ISACs: A non-cytotoxic payload alternative?

Author: Callum Angus, Market Analyst, Hanson Wade Intelligence

Antibody-drug conjugates (ADCs) are a class of biotherapeutic agents that combine the specificity of monoclonal antibodies (mAbs) with the potency of small molecule drug payloads. The most common payloads used in ADCs are cytotoxic drugs that kill cancer cells by disrupting their DNA, microtubules, or other critical cellular processes. However, these cytotoxic drugs can cause off-target toxicity, leading to adverse side effects. With the recent advent of cancer immunotherapy, there are hopes that exploring this in the context of ADCs could hold the answers for overcoming this issue.

Immunotherapy holds the key

The success of immune checkpoint inhibitors on the adaptive immune system in cancer has intensified efforts to utilise the innate immune system in a similar vein. In the context of ADCs, much of the focus of this effort has been on agonists of either the TLR or STING pathways using immune-stimulating antibody conjugates (ISACs). In targeting these pathways in tumours, ISACs can generate a pro-inflammatory or “hot” tumour microenvironment. This change will help to prime an effective adaptive immune response at the site of the malignancy and increase cancer cell killing. Importantly, this is done without direct toxicity towards cells that can subsequently lead to undesired off-target effects.

Big player buy-in

As a nascent therapeutic construct, there are currently only a handful of clinical-stage ISAC assets. Of these, the most advanced currently is Bolt Biotherapeutics’ BDC-1001. This combines the HER2-specific mAb trastuzumab with a TLR7/8 agonist. Following positive preclinical evaluation and topline data from Phase 1 trials, the company recently announced plans to progress BDC-1001 to a Phase 2 trial. Alongside this, they have entered a clinical supply agreement with Roche to provide pertuzumab for a further Phase 2 metastatic breast cancer trial. Regarding STING agonist ISACs, the most advanced currently are two Phase 1 drugs – Mersana Therapeutics’ XMT-2056 and Takeda’s TAK-500. In 2022, Mersana announced a co-development and commercialisation option with GlaxoSmithKline for XMT-2056.

What is evident throughout the clinical picture of ISACs is the presence of some of the largest pharmaceutical companies. This could represent the overall belief in ADC as a modality, but certainly also points to the potential seen in ISACs as a genuine answer to the off-target cytotoxicity issues faced in the ADC space. As our understanding of cancer biology and the immune system continues to evolve, we can expect to see more innovative ISAC constructs that improve patient outcomes and quality of life.


Bolt Biotherapeutics Announces Positive Topline Data from BDC-1001 Phase 1 Dose-Escalation Trial in HER2-Expressing Tumors, Supporting Advancement to Phase 2 Clinical Studies

Mersana Therapeutics Announces Option Agreement with GSK for the Co-Development and Commercialization of XMT-2056, an Immunosynthen ADC Targeting HER2