5:01 PM
Aug 02, 2018
 |  BC Innovations  |  Targets & Mechanisms

Oxitope’s oxidation play

A UCSD group links oxidized lipids to atherosclerosis and spins out Oxitope Inc.

A trio of papers from a UCSD group has found a connection between oxidized lipids and inflammation in atherosclerosis, osteoporosis and ischemia injury, breathing new life into the once popular “oxidation hypothesis” of atherosclerosis.

The authors are spinning out Oxitope Inc. to develop a mAb that selectively targets oxidized forms of lipids.

The oxidation hypothesis, first put forward in 1983 by Michael Brown and Joseph Goldstein, argues that reactive oxygen species (ROS) are the primary drivers of heart disease.

It was based on observations that both activated immune cells and oxidized phospholipids on LDL are the earliest, most reliable markers of atherosclerotic plaques in humans. In addition, preclinical studies had shown that oxidized, but not non-oxidized, forms of lipoproteins are capable of inducing immune cell activation.

However, a string of failed or underwhelming trials in the 1990s and 2000s testing dietary antioxidants such as vitamin E and β-carotene caused the hypothesis to fall out of favor.

According to Joseph Witztum, who led the new atherosclerosis work, those studies were started prematurely, without solid preclinical evidence of efficacy. For example, he said vitamin E “was never shown to effectively prevent atherosclerosis” in animal models, and molecular modeling experiments suggest the supplement may work in the wrong direction by promoting free radical formation.

He argues the oxidation hypothesis has never been properly tested in the clinic or in animal models. The statins and anti-PCSK9 mAbs marketed for atherosclerosis do not constitute direct tests of the hypothesis, he said, as they work by decreasing levels of non-oxidized, rather than oxidized, LDL in blood.

Witztum, who is a professor of medicine at the University of California San Diego and an Oxitope co-founder, thought a naturally occurring mouse antibody, E06, discovered two decades ago in his lab, could serve as a tool to test the theory. E06 selectively binds oxidized lipids and blocks inflammation in vitro.

In the new papers, Witztum’s lab and its collaborators showed a single-chain version of antibody (E06-scFv) provided benefit in mouse models of three diseases, and demonstrated that oxidized lipid-induced activation of macrophages most likely drives inflammation in all three (see “Figure: Calming Macrophages”).

Figure: Calming Macrophages

A trio of papers from University of California San Diego scientists has demonstrated that an antibody against oxidized lipids can stop macrophage-mediated inflammation and treat three different diseases: atherosclerosis, osteoporosis and ischemia-reperfusion injury.

Inset: The antibody is a single chain fragment of a parent mAb that naturally occurs in mice and selectively binds to oxidized epitopes on lipids, sparing non-oxidized lipids. The fragment comprises the heavy and light chains of one binding arm of the parent mAb, which are connected via a synthetic linker.

Left: In LDLR knockout mice fed a high-fat diet to induce atherosclerosis and osteoporosis, levels of oxidized lipids such as oxidized LDL rise, leading to uptake by macrophages, which recognize them as damage-associated molecular signals (DAMPs). The oxidized lipids cause the macrophages to take on a pro-inflammatory M1 phenotype and release inflammatory cytokines such as TNFα and IL-1β.

Right: When the single chain fragment, dubbed E06-scFv, was expressed in the model, it bound to the oxidized lipids and prevented their uptake by macrophages. The result was a shift to a pro-repair M2 phenotype and a decrease in atherosclerotic plaque size and number.

E06-scFv also reduced bone loss in the mice and decreased infarct size in a model of ischemia-reperfusion injury.

IL-1β - Interleukin 1 β; LDLR - Low-density lipoprotein receptor; TNFα - Tumor necrosis factor α


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