US00871.5677B2 (12) United States Patent (10) Patent No.: US 8,715,677 B2 Bartlett et al. (45) Date of Patent: May 6, 2014 (54) IMMUNOLOGICAL USES OF WO WOO145750 6, 2001 MMUNOMODULATORY COMPOUNDS FOR WO WOO2O59 106 38: VACCNE AND ANT-INFECTIOUS DISEASE W8 w885 358. THERAPY WO WO2004103274 12, 2004 WO WO2005OO7190 1, 2005 (75) Inventors: Justin B. Bartlett, Warren, NJ (US); George W. Muller, Bridgewater, NJ OTHER PUBLICATIONS (US); Peter H. Schafer, Randolph, NJ (US); Christine Galustian, Croydon Kaechet al., “Effector and Memory T-cell Differentiation: Implica Surrey (GB); Angus G. Dalgleish, tions for Vaccine Development.” Nature Reviews Immunology Cheam (GB); Brendan Meyer, London 2002:v2:251-262.* Bartlett et al., British Journal of Cancer, 90:955-961 (2004). (GB) Bielekova et al., The Journal of Immunology, 164: 1117-1124 (2000). (73) Assignee: Celgene Corporation, Summit, NJ (US) Cavanagh et al., Int. J. Cancer, 70: 98-105 (1997). Corral et al., The Journal of Immunology, 163:380-386 (1999). Davies et al., Blood, 98: 210-216 (2001). (*) Notice: Subject to any disclaimer, the term of this Dredge et al., Critical Reviews in Immunology, 22(5&6): 425-437 patent is extended or adjusted under 35 (2002). U.S.C. 154(b) by 714 days. Dredge et al., Cancer Immunol. Immunother. 51: 521-531 (2002). Dredge et al., The Journal of Immunology, 168: 4914-4919 (2002). (21) Appl. No.: 11/514,447 Gollob et al., J. Clin. Invest., 102(3): 561-575 (1998). Haslett et al. The Journal of Infectious Diseases, 187: 946-955 (22) Filed: Aug. 31, 2006 (2003). Marriott et al., Clin. Exp. Immunol. 130: 75-84 (2002). (65) Prior Publication Data Marriott et al., Expert Opin. Biol. Ther. 1(4): 1-8 (2001). US 2007/OO48327 A1 Mar. 1, 2007 Schafer et al., The Journal of Pharmacology and Experimental Therapeutics, 305: 1222-1232 (2003). Related U.S. Application Data Schey et al., Journal of Clinical Oncology, 22(16): 1-8 (2004). Galustian et al., “Lenalidomide (Revlimid(R), CC-5013) and (60) Provisional application No. 60/712,823, filed on Sep. Actimid TM (CC-4047) inhibit the function and expansion of Tregu 1, 2005. latory (Treg) cells in vitro: Implications for anti-tumor activity in vivo..” Proc. Am. Assoc. Cancer Res. Ann. Meeting, 47: 1147, Abstract (51) Int. Cl. No. 4882 (XP00 1248611), (2006). A6 IK39/00 (2006.01) Tsenova et al., Antimicrobial Agents and Chemotherapy, 46(6): (52) U.S. Cl. 1887-1895 (2002). USPC ..................................... 424/184.1; 424/277.1 (58) Field of Classification Search * cited by examiner USPC ..................... 514/323, 417; 424/208.1; 435/4 See application file for complete search history. Primary Examiner – Walter Webb (74) Attorney, Agent, or Firm — Jones Day (56) References Cited U.S. PATENT DOCUMENTS (57) ABSTRACT Methods of enhancing immune response to an immunogen in 5,723,283 A * 3/1998 Classen ............................. 435/4 6,281.230 B1* 8, 2001 Muller et al. .... 514/323 a Subject are disclosed. Also disclosed are methods of reduc 2003/0096841 A1* 5/2003 Robarge et al. ............... 514,323 ing the sensitivity to an allergen in a Subject. The methods 2004/002281.0 A1* 2, 2004 Rudenko et al. ........... 424,208.1 comprise the administration of an immunomodulatory com pound in specific dosing regimens that result in enhanced FOREIGN PATENT DOCUMENTS immune response or reduced sensitivity. WO WO901 1764 10, 1990 WO WO93 13772 7, 1993 15 Claims, 21 Drawing Sheets U.S. Patent May 6, 2014 Sheet 1 of 21 US 8,715,677 B2 List of Vaccines Product or trade Antigen(s) Manufacturer (country) name A D iphtheria, tetanus (adsorbed Commonwealth (Australia A iphtheria, tetanus, pertussis Fl eninqOCOccus (polysaccharide AEGEphtheria, tetanus, (acellular) pertussis WYE (US) A iphtheria, tetanus, pertussis, Hib A aemophilus influenzae type b (PRP-T Eter m H epatitis A (inactivated) Chemo-Sero-Therapeutic Reshinst (Japan) A iphtheria (absorbed S evac (Czechoslovakia iphtheria, tetanus (absorbed S evac (Czechoslovakia EGEE pertussis ellow fever AVP (France aemophilus influenzae, type b Anadifteral iphtheria (adsorbed etanus (adsorbed C ellow fever Attenuvax * easles (live, further attenuated nthrax epatitis A B-CAPSA* Haemophilus influenzae type b polysaccharide, 1987 to 1989 BayGam Human immunoglobulin BayHep B Hepatitis Bimmune globulin (human Bay Rab Rabies immune globulin aver Corporation (U.S. BayTet Tetanus immune globulin (human aver Corporation (U.S. Countries Botulism immune globulin (nota vaccine BIK (Japan Bimmugen epatitis B (recombinant, adsorbed, Chemo-Sero-Therapeutic Resh east derived inst (Japan FIG. 1 U.S. Patent May 6, 2014 Sheet 2 of 21 US 8,715,677 B2 Product or trade Antigen(s) Manufacturer (country) ae Anthrax (adsorbed) BPT (U.S.) Biviraten Berna Measles, mumps (live) BER (Switzerland) Botulinum antitoxin (for U.S..mil military use ) C.D.T.C Diphtheria, tetanus (pediatric, adsorbed) Commonwealth (Australia Celluvax Pertussis (acellular CHR (tal ertiva Diphtheria, tetanus, (acellular) pertussis S.D.P.T. ..T. Bis Rudivax Di Te Per Pol Impfstoff i-Te-Pol if-Tet-All Diphtheria, tetanus FTAVAX Diphtheria, tetanus, polio D Te Anatoxal itOxim ouble Aniaen B.l. Diphtheria, tetanus Bengal immunity Co. (India ?yVax X Diphtheria, tetanus (for pediatric use) WYE (U.S. DT TAB Diphtheria, tetanus, Salmonella typhi, AVP (France) Paratyphi A & B TaP (generic Diphtheria, tetanus, (aCellular) pertussis AVP, WYE, GSK (U.S. Measles, rubella (live) eIPV Rubella (live Influenza WYE (U.S.) FIG. 1 (Cont.) U.S. Patent May 6, 2014 Sheet 3 of 21 US 8,715,677 B2 Product Or trade Antigen(s) Manufacturer (country) ae Fuad, Agrippal-S Influenza CHR (Ital FluMist influenza (live, attenuated, intranasal) MED (U.S. Fluoqen Influenza PD (U.S. Fluvirin influenza EVN (U.S. Genevac BPasteur HepatitisB Hexavac Diphtheria, tetanus, pertussis, polio, AVP (Europe) hepatitis B, Hib HibTITER Haemophilus influenzae type b (HbOC) WYE (U.S. Hinkuys karokoe Pertussis (adsorbed) Natl. Public Health Institute Finland Humotet-antiTetanus Hyper-Tet (now called Tetanus immune globulin Bayer Corporation (U.S.) "BayTet" Polio (inactivated Statens Seruminstitut (Denmark Immune Globulin Broad-spectrum immune globulins MA, BPT, New York Blood Ctr, Intramuscular (Human Bayer Corporation, CEN (U.S. Imogam Rabies - HT Rabies immune alobulin AVP (U.S. AVP (U.S. movax Parotiditis Mumps AVP (France) imovax Polio Polio AVP (France) imovax Sarampion Measles AVP (France) moVax D.T. Diphtheria, tetanus F.G. 1 (COnt.) U.S. Patent May 6, 2014 Sheet 4 of 21 US 8,715,677 B2 Product or trade Antigen(s) Manufacturer (country) name movax R.O.R. Measles, rubella, mumps (live) VP (France) movax Rubeola Measles AVP (International) movax Mumps Mumps ( movax Rabies I.M Rabies vaccine (HDCV) AVP (U.S.) Infanrix Diphtheria, tetanus, (acellular) GSK (Belgium, U.S.) pertUSSis pad TP Tetanus, polio AVP (France) POL Polio (enhanced potency, AVP (U.S.) inactivated PV Polio (inactivated ) General term for inactivated Dolio Vaccine stivaC Influenza - JE-VAX Japanese encephalitis AVP (U.S.) Dubbelwaccin Finland Norwa Institute (Switzerland Central Pub Health Lab (Finland CHIR (Italy) Measles, rubella ((Five) 4/74 to 6/78 DowlPitneyMoore (U.S.) Lirugen Measles AVPant) Measles (live) 2165 to 6/78 Dow (U.S.) LM - 3 RIT Measles, mumps, rubella (live) Dong Shin Pharm (Korea) LM-2 RIT Measles, mumps (live) Dong Shin Pharm (Korea) LTEANAS muna Tetanus (adsorbed lmuna S.p. (Slovakia LYMErix * GSK (U.S.) Measles (live, attenuated) IVIRK (U.S.) Rubella (live) MRK (U.S.) Masern-mofstoff SSW Measles (live Measles Vaccine DK3* Measles (live) 1964 to 1972 FIG. 1 (Cont.) U.S. Patent May 6, 2014 Sheet 5 of 21 US 8,715,677 B2 Product or trade Antigen(s) Manufacturer (country) ae Measles Measles (inactivated) 1963 to 1966 Eli Lilly (U.S .) Measles (live) 12/64 to 1974 MenCevax A MenindOCOCCUS (polysaccharide) (Group A) SmithKline/RT (Belgium Meningitec Meningococcus (coniugate) (Group C WYE (U.K., Australia Menomune-A/C/YW-Meningococcus (polysaccharide) AVP (U.S.) 135 Groups A, C, Y, W435 Menpovax 4 Meningococcus (polysaccharide) (Groups A CHIR (Italy) & C Menpovax A+C ( Meruvax * .S.) Meruvax .S.) Mevilin-L* MMRX MMR (aeneric) * Measles, mumps, rubella (live) 4/74 to 61.78 (U.S.U.S.) Moniarix Mopavac Sevac Measles, mumps attenuated Institute of Sera and vaccines live, Czechoslovakia MOPVX Polio (live, Sabin, monovalent types , , Ill) WYE (U.S. Morbilwax Measles (live, attenuated) CHIR (Italy) Morubel ( Moruman Berne Measles immunglobulin ( MoruDar Movivac Measles Clive, attenuated) M-R VAX* Mumaten Berne BER (SWitzerland Mumps (aeneric) * Mumpsumps (live)474(live) 4,74 to 61.78 Mumps (generic) M (U.S. Mumps (generic) M E Mumpsvax * Mutagrip Influenza Nabi-HB Hepatitis B immune (lobulin Nothaw CHI (Ital OmniHIB* Haemophilus influenzae type b (PRP-T GSK, AVP (U.S. OPV General term for Oral polio vaccine FIG. 1 (Cont.) U.S. Patent May 6, 2014 Sheet 6 of 21 US 8,715,677 B2 Product or trade Manufacturer (country) name Orimune olio vaccine (oral, trivalent) U. S.) ariorix umps (live) SmithKline/RT (Belgium)( PavivaC-Sevac Mumps (live) Institute of Immunology Croatia PCV, PCV7 General term for pneumococcal Coniudate (7-Valent Pediarix Diphtheria, tetanus, (acellular) pertussis, GSK (U.S .) hepatitis B, PW edwaxHIB Haemophilus influenzae type b (PRP-OMP) MRK (U.S Diphtheria, tetanus, (acellular) pertussis, AVP (Ca(Canada) entaCel Diphtheria,iphtheria, tetanus, pertussis, polio, Hib A VP (Canada entaCOC D iphtheria, tetanus, pertUSsis, polio, Hib ENTACt-HB iphtheria, tetanus, pertussis, polio, Hib entaVaC Einiphtheria, tetanus, Epertussis, polio, Hib e W al e nt e Diphtheria, tetanus, pertussis, hepatitis B, ttaa Hi b fizer Vax-Measles K* Measleseasles (inactivated)3763(inactivated) 3/63 to 1970 Pfizer (U.S fizerVax-Measles L* easles (live) 2.65 to 1970 Pfizer (U.S. uSerix easles, mumps, rubella neumoVax 23 neumococcal (polysaccharide) RK (U.S.) NU-IMUNE 23 * EEneumoCOCCal (polysaccharide EE (U.S. - OLIACe, D iphtheria, tetanus, pertussis, polio, HB AVP (Ardentina P P V, P P W2 3 eneral term for pneumococcal olysaccharide (23-valent Waf neumococcal (7-valent, Conjugate) E (U.S.) riorix easles, mumps, rubella (live K (U.K.