Targeting of xenografted pancreatic cancer with a new monoclonal antibody, PAM4.
We have examined the ability of murine monoclonal antibody PAM4, directed against a pancreatic cancer-derived mucin, to target human pancreatic cancers carried as xenografts in athymic nude mice. Four tumor lines were used representing the range of expected differentiation; CaPan1, AsPc1, Hs766T, and BxPc3. In each case tumor uptake of PAM4 (range, 21-48% injected dose/g on day 3) was significantly higher than concomitantly administered, nonspecific, isotype-matched Ag8 antibody (range, 3.6-9.3% injected dose/g on day 3). Based upon the biodistribution data the estimated potential radiation dose delivered to the tumors when normalized to the blood dose as an estimate of dose-limiting myelotoxicity would be 13.1-, 2.2-, 3.4-, and 3.3-fold higher than to blood, respectively. PAM4 showed no evidence of targeting to normal tissues, except within the CaPan1 tumor model, where a small but consistent splenic uptake was observed. Splenic targeting was abolished by use of an increased PAM4 protein dose. Targeting of PAM4 to other normal tissues was not affected by the increased protein dose; however, tumor uptake of PAM4 (percentage of injected dose/g) was significantly increased by as much as 3-fold. The ability of PAM4 to target the CaPan1 tumor compared favorably to that of MN14, an anti-carcinoembryonic antigen murine monoclonal antibody. Tumor uptake of PAM4 was much greater than that for MN14 at days 1 and 3, whereas at later time points equivalent accumulations of activity were noted. Estimates of potential radiation doses to the tumor when normalized to the blood dose were 3.0 for MN14 and 9.6 for PAM4. These studies have shown that PAM4 is able to target pancreatic cancer with high specificity, achieving high concentrations at the tumor site. A rationale exists, then, for the performance of a clinical trial of radiolabeled PAM4 in the detection and localization of pancreatic cancer.
Gold
D V
DV
Center for Molecular Medicine and Immunology, Garden State Cancer Center, Newark, New Jersey 07103.
Alisauskas
R
R
Sharkey
R M
RM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D002272:Carcinoembryonic Antigen / Q000276:immunology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009077:Mucins / Q000276:immunology; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D009077:Mucins