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

• Published in: Angewandte Chemie International Edition 2022-01, Vol.61 (1), p.e202109769-n/a
• Main Authors: Faust, Andreas, Bäumer, Nicole, Schlütermann, Alina, Becht, Manuel, Greune, Lilo, Geyer, Christiane, Rüter, Christian, Margeta, Renato, Wittmann, Lisa, Dersch, Petra, Lenz, Georg, Berdel, Wolfgang E., Bäumer, Sebastian
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - chemistry; Adenine - pharmacology; Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacology; Antigens; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bruton's kinase inhibitor; Bruton's tyrosine kinase; Carbocyanines - chemistry; Carbocyanines - pharmacology; CD20 antigen; Cell Proliferation - drug effects; Chronic lymphocytic leukemia; Conjugates; drug delivery; Drug Screening Assays, Antitumor; electrostatic nanocarriers; Enzyme inhibitors; Humans; Internalization; Kinases; Leukemia; Lymphatic leukemia; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - pathology; Macroglobulinemia; Mantle cell lymphoma; Mice; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Piperidines - chemistry; Piperidines - pharmacology; Protamine sulfate; Protein Engineering; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Static Electricity; Targeted cancer therapy; Toxicity; Tumors; Tyrosine; vesicles; Waldenstrom's macroglobulinemia; Xenografts; Xenotransplantation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202109769

Ibrutinib is an inhibitor of Bruton's tyrosine kinase 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. To minimize its toxicities, we linked ibrutinib to a cell‐targeted, internalizing antibody. To this end, we synthesized a poly‐anionic derivate, 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 pharmacological 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 lower doses compared to the original drug. The synthesis, in vitro and in vivo evaluation of a vesicular ibrutinib‐Cy3.5 hosting nanocarrier is reported. In vivo, it shows a significant enrichment of the drug in xenograft lymphoma tumors in immune‐compromised mice and gave a significantly better response at much lower dosage than the original untargeted drug.