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

International Journal of Cancer. Journal International Du Cancer
Baerbel MattheyHinrich Hansen

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 ani...Continue Reading

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Citations

May 29, 2007·Oncogene·I Zafir-LavieY Reiter
May 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Satoshi NagataIra H Pastan
Jan 6, 2011·Expert Opinion on Investigational Drugs·Heiner AdamsAlexandar Tzankov
Oct 30, 2007·Journal of Dermatological Science·Reinhard DummerMirjana Urosevic
Jan 18, 2006·Journal of Cutaneous Pathology·Reinhard DummerMirjana Urosevic
Jul 2, 2020·OncoTargets and Therapy·Shinichi MakitaKensei Tobinai
Apr 17, 2020·Frontiers in Immunology·Hinrich P HansenMichael Hallek
Jan 11, 2007·Cancer Research·Dennis A EichenauerHinrich P Hansen

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