Source: http://www.google.es/patents/US8372393
Timestamp: 2017-12-16 21:06:14
Document Index: 628741258

Matched Legal Cases: ['Application No. 2', 'ART-1', 'art-127', 'art-\u200332', 'art-1', 'art-1', 'art-1', 'art-\u2003127', 'art-1', 'art-1', 'art-1', 'art-\u2003127']

Patente US8372393 - Method of inducing a CTL response - Google Patentes
Disclosed herein are methods for inducing an immunological CTL response to an antigen by sustained, regular delivery of the antigen to a mammal so that the antigen reaches the lymphatic system. Antigen is delivered at a level sufficient to induce an immunologic CTL response in a mammal and the level...http://www.google.es/patents/US8372393?utm_source=gb-gplus-sharePatente US8372393 - Method of inducing a CTL response
Número de publicación US8372393 B2
Número de solicitud US 11/418,397
También publicado como US6977074, US7364729, US20020007173, US20060153858, US20090035252, US20120046638, WO2002062368A2, WO2002062368A3, WO2002062368A8
Número de publicación 11418397, 418397, US 8372393 B2, US 8372393B2, US-B2-8372393, US8372393 B2, US8372393B2
Citas de patentes (149), Otras citas (102), Citada por (2), Clasificaciones (33), Eventos legales (6)
US 8372393 B2
1. A method of inducing or sustaining a CTL response in a mammal, wherein the method comprises:
delivering an antigen to the mammal at a level sufficient to induce a CTL response to the antigen in the mammal, wherein the antigen is delivered to the mammal by pumping a physiologically-acceptable acellular composition of the antigen from a device held external to the mammal's body positioned to deliver the antigen-containing composition so that the antigen reaches the mammal's lymph system; and
maintaining the antigen in the mammal's lymphatic system over time sufficient to induce or maintain the CTL response specific to the antigen.
2. The method of claim 1, wherein said pumping a physiologically-acceptable composition of the antigen comprises pumping from a device held external to the mammal's body through a transmission line.
3. The method of claim 2, wherein said transmission line comprises a catheter.
4. The method of claim 3, wherein said catheter is at least 20 mm in length.
5. The method of claim 1, wherein the antigen is delivered to an area of high lymphatic drainage in the mammal.
6. The method of claim 1, wherein said maintaining step comprises maintaining the antigen in the mammal's lymphatic system sufficient to maintain the CTL response for a period of time that is substantially co-extensive with a desired duration of the CTL response.
7. The method of claim 1, wherein delivery of the antigen is directly to the lymphatic system.
8. The method of claim 7, wherein said delivery of the antigen directly to the lymphatic system comprises delivery to an inguinal or axillary lymph node.
9. The method of claim 1, wherein said delivering comprises delivering the antigen in the form of a vector comprising a nucleic acid encoding the antigen.
10. The method of claim 1, wherein said delivering comprises delivering the antigen in the form of a peptide.
11. The method of claim 1, wherein said antigen is provided as a component of a microorganism or mammalian cell.
12. The method of claim 1, wherein said antigen is a disease-matched antigen.
14. The method of claim 13, wherein said antigen is a tumor-associated antigen.
15. The method of claim 12, wherein said disease is an infectious disease.
16. The method of claim 15, wherein said antigen is a microbial antigen.
17. The method of claim 1, wherein said antigen is a non-peptide antigen.
18. The method of claim 1, wherein said level is sufficient to induce an increase in a pre-existing response.
19. A method of sustaining a CTL response in a mammal, wherein the method comprises:
delivering an antigen to the mammal at a level sufficient to sustain a CTL response to the antigen in the mammal, wherein the antigen is delivered to the mammal by pumping a physiologically-acceptable acellular composition of the antigen from a device held external to the mammal's body positioned to deliver the antigen-containing composition so that the antigen reaches the mammal's lymph system; and
maintaining the antigen in the mammal's lymphatic system over time sufficient to sustain the CTL response specific to the antigen.
This application is a divisional of U.S. patent application Ser. No. 11/313,152 filed Dec. 19, 2005, now U.S. Pat. No. 7,364,729, which is a continuation of U.S. patent application Ser. No. 09/776,232, filed Feb. 2, 2001, now U.S. Pat. No. 6,977,074, which is a continuation-in-part of U.S. patent application Ser. No. 09/380,534, filed Sep. 1, 1999, now U.S. Pat. No. 6,994,851, which is a national stage entry of PCT Application No. PCT/US98/14289, filed Jul. 10, 1998, which is a continuation-in-part of U.S. patent application Ser. No. 08/988,320, filed Dec. 10, 1997, now abandoned, and which claimed priority to Canadian Patent Application No. 2,209,815, filed Jul. 10, 1997, each of which is hereby expressly incorporated by reference in its entirety.
The present application includes a Sequence Listing provided in electronic format on duplicate copies of a CD-ROM marked “Copy 1” and “Copy 2.” The duplicate copies of the CD-ROM each contain a file entitled MANNK.1CP2C1D2.txt created on Aug. 17, 2006 which is 88 kilobytes in size. The information on these duplicate CD-ROMs is incorporated herein by reference in its entirety.
(b) Tumor cells can down regulate MI-IC molecules, resulting in the loss of antigen presentation from the surface of cells, thereby escaping detection by CTL;
A growing repertoire of tumor associated antigens are being discovered that are recognized by CTL. A variety of techniques have been suggested to render these antigens effective in CTL vaccines. These include immunization using synthetic peptide antigens mixed with an immunostimulatory adjuvant, such as the bacterial toxin BCG; immunization with multiple antigenic peptide systems (MAPS), immunization with “professional” antigen presenting cells, which are isolated from the patient, pulsed with peptide antigen and inoculated back into the patient as a vaccine; immunization with peptides designed to stimulate both CTL and T helper cell populations; immunization with viruses or bacteria engineered to express tumor antigens; and immunization with polynucleotide expression vectors (so called DNA vaccines). Unfortunately, none of these approaches has been an unqualified success, As discussed above, the lack of vigorous therapeutic effects with these vaccine platforms reflects at least to some degree problems associated with inducing a strong initial CTL response and with maintaining ongoing “active” CTL immunity.
The antigen can be an 8-10 amino acid peptide. Further, the peptide sequence can be derived from a tumor-associated antigen. Examples of tumor-associated antigens include MelanA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, alpha-fetoprotein, β-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS, and the like.
In contrast to antibody-mediated B cell memory, which is long lived, T cell memory appears to be short lived or non-existent. In accordance with this invention, maintenance of functional T cell memory depends on persistence of antigen through continued, regular administration of the desired antigen. Having made this invention and looking at past concepts that might support this underlying rationale, some evidence includes the observation that delayed type hypersensitivity (DTH) of the tuberculin type (the only functional test for T cell memory in humans), can be elicited only in granulomatous disease, such as tuberculosis (tuberculin test), leprosy (lepromin test), brucellosis (brucellin test), sarcoidosis (Kveim test), Histoplasmosis (histoplasimin test) etc., but no such test could be established for non-granulomatous infectious disease. A factor that all granulomatous diseases have in common, is that the antigen persists within the granuloma—professional antigen presenting cells can use this reservoir to continuously restimulate specific T cells in lymphoid organs. In mice models (see Example 3) it is demonstrated that maintenance of functional CD8+ T cell memory was strictly dependent on continuous antigenic restimulation.
To determine whether a CTL response is obtained in an animal being treated in accordance with this invention, one measures the level of CD8+ cells (i.e. CTL) present in the blood or lymphatic organs such as the spleen or lymph nodes. This determination is done by first measuring the level of CD8+ cells before performing the method of this invention and measuring the level during treatment, e.g. at 7, 10, 20, 40 days, etc. The level or strength of the CD8+ (CTL) response can be assessed in vivo or in vitro. In humans, there exists so far only one in vivo test to measure CD8+ T cell responses, which is a skin test. In this skin test, HLA class I binding peptides are injected, intradermally (such as described in Jäger, E. et al. Granulocyte-macrophage-colony-stimulating Factor Enhances Immune Responses To Melanoma-associated Peptides in vivo Int. J Cancer 67, 54-62 (1996)). If a CTL response is present, these cells will recognize and attack peptide pulsed dermal cells, causing a local inflammatory reaction either via cytokine release or the cytotoxic mechanism (Kündig, T. M., Althage, A., Hengartner, H. & Zinkernagel, R. M. A skin test to assess CD8+ cytotoxic T cell activity. Proc. Natl. Acad Sci. USA 89:7757-776 (1992)). This inflammatory reaction can be quantified by measuring the diameter of the local skin rash and/or by measuring the diameter of the infiltrate (i.e., the swelling reaction). As an alternative to the injection of soluble free peptide, the HLA-class I binding peptide can also be injected intradermally in a bound form, e.g., bound to extracorporally derived dendritic cells. In other mammals, additional, although experimental, in vivo tests to assess CD8+ T cell responses exist. For example, in a mouse model, CD8+ T cell responses can be measured by challenge infection with a vaccinia recombinant virus expressing the peptide used for immunization. While naïve mice succumb to the infection with the vaccina recombinant virus, mice with preexisting CD8+ T cell immunity against the peptide epitope expressed by the vaccinia recombinant virus, are immune to reinfection. The level of immunity to reinfection can be quantified as the factor of reduction of the vaccinia virus titer recovered from mouse organs after challenge infection (Bachmann, M. F. & Kundig, T. M. In vitro vs. in vivo assays for the assessment of T- and B-cell function. Curr. Opin. Immunol. 6, 320-326 (1994)). For example, 5 days after challenge infection, a typical vaccinia recombinant virus titer recovered from a mouse ovary would be around 107 pfu per ovary, whereas the vaccinia recombinant virus titer in a mouse with a preexisting CD8+ T cell response against the recombinant gene product would for example be around 103 pfu per ovary. Such a 10,000 fold-reduction in virus titer reflects biologically significant preexisting CD8+ T cell activity against the recombinant gene product.
Malignant tumors treated according to this invention are classified according to the embryonic origin of the tissue from which the tumor is derived. Carcinomas are tumors arising from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. A melanoma is a type of carcinoma of the skin for which this invention is particularly useful. Sarcomas, which arise less frequently, are derived from mesodermal connective tissues such as bone, fat, and cartilage. The leukemias and lymphomas are malignant tumors of hematopoietic cells of the bone marrow. Leukemias proliferate as single cells, whereas lymphomas tend to grow as tumor masses. The malignant tumors may show up at numerous organs or tissues of the body to establish a cancer. The types of cancer that can be treated in accordance with this invention include the following: bladder, brain, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharangeal, pancreatic, prostate, skin, stomach, uterine, and the like. The present invention is not limited to the treatment of—an existing tumor or infectious disease but can also be used to prevent or lower the risk of developing such diseases in an individual, ie., for prophylactic use. Potential candidates for prophylactic vaccination include individuals with a high risk of developing cancer, i.e., with a personal or tuminal history of certain types of cancer.
The current treatment of malignant melanoma aims at surgical removal of the primary tumor. If metastases are present, chemotherapy and biological response modifiers are additionally used. However, patients with stage IV malignant melanoma are almost invariably incurable and treatments are palliative. Patients with Stage 1V malignant melanoma have a median survival time of approximately one year and only a 10% chance of long-term survival. There is at present no generally accepted standard therapy for metastatic melanoma. Objective response rates to mono- or polychemotherapy are low in comparison with other tumors, reaching no more than 15-35%. An improved treatment outcome in stage IV malignant melanoma seems unachievable either by chemotherapeutic combinations or by increasing doses to levels where autologous bone marrow transplantation becomes necessary. The method of this invention is useful for treating malignant melanoma, even at Stage IV.
To determine whether an antigen is matched to a particular patient, whether human or other animal, the tissue type of the patient is first determined. If human, the tissue must demonstrate the appropriate human leukocyte antigen (HLA) capable of binding and displaying the antigen to CTL. It is preferable that the HLA typing be performed, on the target cells, since a significant portion of tumors escape immune detection by downregulating expression of HLA. Therefore HLA expression on normal cells of the patient does not necessarily reflect that found on tumor cells in their body. A tumor from a patient is also screened to determine if he or she expresses the antigen that is being used in the vaccine formulation. Immunohistochemistry and/or polymerase chain reaction (PCR) techniques both can be used to detect antigen in the tumor cells. Immunohistochemistry offers the advantage in that it stains a cross-section of tumor in a slide preparation, allowing investigators to observe the antigen expression pattern in cross-section of tumor, which is typically heterogeneous for antigen expression. PCR has the advantage of not requiring specific monoclonal antibodies for staining and is a fast and powerful technique. In addition, PCR can be applied in situ. Ideally, both immunohistochemical and PCR methods should be combined when assessing antigen expression in tumors. While the antigen compositions useful in this invention are designed to include the most commonly expressed tumor antigens (as discussed hereafter), not all tumors will express the desired antigen(s). Where a tumor fails to express the desired antigen, the patient is excluded for consideration for that particular antigen composition. Thus, an aspect of this invention is a process for preparing a device useful for providing a sustained CTL response over time by matching a subject's antigen specific to the tumor or pathogen in the subject, preparing a physiologically-acceptable composition of the antigen so matched, and combining the composition in a suitable delivery device as discussed in hereinafter.
Antigens useful in the invention are generally protein-based entities of a molecular weight of up to 100,000 daltons. Appropriate antigens include, but are not limited to differentiation antigens, tumor-specific multilineage antigens, embryonic antigens, antigens of oncogenes and mutated tumor-suppressor genes, unique tumor antigens resulting from chromosomal translocations, viral antigens, and others that may be apparent presently or in the future to one of skill in the art. It is preferable that the antigen be a peptide of 8 to 15 amino acids in length that is an epitope of a larger antigen, i.e. it is a peptide having an amino acid sequence corresponding to the site on the larger molecule that is recognized and bound by a particular T-cell receptor. These smaller peptides are available to one of skill in the art by following the teachings of U.S. Pat. Nos. 5,747,269 to Rarnmensee et al. issued May 5, 1998; 5,698,396 to Pfreundschuh issued Dec. 16, 1997; and PCT Application Numbers PCT/EP95/02593 filed 4 Jul. 1995, PCT/DE96/00351 filed 26 Feb. 1996, all of which are incorporated herein by reference. Additional approaches to epitope discovery are described in U.S. Pat. No. 6,037,135 METHODS FOR MAKING HLA BINDING PEPTIDES AND THEIR USES and U.S. patent application Ser. No. 09/561,074 entitled METHOD OF EPITOPE DISCOVERY both of which are incorporated herein by reference in their entirety.
Differentiation antigens such as MART-1/MelanA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2 and tumor-specific multilineage antigens such as MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15; overexpressed embryonic antigens such as CEA; overexpressed oncogenes and mutated tumor-suppressor genes such as p53, Ras, HER-2/neu; unique tumor antigens resulting from chromosomal translocations; such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR; and viral antigens, such as the Epstein Barr virus antigens EBVA and the human papillomavirus (HPV) antigens E6 and E7. Other large, protein-based antigens include TSP-180, MAGE-4, MAGE-5, MAGE-6, RAGE, NY-ESO, p185erbB2, p180erbB-3, c-met, nm-23HI, PSA, TAG-72, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-Catenin, CDK4, Mum-1, p 15, p 16, 43-9F, 5T4, 791Tgp72, alpha-fetoprotein, β-HCG, BCA225, BTAA, CA 125, CA 15-3\CA 27.29\BCAA, CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733\EpCAM, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90\Mac-2 binding protein\cyclophilin C-associated protein, TAAL6, TAG72, TLP, and TPS. These protein-based antigens are known and available to those of skill in the art in the literature or commercially.
Viral epitopes on MHC class 1 molecules
AA T cell epitope MHC
Virus Protein Position ligand (Antigen) MHC molecule Ref.
Adenovirus 3 E3 9Kd 30-38 LIVIGILIL HLA-A*0201 104
Adenovirus 5 EIA 234-243 SGPSNTPPEI H2-Db 105
Adenovirus 5 EIB 192-200 VNIRNCCYI H2-Db 106
Adenovirus 5 EIA 234-243 SGPSNIPPEI (T > I) H2-Db 106
(SEQ. ID NO.: 4)
CSFV NS 2276-2284 ENALLVALF SLA, haplotype 107
polyprotein (SEQ. ID NO.: 5 d/d
Dengue virus NS3 500-508 TPEGIIPTL HLA-B*3501 108, 109
4 (SEQ. ID NO.: 6
(SEQ. ID NO.: 7)
(SEQ. ID NO.: 8)
(SEQ. ID NO.: 9)
(SEQ. ID NO.: 12)
(SEQ. ID NO.: 20)
(SEQ, ID NO.: 21)
(SEQ, ID NO.: 22)
(SEQ, ID NO.: 23)
(SEQ. ID NO.: 24)
(SEQ. ID NO.: 25)
(SEQ. ID NO.: 26)
(SEQ. ID NO.: 27)
(SEQ. ID NO.: 28)
(SEQ. ID NO.: 29)
(SEQ. ID NO.: 30)
(SEQ. ID NO.: 31)
(SEQ. ID NO.: 32)
(SEQ. ID NO.: 33)
(SEQ. ID NO.: 34)
EBV EBNA-4 416-424 IVTDFSVIK HLA-A*1101 114, 115
(SEQ. ID NO.: 35)
(SEQ. ID NO.: 36)
(SEQ. ID NO.: 37)
(SEQ. ID NO.: 38)
(SEQ. ID NO.: 39)
(SEQ. ID NO.: 40)
(SEQ. ID NO.: 41)
(SEQ. ID NO.: 42)
(SEQ. ID NO.: 43)
(SEQ. ID NO.: 44)
(SEQ. ID NO.: 45)
(SEQ. ID NO.: 46)
(SEQ. ID NO.: 47)
(SEQ. ID NO.: 48)
(SEQ. ID NO.: 49)
(SEQ. ID NO.: 50)
EBV BZLFI 222-231 CPSLDVDSII HLA-B7 111
(SEQ. ID NO.: 51)
(SEQ. ID NO.: 52)
(SEQ. ID NO.: 53)
(SEQ. ID NO.: 54)
(SEQ. ID NO.: 55)
(SEQ. ID NO.: 56)
(SEQ. ID NO.: 57)
(SEQ. ID NO.: 58)
(SEQ. ID NO.: 59)
(SEQ. ID NO.: 60)
HCV env E 44-51 ASRCWVAM HLA-B*3501 146
(SEQ. ID NO.: 61)
protein (SEQ. ID NO.: 62)
(SEQ. ID NO.: 63)
protein (SEQ. ID NO.: 64)
protein (SEQ. ID NO.: 65)
(SEQ. ID NO.: 66)
(SEQ. ID NO.: 67)
(SEQ. ID NO.: 68)
(SEQ. ID NO.: 69)
HCV-1 env E 118-126 GNASRCWVA Patr-B16 151
(SEQ. ID NO.: 70)
(SEQ. ID NO.: 71)
(SEQ. ID NO.: 72)
(SEQ. ID NO.: 73)
(SEQ. ID NO.: 74)
(SEQ. ID NO.: 75)
(SEQ. ID NO.: 76)
HIV gp4l 583-591 RYLKDQQLL HLA_A24 152
(SEQ. ID NO.: 77)
HIV gagp24 267-275 IVGLNKIVR HLA-A*3302 153, 154
(SEQ. ID NO.: 78)
HIV gagp24 262-270 EIYKRWIIL HLA-B8 155, 156
(SEQ. ID NO.: 79)
HIV gagp24 261-269 GEIYKRWII HLA-B8 155, 156
(SEQ. ID NO.: 80)
HIV gagp17 93-101 EIKDTKEAL HLA-B8 155, 157
(SEQ. ID NO.: 81)
(SEQ. ID NO.: 82)
HIV gagp24 267-277 ILGLNKIVRMY HLA-B* 1501 153
(SEQ. ID NO.: 83)
(SEQ. ID NO.: 84)
(SEQ. ID NO.: 85)
(SEQ. ID NO.: 86)
HIV gp120 314-322 GRAFVTIGK HLA-B*2705 160, 184
(SEQ. ID NO.: 87)
(SEQ. ID NO.: 88)
(SEQ. ID NO.: 89)
(SEQ. ID NO.: 90)
(SEQ. ID NO.: 91)
(SEQ. ID NO.: 92)
(SEQ. ID NO.: 93)
HIV gp160 318-327 RGPGRAFVTI H2-Dd 164, 165
(SEQ. ID NO.: 94)
HIV gp120 17-29 MPGRAFVTI H2-Ld 166, 167
(SEQ. ID NO.: 95)
HIV-1 RT 476-484 ILKEPVHGV HLA-A*0201 168, 169
(SEQ. ID NO.: 96)
(SEQ ID NO.: 97)
HIV-1 gp160 120-128 KLTPLCVTL HLA-A*0201 171
(SEQ ID NO.: 98)
(SEQ ID NO.: 99)
(SEQ ID NO.: 100)
HIV-1 gagp 17 77-85 SLYNTVATL HLA-A*0201 173
(SEQ ID NO.: 101)
HIV-1 gp160 315-329 RGPGRAFVTI HLA-A*0201 174
(SEQ ID NO.: 102)
HIV-1 gp41 768-778 RLRDLLLIVTR HLA-A3 175, 178
(SEQ ID NO.: 103)
(SEQ ID NO.: 104)
(SEQ. ID NO.: 105)
(SEQ. ID NO.: 106)
(SEQ. ID NO.: 107)
(SEQ. ID NO.: 108)
(SEQ. ID NO.: 109)
(SEQ. ID NO.: 104)
(SEQ, ID NO.: 110)
(SEQ. ID NO.: 111)
(SEQ. ID NO.: 112)
(SEQ. ID NO.: 113)
HIV-1 gagp 17 24-31 GGKKKYKL HLA-B8 183
(SEQ. ID NO.: 114)
(SEQ. ID NO.: 115)
HIV-1 gagp24 298-306 DRFYKTLRA HLA-B 14 173
(SEQ. ID NO.: 116)
(SEQ. ID NO.: 117)
HIV-1 gagp24 265-24 KRWIILGLNK HLA-B*2705 184, 153
(SEQ. ID NO.: 118)
(SEQ. ID NO.: 97)
(SEQ. ID NO.: 119)
(SEQ. ID NO.: 120)
(SEQ. ID NO.: 121)
(SEQ. ID NO.: 122)
(SEQ. ID NO.: 123)
(SEQ. ID NO.: 124)
(SEQ. ID NO.: 125)
HBV cAg 18-27 FLPSDFFPSV HLA-A*0201 125, 126,
(SEQ. ID NO.: 126) 127
(SEQ. ID NO.: 126)
(SEQ. ID NO.: 127)
(SEQ. ID NO.: 128)
(SEQ. ID NO.: 129)
(SEQ. ID NO.: 130)
(SEQ. ID NO.: 131)
(SEQ. ID NO.: 132)
(SEQ. ID NO.: 133)
(SEQ. ID NO.: 134)
(SEQ. ID NO.: 135)
(SEQ. ID NO.: 136)
(SEQ. ID NO.: 137)
HBV cAg 88-96 YVNVNMGLK HLA-A* 1101 131
(SEQ. ID NO.: 138)
(SEQ. ID NO.: 139)
(SEQ. ID NO.: 140)
(SEQ. ID NO.: 141)
(SEQ. ID NO.: 142)
HCMV gp B 618-628 FIAGNSAYEYV HLA-A*0201 124
(SEQ. ID NO.: 143)
(SEQ. ID NO.: 144)
(SEQ. ID NO.: 145)
(SEQ. ID NO.: 146)
(SEQ. ID NO.: 147)
(SEQ. ID NO.: 148)
(SEQ. ID NO.: 149)
(SEQ. ID NO.: 150)
(SEQ. ID NO.: 151)
HCV env E 66-75 QLRRHIDLLV HLA-A*0201 139
(SEQ. ID NO.: 152)
HCV env E 88-96 DLCGSVFLV HLA-A*0201 139
(SEQ. ID NO.: 153)
HCV env E 172-180 SMVGNWAKV HLA-A*0201 139
(SEQ. ID NO.: 154)
(SEQ. ID NO.: 155)
(SEQ. ID NO.: 156)
(SEQ. ID NO.: 157)
(SEQ. ID NO.: 158)
(SEQ. ID NO.: 159)
(SEQ. ID NO.: 160)
(SEQ. ID NO.: 161)
protein (SEQ. ID NO.: 162)
(SEQ. ID NO.: 163)
(SEQ. ID NO.: 164)
(SEQ. ID NO.: 165)
(SEQ. ID NO.: 166)
(SEQ. ID NO.: 167)
(SEQ. ID NO.: 168)
(SEQ. ID NO.: 169)
(SEQ. ID NO.: 170)
(SEQ. ID NO.: 171)
(SEQ. ID NO.: 172)
(SEQ. ID NO.: 173)
(SEQ. ID NO.: 174)
protein (SEQ. ID NO.: 175)
(SEQ. ID NO.: 176)
(SEQ. ID NO.: 177)
(SEQ. ID NO.: 178)
(SEQ. ID NO.: 179)
HIV- 1 RT 325-333 AIFQSSMTK HLA-A*0301 188
(SEQ..ID NO.: 180)
(SEQ. ID NO.: 181)
(SEQ. ID NO.: 182)
(SEQ. ID NO.: 183)
(SEQ. ID NO.: 184)
(SEQ. ID NO.: 185)
HIV-1 gagp24 167-175 EVIPMFSAL FILA-A26 188
(SEQ. ID NO.: 186)
(SEQ. ID NO.: 187)
(SEQ. ID NO.: 188)
(SEQ. ID NO.: 189)
(SEQ. ID NO.: 190)
(SEQ. ID NO.: 191)
(SEQ. ID NO.: 192)
(SEQ. ID NO.: 193)
HIV-1 gag p24 148-156 SPRTLNAWV HLA-B7 188
(SEQ. ID NO.: 194)
(SEQ. ID NO.: 195)
HIV-1 gp120 303-312 RPNNNTRKSI FILA-B7 188
(SEQ. ID NO.: 196)
(SEQ. ID NO.: 197)
(SEQ. ID NO.: 198)
(SEQ. ID NO.: 199)
(SEQ. ID NO.: 200)
HIV-1 gag p24 183-191 DLNTMLNTV HLA-B14 191
(SEQ. ID NO.: 568)
(SEQ. ID NO.: 201)
HIV-1 pl7 19-27 IRLRPGGKK HLA-B27 188
(SEQ. ID NO.: 202)
(SEQ. ID NO.: 203)
(SEQ. ID NO.: 204)
(SEQ. ID NO.: 205)
(SEQ. ID NO.: 206)
(SEQ. ID NO.: 207)
(SEQ. ID NO.: 208)
P24 (SEQ. ID NO.: 209)
(SEQ. ID NO.: 210)
(SEQ. ID NO.: 221)
HIV-1 gag p24 254-262 PPIPVGDIY HLA-B35 193
(SEQ. ID NO.: 212)
(SEQ. ID NO.: 213)
(SEQ. ID NO.: 214)
HIV-1 gag 245-253 NPVPVGNIY HLA-B35 193
(SEQ. ID NO.: 215)
(SEQ. ID NO.: 216)
HIV-1 gag p24 193-201 GHQAAMQML HLA-B42 188
(SEQ. ID NO.: 217)
(SEQ. ID NO.: 218)
(SEQ. ID NO.: 219)
(SEQ. ID NO.: 220)
HIV-1 gag p24 325-333 NANPDCKTI HLA-B51 188
HIV-1 gag p24 275-282 RMYSPTSI HLA-B52 188
(SEQ. ID NO.: 222)
(SEQ. ID NO.: 223)
HIV-1 gag p24 147-155 ISPRTLNAW HLA-B57 188
(SEQ. ID NO.: 224)
HIV-1 gag p24 240-249 TSTLQEQIGW HLA-B57 188
(SEQ. ID NO.: 225)
HIV-1 gag p24 162-172 KAFSPEVIPMF HLA-B57 188
(SEQ. ID NO.: 226)
HIV-1 gag p24 311-319 QASQEVKNW HLA-B57 188
(SEQ. ID NO.: 227)
HIV-1 gag p24 311-319 QASQDVKNW HLA-B57 188
(SEQ. ID NO.: 228)
(SEQ. ID NO.: 229)
(SEQ. ID NO.: 230)
HIV-1 gag p24 240-249 TSTLQEQIGW HLA-B58 188
(SEQ. ID NO.: 231)
(SEQ. ID NO.: 232)
(SEQ. ID NO.: 233)
(SEQ. ID NO.: 234)
(SEQ. ID NO.: 235)
(SEQ. ID NO.: 236)
(SEQ. ID NO.: 237)
HIV-1 gag p24 168-175 VIPMFSAL HLA-Cw*0102 188
(SEQ. ID NO.: 238)
(SEQ. ID NO.: 239)
(SEQ. ID NO.: 240)
(SEQ. ID NO.: 241)
(SEQ. ID NO.: 242)
(SEQ. ID NO.: 243)
(SEQ. ID NO.: 244)
HIV-1  gag p24 308-316 QASQEVKNW HLA-Cw*0401 521
(SEQ. ID NO.: 245)
HIV-1 IIIB RT 273-282 VPLDEDFRKY HLA-B35 181
(SEQ. ID NO.: 246)
HIV-1 IIIB RT 25-33 NPDIVIYQY HLA-B35 181
(SEQ. ID NO.: 247)
HIV-1 IIIB gp41 557-565 RAIEAQAHL HLA-B51 181
(SEQ. ID NO.: 248)
HIV-1 IIIB RT 231-238 TAFTIPSI HLA-B51 181
(SEQ. ID NO.: 249)
HIV-1 IIIB p24 215-223 VHPVHAGPIA HLA-B*5501 181
(SEQ. ID NO.: 250)
HIV-1 IIIB gp120 156-165 NCSFNISTSI HLA-Cw8 181
(SEQ. ID NO.: 251)
HIV-1 IIIB  gp120 241-249 CTNVSTVQC HLA-Cw8 181
(SEQ. ID NO.: 252)
HIV-1 5F2 gp120 312-320 IGPGRAFHT H2-Dd 198
(SEQ. ID NO.: 253)
HIV-1 5F2 pol 25-33 NPDIVIYQY HLA-B*3501 199
(SEQ. ID NO.: 254)
HIV-1 5F2 pot 432-441 EPIVGAETFY HLA-B*3501 199
(SEQ. ID NO.: 255)
HIV-1 5F2 pol 432-440 EPIVGAETF HLA-B*3501 199
(SEQ. ID NO.: 256)
HIV-1 5F2 pol 6-14 SPAIFQSSM HLA-B*3501 199
(SEQ. ID NO.: 257)
HIV-1 5F2 pol 59-68 VPLDKDFRKY HLA-B*3501 199
(SEQ. ID NO.: 258)
HIV-1 5F2 po1 6-14 IPLTEEAEL HLA-B*3501 199
(SEQ. ID NO.: 259)
HIV-1 5F2 nef 69-79 RPQVPLRPMTY HLA-B*3501 199
(SEQ. ID NO.: 260)
HIV-1 5F2 nef 66-74 FPVRPQVPL HLA-B*3501 199
(SEQ. ID NO.: 261)
HIV-1 5F2 env 10-18 DPNPQEVVL HLA-B*3501 199
(SEQ. ID NO.: 262)
HIV-1 5F2 env 7-15 RPIVSTQLL HLA-B*3501 199
(SEQ. ID NO.: 263)
HIV-1 5F2 pol 6-14 IPLTEEAEL HLA-B51 199
(SEQ. ID NO.: 264)
HIV-1 5F2 env 10-18 DPNPQEVVL HLA-B51 199
(SEQ. ID NO.: 265)
HIV-1 5F2 gagp24 199-207 AMQMLKETI H2-Kd 198
(SEQ. ID NO.: 266)
(SEQ. ID NO.: 267)
(SEQ. ID NO.: 268)
HIV-1 5F2 gp4l 593-607 GIWGCSGKLICTTA HLA-B17 201
(SEQ. ID NO.: 269)
HIV-1 5F2 gp41 753-767  ALIWEDLRSLCLFS HLA-B22 201
(SEQ. ID NO.: 270)
HPV 6b E7 21-30 GLHCYEQLV HLA-A*0201 202
(SEQ. ID NO.: 271)
HPV 6b E7 47-55 PLKQHFQIV HLA-A*0201 202
(SEQ. ID NO.: 272)
(SEQ. ID NO.: 273)
(SEQ. ID NO.: 274)
(SEQ. ID NO.: 275)
(SEQ. ID NO.: 276)
(SEQ. ID NO.: 277)
(SEQ. ID NO.: 278)
(SEQ. ID NO.: 279)
HSV gp B 498-505 SSIEFARL H2-Kb 206
(SEQ. ID NO.: 280)
HSV-1 gp C 480-488 GIGIGVLAA HLA-A*0201 104
(SEQ. ID NO.: 281)
(SEQ. ID NO.: 282)
(SEQ. ID NO.: 283)
(SEQ. ID NO.: 284)
(SEQ. ID NO.: 285)
(SEQ. ID NO.: 286)
Influenza MP 58-66 GILGFVFTL HLA-A*0201 68, 169, 2
(SEQ. ID NO.: 287) 09, 210, 2
Influenza MP 59-68 ILGFVFTLTV HLA-A*0201 168, 212,
(SEQ. ID NO.: 288) 213
(SEQ. ID NO.: 289)
Influenza NP 91-99 KTGGPIYKR HLA-A*6801 215, 216
(SEQ. ID NO.: 290)
(SEQ. ID NO.: 291)
(SEQ. ID NO.: 292)
(SEQ. ID NO.: 293)
(SEQ. ID NO.: 294)
(SEQ. ID NO.: 295)
Influenza PBI 591-599 VSDGGPKLY HLA-A1 214, 29
(SEQ. ID NO.: 296)
Influenza A NP 44-52 CTELKLSDY HLA-A1 29
(SEQ. ID NO.: 297)
(SEQ. ID NO.: 298)
Influenza A NSI 123-132 IMDKNIILKA HLA-A*0201 221
(SEQ. ID NO.: 299)
Influenza A NP 383-391 SRYWAIRTR HLA-B*2705 160, 184
(SEQ. ID NO.: 300)
Influenza A NP 147-155 TYQRTRALV H2-Kd 222, 223
(SEQ. ID NO.: 301)
Influenza A HA 210-219 TYVSVSTSTL H2-Kd 224, 225
(SEQ. ID NO. 302)
Influenza A HA 518-526 IYSTVASSL H2-Kd 224
(SEQ. ID NO. 303)
Influenza A HA 259-266 FEANGNLI H2-Kk 226, 227,
(SEQ. ID NO.: 304) 228
Influenza A HA 10-18 IEGGWTGMI H2-Kk 226, 227,
(SEQ. ID NO.: 305) 228
Influenza A NP 50-57 SDYEGRLI H2-Kk 229, 230
(SEQ. ID NO.. 306)
Influenza a NSI 152-160 EEGAIVGEI H2-Kk 231
(SEQ. ID NO.: 307)
Influenza NP 336-374 ASNENMETM H2Db  168, 222,
A34 (SEQ. ID NO.: 308) 219
A68 (SEQ. ID NO.: 309)
Influenza B NP 85-94 KLGEFYNQMM HLA-A*0201 233
(SEQ. ID NO.: 310)
Influenza B NP 85-94 KAGEFYNQMM HLA-A*0201 234
(SEQ. ID NO.: 311)
JAP (SEQ. ID NO. 312)
JAP (SEQ. ID NO.: 313)
JAP (SEQ. ID NO. 314)
JAP (SEQ. ID NO. 315)
Influenza HA 210-219 TYVSVGTSTI(L > I) H2-Kd 236
JAP (SEQ. ID NO.: 316)
JAP (SEQ. ID NO.: 317)
(SEQ. ID NO.: 318)
(SEQ. ID NO. 319)
(SEQ. ID NO. 320)
(SEQ. ID NO.: 321)
LCMV GP 33-42 KAVYNFATCG H2-Db 243, 244
(SEQ. ID NO.: 322)
(SEQ. ID NO. 323)
protein (SEQ. ID NO. 324)
MMTV env gp 474-482 SFAVATTAL H2-Kd 246
36 (SEQ. ID NO.: 325)
MMTV gag p27 425-433 SYETFISRL H2-Kd 246
(SEQ. ID NO.: 326)
MMTV env gp73 544-551 ANYDFICV H2-Kb 247
(SEQ. ID NO.: 327)
MuLV env p15E 574-581 KSPWFTTL H2-Kb 249, 250
(SEQ. ID NO.: 328)
MuLV env gp70 189-196 SSWDFITV H2-Kb 251, Sijts
(SEQ. ID NO.: 329) et al.
MuLV gag 75K 75-83 CCLCLTVFL H2-Db 252
(SEQ. ID NO.: 330)
MuLV env gp70 423-431 SPSYVYHQF H2Ld 253
(SEQ. ID NO.: 331)
MV F protein 437-447 SRRYPDAVYLH HLA-B*2705 254
(SEQ. ID NO.: 332)
Mv F protein 438-446 RRYPDAVYL HLA-B*2705 255
(SEQ. ID NO. 333)
(SEQ. ID NO.: 334)
(SEQ. ID NO. 335)
(SEQ. ID NO.: 336)
(SEQ. ID NO.: 337)
(SEQ. ID NO.: 338)
virus gp (SEQ. ID NO.: 339)
(SEQ. ID NO.: 340)
Rotavirus VP7 33-40 IIYRFLLI H2-Kb 259
(SEQ. ID NO.: 341)
(SEQ. ID NO.: 342)
(SEQ. ID NO.: 343)
(SEQ. ID NO.: 344)
SIV  gagp11C 179-190 EGCTPYDTNQML Mamu-A*01 266
(SEQ. ID NO.: 345)
(SEQ. ID NO.: 346)
SV NP 324-332 FAPCTNYPAL H2-Kb 263, 264,
(SEQ. ID NO.: 346) 265
(SEQ. ID NO.: 347)
SV40 T 206-215 SAINNYAQKL H2-Db 268, 269
(SEQ. ID NO.: 348)
SV40 T 223-231 CKGVNKEYL H2-Db 268, 269
(SEQ. ID NO. 349)
SV40 T 489-497 QGINNLDNL H2-Db 268, 269
(SEQ. ID NO.: 350)
(501) (SEQ. ID NO.: 351)
(SEQ. ID NO. 352)
(SEQ. ID NO.: 353)
HLA Class I Motifs
HLA-A1 Position (Antigen) Source Ref.
T cell epitopes EADPTGHSY MAGE-1 161-169 27, 28
(SEQ. ID NO.: 354)
VSDGGPNLY Influenza A PB 1591-599 21, 23
(SEQ. ID NO.: 355)
CTELKLSDY Influenza A NP 44-52 23
(SEQ. ID NO.: 356)
EVDPIGHLY MAGE-3 168-176 29, 30
(SEQ. ID NO.: 357)
HLA-A201 MLLSVPLLLG Calreticulin signal sequence 1-10 34, 35, 36, 37
(SEQ, ID NO.: 358)
STBXQSGXQ HBV PRE-S PROTEIN 141-149 43
(SEQ. ID NO.: 359)
YMDGTMSQV Tyrosinase 369-377 45
(SEQ, ID NO.: 360)
ILKEPVHGV HIV-I RT 476-484 4, 31, 47
(SEQ. ID NO.: 361)
LLGFVFTLTV Influenza MP 59-68 4, 39
(SEQ. ID NO,: 362)
LLFGYPVYVV HTLV-1 tax 11-19 40
(SEQ. ID NO.: 363)
GLSPTVWLSV HBV sAg 348-357 48
(SEQ. ID NO.: 364)
WLSLLVPFV HBV sAg 335-343 49, 50, 51
(SEQ. ID NO.: 365)
FLPSDFFPSV HBV cAg 18-27 52
(SEQ. ID NO.: 366)
C L G 0 L L T M V EBV LMP-2 426-434 48
(SEQ. ID NO.: 367)
FLAGNSAYEYV HCMV gp 618-628B 53
(SEQ. ID NO.: 368)
KLGEFYNQMM Influenza BNP 85-94 54
(SEQ. ID NO.: 369)
KLVALGINAV HCV-1 NS3 400-409 55
(SEQ. ID NO,: 370)
DLMGYIPLV HCV MP 17-25 56
(SEQ. ID NO.: 371)
RLVTLKDIV HPV 11 EZ 4-12 34, 35
(SEQ. ID NO.: 372)
MLLAVLYCL Tyrosinase 1-9 57, 58, 59, 68
(SEQ. ID NO-373)
AAGIGILTV Melan A\Mart-127-35 60
(SEQ. ID NO.: 374)
YLEPGPVTA Pmel 17/gp 100 480-488 61
(SEQ. ID NO.: 375)
ILDGTATLRL Pmel 17/gp 100 457-466 62
(SEQ. ID NO.: 376)
LLDGTATLRL Pmel gp1OO 457-466 62
(SEQ. ID NO.: 377)
ITDQVPFSV Pmel gp 100 209-217 62
(SEQ. ID NO.: 378)
KTWGQYWQV Pmel gp 100 154-162 62
(SEQ. ID NO.: 379)
TITDQVPFSV Pmel gp 100 208-217 62
(SEQ. ID NO.: 380)
AFHIIVAREL HIV-I nef 190-198 63
(SEQ. ID NO.: 381)
YLNKIQNSL P. falciparum CSP 334-342 64
(SEQ. ID NO.: 382)
MMRKLAILSV P. falciparum CSP 1-10 64
(SEQ. ID NO.: 383)
KAGEFYNQMM Influenza BNP 85-94 65
(SEQ. ID NO.: 384)
NIAEGLRAL EBNA-1 480-488 66
(SEQ. ID NO.: 385)
NLRRGTALA EBNA-1 519-527 66
(SEQ. ID NO.: 386)
ALAIPQCRL EBNA-1 525-533 66
(SEQ. ID NO.: 387)
VLKDAIKDL EBNA-1 575-582 66
(SEQ. ID NO.: 388)
FMVFLQTHI EBNA-1 562-570 66
(SEQ. ID NO.: 389)
HLIVDTDSL EBNA-2 15-23 66
(SEQ. ID NO.: 390)
SLGNPSLSV EBNA-2 22-30 66
(SEQ. ID NO. 391)
PLASAMRML EBNA-2 126-134 66
(SEQ. ID NO. 392)
RMLWMANYI EBNA-2 132-140 66
(SEQ. ID NO.: 393)
MLWMANYIV EBNA-2 133-141 66
(SEQ. ID NO.: 394)
ILPQGPQTA EBNA-2 151-159 66
(SEQ. ID NO.: 395)
PLRPTAPTTI EBNA-2 171-179 66
(SEQ, ID NO.: 396)
PLPPATLTV EBNA-2 205-213 66
(SEQ. ID NO.: 397)
R M H L P V L H V EBNA-2 246-254 66
(SEQ. ID NO.: 398)
PMPLPPSQL EBNA-2 287-295 66
(SEQ. ID NO.: 399)
QLPPPAAPA EBNA-2 294-302 66
(SEQ. ID NO.: 400)
SMPELSPVL EBNA-2 381-389 66
(SEQ. ID NO.: 401)
DLDESWDYI EBNA-2 453-461 66
(SEQ. ID NO.: 402)
P L P C V L W P VV BZLF1 43-51 66
(SEQ. ID NO.: 403)
SLEECDSEL BZLF1 167-175 66
(SEQ, ID NO.: 404)
EIKRYKNRV BZLFI 176-184 66
(SEQ. ID NO.: 405)
QLLQFIYREV BZLF1 195-203 66
(SEQ. ID NO.: 406)
LLQHYREVA BZLFI 196-204 66
(SEQ. ID NO.: 407)
LLKQMCPSL BZLFI 217-225 66
(SEQ. ID NO.: 408)
SIIPRTPDV BZLFI 229-237 66
(SEQ. ID NO.: 409)
AIMDKNIIL Influenza A NS1 122-130 67
(SEQ. ID NO.: 410)
IMDKNIILKA Influenza A NS1 123-132 67
(SEQ. ID NO. 411)
LLALLSCLTV HCV MP 63-72 69
(SEQ. ID NO.: 412)
ILHTPGCV HCV MP 105-112 69
(SEQ. ID NO.: 413)
QLRRHIDLLV HCV env E 66-75 69
(SEQ, ID NO.: 414)
DLCGSVFLV HCV env E 88-96 69
(SEQ. ID NO.: 415)
SMVGNWAKV HCV env E 172-180 69
(SEQ. ID NO.: 416)
HLHQNIVDV HCV NSI 308-316 69
(SEQ. ID NO.: 417)
FLLLADARV HCV NSI 340-348 69
(SEQ. ID NO.: 418)
GLRDLAVAVEPVV HCV NS2 234-246 69
(SEQ. ID NO.: 419)
SLLAPGAKQNV HCV NS1 18-28 69
(SEQ. ID NO.: 420)
LLAPGAKQNV HCV NS1 19-28 69
(SEQ. ID NO.: 421)
FLLSLGIHL HBV pol 575-583 70
(SEQ. ID NO.: 422)
SLYADSPSV HBV pol 816-824 70
(SEQ. ID NO.: 423)
GLSRYVARL HBV POL 455-463 70
(SEQ. ID NO.: 424)
KIFGSLAFL HER-2 369-377 71
(SEQ. ID NO.: 425)
ELVSEFSRM HER-2 971-979 71
(SEQ. ID NO.: 426)
KLTPLCVTL HIV-I gp 160 120-128 72
(SEQ. ID NO.: 427)
SLLNATDIAV HIV-I GP 160 814-823 72
(SEQ. ID NO.: 428)
VLYRYGSFSV Pmel gp100 476-485 62
(SEQ. ID NO.: 429)
YIGEVLVSV Non-filament forming class I myosin 73
(SEQ. ID NO.: 430) family (HA-2)**
LLFNILGGWV HCV NS4 192-201 74
(SEQ. ID NO.: 431)
LLVPFVQWFW HBV env 338-347 74
(SEQ. ID NO.: 432)
ALMPLYACI HBV pol 642-650 74
(SEQ. ID NO.: 433)
YLVAYQATV HCV NS3 579-587 74
(SEQ. ID NO.: 434)
TLGIVCPIC HIPV 16 E7 86-94 74
(SEQ. ID NO.: 435)
YLLPRRGPRL HCV core protein 34-43 74
(SEQ. ID NO.: 436)
LLPIFFCLWV HBV env 378-387 74
(SEQ. ID NO.: 437)
YMDDVVLGA HBV Pol 538-546 74
(SEQ. ID NO.: 438)
GTLGIVCPI HPV16 E7 85-93 74
(SEQ. ID NO.: 439)
LLALLSCLTI HCV MP 63-72 74
(SEQ. ID NO.: 440)
MLDLQPETT HPV 16 E7 12-20 74
(SEQ. ID NO.: 441)
SLMAFTAAV HCV NS4 174-182 75
(SEQ. ID NO.: 442)
CINGVCWTV HCV NS3 67-75 75
(SEQ. ID NO.: 443)
VMNILLQYVV Glutarnic acid decarboxylase 76
(SEQ. ID NO.: 444) 114-123
ILTVILGVL Melan A/Mart- 32-40 77
(SEQ. ID NO.: 445)
FLWGPRALV MAGE-3 271-279 78
(SEQ. ID NO.: 446)
L L C P A G H A V HCV NS3 163-171 54
(SEQ. ID NO.: 447)
ILDSFDPLV HCV NSS 239-247 54
(SEQ. ID NO.: 448)
LLLCLIFLL HBV env 250-258 79
(SEQ. ID NO.: 449)
LIDYQGMLPV HBV env 260-269 79
(SEQ. ID NO.: 450)
SIVSPFIPLL HBV env 370-379 79
(SEQ. ID NO.: 451)
FLLTRILTI HBV env 183-191 80
(SEQ, ID NO.: 452)
HLGNVKYLV P. faciparum TRAP 3-11 81
(SEQ, ID NO.: 453)
GIAGGLALL P. faciparum TRAP 500-508 81
(SEQ. ID NO.: 454)
ILAGYGAGV HCV NS S4A 236-244 82
(SEQ. ID NO.: 455)
GLQDCTMLV HCV NS5 714-722 82
(SEQ. ID NO.: 456)
TGAPVTYSTY HCV NS3 281-290 83
(SEQ. ID NO.: 457)
VIYQYMDDLV HIV-1RT 179-187 84
(SEQ, ID NO.: 458)
VLPDVFIRCV N-acetylglucosaminyltransferase V 85
(SEQ, ID NO.: 459) Gnt-V intron
VLPDVFIRC N-acetylglucosaminyltransferase V 85
(SEQ. ID NO.: 460) Gnt-V intron
AVGIGIAVV Human CD9 86
(SEQ. ID NO.: 461)
LVVLGLLAV Human glutamyltransferase 86
(SEQ, ID NO.: 462)
ALGLGLLPV Human G protein coupled receptor 86
(SEQ, ID NO.: 463)
GIGIGVLAA HSV-1 gp C 480-488 86
GAGIGVAVL HSV-2 gp C 446-454 86
(SEQ. ID NO.: 464)
IAGIGILAI Pseudorabies gpGIN 455-463 86
(SEQ. ID NO.: 465)
LIVIGILIL Adenovirus 3 E3 9 kD 30-38 86
(SEQ. ID NO.: 466)
LAGIGLIAA S. Lincolnensis ImrA 86
(SEQ. ID NO.: 467)
VDGIGILTI Yeast ysa-1 77-85 86
(SEQ. ID NO.: 468)
GAGIGVLTA B. polymyxa, βcndoxylanase 149- 86
(SEQ. ID NO.: 469) 157
AAGIGIIQI E. coli methionine synthase 590-598 86
(SEQ. ID NO.: 470)
QAGIGILLA E. coli hypothetical protein 4-12 86
(SEQ. ID NO.: 471)
KARDPHSGHFV CDK4w1 22.32 87
(SEQ. ID NO.: 472)
KACDPI-ISGIIFV CDK4-R24C 22-32 87
(SEQ. ID NO.: 473)
ACDPFISGHFV CDK4-R24C 23-32 87
(SEQ. ID NO.: 474)
SLYNTVATL HIV-I gag p 17 77-85 99
(SEQ. ID NO.: 475)
ELVSEFSRV HER-2, m > V substituted 971-979 89
(SEQ. ID NO.: 476)
RGPGRAFVTI HIV-I gp 160 315-329 90
(SEQ. ID NO.: 477)
HMWNFISGI HCV NS4A 149-157 91
(SEQ. ID NO.: 478)
NLVPMVATVQ HCMV pp65 495-504 92
(SEQ. ID NO.: 479)
GLHCYEQLV HPV 6b E7 21-30 93
(SEQ. ID NO.: 480)
PLKQHFQIV HPV 6b E7 47-55 93
(SEQ. ID NO.: 481)
LLDFVRFMGV EBNA-6 284-293 95
(SEQ. ID NO.: 482)
AIMEKNIML Influenza Alaska NS 1 122-130 67
(SEQ. ID NO.: 483)
YLKTIQNSL P. falciparum cp36 CSP 96
(SEQ. ID NO.: 484)
YLNKIQNSL P. falciparum cp39 CSP 96
(SEQ. ID NO.: 485)
YMLDLQPETT HPV 16 E7 11-20* 97
(SEQ, ID NO.: 486)
LLMGTLGIV HPV16 E7 82-90** 97
(SEQ. ID NO.: 487)
TLGIVCPI HPV 16 E7 86-93 97
(SEQ. ID NO.: 488)
TLTSCNTSV HIV-1 gp120 197-205 98
(SEQ. ID NO.: 489)
KLPQLCTEL HPV 16 E6 18-26 97
(SEQ. ID NO.: 490)
TIHDIILEC HPV16 E6 29-37 97
(SEQ. ID NO.: 491)
LGIVCPICS HPV16 E7 87-95 97
(SEQ. ID NO.: 492)
VILGVLLLI Melan A/Mart-1 35-43 68
(SEQ. ID NO.: 493)
ALMDKSLHV Melan A/Mart-1 56-64 68
(SEQ. ID NO.: 494)
GILTVILGV Melan A/Mart-1 31-39 68
(SEQ. ID NO.: 495)
T cell epitopes MINAYLDKL P. Falciparum STARP 523-531 81
(SEQ. ID NO.: 496)
AAGIGILTV Melan A/Mart- 127-35 100
(SEQ. ID NO.: 497)
FLPSDFFPSV HBV cAg 18-27 51
(SEQ. ID NO,: 498)
Motif unknown SVRDRLARL EBNA-3 464-472 101
T cell epitopes (SEQ. ID NO.: 499)
T cell epitopes AAGIGILTV Melan A/Mart-1 27-35 100
FAYDGKDYI Human MHC 1-ot 140-148 99
(SEQ. ID NO.: 500)
(SEQ, ID NO.: 497)
(SEQ. ID NO.: 498)
Motif unknown AAGIGILTV Meland A/Mart-1 27-35 100
T cell epitopes (SEQ. ID NO.: 497)
AAGIGILTV Melan A/Mart-1 27-35 100
ALLAVGATK Pmel17 gp 100 17-25 107
(SEQ. ID NO.: 501)
T cell epitopes R L R D L L L I V T R HIV-1 gp41 768-778 108
(SEQ. ID NO.: 502)
QVPLRPMTYK HIV-1 nef 73-82 109
(SEQ. ID NO.: 503)
TVYYGVPVWK HIV-1 gp120-36-45 110
(SEQ. ID NO.: 504)
RLRPGGKKK HIV-1 gag p 17 20-29 110
(SEQ. ID NO.: 505)
ILRGSVAHK Influenza NP 265-273 21
(SEQ. ID NO,: 506)
RLRAEAGVK EBNA-3 603-611 111
(SEQ. ID NO.: 507)
RLRDLLLIVTR HIV-1 gp41 770-780 112
VYYGVPVWK HIV-I GP 120 38-46 113
(SEQ. ID NO.: 508)
RVCEKMALY HCV NS5 575-583 114
(SEQ. ID NO.: 509)
Motif unknown KIFSEVTLK Unknown; muta melanoma peptide Wolfel et al.,
T cell epitope (SEQ, ID NO.: 510) ted (p 1 83L) 175-183 pers. Comm.
YVNVNMGLK* HBV cAg 88-96 116
(SEQ. ID NO.: 511)
T cell epitopes IVTDFSVIK EBNA-4 416-424 115, 117
(SEQ. ID NO.: 512)
ELNEALELK P53 343-351 115
(SEQ, ID NO.: 513)
VPLRPMTYK HIV-1 NEF 74-82 115
(SEQ. ID NO.: 514)
AIFQSSMTK HIV-1 gag p24 325-333 115
(SEQ. ID NO.: 515)
QVPLRPMTYK HIV-1 nef 73-82 118
(SEQ. ID NO.: 516)
TINYTIFK HCV NSI 238-246 114
(SEQ. ID NO.: 517)
AAVDLSHFLKEK HIV-1 nef 83-94 120
(SEQ. ID NO.: 518)
ACQ G V G G P G G H K HIV-1 I I 1B p24 349-359 122
(SEQ, ID NO,: 519)
HLA-A24 S Y L D S G I H F* β-catenin, mutated 123
(SEQ, ID NO.: 520) (proto-onocogen) 29-37
T cell epitopes RYLKDQQLL HIV GP 41 583-591 124
(SEQ. ID NO.: 521)
AYGLDFYIL P15 melanoma Ag 10-18 125
(SEQ. ID NO.: 522)
AFLPWHRLFL Tyrosinase 206-215 126
(SEQ. ID NO.: 523)
AFLPWHRLF Tyrosinase 206-214 126
(SEQ. ID NO.: 524)
RYSIFFDY Ebna-3 246-253 101
(SEQ. ID NO.: 525)
T cell epitope ETINEEAAEW HIV-1 gag p24 203-212 127
(SEQ. ID NO.: 526)
T cell epitopes STLPETTVVRR HBV cAg 141-151 129
(SEQ. ID NO,: 527)
MSLQRQFLR ORF 3P-gp75 294-321 (bp) 130
(SEQ, ID NO.: 528)
LLPGGRPYR TRP (tyrosinase rel.) 197-205 131
(SEQ. ID NO.: 529)
T cell epitope IVGLNKIVR HIV gag p24 267-267-275 132, 133
(SEQ. ID NO.: 530)
AAGIGILTV Melan A/Mart- 127 35 100
(SEQ. ID NO.: 531)
LUD Date Patent
TRA No. Patent No. Issued Peptide (Antigen) HLA
MAGE-4 5293 5,405,940 11 Apr. 1995 EVDPASNTY HLA-A1
(SEQ. ID NO.: 532)
MAGE-41 5293 5,405,940 11 Apr. 1995 EVDPTSNTY HLA-A1
MAGE-5 5293 5,405,940 11 Apr. 1995 EADPTSNTY HLA-A1
MAGE-51 5293 5,405,940 11 Apr. 1995 EADPTSNTY HLA-A1
MAGE-6 5294 5,405,940 11 Apr. 1995 EVDPIGHVY HLA-A1
5299.2 5,487,974 30 Jan. 1996 MLLAVLYCLL HLA-A2
5360 5,530,096 25 Jun. 1996 MLLAVLYCL HLA-B44
Tyrosinase 5360.1 5,519,117 21 May 1996 SEIWRDIDFA HLA-B44
Tyrosinase 5431 5,774,316 28 Apr. 1998 XEIWRDIDF HLA-B44
MAGE-2 5340 5,554,724 10 Sep. 1996 STLVEVTLGEV HLA-A2
5327 5,585,461 17 Dec. 1996 FLWGPRALV HLA-A2
MAGE-3 5344 5,554,506 10 Sep. 1996 KIWEELSVL HLA-A2
MAGE-3 5393 5,405,940 11 Apr. 1995 EVDPIGHLY HLA-A1
MAGE 5293 5,405,940 11 Apr. 1995 EXDX5Y HLA-A1
(SEQ. ID NO.: 552)
(but not EADPTGHSY)
(SEQ. ID NO.: 553)
E(A/V)D X5 Y
(SEQ. ID NO.: 554)
E(A/V)D P X4 Y
(SEQ. ID NO.: 555)
E(A/V)D P(I/A/T)X3 Y
(SEQ. ID NO.: 556)
E(A/V)D P(I/A/T)(G/S)X2 Y
(SEQ. ID NO.: 557)
E(A/V)D P(I/A/T)(G/S)(H/N)X Y
E (A/V) DP (I/A/T) (G/S) (H/N)
(L/T/V)Y
(SEQ. ID NO.: 559)
MAGE-1 5361 5,558,995 24 Sep. 1996 ELHSAYGEPRKLLTQD HLA-C
(SEQ ID NO: 560) Clone 10
(SEQ ID NO: 564) Clone 10
(SEQ ID NO: 565) Clone 10
(SEQ ID NO: 566) Clone 10
GAGE 5323.2 5,648,226 15 Jul. 1997 YRPRPRRY HLA-CW6
(SEQ. ID NO.: 567)
In a preferred embodiment of the invention an encoded antigen can be delivered in the form of a naked plasmid expression vector. Particularly useful constructs are disclosed in U.S. patent application Ser. No. 09/561,572 entitled EXPRESSION VECTORS ENCODING EPITOPES OF TARGET-ASSOCIATED ANTIGENS which is incorporated herein by reference in its entirety. The feasibility of and general procedures related to the use of naked DNA for immunization are described in U.S. Pat. Nos. 5,589,466, entitled “INDUCTION OF A PROTECTIVE IMMUNE RESPONSE IN A MAMMAL BY INJECTING A DNA SEQUENCE” and 5,679,647, entitled “METHODS AND DEVICES FOR IMMUNIZING A HOST AGAINST TUMOR-ASSOCIATED ANTIGENS THROUGH ADMINISTRATIONS OF NAKED POLYNUCLEOTIDES WHICH ENCODE TUMOR-ASSOCIATED ANTIGENIC PEPTIDES” which are herein incorporated by reference in their entirety. However the former teaches only intramuscular or intradermal injection while the latter teaches only administration to skin or mucosa. Administration directly to the lymphatic system is greatly more efficient (see examples 6-9, below). Single bolus injection into lymph node required only 0.1% of the dose required in order to obtain a similar level of CTL response by intramuscular (i.m.) injection. It is therefore feasible to establish a protective response against systemic viral infection with a single bolus delivered i.ln., but not with a dose nearing the practical limit delivered i.m. Even repeated bolus injections i.m. failed to establish a protective response against a peripheral virus infection or transplanted tumor whereas lower doses administered i.m. were completely effective.
Preferably the pump in the implantable device is an osmotic pump of the type used in the ALZET® model device or the DUROS™ model device pioneered by Alza Corporation, Palo Alto, Calif. or in a device made by Pharmetrix and exemplified in U.S. Pat. No. 4,838,862. The osmotic pump utilizes the osmotic effect using a membrane permeable to water but impermeable to a solute. Osmotic pressure built up in a device is used to deliver a composition at a controlled rate over time. A review by Giancarlo Santus and Richard Baker of “Osmotic Drug Delivery: A Review of the Patent Literature” in the Journal of Controlled Release 35 (1995) 1-21, provides useful guidelines for the type of osmotic pumps that are useful in this invention. The osmotic pump forces the composition through a discharge orifice to discharge the composition, Optionally a delivery line connects to the discharge orifice to position the line suitably for delivery to the lymphatic system of the animal. Patents that describe devices useful in this invention include the following U.S. Pat. Nos. (A) 3,604,417 assigned to American Cyanamid; (B) 4,838,862; 4,898,582; 5,135,498; 5,169,390; and 5,257,987 all assigned to Pharmetrix, (C) 4,340,048; 4,474,575; 4,552,651; 4,619,652; 4,753,651; 3,732,865; 3,760,804; 3,760,805; 3,929,132; 3,995,632; 4,034,756; 4,350,271; 4,455,145; 5,017,381; 5,023,088; 5,030,216; 5,034,229; 5,037,420; 5,057,318; 5,059,423; 5,110,596; 5,110,597; 5,135,523; 5,137,727; 5,174,999; 5,209,746; 5,221,278; 5,223,265; 3,760,984; 3,987,790; 3,995,631; 4,203,440; 4,286,067; 4,300,558; 4,304,232; 4,340,054; 4,367,741; 4,450,198; 4,855,141; 4,865,598; 4,865,845; 4,872,873; 4,929,233; 4,963,141; 4,976,966, all assigned to Alza Corp. Each of the foregoing patents are incorporated herein by reference.
Viruses: LCMV (Armstrong strain) was originally obtained from Dr. M. B. A. Oldstone, Scripps Clinics and Research Foundation, LaJolla, San Diego, Calif. Seed virus was grown on BHK cells and plagued on MC57 cells using an immunological focus assay, as described previously.
C57BL/6 mice were either intravenously injected with a single dose of 50 μg p33 (including 500 ng GM-CSF. Pharmingen) or were implanted with a microsomotic pump releasing a mixture of 50 μg of p33 and 500 ng GM-CSF over a time period of 7 days, or were left naive. After 7 days specific CTL activity was assessed in vivo using anti-viral protection assays. C5713L/6 mice were intravenously challenged with LCMV Armstrong strain (2×103 p.f.u.). After 4 days mice were sacrificed and LCMV titers were determined in spleens using an immunological focus assay. Mice implanted with osmotic pump showed significantly lower virus titers indicating active CTL immunity against the virus (Table V).
To examine whether the potent CTL responses elicited following i.ln. immunization were able to confer protection against peripheral tumors, groups of 6 C57BL/6 mice were immunized three times at 6-day intervals with 10 μg of pEFGPL33A DNA or control pEGFP-N3 DNA. Five days after the last immunization small pieces of solid tumors expressing the gp33 epitope (EL4-33) were transplanted s.c. into both flanks and tumor growth was measured every 3-4d. Although the EL4-33 tumors grew well in mice that had been repetitively immunized with control pEGFP-N3 DNA (FIG. 9), mice which were immunized with pEFGPL33A DNA i.ln. rapidly eradicated the peripheral EL4-33 tumors (FIG. 9).
SYNCHROTOPE TA2M, a melanoma vaccine encoding HLA-A2-restricted tyrosinase epitopes was formulated in 1% Benzyl alcohol, 1% ethyl alcohol, 0.5 mM EDTA, citrate-phosphate, 7.6. Aliquots of 80, 160, and 320 μg DNA/ml were prepared for loading into MINIMED 407C infusion pumps. The catheter of a SILHOUETTE infusion set is placed into an inguinal lymph node visualized by ultrasound imaging. The assembly of pump and infusion set was originally designed for the delivery of insulin to diabetics and the usual 17 mm catheter has been substituted with a 31 mm catheter for this application. The infusion set is kept patent for 4 days (approximately 96 hours) with an infusion rate of about 25 μl/hour resulting in a total infused volume of approximately 2.4 ml. Thus the total administered dose per infusion will be approximately 200, 400, and 800 μg, respectively, for the three concentrations described above. Following an infusion subjects will be given a 10 day rest period before starting a subsequent infusion. Given the continued residency of plasmid DNA in the lymph node after administration (as in example 10) and the usual kinetics of CTL response following disappearance of antigen, this schedule will be sufficient to maintain the immunologic CTL response.
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