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(12) Patent Application Publication (10) Pub. No.: US 2016/0235842 A1 Goldstein Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0235842 A1 Goldstein Et Al US 2016O235842A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0235842 A1 Goldstein et al. (43) Pub. Date: Aug. 18, 2016 (54) MEDICAL USES OF CD38 AGONSTS Publication Classification (71) Applicant: THE BOARD OF TRUSTEES OF (51) Int. Cl. THE LELAND STANFORD JUNOR A 6LX39/395 (2006.01) UNIVERSITY, Palo Alto, CA (US) C07K 16/32 (2006.01) (72) Inventors: Matthew J. Goldstein, Hillsborough, GOIN33/574 (2006.01) CA (US); Ronald Levy, Stanford, CA C07K 6/28 (2006.01) (US); Holbrook Kohrt, San Francisco, (52) U.S. Cl. CA (US) CPC ....... A6IK39/3955 (2013.01); A61K.39/39558 (73) Assignee: The Board of Trustees of the Leland (2013.01); C07K 16/2896 (2013.01); C07K Stanford Junior University, Stanford, 16/2878 (2013.01); C07K 16/2887 (2013.01); CA (US) C07K 16/32 (2013.01); G0IN33/57492 (2013.01); A61K 2039/507 (2013.01) (21) Appl. No.: 14/904,814 (22) PCT Fled: Jul. 15, 2014 (57) ABSTRACT (86) PCT NO.: PCT/US2O14/046705 S371 (c)(1), Methods and compositions relating to medical (e.g., thera (2) Date: Jan. 13, 2016 peutic) use of CD38 agonists are provided. In some embodi ments, the present invention provides methods and composi Related U.S. Application Data tions relating to use of CD38 in the treatment of cancer, (60) Provisional application No. 61/846.372, filed on Jul. particularly to enhance the efficacy of antibody therapy 15, 2013. directed to cancer cells. Patent Application Publication Aug. 18, 2016 Sheet 1 of 10 US 2016/0235842 A1 S.E iC At Act. NK C3S FE FIGURE A 38: R3:388 s 's S t rtrix's88.66% striarristiary 98%.try is sessssssssssssssssssssssssssssssss39.27% C3: FE C38 P 5.64% . 64.69% ------ ------ risis-rr;CD38 PE FGURE B Patent Application Publication Aug. 18, 2016 Sheet 2 of 10 US 2016/0235842 A1 WWWWWWWWWWWWWWWWWWWWWWWWW s *Six-st & grgirt"Rist's "stry" 3. s x-aaaaaaaaaaaaaaaaaaaaaaaaaaa. 8: Patent Application Publication Aug. 18, 2016 Sheet 3 of 10 US 2016/0235842 A1 FIGURE 3A ** ? SR Eine hairs; FIGURE 3B 2. 3.24. east Cacer past 2ra Rikiah Cefixima Patent Application Publication US 2016/0235842 A1 Š sins & ---- -infr firff s:------ rtins rrrrrin is Š. sS$88. „-ºzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz&& FGURE 4A Patent Application Publication Aug. 18, 2016 Sheet 5 of 10 US 2016/0235842 A1 Sri Sigis, is 8 &tx * zºzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz -----zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz, w zzzzz--~~~~~::~~~~;~~~~~::~~~~;~~~~*~~~~ç********^^***^ CD3 perCP C38 FTC FIGURE 48 Patent Application Publication Aug. 18, 2016 Sheet 6 of 10 US 2016/0235842 A1 FGRE 5 - edia ERA, act38 (E3a) friAt a 38 (H37) inst sa E8 - 3. As ai:R2+ acE38 (E84 FAis a HER2 rect38 (HS7 FAss (ER2+aic:38.33}}{{C}37 Abs ar Steeter PSG: Sage:ERS 83 Ra88 Patent Application Publication Aug. 18, 2016 Sheet 7 of 10 US 2016/0235842 A1 FGRE is s 1.8 S. S (.8 -8- Rat g(G(d3, 3, 7) 5 -:- G. CD38 (c3, 18, 7) an -X. oOX4C (d8, 13, 17) 3. -i i ER2 (d3, 10, 17) -C- oi-ER2 (c3, 10, 7) + a C38 (4, 1, 18) ... O HER2 (d3, 10, 7} + c CX43 (d4, 11, 8) 2 . to 2, 3, 4, 5, so Cays after user isociation Patent Application Publication Aug. 18, 2016 Sheet 8 of 10 US 2016/0235842 A1 FGREA : -- Placebo (gG) (d3, d10, d17 -k- aOD20 (d3, d0, d. 7) 1.2- -v- acD38 (d8, d10, d17) . 3. i. 4. 20 30 40 50 60 bays after is or isociatio FGREE -- Facebo (gG) (83, di), (7) -- a CD38 (d3, d0, d47) + at D2 (d4, d, d3) 8s a CD20 (d3, d10, d7) + at D38 (d3, d10, dif) -(- a CD20 (d3, d10, d7) + acD38 d4, d. 1, d8) , . to 20 30 4o so do Days after turn of irociatio Patent Application Publication Aug. 18, 2016 Sheet 9 of 10 US 2016/0235842 A1 FGRE 8 r 1.0 as .6- oo: ays after to irociation -- Placebo (IgG) (d3, d10, d17) aCD2O (d3, d10, d17) aCD38 (d3,( d10, d17) + acD20 (d4, d11, d18) et acD20 (d3, d10, d17) + acD38 (d3, d10, d17) -w- acD38 (d3, d10, d17) - - acD20 (d3, d10, d17) + acD137 (d4, d11, d.18) -K)- aCD20 (d3, d10, d17)+ acD38 (d4, d11, d18) Patent Application Publication Aug. 18, 2016 Sheet 10 of 10 US 2016/0235842 A1 FGURE 9 Fresh, fict-activated NKs Fresh, activated NKS of expression of C38.46% high 8xpression of C38-90% US 2016/0235842 A1 Aug. 18, 2016 MEDICAL USES OF CD38 AGONSTS body therapy a period of time prior to the administering of the CD38 agonist. In particular such embodiments, the period of GOVERNMENT RIGHTS time is selected so that, prior to the administering of the CD38 agonist, CD38 expression has increased on Surfaces of effec 0001. This invention was made with Government support tor cells that mediate antibody-dependent cellular cytotoxic under contract CA153248 awarded by the National Institutes ity (ADCC) upon exposure to tumor cells bound by an anti of Health. The Government has certain rights in this inven tumor antibody. In many embodiments, and particularly in tion. many embodiments in which CD38 agonist therapy is com bined with anti-tumor antibody therapy (especially when BACKGROUND administration of the CD38 agonist therapy is delayed a 0002 Monoclonal antibody therapy is rapidly becoming period of time relative to administration of the anti-tumor the standard of care for many diseases, disorders, and condi antibody therapy) administration of Such therapy results in tions, including certain cancers. Despite the promising activ increased ADCC, presumably mediated by such effector cells ity of monoclonal antibodies, the response rates among with increased CD38 surface expression increase their patients with either refractory or advanced cancer often are ADCC. In some embodiments, apoptosis of the tumor cells only partial, less than 25%, due to various factors. upon administering of the CD38 agonist is increased relative to that observed absent the CD38 agonist. In some embodi SUMMARY ments, tumor growth upon administering of the CD38 agonist 0003. The present invention demonstrates effective treat is reduced relative to that observed absent the CD38 agonist. ment of cancer by agonizing CD38 (i.e., by administration of 0006. In some embodiments, the present invention pro CD38 agonist therapy, for example comprising administering vides methods of administering CD38 agonist therapy a CD38 agonist). Prior to the present invention, CD38 together with agonist therapy directed at one or more induc expressed by tumor cells had been described as a potential ible immune effector cell surface markers other than CD38. In target for inhibitory therapy to treat cancer. According to prior Some embodiments, such methods further involve adminis understanding, therefore, agonizing CD38 would be affirma tering anti-tumor antibody therapy. Thus, in some embodi tively undesirable for cancer patients. The present invention, ments, the present invention provides methods of treating however, establishes that administration of a CD38 agonist cancer that include steps of i) administering anti-tumor anti can enhance the ability of a Subject’s immune system to target body therapy; ii) administering anti-CD38 agonist therapy: and destroy cancer cells. In particular, the present invention and iii) administering agonist therapy targeting at least one demonstrates that agonizing CD38 can increase effector cell inducible immune effector cell surface marker other than killing of tumor cells. As is known in the art, one of the CD38. In some embodiments, (at least one dose of) CD38 mechanisms by which immune effector cells (e.g., natural agonist therapy is administered a first period of time after (at killer NK cells, macrophages, neutrophils, eosinophils) least one particular dose of) anti-tumor antibody therapy. In exert their effects is by destroying target cells that have been Some embodiments, agonist therapy targeting at least one “labeled' (i.e., bound) by antibodies (e.g., that interact with a inducible immune effector cell surface marker other than marker on the target cell Surface). This process is known as CD38 is administered a second period of time after (at least antibody-dependent cellular cytotoxicity (ADCC). The one particular dose of optionally the same particular dose of) present disclosure specifically demonstrates that administra anti-tumor antibody therapy. In some embodiments, the first tion of a CD38 agonist can augment the ADCC capability of and second time periods are relative to the same dose of immune effector cells such as NK cells, in particular against anti-tumor antibody therapy. In some embodiments, the first cancer cells to which an antibody has bound. and second time periods are the same. In some embodiments, 0004. The present invention further demonstrates the util the first and second time periods are different. ity and effectiveness of combining CD38 agonist therapy 0007. In some embodiments, methods of the present with anti-tumor antibody therapy. Still further, the present invention involve determining a CD38 expression level on invention demonstrates the utility and effectiveness of a effector cells in a subject. In some such embodiments, CD38 serial, staged CD38 agonist therapy relative to anti-tumor expression level is determined prior to administering a CD38 antibody therapy. Specifically, the present invention explic agonist. In some embodiments, CD38 expression level is itly establishes that CD38 levels on immune effector cells can determined at multiple time points. In some embodiments, be enhanced by contact with tumor cells bound by anti-tumor CD38 expression level is determined before, substantially antibody (i.e., antibody that specifically binds to a tumor simultaneously with, and/or after administration of one or antigen). Still further, the present invention demonstrates that more doses of a CD38 agonist. In some embodiments, CD38 administration of a CD38 agonist after such enhancement expression level is determined before, substantially simulta achieves remarkably effective killing of the tumor cells.
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