Immune Modulating Antibody-Drug Conjugate (IM-ADC) for Cancer Immunotherapy

Area of Science:

• Oncology
• Immunotherapy
• Drug Development

Background:

• Antibody-drug conjugates (ADCs) and immune checkpoint blockade (ICB) are promising cancer treatments.
• PD-1/PD-L1 interaction is a key target in cancer immunotherapy.
• Existing therapies can be limited by resistance mechanisms.

Purpose of the Study:

• To develop a novel ADC strategy for enhanced cancer treatment.
• To create an ADC that simultaneously blocks PD-1/PD-L1 and modulates the immune response.
• To investigate the efficacy of this novel ADC in overcoming resistance to ICB therapy.

Main Methods:

• Conjugation of anti-PD-L1 THIOMAB with a bifunctional immunomodulator (D18) using a redox-cleavable linker to create ADC HE-S2.
• Evaluation of HE-S2's ability to block PD-1/PD-L1 interaction and activate Toll-like receptor 7/8 (TLR7/8) signaling.
• Assessment of HE-S2's impact on PD-L1 expression through epigenetic regulation and/or IFN-γ induction.
• Comparison of HE-S2 efficacy against D18 combined with anti-PD-L1 antibody in tumor suppression models.

Main Results:

• ADC HE-S2 effectively blocks PD-1/PD-L1 interaction and activates TLR7/8 signaling.
• HE-S2 upregulates targeted PD-L1 expression, increasing sensitivity to PD-1/PD-L1 blockade.
• HE-S2 demonstrated more pronounced tumor suppression compared to combination therapy (D18 + anti-PD-L1 antibody).

Conclusions:

• The novel ADC HE-S2 offers a potent strategy to enhance antitumor immune responses.
• This approach improves sensitivity to immune checkpoint blockade therapy.
• HE-S2 represents a promising advancement in cancer treatment modalities.