Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability

Area of Science:

• Oncology
• Immunotherapy
• Drug Development

Background:

• CD276/B7-H3 is overexpressed in various cancers, making it a promising therapeutic target.
• Previous CD276 antibody-drug conjugates (ADCs) using talirine pyrrolobenzodiazepine (PBD) payloads showed efficacy but had narrow therapeutic indices.

Purpose of the Study:

• To develop a modified, fully human CD276 ADC with an enhanced therapeutic index.
• To demonstrate potent anti-tumor activity against solid tumors with improved safety.

Main Methods:

• Development of a cross-species reactive CD276 ADC (m276-SL-PBD) with a modified talirine PBD payload.
• Genetic and chemical engineering of the ADC, alongside improved purification and payload sensitivity screening.
• Testing in large triple-negative breast cancer xenografts in preclinical models.

Main Results:

• The m276-SL-PBD ADC eradicated large triple-negative breast cancer xenografts (500-1,000 mm³).
• Effective dosing was 10- to 40-fold lower than the maximum tolerated dose, indicating a wider therapeutic index.
• The engineered ADC platform showed potential for potent and selective targeting of multiple solid tumor types.

Conclusions:

• Judicious engineering of CD276 ADCs significantly increases their therapeutic index.
• The developed ADC platform offers a promising approach for treating various solid tumors.
• This work advances ADC development for enhanced cancer therapy.