Carolyn R. Bertozzi, Ph.D., Baker Family Director, Stanford ChEM-H and Anne T. and Robert M. Bass Professor of Chemistry, Stanford University
Bioorthogonal Chemistry Could Yield New Cancer Drugs
Bioortongal chemistry, a chemistry technique that lets reactions take place in cells without impacting normal functions will yield new cancer drugs says Nobel Prize-winning developer Carolyn Bertozzi.
The approach – called bioorthogonal chemistry – is an extension of so-called “click chemistry” in which simple reactions are performed quickly without forming unwanted by-products.
The key difference from click chemistry is that biorthogonal reactions are conducted without catalysts, which means the reaction can take place in cells without damaging their normal functioning.
Cancer Imaging
This attribute gives bioorthogonal chemistry therapeutic potential says Bertozzi, who told delegates at Antibody Engineering and Therapeutics that her Stanford University team first developed it to gain greater insight into the processes going on in diseased cells.
“The reason we even started thinking about this is because of my own longer standing interest in the field of glycoscience, and in particular in how the structures of glycans on the surfaces of cells participate in the biology of the cell.”
The team focused on glycans containing the sugar sialic acid, which are more abundant in cancer cells than in healthy cells, with the initial plan being to use them to detect tumours.
The original idea was to introduce a marked sugar building block – X - into the cell, which would then be displayed on the cell surface. A separate detectable labeling agent – referred to as Y – would be primed to recognize the marked residue that was then added.
“For X and Y to react with each other inside the body of an animal or a human those functional groups must be bioorthogonal, and it was this need that drove us to…try and develop reactions that would meet all the criteria of bioorthogonality.”
Therapeutic antibodies
But as biorthogonal chemistry developed, it became clear that the approach had therapeutic applications Bertozzi said, explaining that the starting point was to establish why cancer cells- overexpress sialic acid-containing glycans.
“We started a project in the lab aimed at trying to understand the origins of this phenotype the significance of this phenotype and asking the question of whether there was a therapeutic intervention that might be based on our learnings.”
Bertozzi and colleagues focused their efforts on the role ligands play in regulating immune response.
“The immune cell has a constellation of receptors and those receptors will engage ligands presented or not by the target cell. Some of the receptors on the immune cell are so called activating receptors…and if there's enough clustering activating receptors that delivers the signal to the immune cell that it's time to fire off a reaction and kill that target cell.
“Now it's a dangerous capability for an immune cell to be able to kill one of your own cells because if it makes a mistake and starts killing healthy cells you'll end up with an autoimmune disease. So to try to mitigate that risk immune cells also have a different category of receptors which are the so-called inhibitory receptors.”
Checkpoint Inhibitors
Inhibitory receptors dampen the immune response, thereby protecting healthy cells. Unfortunately, tumours often overproduce ligands for inhibitory receptors thereby avoiding destruction by the immune systems.
There are a dozen or so approved monoclonal antibody drugs – called checkpoint inhibitors – that bind to receptors or their ligands and block the inhibitory interaction. But checkpoint inhibitors are far from 100% effective with response rates differing between patients and cancer types
“So the big question in the field has been why don't all patients respond to these drugs?.. Is there some other pathway of immune suppression?” Bertozzi said
And part of the answer is related to modulatory receptors found on the surface of virtually all immune cells that bind sialoglycans – the sialic acid binding immunoglobulin like lectin family or the “Sig lec family.”
“Many of the siglec family members have the same inhibitory biochemical signaling mechanism as the T-cell checkpoint receptor PD1… We confirmed that overproduction of sialoglycans engages siglec structures which shuts down the immune response.
“It can even undermine the performance of certain kinds of immune therapies like monoclonal antibodies.”
The research, which was published in 2014, firmly established that the sialic acid sig-lec axis is vital in human cancers and a potential target for a new generation of immune therapies.
New Therapies
So in theory, a MAb that blocks a sig-lec receptor could reduce a cancer cell’s ability to evade the immune response. The tricky part is that there are 14 sig-lec receptors expressed by immune cells and currently researchers do not know which are the most important.
An alternative approach is to remove the sialoglycan ligands on tumour cells using what Bertozzi calls a molecular “lawnmower” – a conjugate molecule combining a MAb and a sialidase enzyme built using bioorthogonal chemistry.
To commercialize the idea Bertozzi cofounded Palleon Pharmaceuticals which is currently preparing an IND filing for its most advanced candidate with the aim of entering clinical trials later this year.
And Palleon is not the only firm working in this area according to Bertozzi, who said “there are many companies now that have made products using biorthogonal chemistry that are in human clinical testing and one company Shasqi here actually has a cancer drug delivery platform in which the bioorthogonal chemistry literally takes place inside human cancer patients’ bodies.
“This is true human clinical performance of an organic chemical reaction. So it's a really exciting time to be at this interface.”
