We. Carson et al., Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells, EUR J IMMUN, 31(10), 2001, pp. 3016-3025
The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase
which is overexpressed in 20% of breast adenocarcinomas and is recognized b
y a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin)
. Natural killer (NK) cells are capable of mediating antibody-dependent cel
l cytotoxicity (ADCC) against antibody-coated targets via their expression
of a low-affinity receptor for IgG (Fc gamma RIII or CD16). NK cells can be
expanded in cancer patients via the administration of low-dose interleukin
-2 (IL-2) and become potent cytotoxic effectors following exposure to high
doses of IL-2. We tested IL-2-activated NK cells against Her2/neu(+) (MCF-7
(Her2/neu)) and Her2/neu(-) (MDA-468) breast cancer cell lines in a 4-h Cr-
51-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (eff
ector: target ratio = 10:1). Specific lysis of rhu4D5-coated MCF-7(Her2/neu
) and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respe
ctively (P < 0.05). Lysis was less than 5 % when targets were treated with
either the non-humanized mu4D5 mAb or control hulgG. Lysis of rhu4D5-coated
MCF-7(Her2/neu) cells was inhibited by 80% when NK cells were pre-treated
with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. E
nhanced ADCC of MCF-7(Her2/neu) target cells was seen when the effector cel
ls consisted of mononuclear cells obtained from a patient demonstrating sig
nificant expansion of NK cells secondary to therapy with low-dose IL-2. Ser
um from patients receiving infusions of rhu4D5 mAb could substitute for exo
genous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumo
r cells in the presence of IL-2 also produced large amounts of IFN-gamma wi
th concomitant up-regulation of cell-surface activation markers CD25 and CD
69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2
therapy in patients with cancers that express the Her2/neu oncogene.