Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

360 17 Immunotoxins and Recombinant Immunotoxins in Cancer Therapy
17.6
Application of Recombinant Immunotoxins
17.6.1
Recombinant Immunotoxins against Solid Tumors
The treatment of solid tumors with immunotoxins is challenging due to their physiological
nature of tight junctions between tumor cells, high interstitial pressure
within tumors and heterogeneous blood supply, and also antigen expression [102].
The greatest need for new therapies is in the treatment of metastatic epithelial cancers,
and immunotoxins can be a useful addition to the standard procedures of surgery,
radiation and chemotherapy.
As already described, the use of recombinant fragments of antibodies for making recombinant
immunotoxins is especially useful for the treatment of solid tumors because
their small size improves tumor penetration. Over recent years, several recombinant
immunotoxins that target solid tumors have been developed (Tab. 17.2); targets
include breast, lung, gastric, bladder and central nervous system cancers. They
are at different stages of clinical development and some are already employed in clinical
trials [1±4].
mAb B3 is an antibody that reacts with the LeYantigen present on cancers of the colon,
breast, stomach, lung and bladder [15]. Early trials with a first-generation immunotoxin
(LMB-1) in which an antibody to LeY (mAb B3) was used to make a chemical
conjugate with PE38 showed significant clinical activity, with responses in colon and
breast cancer [103, 104]. The one complete response and one partial response observed
in this trial were the first major responses to immunotoxins documented for
metastatic breast and colon cancer, respectively.
The B3 antibody was then used to make a single-chain immunotoxin termed
B3(Fv)±PE38 or LMB-7 [81]. LMB-7 has shown good activity against human cancer
xenografts growing in mice [105]and it is also able to cure carcinomatous meningitis
in rats when given by the intrathecal route [106]. A phase I clinical trial with LMB-7
began in 1995 and is nearing completion. During the trial, it became evident that
LMB-7 lost activity when incubated at 37 8C because of aggregation [86, 107], which
greatly limited its ability to penetrate solid tumors.
B3(dsFv)±PE38 (LMB-9) is the dsFv version of LMB-7 [107]with stability improved
over that of LMB-7. This improved stability also allowed it to be used in a continuous-infusion
mode in mice bearing human tumor xenografts; this route of administration
showed an improved therapeutic window over a bolus injection [108]. Clinical
trials with LMB-9 started in the middle of 1998. A different recombinant single-chain
immunotoxin, BR96(scFv)±PE40 was derived from the anti-LeY mAb BR96 and is
also currently undergoing clinical testing [109].
Monoclonal antibody e23 is directed at erbB2 (Her2/neu), which is highly expressed
in many breast, lung, ovarian and stomach cancers. e23(dsFv)±PE38 is a dsFv±immunotoxin
composed of the Fv portion of the e23 antibody and PE38 [68]. This
dsFv±immunotoxin has a significantly improved binding affinity and stability compared
with its scFv analogue, e23(Fv)±PE38 [75]. FRP5scFv±ETA is also a recombi-