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

nant immunotoxin targeting erbB2 [110]. Clinical trials with e23(Fv)±PE38 were initiated
in early 1998. In a phase I study on breast cancer patients, hepatotoxicity was
observed in all patients. Immunohistochemistry showed the presence of erbB2 on
hepatocytes, explaining the liver toxicity of the immunotoxin. This study demonstrated
that targeting of tumors with antibodies to erbB2 armed with toxic agents or
radioisotopes may result in unexpected organ toxicity due to the expression of the
target antigen on normal cells [111].
Other recombinant immunotoxins that have been constructed and have antitumor
activities in vitro and in mouse models in vivo include: B1(Fv)±PE38, also directed
against the LeY antigen [112]; 55.1(Fv)±PE38 and 55.1(dsFv)±PE38, which are directed
at a carbohydrate mucin antigen over-expressed in colon cancers [84];
MR1(Fv)±PE38, constructed by antibody phage-display technology and directed to
a mutant EGF receptor over-expressed in liver and brain tumors [113]; and
SS(Fv)±PE38, a new recombinant immunotoxin specific for mesothelin, a differentiation
antigen present on the surface of ovarian cancers, mesotheliomas and several
other types of human cancers [114]. SS(Fv)±PE38 was constructed from an Fv
fragment that was isolated by antibody phage display from mice that underwent
DNA immunization with a plasmid expressing the cloned antigen [114]. This approach
to antibody formation eliminates the need for the production of proteins
for immunization.
Immunotoxins were also used to target tumors of the central nervous system. Since
the transferrin receptor is expressed on tumor and normal hepatic cells, but not in
normal brain, several trials have targeted anti-transferrin receptor immunotoxins to
brain tumors. These include a conjugate of mAb 454A12 with a recombinant form
of ricin A (plant toxin) [115], a conjugate of human transferrin with a mutant form
of DT [116, 117]and chimeric toxin of recombinant IL-4±PE38 fusion [118, 119].
17.6.2
Recombinant Immunotoxins against Leukemias and Lymphomas
17.6 Application of Recombinant Immunotoxins
Conventional immunotoxins, in which IgGs or Fabs are coupled to toxins, have also
been used to target leukemias and lymphomas. This approach should be quite effective
because many of the tumor cells are in the blood and bone marrow, where they
are readily accessible to the drug. Moreover, fresh cells from patients may be easily
tested for immunotoxin binding and cytotoxic activity.
Immunotoxins have also been developed for indirect treatment of malignancies by
their killing of T cells that mediate graft-versus-host disease (GvHD) in the setting of
allogeneic transplantation. Clinical trials using ricin-based immunoconjugates for
treatment of leukemias have shown some promising results, but dose escalation has
been limited by the side effects of the toxin [2]. In addition, it is important to eliminate
not only easily accessible tumor cells, but also malignant cells that are less accessible.
Therefore, even for leukemias, there is a need to develop small recombinant
immunotoxins that will reach cells outside the circulation. Recombinant immunotoxins
targeted at leukemia and lymphoma antigens have been made with antibody
fragments specific for the subunit of the IL-2 receptor (CD25) and for CD22. In addi-
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