Degrader-Drug Conjugate (DDC) Mediated Immunochemotherapy for Tumor Treatment

Area of Science:

• Oncology
• Immunology
• Drug Development

Background:

• Immunotherapy targeting PD-1/PD-L1 inhibitors shows limited efficacy due to tumor heterogeneity and complex PD-L1 regulation.
• A novel therapeutic strategy is needed to overcome these limitations in cancer treatment.

Purpose of the Study:

• To develop and evaluate a Degrader-Drug Conjugate (DDC) platform for enhanced antitumor efficacy.
• To investigate the synergistic effects of PD-L1 degradation and direct cytotoxic cell killing.

Main Methods:

• Design and synthesis of two DDCs: BMS-RGD-MMAE and BMS-RGD-DXd, comprising a PD-L1 degrader linked to a cytotoxic agent.
• Evaluation of DDC efficacy in vitro, assessing toxin release, plasma stability, and cytotoxicity.
• In vivo assessment of tumor growth inhibition in a preclinical model.

Main Results:

• BMS-RGD-MMAE demonstrated superior toxin release, enhanced plasma stability, and increased cytotoxicity compared to BMS-RGD-DXd.
• The DDC approach effectively promotes PD-L1 degradation via the endosomal-lysosomal pathway, alleviating immunosuppression.
• BMS-RGD-MMAE significantly inhibited tumor growth in vivo through synergistic PD-L1 degradation and toxin-mediated apoptosis.

Conclusions:

• The developed DDC platform, particularly BMS-RGD-MMAE, shows significant potential for improving antitumor efficacy in cancer therapy.
• This DDC strategy offers a promising approach for tumor immunochemotherapy by combining immune modulation with direct tumor cell killing.
• The DDC platform represents a novel advancement in the development of next-generation antitumor therapeutics.