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(12) Patent Application Publication (10) Pub. No.: US 2016/0220631 A1 Mezey Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0220631 A1 Mezey Et Al US 2016O220631A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0220631 A1 Mezey et al. (43) Pub. Date: Aug. 4, 2016 (54) METHODS OF MODULATING Publication Classification ERYTHROPOESS WITH ARGINNE VASOPRESSIN RECEPTOR 1B MOLECULES (51) Int. Cl. A638/II (2006.01) (71) Applicant: THE USA, AS REPRESENTED BY A613 L/404 (2006.01) THE SECRETARY DEPARTMENT A613 L/46.5 (2006.01) OF HEALTH AND HUMAN A638/8 (2006.01) SERVICES, Bethesda, MD (US) A6II 45/06 (2006.01) (52) U.S. Cl. (72) Inventors: Eva M. Mezey, Rockville, MD (US); CPC ............. A61K 38/11 (2013.01); A61 K38/1816 Balazs Mayer, Budakeszi (HU); (2013.01); A61K 45/06 (2013.01); A61 K Krisztian Nemeth, Budapest (HU); 3 1/465 (2013.01); A61 K31/404 (2013.01) Miklos Krepuska, Rockville, MD (US) (73) Assignee: The USA, as represented by the (57) ABSTRACT Secretary, Departm-ent of Health and Disclosed are methods of modulating erythropoiesis with Human Service, Bethesda, MD (US) arginine vasopressin receptor 1B (AVPR1B) molecules, such Appl. No.: as AVPR1B agonists or antagonists. In one example, a (21) 15/022,531 method of stimulating erythropoiesis is disclosed including (22) PCT Fled: Oct. 1, 2014 administering an effective amount of an AVPR1B stimulatory molecule to a subject in need thereof, thereby stimulating (86) PCT NO.: PCT/US2O14/058613 erythropoiesis. Also disclosed is a method of stimulating hematopoetic stem cell (HSC) proliferation which includes S371 (c)(1), administering an effective amount of an AVPR1B stimulatory (2) Date: Mar. 16, 2016 molecule to a subject in need thereof, thereby stimulating HSC proliferation. A method of inhibiting HSC proliferation Related U.S. Application Data including administering an effective amount of an AVPR1B (60) Provisional application No. 61/885,258, filed on Oct. inhibitory molecule to a subject in need thereof, thereby 1, 2013. inhibiting HSC proliferation is provided. Patent Application Publication Aug. 4, 2016 Sheet 1 of 32 US 2016/0220631 A1 F.G. 1A C:33d. yo Ayr 8 Pop8 (Population B) PopB CD34(-) . s ; & ms & s w PopC Population C) MPP3A CD34+ CD48+ CD150 Si3.js; AVR 3 Patent Application Publication Aug. 4, 2016 Sheet 2 of 32 US 2016/0220631 A1 100 i 1Isotype yO Control 8 - s —AVPR1B UnStained Patent Application Publication Aug. 4, 2016 Sheet 3 of 32 US 2016/0220631 A1 FIG. 1E E 80 - t is & E 5 20 S$ w t ti st Alexa-647 FIG. 1F 3 CD34+CD38- (A) (B) S. CD34+CD38+(B) CD34+CD38- (C) S CD34+CD38+(D) > 2 t (D) (C) AVPRB OXR Patent Application Publication Aug. 4, 2016 Sheet 4 of 32 US 2016/0220631 A1 sex Patent Application Publication Aug. 4, 2016 Sheet 5 of 32 US 2016/0220631 A1 GA: G: es ve se ge & Š s * $83. Of 8(iiii is a. * S % & st *o sis 7. { i a. *. S X %, % to 2 Saq Qöjestätti ) Patent Application Publication Aug. 4, 2016 Sheet 6 of 32 US 2016/0220631 A1 a?a Y U2 g g. 6 S. g; e seei s e s K. K. as &H3. 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Patent Application Publication Aug. 4, 2016 Sheet 21 of 32 US 2016/0220631 A1 f CE N: OOWN Patent Application Publication Aug. 4, 2016 Sheet 22 of 32 US 2016/0220631 A1 wo . ww. 3is : S. vis-My woss S, box g b- ->i 3. s g c xx 3 s & r W& i tu o 3-&-&-4 ne is be is one rxas$ 4 s was 4. 4 a S. 4 is s sy & 3. S. & . & s wSa- Ms G 3 * S. u"i. gsk2. 6.is & S w wa S w E is i. if :::::::: 3. 2 if es f s Sysis. Aft 3.N.O.3d 33& Patent Application Publication Aug. 4, 2016 Sheet 23 of 32 US 2016/0220631 A1 FIG. 9D FIG. 9E con Rot (A) AVR REATED (B) AVPR1B AGONST(C) Patent Application Publication Aug. 4, 2016 Sheet 24 of 32 US 2016/0220631 A1 i. OW- SOOO }} 3. Off S.O.O.O.. COROO Patent Application Publication Aug. 4, 2016 Sheet 25 of 32 US 2016/0220631 A1 2. & S 3 s s- & & 3 & S. s & 8 a $3. s 3g s is ti; :is S. Of Oye Patent Application Publication Aug. 4, 2016 Sheet 26 of 32 US 2016/0220631 A1 {iddh ( išx NOISSSaddx3 WNadu Aiyad w wa Š Gr SS S. S. G e S Š S : Y N: ves 9. S i. as gm wa SNSS C&S W C : Patent Application Publication Aug. 4, 2016 Sheet 27 of 32 US 2016/0220631 A1 FIG. 11 EORRAGE iypothaiarius -- YOXA - Sicisey -- - s & SK Ofciatio as yatgy Erythoid developert w Siit Reiciocytes {O} see myS SS '' saw SwsS. sessSS $88.8Y-88.jSS SáS- 33.YC-X is 88-8383-8:3& X. SYS$888;&S SR&R3:SS SS S-$888&SS: SESS Patent Application Publication Aug. 4, 2016 Sheet 28 of 32 US 2016/0220631 A1 www.www.wwww.wwww.www. SSs Pope xxi-xxixe:s is is & Ki-48-'er P-tyS.S. Populatica A s: S& &. R. s S$8- ^x& 88s 8-X MrNina re r r ser r ................ $3$ 3 & Sisi. At8° 38' tax sy N pp. AyrsR Population is Peps iss ... MPP2 & CD34+ & CD48. RS: CD150+ S & ^x8& 8' & 8 SS At Population C posses: - PP3/4: & CD34+ x CE48+ 8 CD150 was 38. waywaywayexityway wayw.8. s: 8 tie is to 88 st S$f- Sisi AVRS Patent Application Publication Aug. 4, 2016 Sheet 29 of 32 US 2016/0220631 A1 F.G. 13 cAMP cc in Hu CD34" cells following stimulation O.8 O. 6 0.4 W. tax g a is an O2 & Patent Application Publication Aug. 4, 2016 Sheet 30 of 32 US 2016/0220631 A1 FIG. 14A Periphera blood GFP, CD45.2+ celis Control (A) i AvPR1B KO (B) (N s wr & s: S. ma & FIG. 14B Bone narrow, GFP, CD45,2+ multi-lineage ces 4 months after transplant F.G. 14C Spieen, GFP, CD45,2+, multi-lineage ceils, 4 months after transplant Patent Application Publication Aug. 4, 2016 Sheet 31 of 32 US 2016/0220631 A1 AVP NOUCED RECOVERY AFTER HEMORRHAGE S NOTAFFECTED BY SPLENECOMY FIG. 15 50 B) Base 2D Patent Application Publication Aug. 4, 2016 Sheet 32 of 32 US 2016/0220631 A1 S. xx S s 2 9/S-88 -ZOOeef 9S887 OO eel W-CL-duo) alHaAv La 99-83t d-LZOO eeuw-z-duod US 2016/0220631 A1 Aug. 4, 2016 METHODS OF MODULATING developing a condition associated with excessive HSC pro ERYTHROPOESS WITH ARGINNE liferation, Such as polycythemia.
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