Abstract 7144: A general method to overcome the binding site barrier in antibody-based therapeutics

Abstract Background: Insufficient intratumoral penetration remains a major limitation of antibody-based therapeutics in solid tumors. The binding site barrier (BSB), driven by high-affinity interactions near perivascular regions, restricts deeper tissue distribution of ADCs and bispecific antibodies and thereby limits their therapeutic index. Current strategies such as co-dosing with parental antibodies or engineering lower-affinity variants are constrained by target specificity and require redesign of each therapeutic. A broadly applicable, novel approaches that transiently modulates BSB without altering antibody structure is needed to improve tumor penetration. Methods: We evaluated DSPE-PEG2000, an FDA-approved amphiphilic phospholipid-polymer conjugate, as a general BSB modulator. Using HER2-, TROP2-, and PD-1/VEGF-targeted therapeutics, we quantified changes in cell-surface engagement, receptor accessibility, and internalization across multiple cancer cell models via flow cytometry, confocal microscopy, and live-cell imaging. In subcutaneous xenograft models, we assessed the intratumoral distribution of Cy3-labeled ADCs and a PD-1/VEGF bispecific antibody using longitudinal IVIS imaging and spatial analysis of tumor sections. Antitumor efficacy was evaluated by tumor growth suppression, treatment durability, and survival. Biosafety assessments included serum chemistry and histopathology of major organs. Results: DSPE-PEG2000 rapidly incorporated into tumor cell membranes and generated a short-range PEG layer that transiently reduced antibody-antigen interactions by 40-60% across diverse targets (e.g., HER2, TROP2, and PD-1/VEGF). This surface modulation did not impair antibody internalization or downstream trafficking. In vivo, DSPE-PEG2000 substantially broadened the intratumoral distribution of ADCs and bispecific antibodies, enabling deeper penetration beyond perivascular regions. The improved spatial delivery translated into greater tumor growth inhibition and prolonged survival, consistent across multiple ADC payloads and antibody architectures. Co-administration did not increase systemic exposure or off-tumor tissue accumulation, and no treatment-related toxicity was observed. Conclusions: DSPE-PEG2000 provides a generalizable, target-independent strategy to overcome the binding site barrier and enhance the distribution and functional efficacy of antibody-based therapeutics in solid tumors. By transiently modulating BSB through membrane-anchored PEG grafting without modifying antibody affinity or structure, DSPE-PEG2000 offers a practical and clinically compatible approach to improve tumor penetration of current and next-generation antibody therapeutics. Citation Format: Yuanzheng Li, Shili Yao, Peng Guo. A general method to overcome the binding site barrier in antibody-based therapeutics 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 7144.