A research group led by Lecturer Man Hagiyama, Lecturer Azusa Yoneshige, and Professor Akihiko Ito from the Department of Pathology, Faculty of Medicine at Kindai University, discovered efficient intracellular uptake of their original CADM1 antibodies after binding to target cancer cells and clarified the uptake mechanism. Administration of the antibody conjugated with an anticancer agent via injection almost completely suppressed cancer growth in a cancer-bearing mouse model. The development of anticancer drugs using the antibodies developed in this study and "drug delivery vectors" for efficient delivery of anticancer drugs to cancer cells is expected to follow. The results were published in the Journal of Controlled Release, an international academic journal, on June 12.
Antibody-drug conjugates are a pharmaceutical product that can efficiently deliver a drug to cancer cells, which are then attacked by the drug. It is composed of three elements: an "antibody" that serves as a carrier to efficiently deliver the drug to cancer cells (drug delivery vector), a "drug" that attacks cancer cells, and a "linker" that connects the drug with the antibody. The research group has been studying CADM1, a membrane protein that acts as an adhesion molecule by penetrating the cell membrane and linking cells. In recent years, the research group has been working on the therapeutic application of their original CAM1 antibodies for neurological diseases.
In this study, the research group succeeded in producing multiple anti-CADM1 antibodies that recognize CADM1, a membrane protein existing on the cell surface. Their mechanisms of action were analyzed. CADM1 structurally belongs to the immunoglobulin superfamily, and these antibodies bind to the surface of CADM1-expressing cells. The produced antibodies A and B were analyzed. The results showed that antibody A was efficiently taken up after its binding to CADM1-expressing cells and that antibody B significantly promoted the uptake of antibody A by cancer cells.
Next, antibody A was labeled with a fluorescent dye and added to the cells to examine its localization. Antibody A accumulated on the surface of the cells within 1 hour after addition. Then, they gradually migrated intracellularly (internalized) over a 10-hour period, but only a portion of the antibody A molecules was internalized. When antibodies A and B were added concurrently, antibody A accumulated on the cell surface within 1 hour and almost all of antibody A molecules migrated intracellularly within 5 hours.
They also found that CADM1 localization on the plasma membrane was caused by migration of the CADM1-antibody B complex to a special compartment called the lipid raft (a spot on the plasma membrane where many transmembrane proteins and other proteins are gathered and transmembrane signaling occurs). The internalized antibody A molecules were found to reach lysosomes, which are intracellular organelles. The research group showed that the intracellular release of MMAE (tubulin polymerization inhibitor: anticancer drug) was likely to occur in lysosomes.
Ito said, "Antibody-drug conjugates are ideal anticancer drugs that can eradicate only cancer cells if their pharmacological efficacy is 100%. The present study proposes a new principle to realize this ideal situation. Although we have only revealed part of the principle, we hope that this study will lead to the development of drugs that promote the internalization of various antibody-drug conjugates. I believe that it brings out more superior properties in antibody-drug conjugates, leading directly to improved therapeutic outcomes."
Journal Information
Publication: Journal of Controlled Release
Title: Efficient intracellular drug delivery by co-administration of two antibodies against cell adhesion molecule 1
DOI: 10.1016/j.jconrel.2024.05.035
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