Biologic properties of a CH2 domain-deleted recombinant immunoglobulin.
Monoclonal antibody (MAb) B72.3 reacts with TAG-72, a high-molecular-weight mucin expressed on several types of human carcinoma, and is currently being used in clinical trials for the diagnosis and therapy of human carcinoma. An expression construct containing cDNA encoding an immunoglobulin (Ig) heavy chain, with the variable region of murine MAb B72.3 and a human Ig constant region with a deletion of the CH2 domain, was generated. Immunoglobulin from the transfectoma with the highest expression of the TAG-72 immunoreactive antibody was designated MAb chimeric (c) B72.3 delta CH2. The pharmacokinetics of serum clearance of iodine-labeled MAbs cB72.3 delta CH2 and the intact cB72.3 were compared in athymic mice. By 24 hr, less than 1% of the cB72.3 delta CH2 was left in the plasma, while 36% of the cB72.3 still remained. The T1/2 alpha values of the cB72.3 delta CH2 and cB72.3 MAbs were 1.7 and 2.4 hr, respectively. The T1/2 beta values were 7.8 hr for the domain-deleted cMAb and 48.9 hr for cB72.3. Biodistribution studies in athymic mice bearing LS-174T xenografts showed a reduction in the percentage of injected dose per gram in tumor with 131I-cB72.3 delta CH2; however, the 131I-cB72.3 delta CH2 both localized to tumors faster and cleared from the blood faster than the 125I-cB72.3 MAb. Only trace amounts of the 131I-cB72.3 delta CH2 were detected in normal tissues, including kidney. The faster clearance rate, more rapid tumor targeting and lack of metabolic uptake in normal tissues demonstrated with the iodine-labeled CH2 domain-deleted cMAb may be an advantage for certain clinical protocols.
Slavin-Chiorini
D C
DC
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Horan Hand
P H
PH
Kashmiri
S V
SV
Calvo
B
B
Zaremba
S
S
Schlom
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism; D001667:Binding, Competitive; D003110:Colonic Neoplasms / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000302:isolation & purification; D007147:Immunoglobulin Light Chains / Q000302:isolation & purification; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D006023:Glycoproteins; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D011994:Recombinant Proteins; C047052:tumor-associated antigen 72