Tumor‐Cell‐Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody‐Inhibitor Conjugates (AiCs)

Tyrosine kinase inhibitors have significantly improved treatment of patients with different malignancies, but their utilization can be compromised by unintended toxicities. Ibrutinib is a first-in-class covalent inhibitor of the Bruton´s tyrosine kinase inhibitor that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities, caused by high dosage. To minimize toxicities of ibrutinib we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate of ibrutinib, ibrutinib-Cy3.5 that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its physiological effectivity. In vivo , we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to significantly lower doses compared to the original untargeted drug . This combination of a cell-determining antibody, electrostatically connected to a molecular targeted inhibitor defines a first-in-class antibody-inhibitor conjugate.