Peptide-based Robust and Innovative Molecular Condensate Engineering for Antibody-Drug Conjugates

forthcoming

Antibody drug conjugates are among the most promising targeted cancer therapies, combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs. Yet, more than 80% of ADC candidates fail to progress beyond early clinical stages. A key reason lies in current conjugation chemistries: lysine- and cysteine-based methods yield heterogeneous products with unstable linkages, poor pharmacokinetics, and high manufacturing inefficiencies, wasting up to 50% of material. Copper-catalyzed click chemistry (CuAAC) offers the promise of precise, site-specific conjugation, but copper toxicity has prevented its industrial use, while copper-free alternatives require costly antibody engineering and compromise reaction kinetics. PRIME-ADC introduces a breakthrough solution: peptide-based biomolecular condensates engineered as programmable microreactors for CuAAC conjugation. These condensates selectively recruit antibodies and hydrophobic drugs into their dense phase, enabling efficient, stoichiometric coupling with controlled drug-to-antibody ratios. At the same time, copper ions remain in the dilute phase and are removed via simple centrifugation, eliminating toxicity risks and simplifying downstream purification. This one-pot, aqueous, and recyclable system yields homogeneous, stable ADCs with predictable pharmacokinetics, while reducing solvent use, energy demand, and purification costs. The proof of concept will validate PRIME-ADC with cetuximab and clinically relevant payloads, benchmark performance against standard chemistries, and demonstrate regulatory-compliant copper clearance. In parallel, business feasibility will be established through market validation, competitive benchmarking, and the design of a spin-out company. If successful, PRIME-ADC will unlock the clinical and commercial potential of next-generation ADCs, reduce environmental burden, and lay the foundation for a high-growth European biotech venture.