Abstract B027: Programmable Raptamers enable a repeatable translational framework for pediatric cancer therapeutics
TL;DR
A new development pathway for pediatric oncology is established in which successive therapeutics are generated using shared scientific, manufacturing, and translational infrastructure, thereby substantially reducing the incremental effort required to develop successive pediatric therapeutics.
Abstract
Despite being the leading disease-related cause of death in children, pediatric cancers comprise less than 1% of cancers, making drug development commercially unattractive. Multi-omics profiling has identified over 150 molecular targets, but drug development still lags substantially. Cell-surface receptors are especially attractive targets: internalizing receptors can deliver cytotoxic payloads, and surface-resident receptors can anchor immune-engagers. Our programmable Raptamer-drug conjugate (RapDC) platform creates a generalizable translational framework to translate validated pediatric receptor targets into therapeutics. Raptamers are synthetic peptidomimetic DNA ligands selected from combinatorial libraries. They combine antibody-like binding with fully synthetic modular manufacturing. Receptor selection, conjugate engineering, and translational evaluation, including target binding, receptor internalization, pharmacology, tumor payload delivery, efficacy, and tolerability, follow a common, reusable workflow independent of the target. CD127 (IL-7 receptor α), expressed in both hematologic malignancies (acute lymphoblastic leukemia; ALL) and solid tumors (osteosarcoma), together with IL1RAP (Ewing sarcoma; ES) and CD70 (diffuse intrinsic pontine glioma; DIPG), were selected to test if a common therapeutic development workflow could be generalized across pediatric cancer lineages. Our high-affinity CD127 Raptamer binds the target (4 nM Kd) and is efficiently internalized. Our lead RapDC demonstrates potent target-dependent cytotoxicity (IC50 ∼35 pM), maintains cytotoxicity in PgP -mediated drug-resistant cells and demonstrates durable tumor control with a 2-fold improved median survival in resistant CDX models (p=0.01). The RapDC showed 12-fold tumor-selective payload retention at 24 hours, and excellent tolerability at >12-fold the efficacious dose. A dual payload construct (MMAE+Exatecan) demonstrated improved IC50 and Emax over RapDCs with either payload alone. To demonstrate generalizability, the same development workflow is being applied to IL1RAP for ES and CD70 for DIPG, supported by Department of Defense and philanthropic funding, respectively. Tumor-associated cell-surface receptors in pediatric cancers can be systematically targeted using programmable synthetic RapDCs. Integrating rapid synthetic discovery, modular conjugate engineering, receptor-informed pharmacology, and a common translational workflow reduces the time, complexity, and resources required to translate validated pediatric cell-surface targets into precision therapeutics. Because the platform is receptor-centric, the same framework is adaptable to drug conjugates, targeted protein degraders, radiotherapeutics, and immune engagers. This establishes a new development pathway for pediatric oncology in which successive therapeutics are generated using shared scientific, manufacturing, and translational infrastructure, thereby substantially reducing the incremental effort required to develop successive pediatric therapeutics. Uksha Saini, Sougata Dey, Stephanie Vega, Dev Chatterjee, Philip Breitfeld, Atul Varadhachary. Programmable Raptamers enable a repeatable translational framework for pediatric cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr B027.
