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(12) Patent Application Publication (10) Pub. No.: US 2016/0263235 A1 CASTAGNE Et Al US 2016026.3235A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0263235 A1 CASTAGNE et al. (43) Pub. Date: Sep. 15, 2016 (54) PEPTIDE THERAPEUTIC CONUGATES AND (60) Provisional application No. 61/200,947, filed on Dec. USES THEREOF 5, 2008. (71) Applicant: ANGIOCHEM INC., MONTREAL (CA) Publication Classification (72) Inventors: JEAN-PAUL CASTAIGNE, (51) Int. Cl. MONT-ROYAL (CA); MICHEL A647/48 (2006.01) DEMEULE, BEACONSFIELD (CA); A638/22 (2006.01) CHRISTIAN CHE, LONGUEUIL C07K I4/575 (2006.01) (CA); CARINE THIOT, PREAUX (52) U.S. Cl. (FR): CATHERINE GAGNON, CPC ..... A61K47/48246 (2013.01); C07K 14/57563 MONTREAL-NORD (CA); BETTY (2013.01); A61 K38/2278 (2013.01); C07K LAWRENCE, BOLTON (CA) 14/5759 (2013.01); A61 K38/2264 (2013.01) (21) Appl. No.: 14/696, 193 (57) ABSTRACT (22) Filed: Apr. 24, 2015 The present invention features a compound having the for mula A-X-B, where A is peptide vector capable of enhancing Related U.S. Application Data transport of the compound across the blood-brain barrier or (63) Continuation of application No. 13/133,002, filed on into particular cell types, X is a linker, and B is a peptide Aug. 9, 2011, now abandoned, filed as application No. therapeutic. The compounds of the invention can be used to PCT/CA2009/001781 on Dec. 7, 2009. treat any disease for which the peptide therapeutic is useful. Patent Application Publication Sep. 15, 2016 Sheet 1 of 49 US 2016/0263235 A1 Peptides Amino acid Sequence : Exendin-4 native 3. HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Exendin-4-Lys(MHA) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPK-(MHA) (CyS32)-Exendin-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPCSGAPPPS . ...vx 8.xxxv-x. Exendin-4 39 s 1 Lys89-MHA (maleimidohexanoic acid) Figure 1 Patent Application Publication Sep. 15, 2016 Sheet 2 of 49 US 2016/0263235 A1 O Y-Null O -- (CyS1)-AN2E. O 2 AN2-(CyS20)- Exendin-4- NH2 (MHA) AN1-(CyS7) Buffer PBS 1X, rt. 1 h 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-AN 5.3 > 85 6.739.38 Figure 2 Patent Application Publication Sep. 15, 2016 Sheet 3 of 49 US 2016/0263235 A1 Exendin-4-(CyS32) (C3) MPA-AN2 (C6) MHA-AN2 (C11) MUA-AN2 Buffer PBS 1X, rt. 1 h O O N O (C3) (C6) (C11) Series II 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 Sep. 15, 2016 Sheet 4 of 49 US 2016/0263235 A1 Exendin-4 Exendin-4-cySAn2 N-terminal Exendin-4-cySAn2 C-terminal Brain Capillaries Parenchyma Figure 4 Patent Application Publication Sep. 15, 2016 Sheet 5 of 49 US 2016/0263235 A1 Weight Days -- Control net First treatment - Exendin (3 ug/kg) -- Exendin (30 ug/kg) EXen-An2 (4.8 ug/kg) - EXen-An2 (48 Jg/kg) Figure 5 Patent Application Publication Sep. 15, 2016 Sheet 6 of 49 US 2016/0263235 A1 Cumulative food intake -H Control ... Exendin-4 (3 ug/kg) -- Exendin-4 (30 ug/kg) -- Exen-An2 (4.8 Lig/kg) -- Exen-An2 (48 ug/kg) Figure 6 Patent Application Publication Sep. 15, 2016 Sheet 7 of 49 US 2016/0263235 A1 Glycemia 20 15 o S & S c 10 - E SS 8 C () 5 3. & O O 2 4. 6 8 10 12 Day -H Control are EXendin-4 (3 Lg/kg) ray- EXendin-4 (30 ug/kg) acro- EXen-An2 (4.8 g/kg) -- EXen-An2 (48 ug/kg) Figure 7 Patent Application Publication Sep. 15, 2016 Sheet 10 of 49 US 2016/0263235 A1 Exendin-4 (Phoenix Pharm.) C3 C6 Exen-4-An2 C11 Exen-4-S4 40 E EXen-An2-An2 3. O 2 1 O Brain Capillaries Parenchyma Figure 9 Patent Application Publication Sep. 15, 2016 Sheet 11 of 49 US 2016/0263235 A1 -- Ctrl -- Exendin-4 (2 g/kg) -- Exen-An2-An2 (4.5 ug/kg) 140 š 120 . E 100 3 C 80 60 9,g 40 s 3 2O O 3. 60 90 Time (min) Figure 10 Patent Application Publication Sep. 15, 2016 Sheet 12 of 49 US 2016/0263235 A1 Total Brain (15 min after IV bolus) 0.05 0.04 0.3 0.02 O. Exendin-4 Exen-An2 (10 uglkg) (16 g/kg) Figure 11A Pancreas (15 min after IV bolus) 2.0 Exendin-4 EXen-An2 (10 ug/kg) (16 g/kg) Figure 11B Patent Application Publication Sep. 15, 2016 Sheet 13 of 49 US 2016/0263235 A1 Dose-response of insulin secretion (RIN-m5F pancreatic cells) Exendin-4 Exendin-An2 30 25 20 15 10. S. N. 8. M 9. s SS S' SS Concentration (nM) Figure 12 Patent Application Publication Sep. 15, 2016 Sheet 14 of 49 US 2016/0263235 A1 Chromatogram 1 Leptin-C11-AN2 before purification (450 mg of crude ) 3:tes mA: 2338 UV spectsu En at 229 inn 583 is - 5. w w w GO 3.5 15 2. 25 Title it is: Figure 13A Chromatogram 2 Leptin-C11-AN2 after purification tv spectrum at 229 m RT(min) Area int. Type Intens. S/N Chromatogram Max.miz Area FraC. O.99 5.9278 Manual 113 22.6 UW Chromatogram, 229 nm 1376.0139 O.8 250 mg recovered ' 1.OO 729.0335 Manual 809 369.8 UW Chromatogram, 229 nm 2063.6313 99.2 > 98% purity \ ...---------" O.O O.5 1.O 15 2.O 2.5 Time(min) Figure 13B Patent Application Publication Sep. 15, 2016 Sheet 15 of 49 US 2016/0263235 A1 . SS S is: iii. Sir Figure 14 Patent Application Publication Sep. 15, 2016 Sheet 16 of 49 US 2016/0263235 A1 O Leptin 20 Leptin-An2 (C3) Leptin-An2 (C6) Leptin-An2 (C11) Brain Capillaries Parenchyma Figure 15 Patent Application Publication Sep. 15, 2016 Sheet 17 of 49 US 2016/0263235 A1 in situ brain perfusion Lean mice DIO mice Leptin protein Leptins-130-An2 Figure 16A Initial After 3 weeks Figure 16B Patent Application Publication Sep. 15, 2016 Sheet 18 of 49 US 2016/0263235 A1 Food intake in Ob/ob mice after 4 hrs Conto Leptin116-130 Leptin116-130-An2 Figure 17A Food intake in oblob mice after 15 hrs Contro Leptin116-130 Leptin116-130-An2 Figure 17B Patent Application Publication Sep. 15, 2016 Sheet 19 of 49 US 2016/0263235 A1 g Leptin1 16-130 (1 mg/mouse) Control Leptin116-130-An2 (2.5mg/mouse) eq. to 1 mg/mouse lays Mice (n=5 per group) received daily IP treatment for 6 days Figure 18 Patent Application Publication Sep. 15, 2016 Sheet 20 of 49 US 2016/0263235 A1 Effect on oblob mice weight gain -: ; ; 3. ECO Lepen-A2 (2.5 ?ing mouse) Treatment daily P Figure 19 Patent Application Publication Sep. 15, 2016 Sheet 21 of 49 US 2016/0263235 A1 Thrombin GST: glutathion-S-transferase v Figure 20 Patent Application Publication Sep. 15, 2016 Sheet 22 of 49 US 2016/0263235 A1 Th rombin Angiopep-2 E eu Val Pro As Gly Serihir Phe Phe Tyr Gly Gly Ser Arg Gilly y; CTG GET CCG CGTGGA TCC ACC T C TAE GGC GG{ AGC (CGT, GCC AAA Bain H Leptin (116-130) Air C. A. --in Asin Phe sys Thr Glu Glu Tyser Cys Ser Leu Pro Gin Thr A A. {C(C AA ( AAg ACC GAG GAG TAAGC GC ICC CTG CCT CAG ACC Ser Gly Lieu Gln Lys Pro Glu Sestop AGT GGC CTG CAG AAG CCA GAG AGCCGA, ATT (CC EcoRI Angiopep-2 Leptin (116-130) Oligo I N. Oligo 3 Oligo 2 N. Oligo 4 Oligol 87 bp 79 bp Oligo 4 BamHI EcoRI 120 bp Figure 21 Patent Application Publication Sep. 15, 2016 Sheet 23 of 49 US 2016/0263235 A1 Eution buffer T Wash EO 55OO 45OO 4. 3S GST-An2 3. 25 2O SO OO 5 Figure 22 Patent Application Publication Sep. 15, 2016 Sheet 24 of 49 US 2016/0263235 A1 Angiopep-2 3.7 7.5 15 1. Gel TriS/Tricine 16.5% Angiopepng IO 2. Angiopep-2 Western blot Figure 23A Inters mAU 300 UV spectrum at 229mm 600 ug recovered 200 > 98% purity 00 20 25 Time min Figure 23B Intens +MS, 0.89-0.96mini (53-57) x104 6 3+(A) Mass 816.707 Spectra 4 2+(A) 1223,5845 2 4+ (A) 62,3140 1631, 1062 0 --- t . ill- ---, -Hr- t I 500 1000 1500 2000 2500 fz Figure 23C Patent Application Publication Sep. 15, 2016 Sheet 25 of 49 US 2016/0263235 A1 Mice in situ brain perfusion 1 5 1 O 5 Synthetic Recombinant Angiopep-2 Figure 24 Patent Application Publication Sep. 15, 2016 Sheet 26 of 49 US 2016/0263235 A1 Parenchyma uptake 15 GST-Leptinso GST-An2-Leptinso 1 O 5. GST GST-An2 GST-Leptino GST-An2-Leptino Figure 25 Patent Application Publication Sep. 15, 2016 Sheet 28 of 49 US 2016/0263235 A1 His-mLeptin His-An2-mLeptin IPTG induction kDa s -- -H 200- i. 66 45. 3 His-An2-mileptin 21 (MW: 20582 Da) Hiss-mLeptin (MW: 18299 Da) ,4 Inclusion bodies Figure 27 Patent Application Publication Sep. 15, 2016 Sheet 29 of 49 US 2016/0263235 A1 MHWGTI, CGFL WLWPYLFYVO AVPIOKVODD TKTLIKTIVT RTN DISHTOS VSSKOKVTGL DFIPGLHPIL TLSKMDOTLA VYOOILTSMP SRNVIOISND LENLRDLLHV LAFSKSCHLP WASGLETLDS LGGVLEASGY STEVVAL SRL OGSTODML WO EDLSPGC Figure 28 Patent Application Publication Sep. 15, 2016 Sheet 30 of 49 US 2016/0263235 A1 Overview of a purification scheme for mLeptin and An2-mLeptin Expression in bacteria v Solubilization of inclusion body proteins v Purification by nickel-affinity chromatography v Refolding by dialysis v Removal of His N-terminal tag by thrombin v Purification by anion-exchange chromatography (Q-Sepharose) Figure 29A Patent Application Publication Sep.
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