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Wistar Joins Global Effort to Expedite Coronavirus Vaccine Development

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Jan. 23, 2020) — The Wistar Institute announces today that they are part of a team to develop a vaccine against the recently emerged strain of coronavirus (2019-nCoV) that has infected hundreds in China and other countries, including the U.S., and resulted in numerous deaths to date. Wistar is part of a collaboration funded by the Coalition for Epidemic Preparedness Innovations (CEPI).

CEPI will fund nearly $9 million to support pre-clinical and clinical research for a vaccine advanced by Inovio Pharmaceuticals, Inc. (NASDAQ: INO), based in part on key technology generated in the lab of David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Endowed Chair in Cancer Research at The Wistar Institute. Wistar’s participation in this developing initiative is based on its experience and suitability of its DNA technology platform to rapidly translate a vaccine against an emerging virus with pandemic potential. Prior work by this team includes development of vaccines for Ebola, Zika and MERS, another coronavirus, during those recent outbreaks.

“Wistar feels compelled to deploy its expertise and its technological advancements to combat global emerging infectious diseases as part of its mission and is proud to be part of one of the first initiatives to approach this evolving global health threat,” said Weiner.

In addition to Wistar and Inovio, the team includes VGXI and Twist Bioscience.

The Weiner laboratory at Wistar is dedicated to accelerating vaccine and immunotherapy technologies for infectious diseases and cancer. Weiner’s research expands upon Wistar’s mission to create new treatments for the most uncompromising diseases and make lifesaving contributions to cancer biology and infectious diseases.

WISTAR’S CORONAVIRUS RESEARCH IN THE NEWS:
The Coronavirus Outbreak Is Far From Over. But Here’s How It Might End., Mar. 24
Court Radio: Coronavirus – Race Against Time: Creating a Vaccine to Fight the Spread with David Weiner, Ph.D., Mar. 8
KYW In Depth: What you need to know about coronavirus in Philadelphia, Mar. 6
Philadelphia Inquirer: Pa. is preparing for coronavirus as CDC warns spread in U.S. may be ‘inevitable’, Feb. 26
The Wall Street Journal: J&J, Sanofi, Inovio Hunt for Coronavirus Vaccines, Feb. 24
TheScientist: Newer Vaccine Technologies Deployed to Develop COVID-19 Shot, Feb. 21
FoxNews (national): Biomedical research expert on race to produce coronavirus vaccine, Feb. 17
NPR: Timetable For A Vaccine Against The New Coronavirus? Maybe This Fall, Feb. 12
Philadelphia Inquirer: Inside a Philadelphia lab, scientists race to design a coronavirus vaccine, Feb. 11
FoxNews (national) America’s Newsroom: Coronavirus vaccine to be developed from digital DNA sequencing, Jan. 30
Fox29: Philadelphia International Airport screening travelers for coronavirus, Jan. 30
KYW radio: Philadelphia scientists already at work on vaccine for coronavirus, Jan. 29
NPR: The State Of A Potential Vaccine For The New Coronavirus, Jan. 29
NBC10: Scientists at Lab in Philadelphia Work to Develop a Vaccine for Coronavirus, Jan. 29
CBS Philly: Wistar Institute In Philadelphia Part Of Team Developing Vaccine Against Deadly Coronavirus, Jan. 24
STAT: How fast can biotech come up with a vaccine for the latest outbreak?, Jan. 24
Philadelphia Inquirer: Philly-area company gets $9 million grant to develop vaccine for new Chinese coronavirus, Jan. 24
Philadelphia Inquirer: Weiner asked to comment on the coronavirus outbreak: Jan. 21

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Digital illustration of DNA with scientific background

Synthetic DNA Technology Applied as a Novel Strategy for Delivery of Anti-HIV Antibodies

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Nov. 8, 2019) — Scientists at The Wistar Institute applied synthetic DNA-based technology to drive in vivo production of broadly neutralizing anti-HIV antibodies in small and large-animal models, providing proof of concept for a simple and effective next generation approach to HIV prevention and therapy. These results were published online in the Journal of Clinical Investigation.

Despite exceptional advances in antiretroviral therapies, there remains a need for new preventive and therapeutic modalities to eliminate HIV infection. Researchers have isolated a number of very potent monoclonal antibodies from infected individuals that can neutralize a diverse array of HIV strains. Such monoclonal antibodies can be manufactured and administered as passive immunotherapy and represent a promising approach currently in early clinical studies.

Widespread use of recombinant monoclonal antibodies, though, remains limited by several factors related to their half-life of expression, production costs supporting high doses needed, temperature stability, formulation issues, and limitations in production of antibody combinations, among others.

“We developed the DMAb platform to allow for direct in vivo production of antibodies through synthetic DNA engineered to provide instructions to the body to make the desired antibodies,” said lead researcher David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research at Wistar. “Based on our early data, we suggest that this platform is worth further investigation as a new strategy for HIV antibody delivery.”

Weiner and collaborators engineered a panel of 16 DMAbs rederiving previously characterized broadly neutralizing antibodies into the DMAb format. These were studied in mice via injection using Cellectra adaptive electroporation to enhance the DNA uptake. Researchers observed rapid DMAb expression and sustained blood levels for several months. Furthermore, in vivo-produced DMAbs displayed strong neutralization ability, comparable to the corresponding recombinant antibodies.

Since the HIV virus is capable of mutating to escape single antibody immunity, combinations of up to four different DMAbs were tested as a strategy to overcome resistance. Total in vivo levels of antibodies produced in combination were comparable to the sum of the levels of the same antibodies administered individually, showing that this platform is flexible and suited for combination therapies with multiple antibodies. Importantly, the data supported that the combination could block more HIV viruses than the single antibodies.

Researchers next explored HIV-1 DMAb delivery in a pilot non-human primate study that is more relevant for translation to humans. Expression was detected as early as three days post-administration of one or two combined DMAbs, which displayed peak activity by 14 days. Importantly, the serum from treated animals had high antiviral activity.

“Although still in early stage of development, DMAbs have significant potential as a tool for treatment of HIV and other diseases and, if successfully translated to the clinic, will provide multiple new avenues for immunotherapy,” said Weiner. “Translational animal studies and clinical development are likely to be a very active area of research providing important information over the next few years.”

Co-authors: Megan C. Wise from Inovio Pharmaceuticals and Ziyang Xu from The Wistar Institute are co-first authors. Other co-authors include: Edgar Tello-Ruiz, Aspen Trautz, Ami Patel, Sarah T.C. Elliott, Neethu Chokkalingam, Sophie Kim, Kar Muthumani, and Daniel W. Kulp from Wistar; Jingjing Jiang, Paul Fisher, Stephany J. Ramos, Trevor R.F. Smith, Janess Mendoza, Kate E. Broderick, and Laurent Humeau from Inovio; Charles Beck, Melissa G. Kerkau, Guido Ferrari, and David C. Montefiori from Duke University.

Work supported by: National Institutes of Health grant U19 Al109646-04 (Integrated Preclinical/Clinical AIDS Vaccine Development Program), The W.W. Smith Charitable Trust and grant 2528109374 from the Martin Delaney Collaboratory: Towards an HIV Cure.

Publication information: In vivo delivery of synthetic DNA-encoded antibodies induces broad HIV-1-neutralizing activity, Journal of Clinical Investigation (2019). Advanced online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Major Grant Awarded to Wistar Supports Development of a Novel Therapeutic Approach for Antibiotic-resistant Bacteria

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (September 12, 2019) — The Wistar Institute has received a grant of approximately $4.6 million from the National Institutes of Health in support of innovative research to tackle antibiotic resistance.

Antimicrobial resistance (AMR) represents an expanding global public health concern. While antibiotic-resistant organisms are appearing at an alarming rate, there has been a 30-year hiatus in the development of novel classes of antibiotics for combatting these infections. Multidrug-resistant Pseudomonas aeruginosa is one of the top microorganisms on the list of priority AMR pathogens compiled by the World Health Organization.

A Wistar team led by David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, is advancing a novel, nontraditional approach to combat multidrug-resistant P. aeruginosa, based on a synthetic DNA technology called DNA-encoded monoclonal antibodies (DMAbs). In a recent study, Weiner and colleagues developed a targeted DMAb approach for AMR and demonstrated that these DMAbs can effectively control multidrug-resistant P. aeruginosa infection in mice.

This grant will now allow for extension of these studies by providing the researchers with $4,624,553 over four years to further implement the DMAb strategy and move it forward toward clinical development.

The Weiner lab developed DMAb technology by designing genetic sequences directly encoding monoclonal antibodies into an optimized DNA platform. These gene sequences are administered in vivo to be expressed locally at the site of injection. The recipient receives a gene-encoded blueprint instructing their cells to produce the encoded monoclonal antibody specifically targeting the bacteria. DMAbs can be developed simply and quickly and are produced directly in the patient, dramatically lowering production timeline and costs associated with manufacturing of conventional antibodies; furthermore, DMAbs do not require expensive cold chain storage and are suitable for delivery in combinations.

“Engineered synthetic DMAbs represent a transformative approach to the production of biomolecules directly in the patient,” said Weiner. “We are honored to receive this funding and feel it is an important recognition of the promise of DMAbs for the growing threat of antibiotic resistance. This support will move us closer to creating an out-of-the-box tool to fight antibiotic-resistant infections that threaten the lives of thousands every year just in the U.S.”

Co-investigators on the grant are assistant professor Farokh Dotiwala, M.B.B.S., Ph.D., associate professor Daniel Kulp, Ph.D., and research assistant professor Ami Patel, Ph.D., of Wistar’s Vaccine & Immunotherapy Center. Inovio Pharmaceuticals is a collaborator on the grant.

The multidisciplinary team will work collaboratively to enhance the existing P. aeruginosa DMAb platform and develop more potent options with improved antigen binding and receptor engagement. They will be further tested in preclinical models to support translation of this DMAb approach and ultimately move it forward to human studies.

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The Wistar Institute is an international leader in biomedical research with special cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Wistar Science is Launchpad for Creating First MERS Vaccine that Has Completed Phase 1 Human Trial

Written by The Wistar Institute on . Posted in Featured News.

Using enhanced DNA vaccine technology, Wistar scientists can speed the development of vaccines for emerging diseases creating impactful countermeasures against outbreaks.

Wistar’s Drs. Kar Muthumani, David Weiner and collaborators unlocked the R&D potential of synthetic DNA vaccines to develop the first synthetic DNA vaccine for Middle East Respiratory Syndrome (MERS) in 11 months (research published in Science Translational Medicine in 2015). The vaccine entered and completed phase 1 human trials in 2017 and results were published on July 24, 2019 in The Lancet Infectious Diseases.

In 2012, the first MERS outbreak occurred in Saudi Arabia. This virus had never been seen before. Spread through camels and bats, MERS is a highly infectious respiratory disease predominant in the Middle East. Fast forward to 2015, when an individual who had contracted MERS returned to South Korea from the Middle East. This led to a South Korean outbreak that resulted in 186 confirmed cases and 38 deaths. The outbreak affected 24 hospitals, led to the temporary closure of more than 2,000 schools, and had a significant impact on the South Korean economy.* In 2018, The World Health Organization (WHO) listed MERS as a potential public health emergency in the annual review of the Blueprint list of priority diseases.

“MERS was such a new emerging infectious disease that no research on it had been done before the 2012 outbreak,” said Muthumani. “But I knew MERS was similar to Severe Acute Respiratory Syndrome (SARS), so I gathered knowledge of the 2001/2002 SARS outbreaks in China/Asia to guide how we would create a MERS vaccine.”

Wistar’s Vaccine & Immunotherapy Center is currently leading the charge for the development of multiple synthetic DNA-based vaccines. A synthetic DNA MERS vaccine works like this: An injection of a simple DNA plasmid tells the body to generate a foreign protein derived from the pathogen, which then causes the immune system to respond and destroy the MERS virus if it were to infect the body.

Though Muthumani and his team had to start from scratch because no reagents were available to design and test vaccine efficacy, Muthumani’s knowledge of SARS — a coronavirus related to MERS — was the blueprint from which they created reagents, a pseudo-virus and developed immune responses to multiple related strains of MERS.

There are several conceptual advantages to synthetic DNA vaccines compared to other vaccine platforms. DNA vaccines possess virtually no risk of causing disease since no infectious agents are injected into the body. DNA vaccines have had an exceptional safety profile in numerous clinical trials over the last 20 years. Additionally, new technologies allow DNA vaccines to be designed and manufactured quickly and inexpensively, which makes them an ideal platform for dealing with rapidly emerging pathogens that develop in underdeveloped regions of the world.

“With how fast pandemics spread in this day and age, this technology to swiftly craft a vaccine against new threats could be revolutionary,” said Muthumani.

*Centers for Disease Control and Prevention

Why Don’t We Respect Bacteria? First Symposium on Bacterial Resistance at Wistar

Written by The Wistar Institute on . Posted in Featured News.

There is an antibiotic crunch happening globally and to address this stalemate, Wistar hosted its first gathering of top scientists working to combat antibiotic resistance. 

The recent U.K. Review on Antimicrobial Resistance outlines the growth in this problem. It predicts an increase in deaths from antimicrobial resistant (AMR) infections from 700,000 per year today, to approximately 10 million per year over the next 30 years, and that the global economic cost of AMR could reach $100 trillion dollars by 2050. 

Bacterial infections are increasingly resistant to our world collection of antibiotics, which were once our best line of defense. Many of these drugs are no longer effective for treating those same infections, and instead are leading to increasingly drug-resistant diseases, even “superbugs.” 

Wistar recently held a scientific symposium to bring experts together and share in the latest discoveries to combat AMR. The Gram-negative Bacterial Resistance Symposium, supported by Pfizer Inc., was one of the few academic-industry conferences exchanging and exploring new ideas to fighting AMR. It featured leaders from across the nation, including Wistar’s very own Drs. David Weiner, Farokh Dotiwala and Ami Patel who spoke to this “post-antibiotic” era we have entered, and provided a vision of new approaches to head off this growing concern.   

Bacteria – A Global Threat

Bacteria are classified into gram-positive and gram-negative, with gram-negative being more resistant to antibiotics due to a thicker, protective outer membrane as well as containing many internal “pump” proteins that recognize and pump out toxic drugs, allowing them to escape the effects of many current antibiotics. Of the top 10 global AMR threats, seven are gram-negative organisms. The top three most deadly threats are gram-negative infections.   

“The World Health Organization lists antibiotic resistance as one of the biggest threats to global health,” said Weiner, executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, during his opening address. “This topic is central now. For your attendance you have an assignment: We can no longer follow what has been done before, but must lead with new approaches and strategies against gram-negative pathogens!”  

Throughout the day, researchers shared challenges and solutions to better understand multidrug-resistant strains like Acinetobacter baumannii (Iraqibacter), Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli (E. coli), malaria, salmonella, shigella, and gonorrhea.

Presenters like Dotiwala, assistant professor in the Vaccine & Immunotherapy Center at Wistar, are thinking outside the box to find new approaches to getting inside gram-negative bacteria and successfully delivering a new type of drug.

Dotiwala is working on a novel class of antibiotics that would target a niche in bacterial enzymes to kill the bacteria and activate the immune system. His research will lead to highly specific antimicrobial strategies against antibiotic-resistant strains as well as promising anti-cancer immunotherapies.

Patel, a research assistant professor in Wistar’s Vaccine & Immunotherapy Center and a collaborator with the Weiner lab, is applying her research developing synthetic DNA vaccines and synthetic DNA-based monoclonal antibodies (DMAbs) to numerous infectious diseases with the hope of moving new therapies forward. 

Patel discussed how the synthetic DNA platform has the potential to prevent and improve recovery from AMR infections of Pseudomonas aeruginosa, an opportunistic organism that is a serious threat in immunocompromised people. In a hospital setting, it is easily spread and can cause pneumonia, blood infections and urinary tract infections. 

Upon closing the symposium with a panel discussion, Dr. Paul Offit, director of the Vaccine Education Center and attending physician in the Division of Infectious Diseases at Children’s Hospital of Philadelphia, said “The post antibiotic era looks like the pre-antibiotic era.” 

He then held up the 1925 book Arrowsmith by Sinclair Lewis, a fictional story about a phage discovery that cures bubonic plague and saves a South American community. Offit asked the panelists what about bacteriophages as a commercial product are holding us back, at least as a personalized approach for patients with highly intractable diseases. All the panelists agreed that the challenges are great and numerous but, as this day showcased, many promising approaches are underway. 

Dr. Sanjay Ram, professor of Medicine at the University of Massachusetts Medical School, showed promising data targeting N. Gonorrheae with designed antibodies and DNA-encoded monoclonal antibodies and suggested they may be game changing. Dr. Daniel Zurawski, chief of Pathogenesis and Virulence at Walter Reed Army Institute of Research, discussed antibody technologies that may be of particular importance for AMR as they can be combined with traditional antibiotics and tested quickly to limit resistance. Dr. Kathrin Jansen, SVP and head of Vaccine Research & Development at Pfizer Inc., commented on vaccine approaches and how researchers should think in terms of personalized treatments and how new immune tools may be very useful. 

Emily Kramer-Golinkoff made an impassioned presentation to the attending researchers that bacteria resistance constitutes the single greatest threat to the Cystic Fibrosis (CF) community. She has advanced-stage CF and is the founder of Emily’s Entourage, a nonprofit that brings together research, patient, pharmaceutical, and biotech communities to raise funds and accelerate R&D development of therapies to benefit patients who carry nonsense mutations and do not respond to current and breakthrough drugs.

“I feel the pressure of time with every single breath I take,” said Emily. “I speak on behalf of myself and every single person fighting this disease. Our lives, our futures are on your shelves, in your hands, and you are the brilliant researchers uniquely capable of developing and shepherding our life-saving therapies through the pipeline and into clinic in record speed.” 

“There is always a human cost to medical breakthroughs, and we pay the highest human cost when we don’t take on the challenges,” concluded Offit.

Symposium on Gram-Negative Bacterial Resistance
Dr. David Weiner

Synthetic DNA-encoded Antibodies Against Zika Virus Shown to be Effective in Preclinical Studies

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Apr. 5, 2019) — A new approach for delivery of DNA-encoded monoclonal antibodies (DMAbs) has been reported by Wistar scientists and their collaborators. This new technology allows direct production of monoclonal antibody-like molecules in living animals.

In this study, published in Molecular Therapy, the researchers focused on developing novel DMAbs for protection against Zika virus (ZIKV) infection. DMAbs achieved persisting antibody expression that provided long-term protection against lethal virus challenge in both small animal and, for the first time, non-human primate preclinical models. This study provides a direct bridge to the clinic, supporting further development of the new DMAb technology towards wider application.

“We showed that the DMAb platform produces fast and transient but sustained antibody expression in the blood of small and large animal models,” said lead researcher David B. Weiner, Ph.D., executive vice president and director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. “These properties, coupled with the ease of production and storage, support further development of DMAbs as a possibly ideal approach during infectious disease outbreaks to provide rapid protection to at-risk individuals and, in the case of Zika, to their offspring as well.”

Monoclonal antibodies (MAb) are a major category of therapeutic agents with potential for prevention and treatment of a host of infectious diseases. However, development and delivery of MAbs is expensive and limits its applications. The current study advances the novel DMAb technology by showing expression and protection from an infectious challenge.

ZIKV is a mosquito-borne infection endemic to several areas of the world and has become an important global public health concern, with more than two billion people at risk. No approved vaccine or treatment is currently available for ZIKV infection, which is associated with severe birth defects and neurological complications in adults. Survivors develop ZIKV-specific protective antibodies that are being studied as candidates for development of recombinant monoclonal antibodies for preventive use. However, this approach poses challenges related to development, delivery, manufacturing and storage.

The Weiner Lab engineered a synthetic plasmid DNA encoding an identified and developed potent anti-ZIKV monoclonal antibody ZK190 that binds to the virus envelope. When injected as DMAb intramuscularly in mice and non-human primates, DMAb-ZK190 resulted in antibody presence in circulating blood for several weeks to months.

Importantly, when the animals were challenged with a lethal dose of ZIKV, DMAb-ZK190 provided protection from both infection and disease.

“Our study represents the first evidence of protection with a nucleic acid-encoded antibody in a non-human primate model of infection with any infectious agent,” said Ami Patel, Ph.D., first author on the study and a research assistant professor in the Wistar Vaccine and Immunotherapy Center. “This takes us one step closer to clinical development of the DMAb platform for its deployment in the areas where it is most needed.”

Co-authors: co-first author Rianne N. Esquivel, Sagar B. Kudchodkar, Daniel H. Park, Hyeree Choi, Piyush Borole, Kanika Asija, Mamadou Bah, Shareef Shaheen, and Kar Muthumani from Wistar; Karin Stettler and Davide Corti from Humabs BioMed, SA; Jeff Allen, Janess Mendoza, Stephanie Ramos, Jing Chen, Jian Yan, Trevor R.F. Smith, Kate Broderick, Ghiabe Guibinga, and Laurent Humeau from Inovio Pharmaceuticals; Amy C. Durham from the University of Pennsylvania School of Veterinary Medicine.

Work supported by: National Institutes of Health grant T32-AI055400 and a grant from the Bill & Melinda Gates Foundation.

Publication information: In vivo delivery of a DNA-encoded monoclonal antibody (DMAb) protects non-human primates against Zika virus, Molecular Therapy (2019). Advanced online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Dr. David Weiner

Wistar’s David B. Weiner, Ph.D., Awarded Prestigious Scientific Achievement Award from Life Sciences Pennsylvania

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Feb. 15, 2019) — David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, has been named the recipient of this year’s Scientific Achievement Award from Life Sciences Pennsylvania. The organization, with its more than 800-member companies, has a single mission to make Pennsylvania a hub of innovation by creating a business and public policy environment that fosters life sciences growth and success.

“Our Scientific Achievement Award recognizes a scientist in the Pennsylvania life sciences community who has demonstrated outstanding achievement by advancing scientific knowledge, innovation, and/or patient care,” said Christopher P. Molineaux, president & CEO of Life Sciences PA. “We can’t think of a better honoree this year than David – considered a founder of the field of synthetic DNA vaccines with more than 30 years of research contributions and scientific influence.”

At Wistar, Weiner directs a translational research laboratory in the area of novel synthetic nucleic acid technologies. His lab’s accomplishments include the first in human studies of DNA vaccines and DNA-encoded monoclonal antibodies for treating and preventing cancer and emerging infectious diseases, clinically important advances in gene expression, optimization and DNA delivery. His lab developed the first clinically efficacious DNA vaccine and has moved synthetic DNA vaccines for Middle Eastern Respiratory Syndrome (MERS), HIV, Ebola, and Zika through development into clinical studies. Weiner is igniting collaboration to also explore combination therapies for ovarian, prostate, and other cancers.

The Weiner Lab has published more than 400 papers, chapters and reviews. Weiner has received multiple awards and honors, including the National Institutes of Health Director’s Transformative Research Award, the Vaccine Industry Excellence Award for Best Academic Research Team, and his lab was named among the Top 20 Translational Research Laboratories of the Year by Nature Biotechnology. He is president of the International Society for Vaccines (ISV) and is an elected Fellow of the American Association for the Advancement of Science. He was named one of the nation’s top 40 most influential Vaccine Scientists in 2014.

“Since his arrival at Wistar, David has tremendously expanded our research enterprise in infectious diseases and cancer, bringing to clinical testing next generation technologies for vaccine and immunotherapy development,” said Dario C. Altieri, M.D., president and CEO of The Wistar Institute and director of its Cancer Center. “Working in seamless partnership with academia, industry and philanthropic foundations, David is redefining concepts of biomedical innovation and scientific preeminence that will benefit millions.”

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Synthetic DNA’s Role in Advancing Next Generation Checkpoint Inhibitors for Cancer Immunotherapy

Written by The Wistar Institute on . Posted in Featured News.

An innovative and original synthetic DNA platform created by Dr. David Weiner and team at Wistar’s Vaccine & Immunotherapy Center continues to make great strides in cancer immunotherapy.

Monoclonal antibody (mAb) therapy is one of the most successful approaches for cancer treatment, representing a specific method to zero in on a defined molecular target in the tumor. Antibody technology is central for cancer immunotherapy, which relies on the ability of mAbs to take the breaks off our immune system by inhibiting immune checkpoint molecules. Traditional mAbs are created from cell lines in highly sterile manufacturing plants and are difficult and expensive to make. The Weiner Lab has overcome challenges associated with therapeutic antibody production by developing a novel molecular platform that delivers DNA instructions to a patient that allow the patient’s body to become the production site of its own highly personalized mAbs.

DNA-encoded monoclonal antibodies (DMAbs) are the resulting products of DNA-delivered instructions for the body to make monoclonal antibodies using its own protein manufacturing machinery. The Weiner Lab is advancing this novel technology for cancer and infectious disease immunotherapy.

In a study that was recently published in the journal Oncotarget, they created synthetic DNA-encoded checkpoint inhibitor antibodies targeting the PD-1 checkpoint molecule. Preclinical data presented in this study demonstrated that a single injection of the highly optimized DMAb versions of PD-1 checkpoint inhibitors is sufficient to achieve a robust expression that lasts for several months in mice.

These results reinforce the findings of a previous study, published a few months ago in the journal Cancer Research, in which Weiner and colleagues developed synthetic DNA-encoded checkpoint inhibitor antibodies targeting CTLA-4, another important cancer checkpoint molecule that blocks anti-cancer immunity.

References:

Simplifying checkpoint inhibitor delivery through in vivo generation of synthetic DNA-encoded monoclonal antibodies (DMAbs), Perales-Puchalt A. et al., Oncotarget, 2019

Synthetic DNA-encoded monoclonal antibody delivery of anti-CTLA-4 antibodies induces tumor shrinkage in vivo, Duperret E.K. et al., Cancer Research, 2018

Deja Flu: Revisiting Influenza 100 Years Later

Written by The Wistar Institute on . Posted in Featured News.

This year marks the 100th anniversary of the 1918 Spanish lnfluenza outbreak, a pandemic that affected millions around the world. Over the decades, advancements in vaccine medicine have saved countless lives, but new tools are still needed to prevent the flu in vulnerable individuals and to make the vaccine more effective. Wistar hopes its new generation synthetic DNA technology will provide a future strategy for the global toolbox against flu.

Now identified as a strain of the H1N1 flu virus, the Spanish flu was an exceptionally lethal strain that took more lives than World War I and World War II combined — killing 20 to 50 million people in mere months — and indiscriminately claimed not only vulnerable individuals but also strong, seemingly healthy young adults. *

The first wave of the outbreak was a mild form that appeared and spread throughout the United States from birds and farm animals to humans. Then as troops deployed during World War I, it traveled to Europe. The second wave of flu became the deadliest—killing people who would otherwise be categorized as healthy—and the effect of military movement helped the virus spread ultimately to Asia. With no treatment or vaccine in place, there was no way to effectively control the spread.

Philadelphia was one of the many urban areas hit hardest by the 1918 pandemic: more than 50,000 people became infected and 12,000 people died.** At a Liberty Loan Parade taking place in the heart of the city along Broad Street, more than 600 people caught the flu while attending the event. Three days after, the city’s 31 hospitals could not keep up fast enough with the demand to take care of the sick.

100 years later, where do we stand with influenza prevention and what strategies are now available to protect us?

The Bill & Melinda Gates Foundation and the Coalition for Epidemic Preparedness Innovations (CEPI) are two global multinational nonprofit organizations advancing science in the form of experimental research that could best respond to a future outbreak before it becomes a pandemic. They, along with health officials and epidemiologists, monitor how emerging viruses can become global health and economic threats. As the world becomes more and more interconnected and borderless, much can be gleaned from past outbreaks like the Spanish flu with the hopes to use that knowledge to prevent future pandemics.

David Weiner, Ph.D., executive vice president of Wistar, director of Wistar’s Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research, and colleagues are funded by the Gates Foundation and CEPI to advance synthetic DNA-based vaccine and antibody technology.

Every year, multiple strains of the flu virus circulate. Six to nine months before the season starts, researchers make an educated guess about which strains will be most prevalent. However, the flu virus can rapidly mutate throughout the season, causing a vaccine directed against a specific circulating strain to become ineffective. If this happens, there is not enough time to make a new vaccine, since the process traditionally takes five to six months.

The Weiner Lab recently published research in the journal Human Gene Therapy on a synthetic DNA vaccine against influenza A, which is responsible for the most severe influenza seasons of the past decade. Using this technology, Weiner created a vaccine cocktail targeting the most probable flu strains circulating during a season, which can offer broad protection against influenza A viruses. The synthetic DNA vaccine being developed by Weiner and his collaborators delivers genetic instructions into the muscle cells to make them produce specific influenza antigens that trigger an anti-flu immune response. Their studies showed that this approach induced increased immunity and protection compared to traditional vaccine technologies.

Though this technology has not been tested in humans for the flu, it is very promising and provides a glimpse of what a new generation of flu vaccine could be: conceptually more safe, potent, faster to make, and easier to distribute and house—a promising strategy against the global threat of influenza.

*Center for Disease Control and Prevention
** “The Flu in Philadelphia,” PBS.org and “Philadelphia was the epicenter of a deadly worldwide flu epidemic 99 years ago,” phillyvoice.com

Microbiology illustration of prescription drug in the human system

Engineered DNA-encoded PCSK9 Inhibitors May Provide an Effective Alternative for Treating High Cholesterol

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Nov. 15, 2018) — Researchers at The Wistar Institute have developed novel synthetic DNA-encoded monoclonal antibodies (DMAbs) directed against PCSK9, a protein key to regulating cholesterol levels in the bloodstream. Results of preclinical studies showed a significant cholesterol decrease, opening the door for further development of this approach as a simple, less frequent and cost-effective therapy, as reported in a paper published online in Molecular Therapy.

Elevated, low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease, the leading cause of death in the U.S. and worldwide. Statins are effective and widely used cholesterol-lowering medications, but have been associated with a number of side effects that have prompted development of alternative treatment strategies, including monoclonal antibodies targeting the PSCK9 protein that result in reduced degradation of LDL-C receptors on liver cells and increased cholesterol clearance from blood circulation.

“Any therapy based on recombinant monoclonal antibodies faces challenges of production among other issues as molecules may be difficult to manufacture and require multiple administrations,” said lead researcher David B. Weiner, Ph.D., executive vice president, director of Wistar’s Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute. “Anti-PCSK9 therapy presents an important opportunity for development of alternative approaches, possibly expanding options for such therapies.”

Weiner and collaborators engineered synthetic DNA constructs that are delivered by intramuscular injection and encode the genetic instructions for the body to make its own functional monoclonal antibodies, entirely bypassing bioprocess and manufacturing factory approaches. This study provides the first proof of principle that such engineered DMAbs may be developed as a new option for coronary artery disease.

The researchers tested expression and activity of the DMAbs targeting PCSK9 in mice. A single intramuscular administration drove robust antibody expression within days and for up to two months, resulting in a substantial increase in the presence of LDL-C receptors on liver cells. This in turn resulted in a significant decrease in total cholesterol and non-high-density lipoprotein cholesterol (non-HDL-C), an important parameter for evaluating cardiovascular risk.

“We are excited about these findings that support the flexibility and versatility of the DMAb platform as a next generation approach that can be optimized for a wide host of applications,” said Makan Khoshnejad, Ph.D., first author on the study and a postdoctoral fellow in the Weiner Lab.

Co-authors of this study from The Wistar Institute include Ami Patel, Krzysztof Wojtak, Sagar B. Kudchodkar, and Kar Muthumani; other co-authors include Laurent Humeau from Inovio Pharmaceuticals, Inc.; and Nicholas N. Lyssenko and Daniel J. Rader from the University of Pennsylvania.

This work was supported by funding from Inovio Pharmaceuticals, Inc.

Development of Novel DNA-encoded PCSK9 Monoclonal Antibodies as Lipid-lowering Therapeutics,
Molecular Therapy (2018). Advance online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.