Emergence of immunoglobulin variants following treatment of a B cell leukemia with an immunotoxin composed of antiidiotypic antibody and saporin.

Glennie, Martin J.; McBride, H M; Stirpe, Fiorenzo; Thorpe, Philip E.; Worth, Andrew; Stevenson, G T

doi:10.1084/jem.166.1.43

Cited by 38 publications

(12 citation statements)

References 37 publications

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“…An additional Id-negative tumour has been obtained in an Id-specific actively immunized mouse. Similar results were obtained by other investigators [10,12,24,32,40,46]. Only one Id-negative variant of the AIdAb-treated mice has lost the expression of IgM on the surface upon the loss of production of light chains.…”

Section: Discussionsupporting

confidence: 93%

Immunotherapy of B lymphoma by anti-idiotype antibodies: Characterization of variant tumour cells appearing a long time after the initial tumour inoculation

Taya

Haimovich

1991

Cancer Immunol Immunother

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Immunotherapy of a murine B-cell lymphoma by antibodies to idiotypic determinants of its IgM, resulted in surviving tumour-free mice. Several of these mice, however, did develop tumours a long time after the initial inoculation of the tumour cells, or upon rechallenge of the survivors with B-lymphoma cells. The presence of tumour cells during this long latent period may have been due to the development in the host of an anti-idiotype immune response. These late-developing tumours were detected by a radioimmunoassay and characterized by immunofluorescent staining and sodium dodecyl sulphate/polyacrylamide gel electrophoresis. Cells of some late-developing tumours lost the idiotype recognized by the antibodies used for the immunotherapy. Several of these tumours expressed IgM on the cell surface, while others did not, because of the absence of light chains. They were identical in the structure of their rearranged mu chain genes proving their derivation from the original inoculation. Cell lines obtained from the late-developing tumours differed in their tumorigenicity. The appearance of idiotype-negative tumour cells as a result of anti-idiotype immunotherapy has a great impact in our efforts to cure lymphoma by this modality.

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Section: Discussionsupporting

confidence: 93%

Immunotherapy of B lymphoma by anti-idiotype antibodies: Characterization of variant tumour cells appearing a long time after the initial tumour inoculation

Taya

Haimovich

1991

Cancer Immunol Immunother

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“…Those leukaemias that did eventually emerge in the two IT cocktail still expressed both target antigens demonstrating that therapy had not selected for antigen-negative variants as has been the case with anti-idiotypic antibodies directed against the cell surface immunoglobulin of B-cell tumours (Glennie et al, 1987). As we have argued previously antigen-expressing tumour cells may have avoided killing by IT either because a small subpopulation of the global tumour cell population were epigenetically down-regulated for antigen expression at the time of treatment or alternatively because small numbers of leukaemia cells were at locations inaccessible to IT at the time of treatment.…”

Section: Discussionmentioning

confidence: 99%

Therapy of human T-cell acute lymphoblastic leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly better than therapy with each individual immunotoxin

et al. 2001

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Immunotoxins (IT) are hybrid molecules comprised of an antibody coupled chemically or genetically to a toxin or ribosome inactivating protein (RIP) such as saporin Kreitman, 1999;Frankel et al, 2000). The antibody component allows for the selective delivery of the toxin to the surface of cells bearing the target antigen. In order to kill the target cell it is an absolute requirement that the conjugate is internalized by receptormediated endocytosis and that subsequently the toxin component is routed to the appropriate intracellular compartment where translocation of the toxin component to the cytosol can take place. Once in the cytosol RIPs such as saporin catalytically inactivate 28S ribosomal RNA via a highly specific N-glycosidase enzymatic activity (Endo, 1988) that results in cessation of protein synthesis in the cell and leads to apoptotic cell death (Bergamaschi et al, 1996). Arguably, the most important factor that theoretically limits the therapeutic efficacy of immunotoxins that have no bystander effect and which therefore have to exert their cytotoxic influence directly on all cells in the tumour, is the heterogeneity of target antigen expression within the global tumour cell population. Thus, relatively small numbers of tumour cells down-regulated or negative for the target antigen would escape killing by any single immunotoxin and if these surviving cells possess growth potential this would lead to subsequent tumour re-growth. One way of overcoming this problem would be to simultaneously target against more than one target molecule on the tumour cell surface in the expectation that multiple antigen-negative tumour cells would occur with a much lower frequency than single antigen-negative cells. There would also be the added bonus that targeting against more than one antigen on the tumour cell surface would ensure delivery of greater and therefore more effective quantities of the cytotoxic agent carried by antibody to tumour cells that were multiple antigen positive. Other factors such as the cell signalling effects and recruitment of cytotoxic host effectors may also work in conjunction to achieve an improved therapeutic effect when combinations of antibody-based therapeutics are utilized. We have In contrast treatment of SCID-CEM mice with a combination of both ITs led not only to a significantly greater delay in time to leukaemia development but also in the numbers of animals remaining leukaemia free (60%). The native HB2 and OKT10 antibodies (both murine IgG 1 antibodies) exerted significant, though relatively weak therapeutic effects, probably mediated through an antibody-dependent cellular cytotoxicity (ADCC) mechanism. Moreover, there was no in vivo additivity of therapeutic effect when both antibodies were used in combination. Apparent, however, was that the combination of HB2-SAPORIN IT with OKT10 antibody led to an intermediate therapeutic effect that was significantly greater than that obtained when either was used alone but significantly less than that obtained when the two IT combination...

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“…with 5 ϫ 10 4 L 2 C leukemic cells (14). The doubling time of these cells in vivo is approximately 19 h, and after such an inoculum untreated animals die approximately 14 days later with a blood white cell count ϳ250,000/ l and extensive tumor in bone marrow, spleen, lymph nodes, and liver.…”

Section: Immunotherapymentioning

confidence: 99%

Thioether-Bonded Constructs of Fab′γ and Fcγ Modules Utilizing Differential Reduction of Interchain Disulfide Bonds

Kan

Anderson

Leong

et al. 2001

The Journal of Immunology

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We describe a two-stage preparation of chemically engineered Ab constructs, employing as modules Fab′γ from mAb or rAb, and Fc from human normal IgG1. A multivalent, optionally multispecific F(ab′)n core is formed in stage one, and one or more Fc modules added in stage two. Examples include bispecific Fab2Fc2 (for simplicity, primes and Greek letters are omitted from names of final constructs) and trivalent Fab3Fc2, which are designed to kill neoplastic cells. An essential element in the construction is the availability of the Fab′ in two reduced forms, Fab′(-sulfhydryl (SH))5 and Fab′-SH. The first is obtained by full reduction of the interchain disulfide bonds (SS) in the F(ab′)2 fragment of IgG. Fab′-SH is obtained by disulfide-interchange reactions on Fab′(-SH)5, whereby the γ-light SS is reconstituted, an unusual intrachain SS forms in the γ-chain hinge, and one hinge SH remains. F(ab′)2 and F(ab′)3 cores are built using partially reduced modules, being given intermodular thioether links that resist reduction. These cores are then fully reduced, making available SH groups for addition of the Fcγ modules. In the final constructs, all intermodular links embody tandem thioether bonds arising at hinge-region cysteines. Cytotoxic activities of representative constructs, and some enhancements deriving from multiple modules, are assessed. In guinea pigs, catabolism of Fab2Fc2 yielded a t1/2 similar to that of human IgG1, although the serum Fab2Fc2 revealed some proteolytic breakdown not shown by the IgG1. Immunotherapy of a guinea-pig leukemia confirmed the ability of these constructs to kill target cells in vivo.

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Emergence of immunoglobulin variants following treatment of a B cell leukemia with an immunotoxin composed of antiidiotypic antibody and saporin.

Cited by 38 publications

References 37 publications

Immunotherapy of B lymphoma by anti-idiotype antibodies: Characterization of variant tumour cells appearing a long time after the initial tumour inoculation

Immunotherapy of B lymphoma by anti-idiotype antibodies: Characterization of variant tumour cells appearing a long time after the initial tumour inoculation

Therapy of human T-cell acute lymphoblastic leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly better than therapy with each individual immunotoxin

Thioether-Bonded Constructs of Fab′γ and Fcγ Modules Utilizing Differential Reduction of Interchain Disulfide Bonds

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