CAR-Ts and the T cell engager, blinatumomab, have demonstrated that redirecting T cells can induce prolonged responses in cancer patients and lead to potential cures. Similarly, cytokine-based therapeutics hold significant anti-tumor promise. However, to date, the therapeutic use of T cell engagers (TCEs) and cytokines has been hindered by significant toxicity and immunogenicity limitations. Amunix has developed a platform to overcome these challenges and deliver the promise of these potent immune stimulators to patients with solid tumor cancers.
Amunix Solution to TCE Toxicity & Immunogenicity: XPATs
XTENylated Protease-Activated T Cell Engagers
Amunix has designed the XPAT™ (XTENylated Protease-Activated T Cell Engager) platform using its longstanding and validated XTEN technology as a mask for TCEs. When combined with our proprietary protease release sites, we can selectively unleash the potent activity of TCEs in the tumor by taking advantage of the high protease activity in the tumor microenvironment. XTEN is an ideal masking device because it can not only extend half-life, but has been demonstrated to have low immunogenicity (>200 patients treated with XTENylated products to-date with no anti-drug antibodies influencing activity).
XPATs Enable Localized Tumor Killing, Limiting Activity in Healthy Tissue Expressing the Target Antigen
XTEN Brings the Precision of Protein Engineering to Improve the Pharmacologic Properties of Drugs
XTEN technology brings the precision of recombinant protein engineering to polymer chemistry. XTEN protein polymers, similar to chemical polymers, have undefined structures (random coil) and use a limited number of specific amino acids, while utilizing recombinant protein expression to achieve defined length and sequence. XTENs are designed for minimal immunogenicity and can be recombinantly fused to therapeutic proteins, such as TCEs, cytokines, and checkpoint inhibitors, to increase their in vivo half-life and mask their activity.
Key Benefits of XPAT Technology
- Improvement of therapeutic index: On-target, off-tumor toxicity of TCEs is often dose-limiting, thus preventing TCEs from achieving therapeutic levels. The mask also has the potential to limit cytokine release syndrome (CRS) and systemic immune activation.
- Expansion of target universe: Tumor exclusive targets are exceptionally rare. Tumor-specific unmasking enables selection of targets with broader expression patterns.
- Validated technology: XTENylated drugs have been dosed in greater than 200 patients with minimal immunogenicity. Human proof of concept of prodrug and protease activation was achieved with Sanofi’s BIVV001, a novel, long-acting Factor VIII.
- Tunability of mask: XTEN length and number, as well as protease release site specificity, can be tuned to optimize therapeutic index and PK.
- Modularity of platform: Universal masks are broadly applicable to different tumor targeting domains (e.g. scFv, VHH, Fab).
- Enhanced efficacy potential: The current XPAT active moiety is a small dual scFv format, which brings T cell and tumor cell into close proximity and enables greater tumor penetration.