title: Phase I clinical evaluation of a new murine monoclonal antibody (Mu-9) against colon-specific antigen-p for targeting gastrointestinal carcinomas.
abstract: BACKGROUND
  Colon-specific antigen-p is a tumor-associated antigen present in approximately 60% of colorectal cancers. Preclinical studies have shown that the murine monoclonal antibody Mu-9 has excellent tumor-targeting abilities; therefore, clinical studies were initiated.
  
  
  METHODS
  The immunoglobulin G and F(ab')2 were radiolabeled with 131I and administered to 13 and 12 patients, respectively, with advanced gastrointestinal cancer (colon, rectal, and pancreatic) for radioimmunodetection or radioimmunotherapy.
  
  
  RESULTS
  Even in patients with highly elevated carcinoembryonic antigen levels, only one patient showed appreciable complexation of the labeled antibody, suggesting the epitope may not be highly expressed in the blood. Fifty percent of 131I-Mu-9 immunoglobulin G was cleared from the blood within 41 +/- 13 hours, while it took only 19 +/- 8 hours for the same amount of 131I-F(ab')2 to be cleared from the blood. Lesion detection in the abdomen, liver, and pelvis was greater than 90% for either the immunoglobulin G or F(ab')2. The dose absorbed by the normal organs, except the kidneys, was two- to threefold less for the F(ab')2 than for the whole immunoglobulin G. The dose to the kidneys was similar for both forms of immunoglobulin. The average tumor dose for 131I-Mu-9 immunoglobulin G was 13.9 +/- 11.0 cGy/mCi, and for 131I-F(ab')2 was 4.9 +/- 2.9. Tumor/red marrow dose ratios for the whole immunoglobulin G were 4.3 +/- 3.0, compared to 3.3 +/- 1.9 for the F(ab')2, suggesting the therapeutic window for the two forms of immunoglobulin may be similar. Eight of nine patients given the whole immunoglobulin G developed highly elevated levels of human anti-mouse antibody, whereas lower values were observed in five of seven patients given the F(ab')2.
  
  
  CONCLUSIONS
  These initial results support the need for further evaluation of Mu-9 immunoglobulin G and F(ab')2 for targeting gastrointestinal cancer for radioimmunotherapy.
authors.affiliation: Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, NJ 07103.
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: R
authors.initials: R
authors.lastname: Vagg
authors.forename: D
authors.initials: D
authors.lastname: Pawlyk
authors.forename: G Y
authors.initials: GY
authors.lastname: Wong
authors.forename: J A
authors.initials: JA
authors.lastname: Siegel
authors.forename: S
authors.initials: S
authors.lastname: Murthy
authors.forename: G M
authors.initials: GM
authors.lastname: Levine
authors.forename: D
authors.initials: D
authors.lastname: Izon
authors.forename: P
authors.initials: P
authors.lastname: Gascon
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000276:immunology*; D014408:Biomarkers, Tumor; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000628:therapy*; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice / Q000276:immunology; D008875:Middle Aged; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; C030139:colon-specific antigen