The use of antibodies as immunodelivery systems is still in its
infancy, Sydney Welt, MD, said at a symposium on Monoclonal Antibodies
and Cancer Therapy, sponsored by the Cancer Research Institute.
Since the majority of antigens are not tumor-specific, antibody
localization must be compared in both tumor and normal antigen-positive
tissue, said Dr. Welt, of the Ludwig Institute for Cancer Research
at Memorial Sloan-Kettering Cancer Center. "Until localization
parameters are precisely and accurately defined, meaningful therapy
trials are premature," he said.
Studies in Colon Cancer
Because the monoclonal antibody (MoAb) A33 is expressed homogeneously
in more than 95% of colon cancers, and reactivity in normal tissue
is restricted to the colonic mucosa, it lends itself well to the
demonstration of specific antigen-dependent localization at the
cell level, he said.
Phase I localization studies at Memorial Sloan-Kettering Cancer
Center demonstrated transient uptake of A33 in the normal bowel
and prolonged retention in tumor tissue. Specificity of localization
was shown using a control IgG.
A phase I/II radioimmunotherapy trial was conducted with a single
dose of murine A33 armed with iodine-131(131I). Of 23 evaluable
patients, antitumor effects were observed in five, despite the
fact that only a single dose was given.
Bone marrow was the dose-limiting organ toxicity. Gastrointestinal
toxicity was minimal, he said, because the normal colon quickly
eliminates the antibody. In the tumor, however, the antibody binds
and remains in place for weeks.
A second phase I/II trial was undertaken using 125I-labeled A33
in 22 patients with advanced colorectal cancer who had failed
conventional chemotherapy. In that trial, 20 patients with radiologic
evidence of disease showed radioisotope localization to disease
sites. Tumor responses were observed in four patients at 125I
doses below those resulting in bone marrow suppression.
With the exception of one patient with transient grade 3 thrombocytopenia,
there were no significant toxicities and no significant GI symptoms.
Murine A33 was used in both trials, necessitating single doses,
since it is immunogenic. As genetically engineered humanized antibodies
become available, researchers may be able to re-treat patients
with MoAb delivery systems. The true response rate cannot be determined,
Dr. Welt said, until multiple doses of humanized antibody can
be given. He noted that such antibodies may be either fully humanized
or chimeric (in which murine sequences are inserted into a "human
These and other studies have "demonstrated that monoclonal
antibodies with very limited normal-tissue reactivity are good
candidates for development as therapeutic agents," Dr. Welt
said. He believes they will most likely be used in combination