Detection of circulating anti-MUC1 mucin core protein antibodies in patients with colorectal cancer

Nakamura, Hideaki; Hinoda, Yuji; Nakagawa, Naoaki; Makiguchi, Yusuke; Itoh, Fumio; Endo, Takao; Imai, Kohzoh

doi:10.1007/s005350050096

Cited by 57 publications

(40 citation statements)

References 19 publications

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“…[33][34][35][36] In this regard, it is of note that specifically blocking the function of a complement regulatory protein without coadmin- In conclusion, the data presented fully support the hypothesis that reversing the effects of complement regulatory proteins expressed on a tumor cell surface will allow more effective immunemediated clearance of tumor cells and improve prospects for successful immunotherapy. The results justify further research and development of strategies to inhibit or downregulate complement regulatory proteins on tumor cells.…”

Section: Discussionsupporting

confidence: 52%

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Imai

Ohta

Okada

et al. 2004

Intl Journal of Cancer

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Key words: complement, Crry, inhibitor, antibody therapyComplement effector systems involved in an immune response to tumor cells can include the amplification of an inflammatory response, recruitment of immune effector cells, opsonization of tumor cells that result in complement-dependent cell-mediated cytotoxicity (CDCC) and enhanced antibody-dependent cell-mediated cytoxicity (ADCC), and direct complement mediated lysis. Normal and tumor cells are protected from complement by the expression of membrane bound complement regulatory proteins, and these proteins are upregulated on some cancers. 1-5 Regulators of complement activation are decay accelerating factor (DAF), membrane cofactor proteins (MCP) and, in rodents only, Crry. Rodent Crry is a structural and functional analog of DAF and MCP. These proteins act early in the pathway and limit C3 deposition/opsonization. CD59 regulates the terminal pathway of complement and controls formation of the cytolytic membrane attack complex (MAC).Many in vitro studies have shown that blocking the function of membrane-bound complement regulatory proteins sensitizes normally resistant tumor cells to antibody-mediated complement deposition and lysis (reviewed in references 6 -8). Complement regulatory proteins expressed on tumor cells have also been shown to enhance tumorigenesis in rodent models. 9 -11 These results have lead to the hypothesis that inhibiting the function of complement regulatory proteins expressed on tumor cells will enhance antibody immunotherapy. However, complement regulatory proteins are widely expressed on normal cells, and targeting inhibitory molecules to complement regulators expressed on tumor cells in vivo is a technical challenge. As a consequence, the effect of inhibiting complement regulatory proteins on tumor cells has not been investigated in a therapeutic protocol in vivo.In the short term, untargeted inhibitors of complement regulatory proteins may not pose serious health concerns in the absence of a specific complement activation signal (e.g., a specific antibody), but a "sink" effect would certainly be a barrier to effectiveness. One approach for targeting and inhibiting complement regulators on tumor cells that has been evaluated in vitro is the use of bispecific antibodies. Bispecific antibodies that recognize both a tumor-associated antigen and a complement regulatory protein (function blocking) have been shown to selectively target and enhance complement sensitivity of tumor cells in vitro. [12][13][14] Nevertheless, the development of bispecific antibodies with relevant specificities for in vivo and clinical testing needs to be preceded by animal testing to show that the concept can be translated into effective cancer therapy. We have investigated whether inhibiting a complement regulatory protein on tumor cells in vivo represents a viable strategy with regard to effect on antibody and complement dependent immune response and therapeutic outcome. For our feasibility study, we use a cancer model consisting of the Crrypositive 13762...

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Section: Discussionsupporting

confidence: 52%

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Imai

Ohta

Okada

et al. 2004

Intl Journal of Cancer

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“…Immune responses to normal cellular proteins also expressed by tumor cells have been demonstrated in cancer patients (27)(28)(29)(30)(31)(32). This is a surprising phenomenon given the usual immunological tolerance to normal tissue Ags.…”

Section: Figurementioning

confidence: 99%

Immune Responses of Breast Cancer Patients to Mutated Epidermal Growth Factor Receptor (EGF-RvIII, ΔEGF-R, and de2–7 EGF-R)

Purev

Cai

Miller

et al. 2004

The Journal of Immunology

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Mutated epidermal growth factor receptor (EGF-RvIII, ΔEGF-R, and de2–7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-specific immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients’ tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.

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“…Interestingly, patients with elevation in parietal cells plus intrinsic factor antibody also reacted against tropomyosin (Table I). Antibodies (18)(19). In addition, antibodies against 5 out of 93 other antigens, including tTG, DPP IV, trypsin, motilin and VIP were detected in 2 out of 3 tested patients' sera (Table I).…”

Section: Resultsmentioning

confidence: 98%

Antibodies as Predictors of Complex Autoimmune Diseases

Vojdani

2008

Int J Immunopathol Pharmacol

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Emerging evidence has suggested environmental factors such as infections and xenobiotics and some dietary proteins and peptides in the pathogenesis of many autoimmune diseases. Considering the fact that autoantibodies can often be detected prior to the onset of a disease, in this study an enzyme immunoassay was used for measurement of antibodies against different highly purified antigens or synthetic peptides originating not only from human tissue, but also from cross-reactive epitopes of infectious agents, dietary proteins and xenobiotics. The measurement of antibodies against a panel of antigens allows for identification of patterns or antibody signatures, rather than just one or two markers of autoimmunity, thus establishing the premise for increased sensitivity and specificity of prediction, as well as positive predictive values. This panel of different autoantibodies was applied to 420 patients with different autoimmune diseases, including pernicious anemia, celiac disease, thyroiditis, lupus, rheumatoid arthritis, osteoarthritis, Addison's disease, type 1 diabetes, cardiovascular disease and autoimmunity, which are presented in this article. In all cases, the levels of these antibodies were significantly elevated in patients versus controls. Antibody patterns related to neuroautoimmune disorders, cancer, and patients with somatic hypermutation will be shown in a subsequent article. We believe that this novel 96 antigen-specific autoantibody or predictive antibody screen should be studied for its incorporation into routine medical examinations. Clinicians should be aware that the detection of antibodies should not automatically mean that a patient will definitely become ill, but would rather give a percentage of risk for autoimmune disease over subsequent months or years.

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Detection of circulating anti-MUC1 mucin core protein antibodies in patients with colorectal cancer

Cited by 57 publications

References 19 publications

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma

Immune Responses of Breast Cancer Patients to Mutated Epidermal Growth Factor Receptor (EGF-RvIII, ΔEGF-R, and de2–7 EGF-R)

Antibodies as Predictors of Complex Autoimmune Diseases

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