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Role of ?-gal epitope/anti-Gal antibody reaction in immunotherapy and its clinical application in pancreatic cancer.

ABSTRACT: Pancreatic cancer is one of the most common causes of death from cancer. Despite the availability of various treatment modalities, such as surgery, chemotherapy and radiotherapy, the 5-year survival remains poor. Although gemcitabine-based chemotherapy is typically offered as the standard care, most patients do not survive longer than 6 months. Therefore, new therapeutic approaches are needed. The ?-gal epitope (Gal?1-3Gal?1-4GlcNAc-R) is abundantly synthesized from glycoproteins and glycolipids in non-primate mammals and New World monkeys, but is absent in humans, apes and Old World monkeys. Instead, they produce anti-Gal antibody (Ab) (forming approximately 1% of circulating immunoglobulins), which specifically interacts with ?-gal epitopes. Anti-Gal Ab can be exploited in cancer immunotherapy as vaccines that target antigen-presenting cells (APC) to increase their immunogenicity. Tumor cells or tumor cell membranes from pancreatic cancer are processed to express ?-gal epitopes. Subsequent vaccination with such processed cell membranes results in in vivo opsonization by anti-Gal IgG in cancer patients. The interaction of the Fc portion of the vaccine-bound anti-Gal with Fc? receptors of APC induces effective uptake of the vaccinating tumor cell membranes by the APC, followed by effective transport of the vaccinating tumor membranes to the regional lymph nodes, and processing and presentation of the tumor-associated antigens. Activation of tumor-specific B and T cells could elicit an immune response that in some patients is potent enough to eradicate the residual cancer cells that remain after completion of standard therapy. This review addresses these topics and new avenues of clinical importance related to this unique antigen/antibody system (?-gal epitope/anti-Gal Ab) and advances in immunotherapy in pancreatic cancer.

SUBMITTER: Tanemura M

PROVIDER: S-EPMC7657191 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Role of α-gal epitope/anti-Gal antibody reaction in immunotherapy and its clinical application in pancreatic cancer.

Tanemura Masahiro M Miyoshi Eiji E Nagano Hiroaki H Eguchi Hidetoshi H Taniyama Kiyomi K Kamiike Wataru W Mori Masaki M Doki Yuichiro Y

Cancer science 20130206 3

Pancreatic cancer is one of the most common causes of death from cancer. Despite the availability of various treatment modalities, such as surgery, chemotherapy and radiotherapy, the 5-year survival remains poor. Although gemcitabine-based chemotherapy is typically offered as the standard care, most patients do not survive longer than 6 months. Therefore, new therapeutic approaches are needed. The α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) is abundantly synthesized from glycoproteins and glycolipids ...[more]

PMID: 23240661

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Project description:The ?-Gal epitope (Gal?1,3Gal?1,4GlcNAc?R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (~1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti?Gal antibody with the ??Gal epitope, humans have a distinct anti???gal reactivity, which is responsible for hyperacute rejection of organs transplanted from ??gal donors. In addition, the ?1,3 galactosyltransferases (?1,3GT) can catalyze the synthesis of the ??Gal epitope. Therefore, the ?1,3GT gene, which encodes the ?1,3GT, is developed profoundly. The distributions of the ??Gal epitope and anti?Gal antibody, and the activation of ?1,3GT, reveal that the enzyme of ?1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human ?1,3?GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the ?1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the ??Gal epitope and anti?Gal antibody, they can be applied to clinical exploitation. Knocking out the ?1,3GT gene will eliminate the xenoantigen, Gal(?1,3)Gal, so that the transplantation of ?1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the ??Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti?Gal?mediated autologous tumor vaccines, which express ??Gal epitope to antigen?presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, ??Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues.

Dataset Information

Role of ?-gal epitope/anti-Gal antibody reaction in immunotherapy and its clinical application in pancreatic cancer.

Publications

Role of α-gal epitope/anti-Gal antibody reaction in immunotherapy and its clinical application in pancreatic cancer.

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