Advantage of the F(ab)'2 fragment over IgG for RIT and PRIT
Radioimmunotherapy (RIT) has proved clinically effective in the treatment of relapsed or consolidating NHL after chemotherapy. However, it is still at the clinical trial stage for the treatment of solid tumors. The efficacy of the treatment on this type of tumor is limited by hematological toxicity, which restricts the activities injected. Pre-targeted radioimmunotherapy (PRIT) enables radiolabeling to be carried out in vivo at a time when the quantities of antigen-targeted vector reach a maximum level in the tumor, but have largely decayed in the bloodstream, thus limiting hematological toxicity. This therapeutic approach would make it possible to use higher radiopharmaceutical activities than those used in RIT, thereby increasing the doses deposited in the tumor and the therapeutic response. Despite encouraging preclinical trials, this approach has failed to live up to expectations in terms of clinical applications. In the context of PRIT using the Inverse Electron Demand Diels Alder (IEDDA) reaction as a method for radiolabeling tumor-targeted vectors, a major research effort has been made to improve the quality of in vivo radiolabeling using tetrazine (Tz) and transcycloctene (TCO) variants whose stability and reactivity have been optimized. Most trials in this field have been carried out using antibodies which, thanks to their long biological half-life, enable prolonged irradiation of tumors. Low-molecular-weight vectors such as affinity proteins or antigen-specific antibody fragments (VHH,scFv, F(ab)) have the advantage of being rapidly eliminated from circulation by renal filtration, but on the other hand, the quantities and residence times of these vectors in the tumor are reduced compared with IgG. F(ab)2 antibody fragments have properties intermediate between those of IgG and low-molecular-weight vectors that could be suitable for PRIT approaches, but they have not yet been evaluated in PRIT using IEDDA. In preparation for a preclinical trial of radioimmunotherapy of triple-negative breast cancer in spontaneously affected dogs, we compared the biodistribution of IgG and its F(ab)2 fragment targeting canine CD138 in a xenogeneic model of canine breast cancer and in a mouse model of colon cancer expressing human ACE antigen. This analysis shows that the use of F(ab)2 fragments improves the therapeutic index compared with IgG. F(ab)2 fragments seem particularly well suited to tumor targeting in PRIT using short-lived isotopes such as 211At.