The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

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The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

August 23, 2016 by 2012pharmaceutical

The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

Reporter: Aviva Lev-Ari, PhD, RN

Significance

Successful tumors are able to evade the immune system, which is otherwise capable of killing transformed cells. Therapies that prevent this evasion have become revolutionary treatments for incurable cancers. One mechanism of evasion is the presentation of sugars, called sialic acids, within the cell surface’s sugar coating, or glycocalyx. Here, we designed biotherapeutic molecules, termed “antibody–enzyme conjugates,” that selectively remove sialic acids from tumor cells. The antibody directs the enzyme to the cancer cells, the enzyme cleaves the sugars, and then the antibody directs immune cells to kill the desialylated cancer cells. The conjugate increased tumor cell killing compared with the antibody alone. Editing the cancer cell glycocalyx with an antibody–enzyme conjugate represents a promising approach to cancer immune therapy.

SOURCE

http://www.pnas.org/content/early/2016/08/16/1608069113.abstract

AUGUST 22, 2016

Stanford chemists develop a new method of cancer immunotherapy

BY AMY ADAMS

A team of Stanford ChEM-H scientists has discovered a novel form of cancer immunotherapy, which works by removing certain sugars from the surface of cancer cells and making those cells visible to the immune system.

“All of the world of immune therapy is now thinking about the immune system as calculating pluses and minuses. If you want to tilt the scale toward immune activation, you can either augment the activator or remove inhibitor, or both,” said Bertozzi, who is also an investigator with the Howard Hughes Medical Institute.

Current immunotherapies on the market work by blocking one of the inhibitory signals that are recognized by the adaptive immune system. Block those and the balance tilts in such a way that the immune system will attack the now recognizable cancer.

Bertozzi’s approach provides a second way of tiling the balance in favor of attack, this time for the innate immune system. She said this study shows just one example of how it could work, but her sugar-removing lawnmower could be used on a wide variety of cell types, not just those expressing HER2, and on different types of sugars.

“It’s almost always the case that you need a component of both the adaptive and innate immunity to get a robust reaction against infectious pathogens, such as during vaccination,” said Bertozzi. “The smart money suggests that the same will be true with tumors.”

Bertozzi said the approach also highlights the importance of paying attention to the much ignored glycocalyx.

SOURCE

Stanford chemists develop a new method of cancer immunotherapy

http://news.stanford.edu/2016/08/22/new-method-cancer-immunotherapy/

A symbolic representation of a glycocalyx chain attached to a cytoskeleton.

IMAGE SOURCE: google images

image glycocalyx

IMAGE SOURCE: google images

Glycocalyx – www.futura-sciences.us576 × 284Search by image

The carbohydrates, glycoproteins and proteoglycans making up the glycocalyx

IMAGE SOURCE: google images

PNAS – Original Article

Precision glycocalyx editing as a strategy for cancer immunotherapy

Author Affiliations

Edited by Laura L. Kiessling, University of Wisconsin-Madison, Madison, WI, and approved July 11, 2016 (received for review May 24, 2016)

Abstract

Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody–sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody–sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody–enzyme conjugates is therefore a promising avenue for cancer immune therapy.

SOURCE

http://www.pnas.org/content/early/2016/08/16/1608069113.abstract