(19) TZZ_ _T

(11) EP 1 928 492 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 39/00 (2006.01) A61K 39/29 (2006.01) 23.02.2011 Bulletin 2011/08 A61K 31/4035 (2006.01) A61P 35/00 (2006.01) A61P 37/00 (2006.01) (21) Application number: 06824878.0 (86) International application number: (22) Date of filing: 31.08.2006 PCT/US2006/034271

(87) International publication number: WO 2007/028047 (08.03.2007 Gazette 2007/10)

(54) IMMUNOLOGICAL USES OF IMMUNODULATORY COMPOUNDS FOR AND ANTI- DISEASE IMMUNOLOGISCHE VERWENDUNGEN VON IMMUNMODULATORISCHEN VERBINDUNGEN FÜR EINEN IMPFSTOFF UND THERAPIE GEGEN INFEKTIONSKRANKHEITEN UTILISATIONS IMMUNOLOGIQUES DE COMPOSES IMMUNOMODULATEURS POUR VACCINS ET TRAITEMENT ANTI-INFECTIEUX DE MALADIES

(84) Designated Contracting States: (74) Representative: Weber, Martin AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Jones Day HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI Rechtsanwälte Attorneys-at-Law Patentanwälte SK TR Prinzregentenstrasse 11 Designated Extension States: 80538 München (DE) AL BA HR MK RS (56) References cited: (30) Priority: 01.09.2005 US 712823 P WO-A-01/45750 WO-A-90/11764 WO-A-93/13772 WO-A-02/059106 (43) Date of publication of application: WO-A-03/024354 WO-A-2004/078928 11.06.2008 Bulletin 2008/24 WO-A-2004/103274 WO-A-2005/007190 US-B1- 6 281 230 (60) Divisional application: 11151126.7 • DREDGE KEITH ET AL: "Protective antitumor immunity induced by a costimulatory thalidomide (73) Proprietor: CELGENE CORPORATION analog in conjunction with whole tumor cell Summit, NJ 07901 (US) is mediated by increased Th1-type immunity" JOURNAL OF , vol. 168, (72) Inventors: no. 10, 15 May 2002 (2002-05-15), pages 4914-4919, • BERTLETT, Justin, B. XP002424845 ISSN: 0022-1767 Warren, NJ 07059 (US) • GALUSTIAN CHRISTINE ET AL: "Lenalidomide • MULLER, George, W. (Revlimid (c), CC-5013) and Actimid (TM) (CC- Rancho Santa Fe, CA 92067 (US) 4047) inhibit the function and expansion of T • SCHAFER, Peter, H. regulatory (Treg) cells in vitro: Implications for Randolph, NJ 07869 (US) anti-tumor activity in vivo." PROCEEDINGS OF • GALUTIAN, Christine THE AMERICAN ASSOCIATION FOR Croydon Surrey CR0 5JD (GB) RESEARCH ANNUAL MEETING, vol. 47, April 2006 • DALGLEISH, Angus, G. (2006-04), page 1147, XP001248611 & 97TH Cheam SM2 7PP (GB) ANNUAL MEETING OF THE AMERICAN- • MEYER, Brendan ASSOCIATION-FOR-CANCER-RESEARCH London SW18 4PA (GB) (AACR); WASHINGTON, DC, USA; APRIL 01 -05, 2006 ISSN: 0197-016X

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 928 492 B1

Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 928 492 B1

Remarks: Thefilecontainstechnicalinformationsubmittedafter the application was filed and not included in this specification

2 EP 1 928 492 B1

Description

[0001] This invention relates to the use of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione or 3-(4-amino-1- oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, in particular as vaccine adjuvants, particularly anticancer vaccine 5 adjuvants. The invention also relates to the uses of immunomodulatory compounds or IMiDs® in combination with to treat or prevent cancer or infectious diseases. Further described are other various uses of immunomodulatory compounds such as reduction or desensitization of allergic reactions.

VACCINES 10 [0002] Vaccines have traditionally consisted of live attenuated pathogens, whole inactivated organisms or inactivated toxins. In many cases, these approaches have been successful at inducing immune protection based on mediated responses. However, certain pathogens, e.g., HIV, HCV, TB, and malaria, require the induction of cell-mediated immunity (CMI). Non-live vaccines have generally proven ineffective in producing CMI. In addition, although live vaccines 15 may induce CMI, some live attenuated vaccines may cause disease in immunosuppressed subjects. As a result of these problems, several new approaches to vaccine development have emerged, such as recombinant protein subunits, synthetic peptides, protein polysaccharide conjugates, and plasmid DNA. While these new approaches may offer im- portant safety advantages, a general problem is that vaccines alone are often poorly immunogenic. Therefore, there is a continuing need for the development of potent and safe adjuvants that can be used in vaccine formulations to enhance 20 their immunogenicity. See, e.g., Edelman, Molecular Biotech. 21: 129-148 (2002); O’Hagan et al., Biomolecular Engi- neering, 18: 69-85 (2001); Singh et al., Pharm. Res. 19(6): 715-28 (2000) for detailed review of the state of the art in vaccine development. [0003] Traditionally, the immunogenicity of a vaccine formulation has been improved by injecting it in a formulation that includes an adjuvant. Immunological adjuvants were initially described by Ramon (1924, Ann. Inst. Pasteur, 38: 1) 25 "as substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." A wide variety of substances, both biological and synthetic, have been used as adjuvants. However, despite extensive evaluation of a large number of candidates over many years, the only adjuvants currently approved by the U.S. Food and Drug administration are aluminum-based minerals (generically called Alum). Alum has a debatable safety record (see, e.g., Malakoff, Science, 2000, 288: 1323), and comparative studies show that it is a weak adjuvant 30 for antibody induction to protein subunits and a poor adjuvant for CMI. Moreover, Alum adjuvants can induce IgE antibody response and have been associated with allergic reactions in some subjects (see, e.g., Gupta et al., 1998, Drug Deliv. Rev. 32: 155-72; Relyveld et al 1998, Vaccine 16: 1016-23). Many experimental adjuvants have advanced to clinical trials since the development of Alum, and some have demonstrated high potency but have proven too toxic for therapeutic use in humans. Thus, an on-going need exists for safe and potent adjuvants. 35 [0004] Cancer vaccines have been a subject of much attention. Recently, there appears to be an emergin consensus that cancer vaccines are less likely to be successful in the context of high tumor buden/load (see, e.g., Nature Medicine Commentary, 10(12): 1278 (2004) and Cancer Immunol. Immunother., 53(10): 844-54 (2004)). This is attiributed to effective tumor-mediated immune suppression due to the secretion of IL-10, TGF-b, and PGE-2, among others. [0005] On the other hand, recent evidence suggests that immediately after tumor resection or ablation, there is leakage 40 of tumor cells in the peripheral blood. Therefore, the presence of tumor antigen in the context of low tumor burden, without associated immune suppression, may enable re-priming of the immune response. Thus, a need exists for an agent that promotes the long-term anti-tumor immunity, possibly through Th1 type cellular immune responses.

REGULATORY T CELLS (TregCells) 45

[0006] Treg cells refer to a population of specialized T cells that express CD4 and CD25. Treg cells are exceptional in that their main function appears to be suppression of function of other cells. In this regard, Treg cells are also referred to as "suppressor cells." It has been reported that a further defining characteristic of Treg cells is their expression of the transcription factor Foxp3. 50 [0007] Due to the variety of their effect, Treg cells have been a subject of a great deal of interest. It has been reported that Treg cells may influence the outcome of , autoimmunity, transplantation, cancer and allergy. It has been suggested that the modes of suppression employed by Treg cells range from the cytokines IL-10 and TGF-β to cell-cell contact via the inhibitory molecule CTLA-4. Recently, it has been reported that dendritic cells (DC) may induce the activation and proliferation of Treg cells, although DC are recognized as powerful activators of immune response due, 55 in part, to their potency as antigen presentation cells (APC). See Yamazaki et al., J Exp. Med., 198: 235 (2003). [0008] Generally, it is believed that Treg cells suppress the immunity of the host, and thus preventing an immunogen (e.g., a vaccine) from invoking effective immune response in the host. On the other hand, the absence of Treg cells can lead to an outburst of immune response, often resulting in inflammation or autoimmunity. Therefore, to maximize the

3 EP 1 928 492 B1

immunity acquired from an immunogen, a balance needs to be achieved with regard to the level or functionality of Treg cells.

GAMMA DELTA (γδ) T CELLS

5 [0009] Human T cells bearing the γδ T cell receptor represent a unique lymphocyte population with characteristic tissue distribution, being present in organized lymphoid tissue as well as skin- and gut-associated lymphoid tissue. γδ T cells are activated in a non-MHC restricted manner by small phosphorylated non-peptidic metabolites, including the prototypic ligand isopentenyl pyrophosphate (IPP). Some γδ T cell ligands are microbial intermediates from the farnsey- lpyrophosphate synthesis pathway, which is ubiquitous and essential for cell survival. This unique antigen specificity 10 has been suggested to be best suited for activation of sentinel cells independently of antigens derived from individual microbes (De Libero, Immunology Today, 18: 22-26 (1997)). Recent data suggest that y8 T cells play a role in tumor surveillance, for example, of spontaneous B cell lymphomas (Street et al, J Exp Med, 199: 879-884(2004)), since these cells have been shown to recognize intermediates of the melavonate pathway, an essential pathway leading to cholesterol biosynthesis (Gober et al, J Exp Med, 197: 163-168 (2003)). These γδ T cell tumor ligands can be enhanced by treatment 15 with amino-bisphosphonates (nitrogen containing bisphosphoante drugs include pamidronate and zolodronate and are used in myeloma treatment), suggesting that pretreatment with these drugs could sensitize tumor cells to γδ T cell- mediated killing. γδ T cells may also be able to augment anti-tumor immunity by enhancing dendritic cell maturation (Ismaili et al, Clin Immunol, 103: 296-302 (2002)). [0010] In non-cancer settings, γδ T cells play a role in protection from viral infection, e.g., West Nile virus (Wang et 20 al, J Immunol, 171: 2524-2531 (2003)). Also, intraepithelial γδ T cells play a protective role in intestinal inflammation (Chen et al, Proc. Natl. Acad. Sci. U.S.A., 99: 14338-14343 (2002); and Inagaki-Ohara et al, Jlmmunol, 173: 1390-1398 (2004)). Furthermore, γδ TCR-bearing dendritic epidermal cells play a role in wound repair (Jameson et al, Science, 296: 747-749 (2002)).

25 IMMUNOMODULATORY COMPOUNDS

[0011] A number of studies have been conducted with the aim of providing compounds that can safely and effectively be used to treat diseases associated with abnormal production of TNF-α. See, e.g., Marriott, J.B., el al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G.W. Muller, et al., Journal of Medicinal Chemistry, 39(17): 3238-3240 (1996); and G.W. 30 Muller, et al., Bioorganic & Medicinal Chemistry Letters, 8: 2669-2674 (1998). Some studies have focused on a group of compounds selected for their capacity to potently inhibit TNF-α production by LPS stimulated PBMC. L.G. Corral, et al., Ann. Rheum. Dis., 58 (suppl I): 1107-1113 (1999). These compounds, which are referred to as IMiDs® (Celgene Corporation) or Immunomodulatory Drugs, show not only potent inhibition of TNF-α but also marked inhibition of LPS induced monocyte IL1β and IL12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, albeit 35 partially. These compounds are potent stimulators of LPS induced IL 10. Id. Particular examples of IMiDs® include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindoles described and claimed in United States Patent Nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al. [0012] WO 2002/059106 relates to certain isoindole-imide compounds and methods for reducing the level of cytokines and their precursors in mammals. WO 2004/103274 relates to methods of treating, preventing and/or managing cancer 40 as well as diseases and disorders associated with, or characterized by, undesired angiogenesis. [0013] The invention relates to a compound, which is 4-(amino)-2-(2,6-dioxo(3-piperidyl)-isoindoline-1,3-dione or 3-(4- amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, for use in eliciting an enhanced immune response from a vaccine in a subject, wherein the compound is formulated for administering to the subject prior to the induction of the vaccine to the subject. The invention further relates to a compound, which is 4-(amino)-2-(2,6-dioxo(3-piperidyl)-isoin- 45 doline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, for use in enhancing an immune response to a in a subject, wherein the compound is formulated for administering to the subject prior to the administration of the vaccine to the subject. The invention also relates to a compound, which is 4-(amino)-2-(2,6- sioxo(3-piperidyl))-isoindoline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, for use in enhancing an immune response to a vaccine against an infectious disease in a subject, wherein the compound is 50 formulated for administering to the subject prior to the administration of the vaccine to the subject. [0014] The disclosure further encompasses the use of IMiDs® in combination of an immunogen (e.g., a vaccine) in specific dosing regimen, providing an enhanced immune responses from the immunogen as compared to the responses obtained when IMiDs® are not used. [0015] The disclosure also encompasses uses for reducing or inhibiting proliferation or immuno-suppressive activity 55 of Treg cells comprising contacting the Treg cell with an immunomodulatory compound of the invention. [0016] The disclosure also encompasses uses for eliciting an enhanced immune response from an immunogen. The disclosure also encompasses uses for eliciting a reduced allergic response from an allergen. The methods comprise administering an immunomodulatory compound of the invention to a subject prior to the exposure of the subject to an

4 EP 1 928 492 B1

immunogen or an allergen. It should be noted that IMiDs® can be additionally admistered during and/or after the subject’s exposure to the immunogen or allergen. [0017] Pharmaceutical compositions, dosing regimen, and combination using an immunomodulatory com- pound are also described. 5 FIG. 1 is a non-limiting list of vaccines that may be used in connection with uses of this invention. FIG. 2A illustrates the effects of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione on the function of regu- latory T cells. FIG. 2B illustrates the effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione on the function of 10 regulatory T cells. FIG. 2C illustrates the effects of thalidomide on the function of regulatory T cells. FIG. 3 illustrates the effects of immunomodulatory compounds of the invention and thalidomide on the expression of Treg marker Foxp3 (Fig. 3A-DMSO control; Fig. 3B-1mM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-di- one; Fig. 3C-0.01mM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione; Fig. 3D-1mM 3-(4-amino-1-oxo-1,3- 15 dihydro-isoindol-2-yl)-piperidine-2,6-dione; Fig. 3E-0.01mM 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine- 2,6-dione; Fig. 3F-1mM thalidomide; and Fig. 3G-0.01mM thalidomide). FIG. 4 illustrates the effects of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and 3-(4-amino-1-oxo-1,3- dihydro-isoindol-2-yl)-piperidine-2,6-dione on the number of regulatory T cells. FIG. 5A illustrates the effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione on the expression 20 of γδ T cells in PMBC activated with IL-2 and IPP. FIG. 5B illustrates the effects of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione on the expression of γδ T cells in PMBC activated with IL-2 and IPP. FIG. 5C illustrates the effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione on the expression of NKG2D in PMBC activated with IL-2 and IPP. 25 FIG. 5D illustrates the effects of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione on the expression of NKG2D in PMBC activated with IL-2 and IPP. FIG. 6 illustrates the effects of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione on the apoptosis in γδ T cells on day 4 (Fig. 6A), day 5 (Fig. 6B), day 6 (Fig. 6C), and day 7 (Fig. 6D) after the treatment. FIGs. 7A and 7B illustrate the comparison of IFN-γ production in cells treated with αCD3 alone (Fig. 7A) and those 30 treated with αCD3 and 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Fig. 7B) in freshly prepared γδ T cells. FIGs. 7C and 7D illustrate the comparison of TNF-α production in cells treated with αCD3 alone (Fig. 7C) and those treated with αCD3 and 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Fig. 7D) in freshly prepared γδ T cells. 35 FIGs. 7E and 7F illustrate the comparison of IFN-γ production in cells treated with IPP alone (Fig. 7E) and those treated with IPP and 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Fig. 7F) in freshly prepared γδ T cells. FIGs. 7G and 7H illustrate the comparison of TNF-α production in cells treated with IPP alone (Fig. 7G) and those treated with IPP and 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Fig. 7H) in freshly prepared γδ T cells. 40 FIG. 8A illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 0.5:1 ratio) without preincubation with pamidronate. FIG. 8B illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 0.5:1 ratio) without preincubation with pamidronate, but with treatment with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3- dione. 45 FIG. 8C illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T =1:1 ratio) without preincubation with pamidronate. FIG. 8D illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 1:1 ratio) without preincubation with pamidronate, but with treatment with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione. FIG. 8E illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 2:1 ratio) without 50 preincubation with pamidronate. FIG. 8F illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 2:1 ratio) without preincubation with pamidronate, but with treatment with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione. FIG. 8G illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 0.5:1 ratio) with preincubation with pamidronate. 55 FIG. 8H illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 0.5:1 ratio) with preincubation with pamidronate and treatment with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione. FIG. 8I illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 1:1 ratio) with preincubation with pamidronate.

5 EP 1 928 492 B1

FIG. 8J illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 1:1 ratio) with preincubation with pamidronate and treatment with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione. FIG. 8K illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 2:1 ratio) with preincubation with pamidronate. 5 FIG. 8L illustrates the IFN-γ production in response to co-culture with RPMI cells with (tumor:γδ T = 2: ratio) with preincubation with pamidronate and treatment with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione. FIG. 9A illustrates the effects of immunomodulatory compounds of the invention on the cytotoxicity of γδ T cells on MM cell lines where the compounds are preincubated with tumor cells. FIG. 9B illustrates the effects of immunomodulatory compounds of the invention on the cytotoxicity of γδ T cells on 10 MM cell lines where the compounds are not preincubated with tumor cells, but are added during the chromium release assay only.

[0018] This invention is based, in part, on the inventors’ discovery that pre-treatment with immunomodulatory com- pounds of the invention, before the introduction of an immunogen (e.g., a vaccine) results in an enhanced immune 15 response in a host, as determined by the experiments decribed herein. Without being limited by a particular theory, the disclosure encompasses administration of an immunomodulatory compound to a host, preferably prior to the introduction of an immunogen, to enhance the function of dendritic cells as antigen presentation cells and/or suppress the proliferation and/or function of Treg cells, resulting in an enhanced immune response in the host. In addition, without being limited by a particular theory, immunomodulatory compounds of the invention augment the innate anti-tumor acitivity of γδ T 20 cells. Furthermore, without being limited by a particular theory, it is also believed that the immunomodulatory compounds of the invention promote successful Th1 type cellular immune responses necessary for efficient long-term anti-tumor activity, thereby delaying or prevent tumor reccurence. [0019] Accordingly, the disclosure encompasses uses for reducing or inhibiting proliferation and/or immuno-suppres- sive activity of regulatory T cells comprising contacting the regulatory T cells with an immunomodulatory compound for 25 a time sufficient for the reduction or the inhibition of proliferation and/or immuno-suppressive activity. [0020] As used herein, and unless otherwise specified, the term "reducing or inhibiting the proliferation," when used in connection with regulatory T cells, means that the number of regulatory T cells in a cell culture or a host treated with an immunomodulatory compound disclosed herein is less than the number of regulatory T cells in a cell culture or a host without the treatment with an immunomodulatory compound disclosed herein, as determined by methods known 30 in the art, some of which are described herein. A typical method involves the staining of a marker and analysis of the stain using, for example, FACS analysis. Preferably, reduced proliferation means the number of T cells in immunomod- ulatory compound treated culture or host is about 10%, 20%, 30%, 50%, 70%, or 90% or less than those in the culture or host without such treatment. [0021] As used herein, and unless otherwise specified, the term "reducing or inhibiting the immuno-suppressive 35 activity," when used in connection with regulatory T cells, means that the immuno-suppressive activity of regulatory T cells, when treated or contacted with an immunomodulatory compound disclosed herein, is lower than those without such treatment or contact. The immuno-suppressive activity can be determined using methods known in the art including those described herein. Typically, the immuno-suppressive activity of regulatory T cells can be assessed by monitoring the proliferation of, for example, anti-CD3 stimulated CD25- cells in response to TCR signal. Preferably, reduced immuno- 40 suppressive activity means the activity of regulatory T cells treated with an immunomodulatory compound disclosed herein is about 10%, 20%, 30%, 50%, 70%, or 90% or less than the activity of those without such treatment. [0022] This invention also encompasses uses for eliciting an enhanced immune response from an immunogen in a subject (e.g., human) comprising administering to the subject an immunomodulatory compound of the invention prior to the administration of the immunogen to the subject. 45 [0023] As used herein, and unless otherwise specified, the term ‘‘immunogen" means any substance or organism that provokes an immune response (produces immunity) when introduced to the body. In some embodiments, an im- munogen can be used in therapeutic settings in a form of a vaccine. [0024] As used herein, and unless otherwise specified, the term ‘‘enhanced immune response" means that, when an immunogen is administered in combination with an immunomodulatory compound according to uses of this invention, 50 there is an increased antibody formation, measured using any standard methods known in the art or described herein, in a subject that receives such an administration as compared to a subject to which same amount of the immunogen alone is administered. As used herein, the term ‘’administration in combination with," used in connection with two or more therapeutic agents, means that such agents are administered simultaneously, concurrently, or sequentially using the same or different routes. Preferably, an enhanced immune response means about 10%, 20%, 30%, 50%, 70%, or 55 100% or greater increase in antibody formation. [0025] In specific embodiments, an immunomodulatory compound is administered to a subject about 30 days, 20 days, 15 days, 12 days, 10 days, 7 days, 5 days, 3 days, 1 day, 12 hours, or 5 hours prior to the administration of the immunogen. In other embodiments, an immunomodulatory compound is administered from about 30 days to about 5

6 EP 1 928 492 B1

hours, from about 20 days to about 5 hours, from about 15 days to about 12 hours, from about 12 days to about 5 hours, from about 10 days to about 12 hours, from about 7 days to about 12 hours, from about 5 days to about 12 hours, from about 5 days to about 1 day, from about 3 days to about 12 hours, or from about 3 days to about 1 day prior to the administration of an immunogen. 5 [0026] In other embodiments, uses of the invention further comprises a second administration of an immunomodulatory compound of the invention after the administration of an immunogen. Without being limited by a particular theory, it is believed that administering an immunomodulatory compound after the administration of an immunogen can enhance the immune response obtained from the immunogen by improving antigen presentation of host cells, enhancing the activity of T cells (e.g., αβ and γδ TCR positive), and generating cytotoxic effector response and long term memory (e.g., 10 The type) immune response. In these embodiments, there are at least two administrations of an immunomodulatory compound of the invention -- one pre-immunogen and one post-immunogen. [0027] In specific embodiments, an immunomodulatory compound of the invention is administered to a subject about 30 days, 20 days, 15 days, 12 days, 10 days, 7 days, 5 days, 3 days, 1 day, 12 hours, or 5 hours after the administration of the immunogen. In other embodiments, an immunomodulatory compound of the invention is administered from about 15 5 hours to about 30 days, from about 5 hours to about 20 days, from about 12 hours to about 15 days, from about 5 hours to about 12 days, from about 12 hours to about 10 days, from about 12 hours to about 7 days, from about 12 hours to about 5 days, from about 1 day to about 5 days, from about 12 hours to about 3 days, or from about 1 day to about 3 days after the administration of an immunogen. [0028] In another aspect, the disclosure encompasses uses for eliciting a reduced allergic response in a subject 20 comprising administering to the subject an immunomodulatory compound disclosed herein prior to the subject’s exposure to an allergen. As used herein, the term "subject’s exposure to allergen" encompasses a subject’s exposure to an allergen which is foreseeable (e.g., intake of food or exposure to the naturally occurring allergens), as well as allergy vaccination where an allergen is administered to a subject according to a dosing scheme over a period of time. Without being limited by a particular theory, it is believed that immunomodulatory compounds not only preferentially induce The 25 immune response, but also inhibit and/or reverse Th2 differentiation, resulting in milder, non-acute immune response to an allergen mediated by Th1 cells. [0029] In specific embodiments, an immunomodulatory compound is administered to a subject about 30 days, 20 days, 15 days, 12 days, 10 days, 7 days, 5 days, 3 days, 1 day, 12 hours, 5 hours, 2 hours, or 30 minutes prior to the subject’s exposure to an allergen. In other embodiments, an immunomodulatory compound is administered from about 30 30 days to about 30 minutes, from about 20 days to about 1 hour, from about 15 days to about 1 hour, from about 12 days to about 30 minutes, from about 10 days to about 2 hours, from about 7 days to about 2 hours, from about 5 days to about 2 hours, from about 5 days to about 1 hour, from about 1 day to about 30 minutes, or from about 1 day to about 2 hours prior to the subject’s exposure to an allergen. [0030] In other embodiments, uses disclosed herein further comprises a second administration of an immunomodu- 35 latory compound after the subject’s exposure to an allergen. Without being limited by a particular theory, it is believed that administering an immunomodulatory compound after the subject’s exposure to an allergen can generate long term memory (e.g., Th1 type) immune response. In these embodiments, there are at least two administrations of an immu- nomodulatory compound - one pre-allergen and one post-allergen. [0031] In specific embodiments, an immunomodulatory compound is administered to a subject about 30 days, 20 40 days, 15 days, 12 days, 10 days, 7 days, 5 days, 3 days, 1 day, 12 hours, or 5 hours after the subject’s exposure to an allergen. In other embodiments, an immunomodulatory compound is administered from about 5 hours to about 30 days, from about 5 hours to about 20 days, from about 12 hours to about 15 days, from about 5 hours to about 12 days, from about 12 hours to about 10 days, from about 12 hours to about 7 days, from about 12 hours to about 5 days, from about 1 day to about 5 days, from about 12 hours to about 3 days, or from about 1 day to about 3 days after the subject’s 45 exposure to an allergen.

IMMUNOGENS AND VACCINES

[0032] Various immunogens may be used in connection with uses of this invention. The immunogens are usually 50 administered to a subject in a form of an immunogenic composition (e.g., a vaccine), but may be administered in any form that is acceptable for use in animals, in particular, humans.

Immunogens

55 [0033] Immunogens that may be used in the immunogenic compositions include antigens from an animal, a plant, a bacteria, a protozoan, a parasite, a virus or a combination thereof. Immunogens may be any substance that under appropriate conditions results in an immune response in a subject, including, but not limited to, polypeptides, peptides, proteins, glycoproteins, lipids, nucleic acids (e.g., RNAs and DNAs) and polysaccharides.

7 EP 1 928 492 B1

[0034] An immunogenic composition may comprise one or more immunogens. The amount of the immunogen used in the compositions may vary depending on the chemical nature and the potency of the immunogen. [0035] Immunogens may be any viral peptide, protein, polypeptide, or a fragment thereof, derived from a virus. [0036] Immunogens used in uses of the invention may be an antigen of a pathogenic virus such as, but are not limited 5 to: adenovirdiae (e.g., mastadenovirus and aviadenovirus), herpesviridae (e.g., herpes simplex virus 1, herpes simplex virus 2, herpes simplex virus 5, and herpes simplex virus 6), leviviridae (e.g., levivirus, enterobacteria phase MS2, allolevirus), poxviridae (e.g., chordopoxvirinae, parapoxvirus, avipoxvirus, capripoxvirus, leporipoxvirus, suipoxvirus, molluscipoxvirus, and entomopoxvirinae), papovaviridae (e.g., polyomavirus and papillomavirus), paramyxoviridae (e.g., paramyxovirus, parainfluenza virus 1, mobillivirus (e.g., measles virus), rubulavirus (e.g., mumps virus), pneumonovirinae 10 (e.g., pneumovirus, human respiratory syncytial virus), and metapneumovirus (e.g., avian pneumovirus and human metapneumovirus), picomaviridae (e.g., enterovirus, rhinovirus, hepatovirus (e.g., human hepatitis A virus), cardiovirus, and apthovirus, reoviridae (e.g., orthoreovirus, orbivirus, rotavirus, cypovirus, fijivirus, phytoreovirus, and oryzavirus), retroviridae (e.g., mammalian type B retroviruses, mammalian type C retroviruses, avian type C retroviruses, type D retrovirus group, BLV-HTLV retroviruses, lentivirus (e.g. human immunodeficiency virus 1 and human immunodeficiency 15 virus 2), spumavirus), flaviviridae (e.g., hepatitis C virus), hepadnaviridae (e.g., hepatitis B virus), togaviridae (e.g., alphavirus, e.g., sindbis virus) and rubivirus (e.g., rubella virus), rhabdoviridae (e.g., vesiculovirus, lyssavirus, ephemero- virus, cytorhabdovirus, and necleorhabdovirus), arenaviridae (e.g., arenavirus, lymphocytic choriomeningitis virus, Ippy virus, and lassa virus), and coronaviridae (e.g., coronavirus and torovirus). [0037] Immunogens used in uses of this invention may be an infectious disease agent including, but not limited to, 20 influenza virus hemagglutinin (Genbank Accession No. JO2132 Air, 1981, Proc. Natl. Acad. Sci. USA 78: 7639-7643; Newton et al., 1983, Virology 128: 495-501), human respiratory syncytial virus G glycoprotein (Genbank Accession No. Z33429; Garcia et al., 1994, J. Virol.; Collins et al., 1984, Proc. Natl. Acad Sci. USA 81: 7683), core protein, matrix protein or any other protein of Dengue virus (Genbank Accession No. M19197; Hahn et al., 1988, Virology 162: 167-180), measles virus hemagglutinin (Genbank Accession No. M81899; Rota et al., 1992, Virology 188: 135-142), herpes simplex 25 virus type 2 glycoprotein gB (Genbank Accession No. M14923; Bzik et al., 1986, Virology 155:322-333), poliovirus I VP1 (Emini et al., 1983, Nature 304:699), envelope glycoproteins of HIV I (Putney et al., 1986, Science 234: 1392-1395), hepatitis B surface antigen (Itoh et al., 1986, Nature 308: 19; Neurath et al., 1986, Vaccine 4: 34), diptheria toxin (Audibert et al., 1981, Nature 289: 543), streptococcus 24M epitope (Beachey, 1985, Adv. Exp. Med. Biol. 185:193), gonococcal pilin (Rothbard and Schoolnik, 1985, Adv. Exp. Med. Biol. 185:247), pseudorabies virus g50 (gpD), pseudorabies virus 30 II (gpB), pseudorabies virus gIII (gpC), pseudorabies virus glycoprotein H, pseudorabies virus glycoprotein E, transmis- sible gastroenteritis glycoprotein 195, transmissible gastroenteritis matrix protein, swine rotavirus glycoprotein 38, swine parvovirus capsid protein, Serpulina hydodysenteriae protective antigen, bovine viral diarrhea glycoprotein 55, Newcastle disease virus hemagglutinin-neuraminidase, swine flu hemagglutinin, swine flu neuraminidase, foot and mouth disease virus, hog cholera virus, swine influenza virus, African swine virus, Mycoplasma hyopneumoniae, infectious bovine 35 rhinotracheitis virus (e.g., infectious bovine rhinotracheitis virus glycoprotein E or glycoprotein G), or infectious laryn- gotracheitis virus (e.g., infectious laryngotracheitis virus glycoprotein G or glycoprotein I), a glycoprotein of La Crosse virus (Gonzales-Scarano et al., 1982, Virology 120: 42), neonatal calf diarrhea virus (Matsuno and Inouye, 1983, Infection and Immunity 39: 155), Venezuelan equine encephalomyelitis virus (Mathews and Roehrig, 1982, J Immunol. 129: 2763), punta toro virus (Dalrymple et al., 1981, in Replication of Negative Strand Viruses, Bishop and Compans (eds.), 40 Elsevier, NY, p. 167), murine leukemia virus (Steeves et al. , 1974, J. Virol. 14:187), mouse mammary tumor virus (Massey and Schochetman, 1981, Virology 115: 20), hepatitis B virus core protein and/or hepatitis B virus surface antigen or a fragment or derivative thereof (see, e.g., U.K. Patent Publication No. GB 2034323A published June 4, 1980; Ganem and Varmus, 1987, Ann. Rev. Biochem. 56:651-693; Tiollais et al., 1985, Nature 317:489-495), antigen of equine influenza virus or equine herpesvirus (e.g., equine influenza virus type A/Alaska 91 neuraminidase, equine influenza virus type 45 A/Miami 63 neuraminidase, equine influenza virus type A/Kentucky 81 neuraminidase equine herpesvirus type 1 glyc- oprotein B, and equine herpesvirus type 1 glycoprotein D, antigen of bovine respiratory syncytial virus or bovine parain- fluenza virus (e.g., bovine respiratory syncytial virus attachment protein (BRSV G), bovine respiratory syncytial virus fusion protein (BRSV F), bovine respiratory syncytial virus nucleocapsid protein (BRSV N), bovine parainfluenza virus type 3 fusion protein, and the bovine parainfluenza virus type 3 hemagglutinin neuraminidase), bovine viral diarrhea 50 virus glycoprotein 48 or glycoprotein 53. [0038] Immunogens used in uses of this invention may also be a cancer antigen or a tumor antigen. Any cancer or tumor antigen known to one skilled in the art may be used in accordance with the immunogenic compositions of the invention including, but not limited to, KS 1/4 pan-carcinoma antigen (Perez and Walker, 1990, J. Immunol. 142: 3662-3667; Bumal, 1988, Hybridoma 7(4): 407-415), ovarian carcinoma antigen (CA125) (Yu et al., 1991, Cancer Res. 55 51(2): 468-475), prostatic acid phosphate (Tailor et al., 1990, Nucl. Acids Res. 18(16): 4928), specific antigen (Henttu and Vihko, 1989, Biochem. Biophys. Res. Comm. 160(2): 903-910; Israeli et al., 1993, Cancer Res. 53: 227-230), melanoma-associated antigen p97 (Estin et al., 1989, J. Natl. Cancer Instit. 81(6): 445-446), melanoma antigen gp75 (Vijayasardahl et al., 1990, J. Exp. Med. 171(4): 1375-1380), high molecular weight melanoma antigen (HMW-MAA)

8 EP 1 928 492 B1

(Natali et al., 1987, Cancer 59: 55-63; Mittelman et al., 1990, J Clin. Invest. 86: 2136-2144), prostate specific membrane antigen, carcinoembryonic antigen (CEA) (Foon et al., 1994, Proc. Am. Soc. Clin. Oncol. 13: 294), polymorphic epithelial mucin antigen, human milk fat globule antigen, colorectal tumor-associated antigens such as: CEA, TAG-72 (Yokata et al., 1992, Cancer Res. 52: 3402-3408), CO17-1A (Ragnhammar et al., 1993, Int. J. Cancer 53: 751-758); GICA 19-9 5 (Herlyn et al., 1982, J Clin. Immunol. 2: 135), CTA-1 and LEA, Burkitt’s lymphoma antigen-38.13, CD19 (Ghetie et al., 1994, Blood 83: 1329-1336), human B-lymphoma antigen-CD20 (Reff et al., 1994, Blood 83: 435-445), CD33 (Sgouros et al., 1993, J. Nucl. Med. 34: 422-430), melanoma specific antigens such as ganglioside GD2 (Saleh et al., 1993, J. Immunol., 151, 3390-3398), ganglioside GD3 (Shitara et al., 1993, Cancer Immunol. Immunother. 36: 373-380), gan- glioside GM2 (Livingston et al., 1994, J Clin. Oncol. 12: 1036-1044), ganglioside GM3 (Hoon et al., 1993, Cancer Res. 10 53: 5244-5250), tumor-specific transplantation type of cell-surface antigen (TSTA) such as virally-induced tumor antigens including T-antigen DNA tumor viruses and Envelope antigens of RNA tumor viruses, oncofetal antigen-alpha-fetoprotein such as CEA of colon, bladder tumor oncofetal antigen (Hellstrom et al., 1985, Cancer. Res. 45: 2210-2188), differentiation antigen such as human lung carcinoma antigen L6, L20 (Hellstrom et al., 1986, Cancer Res. 46: 3917-3923), antigens of fibrosarcoma, human leukemia T cell antigen-Gp37 (Bhattacharya-Chatterjee et al., 1988, J. of Immunospecifically. 15 141: 1398-1403), neoglycoprotein, sphingolipids, breast cancer antigen such as EGFR (Epidermal growth factor recep- tor), HER2 antigen (p 185HER2), polymorphic epithelial mucin (PEM) (Hilkens et al., 1992, Trends in Bio. Chem. Sci. 17: 359), malignant human lymphocyte antigen-APO-1 (Bernhard et al., 1989, Science 245: 301-304), differentiation antigen (Feizi, 1985, Nature 314: 53-57) such as I antigen found in fetal erythrocytes, primary endoderm, I antigen found in adult erythrocytes, preimplantation embryos, I (Ma) found in gastric adenocarcinomas, M18, M39 found in breast epithelium, 20 SSEA-1 found in myeloid cells, VEP8, VEP9, Myl, VIM-D5, D156-22 found in , TRA-1-85 (blood group H), C14 found in colonic adenocarcinoma, F3 found in lung adenocarcinoma, AH6 found in gastric cancer, Y hapten, y Le found in embryonal carcinoma cells, TL5 (blood group A), EGF receptor found in A431 cells , E1 series (blood group B) found in , FC10.2 found in embryonal carcinoma cells, gastric adenocarcinoma antigen, CO-514 (blood group Lea) found in Adenocarcinoma, NS-10 found in adenocarcinomas, CO-43 (blood group Leb), G49 found 25 in EGF receptor of A431 cells, MH2 (blood group ALeb/Ley) found in colonic adenocarcinoma, 19.9 found in colon cancer, gastric cancer mucins, T5A7 found in myeloid cells, R24 found in melanoma, 4.2, GD3, D1.1, OFA-1, GM2, OFA-2, GD2, and M1:22:25:8 found in embryonal carcinoma cells, and SSEA-3 and SSEA-4 found in 4 to 8-cell stage embryos. In one embodiment, the antigen is a T cell receptor derived peptide from a Cutaneous T cell Lymphoma (see, Edelson, 1998, The Cancer Journal 4: 62). 30 [0039] In a preferred embodiment, the immunogenic composition used in uses of this invention is a cancer vaccine. Examples of cancer vaccines include, but are not limited to: antigen modified denritic cell (DC) vaccines such as, but not limited to, Provenge, Neuvenge, Immunovex, Telomerase vaccine, Uvidem, Collidem, DCVax-prostate, and DCVax- brain; peptide vaccines such as, but not limited to, Theratope, L-BLP25, Oncophage (HSPPC-96), GTOPO-99, IGN- 101, FavId, Panvac-VF, Prostvac-VF, Avicine, EP-2101, MyVax, Biovaxid, Mitumomab (IMC-BEC2), IMG-GP75, HER- 35 2 DNA/Protein AutoVac, Zyc 300, and HER-2 protein AutoVac; whole tumor cell vaccines such as, but not limited to, Canvaxin, Ony-P, Melacine, GVAX, GVAX and MDX-010, and Oncovax; and viral vector vaccines such as, but not limited to, ALVAC-CEA/B&1, Allovectin-7, ALVAC, Lovaxin C, AdhTAP(OS-1), TroVax, and MVA-MUC1-IL2 (TG4010). Characteristics of these vaccines are summarized in Tables 1-4. [0040] Immunogens may comprise a virus, against which an immune response is desired. In certain cases, the im- 40 munogenic composition used in methods of this invention comprise recombinant or chimeric viruses. In other.cases, the immunogenic composition comprises a virus which is attenuated. Production of recombinant, chimeric and attenuated viruses may be performed using standard methods known to one skilled in the art. This invention also encompasses a live recombinant viral vaccine or an inactivated recombinant viral vaccine to be formulated in accordance with the invention. A live vaccine may be preferred because multiplication in the host leads to a prolonged stimulus of similar 45 kind and magnitude to that occurring in natural infections, and therefore, confers substantial, long-lasting immunity. Production of such live recombinant virus vaccine formulations may be accomplished using conventional methods involving propagation of the virus in cell culture or in the allantois of the chick embryo followed by purification. [0041] Recombinant virus may be non-pathogenic to the subject to which it is administered. In this regard, the use of genetically engineered viruses for vaccine purposes may require the presence of attenuation characteristics in these 50 strains. The introduction of appropriate mutations (e.g., deletions) into the templates used for transfection may provide the novel viruses with attenuation characteristics. For example, specific missense mutations which are associated with temperature sensitivity or cold adaptation can be made into deletion mutations. These mutations should be more stable than the point mutations associated with cold or temperature sensitive mutants and reversion frequencies should be extremely low. 55 [0042] Alternatively, chimeric viruses with "suicide" characteristics may be constructed for use in the immunogenic compositions. Such viruses would go through only one or a few rounds of replication within the host. When used as a vaccine, the recombinant virus would go through limited replication cycle(s) and induce a sufficient level of immune response but it would not go further in the human host and cause disease.

9 EP 1 928 492 B1

[0043] Alternatively, inactivated (killed) virus may be formulated in accordance with the invention. formulations may be prepared using conventional techniques to "kill" the chimeric viruses. Inactivated vaccines are "dead" in the sense that their infectivity has been destroyed. Ideally, the infectivity of the virus is destroyed without affecting its immunogenicity. In order to prepare inactivated vaccines, the chimeric virus may be grown in cell culture or 5 in the allantois of the chick embryo, purified by zonal ultracentrifugation, inactivated by formaldehyde or β-propiolactone, and pooled. [0044] Completely foreign epitopes, including antigens derived from other viral or non-viral pathogens can also be engineered into the virus for use in immunogenic compositions. For example, antigens of non-related viruses such as HIV (gp160, gp120, gp41) parasite antigens (e.g., malaria), bacterial or fungal antigens or tumor antigens can be 10 engineered into the attenuated strain. Typically such methods include inoculating embryonated eggs, harvesting the allantoic fluid, concentrating, purifying and separating the whole virus, using for example zonal centrifugation, ultracen- trifugation, ultrafiltration, and chromatography in a variety of combinations. [0045] Virtually any heterologous gene sequence may be constructed into the chimeric viruses for use in immunogenic compositions. Preferably, heterologous gene sequences are moieties and peptides that act as biological response 15 modifiers. Preferably, epitopes that induce a protective immune response to any of a variety of pathogens, or antigens that bind neutralizing may be expressed by or as part of the chimeric viruses. For example, heterologous gene sequences that can be constructed into the chimeric viruses include, but are not limited to, influenza and parain- fluenza hemagglutinin neuraminidase and fusion glycoproteins such as the HN and F genes of human PIV3. In addition, heterologous gene sequences that can be engineered into the chimeric viruses include those that encode proteins with 20 immuno-modulating activities. Examples of immuno-modulating proteins include, but are not limited to, cytokines, inter- feron type 1, gamma interferon, colony stimulating factors, interleukin -1, -2, -4, -5, -6, -12, and antagonists of these agents. [0046] Other heterologous sequences may be derived from tumor antigens, and the resulting chimeric viruses be used to generate an immune response against the tumor cells leading to tumor regression in vivo. In accordance with the present invention, recombinant viruses may be engineered to express tumor-associated antigens (TAAs), including 25 but not limited to, human tumor antigens recognized by T cells (Robbins and Kawakami, 1996, Curr. Opin. Immunol. 8: 628-636, incorporated herein by reference in its entirety); melanocyte lineage proteins, including gp100, MART-1/MelanA, TRP-1 (gp75) and tyrosinase; tumor-specific widely shared antigens, such as MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-1, N-acetylglucosaminyltransferase-V and p15; tumor-specific mutated antigens, such as β-catenin, MUM-1 and CDK4; non-melanoma antigens for breast, ovarian, cervical and pancreatic carcinoma, HER-2/neu, human papilloma- 30 virus -E6, -E7, MUC-1.

Vaccines and Target Diseases

[0047] A wide variety of vaccines may be used in connection with uses of this invention. A non-limiting list of vaccines 35 that can be used in connection with this invention is provided in FIG. 1. Target diseases for uses of the invention include cancer, other infectious or inflammatory diseases. [0048] Uses of the invention can be for the treatment of , including, but not limited to, neoplasms, tumors, metastases, or any disease or disorder characterized by uncontrolled cell growth. Specific examples of cancer include, but are not limited to: cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; 40 lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and AIDS-related cancers. Methods of the invention are particularly useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, myelocytic leukemias, and myelodysplastic syndromes including but not limited to 5q minus syndrome, or myelodysplastic syndromes associated with other cytogenic abnormalities. The uses 45 of the invention can be for treating, preventing or managing either primary or metastatic tumors. [0049] Other specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable color- 50 ectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodg- kin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B- Cell lymphoma, low grade follicular lymphoma, metastatic melanoma (localized melanoma, including, but not limited to, ocular melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans 55 cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory , resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, -insensitive prostate cancer,

10 EP 1 928 492 B1

papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. In a specific embodiment, the cancer is metastatic. In another embodiment, the cancer is refractory or resistance to chemotherapy or radiation. [0050] Infectious diseases are caused by infectious agents such as, but not limited to, viruses, bacteria, fungi protozoa, 5 helminths, and parasites. [0051] Examples of viruses that have been found in humans include, but are not limited to, Retroviridae (e.g., human immunodeficiency viruses, such as HIV-1 (also referred to as HTLV-III, LAV or HTLV-III/LAV, or HIV-III; and other isolates, such as HIV-LP); Picornaviridae (e.g., polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g., strains that cause gastroenteritis); Togaviridae (e.g., equine encephalitis 10 viruses, rubella viruses); Flaviridae (e.g., dengue viruses, encephalitis viruses, yellow fever viruses); Coronaviridae (e.g., coronaviruses); Rhabdoviridae (e.g., vesicular stomatitis viruses, rabies viruses); Filoviridae (e.g., ebola viruses); Paramyxoviridae (e.g., parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus); Orthomyxoviridae (e.g., influenza viruses); Bungaviridae (e.g., Hantaan viruses, bunga viruses, phleboviruses and Nairo viruses); Arena viridae (e.g., hemorrhagic fever viruses); Reoviridae (e.g., reoviruses, orbiviurses and rotaviruses); Bimaviridae; Hepad- 15 naviridae (Hepatitis B virus); Parvovirida (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adeno- viridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus); Poxviridae (variola viruses, viruses, pox viruses); and Iridoviridae (e.g., African swine fever virus); and unclassified viruses (e.g., the etiological agents of Spongiform encephalopathies, the agent of delta hepatitis (thought to be a defective satellite of hepatitis B virus), the agents of non-A, non-B hepatitis (class 1=internally 20 transmitted; class 2=parenterally transmitted, e.g., Hepatitis C); Norwalk and related viruses, and astroviruses. [0052] Retroviruses that results in infectious diseases in animals and humans include both simple retroviruses and complex retroviruses. The simple retroviruses include the subgroups of B-type retroviruses, C-type retroviruses and D- type retroviruses. An example of a B-type retrovirus is mouse mammary tumor virus (MMTV). The C-type retroviruses include subgroups C-type group A (including Rous sarcoma virus (RSV), avian leukemia virus (ALV), and avian mye- 25 loblastosis virus (AMV)) and C-type group B (including murine leukemia virus (1VB,V), feline leukemia virus (FeLV), murine sarcoma virus (MSV), gibbon ape leukemia virus (GALV), spleen necrosis virus (SNV), reticuloendotheliosis virus (RV) and simian sarcoma virus (SSV)). The D-type retroviruses include Mason-Pfizer monkey virus (MPMV) and simian retrovirus type 1 (SRV-1). The complex retroviruses include the subgroups of lentiviruses, T-cell leukemia viruses and the foamy viruses. Lentiviruses include HIV-1, but also include HIV-2, SIV, Visna virus, feline immunodeficiency 30 virus (FIV), and equine infectious anemia virus (EIAV). The T-cell leukemia viruses include HTLV-1, HTLV-11, simian T-cell leukemia virus (STLV), and bovine leukemia virus (BLV). The foamy viruses include human foamy virus (HFV), simian foamy virus (SFV) and bovine foamy virus (BFV). [0053] Examples of RNA viruses that are antigenic or immunogenic in vertebrate animals include, but are not limited to, the following: members of the family Reoviridae, including the genus Orthoreovirus (multiple serotypes of both 35 mammalian and avian retroviruses), the genus Orbivirus (Bluetongue virus, Eugenangee virus, Kemerovo virus, African horse sickness virus, and Colorado Tick Fever virus), the genus Rotavirus (human rotavirus, Nebraska calf diarrhea virus, murine rotavirus, simian rotavirus, bovine or ovine rotavirus, avian rotavirus); the family Picornaviridae, including the genus Enterovirus (poliovirus, Coxsackie virus A and B, enteric cytopathic human orphan (ECHO) viruses, hepatitis A virus, Simian enteroviruses, Murine encephalomyelitis (ME) viruses, Poliovirus muris, Bovine enteroviruses. Porcine 40 enteroviruses), the genus Cardiovirus (Encephalomyocarditis virus (EMC), Mengovirus), the genus Rhinovirus (Human rhinoviruses including at least 113 subtypes; other rhinoviruses), the genus Apthovirus (Foot and Mouth disease (FMDV); the family Calciviridae, including Vesicular exanthema of swine virus, San Miguel sea lion virus, Feline picornavirus and Norwalk virus; the family Togaviridae, including the genus Alphavirus (Eastern equine encephalitis virus, Semliki forest virus, Sindbis virus, virus, O’Nyong-Nyong virus, Ross river virus Venezuelan equine encephalitis virus, 45 Western equine encephalitis virus), the genus Flavirius (Mosquito borne yellow fever virus, Dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus, West Nile virus, Kunjin virus, Central European tick borne virus, Far Eastern tick borne virus, Kyasanur forest virus, Louping III virus, Powassan virus, Omsk hemorrhagic fever virus), the genus Rubivirus (Rubella virus), the genus Pestivirus (Mucosal disease virus, Hog cholera virus, Border disease virus); the family Bunyaviridae, including the genus Bunyvirus (Bunyamwera and related viruses, 50 California encephalitis group viruses), the genus Phlebovirus (Sandfly fever Sicilian virus, Rift Valley fever virus), the genus Nairovirus (Crimean-Congo hemorrhagic fever virus, Nairobi sheep disease virus), and the genus Uukuvirus (Uukuniemi and related viruses); the family Orthomyxoviridae, including the genus Influenza virus (Influenza virus type A (many human subtypes), Swine influenza virus, and Avian and Equine Influenza viruses, influenza type B (many human subtypes), and influenza type C (possible separate genus)); the family paramyxoviridae, including the genus 55 Paramyxovirus (Parainfluenza virus type 1, Sendai virus, Hemadsorption virus, Parainfluenza viruses types 2 to 5, Newcastle Disease Virus, Mumps virus), the genus Morbillivirus (Measles virus, subacute sclerosing panencephalitis virus, distemper virus, Rinderpest virus), the genus Pneumovirus (respiratory syncytial virus (RSV), Bovine respiratory syncytial virus and Pneumonia virus of mice); forest virus, Sindbis virus, Chikungunya virus, O’Nyong-Nyong virus, Ross

11 EP 1 928 492 B1

river virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus), the genus Flavirius (Mosquito borne yellow fever virus, Dengue virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley encepha- litis virus, West Nile virus, Kunjin virus, Central European tick borne virus, Far Eastern tick borne virus, Kyasanur forest virus, Louping III virus, Powassan virus, Omsk hemorrhagic fever virus), the genus Rubivirus (Rubella virus), the genus 5 Pestivirus (Mucosal disease virus, Hog cholera virus, Border disease virus); the family Bunyaviridae, including the genus Bunyvirus (Bunyamwera and related viruses, California encephalitis group viruses), the genus Phlebovirus (Sandfly fever Sicilian virus, Rift Valley fever virus), the genus Nairovirus (Crimean-Congo hemorrhagic fever virus, Nairobi sheep disease virus), and the genus Uukuvirus (Uukuniemi and related viruses); the family Orthomyxoviridae, including the genus Influenza virus (Influenza virus type A, many human subtypes); Swine influenza virus, and Avian and Equine 10 Influenza viruses; influenza type B (many human subtypes), and influenza type C (possible separate genus); the family paramyxoviridae, including the genus Paramyxovirus (Parainfluenza virus type 1, Sendai virus, Hemadsorption virus, Parainfluenza viruses types 2 to 5, Newcastle Disease Virus, Mumps virus), the genus Morbillivirus (Measles virus, subacute sclerosing panencephalitis virus, distemper virus, Rinderpest virus), the genus Pneumovirus (respiratory syn- cytial virus (RSV), Bovine respiratory syncytial virus and Pneumonia virus of mice); the family Rhabdoviridae, including 15 the genus Vesiculovirus (VSV), Chandipura virus, Flanders-Hart Park virus), the genus Lyssavirus (Rabies virus), fish Rhabdoviruses, and two probable Rhabdoviruses (Marburg virus and Ebola virus); the family Arenaviridae, including Lymphocytic choriomeningitis virus (LCM), Tacaribe virus complex, and Lassa virus; the family Coronoaviridae, including Infectious Bronchitis Virus (IBV), Mouse Hepatitis virus, Human enteric corona virus, and Feline infectious peritonitis (Feline coronavirus). 20 [0054] Illustrative DNA viruses that are antigenic or immunogenic in vertebrate animals include, but are not limited to: the family Poxviridae, including the genus Orthopoxvirus (Variola major, Variola minor, Monkey pox Vaccinia, Cowpox, Buffalopox, Rabbitpox, Ectromelia), the genus Leporipoxvirus (Myxoma, Fibroma), the genus Avipoxvirus (Fowlpox, other avian poxvirus), the genus Capripoxvirus (sheeppox, goatpox), the genus Suipoxvirus (Swinepox), the genus Parapoxvirus (contagious postular dermatitis virus, pseudocowpox, bovine papular stomatitis virus); the family Iridoviri- 25 dae (African swine fever virus, Frog viruses 2 and 3, Lymphocystis virus of fish); the family Herpesviridae, including the alpha-Herpesviruses (Herpes Simplex Types 1 and 2, Varicella-Zoster, Equine abortion virus, Equine herpes virus 2 and 3, pseudorabies virus, infectious bovine keratoconjunctivitis virus, infectious bovine rhinotracheitis virus, feline rhinotracheitis virus, infectious laryngotracheitis virus), the Beta-herpesviruses (Human cytomegalovirus and cytomeg- aloviruses of swine, monkeys and rodents), the gamma-herpesviruses (Epstein-Barr virus (EBV), Marek’s disease virus, 30 Herpes saimiri, Herpesvirus ateles, Herpesvirus sylvilagus, guinea pig herpes virus, Lucke tumor virus); the family Adenoviridae, including the genus Mastadenovirus (Human subgroups A, B, C, D, E and ungrouped; simian adenoviruses (at least 23 serotypes), infectious canine hepatitis, and adenoviruses of cattle, pigs, sheep, frogs and many other species), the genus Aviadenovirus (Avian adenoviruses), and non-cultivatable adenoviruses; the family Papoviridae, including the genus Papillomavirus (Human papilloma viruses, bovine papilloma viruses, Shope rabbit papilloma virus, and various 35 pathogenic papilloma viruses of other species), the genus Polyomavirus (polyomavirus, Simian vacuolating agent (SV- 40), Rabbit vacuolating agent (RKV), K virus, BK virus, JC virus, and other primate polyoma viruses such as Lympho- trophic papilloma virus); the family Parvoviridae including the genus Adeno-associated viruses, the genus Parvovirus (Feline panleukopenia virus, bovine parvovirus, canine parvovirus, Aleutian mink disease virus, etc). Finally, DNA viruses may include viruses which do not fit into the above families such as Kuru and Creutzfeldt-Jacob disease viruses and 40 chronic infectious neuropathic agents. [0055] Bacterial infections or diseases that can be treated by uses disclosed herein are caused by bacteria including, but not limited to, bacteria that have an intracellular stage in its life cycle, such as mycobacteria (e.g., Mycobacteria tuberculosis, M bovis, M avium, M leprae, or M africanum), rickettsia, mycoplasma, chlamydia, and legionella. Other examples of bacterial infections contemplated include, but are not limited to, infections caused by Gram positive bacillus 45 (e.g., Listeria, Bacillus such as Bacillus anthracis, Erysipelothrix species), Gram negative bacillus (e.g., Bartonella, Brucella, Campylobacter, Enterobacter, Escherichia, Francisella, Hemophilus, Klebsiella, Morganella, Proteus, Prov- idencia, Pseudomonas, Salmonella, Serratia, Shigella, Vibrio, and Yersinia species), spirochete bacteria (e.g., Borrelia species including Borrelia burgdorferi that causes ), anaerobic bacteria (e.g., Actinomyces and Clostridium species), Gram positive and negative coccal bacteria, Enterococcus species, Streptococcus species, Pneumococcus 50 species, Staphylococcus species, Neisseria species. Specific examples of infectious bacteria include, but are not limited to: Helicobacter pyloris, Borelia burgdorferi, Legionella pneumophilia, Mycobacteria tuberculosis, M avium, M. intrac- ellulare, M kansaii, M. gordonae, Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria mono- cytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Streptococcus viridans, Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae, Haemophilus influ- 55 enzae, Bacillus antracis, corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, Clostridium perfringers, Clostrid- ium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Fusobacterium nucleatum, Strepto- bacillus moniliformis, Treponema pallidium, Treponema pertenue, Leptospira, Rickettsia, and Actinomyces israelli. [0056] Fungal diseases that can be treated by methods of the present invention include, but are not limited to, as-

12 EP 1 928 492 B1

pergilliosis, crytococcosis, sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, blastomycosis, zygomycosis, and candidiasis. [0057] Parasitic diseases that can be treated by uses of the present invention include, but are not limited to, amebiasis, malaria, leishmania, coccidia, giardiasis, cryptosporidiosis, toxoplasmosis, and trypanosomiasis. Also encompassed 5 are infections by various worms such as, but not limited to, ascariasis, ancylostomiasis, trichuriasis, strongyloidiasis, toxoccariasis, trichinosis, onchocerciasis, filaria, and dirofilariasis. Also encompassed are infections by various flukes such as, but not limited to, schistosomiasis, paragonimiasis, and clonorchiasis. Parasites that cause these diseases can be classified based on whether they are intracellular or extracellular. An "intracellular parasite," as used herein, is a parasite whose entire life cycle is intracellular. Examples of human intracellular parasites include Leishmania spp., 10 Plasmodium spp., Trypartosoma cruzi, Toxoplasma gondii, Babesia spp., and Trichinella spiralis. An ‘‘extracellular parasite," as used herein, is a parasite whose entire life cycle is extracellular. Extracellular parasites capable of infecting humans include Entamoeba histolytica, Giardia lamblia, Enterocytozoon bieneusi, Naegleria and Acanthamoeba as well as most helminths. Yet another class of parasites is defined as being mainly extracellular but with an obligate intracellular existence at a critical stage in their life cycles. Such parasites are referred to herein as "obligate intracellular 15 parasites." These parasites may exist most of their lives or only a small portion of their lives in an extracellular environment, but they all have at least one obligate intracellular stage in their life cycles. This latter category of parasites includes Trypanosoma rhodesiense and Trypanosoma gambiense, Isospora spp., Cryptosporidium spp, Eimeria spp., Neospora spp., Sarcocystis spp., and Schistosoma spp.

20 ALLERGENS

[0058] The disclosure encompasses uses of reducing or inhibiting allergic reaction to an allergen in a subject comprising administering to the subject an immunomodulatory compound disclosed herein prior to the subject’s exposure to an allergen. Optionally, in addition to the administration before the exposure to an allegen, an immunomodulatory compound 25 may be administered during and/or after the subject’s exposure to an allergen. It is contemplated that any types of exposure to allergens including, but not limited to, the subject’s exposure to naturally occurring allergens, exposure by the intake of food, and exposure through allergy vaccine administration, are encompassed by uses disclosed herein. [0059] Examples of allergens (e.g., naturally occurring or those contained in allergy vaccines) include, but are not limited to, allergens from: 30 mites such as, but not limited to, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Acarus siro, Blomia tropicalis, Chortoglyphus arcuatas, Euroglyphus maynei, Lepidoglyphus destructor, Tyrophagus putrescentiae, and Glyphagus demesticus; venoms such as, but not limited to, Bombus spp., Vespa crabro, Apis mellifera, Dolichovespula spp., Polistes spp., 35 Vespula spp., Dolichovespula maculata, and Dolichovespula arenaria; insects such as, but not limited to, Camponotus pennsylvanicus, Solenopsis invicta, Solenopsis richteri, Periplaneta americana, Blattella germanica, Blatta orientails, Tebanus spp., Musca domestica, Ephemeroptera spp., Culicidae sp., and Heterocera spp.; epithelia, dander, hair and features such as, but not limited to, Serinus canaria, Felis catus (domesticus), Bos 40 taurus, Gallus gallus (domesticus), Canis familiaris, Anas platyrhynchos, Meriones unguiculatus, Capra hircus, Anser domesticus, Cavia porcellus (cobaya), Mesocrietus auratus, Sus scrofa, Equus caballus, Mus musculus, Psittacidae, Columba fasciata, Oryctolagus cuniculus, Rattus norvegicus, and Ovis aries; fungi such as, but not limited to, Cephalosporium acremonium, Alternaria tenuis, Aspergillus glaucus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, 45 Aureobasidium pullulans (Pullularia pullulans), Drechslera sorokiniana, Helminthosporium sativum, Botrytis cine- rea, Candida albicans, Chaetomium globosum, Cladosporium herbarum, Cladosporium sphaerospermum (Ho- modendrum hordei), Drechslera spicifera (Curvularia spicifera), Epicoccum nigrum (Epicoccum purpurascens), Epidermophyton floccosum, Fusarium moniliforme, Fusarium solani, Geotrichum candidum, Gliocladium viride, Helminthosporium solani, Microsporum canis, Mucor circinelloides f. circinelloides, Mucor circinelloides f. lusitan- 50 icus, Mucor plumbeus, Mycogone perniciosa, Neurospora intermedia, Nigrospora oryzae, Paecilomyces variotii, Penicillum brevi-compactum, Penicillum camembertii, Penicillum chrysogenum, Penicillum digitatum, Penicillum expansum, Penicillum notatum, Penicillum roquefortii, Phoma betae, Phoma herbarum, Rhizopus oryzae, Rhizopus stolonifer, Rhodotorula mucilaginosa, Saccharomyces cerevisiae, Scopulariopsis brevicaulis, Serpula lacrymans, Setosphaeria rostrata, Stemphylium botryosum, Stemphylium solani, Trichoderma harzianum, Trichophyton men- 55 tagrophytes, Trichophyton rubrum, and Trichothecium roseum; smuts such as, but not limited to, Ustilago nuda, Ustilago cynodontis, Ustilago maydis, Sporisorium cruentum, Ustilago avenue, and Ustilago tritici; grasses such as, but not limited to, Paspalum notatum, Cynodon dactylon, Poa compressa, Bromus inermis,

13 EP 1 928 492 B1

Phalaris arundinacea, Zea mays, Elytrigia repens (Agropyron repens), Sorghum haelpense, Poa pratensis, Festuca pratensis (elatior), Avena sativa, Dactylis glomerata, Agrostis gigantea (alba), Secale cereale, Leymus (Elymus) condensatus, Lolium perenne ssp. multiflorum, Lolium perenne, Anthoxanthum odoratum, Phleum pratense, Holcus lanatus, Triticum aestivum, and Elymus (Agropyron) smithii; 5 weeds such as, but not limited to, Atriplex polycarpa, Baccharis halimifolia, Baccharis sarothroides, Hymenoclea salsola, Amaranthus hybridus, Xanthium strumarium (commune), Rumex crispus, Eupathium capillifolium, Solidago spp., Amaranthus tuberculatus (Acnida tamariscina), Allenrolfea occidentalis, Chenopodium botrys, Kochia sco- paria, Chenopodium album, Iva xanthifolia, Iva angustifolia, Chenopodium ambrosioides, Artemisia vulgaris, Ar- temisia ludoviciana, Urtica dioica, Amaranthus spinosus, Plantago lanceolata, Iva axillaris, Atriplex lentiformis, 10 Ambrosia dumosa, Ambrosia acanthicarpa, Ambrosia trifida, Ambrosia artemisiifolia, Ambrosia confertiflora, Am- brosia bidentata, Ambrosia psilostachya, Salsola kali (pestifer), Artemisia californica, Artemisia frigida, Artemisia tridentata, Atriplex wrightii, Atriplex confertifolia, and Artemisia annua; trees such as, but not limited to, Acasia spp., Alnus glutinosa, Alnus rubra, Alnus incana ssp. rugosa, Alnus rhombifolia, Fraxinus velutina, Fraxinus pennsylvanica, Fraxinus latifolia, Fraxinus americana, Populus tremu- 15 loides, Myrica cerifera, Fagus grandifolia (americana), Casuarina equisetifolia, Betula lenta, Betula pendula, Betula nigra, Betula occudentalis (fontinalis), Betula populifolia, Acer negundo, Cryptomeria japonica, Juniperus ashei (sabinoides), Juniperus virginiana, Tamarix gallica, Populus balsamifera ssp. trichocarpa, Populus deltoides, Pop- ulus fremoretii, Populus wislizeni, Populus monilifera (sargentii), Cupressus arizonoca, Taxodium distichum, Cu- pressus sempervirens, Ulmus americana, Ulmus crassifolia, Ulmus pumila, Eucalyptus globulus, Celtis occiden- 20 talis, Corylus americana, Corylus avellana, Carya ovata, Carya laciniosa, Carya alba, Juniferus monosperma, Juniperus princhotii, Juniperus scopulorum, Juniperus occidentalis, Robinia pseudoacacia, Mangifera indica, Acer macrophyllum, Acer rubrum, Acer saccharum, Melaleuca quinquenervia (leucadendron), Prosopis glandulosa (ju- liflora), Broussonetia papyrifera, Morus rubra, Morus alba, Quercus gambelii, Quercus velutina, Quercus macro- carpa, Quercus kelloggii, Quercus agrifolia, Quercus lobata, Quercus ilex, Quercus stellata, Quercus rubra, Quer- 25 cus dumosa, Quercus virginiana, Quercus nigra, Quercus garryana, Quercus alba, Olea europaea, Elaegnus angustifolia, Citrus sinensis, Arecastrum romanzoffianum (Cocos plumosa), Carya illnoensis, Schinus molle, Schi- nus terebinthifolius, Pinus taeda, Pinus strobus, Pinus palustris, Pinus ponderosa, Pinus elliottii, Pinus virginiana, Pinus monticola, Pinus echinata, Populus nigra, Populus alba, Ligustrum vulgare, Liquidambar styraciflua, Platanus occidentalis, Platanus orientalis, Platanus racemosa, Platanus acerifolia, Juglans nigra, Juglans californica, Jug- 30 lans regia, Salix lasiolepsis, Salix nigra, and Salix discolor; flowers such as, but not limited to, Chrysanthemum leucanthemum, Taraxacum officinale, and Helianthus annuus; farm plants such as, but not limited to, Medicago sativa, Ricinus communis, Trifolium pratense, Brassica spp., and Beta vulgaris; plant food such as, but not limited to, Prunus dulcis, Malus pumila, Prunus armeniaca, Musa paradisiaca (sapientum), 35 Hordeum vulgare, Phaseolus lunatus, Phaseolus vulgaris, Phaseolus sp., Phaseolus sp., Phaseolus vulgaris, Rubus allegheniensis, Vaccinium sp., Brassica oleracea var. botrytis, Fagopyrum esculentum, Brassica oleracea var. capitata, Theobroma cacao, Cucumis melo, Daucus carota, Brassica oleracea var. botrytis, Apium graveolens var. dulce, Prunus sp., Cinnamomum verum, Coffea arabic, Zea mays, Vaccinium macrocarpon, Cucumis sativus, Allium sativum, Zingiber officinale, Vitis sp., Citrus paradisi, Humulus lupulus, Citrus limon, Lactuca sativa, Agaricus 40 campestris, Brassica sp., Myristica fragrans, Avena sativa, Olea europaea, Allium cepa var. cepa, Citrus sinensis, Vigna unguiculata, Pisum sativum, Prunus persica, Pyrus communis, Piper nigrum, Capsicum annuum var. annu- um, Ananas comosus, Ipomoea batatas, Solanum tuberosum, Rubus idaeus var. idaeus, Oryza sativa, Secale cereale, Sesamum orientale (indicum), Glycine max, Spinacia oleracea, Cucurbita pepo var. melopepo, Fragaria chiloensis, Lycopersicon esculentum (lycopersicum), Brassica rapa var. rapa, Vanilla planifolia, Citrullus lanatus 45 var. lanatus, and Triticun aestivum; fish and shellfish such as, but not limited to, Micropterus sp., Ictalurus punctatus, Mercenaria mercenaria, Gadus morhua, Callinectes sapidus, Platichthys sp., Hippoglossus sp., Homarus americanus, Scomber scombrus, Crassostrea virginica, Sebastes marinus, Salmo salar, Clupeiformes, Pecten magellanicus, Penaeus sp., Salveli- nus sp., and Thunnus. sp.; 50 animal foods such as, but not limited to, Bos taurus, Ovis aries, and Sus scrofa; poultry products such as, but not limited to, chicken (Gallus gallus) products and turkey (Meleagris gallopavo) products; dairy products such as, but not limited to, bovine casein and bovine milk; nuts such as, but not limited to, Bertholletia excelsa, Anacardium occidentale, Cocos nucifera, Corylus americana, 55 Arachis hypogaea, Carya illinoensis, Juglans nigra, and Juglans regia; miscellaneous allergens such as, but not limited to, those from Gossypium hirsutum, Linum usitatissimum, Acaia senegal, Sterculia urens, Astragalus gummifer, Ceiba pentandra, Iris germanica var. florentina, Chrysanthemum cinerariifolium, Bombyx mori, and Nicotiana tabacum;

14 EP 1 928 492 B1

dust such as, but not limited to, barley grain dust, corn grain dust, house dust, mattress dust, oat grain dust, wheat grain dust, and upholstery dust.

IMMUNOMODULATORY COMPOUNDS 5 [0060] As used herein and unless otherwise indicated, the terms "immunomodulatory compounds" and "IMiDs®" (Celgene Corporation) encompass certain small organic molecules that inhibit LPS induced monocyte TNF -α, IL-1β, IL-12, IL-6, MIP-1α, MCP-1, GM-CSF, G-CSF, and COX-2 production. Specific immunomodulatory compounds are discussed below. 10 [0061] TNF-α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF- α is responsible for a diverse range of signaling events within cells. Without being limited by a particular theory, one of the biological effects exerted by the compound of the invention is the reduction of myeloid cell TNF-α production. The compound of the invention may enhance the degradation of TNF-α mRNA. [0062] Further, without being limited by theory, the compound used in the invention may also be a potent co-stimulator 15 of T cells and increase cell proliferation dramatically in a dose dependent manner. The compound of the invention may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compound preferably has anti-inflammatory properties against myeloid cell responses, yet efficiently co-stimulate T cells to produce greater amounts of IL-2, IFN-γ, and to enhance T cell proliferation and CD8+ T cell cytotoxic activity. Further, without being limited by a particular theory, the compound used in the invention may be capable of acting both indirectly 20 through cytokine activation and directly on Natural Killer ("NK") cells and Natural Killer T ("NKT") cells, and increase the NK cells’ ability to produce beneficial cytokines such as, but not limited to, IFN-γ, and to enhance NK and NKT cell cytotoxic activity. [0063] Specific examples of immunomodulatory compounds include cyano and carboxy derivatives of substituted styrenes such as those disclosed in U.S. patent no. 5,929,117; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3y1) isoindolines 25 and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. patent nos. 5,874,448 and 5,955,476; the tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines described in U.S. patent no. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide), substituted 2-(2,6- dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles including, but not limited to, those disclosed in U.S. patent nos. 5,635,517, 6,281,230, 6,316,471, 6,403,613, 6,476,052 and 6,555,554; 1-oxo 30 and 1,3-dioxoisoindolines substituted in the 4- or 5-position of the indoline ring (e.g., 4-(4-amino-1,3-dioxoisoindoline- 2-yl)-4-carbamoylbutanoic acid) described in U.S. patent no. 6,380,239; isoindoline-1-one and isoindoline-1,3-dione substituted in the 2-position with 2,6-dioxo-3-hydroxypiperidin-5-yl (e.g., 2-(2,6-dioxo-3-hydroxy-5-fluoropiperidin-5-yl)- 4-aminoisoindolin-1-one) described in U.S. patent no. 6,458,810; a class of non-polypeptide cyclic amides disclosed in U.S. patent nos. 5,698,579 and 5,877,200; and isoindole-imide compounds such as those described in U.S. patent 35 publication no. 2003/0045552 published on March 6, 2003, U.S. patent publication no. 2003/0096841 published on May 22, 2003, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106). Immu- nomodulatory compounds do not include thalidomide. [0064] Various immunomodulatory compounds disclosed herein contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. The disclosure encompasses the use of stereomerically 40 pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds may be used in uses and com- positions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of 45 Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). [0065] Preferred immunomodulatory compounds disclosed herein include, but are not limited to, 1-oxo-and 1,3 dioxo- 2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Patent no. 5,635,517 which is incorporated herein by reference. These compounds have the structure I: 50

55

15 EP 1 928 492 B1

2 in which one of X and Y is C=O, the other of X and Y is C=O or CH2 , and R is hydrogen or lower alkyl, in particular methyl. Specific immunomodulatory compounds includes, but are not limited to:

5

10

1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;

15

20

1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 25 and

30

35 1,3-dioxo-2-(3-methyl-2,6-dioxopiperidin-3-yl)-4-aminoisoindole, and optically pure isomers thereof. The compounds can be obtained via standard, synthetic methods (see e.g., United States Patent No. 5,635,517, ). The compounds are also available from Celgene Corporation, Warren, NJ. [0066] As used herein, and unless otherwise indicated, the term "optically pure" means a composition that comprises 40 one optical isomer of a compound and is substantially free of other isomers of that compound. For example, an optically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. An optically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical optically pure compound comprises greater than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of other enantiomers of the compound, more preferably 45 greater than about 90% by weight of one enantiomer of the compound and less than about 10% by weight of the other enantiomers of the compound, even more preferably greater than about 95% by weight of one enantiomer of the com- pound and less than about 5% by weight of the other enantiomers of the compound, more preferably greater than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of the other enantiomers of the compound, and most preferably greater than about 99% by weight of one enantiomer of the compound and less than 50 about 1% by weight of the other enantiomers of the compound. [0067] Other specific immunomodulatory compounds belong to a class of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles, such as those described in U.S. patent nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, and International Patent Application No. PCT/US97/13375 (Interna- tional Publication No. WO 98/03502). Representative compounds are of formula: 55

16 EP 1 928 492 B1

5

10 in which:

one of X and Y is C=O and the other of X and Y is C=O or CH2;

(i) each of R1,R2,R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 15 to 4 carbon atoms or (ii) one of R1,R2,R3, and R4 is -NHR5 and the remaining of R1,R2,R3, and R4 are hydrogen;

R5 is hydrogen or alkyl of 1 to 8 carbon atoms; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, or halo; provided that R6 is other than hydrogen if X and Y are C=O and (i) each of R1,R2,R3, and R4 is fluoro or (ii) one 20 of R1, R2, R3, or R4 is amino.

Compounds representative of this class are of the formulas:

25

30

and

35

40

wherein R1 is hydrogen or methyl. In a separate embodiment, the invention encompasses the use of enantiomerically pure forms (e.g. optically pure (R) or (S) enantiomers) of these compounds. 45 [0068] Still other specific immunomodulatory compounds belong to a class of isoindole-imides disclosed in U.S. Patent Application Publication Nos. US 2003/0096841 and US 2003/0045552, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106). Representative compounds are of formula II:

50

55

17 EP 1 928 492 B1

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:

one of X and Y is C=O and the other is CH2 or C=O; 5 1 R is H, (C1-C8 )alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)hetero- 3 3 4 6 5 cycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, C(O)R , C(S)R , C(O)OR ,(C1-C8)alkyl-N(R )2, (C1-C8)alkyl-0R , 5 3 3 3 3’ 3 3’ 5 (C1-C8)alkyl-C(O)OR , C(O)NHR , C(S)NHR , C(O)NR R , C(S)NR R or (C1-C8)alkyl-O(CO)R ; 2 R is H, F, benzyl, (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl; 3 3’ R and R are independently (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4) 10 6 5 alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, (C0-C8)alkyl-N(R )2,(C1-C8)alkyl-OR ,(C1-C8)alkyl- 5 5 5 C(O)OR , (C1-C8)alkyl-O(CO)R , or C(O)OR ; 4 5 R is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkyl-OR , benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocy- cloalkyl, or (C0-C4)alkyl-(C2-C5)heteroaryl; 5 R is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, or (C2-C5)heteroaryl; 15 6 each occurrence of R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C2-C5)heter- 5 6 oaryl, or (C0-C8)a1kyl-C(O)O-R or the R groups can join to form a heterocycloalkyl group; n is 0 or 1; and * represents a chiral-carbon center. 1 In specific compounds of formula II, when n is 0 then R is (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, 20 3 4 6 aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, C(O)R , C(O)OR ,(C1-C8)alkyl-N(R , 5 5 3 5 (C1-C8)alkyl-OR , (C1-C8)alkyl-C(O)OR , C(S)NHR , or (C1-C8)alkyl-O(CO)R ; 2 R is H or (C1-C8)alkyl; and 3 R is (C1-C8)akyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1 -C6)heterocy- 6 5 5 cloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, (C5-C8)alkyl-N(R )(C0-C8)alkyl-NH-C(O)O-R ;(C1-C8)alkyl-OR ,(C1-C8) 25 5 5 5 alkyl-C(O)OR , (C1-C8)alkyl-O(CO)R , or C(O)OR ; and the other variables have the same definitions.

2 [0069] In other specific compounds of formula II, R is H or (C1-C4)alkyl. 1 [0070] In other specific compounds of formula II, R is (C1-C5)alkyl or benzyl. 1 [0071] In other specific compounds of formula II, R is H, (C1-C8)alkyl, benzyl, CH2OCH3, CH2CH2OCH3, or 30

35 [0072] In another embodiment of the compounds of formula II, R1 is

40

45 7 wherein Q is O or S, and each occurrence of R is independently H,(C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, halogen, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl(C2-C5)heteroaryl, (C0-C8)alkyl- 6 5 5 5 5 7 N(R )2,(C1-C8)akyl-OR ,(C1-C8)alkyl-C(O)OR ,(C1-C8)alkyl-O(CO)R , or C(O)OR , or adjacent occurrences of R can be taken together to form a bicyclic alkyl or aryl ring. In other specific compounds of formula II, R1 is C(O)R3. 50 3 5 In other specific compounds of formula II, R is (CO-C4)alkyl-(C2-C5)heteroaryl, (Cl-C8)alkyl, aryl, or (C0-C4)alkyl-OR . [0073] In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl. [0074] In other specific compounds of formula II, R1 is C(O)OR4. [0075] In other specific compounds of formula II, the H of C(O)NHC(O) can be replaced with(C1-C4)alkyl, aryl, or benzyl. [0076] Further examples of the compounds in this class include, but are not limited to: [2-(2,6-dioxo-piperidin-3-yl)- 55 1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide; (2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4- ylmethyl)-carbamic acid tert-butyl ester; 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione; N-(2-(2,6-di- oxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl)-acetamide; N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoi- soindolin-4-yl)methyl}cyclopropyl-carboxamide; 2-chloro-N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}

18 EP 1 928 492 B1

acetamide; N-(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)-3-pyridylcarboxamide; 3-{1-oxo-4-(benzylamino)iso- indolin-2-yl}piperidine-2,6-dione; 2-(2,6-dioxo(3-piperidyl))-4-(benzylamino)isoindoline-1,3-dione; N-{(2-(2,6-dioxo(3- piperidyl))-1,3-dioxoisoindolin-4-yl)methyl}propanamide; N-{(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)me- thyl}-3-pyridylcarboxamide; N-{(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)methyl}heptanamide; N-{(2-(2,6-di- 5 oxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)methyl}-2-furylcarboxamide; {N-(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindo- lin-4-yl)carbamoyl}methyl acetate; N-(2-(2,6-dioxo(3-piperidyl))-1,3 -dioxoisoindolin-4-yl)pentanamide; N-(2-(2,6-dioxo (3-piperidyl))-1,3-dioxoisoindolin-4-yl)-2-thienylcarboxamide; N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl] methyl}(butylamino)carboxamide; N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl] methyl}(octylamino)carboxa- mide; and N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl] methyl}(benzylamino)carboxamide. 10 [0077] Still other specific immunomodulatory compounds belong to a class of isoindole-imides disclosed in U.S. Patent Application Publication Nos. US 2002/0045643, International Publication No. WO 98/54170, and United States Patent No. 6,395,754. Representative compounds are of formula III:

15

20

25 and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:

one of X and Y is C=O and the other is CH2 or C=O; R is H or CH2OCOR’; 30 (i) each of R1,R2,R3,orR4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1,R2,R3,orR4 is nitro or -NHR5 and the remaining of R1,R2,R3,orR4 are hydrogen;

R5 is hydrogen or alkyl of 1 to 8 carbons 35 R6 hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro; R’ is R7-CHR10-N(R8R9); 7 R is m-phenylene or p-phenylene or -(CnH2n)- in which n has a value of 0 to 4; each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene, or -CH2CH2X1CH2CH2- in which X1 is -O-, -S-, or 40 -NH-; R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and * represents a chiral-carbon center.

[0078] Other representative compounds are of formula: 45

50

55 wherein:

one of X and Y is C=O and the other of X and Y is C=O or CH2;

19 EP 1 928 492 B1

(i) each of R1,R2,R3,orR4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1,R2,R3, and R4 is NHR5 and the remaining of R1,R2,R3, and R4 are hydrogen;

R5 is hydrogen or alkyl of 1 to 8 carbon atoms; 5 R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro; 7 R is m-phenylene or p-phenylene or -(CnH2n)- in which n has a value of 0 to 4; each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken 1 1 together are tetramethylene, pentamethylene, hexamethylene, or -CH2CH2 X CH2CH2- in which X is -0-, -S-, or -NH-; and 10 R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl.

[0079] Other representative compounds are of formula:

15

20

in which one of X and Y is C=O and the other of X and Y is C=O or CH2; 25 each of R1 R2,R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1,R2,R3, and R4 is nitro or protected amino and the remaining of R1,R2,R3, and R4 are hydrogen; and R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro. [0080] Other representative compounds are of formula:

30

35

in which: 40

one of X and Y is C=O and the other of X and Y is C=O or CH2;

(i) each of R1 R2,R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1,R2,R3, and R4 is -NHR5 and the remaining of R1,R2,R3, and R4 are hydrogen; 45 R5 is hydrogen, alkyl of 1 to 8 carbon atoms, or CO-R7-CH(R10)NR8R9 in which each of R7,R8,R9, and R10 is as herein defined; and R6 is alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro.

50 Specific examples of the compounds are of formula:

55

20 EP 1 928 492 B1

in which:

one of X and Y is C=O and the other of X and Y is C=O or CH2; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, chloro, or fluoro; 5 7 8 9 R is m-phenylene, p-phenylene or -(CnH2n)- in which n has a value of 0 to 4; each of R and R taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentam- 1 1 ethylene, hexamethylene, or - CH2CH2X CH2CH2- in which X is -O-, -S- or -NH-; and R10 is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl.

10 [0081] Other specific immunomodulatory compounds include, but are not limited to, 1-oxo-2-(2,6-dioxo-3-fluoropipe- ridin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. patent nos. 5,874,448 and 5,955,476. Representative compounds are of formula:

15

20

wherein:

25 Y is oxygen or H2 and each of R1,R2,R3, and R4, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or amino.

[0082] Other specific immunomodulatory compounds include, but are not limited to, the tetra substituted 2-(2,6-diox- 30 opiperdin-3-yl)-1-oxoisoindolines described in U.S. patent no. 5,798,368. Representative compounds are of formula:

35

40 wherein each of R1,R2,R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms. [0083] Other specific immunomodulatory compounds include, but are not limited to, 1-oxo and 1,3-dioxo-2-(2,6-diox- opiperidin-3-yl) isoindolines disclosed in U.S. patent no. 6,403,613. Representative compounds are of formula: 45

50

55 in which

Y is oxygen or H2, a first of R1 and R2 is halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano, or carbamoyl, the second of R1 and R2,

21 EP 1 928 492 B1

independently of the first, is hydrogen, halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano, or carbamoyl, and R3 is hydrogen, alkyl, or benzyl.

[0084] Specific examples of the compounds are of formula: 5

10

15 wherein a first of R1 and R2 is halo, alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms, dialkylamino in which each alkyl is of from 1 to 4 carbon atoms, cyano, or carbamoyl; the second of R1 and R2, independently of the first, is hydrogen, halo, alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms, alkylamino in which alkyl is of from 1 to 4 carbon atoms, dialkylamino in which each alkyl is of from 20 1 to 4 carbon atoms, cyano, or carbamoyl; and R3 is hydrogen, alkyl of from 1 to 4 carbon atoms, or benzyl. Specific examples include, but are not limited to, 1-oxo- 2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline. [0085] Other representative compounds are of formula:

25

30

wherein: 35 a first of R1 and R2 is halo, alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms, dialkylamino in which each alkyl is of from 1 to 4 carbon atoms, cyano, or carbamoyl; the second of R1 and R2, independently of the first, is hydrogen, halo, alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms, alkylamino in which alkyl is of from 1 to 4 carbon atoms, dialkylamino in which each alkyl 40 is of from 1 to 4 carbon atoms, cyano, or carbamoyl; and R3 is hydrogen, alkyl of from 1 to 4 carbon atoms, or benzyl.

[0086] Other specific immunomodulatory compounds include, but are not limited to, 1-oxo and 1,3-dioxoisoindolines substituted in the 4- or 5-position of the indoline ring described in U.S. patent no. 6,380,239 and co-pending U.S. 45 application no. 10/900,270, filed July 28, 2004. Representative compounds are of formula:

50

55 in which the carbon atom designated C* constitutes a center of chirality (when n is not zero and R1 is not the same as R2); one of X1 and X2 is amino, nitro, alkyl of one to six carbons, or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2 independent of the other, is hydroxy or NH-Z; R3 is hydrogen, alkyl of one to six carbons, halo, or haloalkyl;

22 EP 1 928 492 B1

Z is hydrogen, aryl, alkyl of one to six carbons, formyl, or acyl of one to six carbons; and n has a value of 0, 1, or 2; provided that if X1 is amino, and n is 1 or 2, then R1 and R2 are not both hydroxy; and the salts thereof. [0087] Further representative compounds are of formula:

5

10

in which the carbon atom designated C* constitutes a center of chirality when n is not zero and R1 is not R2; one of X1 and X2 is amino, nitro, alkyl of one to six carbons, or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2 15 independent of the other, is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo, or hydrogen; Z is hydrogen, aryl or an alkyl or acyl of one to six carbons; and n has a value of 0, 1, or 2. [0088] Specific examples include, but are not limited to, 2-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl- butyric acid and 4-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-cabamoyl-butyric acid, which have the following struc- tures, respectively, and pharmaceutically acceptable salts, solvates, prodrugs, and stereoisomers thereof: 20

25

30 [0089] Other Representative compounds are of formula:

35

40 in which the carbon atom designated C* constitutes a center of chirality when n is not zero and R1 is not R2; one of X1 and X2 is amino, nitro, alkyl of one to six carbons, or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2 independent of the other, is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo, or hydrogen; Z is hydrogen, aryl, or an alkyl or acyl of one to six carbons; and n has a value of 0, 1, or 2; and the salts thereof. [0090] Specific examples include, but are not limited to, 4-carbamoyl-4-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3- 45 dihydro-isoindol-2-yl}-butyricacid,4-carbamoyl-2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-bu- tyric acid, 2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-4-phenylcarbamoyl-butyric acid, and 2- {4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-pentanedioic acid, which have the following struc- tures, respectively, and pharmaceutically acceptablesalts, solvate, prodrugs, and stereoisomers thereof:

50

55

23 EP 1 928 492 B1

5

10 [0091] Other specific examples of the compounds are of formula:

15

20 wherein:

one of X1 and X2 is nitro, or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2, independent of the other, is hydroxy or NH-Z; 25 R3 is alkyl of one to six carbons, halo, or hydrogen; Z is hydrogen, phenyl, an acyl of one to six carbons, or an alkyl of one to six carbons; and n has a value of 0,1, or 2; and 2 1 if -COR and -(CH2)nCOR are different, the carbon atom designated C* constitutes a center of chirality.

30 [0092] Other representative compounds are of formula:

35

40 wherein:

one of X1 and X2 is alkyl of one to six carbons; each of R1 and R2, independent of the other, is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo, or hydrogen; 45 Z is hydrogen, phenyl, an acyl of one to six carbons, or an alkyl of one to six carbons; and n has a value of 0, 1, or 2; and 2 1 if -COR and -(CH2)nCOR are different, the carbon atom designated C* constitutes a center of chirality.

Still other specific immunomodulatory compounds include, but are not limited to, isoindoline-1-one and isoindoline-1,3- 50 dione substituted in the 2-position with 2,6-dioxo-3-hydroxypiperidin-5-yl described in U.S. patent no. 6,458,810. Rep- resentative compounds are of formula:

55

24 EP 1 928 492 B1

5

10 wherein:

the carbon atoms designated constitute centers of chirality; X is -C(O)- or -CH2-; R1 is alkyl of 1 to 8 carbon atoms or -NHR3; 15 R2 is hydrogen, alkyl of 1 to 8 carbon atoms, or halogen; and R3 is hydrogen, alkyl of 1 to 8 carbon atoms, unsubstituted or substituted with alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, 20 phenyl, unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms, benzyl, unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms, or -COR4 in which R4 is hydrogen, 25 alkyl of 1 to 8 carbon atoms, unsubstituted or substituted with alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms, or 30 benzyl, unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4 carbon atoms.

[0093] All of the compounds described can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically 35 synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques. [0094] Compounds may be small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules. [0095] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, 40 the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

USES FOR TREATMENT AND PREVENTION 45 [0096] The disclosure encompasses uses of treating and/or preventing (e.g., prophylactic treatment such as vacci- nation) of various disorders using the dosing regimen involving an immunomodulatory compounds as described herein. [0097] In one embodiment, this invention encompasses uses for treatment or prevention of cancer. Examples of cancer that can be treated or prevented using uses of the invention include those described above. In some embodiments, 50 cancers to be treated or prevented using uses of the invention are metastatic. In other embodiment, specific cancers that can be treated or prevented by uses of the invention are sarcoma, carcinoma, melanoma, lymphoma and leukemia. [0098] In another embodiment, this invention encompasses uses for vaccinating against cancer by reducing the inhibition of anti-tumor immune response in a subject (e.g., a human) comprising administering to the subject the com- pound of the invention prior to the administration of a cancer vaccine. This invention also encompasses use of the 55 compound of the invention for enhancing immune response to a cancer vaccine in a subject comprising administering to the subject the compound of the invention prior to the administration of a cancer vaccine. Examples of cancer vaccines that can be used in connection with uses of the invention include those listed in Tables 1-4. In specific embodiment, cancers against which vaccination is performed are sarcoma, carcinoma, melanoma, lymphoma and leukemia. In another

25 EP 1 928 492 B1

specific embodiment, the cancer vaccine is an antigen modified denritic cell vaccine, a , a whole tumor cell vaccine, or a . [0099] In another embodiment, this invention also encompasses uses for treatment or prevention of an infectious disease. Examples of infectious diseases that can be treated or prevented using uses of the invention are described 5 above. In some embodiments, infectious diseases that can be treated or prevented by uses of the invention include those caused by viruses, bacteria, fungi, and parasites. [0100] In another embodiment, this invention encompasses uses for vaccinating against an infectious disease by reducing the inhibition of immune response in a subject (e.g., a human) comprising administering to the subject the compound of the invention prior to the administration of a vaccine against an infectious disease. This invention also 10 encompasses use of the compound of the invention for enhancing immune response to a vaccine against an infectious disease in a subject comprising administering to the subject the compound of the invention prior to the administration of the vaccine. Examples of infectious diseases against which a subject can be vaccinated according to uses of the invention are described above. In a specific embodiment, infectious diseases are those caused by viruses, bacteria, fungi, and parasites. In a specific embodiment, the vaccine against an infectious disease is . 15 USES FOR ADMINISTRATION

[0101] Uses encompassed by the disclosure comprise administering one or more immunomodulatory compounds, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, to a subject (e.g., a human) prior to the 20 exposure to or administration of an immunogen or an allergen. [0102] Any route of administration may be used. For example, an immunomodulatory compound can be orally, parenter- ally, transdermally, rectally, sublingually, mucosally, or nasally administered. In addition, an immunomodulatory com- pounds can be administered in a form of pharmaceutical composition and/or unit dosage form. Suitable dosage forms include, but are not limited to, capsules, tablets (including rapid dissolving and delayed release tablets), powder, syrups, 25 oral suspensions and solutions for parenteral administration. Pharmaceutical compositions may contain one of more pharmaceutically acceptable excipients. See, e.g., Rowe et al., Handbook of Pharmaceutical Excipients, 4th Ed. (2003). In addition, an immunomodulatory compound disclosed herein may be included in a kit, which may comprise an immu- nogen or an allergen, one or more other active ingredients, and divices and directions for administration. Other ingredients (e.g., immunogen, allergen, and other active ingredients) may be included in the same formulation with the immunomod- 30 ulatory compound or in separate formulations. [0103] The specific amount of the agent will depend on the specific agent used, the type of disease or disorder being treated or managed, and the amount(s) of an immunomodulatory compound disclosed herein and any optional additional agents concurrently administered to the patient. Typical dosage forms comprise an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof in an amount of from about 0.001 to about 35 150 mg. In particular, dosage forms comprise an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof in an amount of about 0.001, 0.01, 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In a particular embodiment, a dosage form comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-iso- indoline-1,3-dione in an amount of about 0.001, 0.01, 0.1, 1,2, 5, 10, 25 or 50 mg. [0104] In some embodiments, this invention encompasses administration of racemic mixture, optically pure (R)-isomer, 40 or optically pure (S)-isomer of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione. In one specific embodiment, the racemic 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione is administered at an amount of 1, 2, 5, 10, or 25 mg per day. As (S)-isomer of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione is reported to have a higher potency than the racemic mixture, a lower dose can be given when (S)-isomer is used. For examples, (S)- 4-(amino)- 2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione can be administered at an amount of 0.01, 0.1, 1. 2.5, 5, or 10 mg per 45 day. (R)-isomer of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione can be administered at an amount compa- rable to the racemic mixture. [0105] In a specific embodiment, a dosage form comprises 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine- 2,6-dione in an amount of about 0.001, 0.01, 0.1, 1, 5, 10, 25 or 50 mg. Typical dosage forms comprise the second active ingredient in an amount of 1 mg to about 1000 mg, from about 0.01 to about 500 mg, from about 0.1 to about 350 50 mg, or from about 1 to about 200 mg. This invention also encompasses the use of racemic mixture, (S)-isomer, and (R)-isomer of 3-(4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. Typically, racemic 3-(4-amino-1-oxo-1,3- dihydro-isoindol-2-yl)-piperidine-2,6-dione can be administered at an amount of 1, 5, 10, 15, 25, or 50 mg per day. Optical isomers also can be administered at an amount comparable to racemic mixture. Doses can be adjusted depending on the type of disease or disorder being treated, prevented or managed, and the amount(s) of an immunomodulatory 55 compound and any optional additional agents concurrently administered to the patient, which are all within the skill of the art.

26 EP 1 928 492 B1

6. EXAMPLES

6.1 EFFECTS OF IMiDs ON REGULATORY T CELLS

5 [0106] An assay in which the ability of isolated Treg to suppress anti-CD3 mAb activated CD4+CD25- cells was performed. Results showed that pre-incubation of Treg with 4-(amino)2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™) and 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide), but not thalidomide, in- hibits the suppressive function of these cells. The inhibition of T regulatory cell function and production by these com- pounds was shown to be not due to any cytotoxic or apoptotic effects of the IMiDs on the cells, but the inhibition of 10 function was associated with a decrease in FOXP3 expression in CTLA4+CD25highCD4+ cells.

6.1.1 Effects on Treg Function

[0107] Regulatory T cells were isolated by the Dynal T regulatory cell isolation kit, and treated for 24 hours with varying 15 concentrations of an immunomodulatory compound (Actimid™ or lenalidomide) or DMSO. The cells were washed and incubated at a 1:2 ratio with CD25-CD4+ cells, which were also isolated by the Dynal T regulatory cell isolation kit. Results were expressed as the mean % change in proliferation compared to the cpms obtained from DMSO treated CD25+ cells incubated with CD25- cells. As shown in FIG. 2, pre-tratment of CD2S+CD4+ cells with the IMiDs tested significantly increased the proliferation of CD25- cells in the presence of CD25+CD4+ cells as compared to the DMSO 20 treated CD4+CD25+ cells. Thalidomide showed little effect under these assay conditions. The results suggest that the IMiDs tested reduce or inhibit the suppressive activity of regulatory T cells.

6.1.2 Effects on Foxp3 Expression

25 [0108] CD4+CD25+ cells were incubated for 24 hours with varying concentrations of DMSO, Actimid™, lenalidomide, or thalidomide and then washed twice with RPMI medium. Cells were stained with CD152-PE, CD4-PERCP, and CD25- APC. Intracellular Foxp3 staining and CD152 staining were carried out after permeabilizing the CD4+CD25+ cells. Results were expressed as percentage of expression of Foxp3 in the CD4+CD25+ population or the CD4+CD25- population. As shown in FIG. 3, cells pre-treated with the IMiDs showed inhibition of Foxp3 expression, while DMSO and thalidomide 30 showed little effects. The results show that the inhibition of Treg cells by the IMiDs tested may be associated with the compounds ability to inhibit Foxp3 expression.

6.1.3 Effects on Level of Treg Cells

35 [0109] PBMCs were treated with 150U/ml of IL-2. Some of the cultures were also treated with Actimid™ or lenalidomide. Cells were stained with CD25-FITC/CD152-PE/CD4-PerCP/NKG2D-APC and analyzed using a FACSCalibur. As shown in FIG. 4, levels of CD4, CD25high, CD152high expressing cells are reduced in groups pre-treated with an IMiD as compared to the untreated group. The results suggest that the IMiDs of the invention also decrease the levels of regulatory T cells or inhibits the proliferation of such cells. 40 6.2 EFFECTS ON ACOUIRED ANTIBODY RESISTANCE

[0110] Rituximab-resistant cell lines (RRCL) were generated by chronic exposure of Raji cells to escalating doses of rituximab alone (2R) or along with human complement (4RH). Functional assays including antibody-dependant cellular 45 cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) were performed to demonstrate resistance to rituxi- mab. To study the effects of lenalidomide-priming of PBMC’s against RRCL, peripheral blood mononuclear cells from healthy donors were cultured with either DMSO or lenalidoinide (at final concentrations of 10 or 20mg/ml), with or without 51 IL-2 (20IU/ml), over a 5-day period at 37˚C, 5%CO2. Parentral Raji, and RRCL (2R and 4RH) were labeled with Cr and exposed to either rituximab or trastuzumab (Isotype control at 20mg/ml) in the presence of an IMiD or control 50 stimulated-PBMCs (Effector:Target ratio of 40: 1). 51Cr release was measured and the percentage of lysis was calculated. Statistical differences were analyzed by chi-square test. [0111] In vitro exposure of PBMC to IMiD+/-IL-2 improved rituximab-associated ADCC in RRCL. Exposure of PBMC to IMiD+/- IL-2 for 5 days led to a statistically significant increase in rituximab-mediated ADCC in 2R cells [IMiD mean % lysis,26.9+/- 1.18%] [IMiD+IL-2 mean % lysis 38.4+/-4.14%] when compared to control-stimulated PBMC’s [mean % 55 lysis 17.6+/-5.6%]. Similar effects were observed in 4RH cells. The mean % of lysis by ADCC for combination IMiD/IL- 2 exposed PBMC’s on 4RH cells was found to be highest at 38.4+/-4.1%, as compared to IMiD (mean % lysis 26.5+/- 1.83%) or vehicle exposed PBMC’s (mean % lysis 17.6+/-5.69%) (P= 0.01). These results suggest that modulation (e.g., PBMC-priming) of the by the IMiD of the invention (+/-IL-2) improves rituximab anti-tumor activity and

27 EP 1 928 492 B1

may partially overcome rituximab resistance in RRCL via augmentation of ADCC.

6.3 EFFECTS ON GROWTH ARREST AND APOPTOSIS

5 [0112] Direct effects of IMiDs on NHL tumor cells were tested by treating Raji cells with IMiDs alone, or in combination with anti CD20 antibodies B1 or rituxan. IMiD 1 alone caused up to 40% inhibition of proliferation at 10 mM in Raji cells, which corresponded to G1 arrest. In combination with B1, Actimid™ showed a small additive effect at 10 mM, while lenalidomide effects were minimal up to 10 mM. In combination with rituxan, Actimid™ showed a slight additive effect at 10 mM, and lenalidomide showed the same at 50 mM. 10 [0113] A co-culture assay of PBMC and NHL tumor cells were developed as an in vitro model of tumor-host immune system interaction, to further explore the anti-tumor potential of IMiDs in NHL cells. This assay is non-radioactive and flow cytometry based. Using Raji and PBMC, it was shown that pre-treatment of PMBC with an IMiD can enhance the PBMC activity in inducing Raji cell apoptosis in a dose dependent manner. In addition, it was shown that pre-treatment of Raji cells with an IMiD can further enhance the apoptosis induced by PBMC pre-treated with an IMiD. These results 15 suggest that the IMiDs of the invention directly induce NHL tumor cell growth arrest and effectively enhance tumor cell apoptosis induced by PBMC.

6.4 EFFECTS ON HSC EXPANSION

20 [0114] The ability of IMiDs to enhance the expansion of hematopoietic stem cells (HSC) ex vivo in combination with growth factors were tested. It was shown that the IMiDs of the invention dramatically enhance the expansion of CD34+ cells in a serum-free system, achieving up to 100-fold expansion after 14 days in culture. In addition, the IMiDs of the invention enabled a preferential expansion of CD34+CD38- cells, a more immature phenotype. [0115] IMiDs showed similar activities on HSC from all sources tested: bone marrow, cord blood and peripheral blood 25 (steady-state or G-CSF-mobilized). It was also shown that IMiDs can efficiently expand CD34+ cells isolated from frozen cord blood units. [0116] Global gene expression (Affymetrix) analysis of IMiDs-expanded CD34+ cells revealed that the IMiDs of the invention modulate several genes involved in cell differentiation, cell adhesion and cell self-renewal. The IMiDs of the invention also upregulated many genes involved in immune responses and antigen presentation. 30 6.5 EFFECT ON T CELL DIFFERENTIATION

[0117] Effects of IMiDs on T cell differentiation were investigated using various methods. It was demonstrated that, in combination with anti-CD3 stimulation, the IMiD of the invention directly increases expression of Th1 transcription 35 factor T-bet via enhanced T-bet RNA transcription at 4 hours after stimulation. A concomitant decrease in expression of Th2 transcription factor GATA-3 was also observed. The regulation of two key transcription factors by the IMiD favors Th1 differentiation of human naive CD4+ T cells. Enhancement of T-bet by the IMiD results in increased tyrosine phos- phorylation of T-bet, increased expression of IL-12Rβ2, and increased IFN-γ production, compared to treatment with anti-CD3 alone. 40 [0118] A similar effect of the IMiD on T-bet and GATA-3 was also observed in differentiated human Th2 cells in vitro under Th2 polarizing condition. The intracellular cytokine staining of IL-4 and IFN-γ on re-stimulated Th2 cells showed that the IMiD reduced the number of IL-4 producing cells and increased the number of IFN-γ producing cells in the presence of plate bound anti-CD3 antibody. The effect of the IMiD on polarized Th2 cells includes reversal of Th2 cell differentiation and enforcement of IFN-γ expression in IL-4 positive cells, which is greatly enhanced by addition of 45 exogenous IL-12. These results suggest that the IMiDs of the invention not only preferentially induce Th1 immune response by enhancing T-bet, but also inhibit Th2 lineage commitment by reducing GATA-3 expression.

6.6 EFFECTS ON T CELL ACTIVATION

50 [0119] The Gab proteins, including Gab1, Gab2 and Gab3 comprise a growing family of phospho-tyrosine regulated scaffolding molecules involved in RTK signal transduction. Phosphorylation of Gab1 in B cells is associated with PI3- kinase activity and cells proliferation. While Gab 1 is expressed in B cells, only Gab2 is expressed in T cells. Although Gab2 is tyrosine phosphorylated upon TCR activation by ZAP-70, it functions as a negative regulator of TCR signaling via a Shp-2 dependent mechanism. Overexpression of Gab2 in T cells results in the inhibition of IL-2 production (Yamasaki 55 et al., J. Biol. Chem, 2001). The effect of lenalidomide on Gab2 phosphorylation and activation in anti-CD3/CD28 stimulated Jurkat T cells was examined. Lenalidomide inhibited Gab2 phosphorylation dose-dependently (with approx- imately 50% inhibition at about 1 mM) in a manner that correlated with T cell costimulation and enhancement of IL-2 production. The results show that the mechanism of action of lenalidomide is therefore consistent with inhibition of

28 EP 1 928 492 B1

phosphorylation of Gab2 in anti-CD3/CD28-stimulated T cells.

6.7 EFFECTS ON γδ T CELLS

5 6.7.1 Materials and Methods

[0120] Phenotyping of PBMC preparations stimulated with IL-2 and IPP 6 IMiDs: PBMC preparations were obtained and treated weekly with IL-2 and IPP (150 units/ml and 10 uM respectively). Expression of δγ TCR and NKG2D were measured by FACS over a period of three weeks. 10 [0121] Generation of γδ T cells: PBMC preparations were treated with IL-2 (150 units/ml) and IPP (25 uM) weekly. Cultures were split and replenished weekly with fresh IL-2 and IPP and % γδ TCR+ve cells determined by FACS. After 3-4 weeks γδ T cells were purified by negative magnetic separation using CD4+ and CD8+ Dynalbeads and maintained in IL-2. [0122] Measurement of cytokine production in purified γδ T cells and fresh γδ cells in PBMC preparations: 15 Purified γδ T cells were stimulated with IPP 6 IMiDs (10mg/mL) or with the MM cell line RPMI-8226 (6 IMiDs (10mg/mL)) in 24 well plates and were incubated 8-72 hours. Cell-free supernatants were collected and stored at -70˚C until assayed by ELISA. IFN-γ, TNF-α and IL-2 were measured by ELISA (BD pharmingen). For fresh γδ preps, PBMCs were stimulated with plate bound anti-CD3 (1.25 mg/ml) for 48 hours and the expression of TNF-α, IFN-γ, IL-2 and IL-4 were measured by intracellular FACS on cells stained for γδ TCR. 20 [0123] Measurement of apoptosis in γδ cells: Gamma delta T cells were treated with a single dose of 25 mM IPP and weekly with 150U/ml of IL-2 for 4 weeks and 3 days. Cells were then either left untreated or treated with Actimid™, IPP or Actimid™ and IPP. Apoptosis was assessed by staining of cells with annexin V PE and 7-AAD at various time points and analysis using a FACSCalibur. [0124] Cytotoxicity assays: Gamma delta T cells were treated with a single dose of 25 mM IPP and weekly with 25 150U/ml of IL-2 for 3 weeks and 1 day. RPMI-8226 target cells were incubated overnight with 50 mM pamidronate then treated with 3MBq 51Cr. Target, and effector cells were incubated at different ratios and chromium release was assayed after 4 hours. To determine the effects of Actimid™, the compound was either included in the 22 day preincubation before the assay and in the chromium release step, or was included during the chromium release assay.

30 6.7.2 Effects on the Expression of γδ T Cells and NKG2D

[0125] PBMCs were treated with a single dose of 25 mM IPP and then weekly with 150U/ml of IL-2. In addition, some cultures were treated with 10 mM Acdmid™ or lenalidomide. IL-2 treated cells were stained with CD25 FITC/CD4 PE/CD3 PerCP/NKG2D APC, and IL-2 plus IPP treated cells were stained with δγ TCR FITC/alpha beta TCR PE/CD3 Per- 35 CP/NKG2D APC and analysed using a FACSCalibur. [0126] As shown in FIG. 5, cells treated with an immunomodulatory compound of the invention exhibited higher γδ T cells and NKG2D expression. The results show that immunomodulatory compounds of the invention enhance the ex- pression of γδ T cells and NKG2D in PMBCs activated with IL-2 and IPP.

40 6.7.3 Effects of Apoptosis of γδ T Cells

[0127] Gamma delta T cells were treated with a single dose of 25 mM IPP and weekly with 150U/ml of IL-2 for 31 days. Cells were then either left untreated or treated with Actimid™, IPP, or Actimid™ and IPP in combination. Apoptosis was assessed by staining of cells with annexin V PE and 7-AAD at the stated time points and analysis using a FACS- 45 Calibur. Annexin V PE negative/7-AAD negative cells are designated live, annexin V PE positive/7-AAD negative early apoptotic, annexin V PE positive/7-AAD positive late apoptotic and annexin V PE negative/7-AAD positive dead. [0128] As shown in FIG. 6, Actimid™ offered protection against apotosis in γδ T cells with or without IPP. The results suggest that immunomodulatory compounds of the invention protect agains apotosis of γδ T cells.

50 6.7.4 Effects on Cytokine Production by γδ T Cells

[0129] The effects of Actimid™ on IFN-γ, TNF-α and IL-4 were examined in freshly prepared γδ T cells and γδ T cell lines stimulated with IPP. As shown in FIG. 7A, Actimid™ enhanced the production of both IFN-γ and TNF-α in TCR γδ cells from within a freshly prepared PMBC population. In addition, as shown in FIG. 7B, Actimid™ enhanced the production 55 of IFN-γ, but not IL-4, in γδ T cells stimulated with IPP. The results show that immunomodulatory compounds of the invention stimulate the production of IFN-y and TNF-α, but not IL-4.

29 EP 1 928 492 B1

6.7.5 Effects on IFN-γ Production in Response to Varying Tumor to γδ T Cells Ratio

[0130] Tumor cells pre-incubated with (FIG. 8B) or without (FIG. 8A) pamidronate were incubated with δγ T cells at different tumor (RPMI-8226 MM) to γδ T cells ratios as indicated in FIG. 8. Some of the cells were further treated by 5 Actimid™. Intracellular IFN-gamma production was measured by flow cytometry. [0131] As shown in FIGS. 8A and 8B, Actimid™ augmented IFN-γ production by γδ T cells. IFN-γ production increased with increasing tumor to γδ T cells ratio. The results show that immunomodulatory compounds of the invention enhance the production of IFN-γ by γδ T cells, and the effects increase in response to increasing tumor to γδ T cells ratio.

10 6.7.6 Effects on Cytotoxicity of γδ T Cells

[0132] Gamma delta cells were treated with a single dose of 25 mM IPP and weekly with 150U/ml of IL-2 for 22 days. RPMI-8226 target cells were incubated overnight with 50 mM pamidronate, then treated with 3MBq 51Cr. Target and effector cells were incubated at various ratios with fresh Actimid™ and chromium release assayed after 4 hours. Actimid™ 15 was also added to some wells for the 22 day pretreatment with IL-2 and IPP (FIG. 9A) or just for the 4 hr chromium release assay (FIG. 9B). [0133] As shown in FIG. 9, the addition of Actimid™ during either the pretreatment or the chromium relase assay enhanced the cytotoxicity of γδ T cells toward RPMI-8226 MM cell lines, although a better effect was observed with the addition of Actimid™ during the pretreatment of period. The results suggest that immunomodulatory compounds of the 20 invention enhance the cytotoxicity of γδ T cells toward tumor cells, and the effects may be improved by pretreating the tumor cells with the compounds of the invention.

6.8 EFFECTS ON INVARIANT NKT CELLS

25 [0134] The establishment of highly purified primary invariant NKT (iNKT) cell lines from health donors and multiple myeloma (MM) patients has been tested, and the effects of IMiD 2 on iNKT cells were further explored. iNKT cells derived from peripheral blood or bone marrow mononuclear cells were enriched with anti-TCRVα 24 mAb or anti-6B11 mAb and further expanded by several rounds of stimulation with α-GalCer-loaded dendritic cells. Phenotype analysis confirmed 95% purity in expanded iNKT cell lines. No significant phenotypic difference was observed in iNKT cells between healthy 30 donors and MM patients. [0135] Majority of iNKT cells expressed CD161 and CD28, whereas CD56 expression was at very low level. Following anti-CD3 or α-GalCer-loaded dendritic cells stimulation, iNKT cells showed strong proliferative activity as measured by 3H-TdR incorporation assay and production of IFN- γ measured by ELISA. [0136] Next, the effects of IMiD 2, which is known to enhance T cell costimulation and NK cell activity, on iNKT cells 35 were evaluated. From the tests, it was observed that IMiD 2 enhances anti-CD3 mediated proliferation of expanded iNKT cells by 1.4 fold, and the enhanced expression and fluorescent intensity of CD25 (MFI 68.6 versus 28.5) on iNKT cells treated with IMiD 2 compare to untreated iNKT cells. Additionally, compared to the control group stimulated with α-GalCer-loaded dendritic cells alone, IMiD 2 plus α-GalCer-loaded DC also enhanced the production of IL-2. These results provide the preclinical feasibility and rationale to clinically evaluate the efficacy of adoptive transfer of iNKT cells 40 in MM. Additionally, the results demonstrate the ability of the IMiDs of the invention to augment the immunoreactivity of iNKT cells, suggestive of their use in enhancing iNKT cell mediated in myeloma.

6.9 USE WITH HEPATITIS B VACCINE

45 [0137] A two-center, randomized, double-blind, placebo-controlled trial is designed. A single dose of Hepatitis B vaccine is administered to subjects. An IMiD or placebo is administered to 64 patients for 7 days prior to and 7 days after the vaccine. Collection of blood samples for immune analysis is performed prior to the initiation of the IMiD admin- istration, at the time of vaccination, and 7,14, and 28 days after vaccination. Safety assessments is performed at day 14, the last day of study drug. 50 [0138] Subjects may opt for 2nd and 3rd doses of vaccine in order to complete the usual course of hepatitis B vaccination. Opting for additional is not a requirement of this study. Patients opting to receive the second (day 28) and 3rd (6 month) vaccination may have their blood samples collected prior to the 2nd and 3rd and 1 month after 3rd vaccination. The 28 day blood draw serves as the blood draw prior to the 2nd dose of vaccine. The blood draws one month after the 2nd and 3rd dose are not required for subjects wishing to receive the 2nd and 3rd dose of vaccine. 55 [0139] The effect of the IMiD on the response to hepatitis B vaccine in subjects with plasma cell dyscrasias, as measured by change in antibody titer against hepatitis B surface antigen (HbSAg), can be determined following the above procedures. In addition, serum and blood cells can be collected to: a) assess the development of T cell responses against HbSAg following vaccination; b) identify phenotypic changes in peripheral blood cells following the IMiD admin-

30 EP 1 928 492 B1

istration especially with regard to CD3, CD4, CD8 T cells, and NK and NKT cells; and c) determine changes in gene expression profile of immune cells before and after the treatment of the IMiD using micro array protocols.

6.10Treg CELLPHENOTYPINGANDFUNCTIONALANALYSESFROMPATIENTSUNDERGOINGLENALIDOMIDE 5 TREATMENT

[0140] Patients with any malignancy which are selected for lenalidomide treatment in are asked to participate in this study. The cycle of dosing for the patients selected for lenalidomide treatment is 3 weeks of dosing with 25 mg lenalidomide daily, followed by 1 week without dosing, followed by three more weeks of dosing, in repeated cycles. Forty ml samples 10 of blood are collected into heparin tubes and 5 mls into serum tubes at time points from 1 hour to 24 hrs before the first administration of lenalidomide (25 mg/dose) and at 21 days and 49 days after dosing. [0141] The blood in the heparin tubes is layered onto histopaque and spun for 25 minutes at 600 g to separate the buffy coat layer. The buffy coat containing the peripheral blood mononuclear cells and malignant haematogical cells is isolated. The cells isolated are subjected to the following procedures: 15 6.10.1 Phenotype Analysis Using a FACscalibur Machine

[0142] Dominant phenotypes of the PBMCs freshly isolated from each patient are analized, and the percentage of cells in the patients that are of a regulatory T cell phenotype (CD4+CD25+ positive cells, staining positive also for FOXP3 20 and CTLA-4) is measured.

6.10.2 Isolation of CD4+CD25+ cells from the patients PBMCs

[0143] CD4+CD25+ cells and CD4+CD25- cells are isolated from the patients’ PBMCs using standard magnetic bead 25 kits (Invitrogen). The ability in-vitro of the CD4+CD25+ cells to inhibit the proliferation of CD4+CD25- cells, upon stimulation with anti-CD3, is assessed.

6.10.3 Analysis of Serum

30 [0144] Serums are analysed for TGF-beta, IL-10, IL-4, IL-6, IFN-γ and TNF-α concentrations, using methods described herein as well as those well-known in the art.

Claims 35 1. A compound, which is 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydro- isoindol-2-yl)-piperidine-2,6-dione, for use in eliciting an enhanced immune response from a vaccine in a subject, wherein the compound is formulated for administering to the subject prior to the introduction of the vaccine to the subj ect. 40 2. The compound for use of claim 1, wherein the vaccine is a vaccine listed in the following table:

Product or trade name Antigen(s) Manufacturer (country) 45 A.D.T Diphtheria, tetanus (adsorbed) Commonwealth (Australia) A.K.D.S. Diphtheria, tetanus, pertussis AC Vax Meningococcus (polysaccharide) GSK (U.K.)

50 Diphtheria, tetanus, (acellular) Acel-Imunex WYE (U.S.) pertussis ACTAcel Diphtheria, tetanus, pertussis, Hib AVP (Argentina) ActHIB Haemophilus influenzae type b (PRP-T) AVP (U.S.) 55 Chemo-Sero-Therapeutic Resh Inst Aimmugen Hepatitis A (inactivated) (Japan)

31 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Aldiana Diphtheria (absorbed) Sevac (Czechoslovakia) 5 Alditeana Diphtheria, tetanus (absorbed) Sevac (Czechoslovakia) Diphtheria, tetanus (adsorbed), Alditerpera Sevac (Czechoslovakia) pertussis

10 Amaril Yellow fever AVP (France) AMC Haemophilus influenzae, type b Anadifterall Diphtheria (adsorbed) CHIR (Italy) Anatetall Tetanus (adsorbed) CHIR (Italy) 15 Arilvax Yellow fever MEDI (U.K.) Attenuvaxx Measles (live, further attenuated) MRK (U.S.) AVAC-1, AVA Anthrax

20 AVAXIM Hepatitis A Haemophilus influenzae type b B-CAPSAx Mead Johnson (U.S.) (polysaccharide, 1987 to 1989) BayGam Human immunoglobulin Bayer Corporation (U.S.) 25 BayHepB Hepatitis B immune globulin (human) Bayer Corporation (U.S.) BayRab Rabies immune globulin Bayer Corporation (U.S.) BayTet Tetanus immune globulin (human) Bayer Corporation (U.S.) BCG Tuberculosis Multiple manufacturers and countries 30 Begrivac Influenza (split virus) CHIR (Germany) Biavax II x Rubella, mumps (live) MRK (U.S.) Biavax x Rubella, mumps (live) MRK (U.S.) 35 Botulism immune globulin (not a BIG vaccine) Biken-HB Hepatitis B (recombinant) BIK (Japan) Hepatitis B (recombinant, adsorbed, Chemo-Sero-Therapeutic Resh Inst Bimmugen 40 yeast derived) (Japan) BioThrax Anthrax (adsorbed) BPT (U.S.) Biviraten Bema Measles, mumps (live) BER (Switzerland) BVAC Botulinum antitoxin (for U.S. military use) 45 Diphtheria, tetanus (pediatric, C.D.T. Commonwealth (Australia) adsorbed) Celluvax Pertussis (acellular) CHIR (Italy)

x 50 Cendevax Rubella (live) 3/70 to 1976 RIT/SmithKline & French (U.S.) Diphtheria, tetanus, (acellular) Certivax Baxter Hyland (U.S.) pertussis Cocquelucheau Pertussis (adsorbed) AVP (France)

55 Hepatitis B, Haemophilus influenza Comvax MRK (U.S.) type b

32 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Diphtheria, tetanus, (acellular) Daptacel AVP (U.S.) 5 pertussis Diphtheria, tetanus, pertussis D.S.D.P.T. Dong Shin Pharm (Korea) (adsorbed) D.T. Bis Rudivax Diphtheria, tetanus, rubella AVP (France) 10 Di Te Per Pol Impfstoff Diphtheria, tetanus, pertussis, polio BER (Switzerland) Di-Te-Pol Diphtheria, tetanus, polio Statens Seruminstitut (Denmark) Dif-Tet-All Diphtheria, tetanus CHIR (Italy)

15 DIFTAVAX Diphtheria, tetanus, polio DiTe Anatoxal Diphtheria, tetanus (adsorbed) BER (Switzerland) Ditoxim Diphtheria, tetanus (adsorbed) Dong Shin Pharm (Korea) Double Anigen B.I. Diphtheria, tetanus Bengal Immunity Co (India) 20 Dryvax Smallpox WYE (U.S.) DT Diphtheria, tetanus (for pediatric use) AVP (U.S.) DTx Diphtheria, tetanus (for pediatric use) WYE (U.S.) 25 Diphtheria, tetanus, Salmonella typhi, DT TAB AVP (France) Paratyphi A & B Diphtheria, tetanus, (acellular) DTaP (generic) AVP, WYE, GSK (U.S.) pertussis

30 Diphtheria, tetanus, (whole-cell) DTwP (generic)x AVP, WYE, GSK (U.S.) pertussis Dual Antigen SII Diphtheria, tetanus (adsorbed) Serum Institute of India (India) Ecolarixx Measles, rubella (live) RIT/SmithKline (U.S.) 35 elPV Polio (inactivated, enhanced potency) AVP (U.S.) Engerix-B Hepatitis B GSK (U.K., U.S.) Epaxal Bema Hepatitis A - virosomal vaccine BER (Switzerland)

40 Ervevax RA 27/3 Rubella (live) GSK (Belgium) Flu Shield x Influenza WYE (U.S.) Fluad, Agrippal-S I Influenza CHIR (Italy) FluMist Influenza (live, attenuated, intranasal) MEDI (U.S.) 45 Fluogenx Influenza PD (U.S.) Fluvirin Influenza EVN (U.S.) Fluzone Influenza AVP (U.S.)

50 Funed-CEME Diphtheria, tetanus, pertussis Belo Horizonte (Brazil) GenHevac-B Pasteur Hepatitis B Gunevax Rubella CHIR (Italy) Havrix Hepatitis A GSK (U.K., U.S.) 55 H-BIG Hepatitis B immune globulin NABI, Bayer Corporation (U.S.) HbOC Chemical abbreviation for HibTITER WYE (U.S.)

33 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) HBY Hepatitis B (recombinant) KGC (Japan) 5 Heprecomb Hepatitis B (yeast derived) BER (Switzerland) HeptavaxBx Hepatitis B (plasma-derived) 1982 to MRK (U.S.) Hevac B Hepatitis B (plasma derived) AVP (France) 10 Diphtheria, tetanus, pertussis, polio, Hexavac AVP (Europe) hepatitis B, Hib HibTITER Haemophilus influenzae type b (HbOC) WYE (U.S.) Hinkuys karokoe Pertussis (adsorbed) Natl. Public Health Institute (Finland) 15 HPV-77; DK-5 Rubella (live) 1969-1979 MRK (U.S.) HPV-77; DK-12 Rubella (live) 19704973 MRK (U.S.) HRIG Rabies immune globulin AVP; Bayer Corporation (U.S.)

20 Humotet-anti Tetanus Tetanus Wellcome (U.K.) Hyper-Tet (now called "BayTet") Tetanus immune globulin Bayer Corporation (U.S.) IBV Polio (inactivated) Statens Seruminstitut (Denmark) Immune Globulin Intramuscular MA, BPT, New York Blood Ctr, Bayer Broad-spectrum immune globulins 25 (Human) Corporation, CEN (U.S.) Imogam Rabies -HT Rabies immune globulin AVP (U.S.) Imovax Rabies AVP (U.S.) Imovax Parotiditis Mumps AVP (France) 30 Imovax Polio Polio AVP (France) Imovax Sarampion Measles AVP (France) Imovax D.T. Diphtheria, tetanus 35 Imovax Gripe Influenza Imovax R.O.R. Measles, rubella, mumps (live) AVP (France) Imovax Rubeola Measles AVP (International) Imovax Mumps Mumps 40 Imovax Oreillons Mumps AVP (France) Imovax Rabies I.D. (HDCV) AVP (U.S.) Imovax Rabies I.M. Rabies vaccine (HDCV) AVP (U.S.) 45 Diphtheria, tetanus, (acellular) Infanrix GSK (Belgium, U.S.) pertussis Ipad TP Tetanus, polio AVP (France) IPOL Polio (enhanced potency, inactivated) AVP (U.S.) 50 General term for inactivated polio IPV Polio (inactivated) vaccine Istivac Influenza JE-VAX Japanese encephalitis AVP (U.S.) 55 Kaksoisrokote Dubbelvaccin Diphtheria, tetanus (adsorbed) Natl. Public Health Institute (Finland)

34 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Statens Institutt for Folkehelse Kikhoste-Vaksine Pertussis 5 (Norway) Swiss Serum and Vaccine Institute Lancy Vaxina x Smallpox (Switzerland) Lavantuu tirokote Typhoid Central Pub Health Lab (Finland) 10 Liovaxx Smallpox CHIR (Italy) Lirubelx Measles, rubella (live) 4/74 to 6/78 Dow/PitneyMoore (U.S.) Lirugen Measles AVP (Int’l)

15 Lirugenx Measles (live) 2/65 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 Imuna Tetanus (adsorbed) Imuna sp. (Slovakia) 20 LYMErixx Lyme disease GSK (U.S.) Lyovac Attenuvaxx Measles (live, attenuated) MRK (U.S.) Lyovac Meruvaxx Rubella (live) MRK (U.S.) 25 M-R Vax IIx Measles, rubella (live) MRK (U.S.) M-Vaxx Measles (live) 5/63 to 1979 WYE (U.S.) Masern-Impfstoff SSW Measles (live) DK3x Measles (live) 1964 to 1972 Philips Roxane, Inc. (U.S.) 30 Measles (inactivated) 1963 to 1966 Measlesx Eli Lilly (U.S.) Measles (live) 12/64 to 1974 Meningococcus (polysaccharide) Mencevax A SmithKline/RIT (Belgium) (Group A) 35 Meningitec Meningococcus (conjugate) (Group C) WYE (U.K., Australia) Meningococcus (polysaccharide) Menomune-A/C/Y/W-135 AVP (U.S.) (Groups A, C, Y, W435) Meningococcus (polysaccharide) 40 Menpovax 4 CHIR (Italy) (Groups A &C) Menpovax A+C Meningococcus (Groups A & C) CHIR (Italy) Meruvaxx Rubella (live) 6/69 to MRK (U.S.)

45 Meruvax II Rubella (live) MRK (U.S.) Mevilin-Lx Measles (live) Glaxo Operations MMRx Measles, mumps, rubella (live) 6/71 to (U.S.) Measles, mumps, rubella (live) 4/74 to MMR (generic)x Dow Chemical (U.S.) 50 6178 M-M-R II Measles, mumps, rubella (live) MRK (U.S.) Moniarix Pneumococcal (polysaccharide) SmithKline/RIT (Belgium) Institute of Sera and vaccines 55 Mopavac Sevac Measles, mumps attenuated (live) Czechoslovakia

35 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Polio (live, Sabin, monovalent types I, MOPVx WYE (U.S.) 5 II, III) Morbilvax Measles (live, attenuated) CHIR (Italy) Morubel Measles, rubella (live, attenuated) CHIR (Italy)

10 Moruman Berna Measles immunglobulin BER (Switzerland) Measles, mumps, rubella (live, Morupar CHIR (Italy) attenuated) Movivac Measles (live, attenuated)

15 M-R VAXx Measles, rubella (live) 7/71 to MRK (U.S.) Mumaten Berna Mumps (live) BER (Switzerland) Mumps (generic) x Mumps (live) 4/74 to 6178 Dow Chemical (U.S.) Mumps (generic) x Mumps (inactivated) 1950 to 1978 WYE (U.S.) 20 Mumps (generic)x Mumps (inactivated) 1950 to 1977 Eli Lilly (U.S.) Mumpsvax x Mumps (live) MRK (U.S.) Mutagrip Influenza 25 Nabi-HB Hepatitis B immune globulin NABI (U.S.) Nothav Hepatitis A CHI (Italy) Haemophilus influenzae type b (PRP- OmniHIBx GSK, AVP (U.S.) T) 30 OPV General term for oral Orimunex Polio vaccine (oral, trivalent) WYE (U.S.) Pariorix Mumps (live) SmithKline/RIT (Belgium)

35 Pavivac-Sevac Mumps (live) Institute of Immunology (Croatia) General term for pneumococcal PCV. PCV7 conjugate (7-valent) Diphtheria, tetanus, (acellular) Pediarix GSK (U.S.) 40 pertussis, hepatitis B, IPV Haemophilus influenzae type b (PRP- PedvaxHIB MRK (U.S.) OMP) Diphtheria, tetanus, (acellular) Penta AVP (Canada) pertussis, Hib, IPV 45 Diphtheria, tetanus, pertussis, polio, Pentacel AVP (Canada) Hib Diphtheria, tetanus, pertussis, polio, Pentacoq Hib 50 Diphtheria, tetanus, pertussis, polio, PENTAct-HIB Hib Diphtheria, tetanus, pertussis, polio, Pentavac Hib 55 Diphtheria, tetanus, pertussis, hepatitis Pentavalente B, Hib

36 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Pfizer Vax-Measles K x Measles (inactivated) 3/63 to 1970 Pfizer (U.S.) 5 Pfizer Vax-Measles L x Measles (live) 2/65 to 1970 Pfizer (U.S.) Pluserix Measles, mumps, rubella Pneumovax 23 Pneumococcal (polysaccharide) MRK (U.S.) 10 PNU-IMUNE 23x Pneumococcal (polysaccharide) WYE (U.S.) Diphtheria, tetanus, pertussis, polio, POLIAce 1 AVP (Argentina) HIB General term for pneumococcal PPV, PPV23 15 polysaccharide (23-valent) Prevnar Pneumococcal (7-valent, conjugate) WYE (U.S.) Priorix Measles, mumps, rubella (live) GSK (U.K.) Haemophilus influenzae type b (PRP- ProHIBIT x AVP (U.S.) 20 D) PRP-OMP Chemical abbreviation for PedvaxHIB PRP-T Chemical abbreviation for ActHIB

x 25 Purivax Polio (inactivated) 1956 to 1965 MRK (U.S.) QUADRAcel Diphtheria, tetanus, pertussis, polio AVP (Argentina) Diphtheria, tetanus, pertussis, polio, QUADRAcel / Hibest AVP (Argentina) Hib

30 Quadrigenx DTP + polio (1959-1968) PD (U.S.) Quatro-Virelon Diphtheria, tetanus, polio CHI (Germany) Diphtheria, tetanus, pertussis, Hib, Quintuple GSK (Mexico) Polio 35 R-HB Vaccine Hepatitis B (recombinant) Mitsubishi Chem Corp (Japan) R-VAC Rubella (live) Serum Institute (India) RA27/3 Rubella (live) MRK (U.S.)

40 RabAvert Rabies (PCEC) CHl (U.S.) Recombivax HB Hepatitis B (recombinant) MRK (U.S.) Respiratory syncytial virus immune Respigam, RSV-IVIG MEDI (U.S.) globulin (not a vaccine)

45 RIG (generic) Rabies immune globulin Bayer Corporation, AVP (U.S.) Rimevax Measles (live) SmithKline/RIT (Belgium) Rimparix Measles (live) SmithKline/RIT RIT - LM-2 Measles, mumps (live) Dong Shin Pharm (Korea) 50 MT - LM-3 Measles, mumps, rubella (live) Dong Shin Pharm (Korea) RotaShield, RRV-TVx Rotavirus 8/98 to 7/99 WYE (U.S.) Rouvax Measles (live, attenuated) AVP (France)

55 Rubeaten Berna Rubella (live) BER (Switzerland) Rubella (generic)x Rubella (live) 12/69 to 1972 Philips Roxane (U.S.)

37 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Rubellovac Rubella CHIR (Germany) 5 Rubelogenx Rubella (live) 12/69 to 1972 PD (U.S.) Rubeovaxx Measles (live) 2/63 to 1971 MRK (U.S.) Rudi-Rouvax Measles, rubella (live) AVP (France) 10 Rudivax Rubella (live, attenuated) AVP (France) RVA (generic) Rabies vaccine adsorbed BP (U.S.) Sabin General term for oral (live) polio vaccine Sahia Polio (live, oral) Multiple manufacturers 15 General term for injectable (inactivated) Salk polio vaccine Sandovac Influenza x 20 Serobacterin Pertussis - 1945 to 1954 MRK (U.S.) Sii Triple Antigen Diphtheria, tetanus, pertussis Serum Institute (India) Stamaril Yellow fever (live, attenuated) AVP (France) Respiratory syncytial virus immune Synagis (palizivumab) MEDI (U.S.) 25 globulin (not a vaccine) T. Polio Tetanus , polio AVP (Canada) -Institute Pasteur (Tunisia) T.A.B. Typhoid, paratyphoid (A & B) -Pharmaceutical Industries Corp. 30 (Burma) T-Immun Tetanus (adsorbed) Td (generic) Tetanus, diphtheria (adult formulation) AVP, BP (U.S.) Te/Vac/Ptap Tetanus 35 Te Anatoxal Tetanus BER (Europe) Telvaclptap Tetanus Tetagrip Tetanus, influenza AVP (France) 40 Veb Sachsisches Serumwerk Tetamun SSW Tetanus nonadsorbed (fluid) (Germany) Tetamyn Tetanus Bioclon, S.A. De C.V. (Mexico) CHIR (Germany) Veb Sachsisches Tetanol Tetanus (adsorbed) 45 Serumwerk Tetasorbat SSW Tetanus (adsorbed) (Germany) Tetavax Tetanus (adsorbed) AVP (France) Tetracoq 05 Diphtheria, tetanus, pertussis, polio AVP (France) 50 TetrAct-HIB Diphtheria, tetanus, pertussis, Hib Tetramune x Diphtheria, tetanus, pertussis, Hib WYE (U.S.) Diphtheria, tetanus, pertussis, polio - Tetravax" MRK (U.S.) 1959 to 1965 55

38 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Bacillus Calmette-Gudrin vaccine (for Tice BCG OTC (U.S.) 5 TB) TIG Tetanus immune globulin (generic) Bayer Corporation (U.S.) TOPV Trivalent oral polio vaccine Multiple manufacturers and countries

10 Titifica Typhoid and para typhoid Tresivac Lyopholized Measles, mumps, rubella Serum Institute (India) Diphtheria, tetanus, (acellular) Triacel pertussis

15 Diphtheria, tetanus, (acellular) Triacelluvax CHIR (Europe) pertussis Diphtheria, tetanus, (acellular) TriHIBit AVP (U.S.) pertussis, Hib

20 Tri-Immunol x Diphtheria, tetanus, pertussis WYE (U.S.) Trimovax Measles, mumps, rubella (live) AVP (France) Diphtheria, tetanus, pertussis- 1952 to Trinivacx MRK (U.S.) 1964 25 Diphtheria, tetanus, (acellular) Tripacel pertussis Diphtheria, tetanus, (acellular) Tripedia AVP (U.S.) pertussis 30 -Chowgule & Co. (India) -CSL Limited Triple antigen Diphtheria, tetanus, pertussis (Australia) Triple Sabin Polio (live, oral) Triple Diphtheria, tetanus, pertussis 35 Triple Viral Measles, mumps, rubella Diphtheria, tetanus (adsorbed), Trivacuna Leti Laboratory Leti (Spain) pertussis Trivax Diphtheria, tetanus (plain), pertussis Wellcome (U.K.) 40 Diphtheria, tetanus (adsorbed), Trivax-ad -EVN(UK) -Wellcome (UK) pertussis Trivax-Hib Diphtheria, tetanus, pertussis, Hib GSK (UK)

45 Trivb Diphtheria, tetanus, pertussis Measles, mumps, rubella (live, Triviraten BER (Switzerland) attenuated) Trivivac x Diphtheria, tetanus, pertussis MRK (U.S.)

50 Measles, mumps, rubella (live, Institute of Sera & Vaccines Trivivac Sevac attenuated) (Czechoslovakia) TT Tetanus toxoid (generic) AVP (U.S.) TT vaccine Tetanus toxoid (adsorbed) 55 Tussitrupin Forte Pertussis Staatliches Institut (Germany) Twinrix Hepatitis A & B (adult formulation) GSK (U.K., U.S.)

39 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Twinrix Junior Hepatitis A & B (pediatric formulation) GSK (U.S.) 5 Ty2la (Vivotif Berna) Typhoid (live, oral, lyophilized) BER (Switzerland) Tyne Tuberculosis (BCG) Sweden Typherix Typhoid GSK (U.K.) 10 Typhim Vi (ViCPs) Typhoid (parenteral, injectable) AVP (U.S., France) x Typhoid (inactivated, parenteral) WYE (US.) Typhopara-typhoidique Typhoid and para typhoid Finlay Vacunas y Sueros Centro de 15 VA-Mengoc-BC Meningococcal (Groups B & C) Investigation (Cuba) Vaccin Difteric Adsorbit Diphtheria toxoid (adsorbed) Cantacuzino Institute (Romania) Vaccin Combinat Diftero-Tetanic Diphtheria, tetanus (adsorbed) Cantacuzino Institute (Romania)

20 Vaccinum Morbillorum Vivum Measles (five) Moscow Research Institute (Russia) Vacina Triplice Viral Measles, mumps, rubella Vacina Triplice Diphtheria, tetanus, pertussis Instituto Butantan (Brazil) Vacina Dupla Diphtheria, tetanus Instituto Butantan (Brazil) 25 Vaksin Cacar Smallpox Vaksin Serap Diphtheria, tetanus, pertussis Perum Bio Farma (Indonesia) Vaksin Campak Kerig Measles (live, attenuated) Pasteur Institute (Indonesia) Cholera, typhoid and paratyphoid A, B 30 Vaksin Kotipa Perum Bio Farma (Indonesia) & C Vamoavax Measles, mumps (live) Institute of Immunology (Croatia) Vaqta Hepatitis A (inactivated) MRK (U.S.) 35 Behringwerke Aktiengesellschaft Varicellon Varicella zoster immunoglobulin (Germany) Institute of Sera and Vaccine Varie Smallpox (lyophilized) (Czechoslovakia) 40 Varilrix Varicella (live, Oka strain) GSK (Australia, Belgium) Varivax Varicella (live) MRK (U.S.) Vaxem-Hib Haemophilus influenzae type b CHIR (Italy) Vaxicoq Pertussis (adsorbed) AVP (France) 45 Vaxigrip Influenza Vaxipar Mumps (live) CHIR (Italy) VCDT Diphtheria, tetanus Cantacuzino Institute (Romania) 50 VDA Vaccin Difteric Adsorbit Diphtheria Cantacuzino Institute (Romania) ViCPs (Typhim Vi) Typhoid (inactivated, injectable) AVP (U.S.) Variola(smallpox)immuneglobulin(not VIG Distributed by CDC a vaccine) 55 Behringwerke Aktiengesellschaft Virelon T 20 Polio (live, oral, trivalent) (Germany)

40 EP 1 928 492 B1

(continued)

Product or trade name Antigen(s) Manufacturer (country) Virovac Massling, Perotid, Rubella Measles, mumps, rubella 5 Vivotif Berna () Typhoid (oral, live) BER (Switzerland) VT (Vacina Triplice) Diphtheria, tetanus, pertussis Instituto Butantan (Brazil) VTV (Vacina Triplice Viral) Measles, mumps, rubella 10 WR Measles (live, attenuated) Cantucuzino Institute (Romania) Varicella zoster immune globulin VZIG MA (U.S.) (generic) Welltrivax trivalente Diphtheria, tetanus, pertussis 15 YF-VAX Yellow fever AVP (U.S.) Zaantide Diphtheria anti-toxin Inst. of Immunology (Croatia) Zaantite Tetanus anti-toxin Inst. of Immunology (Croatia)

20 Zaditeadvax Diphtheria, tetanus Inst. of Immunology (Croatia) Zaditevax Diphtheria, tetanus Inst. of Immunology (Croatia) Meningococcus (polysaccharide, Zamevax A+C Inst. of Immunology (Croatia) Groups A & C) 25 Zamovax Measles (live) Inst. of Immunology (Croatia) Zamruvax Measles, rubella (live) Inst. of Immunology (Croatia) Zaruvax Rubella (live) Inst. of Immunology (Croatia) Diphtheria, tetanus, pertussis, 30 Zatetravax Inst. of Immunology (Croatia) parapertussis Zatevax Tetanus Inst. of Immunology (Croatia) Zatribavax Diphtheria, tetanus, pertussis Inst. of Immunology (Croatia)

35 Zatrivax Measles, rubella, mumps (live) Inst. of Immunology (Croatia)

3. A compound, which is 4-(wnino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydro- isoindol-2-yl)-piperidine-2,6-dione, for use in enhancing an immune response to a cancer vaccine in a subject, wherein the compound is formulated for administering to the subject prior to the administration of the vaccine to the 40 subject.

4. The compound for use of claim 3, wherein the vaccine is a vaccine against sarcoma, carcinoma, melanoma, lym- phoma and leukemia.

45 5. The compound for use of claim 3, wherein the vaccine is an antigen modified dendritic cell vaccine, a peptide vaccine, a whole tumor cell vaccine, or a viral vector vaccine.

6. A compound, which is 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione or 3-(4-amino-1-oxo-1,3-dihydro- isoindol-2-yl)-piperidine-2,6-dione, for use in enhancing an immune response to a vaccine against an infectious 50 disease in a subject, wherein the compound is formulated for administering to the subject prior to the administration of the vaccine to the subject.

7. The compound for use of claim 6, wherein the infectious disease is a disease caused by a virus, a bacterium, a fungus, and a parasite. 55 8. The compound for use of claim 7, wherein the infectious disease is hepatitis B.

41 EP 1 928 492 B1

9. The compound for use of claim 1, 3, or 6, wherein the compound is formulated to be administered from 10 days to 12 hours prior to the administration of the vaccine, from 7 days to 12 hours prior to the administration of the vaccine, from 5 days to 1 day prior to the administration of the vaccine, or from 3 days to 1 day prior to the administration of the vaccine. 5 10. The compound for use of claim 1, 3 or 6, wherein the compound is further formulated for a second administration after the administration of the vaccine.

11. The compound for use of claim 10, wherein the compound is formulated to be administered from 12 hours to 10 10 days after the administration of the vaccine, from 12 hours to 7 days after the administration of the vaccine, from 1 day to 5 days after the administration of the vaccine, or from 1 day to 3 days after the administration of the vaccine.

Patentansprüche 15 1. Verbindung, die 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindolin-1,3-dion oder 3-(4-Amino-1-oxo-1,3-dihydro-isoin- dol-2-yl)-piperidin-2,6-dion ist, zur Verwendung bei der Anregung einer verstärkten Immunantwort auf eine Vakzine in einem Patienten, wobei die Verbindung zur Verabreichung an den Patienten vor Einführung der Vakzine in den Patienten hergerichtet ist. 20 2. Verbindung zur Verwendung gemäß Anspruch 1, wobei die Vakzine eine Vakzine ist, die in der nachfolgenden Tabelle aufgelistet ist:

25 Produkt- oder Handelsname Antigen(e) Hersteller (Land) A.D.T Diphtherie, Tetanus (adsorbiert) Commonwealth (Australien) A.K.D.S. Diphtherie, Tetanus, Pertussis AC Vax Meningococcus (Polysaccharid) GSK (U.K.) 30 Diphtherie, Tetanus, Pertussis Acel-Imune x WYE (U.S.) (azellulär) ACTAcel Diphtherie, Tetanus, Pertussis, Hib AVP (Argentinien)

35 ActHlB Haemophilus influenzae Typ b (PRP-T) AVP (U.S.) Chemo-Sero-Therapeutic Resh Inst Aimmugen Hepatitis A (inaktiviert) (Japan) Aldiana Diphtherie (absorbiert) Sevac (Tschechoslowakei) 40 Alditeana Diphtherie, Tetanus (absorbiert) Sevac (Tschechoslowakei) Diphtherie, Tetanus (adsorbiert), Alditerpera Sevac (Tschechoslowakei) Pertussis Amaril Gelbfieber AVP (Frankreich) 45 AMC Haemophilus influenzae, Typ b Anadifterall Diphtherie (adsorbiert) CHIR (Italien) Anatetall Tetanus (adsorbiert) CHIR (Italien)

50 Arilvax Gelbfieber MEDI (U.K.) Attenuvax x Masern (lebend, weiter attenuiert) MRK (U.S.) AVAC-1, AVA Anthrax AVAXIM Hepatitis A 55 Haemophilus influenzae Typ b B-CAPSA x Mead Johnson U.S.) (Polysaccharid, 1987 bis 1989)

42 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) BayGam Humanes Immunoglobulin Bayer Corporation (U.S.) 5 BayHepB Hepatitis B Immunoglobulin (human) Bayer Corporation (U.S.) BayRab Tollwut-Immunoglobulin Bayer Corporation (U.S.) BayTet Tetanus-Immunoglobulin (human) Bayer Corporation (U.S.) 10 BCG Tuberkulose Mehrere Hersteller und Länder Begrivac Influenza (Spaltvirus) CHIR (Deutschland) Biavax II x Röteln, Mumps (lebend) MRK (U.S.) Biavax x Röteln, Mumps (lebend) MRK (U.S.) 15 Botulismus-Immunoglobulin (keine BIG Vakzine) Biken-HB Hepatitis B (rekombinant) BIK (Japan) Hepatitis B (rekombinant, adsorbiert, Chemo-Sero-Therapeutic Resh Inst 20 Bimmugen aus Hefe stammend) (Japan) BioThrax Anthrax (adsorbiert) BPT (U.S.) Biviraten Berna Masern, Mumps (lebend) BER (Schweiz) 25 BVAC Botulinum antitoxin (nur für U.S. Militär-Gebrauch) Diphtherie, Tetanus (pädiatrisch, C.D.T. Commonwealth (Australien) adsorbiert) Celluvax Pertussis (azellulär) CHIR (Italien) 30 Cendevax x Röteln (lebend) 3/70 bis 1976 RIT/SmithKline & French (U.S.) Diphtherie, Tetanus, Pertussis Certiva x Baxter Hyland (U.S.) (azellulär) Cocquelucheau Pertussis (adsorbiert) AVP (Frankreich) 35 Hepatitis B, Haemophilus influenza Typ Comvax MRK (U.S.) b Diphtherie, Tetanus, Pertussis Daptacel AVP (U.S.) (azellulär) 40 Diphtherie, Tetanus, Pertussis D.S.D.P.T. Dong Shin Pharm (Korea) (adsorbiert) D.T. Bis Rudivax Diphtherie, Tetanus, Röteln AVP (Frankreich) Di Te Per Pol Impfstoff Diphtherie, Tetanus, Pertussis, Polio BER (Schweiz) 45 Di-Te-Pol Diphtherie, Tetanus, Polio Statens Seruminstitut (Dänemark) Dif-Tet-All Diphtherie, Tetanus CHIR (Italien) DIFTAVAX Diphtherie, Tetanus, Polio 50 DiTe Anatoxal Diphtherie, Tetanus (adsorbiert) BER (Schweiz) Ditoxim Diphtherie, Tetanus (adsorbiert) Dong Shin Pharm (Korea) Double Anigen B.I. Diphtherie, Tetanus Bengal Immunity Co (Indien) Dryvax Pocken WYE (U.S.) 55 Diphtherie, Tetanus (für pädiatrischen DT AVP (U.S.) AVP (U.S.) Gebrauch)

43 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Diphtherie Tetanus (für pädiatrischen DT x WYE (U.S.) 5 Gebrauch) Diphtherie, Tetanus, Salmonella typhi, DT TAB AVP (Frankreich) Paratyphi A & B Diphtherie, Tetanus, Pertussis DTaP (generisch) AVP, WYE, GSK (U.S.) 10 (azellulär) Diphtherie, Tetanus, Pertussis DTwP (generisch) x AVP, WYE, GSK (U.S.) (Ganzzell) Dual Antigen SII Diphtherie, Tetanus (adsorbiert) Serum Institute of India (Indien) 15 Ecolarix x Masern, Röteln (lebend) RIT/SmithKline (U.S.) Polio (inaktiviert, verstärkte eIPV AVP (U.S.) Wirksamkeit) Engerix-B Hepatitis B GSK (U.K., U.S.) 20 Epaxal Berna Hepatitis A -virosomale Vakzine BER (Schweiz) Ervevax RA 27/3 Röteln (lebend) GSK (Belgien) Flu Shield x Influenza WYE (U.S.) 25 Fluad, Agrippal-S I Influenza CHIR (Italien) FluMist Influenza (lebend, attenuiert, intranasal) MEDI (U.S.) Fluogen Influenza PD (U.S.) Fluvirin Influenza EVN (U.S.) 30 Fluzone Influenza AVP (U.S.) Funed-CEME Diphtherie, Tetanus, Pertussis Belo Horizonte (Brasilien) GenHevac B Pasteur Hepatitis B 35 Gunevax Röteln CHIR (Italien) Havrix Hepatitis A GSK (U.K., US.) H-BIG Hepatitis B Immunoglobulin NABI, Bayer Corporation (U.S.)

40 HbOC Chemische Abkürzung für HibTITER WYE (U.S.) HBY Hepatitis B (rekombinant) KGC (Japan) Heprecomb Hepatitis B (aus Hefe stammend) BER (Schweiz) Hepatitis B (aus Plasma stammend) Heptavax B x MRK (U.S.) 45 1982 bis Hevac B Hepatitis B (aus Plasma stammend) AVP (Frankreich) Diphtherie, Tetanus, Pertussis, Polio, Hexavac AVP (Europa) AVP (Europa) Hepatitis B, Hib 50 HibTITER Haemophilus influenzae Typ b (HbOC) WYE (U.S.) Hinkuys karokoe Pertussis (adsorbiert) Natl. Public Health Institute (Finland) HPV-77; DK-5 Röteln (lebend) 1969-1979 MRK. (U.S.) HPV-77; DK-12 Röteln (lebend) 19704973 MRK. (U.S.) 55

44 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) HRIG Tollwut-Immunoglobulin AVP; Bayer Corporation (U.S.) 5 Humotet-anti Tetanus Tetanus Wellcome (U.K.) Hyper-Tet (jetzt "BayTet") Tetanus-Immunoglobulin Bayer Corporation (U.S.) IBV Polio (inaktiviert) Statens Seruminstitut (Dänemark) 10 Immune Globulin Intramuscular MA, BPT, New York Blood Ctr, Bayer Breitenspektrum-Immunoglobuline (Human) Corporation, CEN (U.S.) Imogam Rabies - HT Tollwut-Immunoglobulin AVP (U.S.) Imovax Tollwut AVP (U.S.) 15 Imovax Parotiditis Mumps AVP (Frankreich) Imovax Polio Polio AVP (Frankreich) Imovax Sarampion Masern AVP (Frankreich)

20 Imovax D.T. Diphtherie, Tetanus Imovax Gripe Influenza Imovax R.O.R. Masern, Röteln, Mumps (lebend) AVP (Frankreich) Imovax Rubeola Masern AVP (International) 25 Imovax Mumps Mumps Imovax Oreilions Mumps AVP (Frankreich) Imovax Rabies I.D. Tollwutimpfstoff (HDCV) AVP (U.S.)

30 Imovax Rabies I.M. Tollwutimpfstoff (HDCV) AVP (U.S.) Diphtherie, Tetanus, Pertussis Infanrix GSK (Belgien, U.S.) (azellulär) Ipad TP Tetanus, Polio AVP (Frankreich) 35 Polio (verstärkte Wirksamkeit, IPOL AVP (U.S.) inaktiviert) Allgemeine Bezeichnung für IPV Polio (inaktiviert) inaktivierten Polio-Impfstoff 40 Istivac Influenza JE-VAX Japanische Enzephalitis AVP (U.S.) Kaksoisrokote Dubbelvaccin Diphtherie, Tetanus (adsorbiert) Natl. Public Health Institute (Finnland) Statens Institutt for Folkehelse 45 Kikhoste-Vaksine Pertussis (Norwegen) Swiss Serum and Vaccine Institute Lancy Vaxina x Pocken (Schweiz) Lavantuu tirokote Typhus Central Pub Health Lab (Finnland) 50 Liovax x Pocken CHIR (Italien) Lirubel x Masern, Röteln (lebend) 4/74 bis 6/78 Dow/PitneyMoore (U.S.) Lirugen Masern AVP (Int’I)

55 Lirugen x Masern (lebend) 2/65 bis 6/78 Dow (U.S.) LM - 3 RIT Masern, Mumps, Röteln (lebend) Dong Shin Pharm (Korea)

45 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) LM - 2 RIT Masern, Mumps (lebend) Dong Shin Pharm (Korea) 5 LTEANAS Imuna Tetanus (adsorbiert) Imuna sp. (Slowakei) LYMErix x Lyme-Borreliose GSK (U.S.) Lyovac Attenuvax x Masern (lebend, attenuiert) MRK (U.S.) 10 Lyovac Meruvax x Röteln (lebend) MRK (U.S.) M-R Vax II x Masern, Röteln (lebend) MRK (U.S.) M-Vax x Masern (lebend) 5/63 bis 1979 WYE (U.S.) Masern-Impfstoff SSW Masern (lebend) 15 Measles Vaccine DK3 x Masern (lebend) 1964 bis 1972 Philips Roxane, Inc. (U.S.) Masern (inaktiviert) 1963 bis 1966 Measles x Eli Lilly (U.S.) Masern (lebend) 12/64 bis 1974 Meningococcus (Polysaccharid) 20 Mencevax A SmithKline/RIT (Belgien) (Gruppe A) Meningitec Meningococcus (Konjugat) (Gruppe C) WYE (U.K., Australien) Meningococcus (Polysaccharid) Menomune-A/C/W135 AVP (U.S.) 25 (Gruppen A,C, Y, W435) Meningococcus (Polysaccharid) Menpovax 4 CHIR (Italien) (Gruppen A &C) Menpovax A+C Meningococcus (Gruppen A & C) CHIR (Italien)

30 Meruvax x Röteln (lebend) 6/69 bis MRK (U.S.) Meruvax 11 Röteln (lebend) MRK (U.S.) Mevilin-L x Masern (lebend) Glaxo Operations Masern, Mumps, Röteln (lebend) 6/71 MMR x MRK (U.S.) 35 bis Masern, Mumps, Röteln (lebend) 4/74 MMR (generisch) x Dow Chemical (U.S.) bis 6178 M-M-R II Masern, Mumps, Röteln (lebend) MRK (U.S.) 40 Moniarix Pneumococcal (Polysaccharid) SmithKline/RIT (Belgien) Institute of Sera and vaccines Mopavac Sevac Masern, Mumps (lebend, attenuiert) (Tschechoslowakei) Polio (lebend, Sabin, monovalent Typen 45 MOPV x WYE (US.) I, II, III) Morbilvax Masern (lebend, attenuiert) CHIR (Italien) Morubel Masern, Röteln (lebend, attenuiert) CHIR (Italien)

50 Moruman Berne Masern Immunoglobulin BER (Schweiz) Masern, Mumps, Röteln (lebend, Morupar CHIR (Italien) attenuiert) Movivac Masern (lebend, attenuiert) 55 M-R VAX x Masern, Röteln (lebend) 7/71 bis MRK (U.S.) Mumaten Berne Mumps (lebend) BER (Schweiz)

46 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Mumps (generisch) x Mumps (lebend) 4/74 bis 6178 Dow Chemical (U.S.) 5 Mumps (generisch)" x Mumps (inaktiviert) 1950 bis 1978 WYE (U.S.) Mumps (generisch) x Mumps (inaktiviert) 1950 bis 1977 Eli Lilly (U.S.) Mumpsvax x Mumps (lebend) MRK (U.S.) 10 Mutagrip Influenza Nabi-HB Hepatitis B Immunoglobulin NABI (U.S.) Nothav Hepatitis A CHI (Italien) OmniHIB x Haemophilus influenzae Typ b (PRP-T) GSK, AVP (U.S.) 15 Allgemeiner Begriff für oralen Polio- OPV Impfstoff Orimune x Polio-Impfstoff (oral, trivalent) WYE (U.S.)

20 Pariorix Mumps (lebend) SmithKline/RIT (Belgien) Pavivac-Sevac Mumps (lebend) Institute of Immunology (Kroatien) Allgemeiner Begriff für Pneumokokken PCV, PCV7 Konjugat (7-valent) 25 Diphtherie, Tetanus, Pertussis Pediarix GSK (U.S.) (azellulär), Hepatitis B, IPV Haemophilus influenzae Typ b (PRP- PedvaxHIB MRK (U.S.) OMP)

30 Diphtherie, Tetanus, Pertussis Penta AVP (Canada) (azellulär), Hib, IPV Diphtherie, Tetanus, Pertussis, Polio, Pentacel AVP (Canada) Hib Diphtherie, Tetanus, Pertussis, Polio, 35 Pentacoq Hib Diphtherie, Tetanus, Pertussis, Polio, PENTAct-HIB Hib Diphtherie, Tetanus, Pertussis, Polio, 40 Pentavac Hib Diphtherie, Tetanus, Pertussis, Pentavalente Hepatitis B, Hib

x 45 Pfizer Vax-Measles K Masern (inaktiviert) 3/63 bis 1970 Pfizer (U.S.) Pflzer Vax-Measles L x Masern (lebend) 2/65 bis 1970 Pfizer (U.S.) Pluserix Masern, Mumps, Röteln Pneumovax 23 Pneumokokkal (Polysaccharid) MRK (U.S.) 50 PNU-IMUNE 23 x Pneumokokkal (Polysaccharid) WYE (U.S.) Diphtherie, Tetanus, Pertussis, Polio, POLIAce1 AVP (Argentinien) HIB Allgemeiner Begriff für pneumokokkales PPV,PPV23 55 Polysaccharid (23-valent)

47 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Prevnar Pneumokokkal (7-valent, Konjugat) WYE (U.S.) 5 Priorix Masern, Mumps, Röteln (lebend) GSK (U.K.) ProHIBIT x Haemophilus influenzae Typ b (PRP-D) AVP (U.S.) PRP-OMP Chemische Abkürzung für PedvaxHIB 10 PRP-T Chemische Abkürzung für ActHIB Purivax x Polio (inaktiviert) 1956 bis 1965 MRK (U.S.) QUADRAcel Diphtherie, Tetanus, Pertussis, Polio AVP (Argentinien) Diphtherie, Tetanus, Pertussis, Polio, 15 QUADRAcel/Hibest AVP (Argentinien) Hib Quadrigen x DTP + Polio (1959-1968) PD (U.S.) Quatro-Virelon Diphtherie, Tetanus, Polio CHI (Deutschland) Diphtherie, Tetanus, Pertussis, Hib, 20 Quintuple GSK (Mexiko) Polio R-HB Vaccine Hepatitis B (rekombinant) Mitsubishi Chern Corp (Japan) R-VAC Röteln (lebend) Serum Institute (Indien) 25 RA27/3 Röteln (lebend) MRK (U.S.) RabAvert Tollwut (PCEC) CHI (U.S.) Recombivax HB Hepatitis B (rekombinant) MRK (U.S.) Respiratorisches Synzytial-Virus- 30 Respigam, RSV-IVIG MEDI (U.S.) Immunoglobulin (keine Vakzine) RIG (generisch) Tollwut-Immunoglobulin Bayer Corporation, AVP (U.S.) Rimevax Masern (lebend) SmithKline/RIT (Belgien)

35 Rimparix Masern (lebend) SmithKline/RIT RIT - LM-2 Masern, Mumps (lebend) Dong Shin Pharm (Korea) RIT - LM-3 Masern, Mumps, Röteln (lebend) Dong Shin Pharm (Korea) RotaShield, RRV-TV x Rotavirus 8/98 bis 7/99 WYE (U.S.) 40 Rouvax Masern (lebend, attenuiert) AVP (Frankreich) RubeatenBerna Röteln (lebend) BER (Schweiz) Rubella (generisch) x Röteln (lebend) 12/69 bis 1972 Philips Roxane (U.S.)

45 Rubellovac Röteln CHIR (Deutschland) Rubelogen x Röteln (lebend) 12/69 bis 1972 PD (U.S.) Rubeovax x Masern (lebend) 2/63 bis 1971 MRK (U.S.) Rudi-Rouvax Masern, Röteln (lebend) AVP (Frankreich) 50 Rudivax Röteln (lebend, attenuiert) AVP (Frankreich) RVA (generisch) Tollwutimpfstoff adsorbiert BP (U.S.) Allgemeiner Begriff für oralen (lebend) Sabin Polio-Impfstoff 55

48 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Sahia Polio (lebend, oral) Mehrere Hersteller 5 Allgemeiner Begriff für injizierbaren Salk (inaktivierten) Polio-Impfstoff Sandovac Influenza x 10 Serobacterin Pertussis 1945 bis 1954 MRK (U.S.) Sii Triple Antigen Diphtherie, Tetanus, Pertussis Serum Institute (Indien) Stamaril Gelbfieber (lebend, attenuiert) AVP (Frankreich) Respiratorisches Synzytial-Virus- Synagis (Palizivumab) MEDI (U.S.) 15 Immunoglobulin (keine Vakzine) T. Polio Tetanus toxoid, Polio AVP (Canada) -Institute Pasteur (Tunesien) T.A.B. Typhus, Paratyphus (A & B) -Pharmaceutical Industries Corp. 20 (Burma) T-Immun Tetanus (adsorbiert) Tetanus, Diphtherie (Formulierung für Td (generisch) AVP, BP (U.S.) Erwachsene) 25 TeNac/Ptap Tetanus Te Anatoxal Tetanus BER (Europa) Telvaclptap Tetanus Tetagrip Tetanus, Influenza AVP (Frankreich) 30 Veb Sächsisches Serumwerk Tetamun SSW Tetanus (flüssig, nicht adsorbiert) (Deutschland) Tetamyn Tetanus Bioclon, S.A. De C.V. (Mexico)

35 Tetanol Tetanus (adsorbiert) CHIR (Deutschland) Veb Sächsisches Serumwerk Tetasorbat SSW Tetanus (adsorbiert) (Deutschland) Tetavax Tetanus (adsorbiert) AVP (Frankreich) 40 Tetracoq 05 Diphtherie, Tetanus, Pertussis, Polio AVP (Frankreich) TetrAct-HIB Diphtherie, Tetanus, Pertussis, Hib Tetramune x Diphtherie, Tetanus, Pertussis, Hib WYE (U.S.) Diphtherie, Tetanus, Pertussis, Polio 45 Tetravax x MRK (U.S.) 1959 bis 1965 Bacillus Calmette-Guerin-Vakzine (für Tice BCG OTC (U.S.) TB) TIG Tetanus Immunoglobulin (generisch) Bayer Corporation (U.S.) 50 TOPV Trivalenter oraler Polio-Impfstoff Mehrere Hersteller und Länder Titifica Typhus und Paratyphus Tresivac Lyopholized Masern, Mumps, Röteln Serum Institute (Indien) 55 Diphtherie, Tetanus, Pertussis Triacel (azellulär)

49 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Diphtherie, Tetanus, Pertussis Triacelluvax CHIR (Europa) 5 (azellulär) Diphtherie, Tetanus, Pertussis TriHIBit AVP (U.S.) (azellulär), Hib Tri-Immunol x Diphtherie, Tetanus, Pertussis WYE (U.S.) 10 Trimovax Masern, Mumps, Röteln (lebend) AVP (Frankreich) Diphtherie, Tetanus, Pertussis 1952 bis Trinivac x MRK (U.S.) 1964 Diphtherie, Tetanus, Pertussis 15 Tripacel (azellulär) Diphtherie, Tetanus, Pertussis Tripedia AVP (U.S.) (azellulär) -Chowgule & Co. (Indien) -CSL 20 Triple antigen Diphtherie, Tetanus, Pertussis Limited (Australien) Triple Sabin Polio (lebend, oral) Triple Diphtherie, Tetanus, Pertussis

25 Triple Viral Masern, Mumps, Röteln Diphtherie, Tetanus (adsorbiert), Trivacuna Leti Laboratory Leti (Spanien) Pertussis Diphtherie, Tetanus (gewöhnlich), Trivax Wellcome (U.K.) 30 Pertussis Diphtherie, Tetanus (adsorbiert), Trivax-ad -EVN(UK) -Wellcome (UK) Pertussis Trivax-Hib Diphtherie, Tetanus, Pertussis, Hib GSK (UK)

35 Trivb Diphtherie, Tetanus, Pertussis Masern, Mumps, Röteln (lebend, Triviraten BER (Schweiz) attenuiert) Trivivac x Diphtherie, Tetanus, Pertussis MRK (U.S.) 40 Masern, Mumps, Röteln (lebend, Institute of Sera & Vaccines Trivivac Sevac attenuiert) (Tschechoslowakei) TT Tetanus-Toxoid (generisch) AVP (U.S.) TT vaccine Tetanus-Toxoid (adsorbiert) 45 Tussitrupin Forte Pertussis Staatliches Institut (Deutschland) Hepatitis A & B (Formulierung für Twinrix GSK (U.K., U.S.) Erwachsene) Twinrix Junior Hepatitis A & B (Formulierung für Kinder) GSK (U.S.) 50 Ty21a (Vivotif Berna) Typhus (lebend, oral, lyophilisiert) BER (Schweiz) Tyne Tuberkulose (BCG) Schweden Typherix Typhus GSK (U.K.) 55 Typhim Vi (ViCPs) Typhus (parenteral, injizierbar) AVP (U.S., Frankreich) Typhoid Vaccine x Typhus (inaktiviert, parenteral) WYE (U.S.)

50 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Typhopara-typhoidique Typhus und Paratyphus 5 Finlay Vacunas y Sueros Centro de VA-Mengoc-BC Meningokokkal (Gruppen B & C) Investigation (Kuba) a Vaccin Difteric Adsorbit Diphtherie toxoid (adsorbiert) Cantacuzino Institute (Rumänien)

10 Vaccin Combinat Diftero-Tetanic Diphtherie, Tetanus (adsorbiert) Cantacuzino Institute (Rumänien) Moscow Research Institute Vaccinum Morbillorum Vivum Masern (lebend) (Russland) Vacina Triplice Viral Masern, Mumps, Röteln

15 Vacina Triplice Diphtherie, Tetanus, Pertussis Instituto Butantan (Brasilien) Vacina Dupla Diphtherie, Tetanus Instituto Butantan (Brasilien) Vaksin Cacar Pocken Vaksin Serap Diphtherie, Tetanus, Pertussis Perum Bio Farrna (Indonesien) 20 Vaksin Campak Kerig Masern (lebend, attenuiert) Pasteur Institute (Indonesien) Cholera, Typhus und Paratyphus A, B & Vaksin Kotipa Perum Bio Farma (Indonesien) C

25 Vamoavax Masern, Mumps (lebend) Institute of Immunology (Kroatien) Vaqta Hepatitis A (inaktiviert) MRK (U.S.) Behringwerke Aktiengesellschaft Varicellon Varicella zoster-Immunoglobulin (Deutschland)

30 Institute of Sera and Vaccine Varie Pocken (lyophilisiert) (Tschechoslowakei) Varilrix Varicella (lebend, Oka-Stamm) GSK (Australien, Belgien) Varivax MRK (U.S.) 35 Vaxem-Hib Haemophilus influenzae Typ b CHIR (Italien) Vaxicoq Pertussis (adsorbiert) AVP (Frankreich) Vaxigrip Grippe

40 Vaxipar Mumps (lebend) CHIR (Italien) VCDT Diphtherie, Tetanus Ip Cantacuzino Institute (Rumänien) VDA Vaccin Difteric Adsorbit Diphtherie Cantacuzino Institute (Rumänien) ViCPs (Typhim Vi) Typhus (inaktiviert, injizierbar) AVP (U.S.) 45 Variola (Pocken)-Immunoglobulin VIG Vertrieb durch CDC (keine Vakzine) Behringwerke Aktiengesellschaft Virelon T 20 Polio (lebend, oral, trivalent) (Deutschland) 50 Virovac Massling, Perotid, Rubella Masern, Mumps, Röteln Vivotif Bern (Ty21a) Typhus (oral, lebend) BER (Schweiz) VT (Vacina Triplice) Diphtherie, Tetanus, Pertussis Instituto Butantan (Brasilien) VTV (Vacina Triplice Viral) Masern, Mumps, Röteln 55 VVR Masern (lebend, attenuiert) Cantucuzino Institute (Rumänien)

51 EP 1 928 492 B1

(fortgesetzt)

Produkt- oder Handelsname Antigen(e) Hersteller (Land) Varicella zoster-Immunoglobulin VZIG MA (U.S.) 5 (generisch) Welltrivax trivalente Diphtherie, Tetanus, Pertussis YF-VAX Gelbfieber AVP (U.S.)

10 Zaantide Diphtherie Anti-Toxin Inst. of Immunology (Kroatien) Zaantite Tetanus Anti-Toxin Inst. of Immunology (Kroatien) Zaditeadvax Diphtherie, Tetanus Inst. of Immunology (Kroatien) Zaditevax Diphtherie, Tetanus Inst. of Immunology (Kroatien) 15 Meningococcus (Polysaccharid, Zamevax A+C Inst. of Immunology (Kroatien) Gruppen A & C) Zamovax Masern (lebend) Inst. of Immunology (Kroatien) Zamruvax Masern, Röteln (lebend) Inst. of Immunology (Kroatien) 20 Zaruvax Röteln (lebend) Inst. of Immunology (Kroatien) Diphtherie, Tetanus, Pertussis, Zatetravax Inst. of Immunology (Kroatien) Parapertussis

25 Zatevax Tetanus Inst. of Immunology (Kroatien) Zatribavax Diphtherie, Tetanus, Pertussis Inst. of Immunology (Kroatien) Zatrivax Masern, Röteln, Mumps (lebend) Inst. of Immunology (Kroatien)

30 3. Verbindung, die 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindolin-1,3-dion oder 3-(4-Amino-1-oxo-1,3-dihydro-isoin- dol-2-yl)-piperidin-2,6-dion ist, zur Verwendung bei der Verstärkung einer Immunantwort auf eine Krebsvakzine in einem Patienten, wobei die Verbindung zur Verabreichung an den Patienten vor der Verabreichung der Vakzine an den Patienten hergerichtet ist.

35 4. Verbindung zur Verwendung gemäß Anspruch 3, wobei die Vakzine eine Vakzine gegen Sarkom, Karzinom, Me- lanom, Lymphom und Leukämie ist.

5. Verbindung zur Verwendung gemäß Anspruch 3, wobei die Vakzine eine Antigenmodifizierte dendritische Zellvak- zine, eine Peptidvakzine, eine Ganztumorzellvakzine oder eine virale Vektor-Vakzine ist. 40 6. Verbindung, die 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindolin-l,3-dion oder 3-(4-Amino-1-oxo-1,3-dihydro-isoin- dol-2-yl)-piperidin-2,6-dion ist, zur Verwendung bei der Verstärkung einer Immunantwort auf eine Vakzine gegen eine Infektionskrankheit in einem Patienten, wobei die Verbindung zur Verabreichung an den Patienten vor Verab- reichung der Vakzine an den Patienten hergerichtet ist. 45 7. Verbindung zur Verwendung gemäß Anspruch 6, wobei die Infektionskrankheit eine Krankheit ist, die durch einen Virus, ein Bakterium, einen Pilz oder einen Parasiten verursacht ist.

8. Verbindung zur Verwendung gemäß Anspruch 7, wobei die Infektionskrankheit Hepatitis B ist. 50 9. Verbindung zur Verwendung gemäß Anspruch 1, 3 oder 6, wobei die Verbindung zur Verabreichung von 10 Tagen bis 12 Stunden vor Verabreichung der Vakzine, von 7 Tagen bis 12 Stunden vor Verabreichung der Vakzine, von 5 Tagen bis 1 Tag vor Verabreichung der Vakzine, oder von 3 Tagen bis 1 Tag vor Verabreichung der Vakzine hergerichtet ist. 55 10. Verbindung zur Verwendung gemäß Anspruch 1, 3 oder 6, wobei die Verbindung ferner für eine zweite Verabreichung nach der Verabreichung der Vakzine hergerichtet ist.

52 EP 1 928 492 B1

11. Verbindung zur Verwendung gemäß Anspruch 10, wobei die Verbindung zur Verabreichung von 12 Stunden bis 10 Tagen nach Verabreichung der Vakzine, von 12 Stunden bis 7 Tagen nach Verabreichung der Vakzine, von 1 Tag bis 5 Tagen nach Verabreichung der Vakzine, oder von 1 Tag bis 3 Tagen nach Verabreichung der Vakzine hergerichtet ist. 5

Revendications

1. Composé, à savoir la 4-(amino)-2-(2,6-dioxo(3-pipéridyl)isoindoline-1,3-dione ou la 3-(4-amino-1-oxo-1,3-dihydro- 10 isoindol-2-yl)-pipéridine-2,6-dione, à utiliser pour déclencher une réponse immunitaire amplifiée à partir d’un vaccin dans un sujet, le composé étant formulé pour être administré au sujet avant l’introduction du vaccin dans le sujet.

2. Composé à utiliser selon la revendication 1, dans lequel le vaccin est un vaccin répertorié dans le tableau suivant :

15 Produit ou dénomination Antigène(s) Fabricant (pays) commerciale A.D.T. Diphtérie, tétanos (adsorbé) Commonwealth (Australie) 20 A.K.D.S. Diphtérie, tétanos, coqueluche AC Vax Méningocoque (polysaccharide) GSK (Royaume-Uni) Diphtérie, tétanos, coqueluche Acel-Immunex WYE (USA) (acellulaire) 25 ACTAcel Diphtérie, tétanos, coqueluche, Hib AVP (Argentine) Haemophilus influenzae de type b ActHIB AVP (USA) (PRP-T) Chemo-Sero-Therapeutic Reshinst Aimmugen Hépatite A (inactivé) 30 (Japon) Aldiana Diphtérie (absorbé) Sevac (Tchécoslovaquie) Alditeana Diphtérie, tétanos (absorbé) Sevac (Tchécoslovaquie) Diphtérie, tétanos (adsorbé), 35 Alditerpera Sevac (Tchécoslovaquie) coqueluche Amaril Fièvre jaune AVP (France) AMC Haemophilus influenzae, type b

40 Anadifterall Diphtérie (adsorbé) CHIR (Italie) Anatetall Tétanos (adsorbé) CHIR (Italie) Arilvax Fièvre jaune MEDI (Royaume-Uni) Attenuvaxx Rougeole (vivant, plus atténué) 45 AVAC-1, AVA Anthrax AVAXIM Hépatite A Haemophilus influenzae, type b B-CAPSAx Mead Johnson (USA) 50 (polysaccharide, 1987 à 1989) BayGam Immunoglobuline humaine Bayer Corporation (USA) Immunoglobuline (humaine) BayHep B Bayer Corporation (USA) hépatite B.

55 BayRab Immunoglobuline rabique Bayer Corporation (USA) Immunoglobuline (humaine) BayTet Bayer Corporation (USA) tétanique

53 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 BCG Tuberculose Plusieurs fabricants et plusieurs pays Begrivac Grippe (vaccin à subunités virales) CHIR (Allemagne) Biavax IIx Rubéole, oreillons (vivant) MRK (USA) x 10 Biavax Rubéole, oreillons (vivant) MRK (USA) Immunoglobuline botulique (non BIG vaccin) Biken-HB Hépatite B (recombinant) BIK (Japon)

15 Hépatite B (recombinant, adsorbé, Chemo-Sero-Therapeutic Reshinst Bimmugen Immugen dérivé de levure) (Japon) Bio Thrax Anthrax (adsorbé) BPT (USA) Biviraten Berna Rougeole, oreillons (vivant) BER (Suisse) 20 BVAC Antitoxine botulinique (à usage militaire aux USA) Diphtérie, tétanos (pédiatrique, C.D.T. Commonwealth (Australie) adsorbé) Celluvax Coqueluche (acellulaire) CHIR (Italie) 25 Cendevaxx Rubéole (vivant) 3/70 à 1976 RIT/SmithKline & French (USA) Diphtérie, tétanos, coqueluche Certivax Baxter Hyland (USA) (acellulaire) Cocquelucheau Coqueluche (adsorbé) AVP (France) 30 Hépatite B, Haemophilus Comvax MRK (USA) influenzae, type b Diphtérie, tétanos, coqueluche Daptacel AVP (USA) (acellulaire) 35 Diphtérie, tétanos, coqueluche D.S.D.P.T. Dong Shin Pharm (Corée) (adsorbé) D.T. Bis Rudivax Diphtérie, tétanos, rubéole AVP (France) Diphtérie, tétanos, coqueluche, 40 Di Te Per Pol Impfstoff BER (Suisse) polio Di-Te-Pol Diphtérie, tétanos, polio Statens Seruminstitut (Danemark) Dif-Tet-All Diphtérie, tétanos CHIR (Italie) 45 DIFTAVAX Diphtérie, tétanos, polio DiTe Anatoxal Diphtérie, tétanos (adsorbé) BER (Suisse) Ditoxim Diphtérie, tétanos (adsorbé) Dong Shin Pharm (Corée) Double Antigen B.I. Diphtérie, tétanos Bengal Immunity Co (Inde) 50 Dryvax Variole WYE (USA) Diphtérie, tétanos (à usage DT AVP (USA) pédiatrique) Diphtérie, tétanos (à usage 55 DTx WYE (USA) pédiatrique)

54 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Diphtérie, tétanos, Salmonella DT TAB AVP (France) typhi, Paratyphi A & B Diphtérie, tétanos, coqueluche AVP, GYE, GSK (USA) AVP, GYE, DTAP (générique) DTaP (générique) (acellulaire) GSK (USA) 10 Diphtérie, tétanos, coqueluche DTwP (générique)x AVP ,GYE, GSK USA) (cellule entière) Dual Antigen SII Diphtérie, tétanos (adsorbé) Serum Institute of India (Inde) Ecoaltrixx Rougeole, rubéole (vivant) RIT/SmithKline (USA) 15 eIPV Polio (inactivé, puissance amplifiée) AVP (USA) Engerix-B Hépatite B GSK (Royaume-Uni, USA) Epaxal Berna Hépatite A - vaccin virosomial BER (Suisse)

20 Ervevax RA 273 Rubéole (vivant) GSK (Belgique) Flu Shieldx Grippe WYE (USA) Fluad, Agrippal-SI Grippe CHIR (Italie) FluMist Grippe (vivant, atténué, intranasal) MEDI (USA) 25 Fluogen Grippe PD (USA) Fluvirin Grippe EVN (USA) Fluzone Grippe AVP (USA)

30 Fluned-CEME Diphtérie, tétanos, coqueluche Belo Horizonte (Brésil) GenHevac B Pasteur Hépatite B Gunevax Rubéole CHIR (Italie) Havrix Hépatite A GSK (Royaume-Uni, USA) 35 H-BIG Immunoglobuline de l’hépatite B NABI, Bayer Corporation (USA) Abréviation chimique pour HbOC WYE (USA) HibTITER

40 HBY Hépatite B (recombinant) KGC (Japon) Heprecomb Hépatite B (dérivé de levure) BER (Suisse) Hépatite B (dérivé du plasma) 1982 Heptavax Bx MRK (USA) à

45 Hevac B Hépatite B (dérivé du plasma) AVP (France) Diphtérie, tétanos, coqueluche, Hexavac AVP (France) AVP (France) polio, hépatite B, Hib Haemophilus influenzae, type b HibTITER WYE (USA) 50 (HbOC) Hinkuys Karokoe Coqueluche (adsorbé) Natl. Public Health Institute (Finlande) HPV-77 ; DK-5 Rubéole (vivant) 1969-1979 MRK (USA) HPV-77 ; DK-12 Rubéole (vivant) 19704973 MRK (USA) 55 HRIG Immunoglobuline de la rage AVP; Bayer Corporation (USA) Humotet-anti Tetanus Tétanos Wellcome (Royaume-Uni)

55 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Hyper-Tet (désormais dénommé Immunoglobuline du tétanos Bayer Corporation (USA) « BayTet » IBV Polio (inactivé) Statens Seruminstitut (Danemark) MA, BPT, New York Blood Ctr, Bayer Immune Globulin ImmuneGlobuhn Immunoglobulines à large spectre 10 Corporation, CEN (USA) Imogam Rabies - HT Immunoglobuline de la rage AVP (USA) Imovax Rage AVP (USA) Imovax Paroditis Oreillons AVP (France) 15 Imovax Polio Polio AVP (France) Imovax Sarampion Rougeole AVP (France) Imovax D.T. Diphtérie, tétanos 20 Imovax Gripe Grippe Rougeole, rubéole, oreillons R.O.R. Imovax R.O.R. AVP (France) Rougeole, rubéole, oreillons (vivant) Imovax Rubeola Rougeole AVP (International) 25 Imovax Mumps Oreillons Imovax Oreillons Oreillons AVP (France) Imovax Rabies I.D. Vaccin antirabique (HDCV) AVP (USA)

30 Imovax Rabies I.M. Vaccin antirabique (HDCV) AVP (USA) Diphtérie, tétanos, coqueluche Infanrix GSK (Belgique, USA) (acellulaire) Ipad TP Tétanos, polio AVP (France) 35 IPOL Polio (puissance amplifiée, inactivé) AVP (USA) Terme général pour le vaccin de la IPV Polio (inactivé) polio inactivée Istivac Grippe 40 JE-VAX Encéphalite japonaise AVP (USA) Kaksoisrokote Diphtérie, tétanos (adsorbé) Natl. Public Health Institute (Finlande) Statens Institutt for Folkehelse Kikhoste-Vaksine Coqueluche (Norvége) 45 Swiss Serum and Vaccine Institute Lancy Vaxinax Variole (Suisse) Lavantuu tirokote Typhoïde Central Pub Health Lab (Finlande)

x 50 Liovax Variole CHIR (Italie) Rougeole, rubéole (vivant) 4/74 à Lirubelx Dow/Pitney/Moore (USA) 6/78 Lirugen Rougeole AVP ant I) 55 Lirugenx Rougeole (vivant) 2/65 à 6/78 DOW (USA) LM-3 RIT Rougeole, oreillons, rubéole (vivant) Dong Shin Pharm (Corée)

56 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 LM-2 RIT Rougeole, oreillons, (vivant) Dong Shin Pharm (Corée) LTEANAS Imuna Tétanos (adsorbé) Imuna sp. (Slovaquie) LYMErixx Maladie de Lyme GSK (USA) x 10 Lyovac Attenuvax Rougeole (vivant, atténué) IVIRK (USA) Lyovac Meruvaxx Rubéole (vivant) MRK (USA) M-R Vax IIx Rougeole, rubéole (vivant) MRK (USA) M-Vaxx Rougeole (vivant) 5/63 à 1979 WYE (USA) 15 Masem-Impstoff SSW Rougeole (vivant) Measles Vaccine DK3x Rougeole (vivant) 1964 à 1972 Philips Roxane, Inc. (USA) Rougeole (vivant) 12/64 à 1974 Eli Lilly (USA) Méningocoque (polysaccharide) 20 Mencevax A SmithKline/RIT (Belgique) (Groupe A) Méningocoque (conjugué) (Groupe Meningitec WYE (Royaume-Uni, Australie) C) Méningocoque (polysaccharide) 25 Menomune-A/C/Y/W-135 AVP (USA) (Groupes A, C, Y, W435) Méningocoque (polysaccharide) Menpovax 4 CHIR (Italie) (Groupes A &C) Menpovax A+C Méningocoque (Groupes A &C) CHIR (Italie) 30 Meruvaxx Rubéole (vivant) 6/69 à MRK (USA) Meruvax II Rubéole (vivant) MRK (USA) Mevelin-Lx Rougeole (vivant) Glaxo Operations 35 Rougeole,oreillons,rubéole(vivant) MMRx MMRx (USA) 6/71 à Rougeole,oreillons,rubéole(vivant) MMR (générique)x Dow Chemical (USA) 4/74 à 6178 40 M-M-R II Rougeole, oreillons, rubéole (vivant) MRK (USA) Moniarix Pneumocoque (polysaccharide) SmithKline/RIT (Belgique) Institute of Sera and Vaccines Mopavac Sevac Rougeole, oreillons (vivant) (Tchécoslovaquie) 45 Polio (vivant, de Sabin, types MOPVx WYE (USA) monovalents I, II, III) Morbilvax Rougeole (vivant, atténué) Morubel atténué) CHIR (Italie) 50 Moruman Berne Immunoglobuline de la rougeole BER (Suisse) Rougeole, oreillons, rubéole (vivant, Morupar CHIR (Italie) atténué)

55 Movivac Rougeole (vivant, atténué) M-R VAXx Rougeole, rubéole (vivant) 7/71 à MRK (USA) Mumaten Berne Oreillons (vivant) BER (Suisse)

57 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Mumps (générique)x Oreillons (vivant) 4/74 à 6178 Dow Chemical (USA) Mumps (générique)x Oreillons (inactivé) 1950 à 1978 WYE (USA) Mumps (générique)x Oreillons (inactivé) 1950 à 1977 Eli Lilly (USA) x 10 Mumpsvax Oreillons (vivant) MRK (USA) Mutagrip Grippe Nabi-HB Immunoglobuline de l’hépatite B NABI (USA) Nothav Hépatite A CHI (Italie) 15 Haemophilus influenzae, type b OmniHIBx GSK, AVP (USA) (PRP-T) Terme général pour le vaccin de la OPV polio orale 20 Vaccin antipoliomyélitique (oral, Orimunex WYE(USA) trivalent) Pariorix Oreillons (vivant) SmithKline/RIT (Belgique) Pavivac-Sevac Oreillons (vivant) Institute of Immunology (Croatie) 25 Terme général pour un conjugué PCV, PCV7 pneumocoque (heptavalent) Diphtérie, tétanos, coqueluche Pediarix GSK (USA) (acellulaire), hépatite B, IPV 30 Haemophilus influenzae, type b PedVaxHIB MRK (USA) (PRP-OMP) Diphtérie, tétanos, coqueluche Penta AVP (Canada) (acellulaire), Hib, IPV 35 Diphtérie, tétanos, coqueluche, Pentacel AVP (Canada) polio, Hib Diphtérie, tétanos, coqueluche, Pentacoq polio, Hib 40 Diphtérie, tétanos, coqueluche, PENTAct-HIB polio, Hib Diphtérie, tétanos, coqueluche, Pentavac polio, Hib 45 Diphtérie, tétanos, coqueluche, Pentavalente hépatite B, Hib Pfizer Vax-Measles Kx Rougeole (inactivé) 3/63 à 1970 Pfizer (USA) Pfizer Vax-Measles Lx Rougeole (vivant) 2/65 à 1970 Pfizer (USA) 50 Pluserix Rougeole, oreillons, rubéole Pneumovax 23 Pneumocoque (polysaccharide) MRK (USA) PNU-IMUNE 23x Pneumocoque (polysaccharide) WYE (USA) Diphtérie, tétanos, coqueluche, 55 POILAce1 AVP (Argentine) polio, HIB

58 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Terme général pour un PPV, PPV23 polysaccharide pneumocoque (23 valent) Pneumocoque (conjugué, Prevnar WYE (USA) 10 heptavalent) Priorix Rougeole, oreillons, rubéole (vivant) GSK (Royaume-Uni) Haemophilus influenzae, type b ProHIBITx AVP (USA) (PRP-D) 15 Abréviation chimique pour PRP-OMP PedVaxHIB PRP-T Abréviation chimique pour ActHIB Purivaxx Polio (inactivé) 1956 à 1965 MRK (USA) 20 Diphtérie, tétanos, coqueluche, QUADRAcel AVP (Argentine) polio Diphtérie, tétanos, coqueluche, QUADRAcel/Hibest AVP (Argentine) polio, Hib 25 Quadrigenx DTP + polio (1959-1968) PD (USA) Quatro-Virelon Diphtérie, tétanos, polio CHI (Allemagne) Diphtérie, tétanos, coqueluche, Hib, Quintuple GSK (Mexique) polio 30 R-HB Vaccine Hépatite B (recombinant) Mitsubishi Chem Corp (Japon) R-VAC Rubéole (vivant) Serum Institute (Inde) RA27/3 Rubéole (vivant) MRK (USA)

35 RabAvert Rage (PCEC) CHI (USA) Recombivax HB Hépatite B (recombinant) MRK (USA) Immunoglobuline du virus Respigam, RSV-IVIG respiratoire syncytial (ce n’est pas MEDI (USA) 40 un vaccin) RIG (générique) Immunoglobuline de la rage Bayer Corporation, AVP (USA) Rimevax Rougeole (vivant) SmithKline/RIT (Belgique) Rimparix Rougeole (vivant) SmithKline/RIT 45 RIT-LM-2 Rougeole, oreillons (vivant) Dong Shin Pharm (Corée) MT-LM-3 Rougeole, oreillons, rubéole (vivant) Dong Shin Pharm (Corée) RotaShield, RRV-TVx Rotavirus - 8/98 à 7/99 WYE (USA)

50 Rouvax Rougeole (vivant, atténué) AVP (France) Rubeaten Berna Rubéole (vivant) BER (Suisse) Rubella (générique)x Rubéole (vivant) 12/69 à 1972 Philips Roxane (USA) Rubellovac Rubéole CHIR (Allemagne) 55 Rubelogenx Rubéole (vivant) 12/69 à 1972 PD (USA) Rubeovaxx Oreillons (vivant) 2/63 à 1971 MRK (USA)

59 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Rudi-Rouvax Oreillons, rubéole (vivant) AVP (France) Rudivax Rubéole (vivant, atténué) AVP (France) RVA (générique) Vaccin de la rage adsorbé BP (USA)

10 Terme général pour le vaccin Sabin antipoliomyélitique par voie orale (vivant) Sahia Polio (vivant, voie orale) Plusieurs fabricants Terme général pour le vaccin de la 15 Salk polio injectable (inactivé) Sandovac Grippe Serobacterinx Coqueluche - 1945 à 1954 MRK (USA)

20 Sii Triple Antigen Diphtérie, tétanos, coqueluche Serum Institute (Inde) Stamaril Fièvre jaune (vivant, atténué) AVP (France) Immunoglobuline du virus Synagis (palizivumab) respiratoire syncytial (ce n’est pas MEDI (USA) 25 un vaccin) T. Polio Toxoïde tétanique, polio AVP (Canada) - Institut Pasteur (Tunisie) - T.A.B. Typhoïde, paratyphoïde (A & B) Pharmaceutical Industries Corp.

30 (Birmanie) T-Immun Tétanos (adsorbé) Tétanos, diphtérie (formulation pour Td (générique) AVP, BP (USA) adulte)

35 Te/Vac/Ptap Tétanos Te Anatoxal Tétanos BER (Europe) Telvaclptap Tétanos Tetagrip Tétanos, grippe AVP (France) 40 Veb Sachsisches Serumwerk Tetamum SSW Tétanos non adsorbé (fluide) (Allemagne) Tetamyn Tétanos Bioclon, S.A. De C.V. (Mexique)

45 Tetanol Tétanos (adsorbé) CHIR (Allemagne) Veb Sachsisches Serumwerk Tetasorbat SSW Tétanos (adsorbé) (Allemagne) Tetavax Tétanos (adsorbé) AVP (France)

50 Diphtérie, tétanos, coqueluche, Tetacroq AVP (France) polio TetrAct-HIB Diphtérie, tétanos, coqueluche, Hib Tetramunex Diphtérie, tétanos, coqueluche, Hib WYE (USA) 55 Diphtérie, tétanos coqueluche, polio Tetravaxx MRK (USA) - 1959 à 1965

60 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Vaccin de Calmette et Gudrin (pour Tice BCG OTC (USA) la tuberculose) Immunoglobuline antitétanique YIG Bayer Corporation (USA) (générique) 10 TOPV Vaccin polio trivalent par voie orale Plusieurs fabricants et plusieurs pays Titifica Typhoïde et paratyphoïde Tresivac Lyophilized Rougeole, oreillons, rubéole Serum Institute (Inde) Diphtérie, tétanos, coqueluche 15 Triacel (acellulaire) Diphtérie, tétanos, coqueluche Triacelluvax CHIR (Europe) (acellulaire) Diphtérie, tétanos, coqueluche 20 TriHIBit AVP (USA) (acellulaire), Hib Tri-Immunolx Diphtérie, tétanos, coqueluche WYE (USA) Trimovax Rougeole, oreillons, rubéole (vivant) AVP (France) Diphtérie, tétanos, coqueluche 25 Trinivacx MRK (USA) MRK(USA) -1952 à 1964 Diphtérie, tétanos, coqueluche Tripacel (acellulaire) Diphtérie, tétanos, coqueluche 30 Tripedia AVP (USA) (acellulaire) - Chowgule & Co. (Inde) - CSL Limited Triple Antigen Diphtérie, tétanos, coqueluche (Australie) Triple Sabin Polio (vivant, par voie orale) 35 Triple Diphtérie, tétanos, coqueluche Triple Viral Rougeole, oreillons, rubéole Diphtérie, tétanos (adsorbé), Trivacuna Leti Laboratory Leti (Espagne) 40 coqueluche Diphtérie, tétanos (simple), Trivax Wellcome (Royaume-Uni) coqueluche Diphtérie, tétanos (adsorbé), - EVN (Royaume-Uni) - Wellcome Trivax-ad 45 coqueluche (Royaume-Uni) Trivax-Hib Diphtérie, tétanos, coqueluche, Hib GSK (Royaume-Uni) Trivb Diphtérie, tétanos, coqueluche Rougeole, oreillons, rubéole (vivant, Triviraten BER (Suisse) 50 atténué) Trivivacx Diphtérie, tétanos, coqueluche MRK (USA) Rougeole, oreillons, rubéole (vivant, Institute of Sera and Vaccines Trivivac Serac atténué) (Tchécoslovaquie) 55 TT Toxoïde tétanique (générique) AVP (USA) TT vaccine Toxoïde tétanique (adsorbé)

61 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 Tussitrupin Forte Coqueluche Staatliches Institut (Allemagne) Hépatite A & B (formulation pour Twinrix GSK (Royaume-Uni, USA) adulte) Hépatite A & B (formulation à usage Twinrix Junior GSK (USA) 10 pédiatrique) Typhoïde (vivant, voie orale, Ty2la (Vivotif Berna) BER (Suisse) lyophilisé) Tyne Tuberculose (BCG) Suède 15 Typherix Typhoïde GSK (Royaume-Uni) Typhoïde (par voie parentérale, Typhim (VICPs) AVP (USA, France) injectable) Typhoïde (inactivé, par voie 20 Typhoid Vaccinex WYE (USA) parentérale) Typhopara-thyphoïdique Typhoïde et paratyphoïde Finlay Vacunas y Suenos Centro de VA-Mengoc-BC Méningocoque (groupes B & C) Investigation (Cuba) 25 Vaccin Difteric Adsorbit Toxoïde diphtérique (adsorbé) Cantacuzino Institute (Roumanie) Vaccin Combinat Diftero-Tetanic Diphtérie, tétanos (adsorbé) Cantacuzino Institute (Roumanie) Vaccinum Morbillorum Vivum Rougeole (vivant) Moscow Research Institute (Russie) 30 Vacina Triplice Viral Rougeole, oreillons, rubéole Vacina Triplice Diphtérie, tétanos, coqueluche Instituto Butantan (Brésil) Vacina Dupla Diphtérie, tétanos Instituto Butantan (Brésil) Vaksin Cacr Variole 35 Vaksin Serap Diphtérie, tétanos, coqueluche Perum Bio Farma (Indonésie) Vaksin Campak Kerig Rougeole (vivant, atténué) Institut Pasteur (Indonésie) Vaksin Kotipa paratyphoide A, B & C Perum Bio Farma (Indonesie) 40 Vamoavax Rougeole, oreillons (vivant) Inst. of Immunology (Croatie) Vaqta Hépatite A (inactivé) MRK (USA) Immunoglobuline de la varicelle et Behringwerke Aktiengesellschaft Varicellon du zona (Allemagne) 45 Institute of Sera and Vaccines Varie Variole (lyophilisé) (Tchécoslovaquie) Varilrix Varicelle (vivant, souche Oka) GSK (Australie, Belgique) Varivax Varicelle (vivant) MRK (USA) 50 Vaxem-Hib Haemophilus influenzae, type b CHIR (Italie) Vaxicoq Coqueluche (adsorbé) AVP (France) Vaxigrip Grippe 55 Vaxipar Oreillons (vivant) CHIR (Italie) Produit ou dénomination Antigène(s) Fabricant (pays) commerciale

62 EP 1 928 492 B1

(suite)

Produit ou dénomination Antigène(s) Fabricant (pays) commerciale 5 VCDT Diphtérie, tétanos Cantacuzino Institute (Roumanie) VDA Vaccin Difteric Adsorb it Diphtérie Cantacuzino Institute (Roumanie) ViCPs (Typhim Vi) Typhoïde (inactivé, injectable) AVP (USA) Immunoglobuline de la variole (ce 10 VIG Distribué par CDC Distribué par CDC n’est pas un vaccin) Polio (vivant, par voie orale, Behringwerke Aktiengesellschaft Virelon T 20 trivalent) (Allemagne) Virovac Massling, Perotid, Rubella Rougeole, oreillons, rubéole 15 Vivotif Berna (Ty21a) Typhoïde (par voie orale, vivant) BER (Suisse) VT (Vacina Triplice) Diphtérie, tétanos, coqueluche Instituto Butantan (Brésil) VTV (Vacina Triplice Viral) Rougeole, oreillons, rubéole 20 Oreillons (vivant, atténué) Oreillons VVR Cantacuzino Institute (Roumanie) (vivant, atténué Immunoglobuline de la varicelle et VZIG MA (USA) du zona (générique) 25 Welltrivax trivalente Diphtérie, tétanos, coqueluche YF-VAX Fièvre jaune AVP (USA) Zaantide Antitoxine diphtérique Inst. of Immunology (Croatie) Zaantite Antitoxine tétanique Inst. of Immunology (Croatie) 30 Zaditeadvax Diphtérie, tétanos Inst. of Immunology (Croatie) Zaditevax Diphtérie, tétanos Inst. of Immunology (Croatie) Méningocoque (polysaccharide) Zamevax A+C Inst. of Immunology (Croatie) 35 groupes A & C Zamovax Oreillons (vivant) Inst. of Immunology (Croatie) Zamruvax Rougeole, rubéole (vivant) Inst. of Immunology (Croatie) Zaruvax Rubéole (vivant) Inst. of Immunology (Croatie) 40 Diphtérie, tétanos, coqueluche, Zatetravax Inst. of Immunology (Croatie) paracoqueluche Zatevax Tétanos Inst. of Immunology (Croatie) Zatribavax Diphtérie, tétanos, coqueluche Inst. of Immunology (Croatie) 45 Zatrivax Rougeole, rubéole, oreillons (vivant) Inst. of Immunology (Croatie)

3. Composé, à savoir la 4-(amino)-2-(2,6-dioxo(3-pipéridyl)isoindoline-1,3-dione ou la 3-(4-amino-1-oxo-1,3-dihydro- isoindol-2-yl)-pipéridine-2,6-dione, à utiliser pour amplifier une réponse immunitaire à un vaccin anticancéreux dans 50 un sujet, le composé étant formulé pour une administration au sujet avant d’administrer le vaccin au sujet.

4. Composé à utiliser conformément à la revendication 3, dans lequel le vaccin est un vaccin dirigé contre un sarcome, un carcinome, un mélanome, un lymphome et la leucémie.

55 5. Composé à utiliser conformément à la revendication 3, dans lequel le vaccin est un vaccin dirigé contre des cellules dendritiques, modifié par un antigène, un vaccin peptidique, un vaccin dirigé contre des cellules tumorales entières ou un vaccin à vecteur viral.

63 EP 1 928 492 B1

6. Composé, à savoir la 4-(amino)-2-(2,6-dioxo(3-pipéridyl)isoindoline-1,3-dione ou la 3-(4-amino-1-oxo-1,3-dihydro- isoindol-2-yl)-pipéridine-2,6-dione, à utiliser pour amplifier une réponse immunitaire à un vaccin dirigé contre une maladie infectieuse dans un sujet, le composé étant formulé pour une administration au sujet avant d’administrer le vaccin au sujet. 5 7. Composé à utiliser conformément à la revendication 6, dans lequel la maladie infectieuse est une maladie provoquée par un virus, une bactérie, un champignon et un parasite.

8. Composé à utiliser conformément à la revendication 7, dans lequel la maladie infectieuse est l’hépatite B. 10 9. Composé à utiliser conformément à la revendication 1, 3 ou 6, dans lequel le composé est formulé pour être administré dans un laps de temps de 10 jours à 12 heures précédant l’administration du vaccin, dans un laps de temps de 7 jours à 12 heures précédant l’administration du vaccin, dans un laps de temps de 5 jours à 1 jour précédant l’administration du vaccin ou bien dans un laps de temps de 3 jours à 1 jour précédant l’administration 15 du vaccin.

10. Composé à utiliser conformément à la revendication 1, 3 ou 6, dans lequel le composé est en outre formulé pour une deuxième administration après l’administration du vaccin.

20 11. Composé à utiliser conformément à la revendication 10, dans lequel le composé est formulé pour être administré dans un laps de temps de 12 heures à 10 jours suite à l’administration du vaccin, dans un laps de temps de 12 heures à 7 jours suite à l’administration du vaccin, dans un laps de temps de 1 jour à 5 jours suite à l’administration du vaccin ou bien dans un laps de temps de 1 jour à 3 jours suite à l’administration du vaccin.

25

30

35

40

45

50

55

64 EP 1 928 492 B1

65 EP 1 928 492 B1

66 EP 1 928 492 B1

67 EP 1 928 492 B1

68 EP 1 928 492 B1

69 EP 1 928 492 B1

70 EP 1 928 492 B1

71 EP 1 928 492 B1

72 EP 1 928 492 B1

73 EP 1 928 492 B1

74 EP 1 928 492 B1

75 EP 1 928 492 B1

76 EP 1 928 492 B1

77 EP 1 928 492 B1

78 EP 1 928 492 B1

79 EP 1 928 492 B1

80 EP 1 928 492 B1

81 EP 1 928 492 B1

82 EP 1 928 492 B1

83 EP 1 928 492 B1

84 EP 1 928 492 B1

85 EP 1 928 492 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 6281230 B [0011] [0063] [0067] • US 6458810 B [0063] [0093] • US 6316471 B, G.W. Muller [0011] [0063] [0067] • US 5698579 A [0063] • WO 2002059106 A [0012] • US 5877200 A [0063] • WO 2004103274 A [0012] • US 20030045552 A [0063] [0068] • GB 2034323 A [0037] • US 20030096841 A [0063] [0068] • US 5929117 A [0063] • US 0150401 W [0063] [0068] • US 5874448 A [0063] [0082] • WO 02059106 A [0063] [0068] • US 5955476 A [0063] [0082] • US 6335349 B [0067] • US 5798368 A [0063] [0083] • US 9713375 W [0067] • US 5635517 A [0063] [0065] • WO 9803502 A [0067] • US 6403613 B [0063] [0084] • US 20020045643 A [0078] • US 6476052 B [0063] [0067] • WO 9854170 A [0078] • US 6555554 B [0063] • US 6395754 B [0078] • US 6380239 B [0063] [0087] • US 90027004 A [0087]

Non-patent literature cited in the description

• Edelman. Molecular Biotech., 2002, vol. 21, 129-148 • Inagaki-Ohara et al. Jlmmunol, 2004, vol. 173, [0002] 1390-1398 [0010] • O’Hagan et al. Biomolecular Engineering, 2001, vol. • Jameson et al. Science, 2002, vol. 296, 747-749 18, 69-85 [0002] [0010] • Singh et al. Pharm. Res., 2000, vol. 19 (6), 715-28 • Marriott, J.B. Expert Opin. Biol. Ther., 2001, vol. 1 [0002] (4), 1-8 [0011] • Ramon. Ann. Inst. Pasteur, 1924, vol. 38, 1 [0003] • G.W. Muller et al. Journal of Medicinal Chemistry, • Malakoff. Science, 2000, vol. 288, 1323 [0003] 1996, vol. 39 (17), 3238-3240 [0011] • Gupta et al. Drug Deliv. Rev., 1998, vol. 32, 155-72 • G.W. Muller et al. Bioorganic & Medicinal Chemistry [0003] Letters, 1998, vol. 8, 2669-2674 [0011] • Relyveld et al. Vaccine, 1998, vol. 16, 1016-23 • L.G. Corral et al. Ann. Rheum. Dis., 1999, vol. 58 [0003] (I), 1107-1113 [0011] • Nature Medicine Commentary, 2004, vol. 10 (12), • Air. Proc. Natl. Acad. Sci. USA, 1981, vol. 78, 1278 [0004] 7639-7643 [0037] • Cancer Immunol. Immunother., 2004, vol. 53 (10), • Newton et al. Virology, 1983, vol. 128, 495-501 844-54 [0004] [0037] • Yamazaki et al. J Exp. Med., 2003, vol. 198, 235 • Garcia et al. J. Virol., 1994 [0037] [0007] • Collins et al. Proc. Natl. Acad Sci. USA, 1984, vol. • De Libero. Immunology Today, 1997, vol. 18, 22-26 81, 7683 [0037] [0009] • Hahn et al. Virology, 1988, vol. 162, 167-180 [0037] • Street et al. J Exp Med, 2004, vol. 199, 879-884 • Rota et al. Virology, 1992, vol. 188, 135-142 [0037] [0009] • Bzik et al. Virology, 1986, vol. 155, 322-333 [0037] • Gober et al. J Exp Med, 2003, vol. 197, 163-168 • Emini et al. Nature, 1983, vol. 304, 699 [0037] [0009] • Putney et al. Science, 1986, vol. 234, 1392-1395 • Ismaili et al. Clin Immunol, 2002, vol. 103, 296-302 [0037] [0009] • Itoh et al. Nature, 1986, vol. 308, 19 [0037] • Wang et al. J Immunol, 2003, vol. 171, 2524-2531 • Neurath et al. Vaccine, 1986, vol. 4, 34 [0037] [0010] • Audibert et al. Nature, 1981, vol. 289, 543 [0037] • Chen et al. Proc. Natl. Acad. Sci. U.S.A., 2002, vol. • Beachey. Adv. Exp. Med. Biol., 1985, vol. 185, 193 99, 14338-14343 [0010] [0037]

86 EP 1 928 492 B1

• Rothbard ; Schoolnik. Adv. Exp. Med. Biol., 1985, • Herlyn et al. J Clin. Immunol., 1982, vol. 2, 135 vol. 185, 247 [0037] [0038] • Gonzales-Scarano et al. Virology, 1982, vol. 120, • Ghetie et al. Blood, 1994, vol. 83, 1329-1336 [0038] 42 [0037] • Reff et al. Blood, 1994, vol. 83, 435-445 [0038] • Matsuno ; Inouye. Infection and Immunity, 1983, • Sgouros et al. J. Nucl. Med., 1993, vol. 34, 422-430 vol. 39, 155 [0037] [0038] • Mathews ; Roehrig. J Immunol., 1982, vol. 129, • Saleh et al. J. Immunol., 1993, vol. 151, 3390-3398 2763 [0037] [0038] • Dalrymple et al. Replication of Negative Strand Vi- • Shitara et al. Cancer Immunol. Immunother., 1993, ruses. Elsevier, 1981 [0037] vol. 36, 373-380 [0038] • Steeves et al. J. Virol., 1974, vol. 14, 187 [0037] • Livingston et al. J Clin. Oncol., 1994, vol. 12, • Massey ; Schochetman. Virology, 1981, vol. 115, 1036-1044 [0038] 20 [0037] • Hoon et al. Cancer Res., 1993, vol. 53, 5244-5250 • Ganem ; Varmus. Ann. Rev. Biochem., 1987, vol. [0038] 56, 651-693 [0037] • Hellstrom et al. Cancer. Res., 1985, vol. 45, • Tiollais et al. Nature, 1985, vol. 317, 489-495 [0037] 2210-2188 [0038] • Perez ; Walker. J. Immunol., 1990, vol. 142, • Hellstrom et al. Cancer Res., 1986, vol. 46, 3662-3667 [0038] 3917-3923 [0038] • Bumal. Hybridoma, 1988, vol. 7 (4), 407-415 [0038] • Bhattacharya-Chatterjee et al. J. of Immunospe- • Yu et al. Cancer Res., 1991, vol. 51 (2), 468-475 cifically, 1988, vol. 141, 1398-1403 [0038] [0038] • Hilkens et al. Trends in Bio. Chem. Sci., 1992, vol. • Tailor et al. Nucl. Acids Res., 1990, vol. 18 (16), 17, 359 [0038] 4928 [0038] • Bernhard et al. Science, 1989, vol. 245, 301-304 • Henttu ; Vihko. Biochem. Biophys. Res. Comm., [0038] 1989, vol. 160 (2), 903-910 [0038] • Feizi. Nature, 1985, vol. 314, 53-57 [0038] • Israeli et al. Cancer Res., 1993, vol. 53, 227-230 • Edelson. The Cancer Journal, 1998, vol. 4, 62 [0038] [0038] • Estin et al. J. Natl. Cancer Instit., 1989, vol. 81 (6), • Robbins ; Kawakami. Curr. Opin. Immunol., 1996, 445-446 [0038] vol. 8, 628-636 [0046] • Vijayasardahl et al. J. Exp. Med., 1990, vol. 171 (4), • Jacques, J. et al. Enantiomers, Racemates and 1375-1380 [0038] Resolutions. Wiley-Interscience, 1981 [0064] • Natali et al. Cancer, 1987, vol. 59, 55-63 [0038] • Wilen, S. H. et al. Tetrahedron, 1977, vol. 33, 2725 • Mittelman et al. J Clin. Invest., 1990, vol. 86, [0064] 2136-2144 [0038] • Eliel, E. L. Stereochemistry of Carbon Compounds. • Foon et al. Proc. Am. Soc. Clin. Oncol., 1994, vol. McGraw-Hill, 1962 [0064] 13, 294 [0038] • Wilen, S. H. Tables of Resolving Agents and Optical • Yokata et al. Cancer Res., 1992, vol. 52, 3402-3408 Resolutions. Univ. of Notre Dame Press, 1972, 268 [0038] [0064] • Ragnhammar et al. Int. J. Cancer, 1993, vol. 53, • Rowe et al. Handbook of Pharmaceutical Excipients. 751-758 [0038] 2003 [0103] • Yamasaki et al. J. Biol. Chem, 2001 [0120]

87