Tag: Academic research

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Epigenetic Markers Link Early-Onset Colon and Rectal Cancer to Specific Pesticide

Epigenetic markers linking cancers in young adults to pesticide exposure have been uncovered. Scientists from Spain found that specifically, the pesticide picloram was associated with a higher risk of early-onset colon and rectal cancer, providing another lead to the cause of this disturbing new trend.

Their research paper appeared in Nature Medicine and the lead author is Silvana C. E. Maas, PhD, Cancer Computational Biology Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona.

“This pesticide seems to have a role in early onset colorectal cancer [patients diagnosed before 50 years of age]. Cases of these have been in the last decades and the biology of the tumors (early onset vs. regular onset) is very similar. So the cause of the rise should be something external, the exposome,” senior author José A. Seoane, PhD, told Inside Precision Medicine. Seoane is head of cancer computational biology group, Vall d’Hebron Institute of Oncology, Centro Saturnino, Spain.

“The exposome is any exposure [environmental, life-style, habits, food, pollution, etc.] that affects us during our lifetime, including development,” he added.

Cancer in young adults is a relatively recent phenomenon, brought to attention by many disturbing personal stories, including that of Princess Kate, and some eye-opening statistics. Until now, age has been a top risk factor for cancer.

The incidence of colorectal cancer (CRC), in particular, is rising rapidly in people younger than 50 years and this increase parallels shifts in lifestyle and environmental factors (the exposome). But whether these are indeed linked to the development of early-onset CRC (EOCRC) remains unknown. 

Since there are limited exposome data in most cancer cohorts, this team constructed weighted methylation risk scores as proxies for exposome exposure to pinpoint specific risk factors associated with EOCRC compared to late-onset CRC (LOCRC)—patients diagnosed at age 70+ years. 

“We included in the analysis exposures associated with lifestyle, pollution and pesticides, including picloram. The results (different exposure patterns between early onset and late onset) shows that the early onset cancers have more signal of poor diet, smoking, and picloram,” said Seoane.

He added that, “Several pesticides were included in  the study. We included different pesticides both in the methylation study and in the population study.”

The team’s analysis confirmed previously identified risk factors, including educational attainment, diet and smoking habits. In addition, they identified exposure to the herbicide picloram as a new risk factor in the discovery cohort. Those findings were replicated in a meta-analysis comprising nine CRC cohorts. 

The team then analyzed population-based data from 94 U.S. counties over 21 years and validated the association between picloram use and EOCRC incidence. The association was still statistically significant, after adjusting for socioeconomic factors and other pesticide use.

This research highlights the potential role of the exposome in EOCRC risk, the authors write.

“We are studying how other exposure signals that were not included in this study could be associated with CRC and also other tumors and we are trying to elucidate the mechanisms of action of picloram,” Seoane said.

Other potential causes of EOCRC identified have been linked to diet and pollutants.

 

 

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Early Glucagon Elevation Linked to MASLD in Type 2 Diabetes

Researchers at the German Diabetes Centre have found that glucagon, a hormone that is considered to be a counterbalance to insulin, is elevated early in type 2 diabetes (T2D) and closely linked to the development of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). The findings, published in the journal Diabetes Care, indicate that dysregulation of glucagon occurs soon after diagnosis of type 2 diabetes and is associated with liver fat accumulation, information that could prompt a shift in the understanding of how MASLD progresses and suggesting new ways to treat it.

“Our findings highlight that type 2 diabetes should not be viewed solely from the perspective of insulin action. The liver and the regulation of glucagon play a special role in metabolism,” said senior author Michael Roden, MD, scientific director of the German Diabetes Centre.

The aim of the research was to address unresolved questions about the activity of glucagon in early type 2 diabetes and how it may influence the development of fatty liver disease (MASLD). While insulin resistance is central to diabetes research, glucagon is also known to contribute to elevated blood glucose by stimulating hepatic glucose production. MASLD is also common in people with type 2 diabetes, yet the interaction between liver fat and glucagon regulation is not well understood.

To investigate glucagon’s role in this regard, the researchers analyzed 50 adults with newly diagnosed type 2 diabetes and 50 people with normal glucose tolerance matched for age, sex, and body mass index. Participants underwent mixed-meal tolerance tests to assess glucagon and metabolites, hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, and imaging using magnetic resonance spectroscopy and MRI to quantify hepatic lipid content and visceral fat.

The resulting data indicated that those people with newly diagnosed type 2 diabetes had significantly higher liver fat and elevated glucagon levels both when fasting and after meals.

“Individuals with T2D had an ∼65% higher HLC as well as higher fasting and postprandial glucagonemia (∼30% and ∼75%) than those with NGT,” the research noted. The presence of MASLD, rather than diabetes itself, was associated with higher fasting glucagon levels. Elevated glucagon levels after a meal were specifically linked to liver fat content in those people with type 2 diabetes.

These associations were independent of insulin sensitivity and visceral adipose tissue. “Hyperglucagonemia in the face of higher HLC in early T2D is not due to differences in insulin sensitivity or glucagonotropic metabolites but could suggest hepatic glucagon resistance,” the researchers wrote.

The study also addressed the role of amino acids and nonesterified fatty acids (NEFAs), which previous research has suggested serve as mediators of glucagon secretion. But the current research did not show this to be the case. “This study demonstrates that 1) fasting glucagon concentrations are elevated and tightly associated with MASLD already in newly diagnosed T2D and 2) increased postprandial glucagon levels are positively linked to HLC only in early T2D, but not NGT… but 3) neither amino acids nor NEFAs mediate this hepatopancreatic relationship,” the researchers wrote.

These findings could boost current development of glucagon-based drugs, including dual- and triple-agonists targeting incretin and glucagon receptors, which are already being studied for the treatment of MASLD. The study implicates that altered glucagon physiology in type 2 diabetes may influence how patients respond to drugs, and differences in glucagon signaling may help explain why some therapies appear less effective in individuals with diabetes compared to those without.

While this study was cross-sectional and does establish causality, the researchers pointed to the consistent associations across multiple metabolic measurements as evidence to support further investigation. Additional work could determine whether hepatic glucagon resistance can be directly measured and targeted. Future research will also focus on finding out whether modifying glucagon signaling can alter the progression of MASLD and type 2 diabetes, and how new therapies in development can be personalized for patients with different metabolic profiles.

The post Early Glucagon Elevation Linked to MASLD in Type 2 Diabetes appeared first on Inside Precision Medicine.

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Behavior Change Techniques in Digital Health Interventions for Promoting Adolescent Health Behaviors: Systematic Umbrella Review

Background: Digital health interventions (DHIs) using behavior change techniques (BCTs) show promise in addressing adolescent health behaviors, but evidence of their effectiveness across health behavior domains remains fragmented and poorly summarized. Objective: This systematic umbrella review synthesized evidence from existing systematic reviews on the effectiveness of BCTs within DHI targeting key adolescent health behavior domains: alcohol consumption, tobacco use, physical activity, dietary habits, and obesity management. Methods: We systematically searched PubMed, PsycInfo, Embase, and CINAHL in April 2024 for reviews of DHI for adolescents (10‐19 years old). We coded all identified BCTs using the Behavior Change Technique Taxonomy version 1 (BCTTv1). Data on BCT effectiveness, intervention characteristics, and review quality were extracted and narratively synthesized using AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews 2). Results: A total of 20 reviews, comprising 224,135 participants, were included. These examined DHIs targeting physical activity (7 reviews), dietary habits (3 reviews), alcohol consumption (2 reviews), combined alcohol and nicotine use (1 review), and obesity management (1 review), with an additional 6 reviews covering multiple health behaviors. Across reviews, 65% (13/20) reported statistically significant positive effects on at least one health behavior outcome. “Social support (unspecified)” was the most consistently adopted and effective BCT, especially with parental/peer involvement. The combination of “self-monitoring,” “goal setting,” and “feedback” also commonly appeared in successful interventions. Intervention effectiveness appeared linked to strategic BCT selection and individualization rather than the total number of techniques. The methodological quality of included reviews was predominantly low, with only 2 rated high. Conclusions: This umbrella review identified “social support (unspecified)” as a consistently effective BCT across multiple adolescent health behavior domains, particularly with parental/peer involvement. Intervention success appears linked to targeted and individualized BCT use. Future research should prioritize clarifying the specific components and delivery methods of effective social support, rigorously evaluating BCT configurations in underexplored areas such as adolescent smoking cessation, and examining their long-term impact on behavior change.
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Glioblastoma: Testosterone Supplements Linked to 38% Lower Risk of Death

Researchers at Cleveland Clinic have discovered that androgen hormones such as testosterone can limit the growth of glioblastoma tumors in men. Results published today in Nature show that men receiving testosterone supplements for reasons unrelated to cancer showed a 38% lower risk of death compared to patients not taking these supplements. 

These findings are surprising because testosterone is known to contribute to the growth of other forms of cancer in men, such as prostate cancer, where hormone therapy is used routinely to decrease levels of androgen hormones and block cancer progression. However, these hormones were found to play a very different role in glioblastoma, an aggressive form of brain cancer that is more commonly diagnosed in men. 

“This outcome is a welcome surprise and may potentially offer a lead for new treatments for a kind of cancer that is deadlier in men,” said Anthony Letai, MD, PhD, director of NIH’s National Cancer Institute (NCI).  

In a mouse model of glioblastoma the researchers found that reducing levels of androgen hormones induced overdrive on the hypothalamus-pituitary-adrenal (HPA) axis, a brain circuit that controls reactions to stress and many physiological processes including hormone secretion. This caused a spike in stress hormones that led the brain to reinforce the protective function of the blood-brain barrier and create an immunosuppressive environment in the brain, reducing the ability of immune cells to fight against the tumor. 

“The brain has evolved to keep stuff out and that includes immune cells from elsewhere in the body. It’s a delicate tissue that often doesn’t want huge immune reactions,” said Justin D. Lathia, PhD, professor of cancer sciences and scientific director of the Brain Tumor Center at Cleveland Clinic.

Importantly, this effect was only observed in male mice. In females, changes in testosterone levels did not produce the same effects.

These findings were then confirmed in human samples obtained from 1,300 men with glioblastoma participating in the NIH database Surveillance, Epidemiology, and End Results (SEER). An analysis showed that men who received supplemental testosterone for reasons unrelated to their glioblastoma diagnosis had a 38% lower risk of death than other male patients. 

More research will be needed to better understand the complex pathway activated by testosterone and other androgen hormones. While the current study identified inflammation in the hypothalamus as a potential trigger of HPA axis activation, future work will look for the exact mechanism glioblastoma tumors employ to induce this reaction from an entirely different region of the brain.  

Lathia noted that, although these results do not establish a causal link between testosterone and patient outcomes for men diagnosed with glioblastoma, the study opens the door for future clinical trials that dive deeper into the link between androgen hormones and glioblastoma tumor growth. He added, “An obvious follow-up study would be to find out whether androgen deprivation, which is a common treatment for cancer, is actually detrimental for glioblastoma.” 

 

The post Glioblastoma: Testosterone Supplements Linked to 38% Lower Risk of Death appeared first on Inside Precision Medicine.

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Pancreatic Cancer Shares Genetic Drivers with Obesity and Diabetes

Researchers at the University of Birmingham have found that the same genes are active in pancreatic cancer, obesity, and diabetes. Their findings, published in Cancer Medicine, could finally provide an explanation to why metabolic disease is a major risk factor for pancreatic cancer. 

“We know that people with obesity or diabetes tend to have worse outcomes from pancreatic cancer, but the biological reasons have not been clear,” says Animesh Acharjee, PhD, associate professor of integrative analytics and AI at the University of Birmingham and senior author of the study. “Our study shows that the same genes and inflammatory pathways are active in both metabolic disease and pancreatic cancer, which helps explain this link and points to new opportunities for identifying high‑risk patients and developing more targeted treatments.”

Treatment options are currently limited for patients diagnosed with pancreatic cancer, a form of cancer that is often diagnosed at advanced stages. Only about 15% of patients are eligible for surgery, and about 80% of them relapse after treatment. 

Previously, the researchers had identified a series of genes that were consistently altered in metastatic pancreatic tumors. In the current study, they examined whether these same genes also play a role in metabolic disorders such as obesity and diabetes, which are increasingly recognized as risk factors for pancreatic cancer.  

First, the team analyzed genetic data from publicly available datasets to study how six key drivers of pancreatic cancer behave in healthy individuals compared to people with obesity. These included the ITGAM, PECAM1, CCL5, STAT1, STAT2, and CD44 genes, which are involved in inflammation, immune cell recruitment, and lipid metabolism processes. All six genes were found to be upregulated in individuals with obesity. 

Single-cell RNA sequencing of patient tumor samples revealed that a subset of immune cells, including macrophages and monocytes found within the tumor microenvironment, expressed these core six genes at higher levels than other cells. This discovery suggests this group of cells may be key drivers of tumor progression and recurrence and a potential therapeutic target for the development of targeted therapies.  

Taken together, these findings indicate that immune and inflammatory pathways that drive metabolic disease also play a major role in pancreatic cancer, where they could be involved in immune evasion and recurrence after surgery. Future work will investigate whether modulating the activity of these genes could reduce the chronic inflammation and immune dysregulation that drive the recurrence of pancreatic cancer to improve the success rate of this procedure. Targeting these pathways could offer new therapeutic strategies to manage pancreatic cancer, especially in patients with underlying metabolic conditions.

“This study highlights how chronic inflammation and metabolic dysfunction can intersect with cancer biology,” says Simon Jones, PhD, professor in musculoskeletal aging at the University of Birmingham and team lead for the NIHR Biomedical Research Centre. “Understanding these shared mechanisms is essential if we are to improve outcomes for patients who are living with multiple long‑term conditions alongside cancer.”

 

The post Pancreatic Cancer Shares Genetic Drivers with Obesity and Diabetes appeared first on Inside Precision Medicine.

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The Use of 3D Printing Technology in Rehabilitation for Adults Living With Neurological Conditions: Scoping Review

Background: Neurorehabilitation plays a key role in improving motor recovery for people with neurological conditions. Although 3D printing has emerged as a promising rehabilitation tool, little is known on how it is used for the rehabilitation of adults living with neurological conditions worldwide. Objective: We aimed to provide a comprehensive overview of 3D printing in neurorehabilitation and precisely explore how it is used to improve motor recovery for adults with neurological conditions living in higher- and lower-middle–income countries. Methods: We conducted a scoping review following the Joanna Briggs Institute guidelines. After searching 3 databases (MEDLINE, Web of Science, and Nursing and Allied Health Premium), 2 independent reviewers screened and selected English-language studies involving adults (≥18 years) published between 2019 and 2024 to capture the most recent advancements in this field. We extracted relevant information on neurological conditions, motor recovery outcomes, and types of 3D printing and offered a comparative analysis of 3D printing in physical neurorehabilitation from the perspective of national income levels using a modified Joanna Briggs Institute extraction form. We synthesized the findings narratively with tabular support. Results: After screening 2752 titles and abstracts and 103 (3.7%) full texts, we included 13 (0.5%) studies based on our inclusion criteria. All included studies were conducted in upper-middle–income or high-income countries, and most studies (9/13, 69.2%) focused on stroke, followed by spinal cord injury (2/13, 15.4%), Parkinson disease (1/13, 7.7%), and central nerve disease (1/13, 7.7%). The 3D-printed rehabilitation tools included orthotics (7/13, 53.8% for the upper extremities [UEs]; 3/13, 23.1% for the lower extremities [LEs]), an exoskeleton (1/13, 7.7%; UEs), a modular assistive hand device (1/13, 7.7%; UEs), and an insole (1/13, 7.7%; LEs). In total, 69.2% (9/13) of the studies targeted UE rehabilitation, measured using the Action Research Arm Test, active range of motion, the box and block test, the Fugl-Meyer Assessment, the Modified Ashworth Scale, the manual function test, range of motion, and the Toronto Rehabilitation Institute Hand Function Test, and 30.8% (4/13) targeted LE rehabilitation, measured using the 10-m walk test, anteroposterior ground reaction force analysis, the Barthel index, the Tinetti scale, the RehaWatch system, and the GaitWatch system. Conclusions: Used as a rehabilitation tool, 3D printing technology has demonstrated significant potential in improving upper and lower motor recovery for people with certain neurological conditions in high-middle–income countries. Future research should explore the implementation feasibility and effectiveness of these technologies across different neurological conditions and income settings, particularly in low- and lower-middle–income countries.
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Comparing Usual Care With Coordinated Clinician and Patient Use of Mobile Technology in Primary Care for Patients With Major Depressive Disorder: Practice-Based Pilot Study

Background: Major depressive disorder (MDD) affects millions of Americans each year and is often diagnosed and treated in primary care. Evidence shows that self-management techniques, shared decision-making (SDM), and goal setting are effective strategies for managing MDD, but the required collaboration between patients and primary care clinicians can be difficult. Primary Care Path is a program for supporting depression management in primary care that includes a patient-facing mobile app and an accompanying care team–facing web interface. Leveraging programs that provide clinician-facing software with companion patient-facing mobile technology may help patients and physicians align depression treatment and management goals, support effective SDM, alleviate barriers, and improve both clinical care and patient outcomes. Objective: To pilot-test the use of Primary Care Path for MDD management in primary care and evaluate the impact of its use on depression treatment, symptoms, goal setting and attainment, and SDM. Methods: Four primary care clinical practices in the United States were assigned to program use (2 practices; intervention) versus usual care (2 practices; control). Intervention practices used the Primary Care Path program in their clinics and engaged patient participants in app use for 18 weeks. Clinical care teams engaged with the patient-informed program portal primarily during patient encounters (in-person, virtual or calls). Patient participants were smartphone users aged 18 years and older who were being treated for MDD. Patient participants received online surveys (medication changes, Patient Health Questionnaire-9 [PHQ-9], goal setting and attainment questions, and Shared Decision-Making Questionnaire-9 [SDM-Q-9]) at baseline, 6, 12, and 18 weeks. Results: A total of 76 patient participants (34 intervention; 42 control) were enrolled; the majority were female (27/34, 79%; 32/42, 76%), White (31/34, 91%; 40/42, 95%), non-Hispanic/Latino/a (29/34, 85%; 40/40, 100%), and employed (26/34, 77%; 34/42, 81%). Control patient participants’ conversations with their medical providers increased over the study period, while intervention patient conversations with their medical providers decreased over time. At week 18, intervention participants felt more successful than control in achieving their personalized treatment goals. More intervention patient participants initiated antidepressant medication by weeks 12 (=.03) and 18 (=.04) and switched medications by weeks 6 (=.009) and 12 (=.04) versus control. All patient participants demonstrated significant improvement in PHQ-9 scores throughout the study period (<.001), with no difference in change by group. Clinicians and patients indicated using the program to support SDM, but no significant differences were observed in SDM-Q-9 between intervention and control. Conclusions: Preliminarily, the use of this digital health program related to earlier medication optimization, earlier conversations between patients and medical providers, and patient attainment of goals that matter most to them, indicating that coordinated use of the program by both patients and clinical team members may enhance MDD management in primary care clinical settings.
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Advanced Cardiovascular-Kidney-Metabolic Syndrome Linked to Increased Cancer Risk

Researchers from Japan are calling for increased cross-disciplinary collaboration after showing that people with advanced cardiovascular-kidney-metabolic (CKM) syndrome are at increased risk for cancer.

They explain in Circulation: Population Health and Outcomes that CKM syndrome is a conceptual framework, proposed by the American Heart Association (AHA) in 2023, that captures the interconnected nature of cardiovascular, kidney, and metabolic diseases and reflects the shared risk factors and pathophysiological mechanisms of these diseases.

The current study findings suggest that this framework could also “serve as a valuable, non-invasive stratification tool in precision oncology and preventive medicine,” said Hidehiro Kaneko, MD, PhD, the study’s lead author and associate professor in the department of cardiovascular medicine at the University of Tokyo in Japan.

He told Inside Precision Medicine: “By identifying individuals with advanced CKM (particularly stages 3 and 4), clinicians could tailor and potentially intensify cancer screening protocols for these high-risk patients. This enables more personalized surveillance and early detection strategies that bridge the gap between cardiometabolic management and cancer prevention.”

According to AHA statistics, nearly nine out of 10 adults in the United States have at least one component of CKM syndrome, which includes high blood pressure, abnormal cholesterol, diabetes, obesity, and reduced kidney function.

Although these components of CKM syndrome have each been associated with an increased risk for certain cancers, the relationship between CKM stage and the risk for incident cancer is unclear, as current knowledge is largely derived from studies of individual components rather than the integrated syndrome.

To address this, Kaneko and team analyzed administrative claims data for more than 1.3 million people living in Japan. Of these, 12.5% had CKM stage 0, 9.8% had stage 1, 31.7% had stage 2, 36.3% had stage 3, and 9.8% had stage 4.

The researchers report that, over a median follow-up of 3.4 years, increasing baseline CKM stages were associated with significantly greater cancer incidence.

Specifically, the incidence of cancer was 81.2 cases per 10,000 person–years in people with CKM stage 0, increasing to 97.2, 105.1, 250.9, and 257.7 cases per 10,000 person–years in those with CKM stages 1, 2, 3, and 4, respectively.

After adjustment for age, sex, alcohol consumption, and physical inactivity, individuals with CKM stage 1 or 2 at baseline did not have a significantly increased risk for cancer relative to those with CKM stage 0. However, people with CKM stages 3 and 4 had significant 25% and 30% higher risks for cancer, respectively, than those with stage 0.

When the team analyzed the data by cancer type, they found that the incidence of colorectal, stomach, lung, renal pelvis and ureter, pancreatic, non-Hodgkin lymphoma, bladder, liver, kidney, thyroid, leukemia, and gallbladder cancers increased progressively with higher baseline CKM stages. There was a similar pattern for prostate cancer in men and for breast, cervical, and uterine cancers in women.

Conversely, there was no clear association between baseline CKM stage and the incidence of esophageal cancer, malignant melanoma, or Hodgkin lymphoma.

The associations between CKM stage 3 or 4 and cancer risk were stronger in men than in women and in people younger than 65 years of age relative to older individuals. However, people aged 65 years and older were also at increased risk for cancer even when they had CKM stage 1 or 2 relative to stage 0, whereas younger individuals were not.

Kaneko said that the study highlights a critical need for increased awareness of the link between CKM syndrome and cancer.

“While physicians and the public generally understand that interconnected metabolic and kidney conditions lead to heart disease and stroke, the integrated CKM syndrome is rarely viewed as a significant driver of cancer,” he remarked. “Our study demonstrates a clear, stage-dependent increase in incident cancer risk as CKM progresses, underscoring the need to recognize cancer as a major potential consequence of this multisystem syndrome.”

Kaneko suggested that “this can be addressed by shifting public health messaging to emphasize that proactive lifestyle modifications—such as weight management, a healthy diet, and regular exercise—provide dual protection against both cardiovascular events and cancer.”

He added: “Within the medical community, we should promote the CKM staging framework as a comprehensive health assessment tool, encouraging cross-disciplinary collaboration among cardiologists, nephrologists, endocrinologists, and oncologists to manage these overlapping risks holistically.”

The post Advanced Cardiovascular-Kidney-Metabolic Syndrome Linked to Increased Cancer Risk appeared first on Inside Precision Medicine.

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STAT+: Sanofi asks to pull diabetes drug out of FDA voucher program after political appointee interfered with review

WASHINGTON — Sanofi has asked the Food and Drug Administration to pull its type 1 diabetes drug, teplizumab, out of Commissioner Marty Makary’s new speedy drug review program. 

The move comes after acting Center for Drug Evaluation and Research Director Tracy Beth Høeg disagreed with a staff decision to approve the drug, according to sources familiar with the dispute who requested anonymity due to fear of reprisal. The agency has missed its goal date of April 21 to deliver a decision to Sanofi.

Such decisions are typically made by career scientists. It’s rare for a center director to become involved in scientific review of a single drug, and particularly a political appointee like Høeg. Makary recently told CNBC that he stands behind review teams, and that “disaster” occurs whenever political leaders overrule scientific staff. 

Continue to STAT+ to read the full story…

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Heavy-Chain BsAbs More Manufacturable than Light-Chains

Bispecific antibodies (BsAb) were first approved in 2014. Since then, a total of 19 have been approved globally, and approximately 250 BsAbs are being developed by some 180 companies, according to a report from Research and Markets. As this therapeutic class moves out of the lab and into clinical and commercial sectors, manufacturing may be its biggest challenge.

These dual-targeting compounds are considered difficult to produce, especially at scale. With low yields, potential chain mispairing, stability and aggregation issues, and analytical characterization challenges, biomanufacturers are eager to find expedient solutions. “There is still significant work to be done in bioprocess engineering to substantially improve the efficiency of bispecific antibody design and manufacturing,” Laura A. Palomares, PhD, senior researcher, Universidad Nacional Autónoma de Mexico (UNAM), tells GEN.

To that point, rather than relying upon transient expression systems or evaluating various antibody sequences, Palomares and her team are identifying manufacturable BsAbs by correlating their architectures to growth, productivity, downstream recovery, production of product-related variants, and in vitro binding to Zika virus and transferrin receptor (TfR). They found BsAb architecture is crucial in terms of those manufacturing criteria.

Structure governs performance

Specifically, as much as a 70% difference in productivity was found between symmetric heavy-chain scFv fusion BsAbs—which performed like the parental antibody—and BsAbs that were designed as light-chain scFv fusion, dual-variable domain immunoglobulin (DVD), or asymmetric antibodies. That’s according to a recent study by Palomares, doctoral student Juan Carlos Rivera-Castro, and senior researcher Octavio T. Ramirez, PhD.

Asymmetric BsAbs had the worst culture performance and productivity of the BsAb architectures tested. Asymmetry created imbalanced chain expression and formed homodimeric and half-antibody by-products, they reported, which dropped purity to approximately 68% after protein A purification. They found that binding to the LC-scFV diminished the binding to Zika virus, and that DVD increases it. Also, binding to TfR varied according to BsAb valency and configuration.

In contrast, “Bivalent heavy-chain scFV formats show[ed] stronger apparent binding than monovalent formats,” they report.

For the best manufacturability, the team says, “Avoid the modification of the light chain and preserve symmetric assembly.” This strategy resulted in higher cell viability, productivity, and final purity.

“The construction and head-to-head comparison of various formats, including the effect of the formats on antigen binding, can guide those planning the design and production of BsAbs,” Palomares says, by understanding the relative tradeoffs of various architectures as they design and clone BsAbs for specific functionalities.

“Format selection should prioritize manufacturability, with complex designs reserved for cases with particular functional requirements,” the scientists conclude.

Next steps, Palomares says, are to “determine the in vivo functionality of the constructed formats to neutralize Zika virus after traversing the blood-brain barrier. The results of those experiments will also be useful to scientists interested in BsAb design.”

The post Heavy-Chain BsAbs More Manufacturable than Light-Chains appeared first on GEN – Genetic Engineering and Biotechnology News.