Biodistribution and histological localization of anti-human colon cancer monoclonal antibody (MAb) 1A3: the influence of administered MAb dose on tumor uptake.
Using a murine monoclonal antibody MAb 1A3, which binds to a lipid antigen found enriched in human colon cancer, and MOPC-21 antibody, as a non-specific control, we examined the effect of increasing doses of 125I-labelled MAbs (5 micrograms to 2,000 micrograms) on tumor localization. Biodistribution studies in hamsters with small GW-39 human colon carcinoma tumors [0.44 g +/- 0.014 (SEM)] demonstrated functional saturation of antigen binding sites in tumors when large doses of MAb 1A3 were used. The percentage injected dose bound per gram of tumor (ID/g tumor) remained constant for doses of intact MAb 1A3 less than or equal to 100 micrograms but decreased with doses greater than 100 micrograms, suggesting that a population of antigen binding sites had been saturated. While the percentage ID/g tumor decreased for doses of MAb 1A3 greater than 100 micrograms, the absolute amount specifically bound/g turnover increased (up to the 1,000 micrograms dose), suggesting that another population of less accessible 1A3 antigen could continue to bind MAb 1A3. In contrast, MOPC demonstrated a relatively constant percentage ID/g of tumor (2.26% +/- 0.11) throughout the dose range which was 2-3 times lower than MAb 1A3 (6.8% +/- 0.14) at plateau doses (5-100 micrograms). These data suggest that specific saturation of tumor binding sites was a biphasic phenomenon. Blood and normal tissues did not show binding kinetics suggesting saturation. Results of dose response experiments using MAb 1A3 F(ab')2 fragments (5 micrograms to 1,000 micrograms) closely paralleled those obtained with intact MAb 1A3, but with lower percentages of ID/g tumor, blood and non-tumor tissues as in previous studies with MAb 1A3 and other MAb F(ab')2 fragments. Histological examinations demonstrated that non-specific binding of MOPC or MAb 1A3 to tumor or normal tissues was of such low affinity as to be largely undetected after histological procedures. In contrast, MAb 1A3 (but not MOPC) showed specific cell-binding patterns to tumor but not normal tissues at all doses.
Fenwick
J R
JR
Department of Surgery, Jewish Hospital, Washington University School of Medicine, St. Louis, MO 63110.
Philpott
G W
GW
Connett
J M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000493:pharmacokinetics; D000951:Antigens, Neoplasm / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology; D006224:Cricetinae; D004306:Dose-Response Relationship, Immunologic; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008055:Lipids / Q000276:immunology; D008647:Mesocricetus; D009368:Neoplasm Transplantation; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D008055:Lipids