Investigation of factors influencing the immunogenicity of hCG as a potential cancer vaccine

Article


Kvirkvelia, N., Chikadze, N., Makinde, J., McBride, J., Porakishvili, N., Hills, F., Martensen, P., Justesen, J., Delves, P., Lund, T. and Roitt, I. 2018. Investigation of factors influencing the immunogenicity of hCG as a potential cancer vaccine. Clinical & Experimental Immunology. 193 (1), pp. 73-83. https://doi.org/10.1111/cei.13131
TypeArticle
TitleInvestigation of factors influencing the immunogenicity of hCG as a potential cancer vaccine
AuthorsKvirkvelia, N., Chikadze, N., Makinde, J., McBride, J., Porakishvili, N., Hills, F., Martensen, P., Justesen, J., Delves, P., Lund, T. and Roitt, I.
Abstract

Human hCG and its β‐subunit (hCGβ) are tumour autocrine growth factors whose presence in the serum of cancer patients has been linked to poorer prognosis. Previous studies have shown that vaccines, which target these molecules and/or the 37 amino acid C‐terminal hCGβ peptide (hCGβCTP), induce antibody responses in a majority of human recipients. Here we explored whether the immunogenicity of vaccines containing an hCGβ mutant (hCGβR68E, designed to eliminate cross‐reactivity with luteinizing hormone) or hCGβCTP could be enhanced by coupling the immunogen to different carriers (KLH or Hsp70) using different cross‐linkers (EDC or GAD) and formulated with different adjuvants (RIBI or Montanide ISA720).
While there was little to choose between KLH and Hsp70 as carriers, their influence on the effectiveness of a vaccine containing the BAChCGβR68E mutant was less marked, presumably because being a foreign species, this mutant protein itself might provide T‐helper epitopes. The mutant provided a significantly better vaccine than the hCGβCTP peptide irrespective of the carrier used, how it was cross‐linked to the carrier or which adjuvant was used when hCG was the target. Nonetheless, for use in humans where hCG is a tolerated self‐protein, the need for a carrier is of fundamental importance. Highest antibody titres were obtained by linking the BAChCGβR68E to Hsp70 as a carrier by GAD and using RIBI as the adjuvant, which also resulted in antibodies with significantly higher affinity than those elicited by hCGβCTP peptide vaccine. This makes this mutant vaccine a promising candidate for therapeutic studies in hCGβ‐positive cancer patients.

Research GroupBiomarkers for Cancer group
PublisherWileyBlackwell
JournalClinical & Experimental Immunology
ISSN0009-9104
Electronic1365-2249
Publication dates
Online07 May 2018
Print10 Jul 2018
Publication process dates
Deposited10 Apr 2018
Accepted28 Feb 2018
Output statusPublished
Accepted author manuscript
Copyright Statement

This is the peer reviewed version of the following article: Kvirkvelia, N. , Chikadze, N. , Makinde, J. , McBride, J. D., Porakishvili, N. , Hills, F. A., Martensen, P. M., Justesen, J. , Delves, P. J., Lund, T. and Roitt, I. M. (2018), Investigation of factors influencing the immunogenicity of hCG as a potential cancer vaccine. Clin Exp Immunol, 193: 73-83. doi:10.1111/cei.13131, which has been published in final form at https://doi.org/10.1111/cei.13131. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

Digital Object Identifier (DOI)https://doi.org/10.1111/cei.13131
LanguageEnglish
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Innate immunity and pathogen-host interaction.
Basset, C., Holton, J., O'Mahony, R. and Roitt, I. 2003. Innate immunity and pathogen-host interaction. Vaccine. 21 (Supple), pp. S12-S23. https://doi.org/10.1016/S0264-410X(03)00195-6
Elimination of luteinizing hormone cross-reactive epitopes from human chorionic gonadotropin.
Porakishvili, N., Chiesa, M., Chikadze, N., Martensen, P., Justesen, J., Lund, T., Delves, P. and Roitt, I. 2002. Elimination of luteinizing hormone cross-reactive epitopes from human chorionic gonadotropin. Vaccine. 20 (16), pp. 2053-2059. https://doi.org/10.1016/S0264-410X(02)00051-8
Genes and IgG glycosylation in autoimmune and non-autoimmune strains of mice
Delves, P., Lund, T. and Roitt, I. 2002. Genes and IgG glycosylation in autoimmune and non-autoimmune strains of mice. Trends in Immunology. 23 (4), pp. 213-219. https://doi.org/10.1016/S1471-4906(02)02182-8
The human chorionic gonadotropin-ß arginine68 to glutamic acid substitution fixes the conformation of the C-terminal Peptide
Charrel-Dennis, M., Terrazzini, N., McBride, J., Martensen, P., Justesen, J., Berger, P., Lapthorn, A., Kelly, C., Roitt, I., Delves, P. and Lund, T. 2005. The human chorionic gonadotropin-ß arginine68 to glutamic acid substitution fixes the conformation of the C-terminal Peptide. Molecular Endocrinology. 19 (7), pp. 1803-1811. https://doi.org/10.1210/me.2004-0109
The major hormone-specific epitopes on human chorionic gonadotropin
Charrel-Dennis, M., Jackson, A., Lund, T., Lapthorn, A., Berger, P., Roitt, I. and Delves, P. 2004. The major hormone-specific epitopes on human chorionic gonadotropin. Journal of molecular endocrinology. 32 (2), pp. 571-581.
Immunochemical mapping of gonadotropin
Berger, P., Bidart, J., Delves, P., Dirnhofer, S., Hoermann, R., Isaacs, N., Jackson, A., Klonisch, T., Lapthorn, A., Lund, T., Mann, K., Roitt, I., Schwartz, S. and Wick, G. 1996. Immunochemical mapping of gonadotropin. Molecular and Cellular Endocrinology. 125 (1-2), pp. 33-43. https://doi.org/10.1016/S0303-7207(96)03943-3
Heparin prevents programmed cell death in human trophoblast
Hills, F., Abrahams, V., Gonzalez-Timon, B., Francis, J., Cloke, B., Hinkson, L., Rai, R., Regan, L., Mor, G., Sullivan, M., Lam, E. and Brosens, J. 2006. Heparin prevents programmed cell death in human trophoblast. Molecular Human Reproduction. 12 (4), pp. 237-242.
A low budget luminometer for sensitive chemiluminescent immunoassays
Porakishvili, N., Fordham, J., Charrel-Dennis, M., Delves, P., Lund, T. and Roitt, I. 2000. A low budget luminometer for sensitive chemiluminescent immunoassays. Journal of Immunological Methods. 234 (1-2), pp. 35-42. https://doi.org/10.1016/S0022-1759(99)00198-2
The immune system: second of two parts
Delves, P. and Roitt, I. 2000. The immune system: second of two parts. New England Journal of Medicine. 343 (2), pp. 108-117.
The immune system: first of two parts
Delves, P. and Roitt, I. 2000. The immune system: first of two parts. New England Journal of Medicine. 343 (1), pp. 37-49.
Future prospects for vaccines to control fertility
Delves, P., Lund, T. and Roitt, I. 2002. Future prospects for vaccines to control fertility. Trends in Immunology. 23 (4), pp. 220-221. https://doi.org/10.1016/S1471-4906(02)02183-X
Antifertility vaccines
Delves, P., Lund, T. and Roitt, I. 2002. Antifertility vaccines. Trends in Immunology. 23 (4), pp. 213-219. https://doi.org/10.1016/S1471-4906(02)02182-8
Vaccines for the control of reproduction - status in mammals, and aspects of comparative interest.
Delves, P. and Roitt, I. 2005. Vaccines for the control of reproduction - status in mammals, and aspects of comparative interest. Developments in Biologicals. 121, pp. 265-273.
A longitudinal study of maternal plasma insulin-like growth factor binding protein-1 concentrations during normal pregnancy and pregnancies complicated by pre-eclampsia
Anim-Nyame, N., Hills, F., Soorana, S., Steer, P. and Johnson, M. 2000. A longitudinal study of maternal plasma insulin-like growth factor binding protein-1 concentrations during normal pregnancy and pregnancies complicated by pre-eclampsia. Human Reproduction. 15 (10), pp. 2215-2219. https://doi.org/10.1093/humrep/15.10.2215
Interactions between progesterone receptor isoforms in myometrial cells in human labour
Pieber, D., Allport, V., Hills, F., Johnson, M. and Bennett, P. 2001. Interactions between progesterone receptor isoforms in myometrial cells in human labour. Molecular Human Reproduction. 7 (9), pp. 875-879. https://doi.org/10.1093/molehr/7.9.875
Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro
Mak, I., Brosens, J., Christian, M., Hills, F., Chamley, L., Regan, L. and White, J. 2002. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. Journal of Clinical Endocrinology and Metabolism. 87 (6), pp. 2581-2588. https://doi.org/10.1210/jc.87.6.2581
Progesterone represses interleukin-8 and cyclo-oxygenase-2 in human lower segment fibroblast cells and amnion epithelial cells
Loudon, J., Elliott, C., Hills, F. and Bennett, P. 2003. Progesterone represses interleukin-8 and cyclo-oxygenase-2 in human lower segment fibroblast cells and amnion epithelial cells. Biology of Reproduction. 69 (1), pp. 331-337.
The relationship between insulin and insulin-like growth factor binding protein-1 is modified by pre-eclampsia.
Anim-Nyame, N., Hills, F., Soorana, S., Steer, P. and Johnson, M. 2003. The relationship between insulin and insulin-like growth factor binding protein-1 is modified by pre-eclampsia. Gynecological endocrinology.. 17 (6), pp. 471-476. https://doi.org/10.1080/09513590312331290408
The insulin-like growth factor system in mammalian pregnancy: a workshop report
Carter, A., Hills, F., O'Gorman, D., Robets, C., Soorana, S., Watson, C. and Westwood, M. 2004. The insulin-like growth factor system in mammalian pregnancy: a workshop report. Placenta. 25 (Supple), pp. S53-S56. https://doi.org/10.1016/j.placenta.2004.01.019
Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human
Monk, D., Sanches, R., Arnaud, P., Apostolidou, S., Hills, F., Abu-Amero, S., Murrell, A., Friess, H., Reik, W. and Stanier, P. 2006. Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human. Human Molecular Genetics. 15 (8), pp. 1259-1269. https://doi.org/10.1093/hmg/ddl041
STOX1 is not imprinted and is not likely to be involved in preeclampsia.
Hills, F., Iglesias-Platas, I., Jebbink, J. and Monk, D. 2007. STOX1 is not imprinted and is not likely to be involved in preeclampsia. Nature Genetics. 39 (3), pp. 279-280. https://doi.org/10.1038/ng0307-279
Limited evolutionary conservation of imprinting in the human placenta
Hills, F., Apostolidou, S., Arnaud, P. and Monk, D. 2006. Limited evolutionary conservation of imprinting in the human placenta. Proceedings of the National Academy of Sciences. 103 (17), pp. 6623-6628. https://doi.org/10.1073/pnas.0511031103
Regulation of human villous trophoblast by insulin-like growth factors and insulin-like growth factor-binding protein-1
Hills, F., Chard, T., Elder, M. and Sullivan, M. 2004. Regulation of human villous trophoblast by insulin-like growth factors and insulin-like growth factor-binding protein-1. Journal of Endocrinology. 183 (3), pp. 487-496. https://doi.org/10.1677/joe.1.05867
Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.
Looareesuwan, S., Sjorstrom, L., Krudsood, S., Wilairatana, P., Porter, R., Hills, F. and Warrell, D. 1999. Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria. American Journal of Tropical Medicine and Hygiene. 61 (1), pp. 26-33. https://doi.org/10.4269/ajtmh.1999.61.26
Mechanism of action of the intrauterine contraceptive device: evidence for a specific biochemical deficiency in the endometrium
Seleem, S., Hills, F., Salem, H., El-Nashar, E. and Chard, T. 1996. Mechanism of action of the intrauterine contraceptive device: evidence for a specific biochemical deficiency in the endometrium. Human Reproduction. 11 (6), pp. 1220-1222.