In vivo therapeutic effects of small molecule-drug conjugates enhanced by Fc grafting

Small molecule-drug conjugate (SMDC) shows great potential as a new class of targeted chemotherapeutic agents to tackle cancer. However, its in vivo therapeutic effect is compromised by its poor pharmacokinetic parameters. Herein we describe an approach that enables the precise conjugation of SMDC on N-terminus of the Fc protein to produce a SMDC-Fc bioconjugate (Fc1070) with superior specificity, affinity and potency to tumor cells. In vivo, Fc1070 exhibited an antibody-like pharmacokinetic profile with a long circulation half-life (t1/2 = 79 h) and pro-liver clearance pathway, that is distinct from the parent SMDC (t1/2 = 0.5 h and renal clearance). Intravenous injection of Fc1070 can eliminate the tumor with a single dosing of 7 mg/kg. Coupled with a predefined ligand toolbox, this approach allows the fast generation of other SMDC bioconjugates on demand, thus extending the format easily to other tumor targets. This may provide a general approach for the development of SMDC with enhanced therapeutic properties.