Article

Metalloproteinase inhibition augments antitumor efficacy of the anti-CD30 immunotoxin Ki-3(scFv)-ETA' against human lymphomas in vivo.

Medizinische Klinik I der Universität zu Köln, Cologne, Germany.
International Journal of Cancer (impact factor: 5.44). 10/2004; 111(4):568-74. DOI:10.1002/ijc.20278 pp.568-74
Source: PubMed

ABSTRACT There is increasing evidence that the shedding of extracellular antigen domains impedes selective immunotherapy. One example is CD30, which is overexpressed on the surface of malignant lymphoma cells and has been identified as a promising target for antibody-based immunotherapy. However, CD30 is cleaved from the surface of target cells and the resulting soluble ectodomain (sCD30) is protecting the cells from antibody binding. Shedding can be inhibited by hydroxamate inhibitors of metalloproteinases such as BB-3644. We thus evaluated the influence of BB-3644 on the efficacy of the anti-CD30 single-chain immunotoxin Ki-3(scFv)-ETA'. In vitro, the addition of BB-3644 augmented the antitumor effect of Ki-3(scFv)-ETA' against Hodgkin-derived L540Cy cells by a factor of 2.75. Severe combined immunodeficiency (SCID) mice challenged with CD30-positive L540Cy cells were treated with the immunotoxin. One single nontoxic dose of BB-3644 increased the mean survival time of animals treated concomitantly with Ki-3(scFv)-ETA' to 93 days as compared with 35 days in the control (p = 0.0017). When BB-3644 was continuously delivered using subcutaneously implanted pumps, this effect was even more pronounced with no observed tumor growth in the animals within 200 days. Thus, concomitant application of metalloproteinase inhibitors might become clinically relevant in antibody-based immunotherapy against targets known to be shed from tumor cells.

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    Article: Cell membrane-specific epitopes on CD30: Potentially superior targets for immunotherapy.
    Satoshi Nagata, Tomoko Ise, Masanori Onda, Kazuyasu Nakamura, Mitchell Ho, Andrew Raubitschek, Ira H Pastan
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    ABSTRACT: Because CD30 is highly expressed on Hodgkin's lymphoma and anaplastic large cell lymphoma, it is a promising target for immunotherapy. Soluble CD30, the extracellular domain of CD30 that is shed from the cells, can reduce the effects of CD30-targeting agents by competitive binding. In this study, we identified two epitopes on membrane-associated CD30 that are missing on soluble CD30 probably because of a conformational change upon shedding. These epitopes are potentially superior targets for immunotherapy because targeting them should be free from the competitive effects of soluble CD30. We studied 27 anti-native CD30 mAbs that were assigned to 8 different topographical epitopes. Soluble CD30 was prepared from culture supernatants of L540 cells or Karpas 299 cells. In an ELISA, the mAbs to two epitopes, Ep2 (amino acids 107-153) and Ep7 (amino acids 282-338), showed less than a 2% average cross-reactivity to soluble CD30 compared with a CD30-Fc fusion protein. In addition, these mAbs bound to CD30 on cells in the presence of an excess of soluble CD30. These epitopes (Ep2 and Ep7) are, therefore, more efficiently presented on cell-associated CD30 than on soluble CD30 (membrane-specific epitopes). Also, soluble CD30 in the sera of mice bearing L540 tumors did not form immune complexes with the membrane-specific mAbs analyzed by size-exclusion chromatography. In contrast, mAbs to the other epitopes reacted with both soluble CD30 and membrane CD30. Our results suggest that it may be possible to find membrane-specific epitopes on other immunotherapy target molecules.
    Proceedings of the National Academy of Sciences 06/2005; 102(22):7946-51. · 9.68 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

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20 Jul 2012

Keywords

anti-CD30 single-chain immunotoxin Ki-3(scFv)-ETA'
 
antibody-based immunotherapy
 
BB-3644 augmented
 
clinically relevant
 
concomitant application
 
concomitantly
 
extracellular antigen domains impedes selective immunotherapy
 
Hodgkin-derived L540Cy cells
 
hydroxamate inhibitors
 
malignant lymphoma cells
 
mean survival time
 
metalloproteinase inhibitors
 
resulting soluble ectodomain
 
single nontoxic dose
 
subcutaneously implanted pumps
 
vitro