B7-H3, an emerging immune checkpoint molecule in metastatic CRPC and other cancers

Preliminary findings of Phase I/II dose-expansion study of DS-7300 (a B7-H3 antibody-drug conjugate) in mCRPC patients backed B7-H3 as a potential new target in treatment-resistant prostate cancers (Abstract #87)

Immune-checkpoint inhibitors (ICI) have resulted in significant therapeutic advancements in a wide range of tumor types, including melanoma, NSCLC, bladder, and kidney cancers, among others. However, ICI’s has produced moderate outcomes in advanced prostate cancer, which may be because prostate cancer cells do not express much PD-L1, and thus people with prostate cancer respond less strongly to these treatments. On the other hand, B7-H3 (CD276) has been shown to have immunomodulatory characteristics. B7-H3 is a novel immune checkpoint from the B7 family. At the ASCO GU Symposium 2022, Daiichi Sankyo presented the initial findings from an ongoing Phase I/II dose-escalation study of B7-H3 antibody-drug conjugate DS-7300 for advanced solid tumors, and dose-expansion studies in esophageal squamous cell carcinoma and mCRPC. According to the preliminary, DS-7300 was well tolerated with an acceptable safety profile in patients with mCRPC. At the data cutoff date of August 8, 2021, 29 patients with mCRPC from the United States and Japan were enrolled in parts 1 (n=24) and 2 (n=5). TEAEs occurred in 100% of the patients (n=29). 34.5% had grade≥3 TEAEs, with anemia being the most prevalent(17.2%).. Furthermore, preliminary findings show reductions in prostate-specific antigen (PSA) and bone metastases. To sum it up, the preliminary safety and effectiveness results of DS-7300 are promising, and there is space in the market for such targeted assets. 

Analyst Opinion: While CTLA-4 and PD-L1 are only found sporadically in prostate cancer, B7-H3 is found in abundance. Because B7-H3 is expressed on a variety of tumors but not in normal tissue, it has been postulated that medications in this family may affect B7-H3-expressing cancers while staying safe. Almost every prostate cancer cell, according to scientists, produces some degree of B7-H3, which appears to be associated with quicker recurrence and early metastasis. B7-H3 is considered a potential new target in treatment-resistant prostate cancers. Earlier to DS-7300 Phase I/II findings, two other drugs; Enoblituzumab and MGC018 published at the ESMO Congress 2021 supported the notion that B7-H3 targeted assets can be game-changers. MacroGenics plans to conduct a late-stage study on MGC018 in mCRPC. According to the corporate presentation, the company has planned a late-stage study in mCRPC in late 2022. There are presently no B7-H3-directed medicines approved for the treatment of any cancer.

Several companies, including Xencor (XmAb808), MacroGenics (Enoblituzumab and MGC018), Y-mAbs Therapeutics (Omburtamab), BioAtla (BA3142), Fate Therapeutics (Fate Therapeutics), AbbVie [Mirzotamab clezutoclax (ABBV-155)], GT Biopharma (GTB-5550 B7H3 TriKE)  and others, are attempting to utilize the B3-H7 immune checkpoint in oncology. We anticipate that if their efficacy and safety remain superior to present medicines, this target will generate a large sales product in the future. Such advancement in prostate cancer suggests that the therapy landscape will become more tailored and biomarker-specific soon.