Improved biodistribution and antitumor effects of a Nectin4 and Trop2 bispecific fatty acid-modified nanobody conjugate.

Antibody-drug conjugates (ADCs) have revolutionized cancer treatment by merging the targeting precision of antibodies with the cell-killing power of cytotoxic drugs. Yet traditional IgG-based ADCs suffer from toxicity issues, poor biodistribution, and high manufacturing cost. To overcome these hurdles, we created an innovative Fc-free bispecific nanobody drug conjugate (dtNDC) directed against Nectin4 and Trop2, two antigens highly expressed across many malignant cancers. The dtNDC, equipped with a C18 fatty acid modification, displayed excellent pharmacokinetics with a 20-h plasma half-life and negligible kidney accumulation while achieving rapid tumor uptake (peaking just 2 h post intravenous injection), striking an optimal balance between systemic persistence and tissue penetration. In nonclinical evaluations, Eribulin-loaded dtNDC demonstrated potent antitumor efficacy across three xenograft models. Notably, in MDA-MB-468 cell-based tumor bearing mice, two subcutaneous injection induced tumor free status in all mice; and it could also result in in complete remission following two intravenous administrations in HCC1954 cell xenograft tumors. Histopathological analysis confirmed absence of treatment-related toxicity in vital mouse organs (liver, lung, kidney, heart) at therapeutic doses. These findings position dtNDC as a promising therapeutic combining durable tumor regression with exceptional tolerability. Moreover, its simplified structure and cost-effective manufacturing process make this dtNDC a compelling next-generation therapeutic for cancers.