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Oncogene May 2007As a cancer immunotherapy tool, idiotypes (Ids) have been used in different ways over the last three decades, depending on the actual human tumor cell target. It all... (Review)
Review
As a cancer immunotherapy tool, idiotypes (Ids) have been used in different ways over the last three decades, depending on the actual human tumor cell target. It all started with passive, monoclonal, anti-Id antibody treatment of B-cell lymphoma, a setting in which results were tantalizing, but logistics unsustainable. It then moved toward the development of anti-Id vaccines for the treatment of the same tumors, a setting in which we have recently provided the first formal proof of principle of clinical benefit associated with the use of a human cancer vaccine. Meanwhile, it also expanded in the direction of exploiting the antigenic mimicry of some Ids with Id-unrelated, tumor-associated antigens for the immunotherapy of a number of solid tumors, a setting in which clinical results are still far from being consolidated. All in all, over the years Id-based immunotherapy has paved the way for a number of seminal therapeutic improvements for cancer patients, including the development of most if not all Id-unrelated monoclonal antibodies that have recently revolutionized the field.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Neoplasm; Cancer Vaccines; Humans; Immunotherapy; Neoplasms
PubMed: 17530013
DOI: 10.1038/sj.onc.1210371 -
Clinical Cancer Research : An Official... May 1998We initiated a clinical trial for patients with advanced malignant melanoma treated with an anti-idiotype antibody that mimics the disialoganglioside GD2. We report the... (Clinical Trial)
Clinical Trial
We initiated a clinical trial for patients with advanced malignant melanoma treated with an anti-idiotype antibody that mimics the disialoganglioside GD2. We report the clinical and immune responses of the first 12 patients entered into this trial. Patients received 1-, 2-, 4-, or 8-mg doses of the anti-idiotype antibody mixed with 100 microg of QS-21 adjuvant every other week, four times, and then monthly. Twelve patients have been on trial for 2-23 months, and all of them have generated immune responses. Patients were removed from the study if they demonstrated disease progression. Hyperimmune sera from all 12 patients revealed an anti-anti-idiotypic Ab3 response, as demonstrated by the inhibition of Ab2 binding to Ab1 by patients' immune sera. To further test the anti-anti-idiotypic response, patients' Ab3 antibodies were affinity purified on Sepharose 4B columns containing adsorbed immunizing anti-idiotype immunoglobulin. Purified Ab3 of all patients studied inhibited binding of Ab1 to a GD2-positive cell line. Purified Ab3 also inhibited binding of Ab1 to purified GD2, in a manner comparable to equal quantities of purified Ab1. The patient Ab3 was truly an Ab1' because it specifically bound to purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody was predominantly IgG, with only minimal IgM. The predominant IgG subclass was IgG1, with approximately equal quantities of IgG2, IgG3, and IgG4. These Ab3 antibodies reacted specifically with tumor cells expressing GD2 by immune flow cytometry and immunoperoxidase assays. Five patients' Ab3 antibodies studied for antibody-dependent cellular cytotoxicity were positive. One patient had a complete clinical response, with resolution of soft tissue disease, and six patients had stable disease, ranging from 9 to 23 months, and are being continued on vaccine therapy. Toxicity consisted of local reaction at the site of the injection, including induration and pain that generally resolved within a few days. Mild fever and chills were observed in 75% of the patients but rarely required acetaminophen. There was no additional toxicity, including abdominal pain that was previously seen with infusion of murine monoclonal anti-GD2 antibody. Current trials include patients with stage III melanoma and small cell lung cancer. Future trials will attempt to enhance the antitumor response by the addition of interleukin 2, granulocyte macrophage colony-stimulating factor, and other cytokines, together with the 1A7 vaccine.
Topics: Adult; Aged; Animals; Antibodies, Anti-Idiotypic; Cancer Vaccines; Cell Count; Dose-Response Relationship, Immunologic; Female; Gangliosides; Humans; Immunotherapy; Lymphatic Metastasis; Male; Melanoma; Mice; Middle Aged; Tumor Cells, Cultured
PubMed: 9607568
DOI: No ID Found -
Zentralblatt Fur Bakteriologie :... Nov 1995The hypervariable regions of the immunoglobulins which function as the antigen binding sites are capable of provoking an antibody response and are referred to as...
The hypervariable regions of the immunoglobulins which function as the antigen binding sites are capable of provoking an antibody response and are referred to as anti-idiotypic antibodies. Antisera were raised in rabbits against the idiotypes of a mouse monoclonal antibody HGT3a which binds only to the 38 kDa antigen of the M. tuberculosis complex group of organisms. Idiotype specificity in these antisera was determined by dot ELISA, Western blot and solid phase inhibition assays. In vivo administration of this rabbit anti-idiotypic antibody to Swiss mice evoked an anti-anti-idiotypic antibody response, further confirming the internal antigen mimicry by the anti-idiotypic antibodies of the 38 kDa antigenic epitope and its potential use as a surrogate antigen. Antibody response to the anti-idiotypic antibodies in the sera of patients with pulmonary tuberculosis showed significant correlation with the antibody response to the 38 kDa antigen studied in the same clinical samples indicating a close similarity of the 38 kDa antigen of M. tuberculosis and the rabbit anti-idiotypic antibody produced against MoAb HGT3a.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Bacterial; Antibodies, Monoclonal; Antigens, Bacterial; Immunization; Lipoproteins; Mice; Mycobacterium tuberculosis; Rabbits
PubMed: 9810648
DOI: 10.1016/s0934-8840(11)80893-5 -
Circulation Nov 1989Antibody F(ab')2 fragments derived from the sera of four patients with histology-proven chronic Chagas myocarditis [cF(ab')2]-complexed antibody F(ab')2 fragments of...
Antibody F(ab')2 fragments derived from the sera of four patients with histology-proven chronic Chagas myocarditis [cF(ab')2]-complexed antibody F(ab')2 fragments of children with acute Trypanosoma cruzi infection [aF(ab')2] in significantly higher molar ratios than those measured with F(ab')2 antibody fragments of normal subjects [nF(ab')2] from nonendemic areas (p less than 0.05). Anti-idiotype [cF(ab')2 X aF(ab')2] immune-complex formation was significantly blunted by preabsorption of cF(ab')2 with porcine heart atria sarcolemma (PAMs) immobilized on sepharose beads (inhibition, mean, 78.1 +/- 2.4%, n = 4). cF(ab')2 X nF(ab')2] immune-complex formation was also inhibited by pretreatment of cF(ab')2 with PAMs (inhibition, mean, 48.7 +/- 7.5%, n = 4). The sera of three groups of subjects from a geographic zone endemic for T. cruzi infection in the northeast of Brazil were assayed for free and immune-complexed IgG anti-acute T. cruzi infection F(ab')2. The indexed levels of free IgG anti-idiotype antibody activity and levels of IgG anti-idiotype immune complexes (IC') were markedly elevated in hospitalized patients with severe, decompensated chronic Chagas myocarditis (n = 23), and their IC' indexes were significantly higher than those measured in asymptomatic seropositive subjects from a nearby endemic village of the northeast of Brazil (Moniz Ferreira, n = 92, p less than 0.001) and in healthy seronegative villagers (n = 84, p less than 0.001). There exists a strong correlation between elevated IgG anti-sarcolemma, anti-idiotype activity levels and the clinical and pathologic expression of chronic Chagas myocarditis.
Topics: Adult; Animals; Antibodies, Anti-Idiotypic; Antibodies, Protozoan; Antigen-Antibody Complex; Chagas Cardiomyopathy; Child; Humans; Immunoglobulin Fab Fragments; Immunoglobulin G; Myocarditis; Sarcolemma; Trypanosoma cruzi
PubMed: 2680159
DOI: 10.1161/01.cir.80.5.1269 -
Journal of Immunology (Baltimore, Md. :... Feb 1983To investigate the relationship between antigen-mediated B cell commitment and induction of idiotype (id) suppression, anti-id antibody directed against the major id...
To investigate the relationship between antigen-mediated B cell commitment and induction of idiotype (id) suppression, anti-id antibody directed against the major id (TEPC-15 idiotype or T15id) of the anti-phosphorylcholine (PC) antibody was added at various time intervals to BALB/c spleen cell cultures stimulated with a T-independent PC antigen, R36a. The suppressive effect of anti-T15id antibody on the anti-PC response was rapidly decreased as addition of the antibody was delayed; when anti-T15id antibody was added 6 hr after the initiation of the cultures, only partial suppression was induced, whereas the addition of anti-id antibody after 24 hr did not result in significant suppression of the anti-PC response when compared with similar cultures treated with mock anti-id antibody. This acquisition of resistance to id suppression was completely inhibited by treatment with either sodium azide or colchicine, as well as at temperatures below 20 degrees C. The induction of resistance to id suppression during the preincubation period was dependent on the presence of an immunogenic level of specific antigen. This antigen-mediated B cell commitment did not appear to require macrophages because preincubation of macrophages with antigen did not affect the sensitivity of the B cells to anti-id antibody. These results support the possibility that anti-id antibody inhibits early B cell triggering, which involves an energy-dependent, epitope-mediated, lateral mobility of antigen receptors possibly followed by repolymerization of microtubules.
Topics: Animals; Antibodies, Anti-Idiotypic; Antigens, Bacterial; B-Lymphocytes; Dose-Response Relationship, Immunologic; Immune Tolerance; Immunoglobulin Idiotypes; Lymphocyte Activation; Macrophages; Mice; Mice, Inbred A; Mice, Inbred BALB C; Phosphorylcholine; Receptors, Antigen; Temperature; Time Factors
PubMed: 6600243
DOI: No ID Found -
Immunology Nov 1987Antibody regulation of hapten-specific granulomas was studied in mice in order to assess the relationship between an anti-idiotypic antibody and granuloma formation. An...
Antibody regulation of hapten-specific granulomas was studied in mice in order to assess the relationship between an anti-idiotypic antibody and granuloma formation. An anti-idiotypic antibody was raised against the idiotype of an azobenzenearsonate (ABA)-specific antibody of A/J mice. The anti-idiotypic antibody was subcutaneously (s.c.) administered to syngeneic mice prior to challenge with ABA-coupled polyacrylamide beads injected into the intestinal wall. The results of such a challenge were assessed histologically for granuloma formation at 24-h intervals. Mice primed with anti-Id antibody and challenged with ABA-linked beads developed epithelioid granulomas at 72 and 96 hr post-challenge. Unprimed mice or mice primed with control antibodies did not develop granulomas when challenged with ABA-linked beads. Moreover, we found that priming with anti-Id antibody intravenously (i.v.) resulted in suppression of intestinal granuloma formation that was similar to that observed previously after priming mice i.v. with ABA-coupled spleen cells (Ginsburg et al., 1982). This study demonstrates the induction and suppression of hapten-specific granuloma formation in the intestine by an anti-Id antibody. The observations indicate a role for the idiotype-anti-idiotype interaction in regulation of hapten-specific granuloma formation, and may have implications for the manner in which the host reacts against self in the autoimmune inflammatory process.
Topics: Animals; Antibodies, Anti-Idiotypic; Azo Compounds; Epitopes; Female; Granuloma; Hypersensitivity, Delayed; Immune Tolerance; Immunoglobulin Idiotypes; Intestinal Diseases; Mice; Skin Diseases; T-Lymphocytes; p-Azobenzenearsonate
PubMed: 2444527
DOI: No ID Found -
International Immunopharmacology Oct 2015Increasing evidence has suggested that bispecific and multivalent antibodies which have more antigen binding sites will improve their immunogenicity. The bispecific...
Increasing evidence has suggested that bispecific and multivalent antibodies which have more antigen binding sites will improve their immunogenicity. The bispecific anti-idiotype antibody vaccine G22-I50 was obtained through genetic engineering to enhance the immunogenicity of anti-idiotype antibody vaccines G22 and I50. G22-I50 vaccination could induce anti-tumor immunity in the Balb/c mouse model. The protective and therapeutic efficacy of G22-I50 was also evaluated using the hu-PBL-SCID mouse model injected three times with G22-I50, G22, or I50 mixed with Freund's adjuvant. Results demonstrated that the protective anti-tumor effect of G22-I50 could be relevant with the production of Ab3 antibody and activation of CD8(+) cytotoxic T-lymphocytes. In preventive and therapeutic experiments, G22-I50 could reduce tumor size and prolong the survival time of HNE2-bearing mice (p<0.05). Human CD8(+) T lymphocytes infiltrated the tumor sites, and high levels of human IFN-γ, TNF-α, and caspase-3 were also detected in the tumors from G22-I50-vaccinated and -treated mice. Therefore, the bispecific anti-idiotype antibody vaccine G22-I50 can induce strong humoral and cell-mediated immune responses. This vaccine can be potentially applied to prevent and treat nasopharyngeal carcinoma.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Bispecific; Cancer Vaccines; Carcinoma; Cell Line, Tumor; Disease Models, Animal; Genetic Engineering; Humans; Immunotherapy; Mice; Mice, SCID; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Transplantation; Tumor Burden
PubMed: 26303768
DOI: 10.1016/j.intimp.2015.07.026 -
Infection and Immunity Sep 1994Recently, we described the generation and characterization of an Armenian hamster Ab2 beta anti-idiotype monoclonal antibody (MAb4G2) specific for the binding site of a...
Recently, we described the generation and characterization of an Armenian hamster Ab2 beta anti-idiotype monoclonal antibody (MAb4G2) specific for the binding site of a mouse monoclonal antibody, MAbY1-4A6, directed against the conserved 2-keto-3-deoxyoctulosonate (Kdo)-containing inner-core region of lipopolysaccharide (LPS) (S. K. Field, M. Pollack, and D. C. Morrison, Microb. Pathog. 15:103-120, 1993). In that study, mice and hamster immunized with MAb4G2 generated serum immunoglobulin G and M (IgG and IgM) antibodies which cross-react with Salmonella minnesota R595-chemotype rough mutant LPS (Re-LPS). In this report, we demonstrate that in C3Heb/FeJ mice, MAb4G2 elicits an immune response which is characterized by specific binding of antibody to Re-LPS, as assessed by enzyme-linked immunosorbent assay. The practical use of MAb4G2 as a potentially effective therapeutic agent against gram-negative bacterial sepsis is suggested by the demonstration that immunization of these mice with MAb4G2 results in significant protection of D-galactosamine-sensitized animals against an otherwise lethal dose of Re-LPS. Assessment of the temporal changes in Re-LPS-specific serum antibody titers from mice immunized with MAb4G2 or Re-LPS over a 40-day period indicates that immunization with Re-LPS elicits significantly higher titers of serum IgM antibodies compared with those in animals immunized with MAb4G2. Conversely, two immunizations with MAb4G2 result in an up to 10-fold increase in anti-Re-LPS-specific IgG serum antibody titers relative to those obtained in mice immunized with Re-LPS. Nineteen days after the secondary boost with MAb4G2, anti-Re-LPS-specific IgG serum antibody titers were significantly higher (three- to fourfold) compared with those in Re-LPS-treated animals. Initial immunization with the anti-idiotype antibody primes animals for enhanced secondary responses to Re-LPS, as assessed by the titers of anti-Re-LPS-specific IgG profiles. These data suggest the potential utility of MAb4G2 as a candidate vaccine against the lethal properties of gram-negative bacterial LPS.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Bacterial; Antibodies, Monoclonal; Female; Immunization; Immunoglobulin G; Immunoglobulin M; Lipopolysaccharides; Mice; Mice, Inbred C3H
PubMed: 8063418
DOI: 10.1128/iai.62.9.3994-3999.1994 -
MAbs 2015SM03, a chimeric antibody that targets the B-cell restricted antigen CD22, is currently being clinically evaluated for the treatment of lymphomas and other autoimmune...
SM03, a chimeric antibody that targets the B-cell restricted antigen CD22, is currently being clinically evaluated for the treatment of lymphomas and other autoimmune diseases in China. SM03 binding to surface CD22 leads to rapid internalization, making the development of an appropriate cell-based bioassay for monitoring changes in SM03 bioactivities during production, purification, storage, and clinical trials difficult. We report herein the development of an anti-idiotype antibody against SM03. Apart from its being used as a surrogate antigen for monitoring SM03 binding affinities, the anti-idiotype antibody was engineered to express as fusion proteins on cell surfaces in a non-internalizing manner, and the engineered cells were used as novel "surrogate target cells" for SM03. SM03-induced complement-mediated cytotoxicity (CMC) against these "surrogate target cells" proved to be an effective bioassay for monitoring changes in Fc functions, including those resulting from minor structural modifications borne within the Fc-appended carbohydrates. The approach can be generally applied for antibodies that target rapidly internalizing or non-surface bound antigens. The combined use of the anti-idiotype antibody and the surrogate target cells could help evaluate clinical parameters associated with safety and efficacies, and possibly the mechanisms of action of SM03.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Neoplasm; Antigens, Neoplasm; Biological Assay; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Immunoglobulin Fc Fragments; Male; Mice; Sialic Acid Binding Ig-like Lectin 2
PubMed: 25427174
DOI: 10.4161/19420862.2014.985519 -
Journal of the American Academy of... Sep 1988Over the past two decades it has become clear that the ability of a host to generate antibodies against a wide variety of potential antigens is due to structural... (Review)
Review
Over the past two decades it has become clear that the ability of a host to generate antibodies against a wide variety of potential antigens is due to structural diversity in the antibody molecule within the variable region. This diversity results in sites within the molecule that are themselves immunogenic. These immunogenic sites are called idiotopes, and the collection of idiotopes on a single antibody molecule determines that antibody's idiotype. The idiotype of an antibody molecule is defined serologically by a second antibody termed an anti-idiotype. Anti-idiotypic antibodies can recognize antibody molecules bearing similar or identical structures within the variable regions, which are often on or near sites of antigen binding. Investigation into the nature of idiotype and anti-idiotype interactions has increased our knowledge of antibody structure, antigen-antibody interactions, the regulation of antibody production, and the nature of autoimmune disorders. This review will discuss the nature of idiotypes and anti-idiotypes and their potential role in the diagnosis, management, and treatment of autoimmune, infectious, and malignant diseases.
Topics: Antibodies, Anti-Idiotypic; Antibody Specificity; Autoimmune Diseases; Cross Reactions; Humans; Immunoglobulin Idiotypes; Molecular Structure
PubMed: 3049705
DOI: 10.1016/s0190-9622(88)70212-1