Innate Pharma Results and Business Update

 

• Phase 1/2 dose escalation safety and preliminary efficacy of ANKET^® NK cell engager, SAR'579/IPH6101, developed by Sanofi, showed it was well tolerated with observed clinical benefit in patients with R/R AML (ASCO 2023 annual meeting), FDA Fast Track Designation awarded
• Exclusive worldwide rights granted to Takeda to research and develop antibody drug conjugates (ADC) using a panel of selected Innate antibodies; $5m upfront payment to Innate and up to $410m in future milestones plus royalties
• Proprietary ANKET^® IPH65 IND approved, progressing to Phase 1
• Proprietary IPH45 ADC target, nectin-4 disclosed
• Innate announces new Chief Medical Officer, Sonia Quaratino
• Cash position of €124.7 million¹ as of June 30, 2023, anticipated cash runway into H2 2025
• Conference call to be held today at 2:00 p.m. CEST / 8:00 a.m. EDT

Webcast and conference call will be held today at 2:00 p.m. CEST (8:00 a.m. ET)

Access to live webcast:

https://events.q4inc.com/attendee/859850812

Participants may also join via telephone by registering in advance of the event at

https://registrations.events/direct/Q4E60903

This information can also be found on the Investors section of the Innate Pharma website, www.innate-pharma.com. A replay of the webcast will be available on the Company website for 90 days following the event.

https://www.biospace.com/article/releases/innate-pharma-reports-first-half-2023-financial-results-and-business-update/

Genes behind antibiotic resistance in deadly superbug infections

 Australian researchers have uncovered new genetic insights into Staphylococcus aureus, revealing what makes the bacterium so dangerous when it enters the blood.

While common, Staphylococcus aureus infections -- known as Golden staph -- can be life-threatening if the bacteria enter the bloodstream, causing sepsis. Golden staph is notorious for its ability to become resistant to antibiotics, making it hard to treat, which can lead to adverse health outcomes for patients infected with a drug-resistant form of the bacteria.

In one of the most comprehensive studies of its kind, published in Cell Reports, researchers, led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute), analysed the unique genetic profiles of more than 1,300 Golden staph strains.

By combining this data with patient and antibiotic information, the researchers found that, while patient factors are critical in determining mortality risks, specific genes are linked to antibiotic resistance, along with the bacteria's ability to linger in the blood, evading antibiotics and the immune system.

University of Melbourne Dr Stefano Giulieri, a Clinician-Researcher at the Doherty Institute and first author of the paper, said the findings highlighted the diagnostic power of integrating clinical and genomic data.

"To the best of our knowledge, this is one of the first times that the method we used, called a genome-wide association study (GWAS), has been applied to delve into the role of bacterial genomes, host factors and antibiotics on the course of staphylococcal sepsis," said Dr Giulieri.

"In GWAS, scientists scan the genome of a big collection of bacteria to look for tiny changes (mutations) that show up more often in strains with a certain characteristic, such as antibiotic resistance. Mutations with a strong statistical link are precious clues to figure out how bacteria acquire attributes that are important for patient outcomes.

"Our study uncovered a deeper understanding of the intricate genetic dynamics underlying severe Golden staph infections. It highlights the potential of combining bacterial whole-genome sequencing, clinical data and sophisticated statistical genomics to discover clinically relevant bacterial factors that influence infection outcomes."

University of Melbourne Professor Ben Howden, Director of the Microbiological Diagnostic Unit (MDU) Public Health Laboratory at the Doherty Institute and co-senior author of the paper, said that this work represents a significant advancement in medical research as it reshapes our strategies against complex health challenges like Golden staph infections.

"By revealing the genes responsible for antibiotic resistance in Golden staph, our GWAS is pointing the scientific community to clearer targets for the development of effective solutions to treat Golden staph bloodstream infections," said Professor Howden.

"This knowledge has the potential to shape and enhance our ability to tackle these persistent infections. As bacterial genomes become increasingly available in the clinical routine, we inch closer to customised therapeutic strategies, where treatments will be tailored to the unique genetic makeup of the infecting strain, rather that treating everyone in the same way."

Funding: This research was funded by the National Health and Medical Research Council (NHMRC) and the University of Melbourne.

Journal Reference:

1. Stefano G. Giulieri, Romain Guérillot, Natasha E. Holmes, Sarah L. Baines, Abderrahman Hachani, Ashleigh S. Hayes, Diane S. Daniel, Torsten Seemann, Joshua S. Davis, Sebastiaan Van Hal, Steven Y.C. Tong, Timothy P. Stinear, Benjamin P. Howden. A statistical genomics framework to trace bacterial genomic predictors of clinical outcomes in Staphylococcus aureus bacteremia. Cell Reports, 2023; 113069 DOI: 10.1016/j.celrep.2023.113069

https://www.sciencedaily.com/releases/2023/09/230912113553.htm

Benefits, risks in state-mandated school-based BMI assessments

 A University of Massachusetts Amherst resource economist finds mandated in-school Body Mass Index (BMI) assessments adopted in varying forms by 24 states to combat childhood obesity have the potential to improve the health of some students while introducing body-image issues for others. The research is believed to be the first to assess these policies as a whole, rather than in single states or school districts.

"In states that passed these laws, overweight and obese teens were more likely to correctly describe their bodies as such, compared to states that do not have these mandates," says Brandyn Churchill, assistant professor of resource economics at UMass Amherst. "But the unintended consequence is that non-overweight girls were also more likely to describe themselves as overweight. They were less likely to describe themselves as a healthy weight."

In addition, Churchill finds that overweight teenagers were more likely to report that they were trying to lose weight. He identifies a small but significant decrease in teens' BMI.

"These changes appear to be coming from students who were right on the margin of being overweight," he says.

The study did not detect any meaningful changes in exercise or calorie-limiting behaviors linked to mandated BMI assessments. The findings are based on national and state Youth Risk Behavior Surveys between 1991 and 2017.

Churchill points out that the average BMI of children in the U.S. has been steadily increasing over that span, even as more states enacted mandatory assessments.

"It's hard to look at the change in childhood BMI and say these policies are a resounding success, given the potential unintended consequences for adolescent girls in the form of distorted self-image and body perception," he says. Prior research has found these issues can lead to shame, anxiety, bullying and eating disorders.

While tracking the BMI of children may be a helpful measure in assessing the overall health of young people and even the health of students in each school, Churchill finds there's little evidence that it helps individual students adopt healthier habits. Despite their use by so many states, BMI assessments do not meet American Academy of Pediatrics guidelines for routine health screenings.

"Focusing on ways to encourage or incentivize healthy weight-management practices is beneficial, relative to just telling kids to eat small portions and that they're overweight," Churchill notes.

He concludes it is ultimately up to policymakers to consider the benefits and costs of mandated BMI assessments in schools.

"Are they comfortable with a little more awareness for the overweight kids at the expense of the self-image of the non-overweight girls?" Churchill asks. "That's a policy choice. They have a hard job."

Journal Reference:

1. Brandyn F. Churchill. State‐mandated school‐based BMI assessments and self‐reported adolescent health behaviors. Journal of Policy Analysis and Management, 2023; DOI: 10.1002/pam.22523

https://www.sciencedaily.com/releases/2023/09/230912165708.htm

Breast cancer recurrence may be triggered by chemotherapy injury to non-cancer cells

 A standard chemotherapy drug injures surrounding non-cancer cells, which can then awakens dormant cancer cells and promotes cancer growth, according to a new study publishing September 12 in the open access journal PLOS Biology by Ramya Ganesan of Emory University, US, and colleagues. The finding is important for understanding cancer recurrence and may point to important new targets to prevent it.

Advances in cancer treatment, including chemotherapy, have dramatically reduced mortality for many types of cancer, including breast cancer. Nonetheless, up to 23% of breast cancer patients experience recurrence within the first five years. Treatment is meant to kill all cancer cells, but often, some cells enter a state of dormancy, in which they stop dividing and become unresponsive to chemotherapeutic agents. Recurrence occurs when dormant cells re-awaken and start dividing again.

Some studies have indicated that chemotherapy itself may promote escape from dormancy, but the mechanism of this effect has not been clear. To explore that question, the authors worked with both a cell model and a mouse model of breast cancer. Importantly, the cell model contained both cancer cells and non-cancer stromal cells, connective tissue cells that are found in breast and other tissue. They administered the chemotherapy drug docetaxel at physiologically relevant concentrations, and found that even at very low doses, stromal cells were injured, while cancer cells were not, and that treatment induced cell-cycle reentry in cancer cells.

The driver of this reawakening of dormant cells, the authors showed, was release of two key cell signaling molecules, granulocyte colony stimulating factor (G-CSF) and interleukin-6 (IL-6) by the injured stromal cells, which acted on the dormant cells to promote their growth, both in vitro and in vivo. That provided the team with potential anti-cancer targets, and they showed that antibodies that neutralized either G-CSF or IL-6, or a drug that blocked the mediator of those signals within cancer cells, inhibited awakening from dormancy due to docetaxel treatment.

These findings have several important implications. First, they highlight the importance of surrounding cells, not just the cancer cells themselves, in determining the response to chemotherapy. Second, they provide a possible mechanistic foundation for the observation that high serum levels of IL-6 are associated with early recurrence in breast cancer patients receiving chemotherapy, potentially strengthening the utility of that biomarker in planning treatment. Third, they provide new targets for preventing recurrence.

Dr. Ganesan and Dr.Sukhatme add, "Our paper highlights a deleterious effect of cancer chemotherapy: release of stromal IL-6 and G-CSF by taxane chemotherapy awakened dormant breast cancer cells, a postulated mechanism for tumor relapse. Transient blockade of cytokine signaling during chemotherapy administration may prevent tumor recurrence."

Journal Reference:

1. Ramya Ganesan, Swati S. Bhasin, Mojtaba Bakhtiary, Upaasana Krishnan, Nagarjuna R. Cheemarla, Beena E. Thomas, Manoj K. Bhasin, Vikas P. Sukhatme. Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape. PLOS Biology, 2023; 21 (9): e3002275 DOI: 10.1371/journal.pbio.3002275

https://www.sciencedaily.com/releases/2023/09/230912165730.htm

Compound found in plants inhibits deadly fungi

 A new study finds that a natural compound found in many plants inhibits the growth of drug-resistant Candida fungi -- including its most virulent species, Candida auris, an emerging global health threat. The journal ACS Infectious Diseases published the discovery led by scientists at Emory University.

Laboratory-dish experiments showed that the natural compound, a water-soluble tannin known as PGG, blocks 90% of the growth in four different species of Candida fungi. The researchers also discovered how PGG inhibits the growth: It grabs up iron molecules, essentially starving the fungi of an essential nutrient.

By starving the fungi rather than attacking it, the PGG mechanism does not promote the development of further drug resistance, unlike existing antifungal medications. Laboratory-dish experiments also showed minimal toxicity of PGG to human cells.

"Drug-resistant fungal infections are a growing healthcare problem but there are few new antifungals in the drug-development pipeline," says Cassandra Quave, senior author of the study and assistant professor in Emory School of Medicine's Department of Dermatology and the Center for the Study of Human Health. "Our findings open a new potential approach to deal with these infections, including those caused by deadly Candida auris."

C. auris is often multidrug-resistant and has a high mortality rate, leading the Centers for Disease Control and Prevention (CDC) to label it a serious global health threat.

"It's a really bad bug," says Lewis Marquez, first author of the study and a graduate student in Emory's molecular systems and pharmacology program. "Between 30 to 60% of the people who get infected with C. auris end up dying."

An emerging threat

Candida is a yeast often found on the skin and in the digestive tract of healthy people. Some species, such as Candida albicans, occasionally grow out of control and cause mild infections in people.

In more serious cases, Candida can invade deep into the body and cause infections in the bloodstream or organs such as the kidney, heart or brain. Immunocompromised people, including many hospital patients, are most at risk for invasive Candida infections, which are rapidly evolving drug resistance.

In 2007, the new Candida species, C. auris, emerged in a hospital patient in Japan. Since then, C. auris has caused health care-associated outbreaks in more than a dozen countries around the world with more than 3,000 clinical cases reported in the United States alone.

A 'natural' approach to drug discovery

Quave is an ethnobotanist, studying how traditional people have used plants for medicine to search for promising new candidates for modern-day drugs. Her lab curates the Quave Natural Product Library, which contains 2,500 botanical and fungal natural products extracted from 750 species collected at sites around the world.

"We're not taking a random approach to identify potential new antimicrobials," Quave says. "Focusing on plants used in traditional medicines allows us to hone in quickly on bioactive molecules."

Previously, the Quave lab had found that the berries of the Brazilian peppertree, a plant used by traditional healers in the Amazon for centuries to treat skin infections and some other ailments, contains a flavone-rich compound that disarms drug-resistant staph bacteria.

Screens by the Quave lab had also found that the leaves of the Brazilian peppertree contain PGG, a compound that has shown antibacterial, anticancer and antiviral activities in previous research.

A 2020 study by the Quave lab, for instance, found that PGG inhibited growth of Carbapenem-resistant Acinetobacter baumannii, a bacterium that infects humans and is categorized as one of five urgent threats by the CDC.

The Brazilian peppertree, an invasive weed in Florida, is a member of the poison ivy family. "PGG has popped up repeatedly in our laboratory screens of plant compounds from members of this plant family," Quave says. "It makes sense that these plants, which thrive in really wet environments, would contain molecules to fight a range of pathogens."

Experimental results

The Quave lab decided to test whether PGG would show antifungal activity against Candida.

Laboratory-dish experiments demonstrated that PGG blocked around 90% of the growth in 12 strains from four species of Candida: C. albicans, multidrug-resistant C. auris and two other multidrug-resistant non-albicans Candida species.

PGG is a large molecule known for its iron-binding properties. The researchers tested the role of this characteristic in the antifungal activity.

"Each PGG molecule can bind up to five iron molecules," Marquez explains. "When we added more iron to a dish, beyond the sequestering capacity of the PGG molecules, the fungi once again grew normally."

Dish experiments also showed that PGG was well-tolerated by human kidney, liver and epithelial cells.

"Iron in human cells is generally not free iron," Marquez says. "It is usually bound to a protein or is sequestered inside enzymes."

A potential topical treatment

Previous animal studies on PGG have found that the molecule is metabolized quickly and removed from the body. Instead of an internal therapy, the researchers are investigating its potential efficacy as a topical antifungal.

"If a Candida infection breaks out on the skin of a patient where a catheter or other medical instrument is implanted, a topical antifungal might prevent the infection from spreading and entering into the body," Marquez says.

As a next step, the researchers will test PGG as a topical treatment for fungal skin infections in mice.

Meanwhile, Quave and Marquez have applied for a provisional patent for the use of PGG for the mitigation of fungal infections.

"These are still early days in the research, but another idea that we're interested in pursuing is the potential use of PGG as a broad-spectrum microbial," Quave says. "Many infections from acute injuries, such as battlefield wounds, tend to be polymicrobial so PGG could perhaps make a useful topical treatment in these cases."

Scientists from the University of Toronto are co-authors of the paper, including Yunjin Lee, Dustin Duncan, Luke Whitesell and Leah Cowen. Whitesell and Cowen are co-founders and shareholders in Bright Angel Therapeutics, a platform company for development of antifungal therapeutics, and Cowen is a science advisor for Kapoose Creek, a company that harnesses the therapeutic potential of fungi.

The work was supported by grants from the National Institutes of Health, National Center for Complementary and Integrative Health; the Jones Center at Ichauway, the CIHR Frederick Banting and Charles Best Canada Graduate Scholarship and the Canadian Institutes of Health Research Foundation.

Journal Reference:

1. Lewis Marquez, Yunjin Lee, Dustin Duncan, Luke Whitesell, Leah E. Cowen, Cassandra Quave. Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species. ACS Infectious Diseases, 2023; 9 (9): 1685 DOI: 10.1021/acsinfecdis.3c00113

https://www.sciencedaily.com/releases/2023/09/230913122749.htm

COVID's weakness: Without key proteins, virus cannot infect people

 New UC Riverside research has revealed COVID's Achilles heel—its dependence on key human proteins for its replication—which can be used to prevent the virus from making people sick.

In a paper published in the journal Viruses, the UCR research team describes an important discovery. The protein in COVID that enables the virus to make copies of itself, called N, requires the help of human cells to perform its job.

Genetic instructions in our cells are transcribed from DNA to messenger RNA, and then translated into proteins that enable functions such as growth and communication with other cells. Following this translation event, proteins often need additional modifications by enzymes. These so-called post-translation modifications ensure that proteins are uniquely suited to perform their intended tasks.

COVID takes advantage of a human post-translation process called SUMOylation, which directs the virus' N protein to the right location for packaging its genome after infecting human cells. Once in the right place, the protein can begin putting copies of its genes into new infectious virus particles, invading more of our cells, and making us sicker.

"In the wrong location, the virus cannot infect us," said Quanqing Zhang, co-author of the new study and manager of the proteomics core laboratory at UCR's Institute for Integrative Genome Biology.

Proteomics is the study of all the proteins that an organism makes, how they are modified by other enzymes, and the roles they play in a living organism. "If someone gets an infection, maybe one of his or her proteins will appear differently than it was before. That's what we're looking for in our facility," Zhang said.

In this case, the team designed and conducted experiments that made COVID proteins' post-translational modifications easy to see. "We used fluorescent glow to show us where the virus is interacting with human proteins and making new virions—infectious viral particles," said UCR bioengineering professor and corresponding paper author Jiayu Liao.

"This method is more sensitive than other techniques and gives us a more comprehensive view of all the interactions between the human and viral proteins," he said.

Using similar methods, the bioengineering team previously discovered that the two most common types of flu virus, Influenza A and Influenza B, require the same post-translational SUMOylation modification in order to replicate.

This paper shows that COVID depends on SUMOylation proteins, just as the flu does. Blocking access to the human proteins would allow our immune systems to kill the virus.

Currently the most effective treatment for COVID is Paxlovid, which inhibits virus replication. But patients need to take it within three days following infection. "If you take it after that it won't be so effective," Liao said. "A new medication based on this discovery would be useful to patients at all stages of infection."

The similarities between viruses may enable a whole new class of antiviral medication. With sufficient support, Liao estimates these can be developed within five years.

"I think other viruses might work this way as well," Liao said. "Ultimately, we would like to block the flu as well as COVID, and potentially other viruses such as RSV and Ebola. We are making new discoveries to help make this happen," Liao said.

More information: Vipul Madahar et al, Human Post-Translational SUMOylation Modification of SARS-CoV-2 Nucleocapsid Protein Enhances Its Interaction Affinity with Itself and Plays a Critical Role in Its Nuclear Translocation, Viruses (2023). DOI: 10.3390/v15071600

https://medicalxpress.com/news/2023-09-scientists-uncover-covid-weakness-key.html

Driver of inflammatory bowel disease IDd

 Researchers at UT Southwestern Medical Center have discovered an intracellular mechanism that converts protective intestinal cells into disease-driving pathogenic cells, a finding that could lead to improved treatments for patients with inflammatory bowel disease (IBD).

The research, published in Nature Communications, defines a mechanism by which healthy cells in the gut—known as Th17 cells—are compromised in patients with IBD, producing inflammation that causes abdominal pain, bloating, and other symptoms, along with potentially serious long-term complications.

"Th17 cells are essential for maintaining the integrity of the intestinal barrier and protecting against bacteria and viruses. But in patients with IBD, they become pathogenic, creating the inflammation that underlies the disease," said study leader Venuprasad Poojary, Ph.D., Associate Professor of Internal Medicine and Immunology in the Division of Digestive and Liver Diseases. "Through our research, we now have a better understanding of the intracellular process that converts protective Th17 cells into disease-generating, pathogenic, inflammatory Th17 cells."

The study in mice found that a lipid-interacting protein called Raftlin1 binds to RORγt, a transcription factor in Th17 cells, as IBD develops. Once in place, Raftlin1 attracts phospholipids in the body to combine with the RORγt, eventually turning Th17 cells pathogenic.

The research builds on other cellular studies related to IBD conducted by Dr. Poojary and his lab.

"Identifying the role of Raftlin1 in facilitating the binding of phospholipids to RORγt is a major step forward in our understanding of the diverse and opposing functions of Th17 cells," Dr. Poojary said. "It's an important finding because Th17-targeting therapies have shown promising results with some autoimmune diseases. There is a great need for new pharmaceuticals that can effectively treat IBD, since about a third of patients with the disease don't respond to existing treatments."

More than 3 million Americans suffer from IBD, with Crohn's disease and ulcerative colitis the most common forms. Although the disease is similar to irritable bowel syndrome (IBS), the symptoms of patients with IBD are caused by inflammation in the GI tract, diagnosed through a colonoscopy. That inflammation can permanently damage the intestines, create severe complications throughout the body, and put patients at a higher risk of colon cancer.

"These findings could serve as a platform for therapeutic strategies to control Th17-mediated inflammation in IBD and other diseases," Dr. Poojary said.

More information: Amir Kumar Singh et al, RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation, Nature Communications (2023). DOI: 10.1038/s41467-023-40622-1

https://medicalxpress.com/news/2023-09-driver-inflammatory-bowel-disease.html