Abstract Systemic toxicities and dose-exposure limitations caused by target expression on normal tissues remain major barriers to effective cancer therapy. Tumor-activated masked biologics are a promising strategy to improve safety and efficacy, as highlighted by evolving clinical data with masked T-cell engagers (TCEs) and masked antibody-drug conjugates (ADCs). However, an optimized platform that balances protease specificity, systemic stability, and tumor release kinetics across diverse tumor types is lacking.VORO’s PrimeBody biologics platform employs novel activation linkers that are rapidly cleaved in the tumor microenvironment but are stable in normal tissues, demonstrating substantially improved tumor-selectivity compared to clinical benchmarks. These linkers are coupled with novel, finely tuned affinity-based masking domains to precisely control target affinity and tumor-specific release kinetics. PrimeBody masking is ideal for novel, more potent CD47-targeted biologics to overcome safety limitations caused by ubiquitous CD47 expression in healthy tissues and simultaneously enable enhanced anti-tumor efficacy.VOR-101 is a masked, Fc-enhanced, high-affinity CD47 blocker that remains a latent prodrug until it is activated by proteolytic cleavage in the tumor microenvironment. In vitro, unmasked VOR-101 drives potent phagocytosis (EC ∼20 pM) by primary human macrophages against epithelial cancer cell lines (DLD-1, HCT116, HT29, MCF-7, CAL27), while masked VOR-101 is inert (2,000-fold higher EC). Ex vivo, VOR-101 is rapidly activated by human tumor surgical samples across all tested tumor types yet remains stable and intact in serum from healthy volunteers, cancer patients, and non-human primates for 14 days. In contrast, identical constructs engineered with clinical benchmark linkers exhibited significantly slower tumor activation and rapid serum degradation. Consequently, VOR-101 achieves 700-fold tumor-to-serum selectivity, a major improvement over the 25-fold selectivity observed with benchmark linkers currently in clinical development.In a translational hCD47/hSIRPα mouse model, magrolimab induced 50-60% depletion of red blood cells (RBCs) and exhibited poor systemic exposure (∼10 nM). By contrast, VOR-101 at equimolar dosing achieved ∼1 µM blood concentrations (∼100-fold higher systemic concentration) while maintaining normal RBC counts. In xenograft models, VOR-101 induced durable complete responses that persisted well beyond the dosing period.Together, these findings demonstrate that VOR-101 (a tumor-activated, Fc-enhanced, high-affinity CD47 blocker) significantly improves the therapeutic index in preclinical models compared to clinical comparators. VOR-101 is advancing through IND-enabling studies with potential to exhibit single-agent activity in solid tumors. Citation Format: Aaron Springer, Sophia Lai, Christopher Thanos, Jeffrey Humphrey, Ugur Eskiocak, . Tumor-activated PrimeBody biologics platform enables more potent CD47 targeting and superior therapeutic index in preclinical models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4054.
Springer et al. (Fri,) studied this question.