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(12) Patent Application Publication (10) Pub. No.: US 2003/0226155A1 Sadeghi Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0226155A1 Sadeghi Et Al US 2003O226155A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0226155A1 Sadeghi et al. (43) Pub. Date: Dec. 4, 2003 (54) MODIFIED TRANSFERRIN-ANTIBODY (60) Provisional application No. 60/315,745, filed on Aug. FUSION PROTEINS 30, 2001. Provisional application No. 60/334,059, filed on Nov. 30, 2001. Provisional application No. (75) Inventors: Homayoun Sadeghi, King of Prussia, 60/406,977, filed on Aug. 30, 2002. PA (US); Christopher P. Prior, King of Prussia, PA (US); Andrew Turner, King of Prussia, PA (US) Publication Classification Correspondence Address: MORGAN LEWIS & BOCKUS LLP 51)1) Int. Cl.Cl." ..................... A01K 67/027/027; A61K 39/395;5 1111 PENNSYLVANIAAVENUE NW CO7K 16/46 WASHINGTON, DC 20004 (US) (52) U.S. Cl. ........................ 800/7; 530/391.1; 424/178.1 (73) Assignee: BIOREXIS PHARMACEUTICAL CORPORATION (57) ABSTRACT (21) Appl. No.: 10/384,060 Modified fusion proteins of transferrin and therapeutic pro (22) Filed: Mar. 10, 2003 teins or peptides, preferably antibody variable regions, with Related U.S. Application Data increased Serum half-life or Serum Stability are disclosed. Preferred fusion proteins include those modified so that the (63) Continuation-in-part of application No. 10/231,494, transferrin moiety exhibits no or reduced glycosylation, filed on Aug. 30, 2002. binding to iron and/or binding to the transferrin receptor. Patent Application Publication Dec. 4, 2003 Sheet 1 of 8 US 2003/0226155A1 FG, 1 Alignment of N and C domains Of Transferrin to ShoW Iron Binding residues. CN past.- -WD- - - S.SENSE R RKDEWS - - - - - -VNSVG- E. AKTMNG AN Resor: s Eas.St. NC QRSTGSSE. 0. s SCDPEPSNKNHCR-F EYES (NE SKKDSS FEN-------- NK SEREC UVPOSTGGKNPDPWAKN ! E: SEREE,-KDKACVHKROHLEGSN t - NC --KSKEFCEFREEVs. Riva,SE HDRNTY 23 S. STARty E. N - - - - - - - - - C LEACTFRRP : Similarity Ž: identity 8 Amino acid residues involved in iron binding (*). N domain C domain Asp 63 Asp 392 Tyr 95 Tyr 426 Tyr 188 Tyr 514 His 249 His 585 Indirectly involved in iron binding (t) Lys 296 Arg 632 Binding of Carbonate ion (t) Thr 120 Thr 452 Arg 124 Arg 456 A a 126 Ala 458 Gly 127 Gly 459 Patent Application Publication Dec. 4, 2003 Sheet 2 of 8 US 2003/0226155A1 69 69 69 69 /9 89 89 II6 II6 II6 II6 II/ 8II 8II II9 RNYS NS O Šs S S2 S S SSN-N-Ned '914|-W/Z 22 SYNYNYSSYNYNYS STS NN 2.? % sis & - - - - - - - - Patent Application Publication Dec. 4, 2003 Sheet 3 of 8 US 2003/0226155A1 622 6ZZ 622 682 68Z 682 68Z Z6Z 962 £6Z 68Z SRN NaNNN S1 Li Li Y2C, Ll SA SS N 06Z 062 062 062 £6Z †762 762 06Z Patent Application Publication Dec. 4, 2003 Sheet 4 of 8 US 2003/0226155A1 Patent Application Publication Dec. 4, 2003. Sheet 5 of 8 US 2003/0226155A1 upl1inH 1|Qq0\} 3ShOW 3SJ0H ?u|A08 u3×|9||0 19}} 6?d Patent Application Publication Dec. 4, 2003 Sheet 6 of 8 US 2003/0226155A1 FIG. 3 PEPTIDE DELIVERY USING RECOMBINANT TRANSFERRIN 279 289 33 Patent Application Publication Dec. 4, 2003 Sheet 7 of 8 US 2003/0226155A1 FIG, 4A VH region for anti-TNFO, Antibodies P VH 110 33 108 35 111 37 110 BSG 39 113 SEMSSGSASAPTLFPLYSCENSPSDTSSYAVGCLAQDFLPDSITFSWKY KNNSD 172 VH 114 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 114 P VH 119 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 119 33 168 ISSTRGFPSVLRGGKYAATSQVLLPSKDVMQGTDEHYYCKVQHPNGNKEKNYPLPV - 223 35 168 TSGVHTFPAYLOSSGLYSLSSVVTVPSSSLG--TOTY ICNV NHKPSNTKVDKTVERK 222 37 167 ISGVHTFPAYLOSSGLYSLSSYYTYPSSSLG--TOTY CNV NHKPSNTKVDKTVERK 221 39 173 ISSTRGFPSVLRGGKYAATSQVLLPSKDYMOGTDEHYWCKY QHPNGNKEKNVPLPV - 228 Key. VH VH from Synthetic ScFW Accession no: AF288521 P VH VH from US Patent 5, 698,195 33 WH from ACCeSSiOn no: AB027433 35 VH from ACCeSSiOn no: ABO27 435 37 YH from Accession no: ABO27437 39 WH from ACCeSSiOn no: ABO 27439 % = identity = Similarity Patent Application Publication Dec. 4, 2003 Sheet 8 of 8 US 2003/0226155A1 FG, 4B Y REGION FOR ANTI-TNF-ANTIBODES R CESS33% VL 60 Z P V 58 34 58 36 58 38 58 40 58 V 111 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 111 P V 107 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1 O7 34 116 FIFPPSDEOLKSGTASVYCLLNNFY PREAKVOWKVDNALOSGNSQESVTEQDSKDSTYSL 175 36 115 FIFPPSDEQLKSGTASVYCLLNN FY PREAKVQWKYDNALOSGNSQESVTEQDSKDSTYSL 174 38 115 FIFPPSDEQLKSGTASVYCLLNNFY PREAKNOWKVDNALOSGNSQESVTEQDSKDSTYSL 174 40 116 FIFPPSDEQLKSGTASVYCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL 175 VL 111 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 111 P V 107 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 107 34 176 SSTLTLSKADYEKHKYYACEVTHQGLSSPVTKSFNRGEC 214 36 175 SSTLTLSKADYEKHKLY ACENTHOGLSSPVTKSFNRGEC 213 38 175 SSTLTLSKADYEKHKLYACEVTHQGLSSPVTKSFNRGEC 213 40 176 SSTLTLSKADYEKHKWYACEVTHOGLSSPVTKSFNRGEC 214 Key, VL. YL from Synthetic SCFY Accession no: AF288521 P W L VL from US Patent 5,698,195 34 VL from ACCeSSiOn no: AB027434 36 VL from Accession no: AB027436 38 VL from Accession no: AB027438 40 V from Accession no: AB027440 US 2003/0226155 A1 Dec. 4, 2003 MODIFIED TRANSFERRIN-ANTIBODY FUSION two atoms of iron, which is required for Tf binding to its PROTEINS receptor on a cell and, according to the inventors of these patents, to target delivery of the NGF or CNTF moiety RELATED APPLICATIONS across the blood-brain barrier. Transferrin fusion proteins 0001. This application is a Continuation-In-Part of U.S. have also been produced by inserting an HIV-1 protease application Ser. No. 10/231,494, filed Aug. 30, 2002, which Sequence into Surface exposed loops of glycosylated trans claims the benefit of U.S. Provisional Application 60/315, ferrin to investigate the ability to produce another form of Tf 745, filed Aug. 30, 2001 and U.S. Provisional Application fusion for targeted delivery to the inside of a cell via the Tf 60/334,059, filed Nov. 30, 2001, all of which are herein receptor (Ali et al. (1999) J. Biol. Chem. 274(34):24066 incorporated by reference in their entirety. This application 24073). also claims the benefit of U.S. Provisional Application 0008 Serum transferrin (Tf) is a monomeric glycoprotein 60/406,977, filed Aug. 30, 2002, which is herein incorpo with a molecular weight of 80,000 daltons that binds iron for rated by reference in its entirety. transport in the circulation to various tissues via the trans 0002 U.S. application entitled, “Modified Transferrin ferrin receptor (TfR) (Aisen et al. (1980) Ann. Rev. Biochem. Fusion Proteins, filed on March 2003, is also herein incor 49: 357-393; MacGillivray et al. (1981).J. Biol. Chem. 258: porated by reference in its entirety. 3543-3553, U.S. Pat. No. 5,026,651). Tf is one of the most common Serum molecules, comprising up to about 5-10% of FIELD OF THE INVENTION total Serum proteins. Carbohydrate deficient transferrin occurs in elevated levels in the blood of alcoholics and 0003. The present invention relates to therapeutic pro exhibits a longer half life (approximately 14-17 days) than teins or peptides with extended Serum Stability and/or Serum that of glycosylated transferrin (approximately 7-10 days). half-life fused to or inserted in a transferrin molecule modi See van Eijk et al. (1983) Clin. Chim. Acta 132:167-171, fied to reduce or inhibit glycosylation, and/or reduce or Stibler (1991) Clin. Chem. 37:2029-2037 (1991), Arndt inhibit iron binding and/or transferrin receptor binding. (2001) Clin. Chem. 47(1): 13-27 and Stibler et al. in “Car Specifically, the present invention includes Single chain bohydrate-deficient consumption', Advances in the Bio antibodies fused to or inserted in a transferrin molecule or a sciences, (Ed Nordmann et al.), Pergamon, 1988, Vol. 71, modified transferrin molecule. pages 353-357). BACKGROUND OF THE INVENTION 0009. The structure of Tf has been well characterized and the mechanism of receptor binding, iron binding and release 0004. Therapeutic proteins or peptides, including single and carbonate ion binding have been elucidated (U.S. Pat. chain antibodies, in their native State or when recombinantly Nos. 5,026,651, 5,986,067 and MacGillivray et al. (1983).J. produced are typically labile molecules exhibiting short Biol. Chem. 258(6):3543-3546). periods of serum stability or short serum half-lives. In addition, these molecules are often extremely labile when 0010 Transferrin and antibodies that bind the transferrin formulated, particularly when formulated in aqueous Solu receptor have also been used to deliver or carry toxic agents tions for diagnostic and therapeutic purposes. to tumor cells as cancer therapy (Baselga and Mendelsohn, 1994), and transferrin has been used as a non-viral gene 0005 Few practical solutions exist to extend or promote therapy vector vehicle to deliver DNA to cells (Frank et al., the Stability in Vivo or in vitro of proteinaceous therapeutic 1994; Wagner et al., 1992). The ability to deliver proteins to molecules. Polyethylene glycol (PEG) is a substance that the central nervous system (CNS) using the transferrin can attach to a protein, resulting in longer-acting, Sustained receptor as the entry point has been demonstrated with activity of the protein. If the activity of a protein is pro Several proteins and peptides including CD4 (Walus et al., longed by the attachment to PEG, the frequency that the 1996), brain derived neurotrophic factor (Pardridge et al., protein
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