Fc-Engineered B7-H3 Antibody with Prolonged Serum Half-Life for Enhanced Cancer Therapy

Monoclonal antibodies are revolutionizing the landscape of current cancer treatment, bringing hope to patients with incurable cancers. B7-H3 (CD276) is an attractive therapeutic target for antibody-based therapy due to its low or absent expression in normal tissues and high expression in various types of tumors, including prostate cancer, pancreatic cancer, and high-mortality esophageal squamous cell carcinoma (ESCC). In recent years, various B7-H3-targeting antibodies have been developed for cancer treatment, with a few making their way to clinical trials. One of the lessons learned from these practices is that for effective anticancer treatment, further modification of drug-like properties, particularly serum half-life, is crucial. In this project, we developed a humanized anti-B7-H3 antibody of strong affinity (K_D = 0.545 nM) through a combined mouse immunization and phage display selection, followed by complementary-determining region grafting. Based on this work, we endeavored to further improve its half-life through engineering its constant fragment (Fc) by substituting two key amino acids, M428L and N434S. The resulting antibody, namely, A172-Hu3-LS, exhibited improved affinity to the neonatal Fc receptor (FcRn) while retaining its cytotoxicity against ESCC cells. Further investigation in the human FcRn transgenic mice demonstrated that this Fc-optimized antibody had a prolonged in vivo half-life (7.9 days) and potent antitumor activity. The significance of this Fc-engineering method lies in its ability to enhance the pharmacokinetic properties of therapeutic antibodies and holds potential for optimizing other therapeutic antibodies, paving the way for more effective and durable cancer treatments. While ESCC was the focus of this study, the broad expression of B7-H3 in various cancers suggests that this work may contribute to the treatment of other B7-H3-expressing tumors.