Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity

Area of Science:

• Oncology
• Immunotherapy
• Cancer Drug Development

Background:

• Antibody-drug conjugates (ADCs) are crucial in cancer therapy, often combined with checkpoint inhibitors for enhanced antitumor activity.
• Immunologically cold tumors pose a challenge for checkpoint inhibitor efficacy, necessitating novel treatment strategies.
• Improving treatment durability and overcoming resistance mechanisms are key goals in oncology.

Purpose of the Study:

• To investigate the synergistic efficacy of combining ADCs with immune-stimulating antibody conjugates (ISACs).
• To develop a novel combination therapy for enhancing antitumor activity, particularly in immunologically cold tumors.
• To assess the safety and tolerability of the combined ADC-ISAC treatment.

Main Methods:

• Utilized two non-competitive antibodies to co-target tumor-associated antigen (carcinoembryonic antigen, CEA) for enhanced internalization.
• Engineered an ISAC to improve FcγR engagement for efficient delivery of a STING agonist to immune cells.
• Administered a combination therapy of ADC (SN-38 payload) and ISAC in a preclinical cancer model.

Main Results:

• Combination therapy significantly reduced average tumor volume compared to ADC or PBS treatment alone (~40% and ~30% of ADC and PBS groups, respectively, by day 14).
• The combined approach demonstrated enhanced efficacy, overcoming limitations of single-agent therapies.
• Combination therapy exhibited tolerable side effects, with average weight loss of 7% or less.

Conclusions:

• Mixtures of ADCs and ISACs offer a potent strategy to enhance antitumor efficacy and treatment durability.
• This combination approach shows promise for treating immunologically cold tumors, expanding therapeutic options.
• The developed strategy is adaptable to other ADCs, potentially improving their clinical utility in diverse cancer types.