Naturally Occurring Antibodies Directed Against Carbohydrate Tumor Antigens

Abstract

Healthy persons carry within their pool of circulating antibodies immunoglobulins preferentially of IgM isotype, which are directed against a variety of tumor-associated antigens. In closer scrutiny of their nature, some of these antibodies could be defined as naturally occurring antibodies due to the germline configuration of the variable immunoglobulin region. The majority of these immunoglobulins recognize carbohydrate antigens which can be classified as oncofetal antigens. Many of these IgM antibodies present in the peripheral blood circulation can bind to tumor cells and of these a minor portion are also able to destroy tumor cells by several mechanisms, as for instance complement-mediated cytolysis or apoptosis. It was postulated that anti-carbohydrate antibodies are part of an anti-tumor immune response, while their presence in the peripheral blood of healthy donors is still waiting for a plausible explanation. It may be that recognition of defined epitopes, including carbohydrate sequences, by naturally occurring antibodies constitutes the humoral arm of an anti-tumor immune response as part of the often postulated tumor surveillance. The cytotoxic capacity of these antibodies inspired several research groups and pharmaceutical companies to design novel strategies of immunoglobulin-based anti-tumor immunotherapy.

The (1→6)-β-Glucan Moiety Represents a Cross-Reactive Epitope of Infection-Induced Malignancy Surveillance

“…It has previously been shown that TACA-specific Abs can exert antitumor effect through mechanisms such as direct tumoricidal effect (apoptosis induction), or Ab-dependent cell-mediated cytolysis (ADCC), or activation of the complement system (CDC) (14). In our ADCC assays, hPus-Abs effectively assisted the lysis of the (1→6)-b-glucan glycotope-positive U937 cells by NK cells freshly prepared from human PBMCs (Fig.…”

“…Subsequent studies have confirmed that the modification of cellular glycosylation is indeed a common phenotypic change of cancer cells that mainly affects the outer part of glycans (9)(10)(11)(12)(13)(14). Today, abnormal glycosylation is recognized as one of the hallmarks of cancer cells, and a number of tumor-associated carbohydrate Ags (TACAs) have been identified, which include: 1) H/Le(y)/Le(a) in primary non-small cell lung carcinoma; 2) sialyl-Le(x) (SLe(x)) and sialyl-Le(a) (SLe(a)) in various types of cancer; 3) Tn and sialyl-Tn in colorectal, lung, and many other cancers; 4) GM2, GD2, and GD3 gangliosides in melanoma and neuroblastoma; and 5) globo-H in breast, ovarian, and prostate cancer (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). TACAs may contribute to tumorigenesis and are capable of inducing antitumor adaptive immune responses in cancer patients (8-10, 14, 15).…”

“…Healthy human subjects possess high titer natural Abs (nAbs; mostly IgM, some IgG and IgA) in their circulation that can recognize a variety of Ags (14,(23)(24)(25)(26)(27), mostly carbohydrates that can be classified into three groups: 1) allotransplantation and xenotransplantation Ags (e.g., ABO blood group Ags and a-gal epitopes [Gala1-3Galb1-4GlcNAc-R]) (14,(23)(24)(25); 2) cell-wall components of microorganisms such as b-glucans (24-27); and 3) TACAs (14,15,23). Cross-recognition of the first two groups by the human nAbs is well established (14,(23)(24)(25), but whether human nAbs cross-recognize TACAs and PAMPs has rarely been investigated.…”

“…Cross-recognition of the first two groups by the human nAbs is well established (14,(23)(24)(25), but whether human nAbs cross-recognize TACAs and PAMPs has rarely been investigated. Identification and characterization of microbial carbohydrate Ags capable of inducing antitumor Abs in vivo will provide useful clues for the molecular mimicry hypothesis explaining the antitumor beneficial effect of microbial infections in humans.…”

CD176 antiserum treatment leads to a therapeutic response in a murine model of leukemia

“…Apoptotic destruction induced by CD176 antibody of the natural antibody repertoire may provide an explanation for this phenomenon (13). Tumor-specific apoptosis mediated by natural carbohydrate-reactive IgM antibodies in humans has been observed and may lead to new strategies for anticancer immunotherapy (24). Additionally, CD176 antibody treatment can prevent tumor metastasis (18).…”