Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of Paget's disease.

Nine patients with Paget's disease were treated with 200 U (15 nmol) synthetic salmon calcitonin (sCT) intranasally (in)/day for 12 months. Five of them had received im or in sCT therapy for 1-4 yr up to 0.5-5 yr before this study. Low titer antibodies to sCT were detected in the serum of three of these five patients, but not in the four patients who had not received prior sCT therapy. After 2 months of in sCT administration, four of the former group, but none of the latter group, had antibodies to sCT. After 12 months of treatment, antibodies to sCT were found in all patients who had received sCT earlier and in three of the four patients who had not. The half-maximal inhibition of [125I]sCT binding ranged from 44-284 pmol/L sCT. In a cultured human breast cancer cell line (T47D) cAMP production was stimulated by sCT (EC50, 70 pmol/L). cAMP production stimulated by sCT (5 pmol/L) was reduced to 6-20% of the control value in the presence of serum from patients which inhibited [125I]sCT binding by more than 50% in a dilution of 1:50 or greater. In patients with lower titer antibodies cAMP production was not inhibited. Serum alkaline phosphatase activity was transiently lowered to 79 +/- 6% (+/- SE) of basal levels in the patients who had earlier received sCT (P greater than 0.1), while sustained reduction to between 66 +/- 2% and 84 +/- 6% of basal levels (P less than 0.05) occurred in the patients who had not been treated with sCT previously. In conclusion, reexposure to sCT of five patients with Paget's disease caused secondary antibody responses and clinical resistance.