Stellabody^® Anti-Shield

A bispecific antibody to overcome treatment resistance in hard-to-treat blood cancers.

Stellabody® Anti-Shield (SAS) is a novel bispecific antibody in preclinical development at Burnet Institute. It is designed to restore potent complement-mediated killing in blood cancer cells that have become refractory to standard antibody therapy.

SAS is powered by the Stellabody® platform, Burnet Institute’s proprietary Fc engineering technology, which makes antibodies markedly more potent at killing disease cells.

The challenge: treatment resistance

Antibody therapies, including anti-CD20 antibodies, are a cornerstone of treatment for B-cell malignancies. Many patients nonetheless relapse or become refractory. Under repeated treatment, tumour cells adapt. They reduce expression of the target antigen and increase expression of complement regulatory proteins, which act as checkpoints that restrain complement-dependent cytotoxicity (CDC).

In relapsed or refractory (R/R) disease such as diffuse large B-cell lymphoma (DLBCL), outcomes remain poor. Resistance also limits newer approaches, including T-cell engagers, where loss of the target antigen is a recognised route of relapse.

SAS combines 3 functions in a single molecule.

• Anchor. One arm binds a stable target that remains expressed on resistant cells, so that the therapy no longer depends on the target that has been lost.

• Block. The second arm blocks a complement checkpoint regulator, removing the brakes on complement activation.

• Hexamerise. The Stellabody® Fc drives on-target hexamer formation, amplifying C1q binding and complement-mediated killing.

Preclinical evidence

In a CD20-resistant lymphoma cell model developed at Burnet Institute, SAS restored near-complete CDC at concentrations well below the Cmax of a standard-of-care anti-CD20 antibody, and increased potency 15-fold at EC50 in treatment-resistant cells.

SAS also amplified C3b deposition, a marker of complement activation, more than either the blocking arm or the Stellabody® Fc alone. Binding studies confirmed that a single SAS molecule engages both targets, and SAS outperformed the same binders delivered as mixtures of separate antibodies.

These findings are from in vitro preclinical studies.

A different approach to resistance

Most recent advances in R/R DLBCL redirect T cells to CD20 or CD19. SAS works differently. It removes the brakes on complement killing, an established and validated mechanism, and is built to remain active when CD20 expression is lost. Because SAS does not redirect T cells, it is designed to avoid the cytokine release and neurotoxicity risks associated with T-cell engagers. This remains to be confirmed in clinical development.

Development focus and intellectual property

The platform is designed so that the anchor arm can be substituted, which provides a route to additional haematological malignancies. The Stellabody® Fc is protected by four patent families, including bispecific antibody formats, and has been independently validated by argenx. Further protection is being developed for the Anti-Shield architecture and lead molecules.

Partner with us

Burnet Institute is seeking industry and investment partners to advance Stellabody® Anti-Shield towards IND-enabling development. To discuss partnering, licensing or collaboration, please contact our Commercial Research Team.

Improving the efficacy of cancer, inflammation and infectious disease treatments. Stellabody® Anti-Shield, described above, is the first novel therapeutic candidate that Burnet has built on the Stellabody® platform.

Therapeutic antibody technologies have revolutionised treatments across a spectrum of diseases including cancer, infectious diseases and autoimmunity. However, these treatments have hit a natural potency ceiling as unmodified antibodies, as they occur in nature, do not aggressively engage the immune system. This means unmodified ‘natural’ mAbs are limited in their effectiveness as treatments for eliminating disease cells or for communicating with cells.  

Stellabody^® hexamer technology breaks through these limitations. It’s a transformative discovery that makes use of the multifunctional application of antibodies to disease but dramatically improves the potency of these antibodies and antibody-like biologics. This leads to the creation of function-enhanced therapeutics for the treatment of cancer, inflammation and infection. 

The technology is a change to the Fc tail of antibodies which exploits their natural behaviour, resulting in the formation of hexameric clusters of the antibodies after they bind to their target.

These Stellabody^® hexamers are the ideal launching pad for potently firing immune effector systems or to amplify communication signals to cells. Stellabody^® enables antibodies to kill disease targets by the complement system and can communicate cancer cells to initiate a cell death process called apoptosis. 

The need

The development of antibody and biological therapies has two key challenges: 

1. Monoclonal antibodies and their antibody-like cousins, such as Fc fusion proteins, are potential biological medicines that will readily target cancers, inflammatory cells or microbes but often have insufficient potency and lack efficacy.  

2. Existing antibody therapeutics come with limitations and don’t work for all patients. 

Molecular engineering is needed to: 

• develop new and powerful next-generation therapeutic antibodies.  

• overcome limitations of existing antibody therapeutics to broaden their use to new treatments 

• reach hard-to-treat patient populations. 

This is where Stellabody® technology comes in. 

The technology

Stellabody^® hexamer technology was discovered in the Immune Therapies group at Burnet Institute, a globally recognised laboratory in this field. 

Professor Hogarth has researched antibodies, their effector functions and roles in immunity and inflammation for over 30 years.

How it works

Stellabody^® hexamer technology works by exploiting the normal biology of antibodies and drives them into formation clusters of six antibodies (hexameric clusters) once they have bound to their target e.g. cancer cell. 

Just as flags help in co-ordinated attacks on battlefields, Stellabody® 'on-target' hexamers communicate a powerful danger pattern to the immune system to initiate effector responses to kill targets.   

Molecular patterns are important beyond the function of the immune system. Communication by patterns is a fundamental property of cells and this often occurs through cell surface receptors. In an alternative application, the Stellabody^® hexamer pattern can communicate the amplification of the signals of mAbs binding cell surface receptors.  

Either way, by communicating with immune effector functions or through cell surface receptors, Stellabody^® hexamers confer potent actions on antibody or antibody-like biologicals.

Use cases

Stellabody® is a powerful and versatile technology adaptable to multiple antibody formats against a broad range of targets, with applications in a wide range of disease settings across cancer, inflammation and infectious disease.