A view on

*Repost* Exosomes

In this reposted episode from December 2020, we're exploring how a better understanding of exosomes is leading to new treatments and diagnostic technologies with Uwe Gottschalk. 

According to Uwe, the exosome revolution is already in full march. As researchers begin to identify how these cell-generated, nano-sized delivery drones function in the human body, novel drug delivery prospects are emerging, including applications for cancer, neurodegenerative diseases and spinal cord injury recovery. Perhaps even more exciting is the role exosomes will play in diagnostic applications in the near future, wherein a liquid biopsy, based on a blood sample, would detect cancer or other diseases both more easily and in a more timely fashion than traditional biopsies. One of the many challenges is the ongoing task of defining the manufacturing protocols and processes for this new biotechnological paradigm. Even so, the field is abuzz with new discoveries, trials and general optimism about the potential of these microscopic extracellular delivery vehicles.

Curious to Know More?

Listen to our special, in-house episode of the podcast "A View On" and tune in next time as we are exploring the manufacturing challenges of exosome-based therapies with Codiak Biosciences. 

Episode 5: Importance of Immunogenicity

De-risking Drug Development: Early Testing for Toxicity Saves Time and Resources  

Yvette Stallwood, head of Lonza’s Early Development Services, talks about patient safety and other advantages of early testing for immunogenicity in the drug development pipeline.

 

In the high-stakes drug discovery game, from IND filings all the way up through the clinical trial phase, regulatory authorities are now expecting developers to have an immunogenicity risk strategy in place. “It really is essential that drug developers assess the immunogenicity risk as early as possible in the pipeline, as not only can it impact the functionality of the drug, but it can also be a significant safety risk for the patient,” explains Yvette Stallwood, whose work at Lonza’s Early Development Services (EDS) is helping small and large biotech companies reduce risk with a “Right First Time” approach when developing drug therapies.

Drug candidates often fail during clinical trials due to their toxicity to patients, which is evident, for example, in an immunogenic reaction—where the drug triggers an unwanted immune response known as immunotoxicity. This can result in the loss of years of work and funding. Stallwood and her team encourage their clients to begin with in-silico testing, where up to a thousand digital models of potential immunoresponses can be predicted.  Once the digital models show a candidate to have a low risk of toxicity, the EDS team then moves to human donor cell assays—with the advantage of screening up to fifty different immunotypes. The ideal time to assess immunosafety and immunotoxicity is well before deciding on a molecule as a lead drug candidate. By understanding as much as possible about the potential product through early testing, biotech companies are better equipped to take the correct path to regulatory approval with a drug that is ultimately safer for patients.

Curious to Know More?

Listen to the conversation between A View On host Martina Hestericová and Lonza’s head of EDS Yvette Stallwood as they discuss de-risking the drug development process.

 

KEY TERMS IN CONTEXT:

Anti-drug antibody (ADA) response happens when the patient’s immune system generates antibodies to remove and clear the drug from the body. This can impact the effectiveness of the drug molecule as well as be dangerous for the patient.

Immunogenicity testing is the process by which one can test for the body’s immune response to a drug. With in-silico testing, the screening can be done quickly for a large swath of different immune system typologies before moving on to animal models or, preferably, human cell assays.

Immunosafety and immunotoxicity refer to how potentially safe or toxic the immune system’s reaction to a molecule may be. They deserve the utmost consideration when developing a leading drug candidate.

De-risking is an EDS drug development strategy to ensure clients select the right drug candidate at the approval phase. De-risking avoids costly clinical trial failure through extensive immunotoxicity testing early in the process.

In-silico testing uses computer models to test a molecule’s reaction within an organism, such as a human immune system. The advantage is that they are quick and can test in hundreds and thousands of models. Since they are limited in their nature, they are only a first step. Once a drug candidate is selected as low risk using in-silico testing, further testing is needed using animal models or human cells assays.

Human cell assays, in the context of drug development de-risking, are in-vitro tests that use actual human immune cells to test immune system responses to drug candidates. Although they are more costly and time-consuming than in-silico testing, the precision they offer is essential to establish the appropriate data for selecting lead drug candidates.

Episode 4: Microbiome

Host and Health: Tailoring Personalized Medicine Using The Unique Microbiome Fingerprint 

Professor Eran Elinav from the Weizmann Institute of Science discusses how the interaction between the microbiome and its host is transforming personalized medicine.

 

“I believe that in the next five to ten years, exploiting the potential of the microbiome will be central to personalized and precision medicine,” explains Eran Elinav. His research into this second genome in the human body at the Weizmann Institute of Science in Isreal is shedding light on how these trillions of cells function and interact with their host. The individualized data from the unique microbiome fingerprint can be harnessed to tailor nutritional therapies to improve metabolic functions in the treatment of, for example, obesity and type 2 diabetes—with a wide range of further potential applications. And even small molecules found within the microbiome could themselves be developed into drugs. The future hope lies in the inherent therapeutic translatability of these insights from host-microbiome interaction research into treating the whole spectrum of metabolic diseases.

 

Curious to Know More?

Listen to the conversation between Lonza’s Martina Hestericová and Weizmann Institute of Science Professor and researcher Eran Elinav in this special episode of the "A View On" podcast.

KEY TERMS IN CONTEXT:

Genome: All of the genetic information of an organism. When speaking about the microbiome, it refers to an entirely different organism that is comprised of its own genetic makeup from the host—the interaction between the two genomes is the subject of study known as host-microbiome interaction.

Microbiome: The extremely diverse ecosystem of hundreds, sometimes thousands of different species of microbes found in and on the human body. Microbial biodiversity is key to a healthy microbiome and a poor microbiome is linked to diseases such as inflammatory bowel disease, cancer and possibly some central nervous disorders.

Therapeutic translatability: The ability to translate or apply basic research into therapies for the benefit of humans. As we understand more how the complex microbiome works, Professor Elinav asserts that these insights translate directly into ways to manipulate it and improve health.

Personalised or Precision Medicine: A general trend to adapt treatments to individuals instead of a one-size-fits-all approach. In the context of host-microbiome research, as the microbiome is unique to each individual, it could hold the keys to specialized treatments by harnessing the individualized data.

Episode 3: Antibody Biopolymer Conjugates for Ophthalmology

Bridging Business and Biotechnology: Kodiak Sciences Is Increasing Treatment Efficacy for Retinal Diseases

Victor Perlroth, MD, the Chairman and CEO of Kodiak Sciences, discusses how the company’s ABC platform medicines are designed to treat the leading causes of blindness.

 

Age-related macular degeneration (AMD) is one of the leading causes of blindness in adults worldwide. This disease deteriorates the macula, a miraculous little spot on your retina that allows for precise vision in good light. Although several treatments exist for macular deterioration, they require frequent trips to the doctor’s office for uncomfortable but quick and routine injections directly into the eye. The required frequency of the treatments means that most patients miss appointments, leading to undertreatment of the disease and permanent vision loss. In a manufacturing collaboration with Lonza, Kodiak is designing novel antibody-biopolymer conjugate (or ABC) medicines with the same efficacy and safety with much longer durability, allowing patients to visit the doctor on a realistic schedule over the long term. By focusing on business implementation alongside formidable biotech R&D, Kodiak Sciences is on track to bring together the necessary clinical and manufacturing elements for an FDA filing in 2023.

 

Curious to Know More?

In this most recent episode of “A View On,” Lonza’s Martina Hestericová is joined by Victor Perlroth, MD, the Chairman and CEO of Kodiak Sciences, to talk about the recent developments in AMD treatment research.

 

 KEY TERMS:

 

Age-related macular degeneration (AMD) is a common degenerative disease of the retina. There are two types of AMD:

Dry AMD occurs when the formation of debris (drusen) on the retina causes the macula to deteriorate over time. Patients sometimes experience vision loss and frequently experience substantial functional limitations, including vision fluctuations, loss of peripheral vision, and reduced night vision.

Wet AMD is an advanced form of AMD. While wet AMD represents only 10% of the number of cases of AMD overall, it is responsible for 90% of AMD-related cases of severe vision loss. Wet AMD occurs when the growth of abnormal blood vessels underneath the macula leads to leakage of fluid and blood, which leads to visual distortion, acute vision loss, and total blindness if left untreated.

Vascular endothelial growth factor (VEGF) is a sub-family of factors that stimulate the growth of blood vessels. In the case of AMD, these VEGF are overexpressed, creating leaking in the macula. This leakiness causes fluid to exit from blood vessels, causing swelling – or edema – of the retina and loss of vision.

An antibody biopolymer conjugate (ABC) is Kodiak Science’s proprietary platform for designing and developing drugs into the retina. The antibody in the KSI-301 molecule inhibits VEGF, while the biopolymer is comprised of phosphorylcholine, which creates a sort of “water cloak” around the antibody to increase its effectiveness.

Phosphorylcholine is a natural component of the cell membrane of all the cells in our body, with remarkable properties. It attracts and binds water in a very strong – even permanent – way, creating what is known as “structured water,” which then impacts all biological interactions in the local area.

Episode 2: Horseshoe crabs and recombinant factor C

Safe Jabs Thanks to Horseshoe Crabs: Making Sure Your Injection is Free of Endotoxins

Allen Burgenson, Lonza’s expert for all things testing, speaks to us about the dangers of endotoxin contamination and the future of non-animal testing for it.

 

“Before testing for endotoxins in the 1940s, a physician literally had to gauge the risk to your life because of something called injection fever,” explains Allen Burgenson. Luckily, we’ve come a long way since then. Thanks to advanced testing methods, one can rest assured today that any sort of injection or implant is completely free of dangerous endotoxins. Currently, the predominant mode is Limulus Amebocyte Lysate (LAL) testing, in which scientists harvest the bright blue blood of American Horseshoe Crabs and use the animal’s primitive immune system to look for clotting reactions that would indicate the presence of any endotoxins. The horseshoe crabs, Burgenson explains, survive the extraction unscathed and are safely returned to the waters in less than 24 hours. However, in a continual attempt to remove animals from the testing pipeline, Lonza’s recombinant factor C assay known as PyroGene could eventually replace LAL testing.

Curious to Know More?

In Episode 2 of the new season of the podcast A View On, host Martina Ribarhestericova speaks with Lonza expert Allen Burgenson to discuss his close bond with the American Horseshoe Crab and the history of testing for endotoxin contamination.

 

 KEY TERMS:

Endotoxins are parts of bacterial membranes that could lead to a harmful reaction – or even death – if they enter a patient’s bloodstream or spinal fluid. Surprisingly, we have kilograms of endotoxins in our stomachs, but even little more than a nanogram in the bloodstream could be deadly.

Bacterial endotoxin tests, or BETs, is the general name for all assays used to detect endotoxins.

Rabbit pyrogen tests are BETs that were developed in the 1940s using rabbits as test subjects. To ascertain the endotoxic danger to humans, the scientist observes a rabbit’s reaction to an injection over a period of 3 hours. The European Pharmacopoeia Commission decided in June 2021 to completely replace the rabbit pyrogen test (RPT) within approximately 5 years.

Limulus Amebocyte Lysate (LAL) is an aqueous extract of blood cells (amoebocytes) from the horseshoe crab, Limulus Polyphemus, that enables batch testing of vaccines and other drugs for endotoxins. The crab’s extracted blood is a surprising blue color due to the crabs’ copper-based Hamasyan. The obtained LAL is an opaque white-colored liquid that clots in the presence of any toxicity.

PyroGene recombinant factor C is an animal-free way to test for endotoxins. It was initially developed at the National University of Singapore by Lin Deng and her husband Bo Ho to save money on testing at their relatively small lab. Lonza collaborated with Deng and Ho to become the first company to offer the test on a commercial scale.

Episode 1: Oncolytic viruses

A Welcome Virus: Cracking the Viral Code for the Battle Against Cancer

Chairman and founder of PsiVac, Prof. Ghassan Alusi, and the chief operating officer, Imad Mardini, discuss how the company’s proprietary oncolytic virus platform offers new hope for cancer patients.

During a time when everyone actively fears viruses (especially THE virus) and their mutations, it is only cancer cells that have cause to worry about oncolytic viruses, and rightly so. These mutated viruses are administered directly into a tumor. Once inside, they crack open the tumor’s cells in a process known as lysing that provokes a strong response from the body’s immune system, which has, until then, ignored the cancerous cells. What’s more, the therapy’s attack doesn’t stop at a single tumor. The replicating and lysing viruses release previously hidden tumor-associated antigens (TAAs) that alert the immune system about cancer cells to attack all over the body. The body’s own immune system then goes on to destroy previously unrecognized tumors far removed from the initial injection point.

The biotech company PsiVac advances this technology even further by creating a treatment platform that transforms the adenovirus, aka the common cold, into an especially powerful oncolytic virus. A precision modification in the virus’s DNA improves its efficiency against cancer cells while making it harmless to other cells, rendering the treatment at once more effective and safer for patients.

“Now that the technologies of other forms of immunotherapy are gaining ground, and as cancer remains a major cause of mortality, we now understand there is a huge need for oncolytic viral therapy,” says Prof. Alusi, whose company has planned to start Phase 1 clinical trials later this year. Unlike other immunotherapies, such as patient-centric CAR T-cell therapy, oncolytic viruses can be made in relatively large quantities once their efficacy and safety have been proved.

 

Curious to Know More?

In the first episode of the new season of the podcast A View On, host Martina Ribar Hestericová discusses the current state of oncolytic viruses and their promising applications with Prof. Ghassan Alusi and Imad Mardini.

 

 KEY TERMS:

Cell lysing is the process of breaking down a cell’s membrane, destroying the cell and releasing its contents into the body. If an oncolytic virus lyses a cell, it releases replicated versions of itself as well as antigens helpful in the immune system’s fight against a tumor.

Tumor-associated antigens (TAAs) are released once a cancer cell is lysed, setting the previously dormant immune system into action. The release of TAAs means that the tumor is no longer successfully hiding from the immune system, and the body can begin to fight the disease by its own means.

The cytotoxicity of a virus is the extent to which a virus attacks and destroys cells, often an undesirable event. However, with oncolytic viruses, this cytotoxicity works in a patient’s favor, thanks to gene editing, by being specifically designed to attack cancer cells.

An agnostic oncolytic virus targets not only one or a group of cancers but is effective against all malignant solid palpable tumors. PsiVac’s modified adenovirus has proven agnostic so far, making it a powerful weapon in the fight against cancer.

Episode 11: Season 1 recap

It’s the season finale for A View On, the Lonza podcast. Over the past 12 months of our initial run, we have brought you a series of conversations exploring the new pharma and biotechnology trends. We spoke to Lonza and the industry experts and discussed exciting topics, such as exosomes, stem cells, drug product testing, bioprinting, and much more.

In the latest episode, the podcast host, Lonza’s Martina Ribar Hestericová, recaps the highlights from this season and looks forward to later this year for what is coming up in the next season.

Interested to learn more? Visit our dedicated podcast site on www.lonza.com/a-view-on and don't forget to subscribe!

Episode10: Phage Therapy

Devouring Bacteria: How Phage Therapy Is Shaping Antibacterial Treatments of the Future

In this episode we speak with the CEO of BiomX, Jonathan Solomon, about producing and using phages to test and treat various diseases and conditions.

Until very recently, treating a condition such as acne with an army of microscopic bacteria-destroyers known as phages—bacterial viruses that target and kill specific bacteria—would have seemed highly unlikely. However new research linking acne to an imbalance in the skin’s microbiome has opened the door to innovative treatment approaches. That’s where the biotech company BiomX comes in. Uniting powerful computational science with the inherent capacity of phages to destroy specific bacteria, BiomX creates natural and synthetic phage therapies for some of the most troublesome bacteria-related health issues: acne, atopic dermatitis, cystic fibrosis, inflammatory bowel disease (IBD) and even colorectal cancer. For acne the company has developed a successful cocktail of three different phages to treat the condition, with phase 2 testing close on the horizon. BiomX’s developments in phage therapy promise to change the way we treat imbalances in our microbiome, with potential health benefits for large swaths of the population.

Curious to Know More?

To learn more about BiomX, listen to the conversation with Jonathan Solomon on this episode of A View On: Phage Therapy.

KEY TERMS:

Bacteriophage (also known as a phage): A virus that attacks and devours only bacteria (‘phagein’ in Ancient Greek means to devour). Bacteriophages are bacteria-specific, which is both an advantage and disadvantage in manufacturing treatments. Fun fact: taken altogether, bacteriophages are the most numerous entity on the planet.

Phage cocktail: Since a phage targets and destroys only one type of bacteria, treatments for complex ailments necessitate a mixture, or cocktail, of different phages to be effective.

Phage fermentation: Although destructive, unwanted phages can grow during fermentation processes for wine-making and milk production, fermentation is nevertheless the optimal way to produce phages for therapeutic uses.

Computational (science): Computer modelling of the phage and its potential interaction with specific bacteria (known as in silico testing) allows researchers to develop phage cocktails more efficiently and with a greater chance of success.

Episode 9: Streamlining the cell and gene therapy manufacturing

Delivering Personalized Therapies: Streamlining the Supply Chain for a New Generation of Treatments

In this episode, we speak with Amy DuRoss, Co-Founder and Chief Executive Officer of Vineti, about the challenges facing "just-in-time" manufacturing and delivery of personalized therapies—and the solutions her digital startup provides.

 

According to Amy DuRoss, the COVID-19 vaccine distribution has exposed existing deficiencies in the entire pharmaceutical supply chain. This situation echoes, albeit on a far smaller scale, the distribution complexities of delivering cell and gene therapies (CGT). Unlike more traditional treatments, CGT requires the extraction of live cells from a patient or donor to then be delivered to a manufacturer and make it back to the patient in a timely manner. Her company Vineti "introduces a new level of fidelity, control, and transparency" into the personalized drug delivery process, streamlining CGT distribution through a novel digital orchestration platform. Based on an astute understanding of the behavior of care providers, specialized couriers and CGT manufacturers, her company has developed a software infrastructure that supports this exponentially complex delivery process. By facilitating Good Manufacturing Principles for all required stakeholders in the advanced therapy process, the Vineti platform ensures regulatory compliance and maintains both Chain of Identity and Chain of Custody from cell collection to manufacturer and back to the patient.

 

Curious to Know More?

Take a listen to this episode of A View On: Streamlining Cell and Gene Therapy Manufacturing to learn more about Vineti. At the end of the discussion, as a bonus for our listeners, Amy DuRoss offers insight into some of the difficulties encountered in the COVID vaccine rollout, and how it parallels the complexity of the supply chain for CGT.

 

KEY TERMS:

 

Personalized medicine and therapies, such as cell and gene therapies (CGT), treat patients on a much more individualized basis. They require an unprecedented level of automation and navigation because the materials used to prepare the end product are raw cells originating from a donor or a patient.

Good Manufacturing Principles (or Practices), GMP for short, are practices that ensure adherence to the guidelines put forth by regulatory agencies. They apply to any manufacturing industry but reach an unparalleled level of complexity in CGT production due to the implication of health care providers in the cell extraction and donor matching processes.

A digital orchestration platform such as Vineti's uses the power of data management and user experience design to organize and execute an effective supply chain system in the face of exceptional complexity and strict regulations.

Chains of Identity and Custody in the pharmaceutical supply chain are the cornerstones of regulatory compliance, whereby each step in the process and each individual involved is transparently identifiable in order to reduce the risk of contamination and to eliminate fraud. With CGT production, the process of extracting the raw materials for the treatment directly from the patient or donor multiplies the Chains of Identity and Custody, exponentially increasing the supply chain complexity.

Episode 8: Exosomes

Exosomes Know Where To Go: Using the Body's Own Cell-to-Cell Communication Network for Diagnostics and Drug Delivery

We speak with Uwe Gottschalk, the Chief Scientific Officer of Lonza, about how a better understanding of exosomes is leading to new treatments and diagnostic technologies.

 

According to Uwe Gottschalk, the exosome revolution is already in full march. As researchers begin to identify how these cell-generated, nano-sized delivery drones function in the human body, novel drug delivery prospects are emerging, including applications for cancer, neurodegenerative diseases and spinal cord injury recovery. Perhaps even more exciting is the role exosomes will play in diagnostic applications in the near future, wherein a liquid biopsy, based on a blood sample, would detect cancer or other diseases both more easily and in a more timely fashion than traditional biopsies. One of the many challenges is the ongoing task of defining the manufacturing protocols and processes for this new biotechnological paradigm. Even so, the field is abuzz with new discoveries, trials and general optimism about the potential of these microscopic extracellular delivery vehicles.

Curious to Know More?

Lonza's Chief Scientific Officer gives us his expert insight into exosome research and application in this special, in-house episode of the podcast "A View On."

 

KEY TERMS:

Exosomes are nano-sized delivery vehicles generated by all eukaryotic cells. They are between roughly 30 and 120 nanometers large and originate when endosomes, or intercellular vesicles, are released into the blood, milk or tissue. They then become messengers and surrogates for the original cell. Their surface markers represent a location code and spread through the extracellular space in the body to communicate with other cells and deliver packages.

Extracellular vesicles (EV) are particles released from cells that cannot replicate but otherwise behave like the surrogate cells from which they originate. While there is some overlapping in definition between exosomes and EVs—all exosomes are extracellular vesicles but not vice-versa—exosomes are defined by their size (30 to 120 nm) and their biogenetic origin.

Liquid biopsy: As with a traditional biopsy, a liquid biopsy is a test to diagnose and monitor diseases that uses a blood sample instead of a tissue sample. As a liquid biopsy is not restricted to one tissue or part of the body, the test is less invasive, cheaper and even more precise.

Messenger RNA (mRNA) as a cancer biomarker:  Recent research has proven that mRNA from a blood test can be analyzed to find cancerous and pre-cancerous tumors throughout the body. As exosomes transport and stabilize the otherwise highly unstable mRNA, they could be targets for early detection and treatment in the near future.