Source: http://www.google.com/patents/US7999088?dq=5,545,531
Timestamp: 2016-12-07 22:56:16
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Matched Legal Cases: ['Application No. 20030228634', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 2006', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'ART-1', 'art 75']

Patent US7999088 - Methods and compositions to elicit multivalent immune responses against ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe present invention provides a method of treating cancer by providing to a subject in need thereof an immunogenic composition comprising a nucleic acid construct encoding a polypeptide comprising CTL epitopes PSMA288-297 and PRAME425-433, or a cross-reactive analogue. In embodiments of the present...http://www.google.com/patents/US7999088?utm_source=gb-gplus-sharePatent US7999088 - Methods and compositions to elicit multivalent immune responses against dominant and subdominant epitopes, expressed on cancer cells and tumor stromaAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS7999088 B2Publication typeGrantApplication numberUS 11/454,616Publication dateAug 16, 2011Filing dateJun 16, 2006Priority dateJun 17, 2005Fee statusPaidAlso published asCA2612516A1, CA2612516C, CN101198620A, EP1896494A2, EP1896494B1, EP2385059A2, EP2385059A3, EP2385060A2, EP2385060A3, US8674081, US20070004662, US20110269949, WO2006138567A2, WO2006138567A3Publication number11454616, 454616, US 7999088 B2, US 7999088B2, US-B2-7999088, US7999088 B2, US7999088B2InventorsZhiyong Qiu, Adrian Ion BotOriginal AssigneeMannkind CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (117), Non-Patent Citations (154), Classifications (11), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetMethods and compositions to elicit multivalent immune responses against dominant and subdominant epitopes, expressed on cancer cells and tumor stroma
US 7999088 B2Abstract
In most instances, neoplastic processes evolve to avoid the immune defense mechanisms by employing a range of strategies that result in immune ignorance, tolerance or deviation. Methods that effectively break immune tolerance or repair immune deviation against antigens expressed on cancer cells have been described in the literature (Okano F, et al. J Immunol. 2005, Mar 1;174(5):2645-52; Mocellin S, et al., Exp Cell Res. 2004 Oct 1;299(2);267-78; Banat G A, et al., Cancer Immunol Immunother. 2001 Jan;49(11):573-86) and despite their association with significant levels of systemic immunity, rarely result in reduction of tumor burden. Significant limiting factors impacting this process are sub-optimal trafficking, local activation and/or activity of anti-tumoral effector cells. In fact, it has been shown in most instances that the intra-tumoral presence of immune cells is a rare occurrence—compared to that associated with inflammatory processes such as organ rejection, infections or autoimmune syndromes.
To amplify immune mediated control of tumoral processes, embodiments of the present invention provide immune mediated attack of neovasculature, in addition to direct attack on tumor cells, as a component of a bi- or multi-valent vaccine strategy aimed at establishing an inflammatory environment within the tumor resulting in shrinkage, stabilization or diminution of growth rate and invasion (local or systemic). This methodology can be more effective in controlling tumor processes than strategies that target either cancer cells or the neovasculature alone and has beneficial implications in regard to therapeutic index (efficacy/safety).
In some embodiments, co-targeting of tumor neovasculature and cancerous cells, or of multiple antigens on cancer cells, can be achieved by immunotherapeutic compositions comprising expression vectors such as plasmids that elicit immunity against transformed cells, tumor cells and endothelial cells of the neovasculature. Design of plasmids in a “string of beads” format is accomplished as disclosed in U.S. Patent Publication Application No. 20030228634, entitled “EXPRESSION VECTORS ENCODING EPITOPES OF TARGET-ASSOCIATED ANTIGENS AND METHODS FOR THEIR DESIGN” and herein incorporated by reference in its entirety. A preferred embodiment is a bivalent plasmid comprising immunogenic elements derived from molecule(s) expressed on cancer cells and molecule(s) expressed on neovasculature. In particular embodiments of the invention, such molecules correspond to the PRAME and PSMA epitopes and cross-reactive analogues thereof.
In some embodiments, vectors can be administered in a chronological sequence with other immunogenic agents—such as peptides—for the purpose of amplifying or modulating the therapeutic activity against cancer cells, neovasculature or both (disclosed in U.S. Patent Application Publication No. 20050079152 entitled “METHODS TO CONTROL MHC CLASS I-RESTRICTED IMMUNE RESPONSE”; U.S. Provisional Patent Application No. 60/640,402, filed Dec. 29, 2004, and U.S. Publication No. 20060165711, all entitled METHODS TO ELICIT, ENHANCE, AND SUSTAIN IMMUNE RESPONSE AGAINST MHC CLASS I-RESTRICTED EPITOPES, FOR PROPHYLACTIC OR THERAPEUTIC PURPOSES; and U.S. Provisional Application No. 60/691,581 filed on Jun. 17, 2004, entitled MULTIVALENT IMMUNOTHERAPEUTICS FOR CARCINOMA, and U.S. patent application Ser. No. 11/455,279, entitled MUTLIVALENT IMMUNOTHERAPIES FOR CARCINOMA, filed on date even with this application both entitled, each of which is herein incorporated by reference in its entirety) and balancing the response against subdominant and dominant epitopes.
Inducing immune responses to epitopes that are “subdominant” in context of a native antigen provides benefit in treating cancer since such epitopes can be involved in negative selection (central or peripheral) occurring in diseased individuals. Thus, constructs encompassing multiple copies of a subdominant epitope can be used to induce an increased response against such an epitope while preserving immunity against dominant ones.
Some embodiments relate to bivalent plasmids expressing PRAME and PSMA epitope sequences (such as those disclosed in the U.S. Patent Application Publication Nos. 20030220239, 20050221440, 20050142144 and PCT Patent Publication No. PCT/US/11101 entitled “EPITOPE SEQUENCES” herein each incorporated by reference in its entirety) and methods of use of these compositions, individually or in combination with other plasmids, to elicit a balanced immune response. Such methods can include an initiating or entraining step wherein the composition can be delivered to various locations on the animal, but preferably is delivered to the lymphatic system, for example a lymph node. The entrainment step can include one or more deliveries of that composition, for example, spread out over a period of time or in a continuous fashion over a period of time.
Still other embodiments include plasmids that encode an analogue of either the PSMA or PRAME epitopes. Further embodiments can include different epitopes (such as those disclosed in U.S. Patent Application Publication Nos. 20030220239 and 20040180354 both entitled “EPITOPE SEQUENCES” and herein incorporated by reference in their entirety) and analogues substituted in similar combination as the epitopes expressed in the RP8 and RP12 plasmids and corresponding peptide immunogens (such as those disclosed in U.S. Provisional Patent Application No. 60/691,889 entitled “EPITOPE ANALOGUES”, filed on Jun. 17, 2005, and herein incorporated by reference in its entirety) administered as the amplification portion of the immunization strategy.
FIG. 1. Structure of two monovalent plasmids and one bivalent plasmid.
FIG. 4. ELISpot analysis of PRAME and PSMA depicting induction of bivalent responses achieved by plasmids encompassing epitopes from the different antigens depicted in FIG. 3. Animals were immunized with 2 injections of PRAME/PSMA bivalent plasmid (1 mg/ml) in bilateral lymph nodes. 5×105 isolated splenocytes were incubated with 10 μg PSMA288-297 (SEQ ID NO:6):natural peptide or 10 μg PRAME425-433 (SEQ ID NO:5) natural peptide for 42 hours prior to development. Graphs represent average +/− SEM.
Embodiments relate to compositions that can elicit multivalent immune responses against dominant and subdominant epitopes. Some embodiments also relate to methods of designing the composition by: selecting antigens that are expressed by cancer cells and/or stromal (neovasculature) cells; defining epitopes that can have different intrinsic immune properties, that constitute valid immune targets on such cancer or stromal cells; and modulating the relative number of dominant and subdominant epitopes within a certain molecule (such as a therapeutic vector) by decreasing the ratio between the number of dominant and subdominant epitopes, while providing optimal flanking residues for appropriate generation within processing compartments.
Plasmid construction in preferred embodiments can entail stepwise ligation of sets of long complementary oligonucleotides resulting in the generation of DNA sequence encoding epitopes arrayed as a “string-of-beads.” These DNAs bear appropriate cohesive ends for restriction enzymes that can be used for further ligation with DNAs encoding epitope cluster regions, which are amplified by performing PCR on cloned cDNA for PSMA or PRAME as a template. The entire insert is then ligated into the vector backbone between Afl II and EcoR I restriction sites. The entire coding sequence is verified by DNA sequencing. PCR-based mutagenesis can be used to generate sequence encoding analogue epitope peptide, or to adjust the copies number of dominant/subdominant epitopes to achieve the desired ratio. The sequences of the two plasmids, RP8 and RP12, are described in detail and disclosed as SEQ ID NO.1 and SEQ ID NO.3. For the specific plasmids described herein, the vector backbone is a modified version of pVAX, by Invitrogen (Carlsbad, Calif.), which has been previously disclosed in U.S. Pat. No. 6,709,844 entitled Avoidance of Undesirable Replication Intermediates in Plasmid Propagation, and U.S. patent application Ser. No. 09/561,572 entitled Expression Vectors Encoding Epitopes of Target-Associated Antigens, each of which is hereby incorporated by reference in its entirety. One of skill in the art will recognize that the coding sequences of the present invention can be placed in any nucleic acid vector suitable for use as a vaccine without exceeding the scope of the invention. For example, the sequences encoding the other mentioned plasmids can be inserted into the same or a similar backbone as used in pRP8 and pRP12 plasmids.
The stretch of the first 8 amino acid residues is an artificial sequence that has been shown to facilitate processing of CTL epitopes by immunoproteasomes. The next 9 amino acids (in italics) are PRAME425-433 (SEQ ID NO:5), a potent HLA A2-specific CTL epitope that triggers strong anti-tumor immune responses in both in vitro immunization of human PBMC and in vivo immunization in mice. This PRAME epitope sequence is followed by a segment (amino acid 18-105 of the immunogen) of PRAME422-509, comprising two epitope clusters: PRAME422-443 (SEQ ID NO:26) and PRAME459-487 (SEQ ID NO:27). Two PSMA epitope clusters (in italics), PSMA3-45 (SEQ ID NO:22) (amino acid 108-150;) and PSMA217-297 (SEQ ID NO:24) (amino acid 151-231), are placed after the PRAME epitope cluster. These and other PRAME and PSMA epitope clusters have been disclosed in U.S. patent application Ser. Nos. 10/117,937, 11/067,064, and 11/067,159, each entitled Epitope Sequences and each of which is hereby incorporated by reference in its entirety. These epitope clusters contain a number of predicted HLA A2-specific epitopes and thus can be useful in generating a response to immune epitopes (described in U.S. Patent Application Publication No. 20030215425 entitled EPITOPE SYNCHRONIZATION IN ANTIGEN PRESENTING CELLS and U.S. Patent Application Publication Nos. 20030228634; 20040132088; and 20040203051, entitled EPITOPE CLUSTERS, each of which is hereby incorporated by reference in its entirety). A “string-of-beads” epitope array with multiple copies of PSMA288-297 (GLPSIPVHPI (SEQ ID NO:6); in boldface) constitutes the rest of the polypeptide (amino acid 232-297). Four copies of PSMA288-297 are incorporated with the last copy being an analogue (GLPSIPVHPV; SEQ ID NO:7). Both the native PSMA288-297 and its analogue have been shown to induce significant CTL responses in both in vitro immunization of human PBMC and in vivo immunization in mice with the analogue displaying elevated MHC class I binding and immunogenicity. Between PSMA288-297 epitope sequences are short amino acid sequences designated to be “cleavage helper sequences” to facilitate the processing and liberation of the epitope. These two epitopes are thus encoded in such a manner that they can be expressed, processed, and presented by pAPCs.
For the RP12 plasmid, the amino acid sequence of the encoded polypeptide (275 amino acid residues in length; SEQ ID NO:4) contains one amino acid substrate or liberation sequence and a hybrid “string-of-beads” encompassing a substrate at its C-terminus for the liberation of both the PRAME and PSMA epitopes. The entire polypeptide sequence of the encoded immunogen is shown in FIG. 9. The liberation sequence represented as SEQ ID NO:9 is as follows: KR-SLLQHLIGL-GDAAY-SLLQHLIGL-ISPEKEEQYIA-SLLQHLIGL-KRPSIKR-GLPSIPVHPV.
Segments of amino acid 2-44, 45-126, and 127-213 of the encoded immunogen are epitope clusters joined one to the next: PSMA3-45 (SEQ ID NO:22), PSMA217-297 (SEQ ID NO:23), and PRAME422-509 (SEQ ID NO:21), respectively. In the “string-of-beads” hybrid substrate, there are 3 copies of PRAME425-433 (SLLQHLIGL; in boldface; SEQ ID NO:5) and one copy of PSMA288-297 analogue (GLPSIPVHPV; in sans serif boldface; SEQ ID NO:7) at the C-terminus of the polypeptide. Between the PRAME425-433 and PSMA288-297 epitope sequences are the short amino acid sequences designated to be “cleavage helper sequences” to facilitate processing and liberation of the epitopes. These two epitopes are thus encoded in such a manner that they can be expressed, processed, and presented by pAPCs.
An “entraining” immunogen as contemplated in the present invention includes in many embodiments an induction that confers particular stability on the immune profile of the induced lineage of T cells.
As contemplated in the present invention, the term “amplifying or amplification”, as of a T cell response, includes in many embodiments a process for increasing the number of cells, the number of activated cells, the level of activity, rate of proliferation, or similar parameter of T cells involved in a specific response.
The entrain-and-amplify protocol employed in the present invention is described in greater detail in U.S. Patent Publication No. 20050079152, U.S. Provisional Patent Application No. 60/640,402, and U.S. patent application Ser. No. 11/323,572 each entitled “METHODS TO ELICIT, ENHANCE AND SUSTAIN IMMUNE RESPONSES AGAINST MHC CLASS I-RESTRICTED EPITOPES, FOR PROPHYLACTIC OR THERAPEUTIC PURPOSES” which are incorporated herein by reference in their entirety.
To introduce the immunogenic composition into the lymphatic system of the patient the composition is preferably directed to a lymph vessel, lymph node, the spleen, or other appropriate portion of the lymphatic system. In some embodiments each component is administered as a bolus. In other embodiments, one or more components are delivered by infusion, generally over several hours to several days. Preferably, the composition is directed to a lymph node such as an inguinal or axillary node by inserting a catheter or needle to the node and maintaining the catheter or needle throughout the delivery. Suitable needles or catheters are available made of metal or plastic (e.g., polyurethane, polyvinyl chloride (PVC), TEFLON, polyethylene, and the like). In inserting the catheter or needle into the inguinal node for example, the inguinal node is punctured under ultrasonographic control using a Vialon™ Insyte W™ cannula and catheter of 24G3/4 (Becton Dickinson, USA) which is fixed using Tegaderm™ transparent dressing (Tegaderm™, St. Paul, Minn., USA). An experienced radiologist generally does this procedure. The location of the catheter tip inside the inguinal lymph node is confirmed by injection of a minimal volume of saline, which immediately and visibly increases the size of the lymph node. The latter procedure allows confirmation that the tip is inside the node. This procedure can be performed to ensure that the tip does not slip out of the lymph node and can be repeated on various days after implantation of the catheter.
The therapeutic composition(s) of the present invention may be administered to a patient in a manner consistent with standard vaccine delivery protocols that are well known to one of ordinary skill in the art. Methods of administering immunogenic compositions of the present invention comprising plasmids and peptides or peptide analogues of the TuAAs PRAME and PSMA include, without limitation, transdermal, intranodal, perinodal, oral, intravenous, intradermal, intramuscular, intraperitoneal, and mucosal administration, delivery by injection or instillation or inhalation. A particularly useful method of vaccine delivery to elicit a CTL response is disclosed in Australian Patent No. 739189; U.S. Pat. Nos. 6,994,851 and 6,977,074 both entitled “A METHOD OF INDUCING A CTL RESPONSE”.
In addition to those already disclosed in this application, the following applications are hereby expressly incorporated by reference in their entireties. Useful methods for using the disclosed analogs in inducing, entraining, maintaining, modulating and amplifying class MHC-restricted T cell responses, and particularly effector and memory CTL responses to antigen, are described in U.S. Pat. Nos. 6,994,851 (Feb. 7, 2006) and 6,977,074 (Dec. 20, 2005) both entitled “A Method of Inducing a CTL Response”; U.S. Provisional Application No. 60/479,393, filed on Jun. 17, 2003, entitled “METHODS TO CONTROL MHC CLASS I-RESTRICTED IMMUNE RESPONSE”; and U.S. patent application Ser. No. 10/871,707 (Pub. No. 2005 0079152) and Provisional U.S. Patent Application No. 60/640,402 filed on Dec. 29, 2004, both entitled “Methods to elicit, enhance and sustain immune responses against MHC class I-restricted epitopes, for prophylactic or therapeutic purpose”. The analogs can also be used in research to obtain further optimized analogs. Numerous housekeeping epitopes are provided in U.S. application Ser. Nos. 10/117,937, filed on Apr. 4, 2002 (Pub. No. 20030220239 A1), and 10/657,022 (20040180354), and in PCT Application No. PCT/US2003/027706 (Pub. No. WO04022709A2), filed on Sep. 5, 2003; and U.S. Provisional Application Nos. 60/282,211, filed on Apr. 6, 2001; 60/337,017, filed on Nov. 7, 2001; 60/363,210 filed on Mar. 7, 2002; and 60/409,123, filed on Sep. 5, 2002; each of which applications is entitled “Epitope Sequences”. The analogs can further be used in any of the various modes described in those applications. Epitope clusters, which may comprise or include the instant analogs, are disclosed and more fully defined in U.S. patent application Ser. No. 09/561,571, filed on Apr. 28, 2000, entitled EPITOPE CLUSTERS. Methodology for using and delivering the instant analogs is described in U.S. patent application Ser. No. 09/380,534 and U.S. Pat. No. 6,977,074 (Issued Dec. 20, 2005) and in PCT Application No. PCTUS98/14289 (Pub. No. WO9902183A2), each entitled A “METHOD OF INDUCING A CTL RESPONSE”. Beneficial epitope selection principles for such immunotherapeutics are disclosed in U.S. patent application Ser. Nos. 09/560,465, filed on Apr. 28, 2000, 10/026,066 (Pub. No. 20030215425 A1), filed on Dec. 7, 2001, and 10/005,905 filed on Nov. 7, 2001, all entitled “Epitope Synchronization in Antigen Presenting Cells”; 6, 861, 234 (issued 1 Mar. 2005; application Ser. No. 09/561,074), entitled “Method of Epitope Discovery”; application Ser. No. 09/561,571, filed Apr. 28, 2000, entitled EPITOPE CLUSTERS; application Ser. No. 10/094,699 (Pub. No. 20030046714 A1), filed Mar. 7, 2002, entitled “Anti-Neovasculature Preparations for Cancer”; application Ser. No. 10/117,937 (Pub. No. 20030220239 A1) and PCTUS02/11101 (Pub. No. WO02081646A2), both filed on Apr. 4, 2002, and both entitled “EPITOPE SEQUENCES”; and application Ser. No. 10/657,022 and PCT Application No. PCT/US2003/027706 (Pub. No. WO04022709A2), both filed on Sep. 5, 2003, and both entitled “EPITOPE SEQUENCES”. Aspects of the overall design of vaccine plasmids are disclosed in U.S. patent application Ser. No. 09/561,572, filed on Apr. 28, 2000, entitled “Expression Vectors Encoding Epitopes of Target-Associated Antigens” and U.S. patent application Ser. No. 10/292,413 (Pub. No. 20030228634 A1), filed on Nov. 7, 2002, entitled “Expression Vectors Encoding Epitopes of Target-Associated Antigens and Methods for their Design”; U.S. patent application Ser. No. 10/225,568 (Pub No. 2003-0138808), filed on Aug. 20, 2002, PCT Application No. PCT/US2003/026231 (Pub. No. WO 2004/018666), filed on Aug. 19, 2003, both entitled “EXPRESSION VECTORS ENCODING EPITOPES OF TARGET-ASSOCIATED ANTIGENS”; and U.S. Pat. No. 6,709,844, entitled “AVOIDANCE OF UNDESIRABLE REPLICATION INTERMEDIATES IN PLASMID PROPAGATION”. Specific antigenic combinations of particular benefit in directing an immune response against particular cancers are disclosed in Provisional U.S. patent Application No. 60/479,554, filed on Jun. 17, 2003 and U.S. patent application Ser. No. 10/871,708, filed on Jun. 17, 2004 and PCT Patent Application No. PCT/US2004/019571 (Pub. No. WO 2004/112825), all entitled “Combinations of tumor-associated antigens in vaccines for various types of cancers”. Antigens associated with tumor neovasculature (e.g., PSMA, VEGFR2, Tie-2) are also useful in connection with cancerous diseases, as is disclosed in U.S. patent application Ser. No. 10/094,699 (Pub. No. 20030046714 A1), filed Mar. 7, 2002, entitled “Anti-Neovasculature Preparations for Cancer”. Methods to trigger, maintain, and manipulate immune responses by targeted administration of biological response modifiers are disclosed U.S. Provisional Application No. 60/640,727, filed on Dec. 29, 2004. Methods to bypass CD4+ cells in the induction of an immune response are disclosed in U.S. Provisional Application No. 60/640,821, filed on Dec. 29, 2004. Exemplary diseases, organisms and antigens and epitopes associated with target organisms, cells and diseases are described in U.S. Pat. No. 6,977,074 (issued Dec. 20, 2005) filed Feb. 2, 2001 and entitled “METHOD OF INDUCING A CTL RESPONSE”. Exemplary methodology is found in U.S. Provisional Application No. 60/580,969, filed on Jun. 17, 2004, and U.S. Patent Application No. 2006-0008468-A1, published on Jan. 12, 2006, both entitled “COMBINATIONS OF TUMOR-ASSOCIATED ANTIGENS IN DIAGNOTISTICS FOR VARIOUS TYPES OF CANCERS”. Methodology and compositions are also disclosed in U.S. Provisional Application No. 60/640,598, filed on Dec. 29, 2004, entitled “COMBINATIONS OF TUMOR-ASSOCAITED ANTIGENS IN COMPOSITIONS FOR VARIOUS TYPES OF CANCER”. The integration of diagnostic techniques to assess and monitor immune responsiveness with methods of immunization including utilizing the instant analogs is discussed more fully in Provisional U.S. Patent Application No. 60/580,964 filed on Jun. 17, 2004 and U.S. Patent Application No. US-2005-0287068-A1, published on Dec. 29, 2005) both entitled “Improved efficacy of active immunotherapy by integrating diagnostic with therapeutic methods”. The immunogenic polypeptide encoding vectors are disclosed in U.S. patent application Ser. No. 10/292,413 (Pub. No. 20030228634 A1), filed on Nov. 7, 2002, entitled Expression Vectors Encoding Epitopes of Target-Associated Antigens and Methods for their Design, and in U.S. Provisional Application No. 60/691,579, filed on Jun. 17, 2005, entitled “Methods and compositions to elicit multivalent immune responses against dominant and subdominant epitopes, expressed on cancer cells and tumor stroma”. Additional useful disclosure, including methods and compositions of matter, is found in U.S. Provisional Application No. 60/691,581, filed on Jun. 17, 2005, entitled “Multivalent Entrain-and-Amplify Immunotherapeutics for Carcinoma”. Further methodology, compositions, peptides, and peptide analogs are disclosed in U.S. Provisional Application Nos. 60/581,001 and 60/580,962, both filed on Jun. 17, 2004, and respectively entitled “SSX-2 PEPTIDE ANALOGS” and “NY-ESO PEPTIDE ANALOGS.” Each of the applications and patents mentioned in the above paragraphs is hereby incorporated by reference in its entirety for all that it teaches. Additional analogs, peptides and methods are disclosed in U.S. Patent Application Publication No. 20060063913, entitled “SSX-2 PEPTIDE ANALOGS”; and U.S. Patent Publication No. 2006-0057673 A1, published on Mar. 16, 2006, entitled “EPITOPE ANALOGS”; and PCT Application Publication No. WO/2006/009920, entitled “EPITOPE ANALOGS”; all filed on Jun. 17, 2005. Further methodology and compositions are disclosed in U.S. Provisional Application No. 60/581,001, filed on Jun. 17, 2004, entitled “SSX-2 PEPTIDE ANALOGS”, and to U.S. Provisional Application No. 60/580,962, filed on Jun. 17, 2004, entitled “NY-ESO PEPTIDE ANALOGS”; each of which is incorporated herein by reference in its entirety. As an example, without being limited thereto each reference is incorporated by reference for what it teaches about class I MHC-restricted epitopes, analogs, the design of analogs, uses of epitopes and analogs, methods of using and making epitopes, and the design and use of nucleic acid vectors for their expression. Other applications that are expressly incorporated herein by reference are: U.S. patent application Ser. No. 11/156,253 (Publication No. 20060063913), filed on Jun. 17, 2005, entitled “SSX-2 PEPTIDE ANALOGS”; U.S. patent application Ser. No. 11/155,929, filed on Jun. 17, 2005, entitled “NY-ESO-1 PEPTIDE ANALOGS” (Publication No. 20060094661); U.S. patent application Ser. No. 11/321,967, filed on Dec. 29, 2005, entitled “METHODS TO TRIGGER, MAINTAIN AND MANIPULATE IMMUNE RESPONSES BY TARGETED ADMINISTRATION OF BIOLOGICAL RESPONSE MODIFIERS INTO LYMPHOID ORGANS”; U.S. patent application Ser. No. 11/323,572, filed on Dec. 29, 2005, entitled “METHODS TO ELICIT ENHANCE AND SUSTAIN IMMUNE REPONSES AGAINST MCH CLASS I RESTRICTED EPITOPES, FOR PROPHYLACTIC OR THERAPEUTIC PURPOSES”; U.S. patent application Ser. No. 11/323,520, tiled Dec. 29, 2005, entitled “METHODS TO BYPASS CD4+ CELLS IN THE INDUCTION OF AN IMMUNE RESPONSE”; U.S. patent application Ser. No. 11/323,049, filed Dec. 29, 2005, entitled “COMBINATION OF TUMOR-ASSOCIATED ANTIGENS IN COMPOSITIONS FOR VARIOUS TYPES OF CANCERS”; U.S. patent application Ser. No. 11,323,964, filed Dec. 29, 2005, entitled “COMBINATIONS OF TUMOR-ASSOCIATED ANTIGENS IN DIAGNOSTICS FOR VARIOUS TYPES OF CANCERS”; U.S. Provisional Application Ser. No. 60/691,889, filed on Jun. 17, 2005 entitled “EPITOPE ANALOGS.”
Design of Plasmid Expression Vectors Encoding Immunogens
The plasmids P2 and R2 (also referred to as pCTLR2) contain elements from PSMA (expressed on the neovasculature of a wide range of carcinomas or by prostate carcinoma cells) and PRAME (expressed by cancerous cells), respectively, (FIG. 1). Each insert encompasses a fragment of the antigen's sequence along with multiple copies of an epitope expressed by target cells and addressable via immune mediated attack. Flanking these epitopes are sequences encoding amino acids known to facilitate the processing and generation of epitope peptides in the cellular compartments. In addition, plasmid RP5 encompasses elements from both P2 and R2 with the expressed immunogens adjoined to each other.
lcelgrpsmvwslanpcphcgdrtfydpepilcpcfmpnkrsllqhligl gdaaysllqhliglispekeeqyia sllqhliglkrpsikrsllqhligl Amino acid residues 2 to 89 correspond to an epitope cluster region representing PRAME422-509 (SEQ ID NO:21). Within this epitope cluster region, a number of potential HLA A2-specific CTL epitopes have been found using a variety of epitope prediction algorithms. Amino acid residues 90-150 are an epitope liberation (synchrotope™) sequence with four embedded copies of the PRAME425-433 (SEQ ID NO:5) CTL epitope (boldface). Flanking the defined PRAME CTL epitope are short amino acid sequences that have been shown to play an important role in the processing of the PRAME CTL epitope. In addition, the amino acid sequence ISPEKEEQYIA (SEQ ID NO:28; corresponding to PRAME amino acid 276-286, in italics) is engineered into this string-of-beads region to facilitate the antibody-based detection of expression of encoded polypeptide.
Dominant/Subdominant Hierarchy of Engineered Immunogenic Elements
A study was conducted to assess whether the strategy of engineering elements from different antigens into the same expression vector creates a dominant/subdominant hierarchy amongst those elements.
The corrected percent lysis was calculated for each concentration of effector cells, using the mean cpm for each replicate of wells (FIG. 2). Percent specific lysis was calculated using the following formula: Percent release=100×(Experimental release−spontaneous release)/(Maximum release−spontaneous release). Data are presented as follows: the x-axis shows the effector to target ratio; the y-axis shows the corresponding percentage specific lysis. Results are expressed as % specific cytotoxicity (the plasmid R2 is also referred to a CTLR2).
Structure of Additional Plasmids
To design expression vectors that result in a more balanced immunity against both PRAME and PSMA epitopes (dominant and subdominant in the context of RP5), a set of immunogens was designed and incorporated within the same phasmid backbone by employing various combinations of the three following methods:
1) The ratio between the copy numbers of the PRAME425-433 (SEQ ID NO:5) (dominant) epitope and that of the PSMA288-297 (subdominant) epitope was adjusted in favor of the latter. 2) The less dominant epitope was placed in the C terminal position so that it would have the proper C-terminus independent of proteasomal processing. 3) The less dominant epitope (PSMA) was mutated (one or multiple copies within the expressed insert) to improve intrinsic immunogenic properties such as binding to, and half-life on, class I MHC. FIG. 3 shows the design of the various plasmids made. In FIG. 3, “V” corresponds to PSMA266-297 (SEQ ID NO:29) epitopes that carry an I297V mutation.
Induction of Bivalent Responses Achieved by Plasmids Encompassing Epitopes from Different Antigens
The plasmids designed as described in Example 3 above, were tested to determine their ability to prime a bivalent immune response against the PRAME425-433 (SEQ ID NO:5) and PSMA288-297 (SEQ ID NO:6) tumor associated antigens.
Briefly, spleens were isolated on day 11 from euthanized animals and the mononuclear cells, after density centrifugation (Lympholyte Mammal, Cedarlane Labs, Burlington, N.C.), were resuspended in HL-1 medium. Splenocytes (5×105 or 2.5×105 cells per well) were incubated with 10 μg of PSMA288-297 (SEQ ID NO:6) or PRAME425-433 (SEQ ID NO:5), natural peptide in triplicate wells of a 96 well filter membrane plates (Multi-screen IP membrane 96-well plate, Millipore, Mass.). Samples were incubated for 42 hours at 37° C. with 5% CO2 and 100% humidity prior to development. Mouse IFN-γ coating antibody (IFN-γ antibody pair, U-CyTech Biosciences, The Netherlands) was used as a coating reagent prior to incubation with splenocytes, followed by the accompanied biotinylated detection antibody. GABA conjugate and proprietary substrates from U-CyTech Biosciences were used for IFN-γ spot development. The CTL response in immunized animals was measured 24 hours after development on the AID International plate reader using ELISpot Reader software version 3.2.3 calibrated for IFN-γ spot analysis.
Overall, the results depicted in FIG. 4 show induction of a strong bivalent immunity against both PRAME and PSMA epitopes by the plasmid RP12. Some bivalent immunity against both PRAME and PSMA epitopes was observed with RP9 and to a lesser extent RP13, RP10, RP11 and RP8—all having a more potent representation of the PSMA epitope relative to PRAME epitope as compared to the plasmid RP5 (FIG. 2). This observation is apparently due in part to use of the I297V analogue of PSMA.
Induction of a Bivalent Response by the RP12 Plasmid
Based on the comparison in Example of 4 of the six plasmids (RP8, RP9, RP10, RP11, RP12, and RP13), RP12 was selected for further analysis, as it was the only plasmid that primed a robust, bivalent immune response against both PRAME425-433 (SEQ ID NO:5) and PSMA288-297 (SEQ ID NO:6).
Bivalent Immune Response in Mice Primed with PRAME and PSMA Plasmid and Boosted with Peptide
To determine whether immunization with the plasmids RP12 and RP8 could induce a bivalent response against the tumor associated antigens Prame425-433 and PSMA288-297, following peptide boost with the PSMA288-297 I297V (SEQ ID NO:7) analogue, a tetramer analysis of immunized animals was conducted.
The results shown in FIG. 6, as mean ±SEM of specific CD8+T cell frequency showed that RP12 plasmid elicits a slightly higher PSMA-specific immunity than RP8 prior to peptide boost. In addition, in both the case of RP12 and RP8, the immunity against PRAME was found to be dominant prior to peptide boost. However, after boost with the PSMA subdominant epitope, the immune response against PRAME and PSMA displayed a more balanced profile, particularly in the case of RP12, indicating the benefit of strategies to elicit equilibrated immune responses against epitopes of different immune hierarchy.
Bivalent Immune Response After PSMA Peptide Boost and Subsequent PRAME Peptide Boost
It was examined whether immunization with the plasmids RP12 and RP8 could induce a bivalent response against the PRAME425-433 (SEQ ID NO:5) and PSMA288-297 (SEQ ID NO:6) epitopes those tumor associated antigens, following a first peptide boost with the PSMA288-297 I297V (SEQ ID NO:7) analogue and a second boosting with PRAME425-433 L426Nva, L433Nle (SEQ ID NO:30) peptide analogue.
Briefly, spleens were isolated ten days following the last Prame425-433 L426Nva, L433Nle peptide injection from euthanized animals and the mononuclear cells, after density centrifugation (Lympholyte Mammal, Cedarlane Labs, Burlington, N.C.), were resuspended in HL-1 medium. Splenocytes (2×105 cells per well) were incubated with 10 μg of PSMA288-297 or PRAME425-433, natural peptide in triplicate wells of a 96 well filter membrane plates (Multi-screen IP membrane 96-well plate, Millipore, Mass.). Samples were incubated for 72 hours at 37° C. with 5% CO2 and 100% humidity prior to development. Mouse IFN-γ coating antibody (IFN-γ antibody pair, U-CyTech Biosciences, The Netherlands) was used as a coating reagent prior to incubation with splenocytes, followed by the accompanied biotinylated detection antibody. GABA conjugate and various substrates from U-CyTech Biosciences were used for IFN-γ spot development. The CTL response in immunized animals was measured 24 hours after development on the AID International plate reader using ELISpot Reader software version 3.2.3 calibrated for IFN-γ spot analysis.
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Biol. 281:929-947 (1998).Classifications U.S. Classification536/23.1International ClassificationC07H21/02Cooperative ClassificationA61K2039/70, C07K14/4748, C07K14/705, A61K2039/53, A61K2039/545, A61K39/0011European ClassificationC07K14/47A34, C07K14/705, A61K39/00D6Legal EventsDateCodeEventDescriptionSep 11, 2006ASAssignmentOwner name: MANNKIND CORPORATION, CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:QIU, ZHIYONG;BOT, ADRIAN ION;REEL/FRAME:018284/0456Effective date: 20060802Feb 16, 2015FPAYFee paymentYear of fee payment: 4RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services