Anti-chelate antibodies after intraperitoneal yttrium-90-labeled monoclonal antibody immunoconjugates for ovarian cancer therapy.

Abstract

The development of stable chelating agents for metal isotopes (e.g., 90Y) such as CITC-DTPA, a benzyl-analog of DTPA, allowed us to evaluate the efficacy of 90Y-labeled HMFG1 MAb administered intraperitoneally in patients with ovarian cancer. Our previous studies of 90Y-HMFG1 antibody, however, showed that all patients developed anti-chelate antibody responses (to the macrocycle benzyl-DOTA), resulting in clinical side effects in a significant percentage of this group. We evaluated the immunogenicity of CITC-DTPA (administered to 12 patients as 90Y-HMFG1-CITC-DTPA after coupling it to HSA using solid-phase ELISA. Eleven of 12 evaluable patients developed anti-CITC-DTPA antibodies. Five patients (approximately 40%) developed hypersensitivity syndrome, most likely due to a type III immune reaction (serum sickness). Most patients had a low titer of pre-existing anti-chelate response which correlated positively with post-therapy response levels (p = 0.001). IgM anti-CITC-DTPA antibodies developed 2 wk while IgG antibodies developed 3 wk after treatment. Western blot analysis of post-therapy sera revealed a reaction with HSA-CITC-DTPA (60 kDa band) and no reaction with HSA or HSA-DTPA, whereas pre-therapy sera of the same patients were negative to all antigens. CITC-DTPA is immunogenic in patients after intraperitoneal administration of 90Y-CITC-DTPA labeled MAbs. Self-limiting clinical side effects consistent with a serum sickness-like immune reaction were observed in 5 of 12 patients.