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(2) Patent Application Publication (10) Pub. No.: US 2011/0288011 A1 Castaigne Et Al

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(2) Patent Application Publication (10) Pub. No.: US 2011/0288011 A1 Castaigne Et Al US 2011 02880.11A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2011/0288011 A1 Castaigne et al. (43) Pub. Date: Nov. 24, 2011 (54) PEPTIDE THERAPEUTIC CONJUGATES AND A6IP 3/(){} (2006.01) USES THEREOF A6IP 3/08 (2006.01) A6IP 25/22 (2006.01) (76) Inventors: Jean-Paul Castaigne, Mont-Royal A6IP 25/14 (2006.01) (CA); Michel Demeule, A6IP 25/16 (2006.01) Beaconsfield (CA); Catherine A6IP 25/08 (2006.01) Gagnon, Montreal-Nord (CA); A6IP 25/18 (2006.01) Betty Lawrence, Bolton (CA) A6IP 25/20 (2006.01) A6IP 25/00 (2006.01) (21) Appl. No.: 13/133,002 A6 IP I/18 (2006.01) - A6 HP I/16 (2006.01) - A6 IP I/00 (2006.01) (86) PCT No.: PCT/CA2009/001781 A6IP 13/00 (2006.01) A6IP 9/04 (2006.01) § 371 (Q(t), A6 IP II/00 (2006.01) (2), (4) Date: Aug. 9, 2011 A6IP 3/06 (2006.01) - - - A6IP 29/00 (2006.01) Relatedelate U.S. Applicationpplication DataDat A6IP 35/06) (2006.01) (60) Provisional application No. 61/200,947, filed on Dec. A6IP 43/00 (2006.01) 5, 2008. C07K 14/.435 (2006.01) Publication Classification (52) U.S. Cl. ......... 514/5.3: 530/324; 530/300: 536/23.4; 514/5.8: 514/6.9; 514/16.4: 514/15.7; 514/9.7; (51) Int. Cl. 514/17.8: 514/17.7: 514/21.3; 514/15.4; 514/193; A6 IK 38/22 (2006.01) 514/19.4: 514/19.5: 514/5.5 C07K 19/00 (2006.01) C07K I4/575 (2006.01) (57) ABSTRACT C07H 21/00 (2006.01) A6 HP 3/04 (2006.01) The present invention features a compound having the for A6 HP 3/10 (2006.01) mula A-X-B, where A is peptide vector capable of enhancing A6 HP 9/00 (2006.01) transport of the compound across the blood-brain barrier or A6 HP 9/12 (2006.01) into particular cell types, X is a linker, and B is a peptide A6 IK 38/17 (2006.01) therapeutic. The compounds of the invention can be used to A6 HP 25/28 (2006.01) treat any disease for which the peptide therapeutic is useful. Patent Application Publication Nov. 24, 2011 Sheet 1 of 49 US 2011/0288011 A1 Peptides Amino acid sequence Exendin-4 native HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Exendin-4-Lys(MHA) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPK-(MHA) --- (Cys32)-Exendin-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPCSGAPPPS --- — Exendin-4 1 Lys”-MHA (maleimido hexanoic acid) Figure 1 Patent Application Publication Nov. 24, 2011 Sheet 2 of 49 US 2011/0288011 A1 Q->-NH O D-. , - N O + (Cys1)-AN2 O 2% AN2-(Cys20) Exendin-4 NH2 (MHA) AN1-(Cys7) Buffer PBS 1X, r.t., 1 h And IC Series | Qtty (mg) Purity (%) MW (g/mol) Ex-4-AN2 (N-Terminal) 4.9 > 95 6825.45 Ex-4-AN2 (C-Terminal) 5.5 > 95 6825.48 Ex-4-AN1 5.3 > 85 6739.38 Figure 2 Patent Application Publication Nov. 24, 2011 Sheet 3 of 49 US 2011/0288011 A1 Exendin-4-(Cys32) N (C3) MPA-AN2 (C6) MHA-AN2 (C11) MUA-AN2 Buffer PBS 1X, r.t., 1 h O O N N n H O (C3) (C6) (C11) Series Il Qtty (mg) Purity (%) MW (g/mol) Ex-4-(C3)-AN2 13.5 > 98 6656.21 Ex-4-(C6)-AN2 4.8 > 98 6768.43 Ex-4-(C11)-AN2 8.8 > 90 6698.17 Figure 3 Patent Application Publication Nov. 24, 2011 Sheet 4 of 49 US 2011/0288011 A1 1 -Exendin-4Exendin-4-cysAn2 N-terminal Exendin-4-cysAn2 C-terminal 1 | Brain Capillariesarenchyma Figure 4 Patent Application Publication Nov. 24, 2011 Sheet 5 of 49 US 2011/0288011 A1 Weight i Days --- Control net First treatmenttr —r- Exendin (3 Jg/kg) —y- Exendin (30 Ug/kg) —o- Exen-An2 (4.8 pg/kg) —e— Exen-An2 (48 pg/kg) Figure 5 Patent Application Publication Nov. 24, 2011 Sheet 6 of 49 US 2011/0288011 A1 Cumulative food intake 80 70 60 50 40 30 20 10 Days —º-Control —º- Exendin-4 (3 pg/kg) –7– Exendin-4 (30 pg/kg) —o- Exen-An2 (4.8 pg/kg) —e– Exen-An2 (48 pg/kg) Figure 6 Patent Application Publication Nov. 24, 2011 Sheet 7 of 49 US 2011/0288011 A1 Glycemia 20 10 5 —-- Control —r- Exendin-4 (3 pig?kg) —w- Exendin-4 (30 pg/kg) —c- Exen-An2 (4.8 pg/kg) —e– Exen-An2 (48 pg/kg) Figure 7 Patent Application Publication Nov. 24, 2011 Sheet 10 of 49 US 2011/0288011 A1 - Exendin-4 (Phoenix Pharm.) C3 T]C6 || Exen-4-An2 C11 | |Exen-4-S4 Exen-An2-An2 30 2 0 1 0 Brain Capillaries Parenchyma Figure 9 Patent Application Publication Nov. 24, 2011 Sheet 11 of 49 US 2011/0288011 A1 —º- Ctrl -- Exendin-4 (2 pg/kg) -*- Exen-An2-An2 (4.5 pg/kg) 140 § 120 ..º. E 100 3 2, 80 on ..s. 60 3.§ 40 5£ 20 0 {} 30 50 90 Time (min) Figure 10 Patent Application Publication Nov. 24, 2011 Sheet 12 of 49 US 2011/0288011 A1 Total Brain (15 min after IV bolus) 0.05 5. 0.04 #º 0.03 2 O g | Exendin-4 Exen-An2 (10 pg/kg) (16 pg/kg) Figure 11A Pancreas (15 min after IV bolus) 5 2.0 S. 5 E. O 69 ..? # Exendin-4 Exen-An2 (10 pg/kg) (16 pg/kg) Figure 11B Patent Application Publication Nov. 24, 2011 Sheet 13 of 49 US 2011/0288011 A1 Dose-response of insulin secretion (RIN-m5F pancreatic cells) _ Exendin-4 30 _ Exendin-Anz 2 5 20 5.= 15 5 # 1. 0 Concentration (nM) Figure 12 Patent Application Publication Nov. 24, 2011 Sheet 14 of 49 US 2011/0288011 A1 Chromatogram 1 Leptin-C11-AN2 before purification (450 mg of crude ) fintens : 2000 500 {.{j 0.5 3 o 15 2.3 2.5 Time (min) Figure 13A Chromatogram 2 Leptin-C11-AN2 after purification intens. (mAU] f . & | . 2 UV spectrum at 229 mm 600 400 250 mg recovered * > 98% purity {}_{} 0.5 1..?] 1.5 2.0 2.5 Time [mid] Figure 13B Patent Application Publication Nov. 24, 2011 Sheet 15 of 49 US 2011/0288011 A1 Chromatogram 3 Purification of Leptin-C11-AN2 on AKTA-explorer On column filled of 95 mL of 30RPC resin — fractions } r——, 17 mi /min 15 mi /min 10 mL/min 5 mL/min Figure 14 Patent Application Publication Nov. 24, 2011 Sheet 16 of 49 US 2011/0288011 A1 D. Leptin 20 - Leptin-An2 (C3) | Leptin-An2 (C6) | Leptin-An2 (c11) 1 | 5 Brain Capillaries Parenchyma Figure 15 Patent Application Publication Nov. 24, 2011 Sheet 17 of 49 US 2011/0288011 A1 In situ brain perfusion * 15 [...] Lean mice E | DIOmice Q tº £© 10 E * 5 {} tº: D.# > 0 Leptin protein Leptinité-130'An2 Figure 16A 30 EO) S. .5 20 3. CD .9 º, 10 E (/) Qº D O - - - Initial After 3 weeks Figure 16B Patent Application Publication Nov. 24, 2011 Sheet 18 of 49 US 2011/0288011 A1 Food intake in ob/ob mice after 4 hrs 1.4 1.2 1.0 0.8 –55% 0.6 0.4 0.2 0.0 Control Leptin116-130 Leptin116-130-An2 Figure 17A Food intake in ob/ob mice after 15 hrs 4 +7% 2 -3.3% Control Leptin116-130 Leptin116-130-An2 Figure 17B Patent Application Publication Nov. 24, 2011 Sheet 19 of 49 US 2011/0288011 A1 Leptin116-130 (1 mg/mouse) Control Leptin116-130-An2 (2.5mg/mouse) i eq. to 1 mg/mouse Mice (n=5 per group) received daily IP treatment for 6 days Figure 18 Patent Application Publication Nov. 24, 2011 Sheet 20 of 49 US 2011/0288011 A1 Effect on oblob mice weight gain Lºpº 16-130 (1 mg/mouse) Control i Lepi 15-130-An? (25 mg/mouse) Treatment daily P Figure 19 Patent Application Publication Nov. 24, 2011 Sheet 21 of 49 US 2011/0288011 A1 Thrombin GST-Tag Angiopep-2 GST: glutathion-S-transferase ! Angiopep-2 Figure 20 Patent Application Publication Nov. 24, 2011 Sheet 22 of 49 US 2011/0288011 A1 Thrombin Angiopep-2 Leu Val Pro : Gly Ser?hr Phe Phe Tyr Gly Gly Ser Arg Gly Lys CTG GTT CCG CGTGGA TCC ACC TTT TTC TAT GGC GGC AGC CGT GGC AAA Bamb|I Leptin (116-130) Arg Asn Asn Phe Lys Thr Glu Glu Tyšer Cys Ser Leu Pro Gln Thr CGC AAC AAT TTC AAG ACC GAG GAG TAZNGC TGC TCC CTG CCT CAG ACC Ser Gly Leu Gln Lys Pro Glu Serstop AGT GGC CTG CAG AAG CCA GAG AGKTGA ATT CC EcoRI Angiopep-2 Leptin (116-130) Oligo I N. Oligo 3 | ! Oligo 4 Oligo 1 87 bp | 79 bp Oligo 4 Bambi I EcoRI 120 b p Figure 21 Patent Application Publication Nov. 24, 2011 Sheet 23 of 49 US 2011/0288011 A1 rTAU Wash BDOD sº 5500 5DDD 45UD 4000 3500 3DDD 2500 200D 1500 1000 5DO Figure 22 Patent Application Publication Nov. 24, 2011 Sheet 24 of 49 US 2011/0288011 A1 Angiopep-2 F 3.7 7.5 1. Gel Tris/Tricine 16.5% Angiopep ? *º º 㺠2. Angiopep-2 Western blot Figure 23A Intens. - ?måU] UV spectrum at 229mm 600 pig recovered > 98% purity | | _––-T T __ –——-º-T ——-T -- - - r—r g r— r— 1.5 2.0 2.5 Time (min) Figure 23B Intens --- - x104 +MS, 0.89-0.96min FE 6 816,07073+(A) Mass spectra 4 2+ (A) 1223.5845 2 4+(A) 612.3440 1631.1062 : O r —r- —l- +---" r—— T – 500 1000 Figure 23c 2000 2500 m/z.
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