Anti-Idiotypic and Non-Anti-Indiotypic Antibodies to Okt3 Arising Despite Intense Immunosuppression

Jaffers, Gregory J.; Fuller, Thomas; Cosimi, A. Benedict; Russell, Paul; Winn, Henry J.; Colvin, Robert B.

doi:10.1097/00007890-198605000-00004

Cited by 182 publications

(58 citation statements)

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“…In contrast, the immune response to the OKT3 monoclonal antibody has been shown to be oligoclonal in most patients, 44 expressing both anti-isotypic and anti-idiotypic antibodies despite immunosuppressive therapy, although one patient, like ours, was shown to make only anti-idiotypic antibodies. 8 As discussed above, anti-idiotypic Ab2 antibodies may mimic antigen (Tac) in ligand binding or may themselves serve as immunogen for the production of Ab3 antibodies that mimic the original Ab1 (MAT) in binding antigen (Figure 1). Sequence comparison between cc␣Id and Tac revealed a region of limited homology with Tac at the framework 2/CDR2 junction of the light chain.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Anti-idiotypic antibodies (Ab2), which recognize the antigen binding site of the therapeutic antibody (Ab1), 7 may constitute a portion of this response. 8 The use of chimeric or humanized antibodies that substitute human for rodent constant domains reduces the incidence and intensity of HAMA responses, but the possibility of an anti-idiotypic response remains. [9][10][11][12] Anti-idiotypic antibodies will directly block binding of the therapeutic antibody to the target antigen, and may thereby block the effectiveness of passive immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12] Anti-idiotypic antibodies will directly block binding of the therapeutic antibody to the target antigen, and may thereby block the effectiveness of passive immunotherapy. 8,13 The binding of Ab2 and antigen to sites on the Ab1 antibody may overlap, 14 allowing the Ab2 to mimic the antigen and bind to antigen ligands (eg Ab2 antibodies which develop after treatment with anti-Tac could bind to IL2) ( Figure 1). Furthermore, it was postulated the ('Jerne network hypothesis') that each anti-idiotype antibody may serve as the antigen for the next anti-idiotype along the cascade, yielding further anti-anti-idiotypic antibodies (Ab3, Ab4, etc) while also providing an activating stimulus for the B cell carrying the idiotype it recognises, thus generating an interacting network.…”

Section: Introductionmentioning

confidence: 99%

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Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

1998

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The alpha chain of the interleukin 2 receptor (IL2R␣; Tac) was targeted in clinical trials with adult T cell leukemia using murine anti-Tac antibody. Of 19 patients, a single individual achieved a durable complete remission. The mechanism of this action by murine anti-Tac has not been defined. We examined the hypothesis that the maintenance of the long-term response after treatment might be related to induction of a network of anti-idiotypic antibodies, as proposed in other tumor settings. In contrast to anti-Tac non-responders, the patient was found to have produced a human anti-mouse antibody (HAMA) response, and specifically an anti-idiotypic (

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

1998

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“…The anti T cell antibody, OKT3 has not succeeded in preventing HAMA formation (Jaffers et al, 1986). Immunosuppression with large doses of cyclophosphamide has reduced the incidence of HAMA (Thistlewaite et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Repeated antitumour antibody therapy in man with suppression of the host response by cyclosporin A

Ledermann

Begent²,

Bagshawe³

et al. 1988

Br J Cancer

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Summary Antibody targeted therapy of cancer results in anti-antibody production which prevents repeated treatment. Cyclosporin A (CsA) has been used to suppress this response in patients treated with a radiolabelled antibody to carcinoembryonic antigen (CEA). Patients with CEA producing tumours received a minimum of two courses consisting of an injection of radiolabelled antibody and CsA, 24 mg kg-1 day-1, for 6 days; each course was given at 2 week intervals. Two weeks after the completion of the second course the mean human antimouse antibody (HAMA) levels were 3.5 ug ml -1 (s.d. 2.7) in 3 patients receiving CsA and 1,998 pg ml-1 (s.d. 387) in 3 patients not receiving the drug. Clearance of antitumour antibody was accelerated and tumour localisation absent when HAMA levels exceeded 30 pgml-1. With lower levels of HAMA in the CsA-treated patients, further antitumour antibody accumulated in the tumour after each dose. Further therapy with antitumour antibody and CsA lead to the development of HAMA, but this was less than 25% of the amount in patients not given CsA. In this preliminary study up to 4 times as many doses of antitumour antibody could be usefully given when CsA was used. This increases the potential for effective antibody targeted therapy of cancer.Therapy of cancer with intravenous antitumour mouse monoclonal antibodies alone or conjugated to radionuclides or toxins has produced tumour responses but these are seldom sustained (Meeker et al., 1985, Lenhard et al., 1985, Spitler et al., 1987. Repeated therapy would probably be more effective but is prevented by the formation of human antimouse antibody (HAMA) after one or more injections of antitumour antibody (Meeker et al., 1985, Carrasquillo et al., 1984, Shawler et al., 1985. This causes hypersensitivity reactions and prevents antitumour antibody from localising in the tumour.CsA is a powerful inhibitor of humoral immunity (Borel et al., 1976) and has recently been shown in the accompanying paper to prevent the antibody response to repeated injections of mouse monoclonal antibodies in rabbits (Ledermann et al., 1988 The dose of CsA was adjusted to maintain blood levels between 1,000 and 1,500 ng ml -1 and to prevent a progressive rise in serum creatinine levels. Samples for HAMA were measured before therapy and at intervals after each dose. The distribution of radioactivity in the normal tissues and tumour was determined by planar and single photon emission tomography (SPET) imaging using an IGE Gemini gamma camera.HAMA levels were measured by enzyme immunoassay. Dilutions of serum in PBS containing 0.05% Tween and 0.1% bovine serum albumin were incubated for 2h at room temperature in microtitre wells coated with 10 pgml-l A5B7 in carbonate-bicarbonate buffer, pH 9.6. After washing, wells were incubated with goat anti-human IgG conjugated to alkaline phosphatase (Sigma) followed by the addition of pnitrophenyl phosphate. The absorbance was recorded on a Titertek Multiskan. The assay was standardised using HAMA immunopurified on an A5B7-Sepharose-...

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“…Antibodies could be switched in terms of antigenic targets and species of origin and alternative enzymes are likely to be available but there is no certainty that host responses to one species of immunoglobulin will not cross react with immunoglobulins from another. Human antibodies or humanised foreign antibodies may provide a solution but the fact that host antibodies may be predominantly antiidiotypic (Jaffers et al, 1986) suggests that host immune response will remain a potentially formidable obstacle to repeated treatments unless better ways of inhibiting it are found.…”

mentioning

confidence: 99%

Antibody directed enzymes revive anti-cancer prodrugs concept

1987

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Anti-Idiotypic and Non-Anti-Indiotypic Antibodies to Okt3 Arising Despite Intense Immunosuppression

Cited by 182 publications

References 0 publications

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

Repeated antitumour antibody therapy in man with suppression of the host response by cyclosporin A

Antibody directed enzymes revive anti-cancer prodrugs concept

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