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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2014

Open Access 01-12-2014 | Research

Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice

Authors: Pier Adelchi Ruffini, Audun Os, Riccardo Dolcetti, Geir E Tjønnfjord, Ludvig A Munthe, Bjarne Bogen

Published in: Journal of Translational Medicine | Issue 1/2014

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Abstract

Background

Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine.

Methods

Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients’ cells as well as transfected A20 cells.

Results

DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient’s Id as compared with non targeted control vaccines. Anti–Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients’ V regions were not tumorigenic in mice, preventing tumor challenge experiments.

Conclusions

These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs.
Appendix
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Literature
1.
Park HJ, Neelapu SS: Developing idiotype vaccines for lymphoma: from preclinical studies to phase III clinical trials. Br J Haematol. 2008, 142: 179-191.PubMedCentralCrossRefPubMed
2.
Inoges S, Rodriguez-Calvillo M, Zabalegui N, de CA L-D, Villanueva H, Soria E, Suarez L, Rodriguez-Caballero A, Pastor F, Garcia-Munoz R, Panizo C, Perez-Calvo J, Melero I, Rocha E, Orfao A, Bendandi M: Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst. 2006, 98: 1292-1301.CrossRefPubMed
3.
Schuster SJ, Neelapu SS, Gause BL, Janik JE, Muggia FM, Gockerman JP, Winter JN, Flowers CR, Nikcevich DA, Sotomayor EM, McGaughey DS, Jaffe ES, Chong EA, Reynolds CW, Berry DA, Santos CF, Popa MA, McCord AM, Kwak LW: Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J Clin Oncol. 2011, 29: 2787-2794.PubMedCentralCrossRefPubMed
4.
5.
Lu S, Wang S, Grimes-Serrano JM: Current progress of DNA vaccine studies in humans. Expert Rev Vaccines. 2008, 7: 175-191.CrossRefPubMed
6.
Kawamura H, Berzofsky JA: Enhancement of antigenic potency in vitro and immunogenicity in vivo by coupling the antigen to anti-immunoglobulin. J Immunol. 1986, 136: 58-65.PubMed
7.
Snider DP, Segal DM: Targeted antigen presentation using crosslinked antibody heteroaggregates. J Immunol. 1987, 139: 1609-1616.PubMed
8.
Baier G, Baier-Bitterlich G, Looney DJ, Altman A: Immunogenic targeting of recombinant peptide vaccines to human antigen-presenting cells by chimeric anti-HLA-DR and anti-surface immunoglobulin D antibody Fab fragments in vitro. J Virol. 1995, 69: 2357-2365.PubMedCentralPubMed
9.
Lunde E, Munthe LA, Vabo A, Sandlie I, Bogen B: Antibodies engineered with IgD specificity efficiently deliver integrated T-cell epitopes for antigen presentation by B cells. Nat Biotechnol. 1999, 17: 670-675.CrossRefPubMed
10.
Fredriksen AB, Sandlie I, Bogen B: DNA vaccines increase immunogenicity of idiotypic tumor antigen by targeting novel fusion proteins to antigen-presenting cells. Mol Ther. 2006, 13: 776-785.CrossRefPubMed
11.
Biragyn A, Tani K, Grimm MC, Weeks S, Kwak LW: Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat Biotechnol. 1999, 17: 253-258.CrossRefPubMed
12.
Nchinda G, Kuroiwa J, Oks M, Trumpfheller C, Park CG, Huang Y, Hannaman D, Schlesinger SJ, Mizenina O, Nussenzweig MC, Uberla K, Steinman RM: The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells. J Clin Invest. 2008, 118: 1427-1436.PubMedCentralCrossRefPubMed
13.
Schjetne KW, Fredriksen AB, Bogen B: Delivery of antigen to CD40 induces protective immune responses against tumors. J Immunol. 2007, 178: 4169-4176.CrossRefPubMed
14.
Tunheim G, Thompson KM, Fredriksen AB, Espevik T, Schjetne KW, Bogen B: Human receptors of innate immunity (CD14, TLR2) are promising targets for novel recombinant immunoglobulin-based vaccine candidates. Vaccine. 2007, 25: 4723-4734.CrossRefPubMed
15.
Fredriksen AB, Bogen B: Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences. Blood. 2007, 110: 1797-1805.CrossRefPubMed
16.
Ruffini PA, Grodeland G, Fredriksen AB, Bogen B: Human chemokine MIP1alpha increases efficiency of targeted DNA fusion vaccines. Vaccine. 2010, 29: 191-199.CrossRefPubMed
17.
Froyland M, Ruffini PA, Thompson KM, Gedde-Dahl T, Fredriksen AB, Bogen B: Targeted idiotype-fusion DNA vaccines for human multiple myeloma: preclinical testing. Eur J Haematol. 2011, 86: 385-395.CrossRefPubMed
18.
De Re V, De Vita S, Marzotto A, Rupolo M, Gloghini A, Pivetta B, Gasparotto D, Carbone A, Boiocchi M: Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood. 2000, 96: 3578-3584.PubMed
19.
De Re V, De Vita S, Gasparotto D, Marzotto A, Carbone A, Ferraccioli G, Boiocchi M: Salivary gland B cell lymphoproliferative disorders in Sjogren’s syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins’s lymphomas. Eur J Immunol. 2002, 32: 903-910.CrossRefPubMed
20.
Ivanovski M, Silvestri F, Pozzato G, Anand S, Mazzaro C, Burrone OR, Efremov DG: Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas. Blood. 1998, 91: 2433-2442.PubMed
21.
Bahler DW, Miklos JA, Swerdlow SH: Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood. 1997, 89: 3335-3344.PubMed
22.
Bende RJ, Aarts WM, Riedl RG, de Jong D, Pals ST, van Noesel CJ: Among B cell non-Hodgkin’s lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity. J Exp Med. 2005, 201: 1229-1241.PubMedCentralCrossRefPubMed
23.
Craig VJ, Arnold I, Gerke C, Huynh MQ, Wundisch T, Neubauer A, Renner C, Falkow S, Muller A: Gastric MALT lymphoma B cells express polyreactive, somatically mutated immunoglobulins. Blood. 2010, 115: 581-591.CrossRefPubMed
24.
Ghiotto F, Fais F, Valetto A, Albesiano E, Hashimoto S, Dono M, Ikematsu H, Allen SL, Kolitz J, Rai KR, Nardini M, Tramontano A, Ferrarini M, Chiorazzi N: Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J Clin Invest. 2004, 113: 1008-1016.PubMedCentralCrossRefPubMed
25.
Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J, Foa R, Damle RN, Fais F, Messmer D, Rai KR, Ferrarini M, Chiorazzi N: Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004, 200: 519-525.PubMedCentralCrossRefPubMed
26.
Widhopf GF, Rassenti LZ, Toy TL, Gribben JG, Wierda WG, Kipps TJ: Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood. 2004, 104: 2499-2504.CrossRefPubMed
27.
Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan XJ, Davis Z, van Gastel-Mol EJ, Tresoldi C, Chu CC, Cahill N, Giudicelli V, Tichy B, Pedersen LB, Foroni L, Bonello L, Janus A, Smedby K, Anagnostopoulos A, Merle-Beral H, Laoutaris N, Juliusson G, di Celle PF, Pospisilova S, Jurlander J, Geisler C, Tsaftaris A, Lefranc MP, Langerak AW, Oscier DG: Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012, 119: 4467-4475.PubMedCentralCrossRefPubMed
28.
Os A, Burgler S, Ribes AP, Funderud A, Wang D, Thompson KM, Tjonnfjord GE, Bogen B, Munthe LA: Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells. Cell Rep. 2013, 4: 566-577.CrossRefPubMed
29.
Gleditsch L, Bogen B: A Tcra congenic mouse: V alpha epitope expression is influenced by both Tcra haplotypes and background genes. Immunogenetics. 1992, 35: 153-160.CrossRefPubMed
30.
Menten P, Struyf S, Schutyser E, Wuyts A, De Clerck E, Schols D, Proost P, Van Damme J: The LD78beta isoform of MIP-1alpha is the most potent CCR5 agonist and HIV-1-inhibiting chemokine. J Clin Invest. 1999, 104: R1-R5.PubMedCentralCrossRefPubMed
31.
Chapman CJ, Zhou JX, Gregory C, Rickinson AB, Stevenson FK: VH and VL gene analysis in sporadic Burkitt’s lymphoma shows somatic hypermutation, intraclonal heterogeneity, and a role for antigen selection. Blood. 1996, 88: 3562-3568.PubMed
32.
Arasi VE, Lieberman R, Sandlund J, Kiwanuka J, Novikovs L, Kirsch I, Hollis G, Magrath IT: Antiimmunoglobulin inhibition of Burkitt’s lymphoma cell proliferation and concurrent reduction of c-myc and mu heavy chain gene expression. Cancer Res. 1989, 49: 3235-3241.PubMed
33.
Sahota SS, Townsend M, Stevenson FK: Identification and assembly of V genes as idiotype-specific DNA fusion vaccines in multiple myeloma. Methods Mol Med. 2005, 113: 105-119.PubMed
34.
Brochet X, Lefranc MP, Giudicelli V: IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 2008, 36: W503-W508.PubMedCentralCrossRefPubMed
35.
Dooper MM, Holden L, Faeste CK, Thompson KM, Egaas E: Monoclonal antibodies against the candidate lupin allergens alpha-conglutin and beta-conglutin. Int Arch Allergy Immunol. 2007, 143: 49-58.CrossRefPubMed
36.
Jacobsen JT, Lunde E, Sundvold-Gjerstad V, Munthe LA, Bogen B: The cellular mechanism by which complementary Id + and anti-Id antibodies communicate: T cells integrated into idiotypic regulation. Immunol Cell Biol. 2010, 88: 515-522.CrossRefPubMed
37.
Spang HC, Braathen R, Bogen B: Heterodimeric barnase-barstar vaccine molecules: influence of one versus two targeting units specific for antigen presenting cells. PLoS One. 2012, 7: e45393-PubMedCentralCrossRefPubMed
38.
Grodeland G, Mjaaland S, Tunheim G, Fredriksen AB, Bogen B: The specificity of targeted vaccines for APC surface molecules influences the immune response phenotype. PLoS One. 2013, 8: e80008-PubMedCentralCrossRefPubMed
39.
van Drunen Littel-vanden Hurk S, Hannaman D: Electroporation for DNA immunization: clinical application. Expert Rev Vaccines. 2010, 9: 503-517.CrossRef
40.
Miller RA, Hart S, Samoszuk M, Coulter C, Brown S, Czerwinski D, Kelkenberg J, Royston I, Levy R: Shared idiotypes expressed by human B-cell lymphomas. N Engl J Med. 1989, 321: 851-857.CrossRefPubMed
41.
Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R: Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors. N Engl J Med. 1992, 327: 1209-1215.CrossRefPubMed
42.
Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, Taidi-Laskowski B, Levy R: Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma–long-term results of a clinical trial. Blood. 1997, 89: 3129-3135.PubMed
43.
Timmerman JM, Czerwinski DK, Davis TA, Hsu FJ, Benike C, Hao ZM, Taidi B, Rajapaksa R, Caspar CB, Okada CY, van Beckhoven A, Liles TM, Engleman EG, Levy R: Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood. 2002, 99: 1517-1526.CrossRefPubMed
44.
Timmerman JM, Singh G, Hermanson G, Hobart P, Czerwinski DK, Taidi B, Rajapaksa R, Caspar CB, van Beckhoven A, Levy R: Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res. 2002, 62: 5845-5852.PubMed
45.
Bertinetti C, Zirlik K, Heining-Mikesch K, Ihorst G, Dierbach H, Waller CF, Veelken H: Phase I trial of a novel intradermal idiotype vaccine in patients with advanced B-cell lymphoma: specific immune responses despite profound immunosuppression. Cancer Res. 2006, 66: 4496-4502.CrossRefPubMed
46.
Baskar S, Kobrin CB, Kwak LW: Autologous lymphoma vaccines induce human T cell responses against multiple, unique epitopes. J Clin Invest. 2004, 113: 1498-1510.PubMedCentralCrossRefPubMed
47.
Navarrete MA, Heining-Mikesch K, Schuler F, Bertinetti-Lapatki C, Ihorst G, Keppler-Hafkemeyer A, Dolken G, Veelken H: Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma. Blood. 2011, 117: 1483-1491.CrossRefPubMed
48.
Tobin G, Thunberg U, Karlsson K, Murray F, Laurell A, Willander K, Enblad G, Merup M, Vilpo J, Juliusson G, Sundstrom C, Soderberg O, Roos G, Rosenquist R: Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. Blood. 2004, 104: 2879-2885.CrossRefPubMed
49.
Stamatopoulos K, Belessi C, Hadzidimitriou A, Smilevska T, Kalagiakou E, Hatzi K, Stavroyianni N, Athanasiadou A, Tsompanakou A, Papadaki T, Kokkini G, Paterakis G, Saloum R, Laoutaris N, Anagnostopoulos A, Fassas A: Immunoglobulin light chain repertoire in chronic lymphocytic leukemia. Blood. 2005, 106: 3575-3583.CrossRefPubMed
50.
Bogen B, Ruffini P: Review: to what extent are T cells tolerant to immunoglobulin variable regions?. Scand J Immunol. 2009, 70: 526-530.CrossRefPubMed
51.
Sahota SS, Leo R, Hamblin TJ, Stevenson FK: Myeloma VL and VH gene sequences reveal a complementary imprint of antigen selection in tumor cells. Blood. 1997, 89: 219-226.PubMed
52.
Meeker TC, Lowder J, Maloney DG, Miller RA, Thielemans K, Warnke R, Levy R: A clinical trial of anti-idiotype therapy for B cell malignancy. Blood. 1985, 65: 1349-1363.PubMed
53.
Ai WZ, Tibshirani R, Taidi B, Czerwinski D, Levy R: Anti-idiotype antibody response after vaccination correlates with better overall survival in follicular lymphoma. Blood. 2009, 113: 5743-5746.PubMedCentralCrossRefPubMed
54.
Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R, Watson TM, Reynolds CW, Gause BL, Duffey PL, Jaffe ES, Creekmore SP, Longo DL, Kwak LW: Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med. 1999, 5: 1171-1177.CrossRefPubMed
55.
Neelapu SS, Baskar S, Gause BL, Kobrin CB, Watson TM, Frye AR, Pennington R, Harvey L, Jaffe ES, Robb RJ, Popescu MC, Kwak LW: Human autologous tumor-specific T-cell responses induced by liposomal delivery of a lymphoma antigen. Clin Cancer Res. 2004, 10: 8309-8317.CrossRefPubMed
56.
Martorelli D, Guidoboni M, De Re V, Muraro E, Turrini R, Merlo A, Pasini E, Caggiari L, Romagnoli L, Spina M, Mortarini R, Gasparotto D, Mazzucato M, Carbone A, Rosato A, Anichini A, Dolcetti R: IGKV3 proteins as candidate “off-the-shelf” vaccines for kappa-light chain-restricted B-cell non-Hodgkin lymphomas. Clin Cancer Res. 2012, 18: 4080-4091.CrossRefPubMed
Metadata
Title
Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice
Authors
Pier Adelchi Ruffini
Audun Os
Riccardo Dolcetti
Geir E Tjønnfjord
Ludvig A Munthe
Bjarne Bogen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2014
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-12-207

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