New cancer immunotherapy: The first clinical data of chemically modified antibodies
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New cancer immunotherapy: The first clinical data of chemically modified antibodies
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New cancer immunotherapy: The Nobel Prize team released the first clinical data of chemically modified antibodies.
On April 18, 2023, Palleon Pharmaceuticals announced the results of its Phase 1 clinical trial of E-602, an investigational therapy, at the 2023 Annual Meeting of the American Association for Cancer Research (AACR).
These data prove the mechanism of action of its world’s first sugar immune checkpoint inhibitor and dose-dependent reduction of sialylation modification on the surface of immune cells and activation of the immune system.
In addition, the therapy was well tolerated and had no dose-limiting toxicity. These results support the advancement of E-602 to Phase 2 clinical stage.
Palleon was founded by Professor Carolyn Bertozzi , the winner of the 2022 Nobel Prize in Chemistry and the pioneer of bioorthogonal chemistry . Palleon’s EAGLE (Enzyme-Antibody Glycan Ligand Editing) platform is based on the research results of Professor Carolyn Bertozzi.
Professor Carolyn Bertozzi, picture from standford.edu
A true world first
Palleon said E-602 represents a truly new class of immuno-oncology drug candidates that builds on glycobiology, which offers unprecedented opportunities for drug development in cancer and other diseases. These preliminary clinical data provide the necessary validation to initiate further phase 2 clinical trials.
Professor Carolyn Bertozzi said that it is exciting to see the first clinical results of drug candidates developed on the EAGLE platform . Palleon is advancing a new immune regulatory axis defined by the interaction between sialoglycan and its receptors , which may benefit patients who do not respond to current medications.
Professor Carolyn Bertozzi found in previous research that hypersialylation on the surface of tumor cells and immune cellsis an important reason for cancer immune escape.
Sialoglycan- mediated immune suppression involves more than a dozen inhibitory immune checkpoint receptors, each of which can bind many different sialoglycans. Traditional drug development targeting a one-to-one binding relationship does not apply to the immunomodulatory axis between sialoglycans and their receptors, which has too much redundancy to effectively Target a single receptor or ligand .
Palleon researchers discovered the Achilles’ heel of sialoglycan-mediated immune escape — all Siglec receptors that block the immune system’s killing action depend on the presence of sialic acid . Therefore, if sialylation can be removed from the surface of tumor cells and immune cells, it is expected to activate the immune system and achieve a comprehensive anti-tumor immune response.
E-602 is a fusion protein of engineered human sialidase and human IgG1 Fc region, which is a bifunctional sialidase fusion protein that degrades immunosuppressive saliva on hypersialylated tumor cells and immune cells through sialidase Acid polysaccharides, thereby restoring the body’s anti-tumor immune response.
Principle of action of E602
E602 removes sialylation in tumor cells
E602 removes T cell sialylation
E602 Clinical Trial Data
E602: Desialylation-based cancer therapy
E-602 induces sustained, dose-dependent desialylation of peripheral immune cells
E602 activates circulating immune cells
Specifically, 40 cancer patients received at least one dose of E-602, including 21 patients with colorectal cancer and 10 patients with pancreatic cancer , at doses up to 30 mg/kg tolerated without dose-limiting toxicities.
Dose-dependent desialylation and activation of the immune system was observed through an increase in activated immune cells in the circulation and elevation of circulating cytokines and chemokines . It is reported that the phase 2 clinical trial will also evaluate the clinical activity of E-602 monotherapy in patients with lung cancer and melanoma .
Pioneering bioorthogonal chemistry
Carolyn Bertozzi graduated from Harvard University in 1988. Afterwards, she was a PhD student at the University of California, Berkeley.
In the third year, her supervisor was suffering from rectal cancer and could not give normal research guidance. One year later, her supervisor left California Berkeley to Stanford.
In this case, Carolyn Bertozzi began to self-direct to do experiments, write papers, and apply for funds. In the fourth grade, she published 6 first-author papers, and successfully graduated with a Ph.D. in 1993. After her Ph.D., she applied to the United States Cancer Society postdoctoral fellowship, moving from chemistry to biology.
In 1996, Carolyn Bertozzi joined the University of California, Berkeley as an assistant professor, was promoted to an associate professor in 1999, became a professor in 2002, was elected to the American Academy of Arts and Sciences (AAAS) in 2003, and was elected to the National Academy of Sciences (NAS ) in 2005 . In 2015, she joined Stanford University, where she has been working ever since.
In 2001, K. Barry Sharpless, Morten Meldal and others reported the click reaction between the azide group and the terminal alkyne group catalyzed by copper ions .
Since then, many laboratories have begun to use this efficient reaction to carry out Biomolecular labeling and research. However, the toxicity of copper ions itself limits the application of click chemistry in cells and in vivo.
In 2003, Carolyn Bertozzi proposed Bioorthogonal Chemistry , which can allow exogenous molecules or functional groups to react quickly and efficiently in the complex environment of the organism without affecting the normal reaction between molecules in the organism.
With her efforts, click chemistry has entered a new dimension, realizing copper-free, so it can be safely applied in vivo.
On October 5, 2022, Carolyn Bertozzi from Stanford University, Morten Meldal from the University of Copenhagen, Denmark , and K. Barry Sharpless from the Scripps Research Institute won the 2022 Nobel Prize in Chemistry.
The trio were awarded for their contributions to the development of click chemistry and bioorthogonal chemistry. While Barry and Morten laid the groundwork for click chemistry, Carolyn took click chemistry to the next level and started harnessing it in living organisms.
From laboratory to clinical treatment
Carolyn Bertozzi’s laboratory uses bioorthogonal reactions to track molecular interactions in living organisms and their role in disease, and to label and image cells, tissues, and organs. They also found that glycans on the surface of tumor cells protect tumor cells from the immune system’s killing effects.
Based on these findings, they developed a new class of anticancer drugs that combine glycan-breaking sialidases with tumor-specific antibodies to enhance cancer treatment.
Based on the above findings, Carolyn Bertozzi founded Palleon Pharmaceuticals in 2015, which is dedicated to the development of sugar-mediated immune regulation to treat cancer and inflammatory diseases.
Anticancer effect. Its bifunctional sialidase fusion protein drug E-602, which targets immunosuppressive sialoglycans on tumor cells and immune cells, is in Phase 1/2 clinical trials.
At present, Palleon has a total of 4 tumor R&D pipelines, among which E-602 is the fastest progressing one, which is in the phase 1/2 clinical trial stage.
This is the first engineered human gene fusion protein developed based on Palleon’s EAGLE (Enzyme-Antibody Glycan Ligand Editing) platform, a bifunctional sialidase fusion protein that enzymatically removes tumor cells and The sialoglycans on the surface of immune cells relieve the immunosuppressive effect induced by them, thereby enhancing the anti-tumor immunity.
The remaining three pipelines are bifunctional anti-PD-L1 antibody-sialidase fusion protein , bifunctional anti-HER2 antibody-sialidase fusion protein , and a tumor-associated antigen-sialidase fusion protein with an undisclosed target .
The latter two pipelines are jointly developed with Henlius. In addition, Palleon has three R&D pipelines targeting inflammatory diseases, all of which are currently in the preclinical stage.
References :
https://palleonpharma.com/news/
https://palleonpharma.com/wp-content/uploads/AACR2023_Palleon-04172023-for-Website.pdf
New cancer immunotherapy: The first clinical data of chemically modified antibodies
(source:internet, reference only)
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