Human anti-idiotypic antibodies can be good immunogens as they target FC receptors on antigen-presenting cells allowing efficient stimulation of both helper and cytotoxic T-cell responses

Abstract

Key words: tumour vaccines; helper T-cell responses; blastogenesis; anti-idiotypes; peptidesAnti-idiotypic antibodies that recognise paratopes of anti-tumour antibodies act as internal images of the tumour antigen and thus can be used as surrogate antigens. Although the majority of anti-idiotypic antibodies have been used to stimulate antibody responses, they can also stimulate T cells. Unprimed T cells are stimulated by antigen-presenting cells that take up antigen and present it on MHC molecules in combination with costimulatory signals. Uptake of antigen and expression of costimulatory molecules by antigen-presenting cells are therefore vital for T-cell activation. Antigen can be internalised by pincytosis or more actively by receptor-mediated endocytosis, the latter process being 1,000-fold more efficient. 1 Several scavenging receptors have been identified on antigen-presenting cells including the Fc receptor. 2 More recently, it has been shown that receptor-mediated Fc uptake of antigen/antibody complexes results in the priming of both CD4 and CD8 T-cell responses. 3 These results would suggest that anti-idiotypic antibodies may also be internalised by Fc receptormediated endocytosis and may therefore be very effective immunogens. Two anti-idiotypic antibodies, 105AD7 and 708, have been used to study the role of the Fc region in stimulating T-cell responses by anti-idiotypes.105AD7 is a human anti-idiotypic monoclonal antibody (MAb) that was cloned from a cancer patient receiving the anti-tumour antibody 791T/36 for diagnostic imaging. 4 The antigen recognised by the MAb 791T/36 has been identified as CD55, a complement regulatory protein. 5 CD55 is over-expressed by tumours to protect them from complement attack and thus acts as a tumour-associated antigen. 105AD7 mimics CD55 and can stimulate both T-cell and antibody responses that recognise tumour cells expressing CD55. [5][6][7][8] More recently, neoadjuvant colorectal cancer patients receiving 105AD7 therapy showed a 3-fold increase in tumour cell apoptosis that was associated with infiltration of CD56 and CD4 cells expressing the CD25 activation receptor. 9 -11 708 is a mouse anti-idiotypic antibody that recognises the paratope of the anti-CEA antibody NCRC23 and thus mimics CEA. 708 induces antibody responses that recognise CEA and can stimulate lymphocytes from colorectal cancer patients to respond to in vitro challenge with CEA. 12 This anti-idiotype has recently been cloned and sequenced and shows amino acid homology with CEA.Our study shows that the Fc region of antibodies is important in the presentation of T-cell epitopes. Furthermore, anti-idiotypes expressing human Fc regions are superior to mouse anti-idiotypes in stimulating both helper and cytotoxic T-cell responses and as a result has implications for all antibody-based vaccines.

DNA vaccination with T‐cell epitopes encoded within Ab molecules induces high‐avidity anti‐tumor CD8+ T cells

“…Two of the osteosarcoma patients were cured of their disease and survived for at least 10 years post treatment. When the Fc region of this Ab was removed it displayed 1000-fold less efficiency at stimulating T cells [23]. Immature circulating DC in the blood express only low levels of FcgRI to avoid binding serum Ig, but this is transiently upregulated by IFN-g on extravasation into inflamed tissue [24].…”

Foot-and-Mouth Disease Virus Exhibits an Altered Tropism in the Presence of Specific Immunoglobulins, Enabling Productive Infection and Killing of Dendritic Cells

“…FcR exist in several forms and are expressed by natural killer cells, mast cells, B cells, polymorphonuclear cells, macrophages, and dendritic cells (DC) (reviewed in ref- erence 48). In phagocytes, FcR-mediated uptake of antibodyneutralized pathogens results in degradation, but in antigenpresenting cells (APC), material endocytosed via FcR is preferentially used to stimulate the adaptive immune response with enhanced efficiency (14,17,34,61).…”

Production and characterisation of monoclonal anti-idiotype antibody to Vibrio anguillarum

“…In order to examine whether these mab 2 s represent the internal image of the antigen or belong to Ab 2 -, mice were immunised with mab 2 1E10, 1H5, 1D1 and 1H12, and then antiserum (Ab 3 ) was collected. Direct ELISA and competition binding assay [21] found that human anti-Id antibody can target Fc receptors on antigen-presenting cells, allowing e$cient stimulation of both helper and cytotoxic T cell responses, inducing strong in vitro T cell proliferation and -IFN secretion. Thus, in fish the anti-Id antibody may also stimulate T cell responses.…”