z-logo
Premium
The α‐gal epitope and the anti‐Gal antibody in xenotransplantation and in cancer immunotherapy
Author(s) -
Galili Uri
Publication year - 2005
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/j.1440-1711.2005.01366.x
Subject(s) - epitope , xenotransplantation , immunogenicity , antibody , antibody opsonization , transplantation , biology , virology , immunology , cancer immunotherapy , immunotherapy , microbiology and biotechnology , immune system , medicine , opsonin , surgery
The α‐gal epitope (Galα1‐3Galβ1‐(3)4GlcNAc‐R) is abundantly synthesized on glycolipids and glycoproteins of non‐primate mammals and New World monkeys by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT). In humans, apes and Old World monkeys, this epitope is absent because the α1,3GT gene was inactivated in ancestral Old World primates. Instead, humans, apes and Old World monkeys produce the anti‐Gal antibody, which specifically interacts with α‐gal epitopes and which constitutes ∼1% of circulating immunoglobulins. Anti‐Gal has functioned as an immunological barrier, preventing the transplantation of pig organs into humans, because anti‐Gal binds to the α‐gal epitopes expressed on pig cells. The recent generation of α1,3GT knockout pigs that lack α‐gal epitopes has resulted in the elimination of this immunological barrier. Anti‐Gal can be exploited for clinical use in cancer immunotherapy by targeting autologous tumour vaccines to APC, thereby increasing their immunogenicity. Autologous intact tumour cells from haematological malignancies, or autologous tumour cell membranes from solid tumours are processed to express α‐gal epitopes by incubation with neuraminidase, recombinant α1,3GT and with uridine diphosphate galactose. Subsequent immunization with such autologous tumour vaccines results in in vivo opsonization by anti‐Gal IgG binding to these α‐gal epitopes. The interaction of the Fc portion of the vaccine‐bound anti‐Gal with Fcγ receptors of APC induces effective uptake of the vaccinating tumour cell membranes by the APC, followed by effective transport of the vaccinating tumour membranes to the regional lymph nodes, and processing and presentation of the tumour‐associated antigen (TAA) peptides. Activation of tumour‐specific T cells within the lymph nodes by autologous TAA peptides may elicit an immune response that in some patients will be potent enough to eradicate the residual tumour cells that remain after completion of standard therapy. A similar expression of α‐gal epitopes can be achieved by transduction of tumour cells with an adenovirus vector (or other vectors) containing the α1,3GT gene, thus enabling anti‐Gal‐mediated targeting of the vaccinating transduced cells to APC. Intratumoral delivery of the α1,3GT gene by various vectors results in the expression of α‐gal epitopes. Such expression of the xenograft carbohydrate phenotype is likely to induce anti‐Gal‐mediated destruction of the tumour lesion, similar to rejection of xenografts by this antibody. Opsonization of the destroyed tumour cell membranes by anti‐Gal IgG further targets them to APC, thus converting the tumour lesion, treated by the α1,3GT gene, into an in situ autologous tumour vaccine.

This content is not available in your region!

Continue researching here.

Having issues? You can contact us here