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Archive for the ‘“Antibody–enzyme conjugates”’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.

 

In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

 

Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.

 

References:

 

https://www.biorxiv.org/content/10.1101/849844v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25656706

 

https://www.ncbi.nlm.nih.gov/pubmed/27653600

 

https://www.ncbi.nlm.nih.gov/pubmed/26912368

 

https://www.ncbi.nlm.nih.gov/pubmed/26799208

 

https://www.ncbi.nlm.nih.gov/pubmed/23001146

 

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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”

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 

 

AUGUST 22, 2016

Stanford chemists develop a new method of cancer immunotherapy

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/

 

immobilization-ok

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

IMAGE SOURCE: google images

 

glycocalyx-145E1F0C801699F8CFE

image glycocalyx

IMAGE SOURCE: google images

Glycocalyx

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

  1. Han Xiaoa,b,1,
  2. Elliot C. Woodsa,b,1,
  3. Petar Vukojicica,b, and
  4. Carolyn R. Bertozzia,b,2
  1. 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 

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