ImmunoBody^® Vaccines

Cancer vaccines represent a highly attractive approach to cancer therapy. In contrast to current treatments such as chemotherapy and radiotherapy, small non-toxic doses of a vaccine may be administered to a patient to stimulate an immune response. It is generally accepted that to be effective against cancer, a vaccine needs to target dendritic cells to stimulate both parts of the cellular immune system; the helper cell system (known as the CD4-mediated response) which stimulates inflammation at the tumour site; and the cytotoxic T-lymphocyte or CTL response (known as the CD8-mediated response) in which cells of the immune system are primed to recognise and kill specific cells.

A limitation of many cancer vaccines currently in development is that they cannot specifically target dendritic cells in vivo. Several groups have demonstrated successful vaccination by growing dendritic cells ex vivo, pulsing them with tumour antigens and re-infusing them. However, this procedure is patient specific, time consuming and expensive.

Scancell has developed its breakthrough patent protected ImmunoBody® technology to overcome the present limitations of cancer vaccines.

An ImmunoBody® is a human antibody or fusion protein engineered to express helper cell and CTL epitopes from tumour antigens over-expressed by cancer cells. Antibodies are ideal vectors for carrying T cell epitopes from tumour antigens as they have long half-lives and can effectively target dendritic cells via their Fc receptors, allowing efficient stimulation of both helper and CTL responses.

By changing the expressed epitopes, the technology can be adapted to provide the basis for treating any tumour type and may also be of potential utility in the development of vaccines against hepatitis, HIV and other chronic infectious diseases.

An ImmunoBody® will target the CD64 receptor on dendritic cells in vivo

• Small antigen/antibody complexes are taken up by the Fc receptor on dendritic cells. This results in up-regulation of co-stimulatory molecules and processing and presentation of the antigen on both class I and class II MHC molecules (Regnault et al., 1998: Sugerhus et al., 2002).
• It has been shown in a 300 patient clinical trial that a monomeric human IgG1 monoclonal antibody can also stimulate helper and cytotoxic T lymphocyte (CTL) cell responses with no associated toxicity (Austin et al., 1989,1991; Robins 1991; Denton 1991; Durrant 1994, 2000a,b; Spendlove 1999, 2000; Maxwell-Armstrong 1999a,b 2001; Amin 2000).
• If the Fc region of a human monoclonal anti-idiotypic antibody is removed it is 1,000 fold less efficient at stimulating T cells (Durrant 2001).
• An anti-idiotypic antibody mimicking CEA was very inefficient at stimulating human T cells as a mouse IgG2b (Durrant et al., 1992) but when it was chimerised to a human IgG1 antibody it stimulated CEA specific helper and CTL responses (Durrant et al., 2001, Parsons et al., 2004).
• These results suggest that not only antigen/antibody complexes but also monomeric human IgG1 that express T cell epitopes within their CDR regions can target the Fc receptor on dendritic cells.

References

E.B. Austin, R.A. Robins, L.G.Durrant and R.W. Baldwin (1989). Human monoclonal anti-idiotypic antibody to the tumour associated antibody 791T/36. Immunology, 67, 525.

E.B. Austin, R.A. Robins, R.W. Baldwin and L.G.Durrant (1991). Induction of delayed hypersensitivity to human tumour cells with a monoclonal anti-idiotypic antibody. J. Natl. Cancer Inst. 83:1245-1248.

R. A. Robins, G.W.L. Denton, E.B. Austin, J.D. Hardcastle and L.G.Durrant (1991).Anti-tumour immune responses and interleukin-2 production in colorectal cancer patients by immunisation with human monoclonal anti-idiotypic antibody. Cancer Res., 51:5425-5429.

L.G.Durrant, G.W.L. Denton, E Jacobs, M.Mee, R. Moss,E.B. Austin, R.W. Baldwin, J.D. Hardcastle and R.A. Robins, (1992). Anti-colorectal tumour cellular and humoral responses induced (in rats, mice, and humans) by an idiotypic replica of carcinoembryonic antigen. Int. J. Cancer 50: 811-816.

G.W.L. Denton, L.G.Durrant, J.D. Hardcastle, E.B. Austin and R.A. Robins (1994). Clinical Outcome of Colorectal Cancer Patients treated with Human monoclonal anti-idiotypic antibody. Int. J. Cancer 57:10-14.

L.G.Durrant, D.T.J. Buckley, G.W.L. Denton and R.A. Robins (1994). Enhanced cell mediated tumour killing in patients immunised with human monoclonal anti-idiotypic antibody 105AD7. Cancer Res. 54, 4837-4840.

I. Spendlove, L.Li, J. Carmichael, L.G.Durrant (1999). Decay accelerating factor (CD55): a target for cancer vaccines? Cancer Res. 59, 2282-2287.

C.A. Maxwell-Armstrong, L.G.Durrant, J.H. Scholefield (1999). Immunotherapy for colorectal cancer. Amer. J. Surgery 177, 344-348.

C.A. Maxwell-Armstrong, L.G.Durrant, R.A. Robins, A.M. Galvin, J.H. Scholefield and J.D. Hardcastle (1999). Increased activation of lymphocytes infiltrating primary colorectal cancers following immunisation with the anti-idiotypic monoclonal antibody 105AD7. Gut, Oct 1999, 45(4), p. 593-598.

L.G.Durrant, I. Spendlove, D. J. Buckley and R. A. Robins (2000). 105AD7 cancer vaccine stimulates anti-tumour helper and cytotoxic T cell responses in colorectal cancer patients but repeated immunisations are required to maintain these responses. Int. J.Cancer, 2000, 85(1), p. 87-92.

L.G. Durrant, C Maxwell Armstrong, D. Buckley, S. Amin, R.A. Robins, J. Carmichael and J.H. Scholefield (2000). A Neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, that mimics CD55. Clinical Cancer Research, 2000, 6(2), p. 422-430.

S. Amin, R.A. Robins, C.A. Maxwell-Armstrong, J.H. Scholefield and L.G. Durrant (2000). Vaccine induced apoptosis: a novel clinical trial endpoint? Cancer Res., 2000, 60, p. 3132-3136.

LG Durrant, T Parsons, R Moss, I Spendlove, G Carter and F Carr (2001). Human anti-idiotypic antibodies are good immunogens as they target Fc receptors on antigen presenting cells. Int. J. Cancer. 92,414-420

C Maxwell Armstrong, LG Durrant, D Buckley, P Giullou, Monson, H Calvert, JH Scholefield and JD Hardcastle (2001). Double Blind Randomised Trial of 105AD7 anti-idiotypic antibody in advanced colorectal cancer patients. Br. J. Cancer 84, 1443-1446

LG Durrant and I Spendlove (2001). Immunization against tumor cell surface complement regulatory proteins. CurrOpin Investig Drugs 2:959-966.

A Indar , CA Maxwell-Armstrong, LG Durrant, J Carmichael and JH Scholefield (2001) Current concepts in immunotherapy for treatment of colorectal cancer (2002). JR Coll Surg 47:458-474.

LG Durrant and I Spendlove (2003). Cancer vaccine entering Phase |II clinical trials Expert Opinion Emerging Drugs 8: 489-500.

J M Ramage, R Metheringham, R Moss, I Spendlove, R Rees and L.G.Durrant (2004) Comparison of the immune response to a self antigen after DNA immunisation of HLA*A201/H-2Kb and HHD transgenic mice. Vaccine 22, 1728-1731.

J.M. Ramage , R Metheringham, I Spendlove, R Moss, D.T. Patton, R.C. Rees and LG Durrant (2004). A Tie-2Fc DNA fusion vaccine that targets tumour endothelium. Int J Cancer 110, 245-250.

T Parsons, I Spendlove, R Nirula, M Writer, G Carter, F Carr and LG Durrant (2004). A novel CEA vaccine stimulates, ?IFN secretion and CEA specific CTL responses. Vaccine 3: 3487-3494

K. Pritchard-Jones, I Spendlove, C Wilton, I Lewis, A. Craft, J. Whelan, S. Weden, C. Douglass and L.G. Durrant (2005). A phase II clinical trial with the human anti-idotypic antibody 105AD7 that mimics CD55 in osteosarcoma patients. Br J Cancer. 92(8) 1358-65

Z Madjd , S E Pinder, HL Ploegh , I Spendlove , I O. Ellis and L.G.Durrant (2005).Total loss of HLA class I is an independent indicator of good prognosis breast cancers. Int. J. Cancer 117: 248-255.

LG Durrant and J M Ramage (2005). Development of cancer vaccines to activate cytotoxic T lymphocytes Exp. Opinion in Biological Therapy 5(4) 555-563

Z Madjd , T Parsons, NFS Watson, T Parsons, I Spendlove, IO Ellis and LG Durrant (2005). High expression of Lewisy/b antigens is associated with decreased overall survival in lymph node negative breast carcinomas. Breast Cancer Res 7: 780-787.

N FS Watson, J Ramage, Z Madjd, I Spendlove, IO Ellis, JH Scholefield and LG Durrant (2006). Immunosurveillance is active in colorectal cancer as down regulation but not complete loss of MHC Class I expression correlates with a poor prognosis. Int. J Cancer 118:6-10.

L.G. Durrant, SJ. Harding, NH. Green , LD. Buckberry, and T Parsons (2006). A new anti-cancer glycolipid monoclonal antibody, SC104, which directly induces tumour cell death without immune effector cells. Cancer Res. 66(11) 1-9.

J M Ramage, I Spendlove, R Rees, R Moss, and L.G.Durrant (2006). The use of reverse immunology to identify HLA-A2 binding epitopes in Tie-2. Cancer Immunol Immunother. 55(8):1004-10.

GJ Ullenhag, I Spendlove, NFS Watson, AA Indar, M Dube, A Robins, JH Scholefield and LG Durrant (2006).An adjuvant randomized trial of colorectal cancer patients vaccinated with an anti-idiotypic antibody, 105AD7, mimicking CD55. Clin Cancer research 12(24):7389-96

 

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