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.
Janux product candidates have the potential to generate a tumor-specific immune response that attacks and kills a tumor without destroying a patient’s healthy tissue. Janux’s TRACTr technology platform is designed to enable active drug accumulation in tumors, yet prevent drug accumulation in healthy tissues. We believe the tumor specificity our technology has the potential to deliver strong anti-cancer immunity within the tumor microenvironment but maintain suppression of non-specific systemic immune activation.
In addition to tumor-specific activation, Janux product candidates are designed to also incorporate crossover pharmacokinetics (PK) to minimize activated drug levels in healthy tissue while maintaining high levels of activated drug in a tumor. Upon activation in a tumor, Janux product candidates are designed to be converted from a TRACTr that remains in circulation for a long time (>100 hours) to a TCE that is in circulation for a very short time (<1 hour). Tumor-localized conversion of TRACTr to TCE enables tumor-specific target engagement and anti-tumor immune response. However, any activated TCE that escapes from the tumor microenvironment is rapidly eliminated and thus unable to accumulate in healthy tissue to drive toxicity. This key design feature ensures that there are high levels of TRACTr and activated TCE in the tumor and minimal activated TCE in healthy tissues.
By combining crossover PK with tumor specific activation, Janux product candidates are designed to achieve high safety multiples. In preclinical studies, Janux TRACTrs have demonstrated comparable anti-tumor activity relative to a standard TCE while preventing cytokine release, healthy tissue toxicities, and systemic immune activation. TRACTrs also demonstrated cynomolgus monkey PK consistent with once-weekly dosing in humans.