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Most people on Earth are genetically more similar than different; however, small differences are important in respect of how experts understand complex diseases.

First published in the Daily Maverick 168 weekly newspaper.

The largest genetic study ever undertaken of South Africans has challenged the presumption that all southeastern Bantu-speaking groups are a single genetic entity and this has a huge implication for the study of diseases.

The southeastern Bantu language family includes isiZulu, isiXhosa, siSwati, Xitsonga, Tshivenda, Sepedi, Sesotho and Setswana. Despite linguistic differences, these groups of people are treated mostly as a single group in genetic studies.

Almost 80% of South Africans speak one of the southeastern Bantu languages as their first language. Their origins can be traced to farmers of west central Africa, whose descendants over the past 2,000 years spread south of the equator and into southern Africa.

Professor Michle Ramsay, director of the Sydney Brenner Institute for Molecular Bio-science at the University of the Witwatersrand University (Wits) and the corresponding author of the study, said to investigate this, the largest study with genome-wide genotyping in South African populations was undertaken with 5,000 participants. This is a very detailed analysis of genetic markers across the whole genome.

The research, published in the journal Nature Communications, was carried out by a multidisciplinary team of geneticists, bioinformaticians, linguists, historians and archaeologists at Wits University, including Ramsay, Dhriti Sengupta, Ananyo Choudhury, Scott Hazelhurst, Shaun Aron and Gavin Whitelaw, along with experts at the University of Limpopo and partners in Belgium, Sweden and Switzerland.

The archaeological record and rock art evidence trace the presence of a San-like hunter-gatherer culture in southern Africa to at least 20,000 to 40,000 years ago.

Three sets of migration events have dramatically reshaped the genetic landscape of this geographic region in the last two millennia. The first of these was a relatively small-scale migration of east African pastoralists, who introduced pastoralism to southern Africa about 2,000 years ago. This population was subsequently assimilated by local southern African San hunter-gatherer groups, forming a new population that was ancestral to the Khoekhoe herder populations.

Today, southern African Khoe and San populations collectively refer to hunter-gatherer (San) and herder (Khoekhoe) communities. While Khoe-San groups are distributed over a large geographic area today (spanning the Northern Cape province of South Africa, large parts of Namibia, Botswana, and southern Angola), these groups are scattered, small and marginalised.

The introduction of pastoralism in the region was closely followed by the arrival of the second set of migrants, that is the Bantu-speaking agro-pastoralists. The archaeological record suggests that ancestors of the current-day [Bantu-speaking] populations undertook different waves of migration instead of a single large-scale movement.

The earliest communities spread along the east coast to reach the KwaZulu-Natal south coast by the mid-fifth century AD, while the final major episode of settlement is estimated to be around AD1350. These archaeologically distinct groups gradually spread across present-day South Africa, interacting to various degrees with the Khoe-San groups giving rise to South Africas diverse [Bantu-speaking] communities.

The third major movement into southern Africa was during the colonial era in the last four centuries when European colonists settled in the area. During this period slave trade introduced additional intercontinental gene flow giving rise to complex genomic admixture patterns in current-day southern African populations.

Since these migrations took place, varying degrees of sedentism (the practice of living in one place for a long time), population movements and interaction with Khoe and San communities, as well as people speaking other southeastern Bantu languages, ultimately generated what are today distinct southern African languages such as isiZulu, isiXhosa and Sesotho.

Despite these linguistic differences, these groups are treated mostly as a single group in genetic studies. Understanding genetic diversity in a population is critical to the success of disease genetic studies. If two genetically distinct populations are treated as one, the methods normally used to find disease genes could be error-prone.

Most people on Earth are genetically more similar than different; however, small differences are important in respect to how experts understand complex diseases.

Southeastern Bantu speakers have a clear linguistic division they speak more than nine distinct languages and their geography is clear: some of the groups are found more frequently in the north, some in central, and some in southern Africa. Yet despite these characteristics, the [southeastern Bantu language] groups have so far been treated as a single genetic entity, said Choudhury.

These groups are too different from each other to be treated as a single genetic unit, the research has shown.

We wanted to see whether this population sub-structure could interfere in studies on diseases susceptibility. What we showed is that if you do a study in South Africa on people who self-identify as southeastern Bantu speakers, one cannot treat them as a homogeneous group.

So, if you are treating, say, the Tsonga and the Xhosa as the same population as was often done until now you might get a completely wrong gene implicated for a disease, said Sengupta. There are not major differences, but small cumulative differences in populations that were geographically isolated for about 1,000 years and who encountered and mixed in different ways with other populations (for example the Khoe and San). Many of the differences may not have any phenotypic [observable physical traits] implications, but some may be related to markers that are associated with susceptibility to diseases, said Ramsay.

We wanted to see whether this population sub-structure could interfere in studies on diseases susceptibility. What we showed is that if you do a study in South Africa on people who self-identify as southeastern Bantu speakers, one cannot treat them as a homogeneous group.

If you are doing a case-control study to find genetic markers for association with common diseases like diabetes, cancer or hypertension, and your study cases are predominantly from people of one ethnolinguistic group and your controls are from another, you may find associations that are due to ethnic differences and not association with the disease. So you could make the wrong assumptions about what caused susceptibility to a particular disease, Ramsay added.

A common approach to identify if a genetic variant causes or predisposes a person to a disease is to take a set of individuals with a disease (such as high blood pressure or diabetes) and another set of healthy individuals without the disease, and compare the occurrence of genetic variants in the two sets. If a variant shows a notable frequency difference, it is assumed that the genetic variant could be associated with the disease.

However, this approach depends entirely on the underlying assumption that the two groups consist of genetically similar individuals. One of the major highlights of our study is the observation that Bantu-speakers from two geographic regions or two ethnolinguistic groups cannot be treated as if they are the same when it comes to disease genetic studies, said Choudhury.

The study detected major variations in genetic contribution from the Khoe and San into southeastern Bantu-speaking groups; some groups have received a lot of genetic influx from Khoe and San people, while others have had very little genetic exchange with these groups. This variation ranged on average from about 2% in Tsonga to more than 20% in Xhosa and Tswana.

The study showed that there could be substantial errors in disease gene discovery and disease risk estimation if the differences between south-eastern Bantu-speaking groups are not taken into consideration, said Sengupta.

The genetic data also show major differences in the history of these groups over the past 1,000 years. Genetic exchanges were found to have occurred at different points in time, suggesting a unique journey for each group over the past millennium.

These genetic differences are strong enough to impact the outcomes of biomedical genetic research.

Sengupta emphasised that ethnolinguistic identities are complex and cautioned against extrapolating broad conclusions from the findings: Although genetic data showed differences between groups, there was also a substantial amount of overlap. While findings regarding differences could have huge value from a research perspective, they should not be generalised, she said.

Ramsay said: We would love to expand the Southern African Human Genome Programme we started in 2011 with funding from the Department of Science and Innovation. We had ambitions to sequence 10,000 South African genomes, but there was no funding for this. It is important to consider what we want to achieve from a scientific point of view and then to assess the sample size that would be needed to achieve our goals. These same samples and their associated phenotype data are also being used to do many other studies on genetic associations with cardiometabolic diseases.

The effort is also part of the broader Human Heredity and Health in Africa (H3Africa) consortium, a collaboration between the African Society of Human Genetics, the National Institutes of Health in the US and the Wellcome Trust, to boost the study of genomics and the environmental determinants of diseases that are common among African populations.

Professor Ambroise Wonkam, director of Genetic Medicine of African Populations at the University of Cape Towns Division of Human Genetics, has a vision to work through H3Africa to sequence the genomes of three million people from across the continent. Less than 2% of all human genomes analysed to date have been those of people of African ancestry.

The reference genome sequences built from the Human Genome Project are missing many variants from African ancestral genomes. A 2019 study estimated that a genome representing the DNA of the African population would have about 10% more DNA than the current reference, he writes in Nature. DM168

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How migration events have dramatically reshaped the genetic landscape of Africa - Daily Maverick

Newswise The living organism is kept alive and healthy by an intricate network of biochemical processes. These are remarkably resilient in responding to changes in the environment, but they can sometimes go wrong. A key tenet of medicine is to understand these pathways in order to treat disease more effectively.

Now a research team, led by Professor Daniel Tenen of the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), has found a major molecular switch that controls how cells turn their genes on and off. This process ensures the cell correctly and adequately performs its assigned tasks in the body.

The scientists used hematopoietic stem cells as a case study. These are vital cells that replenish the bodys blood cells throughout life.

A cells genes are encoded in long DNA strands, which are coiled up into highly elaborate structures called chromosomes. For the correct genes to be expressed at the correct times and in correct amounts in the cell, the shape of the chromosomes must be adjusted constantly. This is done by a protein called CTCF, which binds to parts of the DNA that have a particular sequence of codes and makes a loop in the DNA that activates the necessary gene.

However, the scientists found another protein called ZF143 that controls the activity level of CTCF. This so-called zinc finger protein has a protruding molecular appendage that holds a zinc atom and gives the protein the desired chemical properties.

The scientists deactivated ZNF143 by locating and deleting its gene using molecular markers. They found that hematopoietic stem cells without ZNF143 were unable to make new blood cells. In this case, it could cause serious diseases like anaemia.

The teams findings were published in the journal Nature Communications on 4 January 2021.

Their discovery will likely improve the understanding of how normal stem cells function, and could possibly lead to insights into disease. Prof Tenen said, Findings from this study has advanced our understanding of the regulatory mechanisms of CTCF-DNA binding and gene expression. It will be of great interest to investigate whether these findings have relevance to developmental disorders and cancers.

Moving forward, the team plans to study the molecular structure of the proteins involved to further understand the process and how it can be modified.

View the full press release at: https://news.nus.edu.sg/nus-scientists-found-a-key-element-that-affects-how-genes-are-expressed-in-blood-stem-cells/

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NUS scientists found a key element that affects how genes are expressed in blood stem cells - Newswise

Theres a new autoimmune disease player in town: Esker Therapeutics has raised $70 million to work on a new, focused way that can go beyond some of the limitations of JAK1 drugs.

That series A cash comes from Foresite Capital, and, while it has some earlier programs, the main focus for now is on TYK2 inhibitor ESK-001, initially for psoriasis.

TYK2 is a gene that encodes a member of the tyrosine kinase and the well-known Janus kinases (JAKs) protein families. It is a central node in the signaling pathways of cytokines known to be key mediators of inflammation and autoimmune diseases.

In preclinical studies, Esker says its asset showed potent and highly selective TYK2 inhibition, while avoiding unwanted side effects often seen with JAKs.

This put its in the same space as Bristol Myers Squibb and its TYK2 deucravacitinib, which recently outperformed Amgens Otezla in a phase 3 clinical trial of patients with moderate to severe plaque psoriasis and is much closer to a possible approval.

RELATED: AbbVie's Rinvoq rollout on track despite JAK safety concerns, but uncertainty remains: analyst

While looking into psoriasis first, with a phase 1 now ongoing, it will hope to move beyond that into more autoimmune targets, and it hopes bring in the sort of blockbuster sales seen with older meds that have gone after the same indications, like AbbVies Humira.

Autoimmune diseases are the third most common cause of chronic illness. In the U.S. alone, they impact 25 million people and cost more than $100 billion annually, said June Lee, M.D., founder, president and CEO of Esker Therapeutics.

While a number of targeted therapies have emerged in recent decades, response rates to treatments are low, and there remains a significant need for treatments that are specific to certain patient populations and that can be tolerated over long periods of time. Our goal at Esker is to rewrite the autoimmune treatment playbook by developing the right medicine for each patient.

There is also a precision analytics platform powered by Foresite Labs that comes with the biotech. This platform comprises high-quality curated genetic, clinical and health records data, a systems immunology toolkit for prospective data collection and tools for building patient registries, according to the biotech.

Our knowledge of the central molecular players in autoimmune diseases has been greatly enhanced through insights from human genetics and systems immunology, added Vik Bajaj, Ph.D., co-founder and CEO of Foresite Labs and managing director at Foresite Capital.

This platform is already being applied to advance Eskers lead program, ESK-001, in psoriasis, and we believe its utility across autoimmune disease is far larger. We are proud to support Dr. June Lee in launching this transformative company.

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Esker Therapeutics launches with $70M and a focused approach for autoimmune diseases beyond JAKs - FierceBiotech

PHILADELPHIA, May 5, 2021 /PRNewswire/ --When Luke Terrio was about seven months old, his mother began to realize something was off. He had constant ear infections, developed red spots on his face, and was tired all the time. His development stagnated, and the antibiotics given to treat his frequent infections stopped working. His primary care doctor at Children's Hospital of Philadelphia (CHOP) ordered a series of blood tests and quickly realized something was wrong: Luke had no antibodies.

At first, the CHOP specialists treating Luke thought he might have X-linked agammaglobulinemia (XLA), a rare immunodeficiency syndrome seen in children. However, as the CHOP research team continued investigating Luke's case, they realized Luke's condition was unlike any disease described before.

Using whole exome sequencing to scan Luke's DNA, CHOP researchers discovered the genetic mutation responsible for his condition, which prevents Luke and patients like him from making B cells and antibodies to fight infections. The study describing Luke's condition, which CHOP researchers named PU.1 Mutated agammaglobulinemia (PU.MA), was published today in the Journal of Experimental Medicine.

"It can be pretty scary for a family whose child has a mysterious illness" said Neil D. Romberg, MD, an attending physician with the Division of Allergy and Immunology at CHOP and senior author of the paper. "In this case, science provided an explanation, thanks to numerous departments at CHOP, including the Roberts Individualized Medical Genetics Center, the Center for Spatial and Functional Genomics, and the Cancer Center. Understanding the cause of Luke's condition absolutely helped us know what direction to take his therapy."

"I was so impressed with how all of the specialists at CHOP worked together as a team, even though they specialized in different areas," said Luke's mother, Michelle. "They knew something was wrong with Luke, and they didn't stop digging until they figured it out."

Figuring Out the "Why"

To pinpoint the gene at fault, CHOP researchers compared whole exome sequences from 30 patients across the globe who were born without B lymphocytes, the cells which produce antibodies. From the larger group, they identified six patients, including Luke, who had a mutation in a gene called SPI1, which encodes the PU.1 protein. PU.1 helps B lymphocytes developing in bone marrow to open up "doors" in their chromatin, a type of tightly packed DNA. Without PU.1, those door remains shut, and the B cells never form. The six PU.MA patients, who ranged in age from 15 months to 37 years, each had different SPI1 mutations but shared insufficient levels of PU.1, absent B cells and, consequently, zero antibodies.

To validate the roles of SPI1 and PU.1, the researchers used CRISPR to reconstitute the condition in vitro. Using donated cord blood of patients who lacked SPI1 mutations, the researchers employed CRISPR to edit the patients' SPI1 mutations into the donated cord blood genes. After culturing the cells for six weeks and sequencing the cells that survived, they found B cells were specifically intolerant of PU.1 changes.

Treatment Without a Playbook

Because Luke's condition was entirely new, there was no playbook for his family or his medical team to follow. After consulting with the research team, the family decided to proceed with a bone marrow transplant in the hope that the procedure would help him make his own B cells and antibodies. Soon they discovered they had a perfect match living under their own roof: Luke's older brother, Jack.

At three and a half years of age, Jack, who has high-functioning autism, donated his bone marrow to Luke. The transplant was successful at getting Luke to produce his own B cells. Until those B cells are able to create enough protective antibodies by themselves, Luke continues to receive infection protection from the antibody infusions he receives every two weeks.

"We call them his ninjas," said Michelle describing antibodies. "We tell him that he doesn't make his own ninjas, so he needs these ninja infusions to fight the germs and keep him safe."

Thanks to those "ninjas" and his brother's gift of bone marrow, Luke is now an energetic 4-year-old boy who loves Transformers, fire trucks, and his balance bike. Before his bone marrow transplant and the infusions, he needed naproxen twice a day for his joint pain, required leg braces to straighten his legs, and would lie on the floor exhausted tire after 10 minutes of activity. Now, he always seems to be running, often with his dog Charlie chasing behind him.

"Knowing the source of the problem removed the boogeyman for the Terrios and allowed them to move their lives forward," Romberg said. "Figuring out Luke's case not only helped guide his therapy and gave answers to others suffering with this rare condition in some cases for years but also opens the door to learning more about the effects of PU.1 on a variety of more common human diseases and conditions."

Le Coz et al. "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients," Journal of Experimental Medicine, online May 5, 2021, DOI: 10.1084/jem.20201750

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Contact: Camillia TraviaChildren's Hospital of Philadelphia(425) 492-5007traviac@chop.edu

View original content to download multimedia:http://www.prnewswire.com/news-releases/chop-researchers-discover-new-disease-that-prevents-formation-of-antibodies-301284513.html

SOURCE Children's Hospital of Philadelphia

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CHOP Researchers Discover New Disease that Prevents Formation of Antibodies - BioSpace

Guest post by Daphne Zohar, the founder and CEO of PureTech Health, a Boston-based biopharma that is advancing 26 therapeutics and therapeutic candidates through its internal pipeline and its Founded Entities, including two that have received FDA clearance and European marketing authorization.

The news ricocheted through the bio innovation community, sparking alarm and frustration.

Innovators and entrepreneurs, scientists and CEOs reacted with deep concern to the Biden administrations decision this week to support temporarily waiving intellectual property rights for COVID-19 vaccines.

This was the third time in just the past few months that politicians sought to intervene in the biopharma industry with policy proposals that betrayed a deep misunderstanding of the complex engine driving the discovery and development of life-saving and, in this case, pandemic-ending medicines.

First, Rep. Katie Porter (D-CA) released a report blasting mergers and acquisitions (M&A) in the biopharma industry. This report painted a false picture of M&A as a destructive force that supposedly squashes innovation and kills jobs. The Federal Trade Commission then announced an investigation of M&As impact on competition in the industry, spurring an investor sell-off. Actually, M&A is the lifeblood of innovation, funding startups and supporting job creation and development of new cures and bringing them to patients.

(Photo by Michael Brochstein/SOPA Images/LightRocket via Getty Images)

Next, members of Congress renewed a vocal push for legislation to control drug pricing. One proposal would authorize the federal government to impose a tax of up to 95% on the revenue from certain drugs if pharma companies refused to negotiate lower prices. This concept is ill informed and would severely limit the ability of biotech companies to attract the funding needed to advance new cures. While there are absolutely some unjustified price hikes, in many cases, costs to patients are artificially driven up by middlemen. There are much better ideas for reducing the burden of out of pocket costs on patients and their families, including insurance and rebate reform, value based pricing models, and incentives to offset costs for loss-making biotechs.

Then this past week, we have the spectacle of policy makers grabbing headlines with cries to cancel vaccine patents. Its a soundbite solution that would do nothing to address supply bottlenecks or speed near-term production. Instead, it could help our geopolitical rivals steal US technology and make it less likely that industry will jump in to save us from the next pandemic. Without protection for intellectual property, investors wont put up the huge sums, often billions, needed to take a potential cure from initial concept to proven therapy. That means no more vaccines, no more gene therapies for rare disease, no more novel treatments for cancer, Alzheimers disease and other devastating conditions.

The common thread in all these proposals is a rush to act well meaning, perhaps, but coupled with a catastrophic failure to understand the thriving ecosystem put at risk by these policies.

Its as if, having been stung by a bee at a picnic, you hired a squadron of exterminators to destroy every honeybee in the state. You wouldnt fix the problem. You would, however, disrupt a delicate ecosystem in which honeybees play a pivotal role. And the downstream consequences to the environment would be disastrous.

To be clear, Im not arguing that politicians must steer clear of any issue involving biopharma. These are the right problems to focus on and I support smart regulation and sound policy, as does most everyone I know in the industry. But its imperative that lawmakers listen.

Listen to the academic scientists who ask bold questions and run painstaking experiments that sometimes lead to discoveries which reshape our understanding of human biology.

Listen to entrepreneurs like myself who pour everything we have into shepherding those breakthrough discoveries from the lab into a medicine that will make a difference in patients lives, whether that be a novel cancer immunotherapy or a therapy that could potentially address the lung scarring of Long COVID.

Listen to the investors who risk huge sums to back audacious visions: Gene editing to conquer heart disease, mRNA vaccines, or living biotherapeutics to tackle autoimmune diseases. These are technologies you dont know about until they make it through decades of discovery, research, and clinical development. Then you cant imagine modern medicine without them.

Listen, above all, to the patients and their families, many of them living in pain and fear, waiting and praying for new therapies to reach them.

While Im proud to be a biopharma CEO, Ill be the first to say that the industry isnt perfect. Thats why we need smart regulation. But like good medicines, smart policies require a deep understanding of the ecosystem youre trying to modulate.

There are many of us on the frontlines of drug discovery and bio-entrepreneurship who would be happy to work together on smart policies. Well explain the challenges we face and the benefits that flow from our unique ecosystem which nurtures innovation, promotes growth, supports millions of jobs and brings life-saving medicines to market.

Dont let policy-by-soundbite kill the engine that brought you COVID vaccines with 95% efficacy, cures for hepatitis C, and hope for people living with cancer and rare diseases. The world depends on the innovation we nurture. Dont act until you understand it.

Excerpt from:
Congress, These Are The Right Problems But The Wrong Solutions. Dont Make The Mistake Of Killing The Innovation That Brings New Medicines And Jobs. -...

Its the new rallying cry of infectious disease experts across the United States.

Get your second dose.

With nearly a third of the U.S. population now fully vaccinated, a worrisome trend has popped up, according to those experts.

Some people are choosing to take the first of the two-shot series required with both Pfizer and Moderna vaccinations but are opting out of the second shot.

The Centers for Disease Control and Prevention (CDC) reports that about 8 percent of people who have received a first shot of the two-shot vaccines have missed their second shot.

Officials are digging into the situation and speaking out about why getting both shots in the two-shot series is critical.

They say that the second dose not only builds herd immunity, but also strengthens the protection from serious COVID-19 illness and complications.

Many have the illusion they are completely protected (with one of the two shots), but they are not, Dr. William Schaffner, an infectious disease expert at Vanderbilt University School of Medicine in Nashville, Tennessee, told Healthline. Some may lose their prevention ability sooner, and they wont know it.

The first shot is priming the pump, Schaffner said, and the second dose brings up the water.

Dr. John Zaia, the director of the City of Hopes Center for Gene Therapy in the Los Angeles area and a specialist in vaccine research, told Healthline the trend of skipping second doses concerns him.

The virus and its variants, he explained, seek out hosts. That means that with more people vaccinated, the virus may hone in on those who arent fully vaccinated.

With strong variants immerging, Zaia added, he hopes to see everyone take both doses.

Dying from COVID-19, he noted, looks to be almost fully avoidable with two shots.

Zaia points to a study by a team at Houston Methodist Hospital that drilled down on the chances of both developing COVID-19 or dying from it for the fully and partially vaccinated.

In the study, which hasnt been peer reviewed yet, less than 1 percent of those who had taken both shots were hospitalized. That number jumped to more than 3 percent for those who opted for just one of the two shots.

In addition, the study found that the two-shot total dose is 98 percent effective at preventing death from COVID-19, while choosing to stop at one shot drops that down to 64 percent.

Why are people skipping a second dose?

Schaffner sees it as not one big reason but many small ones.

He points to things such as believing one shot protects them enough, fearing sickness from the second dose, preoccupation and difficulty scheduling, and COVID fatigue.

Experts say that if you received your first shot and for whatever reason didnt schedule a second, now is the time to do just that.

Its not too late, Zaia said.

According to the CDC, both the Pfizer and Moderna vaccines can be administered up to 6 weeks after the first dose.

No data is available yet on whether getting a second shot after that 6-week period is effective enough.

Zaia said a persons best plan is to get both within the time frame or as close to it as they can.

If you do decide to get the second dose, be sure to know which shot you had the first time. Most sites will ask to see your vaccination card to confirm that on site.

Schaffner hopes the public listens to the plea of infectious disease experts and rethink the second shot if theyve decided to skip it.

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Important to Get Second Dose of COVID-19 Vaccine - Healthline

BUFFALO, N.Y., May 04, 2021 (GLOBE NEWSWIRE) -- Athenex, Inc., (NASDAQ: ATNX), a global biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies for the treatment of cancer and related conditions, led by its Orascovery platform, today announced that it has acquired Kuur Therapeutics, Inc., the leading developer of off-the-shelf CAR-NKT cell immunotherapies for the treatment of solid and hematological malignancies.

We are excited to add Kuur Therapeutics and its innovative allogeneic CAR-NKT technology to the Athenex platform, said Dr. Johnson Lau, Chief Executive Officer of Athenex. Kuurs innovative technology, combined with our TCR program, could propel us into a leadership position in cell therapy. This platform also has the potential to provide synergies with other assets in our pipeline.

Dr. Dan Lang, President of Athenex Cell Therapy, added, We are thrilled to combine our TCR program with the groundbreaking NKT cell platform developed by Professor Leonid Metelitsa at Baylor College of Medicine and Texas Childrens Hospital. We are confident that we can continue to innovate on the NKT cell platform with Dr. Metelitsa to provide a solution that may address some of the known limitations associated with the first generation of cell therapy treatments focused on autologous CAR-T. We aspire to convert cancer into a chronic disease.

Under the terms of the agreement, Athenex will pay $70 million upfront to Kuur shareholders and certain of its former employees and directors, comprised primarily of equity in Athenex common stock. Additionally, they are eligible to receive up to $115 million of milestone payments, which may be paid, at Athenexs sole discretion, in either cash or additional Athenex common stock (or a combination of both).

Kevin S. Boyle, Sr., Chief Executive Officer of Kuur, stated, CAR-NKT cells offer a distinct set of advantages over other immune effector cells commonly used for cell therapy. We are excited that the leadership at Athenex recognizes the significant potential of this approach to provide effective treatment options for patients with both solid and hematological tumors. The development of these innovative therapies will be accelerated by combining Kuurs experienced team with the extensive resources of Athenex.

About the CAR-NKT Platform and Pipeline

Natural killer T (NKT) cells are innate-like T lymphocytes that express a semi-invariant TCR and preferentially reside in and traffic to tissues, including the liver and bone marrow. Evidence suggests that NKT cells do not mediate graft-versus-host-disease (GvHD) making them an ideal candidate for off-the-shelf CAR therapy.In addition to this differentiated cellular biology, the CAR constructs are engineered to:

As described in Kuurs January 2021 press release, the GINAKIT2 clinical trial is a phase I study of KUR-501, an autologous CAR-NKT cell product, targeting GD2 in patients with relapsed/refractory (R/R) high risk neuroblastoma conducted at Baylor College of Medicine (BCM) and Texas Childrens Hospital.

Out of 10 evaluable patients, one complete response (CR) and one partial response (PR) have been observed to date, with stable disease (SD) in three additional patients. Tumor biopsy shows CAR-NKT cells homing to the neuroblastoma tumor site at all dose levels, which is an important biological property of NKT cells. KUR-501 has so far demonstrated a promising safety profile, with only one case of grade two cytokine release syndrome (CRS) and no cases of immune effector cell-associated neurotoxicity syndrome (ICANS).

Additional data on the GINAKIT2 phase I study will be presented at the American Society of Gene & Cell Therapy (ASGCT) 24th Annual Meeting on May 14, 2021.

The ANCHOR clinical trial is an ongoing phase I study of KUR-502, an allogeneic (off-the-shelf) CAR-NKT cell product, targeting CD19 in adult patients with relapsed/refractory lymphoma and leukemia conducted at BCM.

Out of two evaluable patients, one CR and one PR have been observed to date at the lowest dose level of 1107cells/m2. One patient was initially observed to be a PR four weeks after infusion, but subsequently converted to a CR without additional therapy 12 weeks later. Biopsy of the patients lymph node at five weeks after infusion, prior to conversion to CR status, revealed viable, allogeneic CD19 CAR-NKT cells. The patient with the PR had previously failed autologous CAR-T cell therapy. KUR-502 has so far demonstrated a promising safety profile with no CRS, no ICANS, and no evidence of GvHD.

In 2016, Kuur Therapeutics and BCM signed an exclusive licensing and co-development agreement around cellular immunotherapy products for the treatment of cancer. The co-development collaboration has been instrumental in advancing KUR-501 and KUR-502 into the clinic, and in advancing KUR-503 into IND-enabling preclinical studies. The collaboration accelerated the pioneering work of Dr. Leonid Metelitsa, Professor of Pediatrics Oncology at BCM and Texas Childrens Hospital. Dr. Metelitsa and his team have shown the potential therapeutic advantages of functionally enhanced CAR-modified NKT cells. Dr. Metelitsas research team is part of Texas Childrens Cancer Center and the Center for Cell and Gene Therapy (CAGT) at BCM, Texas Childrens Hospital and Houston Methodist Hospital. The CAGT has more than 20 years of experience working with genetically modified immune cells for the treatment of cancer and has conducted more than 40 clinical studies investigating cellular immunotherapies for the treatment of cancer.

Cooley (UK) LLP is acting as the sole advisor to Athenex, Inc. and SVB Leerink is acting as financial advisor with HMB Legal Counsel acting as legal advisor to Kuur Therapeutics in connection with the transaction.

About KUR-501

KUR-501 is an autologous product in which NKT cells are engineered with a CAR targeting GD2, which is expressed on almost all neuroblastoma tumors, as well as other malignancies. KUR-501 is being tested in the phase 1 GINAKIT2 clinical study (NCT03294954) in patients with R/R high risk neuroblastoma. The single-arm study will evaluate six dose levels of KUR-501 with patients receiving pre-dose lymphodepletion chemotherapy consisting of cyclophosphamide and fludarabine.

Neuroblastoma is a pediatric cancer and patients with R/R high risk neuroblastoma have a poor prognosis and a significant unmet medical need. The KUR-501 development program is also designed to provide autologous proof-of-concept for CAR-NKT cells in solid tumors using a validated target.

The GINAKIT2 study is supported by Kuur Therapeutics and Alexs Lemonade Stand Foundation, conducted by Kuurs collaborator, BCM, and is currently recruiting patients.

About KUR-502

KUR-502 is an allogeneic product in which NKT cells are engineered with a CAR targeting CD19. KUR-502 is built on Kuurs next-generation CAR-NKT platform with novel engineering capabilities that harness and enhance the unique properties of NKT cells. The NKT cells used in Kuurs CAR-NKT platform have a semi-invariant TCR that does not distinguish between self- and non-self-tissues, making the cells unlikely to induce GvHD when given to another person.

The ANCHOR clinical study (NCT03774654) is a phase 1, first-in-human, dose escalation evaluation of KUR-502 in adults with R/R CD19 positive malignancies including B cell lymphomas, acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) The single-arm study will evaluate three dose levels with patients receiving lymphodepletion chemotherapy consisting of cyclophosphamide and fludarabine followed by infusion with KUR-502.

Patients with R/R CD19-positive malignancies have limited effective treatment options. While CD19-directed autologous CAR-T cells are now available for these patients, they are limited by a requirement for patient leukapheresis, delays to receive treatment due to the requirement for autologous manufacturing, and variable final product quality. Off-the-shelf KUR-502 is designed to overcome these limitations.

The ANCHOR study is being sponsored and conducted by Kuurs collaborator, BCM and is currently recruiting patients.

About KUR-503

KUR-503 is an allogeneic product under development in the laboratory of Dr. Andras Heczey, Assistant Professor of Pediatrics in the Section of Hematology-Oncology at BCM and Texas Childrens Hospital. KUR-503 is unique product, in which NKT cells are engineered with a CAR targeting GPC3 (glypican-3) and like all of Kuurs allogeneic products, is built on Kuurs next-generation CAR-NKT platform. GPC3 is a molecule that is highly expressed on most hepatocellular carcinomas (HCC), but not normal liver or other non-neoplastic tissue, making it an ideal target. Because NKT cells traffic to the liver, prevent the formation of new HCC, and their presence in HCC is associated with better outcomes, this platform is an excellent vehicle for delivery of immune effector therapy for patients with HCC. HCC is now the fourth most common cause of cancer related death worldwide, with an estimated 750,000 new cases each year. Although there have been some recent approvals of new agents to treat advanced HCC, these patients still have poor outcomes and there is a significant unmet need.

KUR-503 is currently in preclinical development and the company is planning to initiate a first in human phase 1 clinical trial in 1H 2022.

AboutAthenex, Inc.

Founded in 2003,Athenex, Inc.is a global clinical stage biopharmaceutical company dedicated to becoming a leader in the discovery, development, and commercialization of next generation drugs for the treatment of cancer.Athenexis organized around three platforms, including an Oncology Innovation Platform, a Commercial Platform, and a Global Supply Chain Platform. The Companys current clinical pipeline is derived from four different platform technologies: (1) Orascovery, based on P-glycoprotein inhibitor, (2) Src kinase inhibition, (3) Cell therapy, and (4) Arginine deprivation therapy. Athenexs employees worldwide are dedicated to improving the lives of cancer patients by creating more active and tolerable treatments. For more information, please visitwww.athenex.com.

About Kuur Therapeutics

Kuur Therapeutics (formerly known as Cell Medica) is a clinical-stage biopharmaceutical company focused on the development of off-the-shelf CAR-NKT cell immunotherapies for the treatment of solid and hematological malignancies. The companys revolutionary platform engineers CARs expressed by semi-invariant NKT cells, which combine features of T and NK cells, and is being developed in partnership with Baylor College of Medicine and Texas Childrens Hospital. Allogeneic cell therapy has the potential to be much faster and less expensive than patient-specific autologous products, and NKT cells offer several advantages over other cell types for allogeneic immunotherapy applications. NKT cells have the cytotoxic and anti-tumor properties of conventional T cells, but with other biological attributes that are expected to improve their ability to attack hematological and solid tumors. These include innate tissue and solid tumor homing properties, as well as endogenous anti-tumor activity based on the ability to eliminate immune suppressive cells and activate host immune cells within the tumor microenvironment.

About Baylor College of Medicine

Baylor College of Medicinein Houston is recognized as a premier health sciences university and is known for excellence in education, research, and patient care. It is the only private medical school in the greater southwest and is ranked 22nd among medical schools for research and 17th for primary care by U.S. News & World Report. Baylor is listed 20th among all U.S. medical schools for National Institutes of Health funding and No. 1 in Texas. Located in the Texas Medical Center, Baylor has affiliations with seven teaching hospitals and jointly owns and operates Baylor St. Lukes Medical Center, part of CHI St. Lukes Health. Currently, Baylor has more than 3,000 trainees in medical, graduate, nurse anesthesia, physician assistant, orthotics and genetic counselling, as well as residents and postdoctoral fellows. FollowBaylor College of Medicine on FacebookandTwitter

Forward-Looking Statements

Except for historical information, all of the statements, expectations, and assumptions contained in this press release are forward-looking statements. These forward-looking statements are typically identified by terms such as anticipate, believe, continue, could, estimate, expect, foresee, goal, guidance, intend, likely, may, plan, potential, predict, preliminary, probable, project, promising, seek, should, will, would, and similar expressions. Actual results might differ materially from those explicit or implicit in the forward-looking statements. Important factors that could cause actual results to differ materially include: the development stage of our primary clinical candidates and related risks involved in drug development, clinical trials, regulation, uncertainties around regulatory reviews and approvals; our ability to scale our manufacturing and commercial supply operations for current and future approved products, and ability to commercialize our products, once approved; ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; the preclinical and clinical results for Athenexs drug candidates, which may not support further development of such drug candidates; risks related to counterparty performance, including our reliance on third parties for success in certain areas of Athenexs business; our history of operating losses and our need and ability to raise additional capital; uncertainties around our ability to meet funding conditions under our financing agreements and access to capital thereunder; risks and uncertainties inherent in litigation, including purported stockholder class actions; risks and uncertainties related to the COVID-19 pandemic and its potential impact on our operations, supply chain, cash flow and financial condition; competition; intellectual property risks; uncertainties around our ability to successfully integrate acquired and merged businesses in a timely and cost-effective manner and to achieve synergies; risks relating to doing business internationally and inChina; the risk of development, operational delays, production slowdowns or stoppages or other interruptions at our manufacturing facilities; and the other risk factors set forth from time to time in ourSECfilings, copies of which are available for free in the Investor Relations section of our website athttp://ir.athenex.com/phoenix.zhtml?c=254495&p=irol-secor upon request from our Investor Relations Department. All information provided in this release is as of the date hereof and we assume no obligation and do not intend to update these forward-looking statements, except as required by law.

Athenex Contacts

Investors:

Steve RubisAthenex, Inc.Email:stevenrubis@athenex.com

Daniel Lang, MDAthenex, Inc.Email:danlang@athenex.com

Tim McCarthyLifeSci Advisors, LLCEmail:tim@lifesciadvisors.com

Kuur Therapeutics Contact

Stephanie AscherStern Investor Relations, Inc.212-362-1200 E-mail: Stephanie.ascher@sternir.com

Original post:
Athenex to Acquire Kuur Therapeutics to Expand Cell Therapy - GlobeNewswire