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(12) Patent Application Publication (10) Pub. No.: US 2009/0305978A1 Zane (43) Pub US 20090305978A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0305978A1 Zane (43) Pub. Date: Dec. 10, 2009 (54) METHODS FOR INCREASING THE SIZE OF Related U.S. Application Data ANMALS USING NEEDLELESS DELIVERY CONSTRUCTS (60) Provisional application No. 60/783,534, filed on Mar. 16, 2006. (75) Inventor: Doris Tham Zane, San Mateo, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. JONES DAY A638/27 (2006.01) 222 EAST 41ST ST A6IP 43/00 (2006.01) NEW YORK, NY 10017 (US) (52) U.S. Cl. .......................................................... S14/12 (73) Assignee: TRINITY BIOSYSTEMS, INC., Menlo Park, CA (US) (57) ABSTRACT The present invention relates, in part, to methods for increas (21) Appl. No.: 12/282,853 ing the size of a Subject by administering a delivery construct (22) PCT Fled: Mar. 15, 2007 comprising growth hormone to a Subject. In one aspect, the method for increasing the size of a subject by at least about (86) PCT NO.: PCT/US2007/006590 12% comprises contacting an apical Surface of a polarized epithelial cell of the subject with an amount of a delivery S371 (c)(1), construct comprising growth hormone that is effective to (2), (4) Date: Apr. 20, 2009 increase the size of the subject by at least about 12%. Patent Application Publication Dec. 10, 2009 Sheet 1 of 19 US 2009/0305978A1 Figure 1A Met Ala Giu. Glu Ala Phe Asp Leu Trp Asn. Glu. Cys Ala Iys Ala Cys S O s Val Lieu. Asp Lleu Lys Asp Gly Wall Arg Ser Ser Arg Met Ser Wall Asp 2O 25 30 Pro Ala Ile Aia Asp Thr Asn. Gly Gin Gly Val Lieu. His Tyr Ser Met 35 40 45 Val Lieu. Glul Gilly Gly ASI Asp Alia Leu Lys Lell Ala Ile Asp ASI Ala SO 55 60 Leu Ser Ile Thr Ser Asp Gly Lieu. Thir Ile Arg Lieu. Glu Gly Gly Wall 5S 70 75 8O Glu Pro Asn Llys Pro Val Arg Tyr Ser Tyr Thr Arg Glin Ala Arg Gly 85 SC 95 Ser Trp Ser Leu Asn. Trp Lieu Val Pro Ile Gly. His Glu. Llys Pro Ser OO OS 10 Asn. Ile Lys Val Phe Ile His Glu Lieu. Asn Ala Giy Asn. Glin Leu Ser 15 2O 25 His Met Ser Pro Ile Tyr Thir Ilie Glu Met Gly Asp Glu Lieu Lieu. Ala 13 O 35 40 Lys fell Ala Arg Asp Ala Thr Phe Phe Val Arg Ala His Glu Ser Asn 1.45 SO S5 60 Glu Met Glin. Pro Thr Lieu Ala Ile Ser His Ala Gly Val Ser Val Val - 65 7 O 17S Met Ala Glin Thr Glin Pro Arg Arg Glu Lys Arg Trp Ser Glu Trp Ala 18O 85 19 O Ser Gly Llys Val Lieu. Cys Lieu Lieu. Asp Pro Lieu Asp Gly Val Tyr Asn 195 2CO 2 OS Tyr Lieu Alia Glin Glin Arg Cys Asn Lieu. Asp Asp Thir Trp Gill. Gly Lys 2O 25 22 O Ilie Tyr Arg Wall Leu Ala Gly Asn. Pro Ala Lys His Asp Leu. Asp Ile 225 230 235 24 O Llys Pro Thr Val Ile Ser His Arg Feu. His Phe Pro Glu Gly Gly Ser 245 25 O 255 Teu Ala Ala Luell. Thir Ala. His Glin Ala Cys His Leu Pro Lieu. Glu. Thr 260 26S 27 O Phe Thr Arg His Arg Gln Pro Arg Gly Trp Glu Glin Lieu. Glu Gln Cys 275 280 285 Gly Tyr Pro Val Glin Arg Lieu Val Ala Leu. Tyr Leu Ala Ala Arg Lieu 29 O 29S 3 OO Ser Trp Asn Gin Val Asp Gin Wall Ile Arg Asn Ala Lieu. A la Ser Pro 3 OS 310 3.5 320 Gly Ser Gly Gly Asp Lieu. Gly Glu Ala Ile Arg Glu Gin Pro Glu Gln 3.25 33 O 3.35 Ala Arg Lieu Ala Lieu. Thr Leu Ala Ala Ala Glu Ser Glu Arg Phe val 34 O 34S 350 Arg Glin Gly Thr Gly Asn. Asp Glu Ala Gly Ala Ala Asn Lieu Glin Gly 3.SS 360 365 Gly Lieu. Arg Glin Pro Arg Phe Pro Thir Ilie Pro Leu Ser Arg Leu Phe 370 375 38O Patent Application Publication Dec. 10, 2009 Sheet 2 of 19 US 2009/0305978A1 Figure 1B Asp Asn Ala Met Lieu. Arg Ala His Arg Lieu. His Gln Leu Ala Phe Asp 385 39 O. 395 4 OO Thir Tyr Glin Glu Phe Glu Glu Ala Tyr Ile Pro Llys Glu Glin Lys Tyr 4 O 5 410 45 Ser Phe Lieu. Glin Asn Pro Glin Thr Ser Lieu. Cys Phe Ser Glu Ser Ile 42O 42S 43 O. Pro Thr Pro Ser Asn. Arg Glu Glu. Thr Glin Glin Lys Ser Asn Lieu. Glu 435 440 445 Lieu Lleu. Arg Ile Ser Leu Lleu. Leu le Glin Ser Trp Lieu. Glu Pro Val 450 4S5 46O Glin Phe Leu Arg Ser Val Phe Ala Asn. Ser Leu Val Tyr Gly Ala Ser 46S 470 475 48O Asp Ser Asn Val Tyr Asp I.eu. Lieu Lys Asp Leu Glu Glu Giy Ile Glin 48S 490 495 Thr Lieu Met Gly Arg Lieu. Glu Asp Gly Ser Pro Arg Thr Gly Glin Ile 5 OO SO 5 5. O Phe Lys Gin Thr Tyr Ser Lys Phe Asp Thr Asn. Ser His Asm Asp Asp 55 52O 525 Ala Lieu. Leu Lys Asn. Tyr Gly Lieu. Lieu. Tyr Cys Phe Arg Lys Asp Met S30 S35 S4 O Asp Llys Val Glu Thir Phe Lieu. Arg Ile Val Glin Cys Arg Ser Val Glu S45 550 SS5 S60 Gly Ser Cys Gly Phe 565 Patent Application Publication Dec. 10, 2009 Sheet 3 of 19 US 2009/0305978 A1 Z'OIH (%) u/wouf pezieuoN Patent Application Publication Dec. 10, 2009 Sheet 4 of 19 US 2009/0305978A1 £"OIH Patent Application Publication US 2009/0305978A1 Patent Application Publication US 2009/0305978 A1 Patent Application Publication Dec. 10, 2009 Sheet 7 of 19 US 2009/0305978A1 i Patent Application Publication Dec. 10, 2009 Sheet 8 of 19 US 2009/0305978A1 [10(39usu L'OIH % (OS)HO??3d08 0007I 000ZI 0008 0009 000Z ufu) uo elugouoo Holy Patent Application Publication Dec. 10, 2009 Sheet 9 of 19 US 2009/0305978 A1 (OS)HO?,3,QE) 8"OIH ----?û----- 0009 u/iau) doptsugouolo S), eAp3bog Patent Application Publication Dec. 10, 2009 Sheet 10 of 19 US 2009/0305978 A1 an E 5E 5 5 raw ... t 6. sa 2 e g ati 2 ge 5 S d s (turfu) uosuadio I-SI Patent Application Publication Dec. 10, 2009 Sheet 11 of 19 US 2009/0305978A1 00:09 000; I/Eu) top trueguoo 9-III Patent Application Publication Dec. 10, 2009 Sheet 12 of 19 US 2009/0305978A1 2 Y N d) O r 7 rC enC s s CCs C C C C Cod C ul Osir CO) H5)4-bute 5); un-IeS Patent Application Publication Dec. 10, 2009 Sheet 13 of 19 US 2009/0305978A1 (OS)HO?I5d0£) ZI"{OIH ) (OS)HO?3d09 cs LIII 0s, CO) du-puts soft un-IaS Patent Application Publication Dec. 10, 2009 Sheet 14 of 19 US 2009/0305978A1 s ufu) uo tenuretoo eurolesoopoo Patent Application Publication Dec. 10, 2009 Sheet 15 of 19 US 2009/0305978 A1 #7I"OIH d s 09 s S ma uffu) uoge pueoukoo under Patent Application Publication Dec. 10, 2009 Sheet 16 of 19 US 2009/0305978A1 ?I"OIH (OS)HO?I3rd09 s: 00’I cs (32'0 00'0 u?au) uoteluoouoo unsui esnow Patent Application Publication Dec. 10, 2009 Sheet 17 of 19 US 2009/0305978A1 H 9 |(69,968||T97805(UTZZ ['(ERIT,IT?J? TERTTITOJOT L,ë??,l?JOT Lº??LOZIZI Patent Application Publication Dec. 10, 2009 Sheet 18 of 19 US 2009/0305978A1 S e S s r 3 3 3 s 5 s & ufu) suo Brulauao tuneSHEl Patent Application Publication Dec. 10, 2009 Sheet 19 of 19 US 2009/0305978A1 I-55T==-i 8I(OIH ||| US 2009/0305978 A1 Dec. 10, 2009 METHODS FOR INCREASING THE SIZE OF CD86, TNFC receptor, TOLL receptor, M-CSF receptor, ANMALS USING NEEDLELESS DELIVERY GM-CSF receptor, scavenger receptor, and VEGF receptor. CONSTRUCTS 0007. In certain embodiments, the transcytosis domain is selected from the group consisting of transcytosis domains 1. FIELD OF THE INVENTION from Pseudomonas exotoxin A, botulinum toxin, diptheria toxin, pertussis toxin, cholera toxin, heat-labile E. coli entero 0001. The present invention relates, in part, to methods for toxin, shiga toxin, and shiga-like toxin. increasing the size of a subject by administering a delivery 0008. In certain embodiments, the cleavable linker is construct comprising a growth hormone to a subject. In one cleavable by an enzyme that is selected from the group con aspect, the method comprises contacting an apical Surface of sisting of Cathepsin GI, Chymotrypsin I, Elastase I, Subtilisin a polarized epithelial cell of the subject with an amount of a AI, Subtilisin AII, Thrombin I, and Urokinase I. In certain delivery construct comprising growth hormone that is effec embodiments, the cleavable linker comprises an amino acid tive to increase the size of the subject by at least about 12%. sequence that is selected from the group consisting of Ala Ala-Pro-Phe (SEQID NO.1), Oly-Gly-Phe (SEQID NO.:2), 2. BACKGROUND Ala-Ala-Pro-Val (SEQ ID NO.:3), Gly-Gly-Leu (SEQ ID 0002 Advances in biochemistry and molecular biology NO.4), Ala-Ala-Leu (SEQID NO.:5), Phe-Val-Arg (SEQID have resulted identification and characterization of many NO.:6), Val-Gly-Arg (SEQID NO.:7).
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