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 drugs generate a tumor-specific immune response that attacks and kills a tumor without destroying a patient’s healthy tissue. Furthermore, Janux technology enables active drug accumulation in tumors, yet prevents drug accumulation in healthy tissues. This Janux tumor specificity design allows strong anti-cancer immunity within the tumor microenvironment but maintains suppression of non-specific systemic immune activation.
In addition to tumor-specific activation, Janux drugs 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 drugs are 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 drugs achieve high safety multiples. In preclinical studies, Janux TRACTrs have demonstrated comparable anti-tumor efficacy relative to a standard TCE while preventing cytokine release, healthy tissue toxicities, and systemic immune activation. TRACTrs also demonstrate cynomolgus monkey PK consistent with once-weekly dosing in humans.