Pharmacokinetics, biodistribution, and radioimmunotherapy with monoclonal antibody 776.1 in a murine model of human ovarian cancer.
776.1 is a murine IgG1 monoclonal antibody to the human ovarian cancer antigen CA 125 that has the unique property of having a clear preference for binding to the cell-associated form of the antigen. We have examined the tumor localization properties and efficacy of 776.1 in a subcutaneous OVCAR-3 xenograft mouse model of human ovarian cancer. Biodistribution experiments using (125)I-labeled 776.1 demonstrated a peak uptake in tumors at 72 hours postinjection, with an average of 17.7% of injected dose per gram localized to the tumor. Little uptake in other organs was observed. Further experiments using CA 125-transfected syngeneic tumors, as well as an immunoprecipitation assay using human chimeric 776.1, both clearly demonstrated that 776.1 localizes to the tumor in a CA 125-dependent manner. DOTA-776.1 (1,4,7,10-tetraazacyclododecane-N,N',N",N'" tetraacetic acid-conjugated 776.1) was labeled with (90)Y and used in efficacy studies. [(90)Y-DOTA]776.1 at a single dose of 150 microCi was able to mediate efficient reduction of tumor growth, with regression observed in a subset of animals for a period ranging from 3 to 48 days, equivalent to 3 weekly administrations of cisplatin at 6 mg/kg. No significant regression was observed in groups receiving [(90)Y-DOTA]MOPC-21 control antibody at any dose. These results suggest that 776.1 may be a promising radioimmunotherapeutic agent for the treatment of human ovarian cancer.
Berger
Marc A
MA
Purdue Pharma, L.P., Immunotherapeutics Department, Cranbury, NJ, USA.
Masters
Gregg R
GR
Singleton
Judith
J
Scully
Michael S
MS
Grimm
Lisa G
LG
Soltis
Daniel A
DA
Albone
Earl F
EF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018394:CA-125 Antigen / Q000032:analysis; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D010051:Ovarian Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D018394:CA-125 Antigen; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes