Antibody-mediated co-delivery of programmable drug combinations

Abstract Drug combinations often fail in clinic due to poor disease site tropism and additive toxicities1,2. Targeted delivery by antibody-drug conjugates (ADCs) reduces toxicity for single chemotherapeutic payloads3. Multi-payload ADCs for combination therapy are limited to two chemotherapeutics at fixed ratio due to a lack of efficient linker-payload chemistry and an incomplete understanding of payload combination synergy and toxicity4. We previously developed T1000-payload chemistry for higher ADC stability5-7. Although combinations of synergistic drug payloads delivered individually by T1000-ADCs manifest ratiometric synergy, they also result in additive toxicities. Here we introduce a programmable drug co-delivery architecture called Synergistic Payload-Antibody Ratiometric Conjugate (SPARC) featuring higher efficacy without proportionally increased toxicity. SPARC is based on multi-T1000-payload (MTP) chemistry designed with enhanced steric shielding for less payload release than T1000-ADCs. MTPs are synthesized by orthogonally linking single T1000-payloads by azide–alkyne click chemistry. Site-specific antibody-MTP conjugations8 produce homogenous, stable SPARCs capable of hosting 2-6 drugs from diverse classes, with a tunable payload ratio from 1 to 10 and payload number as high as 30. Comparing to combinations of single-payload ADCs/free drugs, SPARCs display a more precise pharmacological discrimination in vivo-lower off-target additive toxicity due to reduced payload release but higher efficacy in targeted cells by synergistic/additive interactions among pharmacokinetically synchronized payloads. SPARCs combining Topoisomerase I with DNA Damage Response or cell cycle inhibitors display expanded therapeutic window in drug-resistant prostate and breast cancer models. SPARC provides a conceptual and methodological framework for combination therapy discovery and clinical translation. Payload-agnostic SPARC chemistry may resurrect generation of abandoned drugs by repurposing them as deliverable payloads.