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.