Week 3, July 2024: Immunostimulatory ADCs (iADCs)

Immunostimulatory ADCs (iADCs), also known as immune-stimulating antibody conjugates (iSACs), are an advanced form of targeted cancer therapy. They not only activate innate immunity but also stimulate adaptive immunity, providing a dual therapeutic effect to eliminate tumor cells. They combine the specific targeting ability of antibodies with a specific immunostimulant.

Just last week, a study by Mersana Therapeutics demonstrated the potential of their STING (STimulator of InterferoN Genes) agonist iADCs. The STING pathway is a critical component of anti-viral and anti-tumor innate immune responses. Tumor cell-directed STINGa ADCs activate STING in tumor cells and myeloid cells. Administration in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism.

Meanwhile, other biopharmaceutical companies have been developing iADCs both in preclinical and clinical trials, including:

• Preclinical: Bolt Biotherapeutics, Inc. ’s BDC-4182 targeting Claudin 18.2

• Phase 1: Tallac Therapeutics’s TAC-001 to activate B cells to drive an anti-tumor immune response

• Phase 2: Ambrx's ARX788 targeting HER2

• Phase 2/3: Sutro Biopharma, Inc.'s Luvelta (STRO-002) targeting FRα

A recent paper by Fu et al. (2024) describes the various clinical applications and challenges for iADCs. A major challenge is achieving the right balance of agonist potency and dosage, with severe side effects or lower efficacy being the consequences. A solution could be combining immune stimulants with other therapeutic agents to improve tumor targeting and immune response without excessive toxicity. Future developments may involve refining antibody selection, considering both penetration ability and affinity, and closely monitoring immune-related adverse events in clinical trials to improve the therapeutic window of iADCs.