The Challenge: Conventional TCEs
Three properties of existing TCEs have limited their potential to treat solid tumors
Cytokine release syndrome (CRS)
Cytokine release syndrome (CRS). CRS arises from the systemic activation of T cells and can result in life-threatening elevations in inflammatory cytokines such as interleukin-6 (IL-6). Severe and acute CRS leading to dose-limiting toxicities and deaths has been observed upon the dosing of TCEs developed using other platforms to treat cancer patients in prior clinical studies. This toxicity severely restricts the maximum blood levels of TCEs that can be safely dosed.
On-target, healthy tissue toxicity
On-target, healthy tissue toxicity, arising from expression of the tumor target in healthy tissue and scarcity of highly tumor-selective antigens is another limitation hindering the development of TCEs to treat solid tumor cancers. TCEs developed using other platforms not designed for tumor-specific activation have resulted in clinical holds and dose-limiting toxicities resulting from target expression in healthy tissues.
Short half-lives
TCEs quickly reach sub-therapeutic levels after being administered as they are quickly eliminated from the body due to their short exposure half-lives. For this reason, TCEs such as blinatumomab are typically administered by a low-dose, continuous infusion pump over a period of weeks to overcome the challenge of a short half-life and to maintain therapeutic levels of the drug in the body. This continuous infusion dosing regimen represents a significant burden for patients.
Despite the enormous potential of TCEs, systemic immune activation remains a major challenge for this important class of drugs.
First generation TCEs elicit a systemic immune response that not only attacks tumors, but also attacks healthy tissues and can result in life-threatening toxicities.
Second generation TCEs reduce the initial systemic immune response but activated TCE accumulation over time leads to immune activation in healthy tissues and safety limitations. The fundamental deficiencies of 1st and 2nd generation TCEs not only limit development, but also reduce the amount of drug that can be safely administered.
Our TRACTrs and TRACIrs are designed to be activated by tumor-specific proteases but, upon activation, be converted to a form that has a short half-life to eliminate them from the body rapidly should they re-enter the circulatory system.
Our Solution – Janux’s Proprietary TRACTr (tumor activated T cell engager) Platform
Our platforms are designed to offer accuracy, stability, activity, modularity and manufacturability.
Each of our proprietary TRACTrs and TRACIrs is comprised of an antigen-binding domain, a T cell binding domain, domain-optimized peptide masks, an albumin binding domain, and cleavable peptide linkers.
We use proprietary peptide linker sequences composed of tumor protease recognition sites to attach these masks to the antigen binding domains in a way that is designed to make the masks highly sensitive to removal by tumor proteases but highly stable in the absence of these proteases.
The mask is a peptide designed to bind to the tumor or T cell binding domain and inhibit the binding domain’s interaction with its target thereby inhibiting the activation of T cells.
In addition, we attach an albumin binding domain to one mask, which is designed to extend the half-life of our TRACTr product candidates until they become activated inside a tumor.
Our platforms are designed to offer the following features:
Accuracy
By engineering our TRACTrs with novel peptide masks that are designed to be selectively activated in the tumor microenvironment, and designed for any activated TCEs to be rapidly cleared from healthy tissue upon escaping from the tumor, our product candidates have the potential to overcome the toxicity challenges of TCEs and systemic immunotherapies in general.
Stability
We designed our TRACTrs with an albumin binding domain to be stable in the bloodstream and to have a long serum half-life before activation. Our TRACTrs have demonstrated long half-lives in NHPs, which we believe translates to the potential for once-weekly dosing in humans. This is in contrast to first-generation TCEs that are rapidly cleared and require high frequency or continuous dosing.
Activity
Our TRACTrs are designed to be active at low levels of tumor target expression where other treatment modalities lose efficacy. In preclinical studies, our TRACTrs did not require high levels of tumor target expression to activate T cells to kill cancer cells.
Modularity
Our TRACTr platform technology’s modular characteristics enable us to leverage the learnings from the development of our product candidates to progress the discovery process of new TRACTr candidates against a wide variety of targets. For our first three programs, once an antibody was identified, we were able to develop a masked tumor binding domain in less than six months to begin evaluating TRACTr development candidate.
Manufacturability
The production, development, and manufacturing processes of our TRACTr molecules closely resemble those used for monoclonal antibodies with the potential for a relatively lower cost of goods.
