Development of a MMAE-based antibody-drug conjugate targeting B7-H3 for glioblastoma

Area of Science:

• Oncology
• Immunology
• Drug Development

Background:

• B7-H3 (immunoregulatory protein B7-homologue 3) is highly expressed in various cancers, making it a potential therapeutic target.
• Antibody-drug conjugates (ADCs) have shown efficacy in glioblastoma clinical trials.
• Targeted delivery of cytotoxic agents is a key strategy in cancer therapy.

Purpose of the Study:

• To develop and evaluate a novel homogeneous antibody-drug conjugate (ADC) targeting B7-H3 for glioblastoma treatment.
• To assess the in vitro and in vivo efficacy and targeting capabilities of the developed ADC.

Main Methods:

• A homogeneous ADC, 401-4, was created by conjugating Monomethyl auristatin E (MMAE) to a humanized anti-B7-H3 mAb (401) using a divinylsulfonamide-mediated disulfide re-bridging method.
• In vitro cytotoxicity assays were performed on B7-H3-expressing glioblastoma cells.
• In vivo imaging studies using a fluorescently labeled conjugate (401-4-Cy5.5) and antitumor efficacy studies in U87-derived tumor xenografts were conducted.

Main Results:

• The ADC 401-4 demonstrated specific killing of B7-H3-expressing glioblastoma cells, with enhanced efficacy in cells with higher B7-H3 expression.
• In vivo imaging confirmed tumor accumulation and target-specific delivery of the fluorescent conjugate.
• Significant, dose-dependent antitumor activity of 401-4 was observed in U87-derived tumor xenografts.

Conclusions:

• The developed homogeneous ADC, 401-4, targeting B7-H3 exhibits potent and specific antitumor activity against glioblastoma.
• 401-4 demonstrates effective tumor targeting and accumulation, supporting its potential as a therapeutic agent for B7-H3-expressing cancers.