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

Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

On Monday, 7th June 2021, a controversial new Alzheimer’s Disease treatment was licensed in the United States for the first time in nearly 20 years, sparking calls for it to be made available worldwide despite conflicting evidence about its usefulness. The drug was designed for people with mild cognitive impairment, not severe dementia, and it was designed to delay the progression of Alzheimer’s disease rather than only alleviate symptoms.

Vhttps://youtu.be/atAhUI6OMnsII

The Controversies

The route to FDA clearance for Aducanumab has been bumpy – and contentious.

Though doctors, patients, and the organizations that assist them are in desperate need of therapies that can delay mental decline, scientists question the efficacy of the new medicine, Aducanumab or Aduhelm. In March 2019, two trials were halted because the medications looked to be ineffective. “The futility analysis revealed that the studies were most likely to fail,” said Isaacson of Weill Cornell Medicine and NewYork-Presbyterian. Biogen, the drug’s manufacturer revealed several months later that a fresh analysis with more participants found that individuals who got high doses of Aducanumab exhibited a reduction in clinical decline in one experiment. Patients treated with high-dose Aducanumab had 22% reduced clinical impairment in their cognitive health at 18 months, indicating that the advancement of their early Alzheimer’s disease was halted, according to FDA briefing documents from last year.

When the FDA’s members were split on the merits of the application in November, it was rejected. Three of its advisers went public, claiming that there was insufficient evidence that it worked in a scientific journal. They were concerned that if the medicine was approved, it might reduce the threshold for future approvals, owing to the scarcity of Alzheimer’s treatments.

Dr. Caleb Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health, was one of the FDA advisers who was concerned that the data presented to the agency was a reanalysis after the experiment was stopped. It was “like the Texas sharpshooter fallacy,” he told the New York Times, “where the sharpshooter blows up a barn and then goes and paints a bullseye around the cluster of holes he loves.”

Some organizations, such as the non-profit Public Citizen’s Health Research Group, claimed that the FDA should not approve Aducanumab for the treatment of Alzheimer’s disease because there is insufficient proof of its efficacy.

The drug is a monoclonal antibody that inhibits the formation of amyloid protein plaques in the brain, which are thought to be the cause of Alzheimer’s disease. The majority of Alzheimer’s medications have attempted to erase these plaques.

Aducanumab appears to do this in some patients, but only when the disease is in its early stages. This means that people must be checked to see if they have the disease. Many persons with memory loss are hesitant to undergo testing because there is now no treatment available.

The few Alzheimer’s medications available appear to have limited effectiveness. When Aricept, also known as Donepezil, was approved more than 20 years ago, there was a major battle to get it. It was heralded as a breakthrough at the time – partly due to the lack of anything else. It has become obvious that it slows mental decline for a few months but makes little effect in the long run.

The findings of another trial for some patients backed up those conclusions.

Biogen submitted a Biologics License Application to the FDA in July 2020, requesting approval of the medicine.

The FDA’s decision has been awaited by Alzheimer’s disease researchers, clinicians, and patients since then.

Support for approval of the drug

Other groups, such as the Alzheimer’s Association, have supported the drug’s approval.

The Alzheimer’s Association‘s website stated on Friday, “This is a critical time, regardless of the FDA’s final judgment. We’ve never been this close to approving an Alzheimer’s drug that could affect the disease’s development rather than just the symptoms. We can keep working together to achieve our goal of a world free of Alzheimer’s disease and other dementias.”

The drug has gotten so much attention that the Knight Alzheimer Disease Research Center at Washington University in St. Louis issued a statement on Friday stating that even if it is approved, “it will still likely take several months for the medication to pass other regulatory steps and become available to patients.”

Biogen officials told KGO-TV on Monday that the medicine will be ready to ship in about two weeks and that they have identified more than 900 facilities across the United States that they feel will be medically and commercially suitable.

Officials stated the corporation will also provide financial support to qualifying patients so that their out-of-pocket payments are as low as possible. Biogen has also pledged not to raise the price for at least the next four years.

Most Medicare customers with supplemental plans, according to the firm, will have a limited or capped co-pay.

Case studies connected to the Drug Approval

Case 1

Ann Lange, one of several Chicago-area clinical trial volunteers who received the breakthrough Alzheimer’s treatment, said,

It really offers us so much hope for a long, healthy life.

Lange, 60, has Alzheimer’s disease, which she was diagnosed with five years ago. Her memory has improved as a result of the monthly infusions, she claims.

She said,

I’d forget what I’d done in the shower, so I’d scribble ‘shampoo, conditioner, face, body’ on the door. Otherwise, I’d lose track of what I’m doing “Lange remarked. “I’m not required to do that any longer.

Case 2

Jenny Knap, 69, has been receiving infusions of the Aducanumab medication for about a year as part of two six-month research trials. She told CNN that she had been receiving treatment for roughly six months before the trial was halted in 2019, and that she had recently resumed treatment.

Knap said,

I can’t say I noticed it on a daily basis, but I do think I’m doing a lot better in terms of checking for where my glasses are and stuff like that.

When Knap was diagnosed with mild cognitive impairment, a clinical precursor to Alzheimer’s disease, in 2015, the symptoms were slight but there.

Her glasses were frequently misplaced, and she would repeat herself, forgetting previous talks, according to her husband, Joe Knap.

Joe added,

We were aware that things were starting to fall between the cracks as these instances got more often

Jenny went to the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Ohio for testing and obtained her diagnosis. Jenny found she was qualified to join in clinical trials for the Biogen medicine Aducanumab at the Cleveland Clinic a few years later, in early 2017. She volunteered and has been a part of the trial ever since.

It turns out that Jenny was in the placebo category for the first year and a half, Joe explained, meaning she didn’t get the treatment.

They didn’t realize she was in the placebo group until lately because the trial was blind. Joe stated she was given the medicine around August 2018 and continued until February 2019 as the trial progressed. The trial was halted by Biogen in March 2019, but it was restarted last October, when Jenny resumed getting infusions.

Jenny now receives Aducanumab infusions every four weeks at the Cleveland Clinic, which is roughly a half-hour drive from their house, with Joe by her side. Jenny added that, despite the fact that she has only recently begun therapy, she believes it is benefiting her, combined with a balanced diet and regular exercise (she runs four miles).

The hope of Aducanumab is to halt the progression of the disease rather than to improve cognition. We didn’t appreciate any significant reduction in her condition, Jenny’s doctor, Dr. Babak Tousi, who headed Aducanumab clinical studies at the Cleveland Clinic, wrote to CNN in an email.

This treatment is unlike anything we’ve ever received before. There has never been a drug that has slowed the growth of Alzheimer’s disease, he stated, Right now, existing medications like donepezil and memantine aid with symptoms but do not slow the disease’s progression.

Jenny claims that the medicine has had no significant negative effects on her.

There was signs of some very minor bleeding in the brain at one point, which was quite some time ago. It was at very low levels, in fact, Joe expressed concern about Jenny, but added that the physicians were unconcerned.

According to Tousi, with repeated therapy, “blood vessels may become leaky, allowing fluid and red blood cells to flow out to the surrounding area,” and “micro hemorrhages have been documented in 19.1% of trial participants who got” the maximal dose of therapy”.

Jenny and Joe’s attitude on the future has improved as a result of the infusions and keeping a healthy lifestyle, according to Joe. They were also delighted to take part in the trial, which they saw as an opportunity to make a positive influence in other people’s lives.

There was this apprehension of what was ahead before we went into the clinical trial, Joe recalled. “The medical aspect of the infusion gives us reason to be optimistic. However, doing the activity on a daily basis provides us with immediate benefits.”

The drug’s final commercialization announcement

Aducanumab, which will be marketed as Aduhelm, is a monthly intravenous infusion that is designed to halt cognitive decline in patients with mild memory and thinking issues. It is the first FDA-approved medication for Alzheimer’s disease that targets the disease process rather than just the symptoms.

The manufacturer, Biogen, stated Monday afternoon that the annual list price will be $56,000. In addition, diagnostic tests and brain imaging will very certainly cost tens of thousands of dollars.

The FDA approved approval for the medicine to be used but ordered Biogen to conduct a new clinical trial, recognizing that prior trials of the medicine had offered insufficient evidence to indicate effectiveness.

Biogen Inc said on Tuesday that it expects to start shipping Aduhelm, a newly licensed Alzheimer’s medicine, in approximately two weeks and that it has prepared over 900 healthcare facilities for the intravenous infusion treatment.

Other Relevant Articles

Gene Therapy could be a Boon to Alzheimer’s disease (AD): A first-in-human clinical trial proposed

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

https://pharmaceuticalintelligence.com/2021/03/22/gene-therapy-could-be-a-boon-to-alzheimers-disease-ad-a-first-in-human-clinical-trial-proposed/

Alzheimer’s Disease – tau art thou, or amyloid

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/02/15/alzheimers-disease-tau-art-thou-or-amyloid/

Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3

Reporter : Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/10/13/connecting-the-immune-response-to-amyloid-%ce%b2-aggregation-in-alzheimers-disease-via-ifitm3/

Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/27/ustekinumab-new-drug-therapy-for-cognitive-decline-resulting-from-neuroinflammatory-cytokine-signaling-and-alzheimers-disease/

Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/13/alnylam-announces-first-ever-fda-approval-of-an-rnai-therapeutic-onpattro-patisiran-for-the-treatment-of-the-polyneuropathy-of-hereditary-transthyretin-mediated-amyloidosis-in-adults/

Recent progress in neurodegenerative diseases and gliomas

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/28/recent-progress-in-neurodegenerative-diseases-and-gliomas/

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Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

 

Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.

Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.

Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).

A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.

To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as 

  • melanoma,
  • lung,
  • colon, and
  • liver cancer.

Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.

Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.

The Study-

IMAGE SOURCE: Experimental Strategy (Mathewson et al., 2021)

 

The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.

Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of 

  • CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
  • genetic inactivation of KLRB1 or
  • antibody-mediated CD161 blockade

enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.

Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.

In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”

However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by

utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.

References

(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.

Main Source

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. 2021. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell.https://www.cell.com/cell/fulltext/S0092-8674(21)00065-9?elqTrackId=c3dd8ff1d51f4aea87edd0153b4f2dc7

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Other related articles published in this Open Access Online Scientific Journal include the following:

 

Single Cell Sequencing:

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Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology 

On Amazon.com since 12/28/2019

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Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/09/03/single-cell-genomics-directions-in-computational-and-systems-biology-contributions-of-ms-aviv-regev-phd-broad-institute-of-mit-and-harvard-cochair-the-human-cell-atlas-organizing-committee-wit/

 

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https://www.sanger.ac.uk/science/programmes/cellular-genetics

 

4.1.5   Cellular Genomics

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4.1.6   SINGLE CELL GENOMICS 2019 – sometimes the sum of the parts is greater than the whole, September 24-26, 2019, Djurönäset, Stockholm, Sweden http://www.weizmann.ac.il/conferences/SCG2019/single-cell-genomics-2019

Reporter: Aviva Lev-Ari, PhD, RN

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4.1.7   Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM

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https://pharmaceuticalintelligence.com/2019/05/23/newly-found-functions-of-b-cell/

 

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Immunotherapy may help in glioblastoma survival

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

https://pharmaceuticalintelligence.com/2019/03/16/immunotherapy-may-help-in-glioblastoma-survival/

 

New Treatment in Development for Glioblastoma: Hopes for Sen. John McCain

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/25/new-treatment-in-development-for-glioblastoma-hopes-for-sen-john-mccain/

 

Funding Oncorus’s Immunotherapy Platform: Next-generation Oncolytic Herpes Simplex Virus (oHSV) for Brain Cancer, Glioblastoma Multiforme (GBM)

Reporter: Aviva Lev-Ari, PhD, RN

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Glioma, Glioblastoma and Neurooncology

Curator: Larry H. Bernstein, MD, FCAP

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Positron Emission Tomography (PET) and Near-Infrared Fluorescence Imaging:  Noninvasive Imaging of Cancer Stem Cells (CSCs)  monitoring of AC133+ glioblastoma in subcutaneous and intracerebral xenograft tumors

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/29/positron-emission-tomography-pet-and-near-infrared-fluorescence-imaging-noninvasive-imaging-of-cancer-stem-cells-cscs-monitoring-of-ac133-glioblastoma-in-subcutaneous-and-intracerebral-xenogra/

 

Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

Eric Fine* (1), Mike Briggs* (1,2), Raphael Nir# (1,2,3)

https://pharmaceuticalintelligence.com/2013/07/15/gamma-linolenic-acid-gla-as-a-therapeutic-tool-in-the-management-of-glioblastoma/

 

 

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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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