TRAIL-2 (DR5) is a cancer target of great interest due to its role in inducing programmed cell death, but it has historically been difficult to target effectively. TRAIL-2 agonists have demonstrated impressive preclinical efficacy but little to no clinical benefit in human studies when monoclonal antibodies were used as single agents or in combination with various chemotherapies. Preclinical efficacy was predicated on extensive cross-linking of TRAIL receptor-targeted monoclonal antibodies, but it is likely that in humans, the antibodies did not achieve the requisite cross-linking. A multi-valent antibody approach has the potential to more effectively agonize the receptor while concomitantly engaging and blocking growth factor or survival receptors on the same cancer cell.
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Zyngenia Inc. is developing a series of Zybodies using several core scaffold mAbs that recognize different tumor antigens, including Her1 or Her2. In addition, these Zybodies contain multiple identical TRAIL-2-targeting modular recognition domains (tunable valency up to hexavalent).
This approach provides more effective TRAIL-2 cross-linking (via agonistic modular recognition domains) alongside simultaneous targeting to tumor cells and the inhibition of tumor growth (via antagonistic mAbs and/or modular recognition domains). Zyngenia Inc.’s preclinical studies have demonstrated that these Zybodies are potent and able to induce cell death and that this activity is dependent on both the multi-valency and multi-specificity of the molecules. Additional preclinical studies are underway to further explore the potential of this approach.