Allicin in Wonderland

Weizmann Institute Scientists “Weaponize” an Antibody To Deliver Continuous Attacks On Cancer Cells

In a recent study published in Molecular Cancer Therapeutics, researchers at the Weizmann Institute of Science paired the active ingredient of a garden remedy with advanced bio-technology to deliver a powerful punch against cancer. The cancer killing effectiveness lies in their technique of arming a cancer-targeting antibody with the destructive potential of the dietary molecule otherwise known as “allicin.”

Allicin is the product of an interaction between an enzyme, alliinase, and the small chemical alliin, which occurs naturally in plants such as garlic and onion as a defense mechanism against soil fungi, bacteria and parasites. Allicin molecules can easily penetrate biological membranes and kill cells, but their potency is short-lived hence the difficulty in finding a system to deliver them to a specific site. “The medicinal value of garlic is no longer an ancient Chinese secret,” says the Institute’s Prof. David Mirelman. “Years of scientific research led to the identification and understanding of allicin’s mode of activity and we are currently studying ways to target and deliver its toxic punch.”

The team, including Mirelman, Prof. Meir Wilchek, Drs. Fabian Arditti, Talia Miron and Aharon Rabinkov of the Biological Chemistry Department, and Prof. Yair Reisner of the Immunology Department, together with Prof. Berrebi of Rehovot’s Kaplan Hospital, adopted an approach that fastens the enzyme alliinase onto a specific antibody already in clinical use, Rituximabâ, designed to target and lock on to the surface of certain types of cancer cells such as lymphoma. When administered alone, Rituximabâ serves as a marker and docking point for the body’s own immune system to kill the cancer cell. The Institute team demonstrated that cancer cells could be destroyed more efficiently by arming this antibody: They first chemically bound alliinase to Rituximabâ and then injected this conjugate into mice that had been implanted with human lymphoma cancer cells. As predicted, the Rituximabâ, with the attached alliinase in tow, soon found and bound to the target cancer cells. Subsequently, the mice were repeatedly injected with the inert chemical alliin which, upon contact with alliinase, was processed into allicin molecules directly on the cancer cell’s surface. Within three days, almost all of the human lymphoma cancer cells were destroyed in those mice treated with the conjugate and alliin, while hardly any cancer cell destruction occurred in the control mice who received the conjugate alone.

Although other approaches use a method that directly binds anti-cancer drug molecules to an antibody, this study applied a method Mirelman refers to as “weaponizing” an antibody, so called because it affords the continuous production and delivery of cancer-killing bullets: The alliinase that is bonded to the Rituximabâ sits on the target cell and continuously reacts with alliin molecules that are injected at intervals, producing a steady supply of allicin to penetrate and kill the cancer. The production of allicin can be “turned off” by the ceasing the administration of the ammunition – alliin.

“This study was a proof of principle,” says Mirelman, “demonstrating the effectiveness of this technology for the selective killing of unwanted cells.” Given that the active component is a familiar dietary element, and that specific antibodies such as Rituximabâ are increasingly in clinical use, the scientists hope the way will be paved for the new technology to be developed into useful therapies.

Prof. David Mirelman’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the M.D. Moross Institute for Cancer Research; Ms. Erica A. Drake, Scarsdale, NY; Mr. and Mrs. Henry Meyer, Wakefield, RI; Mr. Nathan Minzly, UK; and the late Claire Reich, Forest Hills, NY. Prof. Mirelman is the incumbent of the Besen-Brender Chair of Microbiology and Parasitology.

Switching to Chemistry

Researchers at the Weizmann Institute of Science have demonstrated a new kind of electrical switch, formed of organic molecules, that could be used in the future in nanoscale electronic components.

Their approach involved rethinking a phenomenon that drives many of today’s high-speed semiconductors. Negative differential resistance (NDR), as the phenomenon is called, works contrary to the normal laws of electricity, in which an increase in voltage translates into a direct increase in current. In NDR, as the voltage steadily increases, the current peaks and then drops off, essentially allowing one to create a switch with no moving parts. But until now, those attempting to recreate NDR at the molecular scale had only managed it at extremely low temperatures.

Prof. David Cahen of the Institute’s Materials and Interfaces Department and graduate student Adi Salomon thought research carried out by Salomon and others in Cahen’s lab during her M.Sc. studies on connections between metal wires and organic (carbon based) molecules might hold part of the key to usable nanoscale NDR. They had found that, like people, molecules and metal wires need chemistry between them for barriers to be lowered and the juice to really flow. For a given voltage, if the molecules are held to the wire by chemical bonds (in which the two are linked by shared electrons), the current flowing through them will be many times higher than if they are only touching a mere physical bond.

Using this insight, the team designed organic molecules that pass electricity through chemical bonds at a lower voltage, but through physical bonds at a higher voltage. As the voltage approaches the higher level, sulfur atoms at one end of the molecule loosen their chemical bonds with the wire, and the current drops off as the switchover occurs.

But the molecules, once the chemical bond to the wire was broken, tended to move apart, preventing them from switching back to the chemically-bonded state. Prof. Abraham Shanzer of the Organic Chemistry Department, who had worked with the team on the original molecular design, now helped them to create long add-on tails to hold the molecules in place with a weak attraction. Now, the NDR in their molecules was stable, reversible and reproducible at room temperature.

Possible applications include nanoscale electronic memory and heat-sensing switches. The future of miniaturized electronics may lie in methods that combine chemistry with nanoscience, say the scientists. “We don’t take human-sized objects and try to scale them down, but create new things from the universe of possibilities open to chemists that are specifically designed to function in the nanoworld.”

Prof. David Cahen’s research is supported by the Minerva Stiftung Gesellschaft fuer die Forschun M. B. H.; the Wolfson Advanced Research Center; the Philip M. Klutznick Fund for Research; Delores and Eugene M. Zemsky; and the Weizmann-Johns Hopkins Research Program. Prof. Cahen is the incumbent of the Rowland Schaefer Professorial Chair in Energy Research.

Two are Better than One

Cancer patients may one day benefit from treatment with mixtures of customized antibodies. In a study published recently in the Proceedings of the National Academy of Sciences (USA), a team of Weizmann Institute scientists have demonstrated how the right combination might form a web that destroys the cancer cell’s communication network, ultimately demobilizing the cell.

Three decades of intensive cancer research led to the identification of a family of receptors, known as HER, that sit antenna-like on the outside of the cell wall and are implicated in certain types of cancer. A team of researchers under Prof. Yosef Yarden, Dean of the Weizmann Institute’s Feinberg Graduate School and a professor in the Institute’s Biological Regulation Department, had previously found that, under certain conditions, the HER2 receptor amplifies the growth signal received by the cell. Yarden and Prof. Michael Sela, former president of the Weizmann Institute of Science, and currently a professor in the Institute’s Immunology Department, teamed up to create a strategy for the customization of antibodies that work independently to engage these cancer-specific receptors and shut down the attendant signaling network. The study was carried out in cooperation with researchers from Targeted Molecular Diagnostics, Westmont, IL, USA.

In experiments conducted in vitro and in lab mice, the researchers exposed the cancer cells to two different antibodies that link up to HER2 receptors. In a synergistic action, the antibodies were shown to cooperate rather than compete for distinctly different attachment points on the architecture of the receptors, resulting in the assembly of a large, springy molecular scaffolding between the receptor towers. The interlocking system grips and pulls the receptors towards each other until they collapse inward like overloaded laundry lines. The stressed receptors become engulfed by the cell, and thus cease signaling. In response, the cell halts growth and, when chemotherapy is used in combination with the immunotherapy, it dies.

According to Sela, the study sheds light on the synergy at work in the antibody-receptor therapy system. The results demonstrate that with the right combination of antibodies, receptor degradation is accelerated: it’s more than three times as effective as a single antibody in inhibiting HER2 signaling.

“Understanding how HER receptor degradation works could enhance weak therapeutic efficacy, as well as provide ways to sensitize patients to overcome inherent or acquired resistance to cancer treatment,” says Yarden.

Prof. Yosef Yarden’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; the Dolfi and Lola Ebner Center for Biomedical Research; the J & R Center for Scientific Research; the Aharon Katzir-Katchalsky Center; the M.D. Moross Institute for Cancer Research; the Willner Family Center for Vascular Biology; the Batsheva De Rothschild Foundation; Dr. Marvin Klein, Farmington Hills, MI; Mr. & Mrs. Bram Laub, Belgium; and the Herbert J. Seligmann Charitable Trust. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.

Prof. Michael Sela’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine, and the Dolfi and Lola Ebner Center for Biomedical Research. Prof. Sela is the incumbent of the W. Garfield Weston Professorial Chair of Immunology.