All posts by medical

Cell Biology

Glitches in DNA replication have important implications for treating cancer – News-Medical.Net

USC researchers peering deep inside a living cell have discovered something surprising: Its system for preventing genetic damage linked to diseases can fail so badly that the cell would be better off without it.

It's a paradoxical finding because it challenges the idea that tiny protein guardians of cell division always offer protection, yet the study shows that they can at times allow bad things to happen simply by doing their job too well.

The findings have important implications for treating cancer. In addition, glitches in DNA replication lead to other genetic diseases, including birth defects, autism and neurological impairments.

A cell's ability to make new cells is also important to sustain tissues and organs.

Generally, cells respond to errors during DNA replication by deploying monitoring proteins, called checkpoints, that serve to recognize the problem and stop cell division so that chromosome damage is prevented. This study makes the unexpected finding that in certain forms of replication stress, an active checkpoint actually allows cells to divide, causing worse damage than if it were missing entirely."

Susan Forsburg, Study Senior Author and Distinguished Professor, Department of Biology, USC Dornsife College of Letters, Arts and Sciences

The findings appear in a scientific paper published today in the journal Molecular and Cellular Biology.

This is fundamental research into the principles of how cells operate, how they divide to form new cells and how built-in molecular checks and balances ensure that cell division occurs correctly.

It's the sort of foundation upon which clinicians and translational scientists can find better ways to treat diseases.

"We are interested in how problems in DNA replication lead to bad things for cells and people, including cancer," Forsburg said.

For the study, the scientists utilized a type of yeast -- Schizosaccharomyces pombe -- with chromosomes similar to those in humans and that uses the same genes to maintain those chromosomes. It's been proven as an important model for cell division.

"The analogy I use is comparing a Mercedes and a lawnmower," Forsburg said.

"If you're trying to understand the basic principles of an internal combustion engine, the lawnmower is a simplified version of the Mercedes engine."

"The yeast uses the same genes we do, and every gene we study has a human equivalent, with nearly all of them linked to cancer."

In the study, the scientists examined how cells respond to a defect supervised by an important gene called CDS1.

It functions like a guardian for the DNA replication process, and it has an analog in humans called CHEK1.

As a checkpoint, the gene ensures the DNA is smoothly copied before cell division. Usually, when something goes wrong that hinders DNA replication, the gene stops cells from dividing until they can fix the problem.

Otherwise, cells would divide without properly replicated DNA, which has deadly consequences.

Cancer treatments often combine drugs that hinder DNA replication with compounds that block the checkpoint, like a poison pill to drive the tumor cells into a lethal division.

This study finds a condition where that poison pill backfires.

"We found that the active checkpoint actually allowed the cells to divide abnormally," Forsburg said.

"Unexpectedly, when we deleted the replication checkpoint, the mutant cells didn't divide because another damage control mechanism kicked in to stop the unwanted cell divisions."

Study will lead to better understanding of cells, improved cancer treatments.

How can a gene that seeks to help keep the cell healthy mess up so badly that it perpetuates harm to the tissue or organ? In certain instances, it seems the checkpoint gets blindsided and continues doing its job when it would be better if it took the day off.

Forsburg explained: "Our experiments examined a very specific defect in DNA replication, and it appears that this created a perfect storm."

"The checkpoint didn't know what to do with it. Its best effort to protect the cells actually allowed them to slip into lethal divisions."

The findings help advance understanding of the inner workings of cells and how cancer treatments can be improved.

This year, an estimated 1.8 million new cancer cases will be diagnosed and 606,520 cancer deaths will occur in the United States, according to the American Cancer Society.

Source:

Journal reference:

Waku, T., et al. (2020) NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression. Molecular and Cellular Biology. doi.org/10.1128/MCB.00010-20.

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Glitches in DNA replication have important implications for treating cancer - News-Medical.Net

Cell Biology

Berkeley Lights announces Opto antigen-presenting bead kit to accelerate the expansion of antigen-specific T cells used to develop cell-based…

Jun 25 2020

Berkeley Lights, Inc., a leader in Digital Cell Biology, today announced the Opto Antigen-Presenting Bead (APB) kit, a new reagent kit that activates and expands antigen-specific T cells in peripheral blood to create artificial T cells.

The APB kit is ten times more effective than the current, standard dendritic cell process, which is used for antigen discovery for cancer vaccines, TCR discovery for transgenic TCR cell therapy, and expansion of antigen-specific T cells for endogenous T cell therapy.

The APB kit is a part of the companys Opto Cell Therapy Development 2.0 workflow and with this new kit, scientists can measure multiple cytokines, visualize tumor cell killing, and expand & validate rare T cells on the Beacon and LightningTM systems. The functional properties of the resulting T cells are assayed and recovered for TCR or genome sequencing.

T cell-based therapies are showing great promise for cancer treatment, said John Proctor, Ph.D., Senior Vice President of Marketing at Berkeley Lights.

Our APB kit will provide scientists developing these therapies with a way to rapidly identify existing T cells that will react to tumor antigens and expand them to generate enough antigen-specific T cells for use in TCR discovery and production of T cell therapies. Ultimately, we believe the APB kit will enable scientists to move to the next step of developing T cell-based therapies more quickly and efficiently.

The APB kit allows scientists to load any peptide onto a bead and measure critical peptide-Human Leukocyte Antigen (HLA) interactions before stimulating antigen-specific T cells with the best peptides. This new workflow removes the need to assay ineffective peptides that do not bind to the HLA complex in the first place.

The APB kit consists of beads coated with co-stimulatory antibodies, an HLA complex that measures the degree of loading and stability of the peptide, and tetramers that stain the antigen-specific T cells that are generated. By replacing the role of dendritic cells in T cell workflows, this kit enables Berkeley Lights customers to save time and costs by removing variability in antigen presentation.

The Opto Antigen-Presenting Bead (APB) kit will be available in early Fall 2020. More information can be found here: http://www.berkeleylights.com. Berkeley Lights Beacon and Lightning systems and Culture Station instruments are for research use only. Not for use in diagnostic procedures.

Berkeley Lights is a leading Digital Cell Biology company focused on enabling and accelerating the rapid development and commercialization of biotherapeutics and other cell-based products for our customers.

The Berkeley Lights Platform captures deep phenotypic, functional, and genotypic information for thousands of single cells in parallel and can also deliver the live biology customers desire in the form of the best cells.

Our platform is a fully integrated, end-to-end solution, comprised of proprietary consumables, including our OptoSelect chips and reagent kits, advanced automation systems, and application software. We developed the Berkeley Lights Platform to provide the most advanced environment for rapid functional characterization of single cells at scale, the goal of which is to establish an industry standard for our customers throughout their cell-based product value chain.

Our mission is to accelerate the use of cell-based products by providing researchers access to the Berkeley Lights Platform to find the best cells in a fraction of the time and at a fraction of the cost of traditional methods.

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Cell Biology

Study reveals images of the coronavirus forming tentacles in cells — but monstrous discovery helps identify new treatment – Milwaukee Journal…

Startling, never-before-seen images show that the new coronavirus hijacks proteins in our cells to create monstrous tentacles that branch out and may transmit infection to neighboring cells.

Thefinding, accompanied byevidence ofpotentially more effective drugs against COVID-19,was published Saturday in the journalCellby an international team of scientists.

Fluorescence microscopy image of human epithelial cells taken from the colon and infected with SARS-CoV-2, the virus, that causes COVID-19. The infected cells produce tentacles, known formally as filopodia ( in white) extending out from the cell surface containing viral particles (M protein in red).(Photo: Dr. Robert Gross, University of Freiburg)

By focusing on the fundamental behavior of the virus how it hijacks key human proteins and uses them to benefit itself and harm us the team wasable to identify a family of existing drugs called kinase inhibitors that appear to offerthe most effective treatment yet forCOVID-19.

"We've tested a number of these kinase inhibitors and some are better than remdesivir," said Nevan Krogan, one of more than 70authors of the new paper, and director of the Quantitative Biosciences Instituteat the University of California, San Francisco.

While remdesivir has yet to beapproved for use against COVID-19,U.S.regulatorsare allowing "emergency use" of the drug inhospitalized patients.

Krogan said tests ofkinase inhibitors showed some, including Gilteritnib and Ralimetinib, required lower concentrations thanremdesivir in order tokill off 50% of the virus.

The new study, whichinvolvedexperiments using cells from humans and othersfrom African green monkeys, shows that the virus known as SARS-CoV-2is especially adept at disrupting vital communications. These communicationstake place both withincells and from one cell to another.

Electron microscopy image of cells from the kidney of a female African green monkey that have been infected with SARS-CoV-2, the virus that causes COVID-19. Infected cells produce tentacles known formally as filopodia (orange) extending out from the cell surface to enable budding of viral particles (blue) and infection of nearby cells.(Photo: Dr. Elizabeth Fischer, NIAID/NIH)

"This paper shows just how completely the virus is able to rewire all of the signals going on inside the cell. That's really remarkable and it's something that occurs very rapidly (as soonas twohours after cells are infected)," said Andrew Mehle, an associate professor of medical microbiology and immunology at the University of Wisconsin-Madison.

The communicationssystemknown ascell signaling, allowscells to grow, and to detect and respond to outside threats. Errors in cell signaling can lead to such illnesses as cancer and diabetes.

RELATED:"Something we've never seen before: Scientists still trying to understand baffling, unpredictable coronavirus"

Mehle, who was not involved in the study, said the work shows that scientists are contending with a daunting enemy in thenew conronavirus. "These are highly efficient, evolutionarily-tuned machines that will make it very challenging to develop therapeutics," he said.

From early in the pandemic, Krogan and his colleagues have taken adifferentapproach from that of manyresearchers seeking treatments for the new virus.

Many scientists have been screeningthousands of drugs already approved for other uses to determine if theycan also be used to treat COVID-19.

"We're not doing that," Krogan said. "We're saying 'Let's understand the underlying biology behind how the virus infects us, and let's use that against the virus.'"

In thesearch for treatments, many scientists have homed inonkey proteins in the virus especially the Spike protein, which allowsthe viral cellsto attach themselves to human cells.

Fluorescence microscopy image of of human epithelial cells taken from the colon and infected with SARS-CoV-2, the virus that causes COVID-19.Viral N protein (red) hijacks human Casein Kinase II (green; co-localization in yellow) to putatively produce branching filopodia protrusions (white outline boxes) to enable budding of viral particles and infection of nearby cells.(Photo: Dr. Robert Gross, University of Freiburg)

Krogan and his team looked in the opposite direction, focusingon the human proteins, instead of those in the virus. Dozens ofhuman proteins play a critical role in the disease processbecause the virusneeds themto infect people and to make copies of itself.

There is an important advantage to developing treatments aimed atthe human, rather than the viral, proteins. Viral proteins can mutate causing them to develop resistance to the drugs targeted to them. Human proteins are far less likely to mutate.

In April,Krogan and his colleaguespublished a study in the journal Nature showing that332 human proteinsinteract with 27 viral proteins.

Feixiong Cheng, a PhD researcher who runs a lab at Cleveland Clinic Genomic Medicine Institute, called themapping ofinteractions between theseproteins "a novel" and "powerful" strategy for findingexisting drugs that might helpCOVID-19 patients.

RELATED:Two classes of drugs found that may treat COVID-19

In the new study, Krogan's international teamlooked deeper into the biology, focusing onhow the new coronavirus changes a complex process called phosphorylation. Thisprocess acts as a series ofon-off switches for differentcell activities, includinggrowth, division, deathand communicationwith one another.

"What they've done is really a fantastic next step," said Lynne Cassimeris, a professor of biological sciences at Lehigh University, explaining that the work builds on the previous paper and applies knowledge of cell biologygained over the last30 years.

"It's an amazing leap. We know that the virus has to be manipulating these human proteins. Now we have a list of what is changing over time."

Cassimeris said that mapping these changesallows researchers to seek drugs thatcan intervene at specific points.

The scientists found that on-off switcheschanged significantly in 40 of the 332 proteins that interact with the new coronavirus.

Thechanges occur because the viruseither dialsup or down49 enzymes called kinases. The dialing up or down ofkinases cause them to alter40 of the proteins that interact with virus.

Imagine the kinases as guards protecting our health until the new coronavirus turns them against us. In each case, however, the new study identified treatments that can stopthe virus from turningguards into assailants.

The virus most powerfully hijacks a kinase called CK2, which plays a key role in the basic frameof thecell as well asitsgrowth, proliferation and death.

This led the scientists to investigatea drug called Silmitasertib. Tests found this druginhibits CK2and eliminatesthe new coronavirus.

Electron microscopy image of cells from the kidney of a female African green monkey, which have been infected with SARS-CoV-2, the virus that causes COVID-19. Infected cells produce tentacles known formally as filopodia (blue) extending out from the cell surface to enable budding of viral particles (orange) and infection of nearby cells.(Photo: Dr. Elizabeth Fischer, NIAID/NIH)

They also found that the virus has a dramatic effect on a pathway a group of kinases that forma cascade a little like falling dominoes. The virus hijacksthis cascade so that the end result becomesa dangerous overreaction by ourimmune system.

The study's findingon this pathwaymay help to explainthe extreme overreaction acytokine storm that causes the immune system to kill both healthy anddiseased tissue, leadingtomore than half of the deaths from COVID-19.

RELATED:UW joins drug trial aimed at stopping haywire immune response

Here too, the scientists were able to identify treatments, including the experimental cancerdrug Ralimetinib, whichmay preventthe immune system overreaction.

Authors of the new study also found that the virus harms a family of kinasescalled CDKs. Theseplay roles incell growth and in the response toDNAdamage. An experimental drug called Dinaciclib may be effective in thwarting thisviral assault.

Finally, Krogan and his colleagues found that the virus also hijack a kinase that helps cells stay healthy in different environments and cleans out damaged cells.A small molecule called Apilimod targets this kinase and has been able to hinderthe virus in lab tests.

Krogan, who is also an investigator at the Gladstone Institutes at UCSF, said the strategy of examining the human kinases affected by the virus has provedfruitful.

"The kinases are a very druggable set of proteins in our cells," he said.

Email him at mark.johnson@jrn.com; follow him on Twitter: @majohnso.

Our subscribers make this reporting possible. Please consider supporting local journalism by subscribing to the Journal Sentinel at jsonline.com/deal.

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Study reveals images of the coronavirus forming tentacles in cells -- but monstrous discovery helps identify new treatment - Milwaukee Journal...

Cell Biology

Synthetic Biology Market is Projected to Expand at a CAGR of 26.3% from 2019 to 2027 – 3rd Watch News

Synthetic Biology Market: Introduction

Transparency Market Research has published a new report titled, Synthetic Biology Market. According to the report, the globalsynthetic biology marketwas valued atUS$ 4.96 Bnin2018and is projected to expand at a CAGR of26.3%from2019to2027.

In terms of product, the core product segment accounted for major share of the global synthetic biology market in2018. The segment is anticipated to witness strong growth from2019to2027. The core product segment is further sub-segmented into synthetic DNA, synthetic genes, synthetic cells, XNA (xeno nucleic acid), and chassis organisms. The synthetic DNA sub-segment accounted for major share of the global synthetic biology market due to the increasing research & developmental activities associated to this sub-segment and increased penetration in the market.

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Based on technology, the genome engineering segment held a major share in2018in synthetic biology market, due to its ability to make alterations to the genome of the living cell, and thereby gaining attention of the scientists and key players.

Based on application, the health care segment held a prominent share in2018in synthetic biology market due to increase in prevalence of various diseases, rise in key players, and expanding infrastructure as well as increasing focus of government in treatments and facilities in health care

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Global Synthetic biology Market: Prominent Regions

North America held the largest share of the global synthetic biology market in 2018. North America accounted for significant share of the global synthetic biology market in2018.The market in the region is likely to grow at a rapid pace during the forecast period.

The U.S. is projected to dominate the synthetic biology market in the region during the forecast period, owing to early adoption of technologies. The country is anticipated to be the most attractive market for synthetic biology, with high attractiveness index.

Global Synthetic Biology Market: Key Players

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Synthetic Biology Market is Projected to Expand at a CAGR of 26.3% from 2019 to 2027 - 3rd Watch News

Cell Biology

All About the Berkeley Lights Stock IPO – Nanalyze

For some reason, IPOs are coming out of the woodwork these days. Seems strange when you consider that just three months ago, all hell was breaking loose, and everyone seems to have forgotten about that. In fact, since the first-ever mention of the Woohoo Flu, the Nasdaq has gone up by +13%. Maybe everyones rushing to IPO before the door slams shut again?

It was only several months ago that we wrote about How Berkeley Lights Enables Synthetic Biology, and now theyve filed for an IPO, which means we get to take a look under the hood. Well assume youre already familiar with the company from our previous piece and jump right into their S-1 filing to look for juicy insights.

The value proposition on offer from Berkeley Lights is that researchers can do a lot more, with a lot less, and do it much quicker. An entire roomful of equipment can be replaced with a single platform called The Beacon Optofluidic System where wells are replaced with chips. (Remember organs-on-a-chip? Well this is lab-on-a-chip.) The core technology behind the Beacon platform are OptoSelectchipsthat contain thousands of NanoPen chambers which are like wells on a microplate.

The chips you see above are capable of not only sorting cells, but measuring their characteristics. All of this takes place rapidly, at scale. The platform is operated through an easy-to-use software interface which guides the entire laboratory workflow which thanks to automation can operate at lightening speeds. For example, discovering an antibody is a process that would typically take about three months. Using the Beacon platform, that same process takes just a single day.

Cells are microscopic factories that make minute amounts of a variety of valuable proteins, such as antibodies, and therefore require a high degree of precision when analyzed individually, Berkeley Lights correctly points out. Now, just imagine taking thousands of cells and measuring the individual characteristics of each cell to only select a chosen few. These capabilities can be configured as customized workflows which are unique to a customers particular requirements, something that translates into a total addressable market of approximately $23billion:

It all works out to about 1,600companies, academic institutions, and governmental and other organizations which Berkeley can sell their Beacon platform to using three different revenue models:

The company also talks about the Berkeley Lights BioFoundry which may develop proprietary valuable biological assets they could sell or license to customers, such as functionally validated antibodies or new organisms applicable to synthetic biology.

Since the first commercial sale of Beacon in the United States in December 2016, Berkeley Lights has just dipped their toes in the water with 45 customers and an install base of 54 Beacon machines. The customer list includes eight of the ten largest biopharmaceutical companies in the world who comprised 18% of their total revenues in 2019 which came in at $56.7 million, a growth of +81% over 2018 revenues of $31.3 million.

About 70% of their 2019 revenues came from direct sales while the other 30% came from strategic partnerships like the one with Ginkgo Bioworks we discussed in our previous article. A breakdown of revenues by addressable markets shows that most the money in 2019 came from the antibody therapeutics segment:

We also see heavy spending on R&D at around $38 million in 2019, a number thats equivalent to 67% of revenues at the moment (nearly 42% of all 210 employees work in R&D). That spending is to ensure their intellectual property moat is strong and to stay well ahead of any competitors, or in the case of Berkeley Lights, potential competitors.

One valuable piece of information presented in the S-1 filing is a list of names that Berkeley Lights describes as potential competitors. The use of the word potential implies that the Beacon platform is so advanced that their nearest competitors can only accomplish parts of what they do. Being able to discover an antibody in a single day vs. three months is an exponential leap forward, and represents an entirely new way of doing things, as opposed to incremental improvements over existing methods. Lets quickly look at the names Berkeley Lights listed as potential competitors.

Maybe were overthinking Berkeley Lights use of the term potential competitors, but were inclined to think that at least some of that lab equipment being replaced by a single Beacon platform comes from the first three companies listed above that all seem to be more mature, with each claiming high levels of industry adoption. The fourth company is a relatively new startup that seems to be making similar claims as Berkeley Lights regarding their ability to sort cells at scale:

Investors must love how the core technology developed by Berkeley Lights, the OptoSelect chips, also happen to be consumables. In some business models, companies will simply give away a platform because high-margin consumables will more than pay for it over a short period of time. Investors will want to watch how the new subscription service evolves, and use number of customers and machines deployed as key metrics.

In the companys words, a key factor to our future success will be, our ability to increase the adoption of our platform. They have eight of the largest biopharma companies as reference clients. Now, their 37 salespeople need to go out and get these machines in the hands of the remaining 1,555 possible customers theyve identified.

If the IPO proceeds as planned, shares of Berkeley Lights will trade under the ticker BLI.

Here at Nanalyze, we hold the lion's share of our investing dollars in a portfolio of 30 dividend growth stocks. Find out which ones in the Quantigence Dividend Growth Investing report freely available to Nanalyze Premium subscribers.

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All About the Berkeley Lights Stock IPO - Nanalyze

Cell Biology

Versatile Vaccinex Needs A Trial Or Partner Win, But Scaled Down Operation May Be More Likely – Seeking Alpha

Investment Thesis

Vaccinex share price performance since IPO. Source: TradingView.

A review of Vaccinex's (VCNX) recent share price performance and funding runway might persuade investors to leave this early stage biotech stock well alone, but there is also a case to be made that the stock represents a risky potential buying opportunity ahead of some make-or-break trial results.

Vaccinex's lead candidate, Pepinemab - an inhibitor of semaphorin 4D ("SEMA4D") is a unique and potentially effective treatment not only for neurodegenerative diseases, but also for oncological indications.

So far, the treatment has failed to wow investors. A disappointing IPO that raised $39.6m - at the lower end of the company's $12 to $15 price range - generated little follow-on enthusiasm and the company's stock quickly fell to just $3.7.

Vaccinex's news-flow - from presenting data related to its SEMA4D antibody platform, ActivMAb antibody discovery platform, and Natural Killer T-cell vaccine platform, to updates from its 2 major clinical trials - for Huntington's disease and non-small cell lung cancer ("NSCLC") - has succeeded in lifting the share price to highs of $8 in May '19, $7 in September '19 and $7 in January this year. Trading volumes on each occasion were thin, however, and gains short-lived. As such, the company has struggled to raise cash and faces a mounting funding crisis.

On the flip side, major potential price catalysts lie ahead for the company. Full results from its phase 2 Huntington's SIGNAL study of Pepinemab are due to be announced in October, and the trial has already returned some positive results, with patients showing improvement in brain metabolism, halted brain atrophy and an easing of motor and cognitive symptoms after 6 months of treatment vs. placebo.

Meanwhile data from a phase 1/2b study of Pepinemab and Merck KGaA / Pfizer's (NYSE:PFE) Bavencio for NSCLC showed that 81% of patients treated experienced either a partial response or stable disease response, but it appears the company has not persuaded Merck KGaA to partner on a registrational trial that would progress the indication towards approval and commercialization.

Vaccinex's management say that they are considering trials for other oncological indications, provided they can find a suitable partner. The company expects to receive funding from the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation to begin a study of Pepinemab in Alzheimer's patients, but enrollment has been delayed by COVID-19.

The company urgently requires fresh funding, or a partner, without which it will be forced to significantly scale down operations. There are several scenarios that I believe could play out for the company. One is that the stock remains stable until October, and when the full data from SIGNAL is released, rises on positive results, allowing the company to raise funding and proceed with a pivotal trial (it has already both Orphan Drug and fast-track designation from the FDA). Another is that the company is able to find a partner to further its oncological trials, which again is likely to lift the share price. A third is that the company uses its limited funding from Alzheimer's agencies to progress a trial for that indication. Failure to progress on any of these fronts would likely result in an eventual delisting from the NASDAQ.

In the rest of this article I will provide more detail on the company and try to determine the most likely outcome for this Rochester, New York based microcap. I suspect that October won't deliver the major price catalyst the company is looking for, due to insufficient efficacy, but longer term, its work could attract the backers it needs to support share price gains.

Vaccinex has been in existence since 2001 having been founded by President and CEO Maurice Zauderer, an academic who was an Associate Professor at the University of Rochester, senior faculty member at Columbia University and visiting scientist at National Cancer institute, Ontario Cancer Institute and Laboratory of Cell Biology. The rest of the management team and board combines a blend of academic and investment backgrounds, with some biotech experience, including at Biogen (BIIB) and Surface Oncology (NASDAQ:SURF).

The company has developed 3 platform technologies - its SEMA4D antibody platform and ActivMab discovery platform - marketed on the company website as an outsource-able mammalian cell based antibody discovery platform with unique multi-pass membrane target capabilities - and a Natural Killer T vaccine discovery platform.

As mentioned, the company's lead candidate is Pepinemab, a monoclonal antibody targeting SEMA4D. Within the neurology setting, SEMA4D controls activity of certain cells - most notably astrocytes and microglia, the innate inflammatory cells of the brain, whose activation is thought to contribute to neurodegenerative processes.

Pepinemab (VX15) blocks activities of SEMA4D. Source: company website.

Astrocytes and microglia are involved in the down-regulation of both glutamate receptors and glucose transporters but in their inflammatory state - which can be triggered by up-regulation of SEMA4D - the cells are unable to perform their normal functions and instead initiate secretion of inflammatory cytokines leading to the breakdown of neural networks and, Vaccinex believes the onset of diseases such as Huntington's, Alzheimer's, MS and ALS.

In the oncological setting, SEMA4D is also expressed by many types of tumor cells and may be correlated with tumor aggression and the blocking of immune cell infiltration and activity in tumors.

Vaccinex current pipeline. Source: company website.

Besides the Huntington's, Alzheimer's and NSCLC trials, Vaccinex has studies ongoing for Pepinemab with third party investigators in osteosarcoma and melanoma and certain other "window of opportunity" studies for other indications. There are 2 other candidates in limited development. VX5 - a human antibody to CXCL13, a molecule that regulates the formation of immune tissues - and VX25 - an investigational, bi-specific molecule, involved in the activation and targeting of NKT cell stimulation for cancer immunotherapy.

Prior to its IPO, Vaccinex obtained funding (according to the company's 2109 10K submission) by entering into numerous financing arrangements with Canadian Investment groups, including FCMI Financial. These complex arrangements culminated in a licensing agreement with a group of investors - including FCMI - known as VX3 - who agreed to various milestone payments up to a value of $32m in exchange for the rights to market and sell Pepinemab in the US and Canada.

Post IPO, the company has raised (that I can find, on top its initial $39.6m) amounts of $13.8m and $7.5m and has agreements in place with brokerages Jefferies and Keystone to sell up to $11.5m and $5.0m of shares, respectively, and has also received a small $1.1m loan via the CARES act. At the end of 2019 the company reported an accumulated deficit of $248.6m.

On one hand, investors could take the view that Vaccinex has burnt through a considerable amount of cash without having much to show for it. On the other, Vaccinex has now treated >300 patients across the 2 cohorts of its Huntington's trial and seems to have uncovered some promising, if inconclusive results, and treated 62 patients in its NSCLC trials, again delivering results that appear to be borderline sufficient to warrant further trial progression.

Although securing a high-profile partner such as Merck KGaA (known as EMD Serono in the US owing to sharing its name with Merck & Co.), and its drug - the PD-L1 inhibitor co-developed with Pfizer - Bavencio, could be seen as a coup for Vaccinex, in truth, the company still had to fund the investigational new drug application ("IND"), for this study, and shared trial costs, which may not have been such a wise move.

In 2019, trial costs accounted for $18.8m of the company's total R&D expenses. Although the company does not break down the individual costs of the Huntington's vs. NSCLC trials, we can assume a reasonable chunk of this was spent on NSCLC.

Merck KGaA and Pfizer's Bavencio was designed to compete with the likes of US Merck's (MRK) PD-1 inhibitor and mega-blockbuster Keytruda, and Bristol Myers Squibb's (BMY) Opdivo, but to date it has been a disappointment, struggling to secure approvals, and failing to meaningfully outperform its rivals across any indication - the drug pulled in sales of just $114m for Merck KGaA in 2019 whilst Opdivo and Keytruda are multi-billion sellers.

Being a huge market, NSCLC treatment is hugely competitive, and therefore I suspect it would have taken a small miracle for Pepinemab / Bavencio to return the kinds of results required to pursue an approval from the FDA. Instead, although I am not an expert of judging clinical trials, the results do not appear to have demonstrated sufficient promise or efficacy, have not impressed the market, and the experiment now appears to have been all but abandoned.

Having said that, whilst Vaccinex seems to have drawn a line under Pepinemab for NSCLC for now, it is possible that the trial has at least increased the value of Pepinemab as an asset, and perhaps there is a biotech or pharma out there that would consider an acquisition of Vaccinex, or an offer for its lead candidate, should the company's financial woes worsen, and it reach the point of no return.

In a recent Virtual Investor Fireside Chat, Vaccinex CEO Maurice Zauderer spent the majority of the call discussing the progress made in the Huntington's SIGNAL trial, which builds on preclinical studies in an animal model of Huntington's and safety data from a Phase 1 dose-escalation clinical trial of Pepinemab in MS patients that was completed in November 2014.

Data from Cohort A of the trial - which enrolled 36 patients - showed in April 2017 that treatment with Pepinemab induced a sharp increase in glucose metabolism in the brain as detected by FDG-PET imaging, which informed the design of the B Cohort of the trial, which has returned some results of note. After 6 months, Pepinemab-treated patients experienced a significant increase in brain metabolic activity in regions of interest in the brain, plus the treatment demonstrated protection against brain atrophy, and improved motor and cognitive function.

Vaccinex has released detailed data from the trial, and, since FDG-PET is also a clinically relevant biomarker in Alzheimer's, have used the data to justify its move into Alzheimer's treatment. Again, not being an expert in the underlying science, it is hard to judge the merits of this trial or whether the results justify the significant expenditure. What is evident is that SEMA4D blocking is a highly differentiated approach to treating a devastating disease with no known cure, and we also know that the FDA has awarded Pepinemab a coveted fast track designation, which will make it easier for Vaccinex to make a regulatory submission, possibly - according to the trials' Principal Investigator Andrew S. Feigin, MD - treating the current trial as its pivotal trial.

As with Vaccinex's NSCLC trial, there is potentially enough promising data to continue with the study, but equally, potentially not enough to generate real excitement or support amongst the investment community.

I recently covered another small cap stock, Cassava Sciences, (SAVA), whose stock had collapsed from $10, to $2 based on its inability to successfully convert the early promise of an Alzheimer's treatment into a pivotal trial success. In reality, perhaps it was over-ambitious of Cassava to believe it had a potential Alzheimer's treatment given the long history of failed attempts to develop drugs to treat the disease, and the extraordinarily complex nature of neurodegenerative diseases as a whole. Still, with ongoing funding from the Alzheimer's Association, Cassava is working back through its data to identify areas it can improve upon, and has been rewarded by investors for its efforts, with its shares now trading up 67% at $3.36.

I share this information because I think that Vaccinex may fall into a similar category. Whether Vaccinex has been let down by those responsible for the investor relations side of the business, who have failed to drum up enthusiasm for the work the company's scientists are doing, or whether it is the opposite - Vaccinex's data did not ever really justify a stock market listing - is open to discussion.

What I think is most likely to happen to Vaccinex is that it will not immediately find support either for progressing Pepinemab for NSCLC, or for Huntington's - unless the full data from SIGNAL is exceptional - which is, to my mind, so unlikely that it may as well be discounted. But I don't see this as the end of the company as a going concern, rather I think that it can cut its losses , stop funding trials that burn through >$20m per annum, accept funding from its Alzheimer's backers and continue its research on a smaller scale.

As with Cassava, this would generally support the company's current share price, whose recent spikes I would put down to insider buys rather than new backers or heightened interest in its progress. This thesis does support potential price gains, however, because the company can drip feed its progress to the market without the pressure of having to support an unrealistic valuation, or of having to constantly try to raise funding in the hundreds of millions - as it appears to have attempted, and failed to do with a recent filing for a shelf offering.

I hope I am wrong and the Huntington's trial delivers excellent results, which would be a great coup for the company and its investors, and most importantly for patients suffering from this horrendous disease. But a more realistic scenario sees Vaccinex scaling down its operations and focusing on small wins. That is natural for a drug development company, and with such a strategy in place, it might, down the line, secure the investor goodwill the company needs to start scaling the mountain again.

If you like what you have just read and want to receive at least 4 exclusive stock tips every week focused on Pharma, Biotech and Healthcare, then join me at my marketplace channel, Haggerston BioHealth. Invest alongside the model portfolio or simply access the investment bank-grade financial models and research. I hope to see you there.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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Versatile Vaccinex Needs A Trial Or Partner Win, But Scaled Down Operation May Be More Likely - Seeking Alpha

Cell Biology

Researchers successfully use CAR-T therapy in blood cancer patients – News-Medical.Net

A method known as CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

It modifies a patient's own T-cells by adding a piece of an antibody that recognizes unique features on the surface of cancer cells.

In a new study, researchers report that they have dramatically broadened the potential targets of this approach - their engineered T-cells attack a variety of solid-tumor cancer cells from humans and mice.

They report their findings in the Proceedings of the National Academy of Sciences.

"Cancer cells express on their surface certain proteins that arise because of different kinds of mutations," said Preeti Sharma, a postdoctoral researcher at the University of Illinois at Urbana-Champaign who led the research with biochemistry professor David Kranz.

Kranz is a member of the Cancer Center at Illinois and an affiliate of the Carl R. Woese Institute for Genomic Biology, also at the U. of I. "In this work, we were looking at protein targets that have short sugar chains attached to them."

The abnormally short sugar chains on some types of cancer cells result from mutations that disrupt the molecular pathway that attaches these sugars to proteins, Sharma said. Drugs that bind to the aberrant sugars preferentially recognize cancer cells and spare healthy cells.

CAR-T therapy is a promising treatment for patients with certain types of blood cancers. But identifying binding sites in solid tumors has been more difficult, Kranz said.

"A major challenge in the field has been to identify targets that exist on cancer cells in solid tumors that are not present on normal tissue," he said.

The team started with a piece of an antibody that could serve as a receptor. The antibody was known to interact with a specific type of abnormally formed sugar attached to a protein on solid-tumor cancer cells in mice.

We realized that because this receptor binds both to the protein and the sugar on the surface of the cancer cell, there might be room to change the antibody so that it can bind to more than one protein attached to the short sugar. This could make it broadly reactive to different kinds of cancers."

Preeti Sharma, Postdoctoral Researcher, University of Illinois at Urbana-Champaign

Study co-author Qi Cai, another postdoctoral researcher in the Kranz lab, tested whether changes in the sequence of amino acids in the vicinity of the abnormal sugar affected the receptor's binding to the site. This allowed the team to determine if the antibody could be slightly changed to accommodate other sugar-linked cancer targets.

They conducted a series of mutation experiments focused on the essential parts of the antibody, Sharma said.

"We generated almost 10 million mutant versions of our receptor, and then we screened those to find the property we wanted," she said. "In this case, we wanted to broaden the specificity of that antibody so that it reacts not only to the mouse target but also to human targets."

Once they found the antibodies with the desirable traits, the researchers engineered them into T-cells and tested them with mouse and human cancer cell lines.

"Our engineered T-cells are showing activity against both human and mouse cancer cell lines," Sharma said. "And the T-cells can now recognize several different proteins that have short sugars attached to them.

This is really important because in cancer therapy, most of the time you are going after a single target on a cancer cell. Having multiple targets makes it very difficult for the cancer to evade the treatment."

"Although these engineered cells are early in development, we are particularly excited that we can use the same T-cell product to study efficacy and safety against cancers in mice and humans," Kranz said.

Source:

Journal reference:

Sharma, P., et al. (2020) Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.1920662117.

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Researchers successfully use CAR-T therapy in blood cancer patients - News-Medical.Net

Neuroscience

Mason Slaine Donates $1.5 Million in support of Boca Regional’s Keeping the Promise Capital Campaign – Baptist Health South Florida

June 30th, 2020 Baptist Health South Florida

BOCA RATON, FL June 30, 2020 Boca Raton Regional Hospital has received a significant commitment from Mason Slaine, in the amount of $1.5 million, towards Keeping the PromiseThe Campaign for Boca Raton Regional Hospital. Mason joins other notable philanthropists throughout our community who have generously contributed seven and eight-figure gifts to the capital campaign that now boasts $163 million raised thus far. In recognition of Masons generosity, the new Patient Admissions Area in the new patient tower will be named in his honor.

Mr. Slaine has been an extraordinary advocate and very active in our plans since he became involved with Boca Regional a few short years ago, said Lincoln Mendez, CEO of Boca Raton Regional Hospital. We are delighted to have him as a member of our family, as a Foundation Board member and as a lead donor to our Keeping the Promise campaign.

Slaine has served on both the Executive and Audit Committees since he joined the Boca Raton Regional Hospital Foundation in 2016. His $1.5 million gift is his second major philanthropic effort for Boca Raton Regional Hospital: Mason made a similar generous gift to the Marcus Neuroscience Institute a few years ago. In exchange for that gift, the Courtyard adjacent to the Institute bears his name and welcomes staff and visitors to a convenient and enjoyable outdoor space for a break and some respite.

Our communitys healthcare is vital, and that has been particularly understated in the last few months as we all navigate through COVID-19, said Slaine. I have always believed that Boca Regional is uniquely qualified to provide the highest quality of care we all need. I have personally utilized medical services, as well as family members have been cared for at the Hospital, so the facility and the people hold a special place in my heart. I believe in Keeping the Promise and in the next generation of healthcare it will bring. I am proud to be part of it.

The $250 million Keeping the Promise campaign is the largest campaign in the hospitals history. It is supporting major campus redevelopment plans including at the centerpiece, a new patient tower featuring all new surgical suites, an inviting patient lobby and all private patient rooms exceeding the latest safety standards for patient care. The Marcus Neuroscience Institute staff and capital investments are underway targeting all neuroscience programs with an emphasis on neurovascular/stroke, central nervous system, tumor, spine and epilepsy/seizure disorders. In the current hospital building, all existing rooms will be converted to private in a comprehensive renovation of all patient units. A new 972-car parking garage opened recently and will be connected to the Marcus Neuroscience Institute and the new tower when construction is complete. These investments are the initial steps toward an even broader vision for the campus with greater access points and even more specialties including a new Medical Arts Pavilion with an outpatient surgery center, physician offices and an additional parking garage.

###

About Boca Raton Regional Hospital FoundationThe Boca Raton Regional Hospital Foundation, Inc. is a not-for-profit organization for Boca Raton Regional Hospital. Boca Raton Regional Hospital is an advanced, tertiary medical center (BRRH.com) with 400 beds, 2,800 employees and more than 800 primary and specialty physicians on staff. The Hospital is a recognized leader in Oncology, Cardiovascular Disease and Surgery, Minimally Invasive Surgery, Orthopedics, Womens Health, Emergency Medicine and the Neurosciences, all of which offer state-of-the-art diagnostic and imaging capabilities. The Hospital is a designated Comprehensive Stroke Center by the Florida Agency for Health Care Administration (AHCA). BRRH is recognized in U.S. News & World Reports 2019 2020 Best Hospitals listing as a Top Ranked Regional Hospital, for the fourth consecutive year, and the highest ranked hospital in Palm Beach County. Boca Raton Regional Hospital is a part of Baptist Health South Florida.

Media Contacts:

For Boca Raton Regional Hospital:Michael Mauckermmaucker@brrh.com561-955-4706

For Boca Raton Regional Hospital Foundation:Jennifer Rohloffjrohloff@brrh.com561-955-3329

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Mason Slaine Donates $1.5 Million in support of Boca Regional's Keeping the Promise Capital Campaign - Baptist Health South Florida

Neuroscience

June: New research in Brain Pathology | News and features – University of Bristol

Bristol scientists have discovered a novel pathology that occurs in several human neurodegenerative diseases, including Huntingtons disease.

The article, published in Brain Pathology, describes how SAFB1 expression occurs in both spinocerebellar ataxias and Huntington's disease and may be a common marker of these conditions, which have a similar genetic background.

SAFB1 is an important protein controlling gene regulation in the brain and is similar in structure to other proteins associated with neurodegenerative diseases of age. The team, from the University of Bristols Translational Health Sciences, wanted to find out if this protein might be associated with certain neurodegenerative conditions.

The researchers analysed SAFB1 expression in the post-mortem brain tissue of spinocerebellar ataxias (SCAs), Huntingtons disease (HD), Multiple sclerosis (MS), Parkinsons disease patients and controls.

They found that SAFB becomes abnormally expressed in the nerve cells of brain regions associated with SCA and HD. Both of these conditions are associated with a specific pathology, called a polyglutamine expansion (an amino acid repeat), which only occurs in SCAs and HD. The same pathology was therefore not seen in control Parkinson's disease or multiple sclerosis.

These novel findings highlight a previously unknown mechanism causing disease which, importantly, suggests SAFB1 may be a diagnostic marker for polyglutamine expansion diseases, such as HD said lead author, James Uney, Professor of Molecular Neuroscience at the University of Bristol.

We were also able to demonstrate how SAFB1 binds the SCA1 gene with the disease causing polyglutamine expansion (which causes spinocerebellar ataxia 1). As well as identifying a possible diagnostic marker, these findings open up the possibility of developing new therapeutic treatments for these rare but devastating neurodegenerative diseases.

The next step is to establish whether inhibiting SAFB1 expression protects patients.

Professor Uney said there was scope in the future to broaden the study to include other diseases, such as Alzheimer's, disease.

Paper:

'Abnormal expression of the scaffold attachment factor 1 in spinocerebellar ataxias and Huntingtons chorea,'in Brain Pathology.

This workwas supported by the BBSRC and the Medical Research Council, UKRI.

The study was made possible by the Bristol Brain Bank and the MRC-funded London Neurodegenerative Diseases Brain Bank at KCL.

Translational Health Sciences at the University of Bristol

Supported by funders such as the NIHR, the Medical Research Council, and charities such as the Wellcome Trust and British Heart Foundation, our research delivers pioneering treatments for patients and groundbreaking discoveries in basic science, across fields including neuroscience and endocrinology, cardiovascular sciences, and a range of other key areas.

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June: New research in Brain Pathology | News and features - University of Bristol

Neuroscience

Small RNA regulates tau-related disease | NIA – National Institute on Aging

Sex differences can affect Alzheimers and other neurological disease outcomes. According to an NIA-supported study published in Nature Neuroscience, a small genetic molecule, called a microRNA, regulates some immune cell gene expression and the density of neurotoxic brain tangles in a sex-specific manner.

In Alzheimers disease, the protein tau clumps to form clumps of tangled fibers in the brain. Microglia immune cells of the brain and spinal cord are implicated in the accumulation of tau tangles in the brain. MicroRNAs regulate many of the genes in microglia. Led by researchers at Weill Cornell Medicines Appel Alzheimers Disease Research Institute in New York, the study was aimed at learning whether microglial miRNAs in mouse models regulate microglial gene expression and tau tangle pathology in a sex-specific manner.

Using a specific mouse model representing tau-related neurodegenerative disease, the researchers examined whether male and female microglia respond differently to tau tangles. Although they found that the densities of tau tangles were similar in male and female mice, gene regulation was altered to a far greater extent in the male microglia. These study results suggest sex-specific microglial responses to similar levels of tau tangles.

Using a mouse model that had microglial miRNAs removed, the researchers found sex-dependent differences in both the density of tau tangles and microglial gene regulation. Specifically, in the absence of microglial miRNAs, male mice had a higher density of tau tangles than female mice. In addition, the male microglia had an increased expression of genes involved in inflammation and phagocytosis a major mechanism to remove cell debris as well as genes characteristic of disease-associated microglia (DAMs). The researchers proposed that these differences may be exacerbated by age and tau-related disease, because the DAM genes were not active in younger mice.

The study findings illuminate the role of microglial miRNAs as one of potential key contributors to sex-specific phenotypes observed in neurological diseases. Additional research is needed to further expand the understanding of microglial biology in the context of neurodegenerative diseases.

This research was funded in part by NIA grants 1R01AG054214-01A1, U54NS100717, R01AG051390 and F31AG058505.

These activities relate to NIAs AD+ADRD Research Implementation Milestone 2.D. Create programs in basic, translational and clinical research aimed at comprehensive understanding of the impact of sex differences on the trajectories of brain aging and disease, phenotypes of AD and ADRD risk and responsiveness to treatment.

Reference: Kodama L, et al. Microglial microRNAs mediate sex-specific responses to tau pathology. Nature Neuroscience. 2020;23(2):167-171. doi: 10.1038/s41593-019-0560-7.

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Small RNA regulates tau-related disease | NIA - National Institute on Aging