Cancer Immunology, Immunotherapy

, Volume 61, Issue 9, pp 1535–1546 | Cite as

Animal models for IgE-meditated cancer immunotherapy

  • Tracy R. Daniels
  • Otoniel Martínez-Maza
  • Manuel L. Penichet
Symposium-in-writing paper


Although most monoclonal antibodies developed for cancer therapy are of the IgG class, antibodies of the IgE class have certain properties that make them attractive as cancer therapeutics. These properties include the superior affinity for the Fc epsilon receptors (FcεRs), the low serum level of IgE that minimizes competition of endogenous IgE for FcεR occupancy, and the ability to induce a broad and vigorous immune response through the interaction with multiple cells including mast cells, basophils, monocytes, macrophages, dendritic cells, and eosinophils. Tumor-targeted IgE antibodies are expected to harness the allergic response against tumors and activate a secondary, T-cell-mediated immune response. Importantly, the IgE antibody can be used for passive immunotherapy and as an adjuvant of cancer vaccines. However, there are important limitations in the use of animal models including the fact that human IgE does not interact with rodent FcεRs and that there is a different cellular distribution of FcεRs in humans and rodents. Despite these limitations, different murine models have been used with success to evaluate the in vivo anti-cancer activity of several IgE antibodies. These models include wild-type immunocompetent animals bearing syngeneic tumors, xenograft models using immunocompromised mice bearing human tumors and reconstituted with human effector cells, and human FcεRIα transgenic mice bearing syngeneic tumors. In addition, non-human primates such as cynomolgus monkeys can be potentially used for toxicological and pharmacokinetic studies. This article describes the advantages and disadvantages of these models and their use in evaluating the in vivo properties of IgE antibodies for cancer therapy.


IgE Animal models Cancer AllergoOncology Immunotherapy 



Our work has been supported in part by the NIH/NCI grants K01CA138559, R41CA137881, R01CA1368413, K01CA138559, R01CA57152, R01CA121195, the Susan G. Komen Breast Cancer Foundation Basic, Clinical and Translational Research Grant BCTR0706771, and the NIH Fogarty AITRP-AIDS Malignancies Program D43TW000013-S1.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Helguera G, Daniels TR, Rodriguez JA, Penichet ML (2010) Monoclonal antibodies, human engineered. In: Flickinger M (ed) Encyclopedia of industrial biotechnology: bioprocess, bioseparation, and cell technology. Wiley, New YorkGoogle Scholar
  2. 2.
    Jensen-Jarolim E, Achatz G, Turner MC, Karagiannis S, Legrand F, Capron M, Penichet ML, Rodriguez JA, Siccardi AG, Vangelista L, Riemer AB, Gould H (2008) AllergoOncology: the role of IgE-mediated allergy in cancer. Allergy 63:1255–1266PubMedCrossRefGoogle Scholar
  3. 3.
    Penichet ML, Jensen-Jarolim E (2010) Cancer and IgE: introducing the concept of AllergoOncology. Springer, New YorkGoogle Scholar
  4. 4.
    Gould HJ, Sutton BJ (2008) IgE in allergy and asthma today. Nat Rev Immunol 8:205–217PubMedCrossRefGoogle Scholar
  5. 5.
    Cooper PJ, Ayre G, Martin C, Rizzo JA, Ponte EV, Cruz AA (2008) Geohelminth infections: a review of the role of IgE and assessment of potential risks of anti-IgE treatment. Allergy 63:409–417PubMedCrossRefGoogle Scholar
  6. 6.
    Watanabe N, Bruschi F, Korenaga M (2005) IgE: a question of protective immunity in Trichinella spiralis infection. Trends Parasitol 21:175–178PubMedCrossRefGoogle Scholar
  7. 7.
    Hardwick N, Chain B (2011) Epitope spreading contributes to effective immunotherapy in metastatic melanoma patients. Immunotherapy 3:731–733PubMedCrossRefGoogle Scholar
  8. 8.
    Kinet JP (1999) The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 17:931–972PubMedCrossRefGoogle Scholar
  9. 9.
    Bieber T (1997) Fc epsilon RI on human epidermal Langerhans cells: an old receptor with new structure and functions. Int Arch Allergy Immunol 113:30–34PubMedCrossRefGoogle Scholar
  10. 10.
    Bieber T (1997) Fc epsilon RI-expressing antigen-presenting cells: new players in the atopic game. Immunol Today 18:311–313PubMedCrossRefGoogle Scholar
  11. 11.
    Maurer D, Ebner C, Reininger B, Fiebiger E, Kraft D, Kinet JP, Stingl G (1995) The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation. J Immunol 154:6285–6290PubMedGoogle Scholar
  12. 12.
    Maurer D, Fiebiger S, Ebner C, Reininger B, Fischer GF, Wichlas S, Jouvin MH, Schmitt-Egenolf M, Kraft D, Kinet JP, Stingl G (1996) Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation. J Immunol 157:607–616PubMedGoogle Scholar
  13. 13.
    Turner MC (2010) Epidemiological evidence: IgE, atopy, and solid tumors. In: Penichet ML, Jensen-Jarolim E (eds) Cancer and IgE: introducing the concept of AllergoOncology. Springer, New York, pp 47–78Google Scholar
  14. 14.
    Manz RA, Hauser AE, Hiepe F, Radbruch A (2005) Maintenance of serum antibody levels. Annu Rev Immunol 23:367–386PubMedCrossRefGoogle Scholar
  15. 15.
    Achatz G, Achatz-Straussberger G, Feichtner S, Koenigsberger S, Lenz S, Peckl-Schmid D, Zaborsky N, Lamers M (2010) The biology of IgE: molecular mechanism restraining potentially dangerous high serum IgE titres in vivo. In: Penichet ML, Jensen-Jarolim E (eds) Cancer and IgE: introducing the concept of AllergoOncology. Springer, New York, pp 13–36Google Scholar
  16. 16.
    Preithner S, Elm S, Lippold S, Locher M, Wolf A, da Silva AJ, Baeuerle PA, Prang NS (2006) High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G. Mol Immunol 43:1183–1193PubMedCrossRefGoogle Scholar
  17. 17.
    Daniels TR, Rodriguez JA, Ortiz-Sanchez O, Helguera G, Penichet ML (2010) The IgE antibody and its use in cancer immunotherapy. In: Penichet ML, Jensen-Jarolim E (eds) Cancer and IgE: introducing the concept of allergooncology. Springer, New York, pp 159–184Google Scholar
  18. 18.
    Ravetch JV, Kinet JP (1991) Fc receptors. Annu Rev Immunol 9:457–492PubMedCrossRefGoogle Scholar
  19. 19.
    Gould HJ, Sutton BJ, Beavil AJ, Beavil RL, McCloskey N, Coker HA, Fear D, Smurthwaite L (2003) The biology of IgE and the basis of allergic disease. Annu Rev Immunol 21:579–628PubMedCrossRefGoogle Scholar
  20. 20.
    Hibbert RG, Teriete P, Grundy GJ, Beavil RL, Reljic R, Holers VM, Hannan JP, Sutton BJ, Gould HJ, McDonnell JM (2005) The structure of human CD23 and its interactions with IgE and CD21. J Exp Med 202:751–760PubMedCrossRefGoogle Scholar
  21. 21.
    Conrad DH (1990) Fc epsilon RII/CD23: the low affinity receptor for IgE. Annu Rev Immunol 8:623–645PubMedCrossRefGoogle Scholar
  22. 22.
    McCloskey N, Hunt J, Beavil RL, Jutton MR, Grundy GJ, Girardi E, Fabiane SM, Fear DJ, Conrad DH, Sutton BJ, Gould HJ (2007) Soluble CD23 monomers inhibit and oligomers stimulate IgE synthesis in human B cells. J Biol Chem 282:24083–24091PubMedCrossRefGoogle Scholar
  23. 23.
    Delespesse G, Sarfati M, Wu CY, Fournier S, Letellier M (1992) The low-affinity receptor for IgE. Immunol Rev 125:77–97PubMedCrossRefGoogle Scholar
  24. 24.
    Dombrowicz D, Quatannens B, Papin JP, Capron A, Capron M (2000) Expression of a functional Fc epsilon RI on rat eosinophils and macrophages. J Immunol 165:1266–1271PubMedGoogle Scholar
  25. 25.
    Hakimi J, Seals C, Kondas JA, Pettine L, Danho W, Kochan J (1990) The alpha subunit of the human IgE receptor (FceRI) is sufficient for high affinity IgE binding. J Biol Chem 265:22079–22081PubMedGoogle Scholar
  26. 26.
    Bettler B, Hofstetter H, Rao M, Yokoyama WM, Kilchherr F, Conrad DH (1989) Molecular structure and expression of the murine lymphocyte low-affinity receptor for IgE (Fc epsilon RII). Proc Natl Acad Sci USA 86:7566–7570PubMedCrossRefGoogle Scholar
  27. 27.
    Wang B, Rieger A, Kilgus O, Ochiai K, Maurer D, Fodinger D, Kinet JP, Stingl G (1992) Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med 175:1353–1365PubMedCrossRefGoogle Scholar
  28. 28.
    Conrad DH, Wingard JR, Ishizaka T (1983) The interaction of human and rodent IgE with the human basophil IgE receptor. J Immunol 130:327–333PubMedGoogle Scholar
  29. 29.
    Nagy E, Berczi I, Sehon AH (1991) Growth inhibition of murine mammary carcinoma by monoclonal IgE antibodies specific for the mammary tumor virus. Cancer Immunol Immunother 34:63–69PubMedCrossRefGoogle Scholar
  30. 30.
    Kershaw MH, Darcy PK, Trapani JA, Smyth MJ (1996) The use of chimeric human Fc(epsilon) receptor I to redirect cytotoxic T lymphocytes to tumors. J Leukoc Biol 60:721–728PubMedGoogle Scholar
  31. 31.
    Panaccio M, Gillespie MT, Walker ID, Kirszbaum L, Sharpe JA, Tobias GH, McKenzie IF, Deacon NJ (1987) Molecular characterization of the murine cytotoxic T-cell membrane glycoprotein Ly-3 (CD8). Proc Natl Acad Sci USA 84:6874–6878PubMedCrossRefGoogle Scholar
  32. 32.
    Mathieson BJ, Campbell PS, Potter M, Asofsky R (1978) Expression of Ly 1, Ly 2, Thy 1, and TL differentiation antigens on mouse T-cell tumors. J Exp Med 147:1267–1279PubMedCrossRefGoogle Scholar
  33. 33.
    Topalian SL, Kasid A, Rosenberg SA (1990) Immunoselection of a human melanoma resistant to specific lysis by autologous tumor-infiltrating lymphocytes. Possible mechanisms for immunotherapeutic failures. J Immunol 144:4487–4495PubMedGoogle Scholar
  34. 34.
    Hogarth PM, Henning MM, McKenzie IF (1982) Alloantigenic phenotype of radiation-induced thymomas in the mouse. J Natl Cancer Inst 69:619–626PubMedGoogle Scholar
  35. 35.
    Reali E, Greiner JW, Corti A, Gould HJ, Bottazzoli F, Paganelli G, Schlom J, Siccardi AG (2001) IgEs targeted on tumor cells: therapeutic activity and potential in the design of tumor vaccines. Cancer Res 61:5517–5522PubMedGoogle Scholar
  36. 36.
    Nigro EA, Brini AT, Soprana E, Ambrosi A, Dombrowicz D, Siccardi AG, Vangelista L (2009) Antitumor IgE adjuvanticity: key role of Fc epsilon RI. J Immunol 183:4530–4536PubMedCrossRefGoogle Scholar
  37. 37.
    Gong J, Yang NS, Croft M, Weng IC, Sun L, Liu FT, Chen SS (2010) The antigen presentation function of bone marrow-derived mast cells is spatiotemporally restricted to a subset expressing high levels of cell surface FcepsilonRI and MHC II. BMC Immunol 11:34PubMedCrossRefGoogle Scholar
  38. 38.
    Yoshimoto T, Yasuda K, Tanaka H, Nakahira M, Imai Y, Fujimori Y, Nakanishi K (2009) Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4 + T cells. Nat Immunol 10:706–712PubMedCrossRefGoogle Scholar
  39. 39.
    Kershaw MH, Darcy PK, Trapani JA, MacGregor D, Smyth MJ (1998) Tumor-specific IgE-mediated inhibition of human colorectal carcinoma xenograft growth. Oncol Res 10:133–142PubMedGoogle Scholar
  40. 40.
    Mount PF, Sutton VR, Li W, Burgess J, Mc KIF, Pietersz GA, Trapani JA (1994) Chimeric (mouse/human) anti-colon cancer antibody c30.6 inhibits the growth of human colorectal cancer xenografts in scid/scid mice. Cancer Res 54:6160–6166PubMedGoogle Scholar
  41. 41.
    Teng MW, Kershaw MH, Jackson JT, Smyth MJ, Darcy PK (2006) Adoptive transfer of chimeric FcepsilonRI gene-modified human T cells for cancer immunotherapy. Hum Gene Ther 17:1134–1143PubMedCrossRefGoogle Scholar
  42. 42.
    Eshhar Z, Waks T, Gross G, Schindler DG (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 90:720–724PubMedCrossRefGoogle Scholar
  43. 43.
    Gould HJ, Mackay GA, Karagiannis SN, O’Toole CM, Marsh PJ, Daniel BE, Coney LR, Zurawski VR Jr, Joseph M, Capron M, Gilbert M, Murphy GF, Korngold R (1999) Comparison of IgE and IgG antibody-dependent cytotoxicity in vitro and in a SCID mouse xenograft model of ovarian carcinoma. Eur J Immunol 29:3527–3537PubMedCrossRefGoogle Scholar
  44. 44.
    Karagiannis SN, Wang Q, East N, Burke F, Riffard S, Bracher MG, Thompson RG, Durham SR, Schwartz LB, Balkwill FR, Gould HJ (2003) Activity of human monocytes in IgE antibody-dependent surveillance and killing of ovarian tumor cells. Eur J Immunol 33:1030–1040PubMedCrossRefGoogle Scholar
  45. 45.
    Karagiannis SN, Bracher MG, Hunt J, McCloskey N, Beavil RL, Beavil AJ, Fear DJ, Thompson RG, East N, Burke F, Moore RJ, Dombrowicz DD, Balkwill FR, Gould HJ (2007) IgE-antibody-dependent immunotherapy of solid tumors: cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells. J Immunol 179:2832–2843PubMedGoogle Scholar
  46. 46.
    Karagiannis SN, Bracher MG, Beavil RL, Beavil AJ, Hunt J, McCloskey N, Thompson RG, East N, Burke F, Sutton BJ, Dombrowicz D, Balkwill FR, Gould HJ (2008) Role of IgE receptors in IgE antibody-dependent cytotoxicity and phagocytosis of ovarian tumor cells by human monocytic cells. Cancer Immunol Immunother 57:247–263PubMedCrossRefGoogle Scholar
  47. 47.
    Jackson DJ, Kumpel BM (1997) Optimisation of human anti-tetanus toxoid antibody responses and location of human cells in SCID mice transplanted with human peripheral blood leucocytes. Hum Antibodies 8:181–188PubMedGoogle Scholar
  48. 48.
    Chen Q, Khoury M, Chen J (2009) Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci USA 106:21783–21788PubMedCrossRefGoogle Scholar
  49. 49.
    Fuss IJ, Kanof ME, Smith PD, Zola H (2009) Isolation of whole mononuclear cells from peripheral blood and cord blood. Curr Protoc Immunol Chap 7:Unit7 1Google Scholar
  50. 50.
    Dombrowicz D, Brini AT, Flamand V, Hicks E, Snouwaert JN, Kinet JP, Koller BH (1996) Anaphylaxis mediated through a humanized high affinity IgE receptor. J Immunol 157:1645–1651PubMedGoogle Scholar
  51. 51.
    Dombrowicz D, Lin S, Flamand V, Brini AT, Koller BH, Kinet JP (1998) Allergy-associated FcRbeta is a molecular amplifier of IgE- and IgG-mediated in vivo responses. Immunity 8:517–529PubMedCrossRefGoogle Scholar
  52. 52.
    Fung-Leung WP, De Sousa-Hitzler J, Ishaque A, Zhou L, Pang J, Ngo K, Panakos JA, Chourmouzis E, Liu FT, Lau CY (1996) Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor alpha chain respond to human IgE in mast cell degranulation and in allergic reactions. J Exp Med 183:49–56PubMedCrossRefGoogle Scholar
  53. 53.
    Dombrowicz D, Flamand V, Brigman KK, Koller BH, Kinet JP (1993) Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene. Cell 75:969–976PubMedCrossRefGoogle Scholar
  54. 54.
    Allen LC, Kepley CL, Saxon A, Zhang K (2007) Modifications to an Fcgamma-Fcvarepsilon fusion protein alter its effectiveness in the inhibition of FcvarepsilonRI-mediated functions. J Allergy Clin Immunol 120:462–468PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang K, Kepley CL, Terada T, Zhu D, Perez H, Saxon A (2004) Inhibition of allergen-specific IgE reactivity by a human Ig Fcgamma-Fcepsilon bifunctional fusion protein. J Allergy Clin Immunol 114:321–327PubMedCrossRefGoogle Scholar
  56. 56.
    Zhu D, Kepley CL, Zhang M, Zhang K, Saxon A (2002) A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nat Med 8:518–521PubMedCrossRefGoogle Scholar
  57. 57.
    Daniels TR, Leuchter RK, Quintero R, Helguera G, Rodríguez JA, Martínez-Maza O, Schultes BC, Nicodemus CF, Penichet ML (2011) Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells. Cancer Immunol Immunother [Epub ahead of print]Google Scholar
  58. 58.
    Tang Y, Lou J, Alpaugh RK, Robinson MK, Marks JD, Weiner LM (2007) Regulation of antibody-dependent cellular cytotoxicity by IgG intrinsic and apparent affinity for target antigen. J Immunol 179:2815–2823PubMedGoogle Scholar
  59. 59.
    Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (2009) Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer. J Clin Oncol 27:1685–1693PubMedCrossRefGoogle Scholar
  60. 60.
    Hoopmann M, Sachse K, Valter MM, Becker M, Neumann R, Ortmann M, Gohring UJ, Thomas A, Mallmann P, Schondorf T (2010) Serological and immunohistochemical HER-2/neu statuses do not correlate and lack prognostic value for ovarian cancer patients. Eur J Cancer Care (Engl) 19:809–815CrossRefGoogle Scholar
  61. 61.
    Triulzi C, Vertuani S, Curcio C, Antognoli A, Seibt J, Akusjarvi G, Wei WZ, Cavallo F, Kiessling R (2010) Antibody-dependent natural killer cell-mediated cytotoxicity engendered by a kinase-inactive human HER2 adenovirus-based vaccination mediates resistance to breast tumors. Cancer Res 70:7431–7441PubMedCrossRefGoogle Scholar
  62. 62.
    Helguera G, Rodriguez JA, Daniels TR, Penichet ML (2007) Long-term immunity elicited by antibody-cytokine fusion proteins protects against sequential challenge with murine mammary and colon malignancies. Cancer Immunol Immunother 56:1507–1512PubMedCrossRefGoogle Scholar
  63. 63.
    Helguera G, Rodriguez JA, Penichet ML (2006) Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors. Mol Cancer Ther 5:1029–1040PubMedCrossRefGoogle Scholar
  64. 64.
    Weichman BM, Hostelley LS, Bostick SP, Muccitelli RM, Krell RD, Gleason JG (1982) Regulation of the synthesis and release of slow-reacting substance of anaphylaxis from sensitized monkey lung. J Pharmacol Exp Ther 221:295–302PubMedGoogle Scholar
  65. 65.
    Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX (2006) Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother 55:717–727PubMedCrossRefGoogle Scholar
  66. 66.
    Braen AP, Perron J, Tellier P, Catala AR, Kolaitis G, Geng W (2010) A 4-week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys. Int J Toxicol 29:259–267PubMedCrossRefGoogle Scholar
  67. 67.
    Berek J, Taylor P, McGuire W, Smith LM, Schultes B, Nicodemus CF (2009) Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol 27:418–425PubMedCrossRefGoogle Scholar
  68. 68.
    Braly P, Nicodemus CF, Chu C, Collins Y, Edwards R, Gordon A, McGuire W, Schoonmaker C, Whiteside T, Smith LM, Method M (2009) The Immune adjuvant properties of front-line carboplatin-paclitaxel: a randomized phase 2 study of alternative schedules of intravenous oregovomab chemoimmunotherapy in advanced ovarian cancer. J Immunother 32:54–65PubMedCrossRefGoogle Scholar
  69. 69.
    King DM, Albertini MR, Schalch H, Hank JA, Gan J, Surfus J, Mahvi D, Schiller JH, Warner T, Kim K, Eickhoff J, Kendra K, Reisfeld R, Gillies SD, Sondel P (2004) Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. J Clin Oncol 22:4463–4473PubMedCrossRefGoogle Scholar
  70. 70.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354PubMedCrossRefGoogle Scholar
  71. 71.
    Lafky JM, Wilken JA, Baron AT, Maihle NJ (2008) Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer. Biochim Biophys Acta 1785:232–265PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Tracy R. Daniels
    • 1
  • Otoniel Martínez-Maza
    • 2
    • 3
    • 4
    • 5
  • Manuel L. Penichet
    • 1
    • 2
    • 3
    • 6
  1. 1.Division of Surgical Oncology, Department of Surgery, David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA
  2. 2.Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA
  3. 3.Jonsson Comprehensive Cancer CenterUniversity of California, Los AngelesLos AngelesUSA
  4. 4.Department of Obstetrics and Gynecology, David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA
  5. 5.Department of Epidemiology, School of Public HealthUniversity of California, Los AngelesLos AngelesUSA
  6. 6.The Molecular Biology InstituteUniversity of California, Los AngelesLos AngelesUSA

Personalised recommendations