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

The article introduces a novel approach to creating multi-specific therapeutics, known as catamers. These are produced using modified nucleic acids as a scaffold, with multiple warheads attached via Watson-Crick interactions. Warheads may include ligand-binding modules, protease-cleavage sites, and toxins, each covalently bound to an oligonucleotide connected to the catamer scaffold.

The assembly of these catamer components post-synthesis is dictated by Watson-Crick base pairs on the oligonucleotides, determining the arrangement of warheads on the complete catamer.

Unlike aptamers, catamers can incorporate aptamers, small molecules, and peptides. The primary objective of catamers is to tackle three major challenges that have hindered the development of multi-specific therapeutics: (i) optimizing rate, (ii) reducing manufacturing cost, and (iii) mitigating unpredictable immunogenicity (Amash et al., 2024 PMID: 39189686).

The synthetic nature of catamers, which does not rely on cultured cells for production, is a significant advantage due to these design features. However, the efficacy of this approach requires further experimental validation.

A proof-of-concept example of a catamer is a prostate-specific membrane antigen (PSMA)-targeted toxin conjugate. Molecular simulations suggest that this catamer exhibits structural properties that support its intended pharmacology. Importantly, the catamer's design directly addresses a key limitation of antibody drug-conjugates (ADCs): off-target toxicity resulting from toxin release following pinocytosis by healthy cells in contact with the bloodstream.