Abstract

Antibody-targeted radioimmunotherapy holds significant potential for solid tumor treatment. However, intact antibodies (IgG) and fragments (F(ab’) 2 ) may exhibit distinct pharmacokinetic and radiation delivery properties due to differences in molecular size and Fc functionality. TROP2 is highly overexpressed in most malignant tumors but minimally expressed in normal tissues. Therefore, the anti-TROP2 antibody was selected as the targeting agent in this study. We prepared the F(ab’) 2 antibody fragments of anti-TROP2 antibody and systematically compared the in vitro and in vivo behaviors of [ 177 Lu]Lu-DOTA-anti-TROP2 antibody and [ 177 Lu]Lu-DOTA-anti-TROP2-F(ab’) 2 antibody fragments to optimize radioligand therapy strategies. Cell binding assays were conducted to evaluate their TROP2 antigen binding affinity. In vivo distributions in tumors and normal organs were investigated through Micro-SPECT/CT imaging and biodistribution studies using tumor-bearing mice. The results demonstrated that, compared to the anti-TROP2 antibody, the anti-TROP2-F(ab’) 2 antibody fragments exhibited superior blood clearance kinetics as well as lower accumulation in liver and spleen. This could reduce the radiation side effects of [ 177 Lu]Lu-DOTA-anti-TROP2-F(ab’) 2 antibody fragments on bone marrow or other full-antibody target normal organs. However, cutting Fc from the full anti-TROP2 antibody increased renal accumulation and exhibited shedding phenomena following tumor targeting.