Characterization and biodistribution of recombinant and recombinant/chimeric constructs of monoclonal antibody B72.3.
B72.3 is a murine monoclonal antibody (IgG1) that recognizes a tumor-associated glycoprotein, termed TAG-72. B72.3 has been shown, using a variety of methodologies, to have a high degree of selective reactivity for colorectal, ovarian, lung, and breast carcinomas. Radiolabeled B72.3 has been administered both i.v. and i.p. in patients with colorectal and ovarian cancer as well as other carcinomas and has been shown to selectively bind to approximately 70-80% of metastatic lesions. Greater than 50% of the patients that have been treated with B72.3 have developed an immunological response to murine IgG after a single injection. In an attempt to minimize the immune response of these patients to the administered murine monoclonal antibody, we developed a recombinant form of the murine B72.3 as well as a recombinant/chimeric antibody, using the variable regions of the murine B72.3 and human heavy chain (gamma 4) and light chain (kappa) constant regions. We report here that both the recombinant B72.3 [rB72.3] and the recombinant/chimeric B72.3 [cB72.3(gamma 4)] IgGs maintain the tissue binding and idiotypic specificity of the native murine IgG. The native B72.3, rB72.3, and cB72.3(gamma 4) IgGs were radiolabeled and the biodistribution of these IgGs was studied in athymic mice bearing human colon carcinoma xenografts (LS-174T). Differences were observed between the cB72.3(gamma 4) and the native B72.3 in the percentage of injected dose/g that localized in the tumor. The somewhat lower absolute amounts of the cB72.3(gamma 4) in the tumor are mostly likely due to the observed more rapid clearance from the blood and body of the mouse as compared to the native B72.3 and rB72.3. All three forms [native B72.3, rB72.3, and cB72.3(gamma 4)] of the IgG, however, were able to localize the colon tumor with similar radiolocalization indices [percentage of injected dose/g in tumor divided by the percentage of injected dose/g in normal tissue].
Colcher
D
D
Division of Cancer Biology and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892.
Milenic
D
D
Roselli
M
M
Raubitschek
A
A
Yarranton
G
G
King
D
D
Adair
J
J
Whittle
N
N
Bodmer
M
M
Schlom
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000302:isolation & purification; D000951:Antigens, Neoplasm / Q000276:immunology*; D006224:Cricetinae; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D007457:Iodine Radioisotopes; D008657:Metabolic Clearance Rate; D051379:Mice; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D006023:Glycoproteins; D007074:Immunoglobulin G; D007130:Immunoglobulin Idiotypes; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins