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Updated: Jul 9, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability
Yang Feng1, Jaewon Lee1, Liping Yang1
1Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD 21702, USA.
Abstract:
CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types.
Insights
A novel CD276 antibody-drug conjugate (ADC) demonstrates potent cancer cell targeting and eradication of large tumors. This engineered ADC offers a significantly improved therapeutic index for solid tumor treatment.
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.
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