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 cassette").
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 with chemotherapy.