MURINE MONOCLONAL ANTIBODY-VINCA CONJUGATE KS1 4-DAVLB HYDRAZIDE - PHASE 1 STUDIES IN PATIENTS WITH ADENOCARCINOMA/

The murine monoclonal antibody KS1/4 has been conjugated to the desace tyl derivative of the oncolytic agent vinblastine hydrazide (DAVLBH). Fifteen patients with lung, colon, pancreatic, or ovarian cancer were administered single infusions and eight patients received multiple dos es of the conjugate KS1/4-DAVLBH (LY203725). Duodenitis occurred in tw o patients receiving single infusions and in one patient receiving mul tiple infusions. Multiple infusions of the conjugate, however, resulte d in 4 of 8 patients developing other clinically dose limiting toxicit ies. Human anti-mouse antibodies (HAMA) were detected in 12 of the 15 patients who received single infusions and in 5 of the 8 patients rece iving multiple infusions. Anti-vinca responses were found in 4 of the 12 HAMA positive single dose patients and in 2 of the 5 multi-dose pat ients with HAMA responses. Two patients who developed high HAMA titers had type 3 (immune complex) immunopathologic reactions. The formation of the immune complexes was associated with disappearance of circulat ing KS1/4 and serum complement activity. Two other patients who develo ped HAMA had drops in KS1/4 and complement levels but no adverse clini cal reactions which could be associated with the HAMA. The results poi nt to the need to create less immunogenic formats for site-directed th erapy strategies from both the antibody perspective and chemical modif ications to the antibody.