An antibody-drug conjugate (ADC) consists of a monoclonal antibody bound to a drug via a linker, enabling the targeted delivery of therapeutics to enhance therapeutic efficacy and reduce systemic toxicity. Currently, all clinically approved ADCs use full-length IgG monoclonal antibodies, which are predominantly IgG1.[1] However, to develop next-generation therapeutics, investigators are increasingly harnessing the benefits of heavy-chain-only antibodies (HCAbs). When derived from Harbour Mice®, fully human HCAbs offer a smaller format (i.e., ~80 kDa) for improved tissue penetration, higher stability, and lower immunogenicity.
Conventionally, ADCs are linked to small-molecule drugs. However, emerging modalities leverage the specificity of monoclonal antibodies to expand the therapeutic index of radiotherapeutics, peptides, oligonucleotides, and other biologics.
Bioconjugation of oligonucleotides to antibodies (i.e., Antibody-oligonucleotide conjugate, AOC) is a powerful approach that expands the therapeutic potential of small interfering RNA (siRNA) or antisense oligonucleotides (ASOs) by improving their stability, targeting, and uptake.[2]
As with ADCs, developing AOCs requires the careful selection and implementation of bioconjugation strategies to achieve the desired drug-to-antibody ratio (DAR).[3] Sub-optimal bioconjugation methods can lead to heterogeneous AOC products, which may affect the efficacy, pharmacokinetics, and safety of the final product.[4]
Nona Biosciences has developed an efficient method for the Site-specific Conjugation of Oligonucleotides to HCAbs. Oligonucleotides can be directly conjugated to HCAbs at one (i.e., HCAbs with a C to S mutation) or two cysteine residues by leveraging either cleavable or non-cleavable linkers, resulting in highly homogeneous DAR1 or DAR2 AOCs able to achieve high-knockdown efficiency.
