ES2553270T3 - Nuevo epítopo inmunogénico para inmunoterapia - Google Patents
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- ES2553270T3 ES2553270T3 ES12191621.7T ES12191621T ES2553270T3 ES 2553270 T3 ES2553270 T3 ES 2553270T3 ES 12191621 T ES12191621 T ES 12191621T ES 2553270 T3 ES2553270 T3 ES 2553270T3
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Abstract
Péptido consistente en la secuencia de aminoácidos KLMDLDVEQL conforme a la SEQ ID N.º 3 que induce la reacción cruzada de linfocitos T con dicho péptido para el uso como medicamento contra el cáncer.
Description
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oxidase, in colon cancer and inflammatory bowel disease. J Pathol. 2005, 207,164-176).
El análisis inmunohistoquímico ha demostrado que la NOX1 se expresa de forma constitutiva en las células mucosas superficiales. Los adenomas y los adenocarcinomas bien diferenciados presentan la expresión de NOX1 regulada al alza.
El factor nuclear (NF)-kappaB se activó predominantemente en células de adenoma y adenocarcinoma que expresaban NOX1 en abundancia, lo cual indica que la NOX1 podría estimular las vías antiapoptóticas que dependen del NF-kappaB en los tumores de colon (Fukuyama, M. et al. Overexpression of a novel superoxideproducing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon. Cancer Lett. 2005, 221, 97-104).
Se ha descrito que la señalización de Wnt3a/beta-catenina induce la expresión de NOX1 (Petropoulos, H. & Skerjanc, I. S. Beta-catenin is essential and sufficient for skeletal myogenesis in P19 cells. J Biol Chem. 2002, 277, 15393-15399).
Recientemente se ha planteado que las especies reactivas de oxígeno (ROS) inducen la apoptosis endotelial, fenómeno que a su vez induce la expresión de varias moléculas de adhesión para las células tumorales. Esto significaría que alterando la producción de ROS tal vez se podría impedir la recidiva del tumor en sitios distantes (Ten, KM, van der Wal, JB, Sluiter, W, Hofland, LJ, Jeekel, J, Sonneveld, P, and van Eijck, CH; The role of superoxide anions in the development of distant tumor recurrence, Br J Cancer, 2006, 95,1497-1503).
Antígeno nuclear de células en proliferación (PCNA)
El PCNA se halla en el núcleo y es un cofactor de la ADN-polimerasa delta. La proteína codificada actúa como un homotrímero y ayuda a mejorar la procesividad de la síntesis de la hebra conductora durante la replicación del ADN. Así pues, se expresa en todas las células en proliferación, especialmente en las células tumorales, y se usa como marcador para detectar la proliferación.
ADN-topoisomerasa II
Los genes TOP2A y TOP2B codifican isoformas de una ADN-topoisomerasa, enzima que controla y altera los estados topológicos del ADN durante la transcripción. Esta enzima nuclear interviene en procesos como la condensación cromosómica, la separación de las cromátidas y el alivio de la tensión torsional que aparece durante la replicación y la transcripción del ADN. Las ADN-topoisomerasas catalizan la rotura transitoria y la religazón de las dos hebras de la doble hélice de ADN, lo que las permite girar libremente una respecto a la otra, alterando de ese modo la topología del ADN. Las dos isoformas de la enzima son probablemente el producto de un fenómeno de duplicación génica. El gen que codifica la forma alfa está localizado en el cromosoma 17 y el gen beta en el cromosoma 3.
El gen TOP2A es la diana de varios fármacos antitumorales y diversas mutaciones del mismo han sido vinculadas con el desarrollo de resistencia farmacológica.
TOP2A es adyacente a HER-2, el oncogén amplificado con más frecuencia en el cáncer de mama, en el sitio cromosómico 17ql2-q21 y aparece amplificado o eliminado, con igual frecuencia, en casi el 90% de los tumores primarios de mama HER-2 positivos (Jarvinen, TA and Liu, ET; Topoisomerase II alpha gene (TOP2A) amplification and deletion in cancer-more common than anticipated, Cytopathology, 2003, 14, 309-313). También se han descrito amplificaciones de TOP2A en otros tipos de cáncer.
Sin TOP2A la replicación del ADN y la división celular son imposibles. Ello lo ha convertido en la diana principal de muchos regímenes de tratamiento antitumoral, aunque el mecanismo exacto con el que destruye las células aún escapa a nuestro conocimiento (Kellner, U,Sehested, M, Jensen, PB,Gieseler, F, and Rudolph, P; Culprit and victim -DNA topoisomerase II, Lancet Oncol., 2002, 3, 235-243). El éxito de esta estrategia se ve mermado por la aparición de resistencia espontánea, y los daños del ADN causados por los fármacos pueden potenciar la malignidad. Datos recientes apuntan a que la amplificación y la deleción de TOP2A podrían estar detrás tanto de la sensibilidad como de la resistencia vinculadas a la quimioterapia con inhibidores de TOP2A, dependiendo del defecto genético específico en el locus de TOP2A.
No está claro si la implicación de TOP2B en el cáncer es similar a la de TOP2A o si existe una diferencia importante entre ambas isoformas. TOP2B puede al menos complementar parte de la actividad de TOP2A (Sakaguchi, A and Kikuchi, A; Functional compatibility between isoform alpha and beta of type II DNA topoisomerase, J Cell Sci., 2004, 117, 1047-1054).
Molécula de adhesión celular 5 relacionada con el antígeno carcinoembrionario
El antígeno carcinoembrionario (CEA = CEACAM5) es una proteína de membrana de 180 kDa fuertemente glucosilada compuesta por tres unidades repetidas similares a la región C2 de Ig flanqueadas por una región Nterminal similar a la región V de Ig, y una región C-terminal que alberga una región de enlace con
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glucofosfatidilinositol (Hegde, P,Qi, R, Gaspard, R, Abernathy, K, Dharap, S, Earle-Hughes, J, Gay, C, Nwokekeh, NU, Chen, T, Saeed, Al, Sharov, V, Lee, NH, Yeatman, TJ, and Quackenbush, J; Identification of tumor markers in models of human colorectal cancer using a 19,200-element complementary DNA microarray, Cancer Res., 2001, 61, 7792-7797).
Como antígeno oncofetal, la CEA se expresa durante el desarrollo del feto, pero también en el epitelio gastrointestinal del adulto, aunque en niveles bajos. La CEA aparece sobreexpresada en un alto porcentaje de tumores humanos, entre ellos el 90% de los tumores de cáncer gastrointestinal, colorrectal y pancreático, en el 70% de las células del cáncer de pulmón amicrocítico y el 50% de los tumores de mama (Thompson, JA, Grunert, F, and Zimmermann, W; Carcinoembryonic antigen gene family: molecular biology and clinical perspectives, J Clin Lab Anal., 2005, 5, 344-366). Debido a su alta expresión en las células tumorales y su secreción en el suero, la CEA ha sido ampliamente usada como marcador tumoral (Sikorska, H, Shuster, J, and Gold, P; Clinical applications of carcinoembryonic antigen, Cancer Detect. Prev., 1988, 12, 321-355) y es el marcador sérico estándar para el seguimiento del cáncer colorrectal (Locker, GY, Hamilton, S, Harris, J, Jessup, JM, Kemeny, N, Macdonald, JS, Somerfield, MR, Hayes, DF, and Bast, RC, Jr.; ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer, J Clin Oncol, 2006, 24, 5313-5327).
A pesar de su sobreexpresión en las células tumorales, los pacientes oncológicos no suelen mostrar una respuesta inmunitaria contra este antígeno (Orefice, S, Fossati, G, Pietrojusti, E, and Bonfanti, G; Delayed cutaneous hypersensitivity reaction to carcinoembryonic antigen in cancer patients, Tumori, 1982, 68, 473-475). El sistema inmunitario suele desarrollar toleranciaa la CEA porque en el organismo se expresa de ordinario en niveles bajos. Con todo, una serie de ensayos clínicos con vacunas ha demostrado la inmunogenicidad de la CEA (Sarobe, P, Huarte, E, Lasarte, JJ, and Borras-Cuesta, F; Carcinoembryonic antigen as a target to induce anti-tumor immune responses, Curr. Cancer Drug Targets., 2004, 4, 443-454), especialmente en el carcinoma colorrectal (CCR) (Mosolits, S, Ullenhag, G, and Mellstedt, H; Therapeutic vaccination in patients with gastrointestinal malignancies. A review of immunological and clinical results, Ann. Oncol., 2005, 16, 847-862), siendo el antígeno asociado a tumor (TAA) con el mayor número de plataformas vacunales probadas en este tipo de tumor (von Mehren, M; Colorectal cancer vaccines: what we know and what we don't yet know, Semin. Oncol., 2005, 32, 76-84).
En el caso de CEA se han descrito varios epítopos para los linfocitos T cooperadores y citotóxicos (Crosti, M, Longhi, R, Consogno, G, Melloni, G, Zannini, P, and Protti, MP; Identification of novel subdominant epitopes on the carcinoembryonic antigen recognized by CD4+ T-cells of lung cancer patients, J Immunol., 2006, 176, 5093-5099; Novellino, L, Castelli, C, and Parmiani, G; A listing of human tumor antigens recognized by T-cells: March 2004 update, Cancer Immunol. Immunother., 2004, 54, 187-207; Ruiz, M, Kobayashi, H, Lasarte, JJ, Prieto, J, Borras-Cuesta, F, Celis, E, and Sarobe, P; Identification and characterization of a T-helper peptide from carcinoembryonic antigen, Clin Cancer Res., 2004, 10, 2860-2867), lo que ha dado pie a una serie de ensayos con vacunas peptídicas en el marco del CCR (Babatz, J, Rollig, C, Lobel, B, Folprecht, G, Haack, M, Gwither, H, Kohne, CH, Ehninger, G, Schmitz, M, and Bornhauser, M; Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells, Cancer Immunol. Immunother., 2006, 55, 268-276; Fong, L, Hou, Y, Rivas, A, Benike, C, Yuen, A, Fisher, GA, Davis, MM, and Engleman, EG; Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy, Proc. Natl. Acad. Sci. U. S. A, 2001, 98, 8809-8814; Liu, KJ, Wang, CC, Chen, LT, Cheng, AL, Lin, DT, Wu, YC, Yu, WL, Hung, YM, Yang, HY, Juang, SH, and Whang-Peng, J; Generation of carcinoembryonic antigen (CEA)-specific T-cell responses in HLA-A*0201 and HLA-A*2402 late-stage colorectal cancer patients after vaccination with dendritic cells loaded with CEA peptides, Clin Cancer Res., 2004, 10, 2645-2651; Matsuda, K, Tsunoda, T, Tanaka, H, Umano, Y, Tanimura, H, Nukaya, I, Takesako, K, and Yamaue, H; Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide-pulsed dendritic cells, Cancer Immunol. Immunother., 2004, 53, 609-616; Ueda, Y, Itoh, T, Nukaya, I, Kawashima, I, Okugawa, K, Yano, Y, Yamamoto, Y, Naitoh, K, Shimizu, K, Imura, K, Fuji, N, Fujiwara, H, Ochiai, T, Itoi, H, Sonoyama, T, Hagiwara, A, Takesako, K, and Yamagishi, H; Dendritic cell-based immunotherapy of cancer with carcinoembryonic antigenderived, HLA-A24-restricted CTL epitope: Clinical outcomes of 18 patients with metastatic gastrointestinal or lung adenocarcinomas, Int. J Oncol., 2004, 24, 909-917; Weihrauch, MR, Ansen, S, Jurkiewicz, E, Geisen, C, Xia, Z, Anderson, KS, Gracien, E, Schmidt, M, Wittig, B, Diehl, V, Wolf, J, Bohlen, H, and Nadler, LM; Phase I/II combined chemoimmunotherapy with carcinoembryonic antigen-derived HLA-A2-restricted CAP-1 peptide and irinotecan, 5fluorouracil, and leucovorin in patients with primary metastatic colorectal cancer, Clin Cancer Res., 2005,11, 59936001). Estos y otros ensayos clínicos ejecutados hasta la fecha han demostrado la seguridad de las vacunaciones con CEA y han aportado pruebas de la inducción de una respuesta inmunitaria contra este antígeno (von Mehren, M; Colorectal cancer vaccines: what we know and what we don't yet know, Semin. Oncol., 2005, 32, 76-84).
Gen inducido por el factor de crecimiento transformante, beta (TGFBI)
El TGFBI fue identificado por primera vez como un gen inducible por el TGF-beta en una estirpe celular de adenocarcinoma de pulmón humano. Codifica una proteína segregada en la matriz extracelular, que supuestamente participa en la fijación celular y en la composición de dicha matriz.
También se ha demostrado que el TGFBI es uno de los genes cuya expresión es más elevada en el cáncer colorrectal, además de expresarse también mucho en el adenoma. Los resultados obtenidos con la PCR cuantitativa
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demuestran la fuerte elevación tanto en tumores sin purificar como en células epiteliales tumorales purificadas. En consonancia, los experimentos de hibridación in situ revelan que el TGFBI se expresa en muchos tipos de células, tanto en el compartimento estromal como epitelial (Buckhaults, P, Rago, C, St, CB, Romans, KE, Sana, S, Zhang, L, Vogelstein, B, and Kinzler, K. W; Secreted and cell surface genes expressed in benign and malignant colorectal tumors, Cancer Res., 2001, 61, 6996-7001).
En un metanálisis de estudios que investigaron la expresión génica en el carcinoma colorrectal, el TGFBI fue identificado como uno de los nueve únicos genes que aparecían regulados al alza reiteradamente (4 estudios de TGFBI) (Shih, W, Chetty, R, and Tsao, MS; Expression profiling by microarrays in colorectal cancer, Oncol. Rep., 2005, 13, 517-524).
En tejidos de páncreas humano se apreció un incremento de 32,4 veces en los niveles del ARNm del TGFBI en tumores pancreáticos en comparación con los tejidos de control normales. Los análisis de hibridación in situ revelaron que el ARNm del TGFBI se expresaba principalmente en células cancerosas del interior de la masa tumoral pancreática (Schneider, D, Kleeff, J, Berberat, PO, Zhu, Z, Korc, M, Friess, H, and Buchler, MW; Induction and expression of betaig-h3 in pancreatic cancer cells, Biochim. Biophys. Acta, 2002, 1588, 1-6).
El TGFBI ha sido identificado como un gen promotor de la angiogénesis en un modelo in vitro. Además, en varios tumores se ha detectado un aumento drástico de su expresión. Oligonucleótidos antisentido dirigidos contra el TGFBI bloquearon tanto la expresión génica como la formación del tubo endotelial in vitro, lo cual parece indicar que el TGFBI puede desempeñar un papel esencial en las interacciones entre la matriz y la célula endotelial (Aitkenhead, M, Wang, SJ, Nakatsu, MN, Mestas, J, Heard, C, and Hughes, CC; Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM, Microvasc. Res., 2002, 63, 159171).
Proteína tirosina fosfatasa, de tipo receptor, Zeta 1 (PTPRZX)
El PTPRZ1 es miembro de la familia de las proteínas tirosina fosfatasa de tipo receptor que codifica una proteína de membrana de un solo paso de tipo 1 dotada de dos dominios citoplasmáticos de tirosina fosfatasa, un dominio alfaanhidrasa carbónica y un dominio de fibronectina de tipo III. La expresión de este gen es inducida en células de cáncer gástrico (Wu, CW, Li, AF, Chi, CW, and Lin, WC; Protein tyrosine-phosphatase expression profiling in gastric cancer tissues, Cancer Lett., 2006, 242, 95-103), en los oligodendrocitos remielinizantes de las lesiones de la esclerosis múltiple (Harroch, S, Furtado, GC, Brueck, W, Rosenbluth, J, Lafaille, J, Chao, M, Buxbaum, JD, and Schlessinger, J; A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions, Nat. Genet., 2002, 32,411-414), y en células de riñón embrionarias humanas en condiciones hipóxicas (Wang, V, Davis, DA, Haque, M, Huang, LE, and Yarchoan, R; Differential gene up-regulation by hypoxiainducible factor-1 alpha and hypoxia-inducible factor-2 alpha in HEK293T-cells, Cancer Res., 2005, 65, 3299-3306).
Tanto la proteína como el transcrito se sobreexpresan en las células de glioblastoma, promoviendo su migración haptotáctica (Lu, KV, Jong, KA, Kim, GY, Singh, J, Dia, EQ, Yoshimoto, K, Wang, MY, Cloughesy, TF, Nelson, SF, and Mischel, PS; Differential induction of glioblastoma migration and growth by two forms of pleiotrophin, J Biol Chem., 2005, 280,26953-26964).
Además, el PTRPZ1 aparece amplificado con frecuencia a nivel del ADN genómico en el glioblastoma (Mulholland, PJ, Fiegler, H, Mazzanti, C, Gorman, P, Sasieni, P, Adams, J, Jones, TA, Babbage, JW, Vatcheva, R, Ichimura, K, East, P, Poullikas, C, Collins, VP, Carter, NP, Tomlinson, IP, and Sheer, D; Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme, Cell Cycle, 2006, 5, 783-791).
Cinasa Janus y proteína interaccionante con los microtúbulos 2 (JAKMIP2)
La JAKMIP2 ha sido identificada como una de las muchas dianas ulteriores confirmadas y presuntas de PAX3-FKHR que aparecen muy sobreexpresadas en el rabdomiosarcoma pediátrico de subtipo alveolar o ARMS (Lae, M, Ahn, E, Mercado, G, Chuai, S, Edgar, M, Pawel, B, Olshen, A, Barr, F, and Ladanyi, M; Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas, J Pathol., 2007, 212,143-151).
Fibronectina 1 (FN1)
La fibronectina es una glucoproteína de alto peso molecular que contiene alrededor de un 5% de glúcidos y que se une a proteínas receptoras que atraviesan la membrana celular, las integrinas. Además de a las integrinas, también se une a componentes de la matriz extracelular como el colágeno, la fibrina y la heparina. Existen varias isoformas de la fibronectina, todas producto del mismo gen. Las fibronectinas desempeñan un papel esencial en el mantenimiento de la morfología celular normal, la adhesión y la migración celular, la hemostasia, la trombosis, la cicatrización de heridas, la diferenciación y la proliferación (Hynes, RO; Fibronectins, Sci. Am., 1987, 254, 42-51).
La fibronectina polimérica, sFN, se forma in vitro tratando la fibronectina soluble con un péptido de 76 aa, el III1-C (llamado anastelina), que deriva de la primera repetición de tipo III de la fibronectina. Los estudios in vivoconratones portadores de tumores han demostrado que la aplicación sistémica de anastelina o de sFN suprimía el crecimiento,
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la angiogénesis y la metástasis tumorales (Yi, M and Ruoslahti, E; A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis, Proc. Natl. Acad. Sci. U. S. A, 2001, 98, 620-624). Anginex es un péptido sintético de 33 aminoácidos que se modeló originalmente para reproducir la estructura en lámina beta de proteínas antiangiogénicas. Se ha demostrado que anginex inicia la polimerización de la fibronectina y es inactivo en ratones que carecen de fibronectina plasmática (Akerman, ME, Pilch, J, Peters, D, and Ruoslahti, E; Angiostatic peptides use plasma fibronectin to home to angiogenic vasculature, Proc. Natl. Acad. Sci. U. S. A, 2005, 102, 2040-2045). Un estudio examinó los efectos de la fibronectina sobre la insuficiencia hepática fulminante provocada con Dgalactosamina (GalN)/lipopolisacárido (LPS) en ratones. Los resultados sugieren que la fibronectina protegió contra la insuficiencia hepática provocadapor GalN/LPS a través de un mecanismo que implica la inhibición de la activación del NF-kappaB, lo que causó la regulación a la baja del TNF-alfa y la regulación al alza de la IL-10, así como la elevación del Bcl-xL que indujo el bloqueo de las señales apoptóticas, procesos que culminaron en la supresión de la apoptosis de los hepatocitos causada por GalN/LPS (Qiu, Z, Kwon, AH, Tsuji, K, Kamiyama, Y, Okumura, T, and Hirao, Y; Fibronectin prevents D-galactosamine/lipopolysaccharide-induced lethal hepatic failure in mice, Shock, 2006, 25, 8087). Otros resultados indican que la fibronectina estimula la proliferación de las células de carcinoma de pulmón humano y disminuye la apoptosis in vitro al inducir la expresión del gen COX-2 y la biosíntesis de PGE2 (Han, S, Sidell, N, Roser-Page, S, and Roman, J; Fibronectin stimulates human lung carcinoma cell growth by inducing cyclooxygenase-2 (COX-2) expression, Int. J Cancer, 2004, 111,322-331).
Se ha demostrado que la fibronectina sufre un corte y empalme alternativo únicamente durante la organogénesis y la oncogénesis. Una de esas variantes de corte y empalme, la fibronectina con dominio extra B (ED-B), normalmente no aparece en los tejidos adultos normales y ha sido propuesta como marcador de la angiogénesis tumoral (Khan, ZA, Caurtero, J, Barbin, YP, Chan, BM, Uniyal, S, and Chakrabarti, S; ED-B fibronectin in non-small cell lung carcinoma, Exp. Lung Res., 2005, 31, 701-711). Mhawech et al. demostraron que los pacientes afectados por tumores de cabeza y cuello con tinción positiva para la EDB tienden a tener una supervivencia significativamente más corta (Mhawech, P, Dulguerov, P, Assaly, M, Ares, C, and Allal, AS; EB-D fibronectin expression in squamous cell carcinoma of the head and neck, Oral Oncol., 2005, 41, 82-88).
La expresión de la fibronectina regula la angiogénesis y la vasculogénesis y participa en las respuestas del tejido cerebral a la isquemia y las crisis epilépticas. La expresión génica de la fibronectina apareció significativamente elevada (p < 0,05) en los fibroblastos del síndrome de Sturge y Weber en comparación con la de fibroblastos procedentes de piel normal de individuos afectados por el síndrome (Comi, AM, Hunt, P, Vawter, MP, Pardo, CA, Becker, KG, and Pevsner, J; Increased fibronectin expression in sturge-weber syndrome fibroblasts and brain tissue, Pediatr. Res., 2003, 53, 762-769). La concentración de fibronectina era notablemente superior en tumores malignos de ovario en comparación con tumores benignos de dicho órgano y los ovarios normales. La concentración de fibronectina aparece significativamente elevada en pacientes con cáncer de ovario recidivante frente al mismo tipo de pacientes sin recidiva. La expresión de enzimas matriolíticos y de fibronectina procedentes del tumor son importantes para el crecimiento de los tumores ováricos (Demeter, A, Szirmai, K, Olah, J, Papp, Z, and Jeney, A; Elevated expression of matrix metalloproteinase-9, and fibronectin concentration in recurrent epithelial ovarian cancer, Orv. Hetil., 2004, 145, 1617-1624). El hecho de que la fibronectina fuera uno de los dos únicos genes regulados significativamente a la baja entre 1176 genes analizados en un estudio refuerza la hipótesis de su actuación como un importante gen supresor de las metástasis en el cáncer mamario (Urtreger, AJ, Werbajh, SE, Verrecchia, F, Mauviel, A, Puricelli, LI, Kornblihtt, AR, and Bal de Kier Joffe ED; Fibronectin is distinctly downregulated in murine mammary adenocarcinoma cells with high metastatic potential, Oncol. Rep., 2006,16, 14031410).
Un artículo publicado describe que tres péptidos solubles de la fibronectina (RGD, CS-1 y FN-C/H-V) inducen la apoptosis en los fibroblastos de pulmón. La apoptosis se produjo por disrupción de la adhesión (anoikis). El uso de péptidos pequeños de la fibronectina para promover la apoptosis de los fibroblastos merece ser estudiado en profundidad como posible tratamiento antifibrótico (Hadden, HL and Henke, CA; Induction of lung fibroblast apoptosis by soluble fibronectin peptides, Am. J Respir. Crit Care Med, 2000, 162, 15531560). Otro estudio ha demostrado que la fibronectina estimula la proliferación de las células del carcinoma de pulmón amicrocítico humano (NSCLC). Han demostrado que la fibronectina aumenta la proteína MMP-9, la expresión de ARNm y la actividad gelatinolítica en las células de NSCLC (Han, S, Ritzenthaler, JD, Sitaraman, SV, and Roman, J; Fibronectin increases matrix metalloproteinase 9 expression through activation of c-Fos via extracellular-regulated kinase and phosphatidylinositol 3-kinase pathways in human lung carcinoma cells, J Biol Chem., 2006, 281, 29614-29624). Un estudio investigó si los efectos supresores de tumores de compuestos de la vitamina D (VD) también podrían estar mediados por mecanismos que rigen la adhesividad celular. La introducción de ARN pequeños de interferencia contra la fibronectina regujo a la baja su expresión, así como la adhesividad de las células a una matriz de colágeno de tipo I. Sus hallazgos ponen de manifiesto la trascendencia de la fibronectina en la modulación de la adhesividad de las células de cáncer de tiroides y, al menos en parte, en la mediación de las acciones de la vitamina D en el crecimiento de las células neoplásicas (Liu, W, Asa, SL, and Ezzat, S; lalpha,25-Dihydroxyvitamin D3 targets PTENdependent fibronectin expression to restore thyroid cancer cell adhesiveness, Mol. Endocrinol., 2005, 19, 23492357).
La generación de isoformas de la fibronectina asociadas a tumor permite el desarrollo de ligandos específicos (p. ej., anticuerpos), que pueden ser usados para la administración selectiva de agentes terapéuticos en el entorno tumoral. La fibronectina es una diana de la intervención biomolecular, tanto en el desarrollo de moléculas inhibidoras que
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una amplia variedad de secuencias de ADN distintas para introducirlo en un hospedador adecuado. El ADN acompañante dependerá de la naturaleza del hospedador, el modo de introducir el ADN en su interior y de si se pretende que se integre o que se mantenga como un episoma.
En general, el ADN se inserta en un vector de expresión, como un plásmido, con la orientación apropiada y el marco de lectura correcto para asegurar la expresión. Si es necesario, el ADN se puede enlazar con secuencias nucleotídicas de control que regulan la transcripción o la traducción y que son reconocidas por el hospedador deseado, aunque en general tales controles ya suelen estar incluidos en el propio vector de expresión. A continuación, el vector se introduce en el hospedador mediante técnicas estándar. En general, el vector no consigue transformar todos los hospedadores,lo que hará necesario seleccionar las células hospedadoras que hayan quedado transformadas. Una técnica de selección consiste en incorporar en el vector de expresión una secuencia de ADN con los elementos de control necesarios que codifique un rasgo seleccionable en la célula transformada, como por ejemplo de resistencia a antibióticos.
Otra alternativa consiste en incorporar el gen de ese rasgo seleccionable en otro vector con el que se cotransforma la célula hospedadora.
Las células hospedadoras que hayan sido transformadas con el ADN recombinante como el descrito se cultivarán durante el tiempo suficiente y en las condiciones apropiadas que las personas versadas en la técnica conocen a la vista de las enseñanzas reveladas en la presente memoria para que el polipéptido pueda expresarse y, finalmente, ser recuperado.
Son muchos los sistemas de expresión conocidos, la invención proporciona una célula hospedadora que comprende un ácido nucleico o un vector de expresión para el uso acorde con la presente invención, en que dicha célula hospedadora es una célula presentadora de antígeno.
Un típico plásmido que sirve como vector para células de mamífero es el pSVL disponible en Pharmacia, Piscataway, NJ, EE. UU. Un ejemplo de vector de expresión inducible para mamífero es el pMSG, también suministrado por Pharmacia. Otros vectores plasmídicos de levadura son pRS403-406 y pRS413-416, en general proveidos por Stratagene Cloning Systems, La Jolla, CA 92037, EE. UU. Los plásmidos pRS403, pRS404, pRS405 y pRS406 son plásmidos integrativos de levadura (YIp) que incorporan los marcadores seleccionables de levadura HIS3, TRP1, LEU2 y URA3. Los plásmidos pRS413-416 son plásmidos centroméricos de levadura (Ycp). En la técnica se conocen otros vectores y sistemas de expresión aptos para el uso con una variedad de células hospedadoras.
La transformación de las células hospedadoras adecuadas con el constructo de ADN como el descrito se consuma con métodos consabidos que normalmente dependen del tipo de vector utilizado. En lo referente a la transformación de células hospedadoras procariotas, véanse por ejemplo Cohen et al. (1972) Proc. Natl. Acad. Sci. USA 69, 2110, y Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, EE. UU. La transformación de células de levadura aparece descrita en Sherman et al (1986) Methods In Yeast Genetics, A Laboratory Manual, Cold Spring Harbor, NY, EE. UU. El método de Beggs, Nature 1978, 275,104-109 también resulta útil. En lo que concierne a los reactivos adecuados para transfectar las células de vertebrados, por ejemplo el fosfato de calcio y el DEAE-dextrano o las formulaciones con liposomas, se pueden adquirir de Stratagene Cloning Systems, o Life Technologies Inc., Gaithersburg, MD 20877, EE. UU. La electroporación también es útil para la transformación y/o transfeccion de las célulasy es perfectamente conocida su aplicación en la transformación de células de levadura, bacteria, insecto y vertebrado.
Las células transformadas con éxito, es decir, las que contengan un constructo de ADN como el descrito, se pueden identificar con técnicas bien conocidas como la PCR. Otra alternativa consiste en detectar la presencia de la proteína en el sobrenadante por medio de anticuerpos.
Se apreciará que ciertas células hospedadoras de la invención son útiles para la preparación de péptidos de la invención. Por ejemplo, se pueden utilizar células presentadoras de antígeno como las células dendríticas para expresar los péptidos de tal forma que puedan ser cargados en las moléculas MHC oportunas.
La célula hospedadora es una célula presentadora de antígeno, en particular una célula dendrítica. Células presentadoras de antígeno cargadas con una proteína de fusión recombinante que contiene fosfatasa ácida prostática (PAP) están siendo investigadas en este momento como tratamiento para el cáncer de próstata (Sipuleucel-T) (Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM.; Placebo-controlled phase 3 trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer; J Clin Oncol. 2006; 24(19):3089-3094; Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM, Small EJ; Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (Provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy; Cancer. 2006; 107(l):67-74).
Otro aspecto de la invención proporciona un método para producir un péptido o proteína de fusión como los descritos. El método comprende el cultivo de la célula hospedadora y el aislamiento del péptido a partir de dicha célula o de su medio de cultivo.
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(Morgan, RA, Dudley, ME, Wunderlich, JR, Hughes, MS, Yang, JC, Sherry, RM, Royal, RE, Topalian, SL, Kammula, US, Restifo, NP, Zheng, Z, Nahvi, A, de Vries, CR, Rogers-Freezer, LJ, Mavroukakis; SA, and Rosenberg, SA; Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes, Science, 2006, 314 (5796): 126-129).
Cualquier molécula para el uso de la invención, ya sea péptido, ácido nucleico, vector de expresión o célula es útil para el tratamiento del cáncer. Por consiguiente, cualquier molécula como la descrita puede ser utilizada como medicamento o en la fabricación de un medicamento. La molécula puede ser utilizada sola o combinada con otra molécula o moléculas como las descritas o con cualquier o cualesquier moléculas conocidas.
Preferiblemente, el medicamento es una vacuna. La vacuna puede administrarse directamente al paciente, en el órgano afectado o por vía sistémica, o aplicarse ex vivo a células derivadas del paciente o a una estirpe celular humana que después se administra al paciente, o utilizarse in vitro para seleccionar una subpoblación de células inmunitarias derivadas del paciente que después se le vuelven a administrar. Si el ácido nucleico se administra a células in vitro, puede ser útil que estas células sean transfectadas para que expresen simultáneamente citocinas inmunoestimuladoras, como la interleucina-2. El péptido puede ser sustancialmente puro, o combinarse con un adyuvante inmunoestimulador (véase abajo) o utilizarse en combinación con citocinas inmunoestimuladoras, o bien administrarse mediante otro sistema de liberación adecuado, como por ejemplo liposomas. El péptido también se puede conjugar con un transportador adecuado como la hemocianina de lapa californiana (KLH) o el manano (véase WO 95/18145 y Longenecker et al. (1993) Ann. NY Acad. Sci. 690, 276-291). El péptido también puede estar marcado, o ser una proteína de fusión, o ser una molécula híbrida. Se espera que los péptidos de la presente invención estimulen a los CTL CD4 o CD8. No obstante, la estimulación es más eficiente si se cuenta con la ayuda de los linfocitos T positivos para el CD opuesto. Así pues, en el caso de los epítopos de MHC de clase II que estimulan a los CTL CD4, el compañero de fusión o las secciones de una molécula híbrida adecuada proporcionan epítopos que estimulan a los linfocitos T CD8-positivos. Y viceversa, en los epítopos de MHC de clase I que estimulan a los CTL CD8, la pareja de fusión o las secciones de una molécula híbrida proporcionan epítopos que estimulan a los linfocitos T CD4-positivos. Los epítopos estimuladores de los CD4 y los CD8 son bien conocidos en la técnica e incluyen los identificados en la presente invención.
La vacuna comprende al menos un péptido, preferiblemente dos a 50, más preferiblemente dos a 25, incluso más preferiblemente dos a 15 y más preferiblemente dos, tres, cuatro, cinco, seis, siete, ocho, nueve, diez, once, doce o trece péptidos como los dados a conocer o péptidos adicionales. Los péptidos pueden derivar de uno o más TAA específicos y se pueden unir a moléculas MHC de clase I y/o II.
Preferiblemente, cuando el péptido para el uso de la invención se usa en una vacuna o medicamento de la invención, está presente en forma de sal, como por ejemplo, una sal de acetato o una sal de cloruro. El ejemplo 7 presenta estudios con la vacuna IMA-910, que contiene algunos de los péptidos de la presente invención y describe la preparación de la misma con péptidos en forma de sal y su tamaño de partícula.
El polinucleótido puede ser sustancialmente puro, o estar contenido en un vector o en un sistema de liberación adecuado. El ácido nucleico puede ser ADN, ADNc, ARN o una combinación de los mismos. Los métodos para diseñar e introducir ese ácido nucleico son bien conocidos por los expertos en la materia. Se puede obtener una visión general por ejemplo en S. Pascolo: Vaccination with messenger RNA Methods Mol Med 2006, 127; 23-40; R. Stan, JD Wolchok and AD Cohen DNA vaccines against cancer Hematol Oncol Clin North Am 2006, 3; 613-636 or A Mahdavi and BJ Monk Recent advances in human papillomavirus vaccines Curr Oncol Rep 2006, 6, 465-472. Las vacunas polinucleotídicas son fáciles de preparar, pero el mecanismo por el cual tales vectores inducen la respuesta inmunitaria no se conoce con exactitud. Los vectores y sistemas de liberación adecuados incluyen los de ADN y/o ARN viral, como los sistemas basados en adenovirus, virus vacunal, retrovirus, herpesvirus, virus adeno-asociados o híbridos que contienen elementos de varios virus. Los sistemas de liberación no virales incluyen lípidos catiónicos y polímeros catiónicos que son bien conocidos como técnicas para la introducción de ADN. Los métodos de introducción físicos, como la «pistola génica», también pueden utilizarse. El péptido o péptidos codificados por el ácido núcleico pueden ser una proteína de fusión, por ejemplo con un epítopo que estimule los linfocitos T para el respectivo CDR opuesto, tal y como se ha indicado antes.
El medicamento de la invención también puede incluir uno o varios adyuvantes. Los adyuvantes son sustancias que potencian o estimulan de forma inespecífica la respuesta inmunitaria (p. ej. respuestas inmunitarias mediadas por CTL y linfocitos T cooperadores (TH) contra un antígeno, y podrían ser considerados útiles en el medicamento de la presente invención. Entre los adyuvantes adecuados se incluyen, entre otros: 1018 ISS, sales de aluminio, Amplivax, AS15, BCG, CP-870. 893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, JuvImmune, LipoVac, MF59, lípido monofosforilo A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, sistema de vectores PepTel®, micropartículas de PLG, resiquimod, SRL172, virosomas y otras partículas seudovíricas, YF-17D, VEGF trap, R848, beta-glucano, Pam3Cys, estimulón QS21 de Aquila, que deriva de la saponina, extractos de micobacterias y miméticos sintéticos de la pared bacteriana, y otros adyuvantes patentados como Detox de Ribi, Quil o Superfos. Se prefieren los adyuvantes como el adyuvante de Freund o el GM-CSF. Varios adyuvantes inmunitarios (p. ej., MF59) específicos para las células dendríticas y su preparación han sido descritos con anterioridad (Dupuis M, Murphy TJ, Higgins D, Ugozzoli M, van Nest G, Ott G, McDonald DM; Dendritic cells internalize vaccine adjuvant after
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