Advancements in B7-H3 Targeted Therapy: The Emergence of DS-5573a as an Effective Antitumor Agent

A study has been conducted to develop monoclonal antibodies (mAbs) targeting B7-H3, a protein highly expressed in various human tumors and linked to poor patient outcomes. The research team successfully created a mouse anti-human B7-H3 antibody, M30, which demonstrated antitumor properties. This antibody was then humanized into Hu-M30, and an afucosylated version, DS-5573a, was also produced.

The DS-5573a mAb was characterized and its antitumor capabilities were tested both in vitro and in vivo. The analysis revealed that B7-H3 is broadly expressed across different cancer cell lines and that DS-5573a can bind to the IgC1 and IgC2 domains of human B7-H3. The mAb showed significantly enhanced antibody-dependent cellular cytotoxicity (ADCC) against cancer cell lines expressing medium to high levels of B7-H3, such as MDA-MB-231 and NCI-H322. Notably, DS-5573a induced high ADCC activity against the low B7-H3-expressing cancer cell line COLO205, while Hu-M30 had minimal effect.

Furthermore, DS-5573a was identified as a novel anti-B7-H3 antibody with the ability to mediate antibody-dependent cellular phagocytosis. In terms of in vivo antitumor efficacy, DS-5573a exhibited dose-dependent and significant tumor reduction in SCID mice bearing MDA-MB-231 tumors, which have functional natural killer cells and macrophages. However, it showed little efficacy in NOG mice, which lack natural killer cells and have diminished macrophage function.

These findings indicate that the antitumor activity of DS-5573a is mediated by effector cells and suggest that this mAb has the potential to be a promising therapeutic agent for patients with a variety of B7-H3-expressing tumors.