Antibody-drug conjugates (ADCs) have transformed cancer treatment by delivering chemotherapy directly to tumors. Drugs like trastuzumab deruxtecan (T-Dxd) have improved survival for patients with HER2-positive breast cancer. Yet, limitations remain. ADCs are large molecules, which restrict tumor penetration, reduce blood-brain barrier (BBB) permeability, and prolong exposure to healthy tissues. These challenges create a need for next-generation therapies.

Nanobody-drug conjugates (NDCs) offer a promising alternative. Nanobodies, derived from camelid antibodies, are small, stable, and highly specific. Their compact size enables deeper tumor penetration and improved transport across barriers like the BBB. In recent studies, novel anti-HER2 nanobodies showed strong target affinity and robust tumor inhibition.

One candidate, VHH3-Fc, demonstrated 4–5 times higher distribution in both subcutaneous and intracranial tumors compared with trastuzumab. It also achieved superior permeability in in vitro BBB models. When conjugated with cytotoxic payloads such as MMAE or Dxd, nanobody fusions generated highly potent NDCs. These NDCs not only matched but outperformed T-Dxd in preclinical models, even at lower drug-to-antibody ratios.

Importantly, the pharmacokinetics of NDCs differ from ADCs. In mouse studies, VHH3-Fc-Dxd cleared faster from the bloodstream, reducing systemic exposure while maintaining higher tumor distribution. This balance may widen the therapeutic window, allowing more effective treatment with fewer side effects.

Molecular analysis provided further insights. Treated tumor tissues revealed activation of the cGAS-STING-IFN pathway, a critical immune response mechanism. Compared with T-Dxd, VHH3-Fc-Dxd produced stronger modulation of gene expression and protein activity, suggesting a dual effect: direct tumor killing and enhanced immune engagement.

Together, these results highlight the potential of nanobody-drug conjugates as the next wave of targeted therapies. By combining improved tumor penetration, BBB permeability, and differentiated pharmacokinetics, NDCs could address the shortcomings of current ADCs and expand treatment options for difficult-to-treat cancers.

As oncology continues to move toward precision medicine, innovations like NDCs illustrate how antibody engineering can reshape therapeutic strategies. The path ahead includes further clinical evaluation, but early findings mark a significant step forward for HER2-targeted therapy and beyond.

Source: Nature