ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.1

年代:1997

数据来源: MAL

摘要:

Carbohydrate antigens have been identified as significant antigens in many human tumors either by analyzing antibodies in patients' sera or by using monoclonal antibodies of either mouse or human origin. Three carbohydrate epitopes present on cancer-associated mucins [sialyl-Lewis A (SLA), sialyl-Lewis X (SLX), and siayl-Tn (STn)] may have functional significance in metastasis. Subsequently, these antigens are considered as targets for active specific immunotherapy. Carbohydrates, as T-cell-independent antigens, often elicit diminished immune responses. To overcome this drawback, carbohydrates are typically coupled to protein carriers to elicit immunoglobulin G (IgG) responses as opposed to low-affinity IgM responses, which oftentimes accompanies carbohydrate-based immunizations. In addition, some complex carbohydrates are difficult to synthesize. This latter aspect is further magnified if one considers that clustering of epitopes on neoglycoproteins must be emulated in the synthesis process, leading to multiple presentation or tandem repeats of the synthetic carbohydrate immunogen. Here, we examine the hypothesis that peptides that mimic carbohydrates might be developed to induce immune responses that target and mediate the killing of tumor cells, particularly breast cancer cells in an adjuvant-type setting. We have found that carbohydrate-mimicking peptides retain carbohydrate-like conformations, inducing anti-carbohydrate immune responses against breast tumor cells and mediating their killing by a complement-dependent mechanism.

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.3

年代:1997

数据来源: MAL

摘要:

The general responsiveness of human melanoma to immunotherapy has been well established, but active immunotherapy of melanoma has been hampered by insufficient information on the immunogenicity of melanoma antigens in patients. We have attempted to identify melanoma-associated antigens recognized by patients' B cells using an antibody phage display approach. Antibody display on filamentous phages allows direct screening of cDNA libraries for expression of cell-surface-reactive antibodies, without the need for antibody production and purification using bacteria or eukaryotic cell systems. This approach was used to identify melanoma-associated cell-surface antigens recognized by patients' B cells. Antibodies produced by the B cells of a melanoma patient (in remission for>7 years following periodic vaccination with allogeneic melanoma cell vaccine) were displayed as Fabs on the surfaces of filamentous phages. A library of 108phages was absorbed to normal melanocytes, followed by phage binding to and elution from melanoma cells (human lymphocyte antigen nonmatched and vaccine melanoma cells). Phages were further selected for reactivities with tunicamycin-treated melanoma cells. These procedures resulted in a>106-fold enrichment of tumor-specific phages from the original phage library. One phage-Fab bound to melanoma cells, other tumor cells, and a few normal cells in cultured cell lines and in tissue sections.

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.11

年代:1997

数据来源: MAL

摘要:

An antiidiotypic/clonotypic marker, designated 1F7, is restricted to antibodies directed to human immunodeficiency virus type 1 (HIV-1) envelope, core, and reverse transcriptase proteins. 1F7-Id is shared by more than 70% of HIV-infected individuals, arising early and persisting throughout all disease stages. To study the specificity and biological function of this cross-reactive idiotypic marker, and to explore its potential in therapeutics, we have sought an appropriate animal model. 1F7-Id+ antiviral antibodies are found among experimentally HIV-1IIIB-infected chimpanzees; however, these rare and expensive animals do not develop acquired immunodeficiency syndrome (AIDS), and so are not an appropriate model. We now report the presence in rhesus monkeys of 1F7-Id on antibodies to the external envelope glycoproteins of simian immunodeficiency virus (SIV). This may be surprising, in view of the genetic and serologic differences between SIV and HIV-1, but is in accord with the occurrence of 1F7-Id on antibodies reacting with a broad range of HIV-1 strains. We also found 1F7-Id on anti-gp120 antibodies in rhesus monkeys infected with chimeric immunodeficiency viruses (SHIV) expressing theenv, tat, andrevgenes of HIV-1 on a backbone of SIV. Both SIV and SHIV cause AIDS in these monkeys. Thus, SIV- and SHIV-infected rhesus monkeys are suitable models for exploring the role of 1F7 in AIDS pathogenesis and prevention. Experiments are underway using MAb 1F7 to test the hypothesis of deceptive imprinting in AIDS.

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.17

年代:1997

数据来源: MAL

摘要:

Clinical studies with the human anti-idiotypic antibody 105AD7 have clearly shown that 791Tgp72 is a good target antigen for cell-mediated immunity. No antibody-related toxicity was observed in any of the 135 patients entered into phase I/II clinical trials of 105AD7, whereas both helper and cytotoxic T-cell responses were induced. The helper responses were exemplified by induction of interleukin-2 (IL-2), antigen-specific blastogenesis, and enhanced natural killer (NK) activity. Anti-tumor cytotoxicity was measured directly and was supported by activation of circulating CD8 cells. In this study, it is shown that a 100-μg injection of 105AD7 was more effective than the 200-μg dose. Enhanced IL-2 production was observed following 15/19 injections of 100 μg of 105AD7 whereas only 4/11 injections of 200μg of 105AD7 induced responses (p<0.02). Similarly, time to progression was significantly (p<0.05) slower (median 6 m) in patients injected with 100 μg than patients receiving the higher dose, suggesting that 100 μg or lower may be the optimal dose. The standard dose for hepatitis vaccination is 10 μg.In vitroblastogenesis assays on naive donors have shown that a dose of 105AD7, which is either too high or too low, fails to activate T cells. The optimal dosein vitrois

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.23

年代:1997

数据来源: MAL

摘要:

Because of its high energy beta emissions and imageable gamma emissions,188Re represents an attractive isotope to radiolabel monoclonal antibodies (mAb) recognizing human tumor-associated antigens for radioimaging and radioimmunotherapy in patients with malignant diseases. The application of188Re is, however, hindered by the denaturation of a sizable proportion of antibody molecules during the labeling process. To overcome this problem, we have combined radiolabeling of mAb with188Re with purification of immunoreactive188Re-labeled mAb by affinity chromatography over columns of anti-idiotypic (anti-id) mAb. Utilizing the anti-high-molecular-weight melanoma-associated antigen (HMW-MAA) mAb 763.74 as a model system, we found that the immunoreactivity of mAb 763.74 labeled with188Re to a specific activity of 1 mCi/mg increased from about 50% to at least 80% following passage over columns of immobilized anti-id mAb. Moreover, between 90-100% of immunoreactive mAb contained in radiolabeled preparations could be recovered from anti-id mAb columns. These results indicate that the procedure we have described may facilitate the application of188Re for immunoscintigraphy and immunotherapy of malignant diseases.

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.27

年代:1997

数据来源: MAL

摘要:

We have generated an immunoglobulin G1(IgG1) murine monoclonal anti-idiotype antibody (Ab2) designated ACA125, which mimics a specific epitope on the tumor-associated antigen CA125. This antigen is expressed by most of malignant ovarian tumors. Patients with CA125-positive tumors are immunologically tolerant to CA125. We used ACA125 as a surrogate for the tumor-associated antigen CA125 for vaccine therapy of 16 patients with advanced epithelial ovarian cancer or recurrences. Each of the patients received a minimum of 3 injections up to 19 injections of the complete anti-idiotype MAb ACA125 at a dosage of 2 mg per injection. Nine of 16 patients developed anti-anti-idiotypic (Ab3) responses to the ACA125. All 9 patients generated specific anti-CA125 antibody demonstrated by reactivity with purified CA125. Nine of 16 patients developed a CA125-specific cellular immune response by their peripheral blood lymphocytes (PBL) and 3 of 16 showed an increase in γ-interferon concentrations accompanied by Ab3 responses. Toxicity was limited to abdominal pain in one case, which led to the withdrawal of further immunizations. The median progression free survival in those patients, who showed a specific immune response to the tumor-associated antigen CA125, was 11.0 ± 5.6 months without any other therapy, in contrast to 8.0 ± 4.2 months in the anti-anti-idiotype negative group. This is the first report of the induction of a specific active immunity to the tumor-associated antigen CA125 in patients with advanced ovarian cancer treated with an anti-idiotype antibody that "mimics" CA125. Patients showed the development of a specific humoral and cellular immune reponse to an otherwise nonimmunogenic tumor antigen. The immune responses in patients treated with this anti-idiotype vaccine, the low rate of side effects, and the improved time to progression after the induction of a specific immune response against the tumor-associated antigen CA125 justify follow-up clinical trials in advanced ovarian cancer patients with minimal residual disease in an adjuvant approa

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.33

年代:1997

数据来源: MAL

摘要:

Various immunological parameters were studied in 100 ovarian cancer patients injected with the OVAREX™ therapeutic vaccine (the functional component of which is anti-CA125 MAb-B43.13) to explain the serendipitous observation of prolonged survival after such treatment. In addition to CA125-specific humoral and cellular responses, interferon-γ (IFN-γ) was also found to be induced in those patients receiving the vaccine.In vitrostudies indicated that the expression of MHC I, MHC II, and ICAM I in ovarian tumor cells were upregulated in response to IFN-γ. Such tumor cells were also found to be more sensitive to CA125-specific cytotoxic T cells compared to cells that were not incubated with I

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.41

年代:1997

数据来源: MAL

摘要:

The F(ab′)2fragment of the murine monoclonal anti-idiotypic antibody ACA125 mimicking the tumor-associated antigen CA125 is used as a vaccine for the induction of an anti-tumoral immunity in patients with ovarian carcinoma. We tried to generate a single-chain fragment (ScFv) composed of ACA125 heavy- and light-chain variable domains connected by a polypeptide linker as an alternative to the corresponding F(ab′)2fragment. Heavy- and light-chain genes of antibody-producing mouse hybridoma cell line were amplified separately and assembled into a ScFv gene with linker DNA by the polymerase chain reaction (PCR). The ScFv gene was ligated into the phagemid vector pCANTAB5E, which allows the production of both phage-displayed and soluble ScFv. TransformedEscherichia coliTG1 cells were infected with M13K07 helper phage to yield recombinant phage, which display ScFv fragments as a g3p fusion protein on the surface of the filamentous phage M13. Recombinant phages could be selected by binding to the idiotypic antibody OC125 after one round of panning and directly used to reinfectE. coliTG1 cells. TheE. colinonsuppressor strain HB2151 was infected with an antigen-positive phage clone, previously screened by enzyme-linked immunosorbent assay (ELISA), to express soluble ScFv fragments. Functional soluble ScFv binding to the idiotypic antibody OC125 F(ab′)2could be detected in the bacterial periplasm by Western blot and ELISA. The variable heavy- and light-chain genes of the ACA125 ScFv fragment were further sequenced and compared with known antibody sequ

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.47

年代:1997

数据来源: MAL

摘要:

Based on the network theory, anti-tumor antibodies (Ab1) can trigger the immune system of the host into a response against tumor cells. Through an immunological cascade, anti-idiotypic antibodies bearing the internal image of epitopes of the nominal antigen (Ab2β) are produced that themselves can induce cellular and humoral cytotoxic effects against the antigen-expressing tumor cell. Formation of such antibodies has been shown to be associated with prolonged survival of melanoma, colorectal, and ovarian carcinoma patients. We studied anti-idiotypic antibody (Ab2) responses and clinical outcome of 31 ovarian cancer patients receiving the monoclonal antibody (MAb) B72.3, which targets the ovarian carcinoma associated antigen TAG-72. All patients were treated by surgery and polychemotherapy, which was followed by repeated (mean of 4) injections of 1 mg of the MAb B72.3. A remarkable anti-idiotypic anti-B72.3 response arose in 19 patients, with 9 of them showing a major response with Ab2 serum concentrations greater than 1,000 U/ml ("high-responders"). The median disease-free survival time, as well as the median survival time of these high-responders, was increased as compared to the low- or no responders. Evaluating our data, we conclude that monoclonal antibody treatment with the MAb B72.3 may induce humoral immunological responses in about two-thirds of our study group, although a positive clinical effect may only be expected in patients with excessive anti-idiotypic antibody formation

ISSN:0272-457X    

DOI:10.1089/hyb.1997.16.53

年代:1997

数据来源: MAL