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(12) Patent Application Publication (10) Pub. No.: US 2008/0241135 A1 Olson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0241135 A1 Olson Et Al US 20080241135A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0241135 A1 Olson et al. (43) Pub. Date: Oct. 2, 2008 (54) METHODS FOR REDUCINGVIRAL LOAD IN 60/711,528, filed on Aug. 26, 2005, provisional appli HIV-1-INFECTED PATIENTS cation No. 60/715,619, filed on Sep. 9, 2005. (75) Inventors: William C. Olson, Ossining, NY Publication Classification (US); Paul J. Maddon, Scarsdale, NY (US); Daniel C. Pevear, (51) Int. Cl. Medford, MA (US); Robert J. A 6LX 39/395 (2006.01) Israel, Suffern, NY (US); Jose D. A6IP 43/00 (2006.01) Murga, Rosedale, NY (US) (52) U.S. Cl. ..................................................... 424/133.1 Correspondence Address: (57) ABSTRACT COOPER & DUNHAM, LLP 1185 AVENUE OF THE AMERICAS This method provides a method for reducing HIV-1 viral load NEW YORK, NY 10036 in an HIV-1-infected human subject which comprises admin istering to the subject at a predefined interval effective HIV-1 (73) Assignee: Progenics Pharmaceuticals, Inc. viral load-reducing doses of (a) a humanized antibody desig nated PRO 140, or of (b) an anti-CCR5 receptor monoclonal (21) Appl. No.: 11/894,762 antibody. This invention also provides a method for inhibiting in a human Subject the onset or progression of an HIV-1- (22) Filed: Aug. 20, 2007 associated disorder, the inhibition of which is effected by inhibiting fusion of HIV-1 to CCR5"CD4" target cells in the Related U.S. Application Data Subject. This invention also provides a method for treating a subject infected with HIV-1 comprising administering to the (63) Continuation of application No. 1 1/491.330, filed on subject (a) a monoclonal antibody which (i) binds to a CCR5 Jul. 21, 2006. receptor on the surface of the subject's CD4 cells and (ii) (60) Provisional application No. 60/702,064, filed on Jul. inhibits fusion of HIV-1 to the subject's CCR5"CD4+ cells, 22, 2005, provisional application No. 60/701,889, and (b) a non-antibody CCR5 receptor antagonist, in amounts filed on Jul. 23, 2005, provisional application No. effective to treat the subject. 12 Patent Application Publication Oct. 2, 2008 Sheet 1 of 22 US 2008/0241135 A1 JR-FL (B) CC 1/8 5 (B) DJ258 (A) OU151 (C) Overal Figure 1 Patent Application Publication Oct. 2, 2008 Sheet 2 of 22 US 2008/0241135 A1 In PBMC in ceMico Macrophage toc (trans) 100 10 - E e 1EER g i 9. EER 1 EEE CC1/85 SF162 JR-FL Average Figure 2 Patent Application Publication Oct. 2, 2008 Sheet 3 of 22 US 2008/0241135 A1 1.OO O 10 O.O1 or n - vur a co M D G) se N 2 ... e. g. et s see Virus Patent Application Publication Oct. 2, 2008 Sheet 4 of 22 US 2008/0241135 A1 PRO 140 concentration, grin 2 ? G ga Cl 0.001 O O1 O. 1 1 O OO 1000 PRO 140 concentration, ug/mL C O sc C 9. O.OO O.O1 O. 1 O 1 OO 1000 Figure 3 (cont) Patent Application Publication Oct. 2, 2008 Sheet 5 of 22 US 2008/0241135 A1 1 OO 5 80 g C 60 is 40 9. (1) ol. 20 O O. 1 1 10 1OO PRO 140 concentration, g/ml Figure 4 Patent Application Publication Oct. 2, 2008 Sheet 6 of 22 US 2008/0241135 A1 g - e "P-0.01 (n5) - 1 S2 -15 s 2 O 2 4. 6 8 10 12 Treatment Time, days 1 mg i.p. PRO 140-TREATED A UNTREATED Figure 5 Patent Application Publication Oct. 2, 2008 Sheet 7 of 22 US 2008/0241135 A1 Percent Gated O ev as S S 3. 3 3 3 3 S. S. 3 3 Figure 6 Patent Application Publication Oct. 2, 2008 Sheet 8 of 22 US 2008/0241135 A1 r 3 ve s (u/6) uoeupueouoo Patent Application Publication Oct. 2, 2008 Sheet 9 of 22 US 2008/0241135 A1 -O- Cohort 1 (n=4) - - - - Cohort 2 (n=4) rit' Placebo (n=2) Median RANTES conc., pg/mL 3000 1 OO O 1 2 3 4. Time, weeks Figure 8 Patent Application Publication Oct. 2, 2008 Sheet 10 of 22 US 2008/0241135 A1 Scheme 1. The S2 Displacement Route C." -a-rock,24 ?H, OCH FC THF/-7go C 2 70- 8O 25 R FC o'-' is:-(S-CBS Msc 1 EN catalyut FC CHC / Oc 4. R = CH 90-9S 5. R = CH 25. Rs och 26a. R as OCH 9. R R H N Neoc s OMs FC K.co/CH3CN a Crs N NEOC 50-60 S. R = CH R is CH (SS) 27. Rs OCH (As n Sep'd from 10-159 of N 1. benzylic dustereoner ---As per Ref. 7 E. fa t 2" 55-60% for 5 steps 12. R = CH (s, s 30. R = OCH (RS) O Figure 9 Patent Application Publication Oct. 2, 2008 Sheet 11 of 22 US 2008/0241135 A1 Patent Application Publication Oct. 2, 2008 Sheet 12 of 22 US 2008/0241135 A1 ),“TO,HovgyÑq'nuoº?loOo)(I)i·ºººººººº-bº?º••••••ºAwa/ºw(q)awarianosangoais'nnuae,, Patent Application Publication Oct. 2, 2008 Sheet 13 of 22 US 2008/0241135 A1 Patent Application Publication Oct. 2, 2008 Sheet 15 of 22 US 2008/0241135 A1 i Y )-(f >O- se gs N : Na l -X.Y ge : L Patent Application Publication Oct. 2, 2008 Sheet 16 of 22 US 2008/0241135 A1 Figure 12 Patent Application Publication Oct. 2, 2008 Sheet 17 of 22 US 2008/0241135 A1 O) O O 9 s D vp Pue unous Patent Application Publication Oct. 2, 2008 Sheet 18 of 22 US 2008/0241135A1 Q O auae 3. r a-s s q 9. & a s a s & fouliuoko ) peon poud paid 5 S. g 3se D 9 3. s useum - & 8 & 3 s & O to luogo (x) peon poud pad Patent Application Publication Oct. 2, 2008 Sheet 19 of 22 US 2008/0241135 A1 *:ii) tx sistant Wirts 40 O O t so 2O A-Dopic 0.000 0.00 O.01 O. CW PA4 IgMind Figure 14 (cont t) Patent Application Publication Oct. 2, 2008 Sheet 20 of 22 US 2008/0241135 A1 C PRO 140 A UK-427.857 V PRO 40 + ox-427. 857 O (A) 2 s C 5 9 g C 9. -2 - 1 O 1 2 3 log concentration (nM) O SCI-D A UK-427, 857 V SC-D + UK-427 57 C O u) 2 s o C 9. O C 9. -2 - 1 O 1 2 3 log Concentration (nM) Figure 15 Patent Application Publication Oct. 2, 2008 Sheet 21 of 22 US 2008/0241135 A1 u go PRO 140 sO A OK - 827. 57 C O SCEI-D O O C C o -3 -2 - 1 O 2 3 4 5 competitor log concentration (nM) i i. O PRO 140 O A UK-427, s 57 C O SC-D 9. o C .C. ... O ON -3 -2 - 1 O 1 2 3 4. 5 competitor log concentration (nM) Figure 16 Patent Application Publication Oct. 2, 2008 Sheet 22 of 22 US 2008/0241135 A1 A UK- 427, 857 O SCI-D - 1 O 1 2 3 4. log competitor concentration (nM) Co PRO 140 A UK-827, B57 O scs-D -1 O 1 2 3 4. log competitor concentration (nM) Figure 17 US 2008/0241135 A1 Oct. 2, 2008 METHODS FOR REDUCINGVIRAL LOAD IN 1998; Dragic et al., 1997: Littman, 1998). The CC-chemok HIV-1-INFECTED PATIENTS ine receptor 5 (CCR5) is the major co-receptor for macroph age-tropic (R5) strains, and plays a crucial role in the trans mission of HIV-1 (Berger, 1997; Bienias Zetal., 1998; Dragic 0001. This application claims benefit of U.S. Provisional et al., 1997: Littman, 1998).T cell line-tropic (X4) viruses use Application No. 60/702,064, filed Jul. 22, 2005: U.S. Provi CXCR4 to enter target cells, and usually, but not always, sional Application No. 60/701,889, filed Jul. 23, 2005: U.S. emerge late in disease progression or as a consequence of Provisional Application No. 60/711,528, filed Aug. 26, 2005; and U.S. Provisional Application No. 60/715,619, filed Sep. virus propagation in tissue culture. Some primary HIV-1 iso 9, 2005; the contents of each of which in its entirety is hereby lates are dual-tropic (R5x4) since they can use both co-recep incorporated by reference into this application. tors, though not always with the same efficiency (Connor et 0002 This invention was made with support under United al., 1997; Simmons et al., 1996). Binding of gp120 to a States Government Grant Nos. AIO46871 and AIO66329 from chemokine receptor in turn triggers conformational changes the National Institute of Allergy and Infectious Diseases. in the viral transmembrane glycoprotein gp41, which medi Accordingly, the United States Government has certain rights ates fusion of the viral and cellular membranes. in the Subject invention. 0006 Each stage of this multi-step process can be blocked 0003. Throughout this application, various publications with inhibitors of the appropriate viral or cellular protein, and are referenced in parentheses by author name and date, or by the inhibitors of gp120, gp41, CD4 and coreceptor are col a patent or patent publication number. Full citations for these lectively known as entry inhibitors. Entry inhibitors represent publications may be found at the end of the specification at least 4 distinct classes of agents based on their molecular immediately preceding the claims.
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