The development of stable
immunoconjugates by the advent of macrocyclic
metal chelating agents (
DOTA) has enabled us to study the ability of 111In-DOTA-labeled
monoclonal antibodies to detect
tumor lesions in a pilot radioimmunolocalization study, as well as to evaluate the kinetics, toxicity, and efficacy of i.p. administered 90Y-DOTA-labeled murine
monoclonal antibody in a Phase I/II clinical trial of advanced
ovarian cancer. The development of
serum sickness-like reactions in three of six treated patients, in the absence of previous
monoclonal antibody administration, led us to study the potential immunogenicity of the new chelate. Six patients with
ovarian cancer received 25 mg of HMFG1
monoclonal antibody coupled with 90Y-DOTA (doses of radioactivity, 15 to 25 mCi), administered i.p. Eight patients with various malignant
tumors received low doses (220 micrograms to 1 mg) of
monoclonal antibodies, labeled with
111In-DOTA, i.v. for imaging studies. Using a solid-phase
enzyme-linked
immunosorbent assay method, the immunogenicity of
DOTA was evaluated. Serial dilutions of patients' sera, before and after imaging or
therapy with
DOTA-coupled
monoclonal antibodies, as well as sera from patients who did not receive
DOTA-coupled antibody, were screened on
enzyme-linked
immunosorbent assay plates coated with
human serum albumin (HSA), HSA-2-iminothiolane, and HSA-2-iminothiolane-benzyl-DOTA. All patients treated with i.p.
monoclonal antibody developed anti-
DOTA antibodies. Four of eight patients who received i.v. "imaging" doses of
DOTA-coupled
monoclonal antibody developed
antibodies against
DOTA. The levels of anti-
DOTA response correlated with the amount of injected
radioimmunoconjugate (r = 0.889, P less than 0.001). None of the patients who received
DOTA-coupled antibody had detectable
antibodies against the macrocycle before
immunoconjugate administration. We then addressed further the restriction of the immune response against the macrocycle. We found that there was no or very low response against the aromatic ring attached to
DOTA. Most, if not all, of the immune response is directed against the
DOTA ring structure. Affinity purification of anti-
DOTA antibody from serum enabled quantitation of these
antibodies in the serum of patients. An inverse, statistically significant correlation was observed between the percentage of binding inhibition of a patient's serum to
DOTA, by HSA-2-iminothiolane-DOTA (100 micrograms/ml) and the level of anti-
DOTA immunoglobulin in the serum.(ABSTRACT TRUNCATED AT 400 WORDS)