Week 3, August 2026: Targeting Pathological Protein Aggregates with Antibodies

Therapeutic antibodies are often used to block receptors or neutralize soluble molecules. Another approach is to use antibodies to recognize abnormal forms of proteins that have accumulated in tissues and help the immune system remove them.

This strategy is being investigated in diseases involving amyloid, a highly organized form of protein aggregate. Two areas illustrate both its potential and its unanswered questions: transthyretin amyloid cardiomyopathy (ATTR-CM) and Alzheimer’s disease.

Recognizing the abnormal form of a protein

For an antibody aimed at a protein aggregate, ideally, the antibody should distinguish the disease-associated form from the protein’s normal form.

This idea is important for several antibodies in development for ATTR-CM. In this disease, transthyretin (TTR) becomes unstable, misfolds and accumulates as amyloid in the heart. Existing TTR stabilizers and silencers can slow the formation of additional amyloid, but they do not directly remove deposits that are already present.

Two investigational antibodies take a different approach:

1. Cliramitug is a recombinant human monoclonal antibody. It is designed to selectively bind misfolded and aggregated TTR while avoiding normally folded TTR. After binding, it can recruit phagocytic immune cells, which remove antibody-tagged material. (Neurimmune AG + Alexion Pharmaceuticals, Inc., AstraZeneca Rare Disease)

2. Coramitug is a humanized monoclonal antibody that also targets misfolded TTR and is designed to promote removal of TTR amyloid through antibody-mediated phagocytosis. (Novo Nordisk)

In this way, these antibodies are intended to address material that has already accumulated rather than only reducing the supply of new amyloid-forming protein.

ATTR-CM puts amyloid depletion to the test

Early clinical findings suggest that antibody-mediated amyloid depletion can produce measurable biological effects, although whether these effects translate into better long-term clinical outcomes remains under investigation.

A 2026 Nature Medicine report followed 23 participants who continued cliramitug treatment after a first-in-human study. With a median follow-up of 29.3 months, investigators observed further reductions in imaging measures used as surrogate markers of cardiac amyloid burden, along with improvements in biomarkers including NT-proBNP and troponin T. However, the extension was small and open-label, and most participants were also receiving tafamidis. The authors therefore described the findings as requiring confirmation in a larger controlled trial.

Cliramitug is now being evaluated in the Phase 3 DepleTTR-CM study, which is examining outcomes including all-cause mortality and cardiovascular clinical events.

Coramitug has also produced encouraging but mixed Phase 2 findings. In a randomized study of 104 treated participants with ATTR-CM, the 60 mg/kg dose produced a 48% reduction in NT-proBNP relative to placebo at 52 weeks. However, neither coramitug dose produced a statistically significant improvement over placebo in the 6-minute walk test, a measure of functional exercise capacity.

Coramitug is now being studied in the Phase 3 CLEOPATTRA trial, which is designed to evaluate cardiovascular outcomes in people with ATTR-CM.

These studies highlight an important difference: reducing an amyloid deposit or changing a disease biomarker is not the same as demonstrating that patients live longer or function better.

What Alzheimer’s disease has taught us about amyloid clearance

That difference is especially relevant because antibody-mediated amyloid removal has already been studied extensively in Alzheimer’s disease.

Anti-amyloid-beta monoclonal antibodies are designed to target forms of amyloid-beta associated with plaques in the brain. Several have demonstrated that antibodies can substantially reduce brain amyloid. But the relationship between amyloid removal and clinical benefit remains debated.

A 2026 review evaluated 17 randomized studies involving 20,342 participants and seven different anti-amyloid-beta antibodies. Across the studies reviewed, the authors concluded that the effects on cognitive function and dementia severity at 18 months were small or absent, while effects on functional ability were small at best. The review also found an increased risk of amyloid-related imaging abnormalities, including brain swelling and small bleeds detected by imaging.

Importantly, these findings concern amyloid-beta antibodies in Alzheimer’s disease and should not be assumed to apply directly to ATTR-CM. The diseases involve different proteins, organs and clinical outcomes. What Alzheimer’s provides is a broader lesson for aggregate-targeting antibodies: successful target removal needs to be evaluated separately from meaningful clinical benefit.

From antibody binding to disease modification

Thus, several questions need to be answered experimentally:

• Specificity: Does the antibody recognize the disease-associated form of the protein while limiting binding to its normal form?

• Clearance: Does binding actually promote removal of the pathological material?

• Biological effect: Does reducing the aggregate improve relevant measures of tissue or organ function?

• Clinical effect: Do those biological changes ultimately translate into outcomes that matter to patients?

The ATTR programs are particularly informative because late-stage studies are now testing whether removing cardiac TTR amyloid can produce clinical benefits beyond changes in imaging and biomarkers.

Cliramitug and coramitug show that antibodies can be designed to recognize abnormal forms of TTR and promote their clearance. What remains to be established is whether sustained amyloid depletion can meaningfully alter the course of ATTR-CM. The experience with anti-amyloid antibodies in Alzheimer’s disease provides a useful reminder that recognition, clearance and clinical benefit are related—but they are not interchangeable endpoints.