# Next‐Generation HER‐2 Tumor‐Targeted Delivery of the STING Agonist Immune‐Stimulating Antibody Conjugate (ISAC) Improves Anticancer Efficacy and Induces Immunological Memory

## TL;DR

A new antibody conjugate targeting HER2 tumors with a STING agonist improves cancer treatment and creates immune memory.

## Contribution

A novel STING agonist ISAC with an optimized noncleavable linker shows superior efficacy and stability over existing HER2-targeted therapies.

## Key findings

- The STING agonist ISAC is well tolerated and shows potent antitumor activity in mouse models.
- The STING pathway primarily mediates antitumor effects through immune cell activation.
- The ISAC induces immune memory and rapid re-killing of previously treated HER2 tumors.

## Abstract

Recently, rapidly evolving STING‐based immunotherapies have offered novel therapeutic options for various cancer types. However, systemic administration of STING agonists raises safety concerns, and intratumoral injection is constrained by tumor accessibility. Herein we developed an immune‐stimulating antibody conjugate (ISAC) that links STING agonists to antibodies that target HER2‐positive tumor cells via a cleavable linker. In vivo studies demonstrated that the STING agonist ISAC is well tolerated and exhibits potent antitumor activity in syngeneic mouse tumor models. Investigations in STING‐knockout HER2‐positive tumor cells and STING‐knockout mouse models revealed that the STING pathway primarily mediates antitumor effects upon the activation of immune and tumor cells and that the activation of immune cells plays a stronger role. Additionally, our findings indicate that the STING agonist ISAC enhances both innate and adaptive antitumor immune responses, leading to sustained antitumor activity and the establishment of immune memory. These outcomes support the clinical development of the STING agonist ISACs.

A novel immune‐stimulating antibody‐drug conjugate, which links STING agonists to anti‐HER2 mAb through an optimized noncleavable Linker, remains highly stable at DAR = 5.7 and demonstrates superior efficacy over marketed HER2‐targeted ADCs in multiple tumor models with high, low, and drug‐resistant HER2 expression. And it shows good immune memory against HER2 tumors that have been killed before, thereby achieving rapid re‐killing.