Immune-Stimulating Antibody Conjugates (ISACs)

Immune-stimulating antibody conjugates (ISACs) are engineered monoclonal antibodies coupled to synthetic PRR ligands that potentiate immune responses by triggering the production of pro-inflammatory cytokines and chemokines. These types of bioconjugates represent promising avenues for cancer immunotherapy. Indeed, they allow the precise targeting and PRR ligand delivery into cancer cells (over)expressing a specific tumor antigen, thus improving the therapeutic index versus free PRR agonists [1]. They have demonstrated robust activity as monotherapy or in combination therapies in pre-clinical studies and are now entering clinical trials [1-4].

Key factors

ISAC-mediated immune responses

ISACs share a similar design and engineering, and sometimes denomination, with antibody-drug conjugates (ADCs). Monoclonal antibodies are coupled, through a chemical linker, to a cytotoxic payload for ADCs,  or a conjugatable PRR ligand for ISACs. Each element can affect the final efficacy and safety of the bioconjugate. The selection of target antigen and the conjugation method are also key determinants of ISAC potency [5, 6]. 

Learn more about bioconjugation

Mechanisms of action

ISACs potentiate anti-tumor immune responses by:
- Tumor cell killing through antibody-mediated effector functions upon specific recognition of tumor antigen by the mAb variable region and binding of the mAb Fc fragment by FcγR-expressing cells, or complement,
- PRR activation in the tumor target cell or neighboring myeloid cells after ISAC internalization.
These two events act in synergy to induce the secretion of pro-inflammatory cytokines, recruitment of immune cells to the tumor site, and antigen presentation to tumor-specific T cells [1, 7].   

InvivoGen offers biological tools for building ISACs:

• Conjugatable PRR ligands: a series of TLR7 and STING agonists, either pre-linked or not
• Anti-HER2-Tra-hIgG1: a monoclonal human IgG1 antibody against HER2, one of the prototypical target antigens for ADCs

References:

1. Ackerman S.E. et al., 2021. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat. Cancer. 2(1):18.
2. https://clinicaltrials.gov/ct2/show/NCT04278144
3. https://clinicaltrials.gov/ct2/show/NCT04460456
4. https://www.mersana.com/pipeline/overview/
5. Fu Z. et al., 2022. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Sig. Transduct. Target. Ther. 7:93.
6.  Drago J.Z. et al., 2021. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol. 18-6):327.
7.  Demaria O. & Vivier E., 2020. ISACs take a Toll on tumors. Nat Cancer. 2(1):12.