Catamers: Multi-specific therapeutics that concatenate individual warheads on a DNA scaffold via Watson-Crick interactions

We describe the concept for a new modality to create multi-specific therapeutics that utilizes modified nucleic acids as a scaffold to concatenate multiple warheads (hence called 'catamers'). Catamers are assembled via Watson-Crick interactions into multi-specific molecules from individual components such as ligand-binding modules, protease-cleavage sites, and toxins. Each warhead is covalently bound to an oligonucleotide, which in turn is connected to the catamer scaffold. Post-synthesis of the individual catamer components, they are annealed together such that Watson-Crick base pairs on the oligonucleotides dictate the organization of the warheads on the complete catamer. Notably, catamers are not aptamers, though they can contain aptamers as warheads, along with small molecules and peptides. By design, catamers are intended to address three key problems that have hamstrung the field of multi-specifics: (i) optimization rate; (ii) manufacturing cost; and (iii) unpredictable immunogenicity (Amash et al., 2024 PMID: 39189686). Catamers are purely synthetic and do not require cultured cells to produce. These advantages are based on the underlying design of the catamer and will require experimental validation in future studies. As a proof-of-concept catamer, we focus on a prostate-specific membrane antigen (PSMA)-targeted toxin conjugate. In molecular simulations, this catamer displays structural characteristics to support its intended pharmacology. Importantly, the design addresses one of the key shortcomings of antibody drug-conjugates (ADCs): off-target toxicity caused by release of the toxin after pinocytosis by healthy cells in contact with the blood.