A Moderate-Affinity Antibody-Drug Conjugate Targeting B7-H3 Exerts Potent Antitumor Efficacy

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• B7-H3 is overexpressed in many solid tumors, making it a promising target for cancer therapy.
• Antibody-drug conjugates (ADCs) targeting B7-H3, such as DS7300a and MGC018, are under clinical investigation.
• CD276-8 ADC is a novel B7-H3-targeting ADC developed for potential antitumor applications.

Purpose of the Study:

• To develop and characterize CD276-8 ADC, an antibody-drug conjugate targeting B7-H3.
• To evaluate the in vitro and in vivo efficacy, pharmacokinetics, and developability of CD276-8 ADC.
• To explore the role of antibody affinity in optimizing ADC-based cancer therapeutics.

Main Methods:

• CD276-8 ADC was constructed using an anti-B7-H3 antibody, a cleavable linker, and DXd payload.
• In vitro assays assessed binding affinity, internalization, and cytotoxicity.
• In vivo studies in mouse models evaluated pharmacokinetics and antitumor activity.
• Developability was assessed through stability and freeze-thaw studies.

Main Results:

• CD276-8 ADC showed moderate binding affinity and acceptable in vitro internalization.
• The ADC demonstrated potent in vivo antitumor activity in B7-H3-positive xenograft models.
• Pharmacokinetic profiles were acceptable, and developability assessments indicated suitability for further development.
• In vitro cytotoxicity was less potent, suggesting a potential area for optimization.

Conclusions:

• CD276-8 ADC, a B7-H3-targeting ADC with moderate affinity delivering DXd, exhibits significant in vivo antitumor efficacy.
• The combination of moderate affinity and favorable pharmacokinetics contributes to its potent therapeutic effect.
• Affinity optimization represents a viable strategy for enhancing ADC efficacy in B7-H3-expressing solid tumors.
• CD276-8 ADC shows promise as a potential treatment for B7-H3-positive solid malignancies.