheet 5 of 62 US 2016/0367695 A1 FIGURE Sa: Heavy chain (SEQ ID NO:180) : 1 EVOLLESGGGLVOPGGSLRLSCAVSGETFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYY 60 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTV 120 12 LO 180 181 SSGLYSLSSVVTVPsssTGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP 240 24, 3OO 301 I 360 361. TKNOWSLTCLVKGFYPSDIAVEWESNGOPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWO 420 421. DLPOTHSLGSRRTLMLLACMRRISLFSCLK 480 48. DRHDFGFPOEEFGNOFOKAETIPvt. HEMIQQIFNLFSTKDSSAAWDETILDKFYTETYQQ SA 541 LNDLEACVIQGWGVTETPLMKEDSILAVRKYFORITLYLKEKKYSPCAWEVVRDEIMRSF 600 601 SLSTNLQESLRSKE 64 Light chain (SEQ ID NO:134): 60 2O 180 181 LSKADY 24 double underlined: antibody heavy and light chains single underlined: cytokine single underlined & bold: attenuating mutation G005-HC-LO-IFNo.(A145D) igg4 Patent Application Publication Dec. 22, 2016 Sheet 8 of 62 US 2016/0367695A1 FIGURE 5d: Heavy chain (SEQ ID NO:324) : l QVCLKOSGPGIVQPSQSLSLTCTVSGESLTSYGVHWVRQPPGKGLEWLGWIWSGGSTDYN 60 61 SA 120 1.21 180 81 240 241 300 3O1 ------------- m 360 361 LTKNQVSLTCLVKG ESNGQPENNYKTTPPVL SRW 420 421 QQGNVFSCSVMHEAL TQKSLSLSPGKSGGGGSGGGGSGGGGSPWEPGEDSKDVAAP 480 481 HRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCF 540 541 QSGFNEETCLVKIITGLLEFEVYLEYLONRFESSEEQARAVOMSTKVLIQFLOKKAKNLD 600 601 AITTPDETINASLLTKLQAQNQWLQDMTTELILRSFKEFLQSSLEALRQM 650 Light chain (SEQ ID NO:312) : 1 SIVMTOTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYASNRYTGVPD 60 120 180 215 double underlined: antibody heavy and light chains Single underlined: cytokine single underlined si bold: attenuating mutation italic: i.inker sequence HB95-HC-L16-IL-6(RI79E) iggi Patent Application Publication Dec. 22, 2016 Sheet 10 of 62 US 2016/0367695A1 FIGURE 6: Non-Targeted IFNo. Activity S Construct EC50(pM) g g - FNC. 19 s -- Rituximab-HC-L6-IFNOlgG1 5.9 : -e- isotype-HC-L6-FNC. igG1 8.0 E o - 0.0001 0.01 100 10000 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 11 of 62 US 2016/0367695A1 FIGURE 7: Targeted IFNo. Activity (Daudi) 1500000 E Construct IC50(pM) 2. 1000000 -- Rituximab-HC-L6-IFNo. IgG1 0.40 -- IFNO. 13 500000 E O 0.001 0.01 0.1 10 100 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 12 of 62 US 2016/0367695A1 FIGURE 8: Targeted IFNo. Activity (Daudi) 1 2 5 O O O O 1000000 Construct IC50(pM) -- Rituximab-HC-L6-IFNo. IgG1 0.18 -er isotype-HC-L6-FNo. lgG1 2.2 2575O5 OOO OOO OOO OOO O 0.001 0.01 0.1 1 10 100 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 13 of 62 US 2016/0367695A1 FIGURE 9: Non-Targeted IFNa Activity 6000 Construct EC50(pM) S -- FNC. 5.7 -- Rituximab-HC-L6-IFNa IgG1 22 2 4000 -- Rituximab-HC-L6-IFNg (R144A) gG1 2200 -- Rituximab-HC-L6-IFNo. (A145G) IgG1 2800 2000 -- Rituximab-HC-L6-IFNo. (R33A+YNS) IgG1 6100 -o- isotype-HC-L6-IFNo. IgG1 18 O 0.01 100 0000 OOOOOO IFNo. equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 14 of 62 US 2016/0367695A1 FIGURE 10: Non-Targeted IFNo. Activity Construct EC50 5000 Rituximab-HC-L6-FNo, IgG1 5.6 is 4000 Rituximab-HC-6-FNg (R33A) gG1 ND o Rituximab-HC-6-FNo. (R144A + YNS) IgG1 1700 3000 is 2000 E 1000 O 10-2 100 102 104 106 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 15 of 62 US 2016/0367695A1 FIGURE 11: Targeted IFNo. Activity (Daudi) 2000000 Construct IC50(pM) S -0- IFNo. 12 1500000 Rituximab-HC-L6-IFNo, IgG1 0.33 8 Rituximab-HC-L6-IFNa (R144A)lgG1 1.4 1000000 - Rituximab-HC-L6-IFNo. (A145G) IgG1 1.1 2 500000 Rituximab-HC-L6-IFNo. (R33AEYNS) IgG1 0.74 isotype-HC-L6-IFNo, IgG1 2. O 0.0001 0.01 1 100 10000 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 16 of 62 US 2016/0367695A1 FIGURE 12: Targeted ifno. Activity (Daudi) Construct EC50 1,5006 O Rituximab-HC-L6-IFNo. IgG1 0.2 Rituximab-HC-L6-FNo. (R33A) gG1 340 1000000 o Rituximab-HC-L6-IFNo. (R144A+YNS) IgG1 3.3 500000 0.0001 0.01 1 100 10000 1000000 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 18 of 62 US 2016/0367695A1 FIGURE 14: 40000 -O- X355/02 IgG1 -- X355/04 IgG1 30000 -- X355/07 IgG1 s -v- X910/12 gC1 20000 -- X913/15 g61 10000 -er negative control gG1 rate anti FC O s S. s. N S S Patent Application Publication Dec. 22, 2016 Sheet 19 of 62 US 2016/0367695A1 FIGURE 15: Non-Targeted IFNo. Activity Construct EC50 (pM) -- FNO. 0.726 -e- GOO5-HCLO-IFNo. IgG4 195 O 0.0001 0.01 1 1OO 10000 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 20 of 62 US 2016/0367695A1 FIGURE 16: Targeted IFNo. Activity (ARP1) 5OOOOO S. Construct IC50 o 400000 -- FNC. 14.7O 300000 -e- G005-HC-LO-IFNo.g64 4,079 8 200000 . 100000 { O 0.01 1 100 10000 IFNo. equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 21 of 62 US 2016/0367695A1 FIGURE 17: Non-Targeted FNot Activity r Construct EC50 o 4000 -- FN 3O 30- -- G005-HC-L6-IFNa (R144A) igG4 11,000 8. - A - GD05-HC-LO-IFNa (R 144A) igG4 30,000 200 mir G005-Hc-L6-IFNa (R144A) igG1 2600 E 1000- G005-HC-LO-IFNoy (R144A) igG1 6800 0.000 OO1 10 IFNo. equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 22 of 62 US 2016/0367695A1 FIGURE 18: Non-Targeted IFNot Activity 6000 Construct . EC50(pM) g4000 -O- FNC. O.O87 - - G005-HC-L0-IFNo. (A145G)lgG1 510 £2000 * - G005-HC-L6-IFNo. (A145G)lgG1 730 -- G005-HC-L6-IFNcy (A145G)lgG4 2200 0.0001 0.01 1 100 OOOO 1000000 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 23 of 62 US 2016/0367695A1 FIGURE 19: Non-Targeted IFNo. Activity 25 - Construct . EC50(pM) 3 -- IFNO. 0.21 -0- G005-LC-L6-IFNo. (A145G) IgG1 12000 2 -6- G005-LC-LO-IFNo. (A145G) gG1 24000 - 0.0001 0.01 1 100 10000 1000000 IFNo, equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 24 of 62 US 2016/0367695A1 FIGURE 20: Targeted IFNo. Activity (Daudi) 1500000 Construct IC50(pM) as n -o- FNo. 0.77 g 1OOOOOO - a G005-HC-L6-IFNo. (R144A) gG4 1.3 -- G005-HC-LO-IFNo. (R144A) gG4 2.7 2 500000 - GOO5-HC-L6-IFNo. (R.144A) g(G1 1.9 E re- G005-HC-LO-IFNo. (R144A) gG1 7.3 O 0.0001 0.01 100 10000 IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 25 of 62 US 2016/0367695A1 FIGURE 21: Targeted IFNo. Activity (Daudi) 2OOOOOO C50(pM) S. a 1500000 - - FNC. 0.48 g - - G005-HC-LO-IFNo. (A145G) gG1 O.74 1000000 -- G005-HC-L6-LFNo. (A145G) gCS1 1.0 S -- G005-HC-L6-IFNo. (A145G) igG4 0.59 E 500000 - 0. O.OOO 0.01 100 OOOO IFNo equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 26 of 62 US 2016/0367695A1 FIGURE 22: Targeted IFNo. Activity (Daudi) 1500000 S n Construct . IC50(pM) 1000000 -- FNC. 11 : -- G005-LC-L6-IFNo. (A145G) lgG1 8.5 2 500000 -- G005-LC-LO-IFNo. (A145G) gG1 21 E m O 0.0001 0.01 f 100 1OOOO FNo. equivalents (pM) Patent Application Publication Dec. 22, 2016 Sheet 27 of 62 US 2016/0367695A1 FIGURE 23: Targeted IFNo. Activity (ARP-1) 600000 Construct . IC500p) 2. -- FNo. 6.O n * - G005-HC-L6-IFNo. (R144A) igG1 21 400000 rar G005-HC-LO-IFNo. (R144A) gG1 110 -- G005-HC-L6-IFNo. (R144A) g(G4 28 200000 -- G005-HC-LO-IFNo. (R144A) g(G4 85 E s - 0.01 1 100 0000 IFNot equivalents (pM) Patent Application Publication Dec.
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