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.
The use of antibodies as immunodelivery systems is still in itsinfancy, Sydney Welt, MD, said at a symposium on Monoclonal Antibodiesand Cancer Therapy, sponsored by the Cancer Research Institute.
Since the majority of antigens are not tumor-specific, antibodylocalization must be compared in both tumor and normal antigen-positivetissue, said Dr. Welt, of the Ludwig Institute for Cancer Researchat Memorial Sloan-Kettering Cancer Center. "Until localizationparameters are precisely and accurately defined, meaningful therapytrials are premature," he said.
Studies in Colon Cancer
Because the monoclonal antibody (MoAb) A33 is expressed homogeneouslyin more than 95% of colon cancers, and reactivity in normal tissueis restricted to the colonic mucosa, it lends itself well to thedemonstration of specific antigen-dependent localization at thecell level, he said.
Phase I localization studies at Memorial Sloan-Kettering CancerCenter demonstrated transient uptake of A33 in the normal boweland prolonged retention in tumor tissue. Specificity of localizationwas shown using a control IgG.
A phase I/II radioimmunotherapy trial was conducted with a singledose of murine A33 armed with iodine-131(131I). Of 23 evaluablepatients, antitumor effects were observed in five, despite thefact that only a single dose was given.
Bone marrow was the dose-limiting organ toxicity. Gastrointestinaltoxicity was minimal, he said, because the normal colon quicklyeliminates the antibody. In the tumor, however, the antibody bindsand remains in place for weeks.
A second phase I/II trial was undertaken using 125I-labeled A33in 22 patients with advanced colorectal cancer who had failedconventional chemotherapy. In that trial, 20 patients with radiologicevidence of disease showed radioisotope localization to diseasesites. Tumor responses were observed in four patients at 125Idoses 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 antibodiesbecome available, researchers may be able to re-treat patientswith MoAb delivery systems. The true response rate cannot be determined,Dr. Welt said, until multiple doses of humanized antibody canbe given. He noted that such antibodies may be either fully humanizedor chimeric (in which murine sequences are inserted into a "humancassette").
These and other studies have "demonstrated that monoclonalantibodies with very limited normal-tissue reactivity are goodcandidates for development as therapeutic agents," Dr. Weltsaid. He believes they will most likely be used in combinationwith chemotherapy.