Biologic properties of a Ch2 domain‐deleted recombinant immunoglobulin

Abstract

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 C_H2 domain, was generated. Immunoglobulin from the transfectoma with the highest expression of the TAG-72 immunoreactive antibody was designated MAb chimeric (c) B72.3°C_H2. The pharmacokinetics of serum clearance of iodine-labeled MAbs cB72.3°C_H2 and the intact cB72.3 were compared in athymic mice. By 24 hr, less than 1% of the cB72.3°C_H2 was left in the plasma, while 36% of the cB72.3 still remained. The T_1/2β values of the cB72.3°C_H2 and cB72.3 MAbs were 1.7 and 2.4 hr, respectively. The T_1/2β 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 ¹³¹1-cB72.3°C_H2; however, the ¹³¹1-cB72.3ΔC_H2 both localized to tumors faster and cleared from the blood faster than the ¹²⁵1-cB72.3 MAb. Only trace amounts of the ¹³¹1-CB72.3°C_H2 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 C_H2 domain-deleted cMAb may be an advantage for certain clinical protocols.