High level expression of functional human IgMs in human PER.C6 cells.

Natural IgM antibodies play an important role in the body's defense mechanisms against transformed cells in the human body and are currently being exploited both in prognoses of malignant lesions and in the therapy of cancer patients. However, despite growing interest and clinical promise, thus far the IgM class of antibodies has failed to gain widespread commercial interest as these are considered to be difficult to produce recombinantly. IgMs are polymeric and have a relatively large mass.

Diagnostic and therapeutic potential of a human antibody cloned from a cancer patient that binds to a tumor-specific variant of transcription factor TAF15.

Human hybridoma technologies permit the cloning of patient antibodies that may have desirable qualities. In this study, we report the isolation of a natural IgG antibody from a stomach cancer patient that illustrates novel diagnostic and therapeutic uses. Human antibody PAT-BA4 recognizes a tumor-specific variant of the transcription factor TATA-binding protein-associated factor 15 (TAF15) that is expressed on the plasma membrane of stomach cancer and melanoma cells but not healthy tissues.

Natural antibodies and cancer.

The innate or natural immunity is the basis and key for all immune processes. Specific receptors on macrophages, dendrites, NK cells and natural antibodies producing B cells act as a first line defense and remove all 'foreign' and potentially harmful substances, that is, bacteria, viruses, cellular waste, modified molecules and, most importantly, cancer cells. Recognition and removal of transformed cells is a lifelong task of immune surveillance processes.

Natural human immunoglobulins in cancer immunotherapy.

The natural or innate immunity is the first-line defense against transformed cells. It guarantees the recognition and removal of malignant cells at an early stage and makes manifest cancers an exceptional event. Natural antibodies, which are predominantly IgM molecules, play a major role in these defense mechanisms and they have some typical features in common.

Neoadjuvant therapy of gastric cancer with the human monoclonal IgM antibody SC-1: impact on the immune system.

Adjuvant therapies for minimal residual disease are a promising approach to improve the poor survival rates after surgery of gastric tumors. A pilot study of a neoadjuvant therapy was performed using a human monoclonal IgM antibody (SC-1) specifically inducing apoptosis in signet ring cell stomach carcinomas. However, scarce information exists on how such a treatment affects the immune system, in particular what are the effects of apoptosis induction and infusion of large amounts of IgM.

A new tumor-specific variant of GRP78 as target for antibody-based therapy.

The chaperone GRP78 is a member of the heat-shock protein 70 (HSP70) family and is responsible for cellular homeostasis by preventing stress-induced apoptosis. GRP78 is expressed in all cells of the body. In malignant cells, which are permanently exposed to environmental stress, GRP78 is overexpressed and increased levels can be found in the cytoplasm and on the cell membrane.

Tumors: too sweet to remember?

Immunity, based on a natural and an educated system, is responsible for recognition and elimination of infectious particles, cellular waste, modified self and transformed cells. This dual system guarantees that dangerous particles are removed immediately after appearance and that a memory with maturated weapons exists, if the organism is re-infected by the same particle. For malignant cells, however, the immune response seems to be restricted to innate immunity, because at least for the humoral response, all so far detected tumor-specific antibodies belong to the natural immunity.

Natural antibodies and cancer.

Immunity is not only responsible for recognition and elimination of infectious particles, but also for removal of cellular waste, modified self structures and transformed cells. Innate or natural immunity acts as a first line defense and is also the link to acquired immunity and memory. A striking phenomenon of immunity against malignant cells is that neither in animals nor in humans affinity-maturated tumor-specific IgG antibodies have been detected so far.

The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein.

Lipids are essential for normal and malignant cells during growth and differentiation. The turnover is strictly regulated because an uncontrolled uptake and accumulation is cytotoxic and can lead to lipoapoptosis: lipoptosis. The human monoclonal antibody SAM-6 binds to a cell surface receptor on malignant cells and to oxidized low-density lipoprotein (LDL).

Natural IgM antibodies: from parias to parvenus.

Over the years, natural IgM antibodies were considered as the parias among the immune competent molecules. Their characteristic properties, like low affinity, cross-reactivity and pentameric structure, were assessed as difficult and nebulous. Today, mainly based on the persistent work of a few researchers and the key discoveries on innate immunity, natural IgM antibodies are "back on stage".

Natural IgM antibodies: the orphaned molecules in immune surveillance.

Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over the years, these molecules were considered as the pariahs among the immune competent molecules and their characteristic properties, like low affinity, cross-reactivity and pentameric structure, were assessed as useless, difficult, nebulous, etc. Today, mainly based on a few scientists' persistent work and the key discoveries on innate immune recognition, natural IgM antibodies are "back on stage".

The "early birds": natural IgM antibodies and immune surveillance.

Precancerous epithelial lesions are sites of uncontrolled cellular proliferation generated by irreversible genetic alterations. Not all of those lesions progress to invasive cancer, some may even regress, but the early detection of abnormal cells can be crucial for patient survival. Immune surveillance mechanisms are responsible for the removal of transformed cells and antibodies play an important role in these immune processes.

Human antibody SC-1 reduces disseminated tumor cells in nude mice with human gastric cancer.

Advanced gastric cancer is a systemic disease that requires adjuvant therapy targeted at eliminating disseminated tumor cells (DTCs). We investigated whether the apoptosis-inducing human monoclonal IgM antibody SC-1 was able to reduce the number of disseminated gastric cancer cells in blood and bone marrow. Human gastric tumor specimens with positive expression of the SC-1 receptor were transplanted in nude mice with metastasizing gastric cancer.

PAM-1, a natural human IgM antibody as new tool for detection of breast and prostate precursors.

Early detection and differential analysis of premalignant lesions are very important for both prognosis and therapy of cancer patients. A good source of diagnostic tools is the natural antibody pool of humans. Tumor-specific antibodies can be established by using hybridoma technology.

Lipoptosis: tumor-specific cell death by antibody-induced intracellular lipid accumulation.

A balanced lipid metabolism is crucial for all cells. Disturbance of this homeostasis by nonphysiological intracellular accumulation of fatty acids can result in apoptosis. This was proven in animal studies and was correlated to some human diseases, like lipotoxic cardiomyopathy.

Natural IgM antibodies, the ignored weapons in tumour immunity.

During its lifetime each multi-cellular organism is permanently exposed to infectious agents and transformed cells. Without an early recognition and a rapid elimination system, there would be no development and no life. The innate or natural immunity, seems to be more important for the detection of "foreign" cells and particles than has been thought.

CFR-1 receptor as target for tumor-specific apoptosis induced by the natural human monoclonal antibody PAM-1.

The human monoclonal antibody PAM-1 was isolated from a patient with stomach cancer. The germ-line coded IgM antibody identifies a recently described 130 kDa variant of CFR-1 (cysteine-rich fibroblast growth factor receptor 1). This CFR-1/PAM-1 receptor is post-transcriptionally modified and over-expressed on human epithelial tumors and carcinoma pre-cancer lesions such as H.

Natural IgM antibodies and immunosurveillance mechanisms against epithelial cancer cells in humans.

Malignancy is like a chronic disease, and the immune system is permanently involved in recognizing and eliminating the transformed cells. The human hybridoma technology offers the unique opportunity to study the mechanisms, structures, and targets involved in recognition and elimination of aberrant cells. Thousands of tumor-reactive human monoclonal antibodies were isolated by this technique from cancer patients and from healthy donors, and all of these antibodies were IgM antibodies; no IgG and IgA antibodies were found.

Nature's best weapons to fight cancer. Revival of human monoclonal IgM antibodies.

The unique features of monoclonal antibodies (specificity, effectiveness, purity and unlimited reproducibility) make them ideal tools for the specific treatment of all kind of diseases. The third generation of monoclonal antibodies for the treatment of human diseases will be, after murine and "humanised" murine immunoglobulins, fully human antibodies. The best source of human monoclonal antibodies are the antibody pools of cancer patients themselves with the best technique for generating them being conventional human hybridoma technology.

Human monoclonal IgM antibodies with apoptotic activity isolated from cancer patients.

Monoclonal antibodies are accepted as ideal adjuvant therapeutic reagents for all kinds of diseases. Polyvalent (cross-linking) and low-mutated IgM antibodies (less immunogenic) are believed to be the most effective weapons against cancer. The best sources for these types of antibodies are the cancer patients themselves.

Cysteine-rich fibroblast growth factor receptor 1, a new marker for precancerous epithelial lesions defined by the human monoclonal antibody PAM-1.

Precancerous epithelial lesions are sites of uncontrolled cellular proliferation, generated by irreversible genetic changes. Not all of these lesions progress to invasive cancer, some may even regress, but early detection of abnormal cells can be crucial for survival of the patient. Diagnosis is mainly performed by using morphological parameters.

[Induction of apoptosis by preoperative passive immunotherapy in resectable stomach carcinoma].

The antibody SC-1 is a human IGM molecule, which binds to a tumor specific receptor. This SC-1 receptor is detectable on biopsies, it is present in about 50% of gastric cancers. After binding of the antibody to the receptor the tumor cells go into apoptosis.

Disparity between mucosal and serum IgA and IgG in Helicobacter pylori infection.

Mucosal IgA and IgG are involved in the immune defense against Helicobacter pylori in infected patients. In contrast to IgG, IgA is transported into the gastric lumen and is responsible for the first-line defense. Therefore antigens recognized by mucosal IgA are possible candidates for vaccination.

Regulation of the new coexpressed CD55 (decay-accelerating factor) receptor on stomach carcinoma cells involved in antibody SC-1-induced apoptosis.

The human monoclonal antibody SC-1 was isolated from a patient with a diffuse-type adenocarcinoma of the stomach using somatic cell hybridization. The immunoglobulin (Ig)M antibody reacts specifically with diffuse- (70%) and intestinal-type (25%) gastric adenocarcinoma and induces apoptosis in vitro and in vivo. When used in clinical trials with stomach carcinoma patients, significant apoptotic and regressive effects in primary tumors have been observed with the antibody SC-1.