Arteriosclerosis

Inhibition of arteriosclerosis by blocking lipid uptake to foam cells

During atherosclerosis, inflammatory cells (e.g., monocytes) invade the vessel wall and differentiate into foam cells which accumulate lipids and cholesterol. Existing therapies for the treatment of atherosclerosis intend to inhibit the uptake or the synthesis of cholesterol (e.g. by statins) which is, however, accompanied by negative secondary side effects.

CD68-Fc is a recombinant protein which specifically interferes with the generation of foam cells. This agent was originally conceived at the group of Meinrad Gawaz at the Medical Clinic III of the University of Tübingen. The drug inhibits the cellular uptake of cholesterol by binding to oxidized LDL (“oxLDL”), and thereby prevents oxLDL uptake to foam cells in atherosclerotic plaques, and reduced local inflammation of the vascular wall, with the potential to reverse plaque progression. CD68-Fc almost completely inhibited the progression of atherosclerosis in mouse models, and significantly reduced the risk of plaque rupture. CD68-Fc will be developed to treat high risk atherosclerotic patients.

References

  • Daub K, Siegel-Axel D, Schönberger T, Leder C, Seizer P, Müller K, Schaller M, Penz S, Menzel D, Büchele B, Bültmann A, Münch G, Lindemann S, Simmet T, Gawaz M. Inhibition of foam cell formation using a soluble CD68-Fc fusion protein. J Mol Med. 2010, 88:909-920
  • Zeibig S, Li Z, Wagner S, Holthoff HP, Ungerer M, Bültmann A, Uhland K, Vogelmann J, Simmet T, Gawaz M, Münch G. Effect of the oxLDL binding protein Fc-CD68 on plaque extension and vulnerability in atherosclerosis. Circulation Research 2011; 108:695-703
  • Zeibig S, Büttcher M, Goebel S, Pauli J, Hunger A, Ungerer M, Gawaz M, Münch G. The scavenger receptor CD68 regulates oxidized low-density lipoprotein (oxLDL) deposition in atherosclerotic vessels at an early stage of atherosclerosis in ldlr-/-apobec-/- mice. Cell Physiol Biochem 2019, 46; in press

Homing of endothelial precursor cells to vascular lesions and plaques

Endothelial progenitor cells have been described as important players in recent years, which protect against cardiovascular disease. Accordingly, people who possess increased amounts of these cells are less prone to complications of  these diseases.

The anti-CD133-antibody fusion protein is a recombinant protein, which specifically binds to atherosclerotic plaques, and then bi-specifically binds to circulating progenitor cells. This agent was originally conceived at the group of Meinrad Gawaz at the Medical Clinic III of the University of Tübingen. The approach allows to optimally trap the endogenously occurring progenitor cells for accelerated plaque healing, without having to inject external cells to the respective patient (which would incur a relevant oncogenic risk).

Efficacy of the anti-CD133-antibody fusion protein has been shown in several models of vascular injury.

References