C4A family

Scientists studied two complement components that are important parts of the immune system and are linked to schizophrenia and autoimmune disorders. They studied the link between two protein concentrations -- C3 and C4 -- in over 68,000 newborn babies and the risk of developing six mental disorders later in life. Research led by Professor John McGrath from the University of Queensland found that the concentration of the C4 protein, an important part of the immune system, was not associated with risk of mental disorders. However, the research also showed that a higher concentration of the C3 protein reduces the risk of schizophrenia in women, and studies based on the genetic correlates of C4 found strong links with several autoimmune disorders. Professor John McGrath from UQ's Queensland Brain Institute said his colleagues at Aarhus University in Denmark looked at two complement components linked to schizophrenia and autoimmune disorders. "These complement components are proteins that work with your immune system, helping to protect your body from infection and autoimmune disorders. "We studied the link between two protein concentrations -- C3 and C4 -- in over 68,000 newborn babies and the risk of developing six mental disorders later in life," Professor McGrath said. "A growing body of evidence links C4 to brain development, which could subsequently have implications for the risk of mental disorders. "However, in our study, we found no associations between C4 concentration and mental health disorders. "In an expanded sample, we found higher C3 concentration was associated with a reduced risk of schizophrenia in females only." The research team also examined the link between the genetic correlates of these two proteins and the risk of autoimmune disorders, finding that C4 was linked with an altered risk of five types. "Higher C4 concentration was associated with a lower risk of several autoimmune disorders and a higher risk of others," Professor McGrath said. "The mechanisms underpinning the links between C4 and the increased or decreased risk of autoimmune disease are not well understood yet. "We hope our findings will guide future research into the association between these two complement components and health outcomes." The study was published in Cell Genomics. Professor McGrath's work is funded by the Danish National Research Council, and the Queensland Centre for Mental Health Research.

Merck will have the option to license a total of four protein degradation targets from C4. Merck & Co. was the talk of the town in Madrid after signing a multi-billion dollar antibody drug conjugate (ADC) deal with Daiichi Sankyo to open this year’s European Society for Medical Oncology annual meeting. Now the Keytruda maker is back to the dealmaking table, and looking at antibody conjugates from a different lens. The pharma is paying $10 million upfront to C4 Therapeutics to develop an exclusive degrader-antibody conjugate (DAC), a play on words that summarizes C4’s protein degrader offering. C4 also stands to make $600 million in biobucks on the single asset, according to Tuesday's announcement. Merck has the option to license three additional DACs from the biotech that, if pursued, would push the total value of the deal to $2.5 billion.  C4 is one of a growing number of targeted protein degradation biotechs that have entered the fold in recent years, including the likes of Nurix, Amphista, PeptiDream and Proxygen. C4’s platform differentiates itself by developing two types of degraders: one that binds directly to the E3 ligase (known as a molecular glue) creating a new landing for that disease-causing protein; and another that binds to both the protein and ligase independently. The hope is that this will vastly expand the scope of problematic proteins that targeted degradation could deal with.  Merck is C4’s fourth collaboration, including prior pacts with Biogen and Roche. The deal with Biogen aims C4’s Torpedo platform at neurological diseases, namely Parkinson’s and Alzheimer’s. The deal with Roche is broader, with the partners not specifying disease areas of interest, and was expanded in 2019. What is known is that the Swiss pharma handed back an epidermal growth factor receptor (EGFR) target back in 2020.  C4 launched in 2015 out of the lab of Jay Bradner, M.D., back when he was a physician-scientist at the Dana-Farber Cancer Institute. Shortly after the biotech’s founding, Bradner, who is credited as one of C4’s scientific co-founders, was hired as president of the Novartis Institutes for BioMedical Research.  Beyond its business development ventures, C4 is growing an internal pipeline that includes two clinical-stage meds. The lead asset is a molecular glue targeting IKZF1 and IKZF3 for patients with multiple myeloma and non-Hodgkin’s lymphomas. C4 previously decided not to advance a third clinical-stage candidate, CFT8634, due to “insufficient single agent efficacy.”  

DNA sequencing technology has progressed significantly in the 20 years since the Human Genome Project published the original human genome map. Scientists have released the first draft of the human pangenome reference, a new blueprint of human DNA built on data from a much more diverse cohort than the original. “We’re going to be able to understand forms of genetic variation in genes that we never could characterize properly before,” senior author Evan Eichler, Ph.D., based at the University of Washington School of Medicine in Seattle, said during a press briefing. Eichler and the other scientists behind the effort are members of the Human Pangenome Reference Consortium, an international group backed by the National Institutes of Health’s National Human Genome Research Institute.  Several papers describing the developments were published May 11 in Nature. The initiative builds on past attempts to make the human genome reference more accurate. When the results of the Human Genome Project were published in 2003, the sequence was about 90% done. While many updates and corrections have been made over the years as technology has improved, only in March 2022 was it officially completed, thanks to an undertaking by researchers with the Telomere-to-Telomere Consortium. (Many of those same scientists are also part of the Human Pangenome Reference Consortium.) The latest updates are a significant step toward making scientists’ guide to the human genome better represent the global population. While the original map ushered in a wave of biomedical progress, it was built on genomic data from just 20 people—most of it from one individual. The latest draft incorporates two genetic sequences each from 47 people, all of them genetically diverse. That number is slated to grow to 350 by mid-2024. “We refer to [the original human genome sequence] constantly when we talk about genes,” senior author Benedict Paten, Ph.D., of the UC Santa Cruz Genomics Institute, said. “The problem with the current reference is that it is both incomplete and it lacks diversity. Concretely, it lacks the things that make us different genetically, and thus the interesting things.” If you took the genetic sequences of two individuals and laid them side by side, 99.6% of the data would match up. But the differences are what’s important. They explain why one person might be more likely than the other to develop a heart condition or cancer, for instance—or, if both have the same disease, could predict whether one might benefit more from a specific treatment. Having data from too few individuals creates blind spots. A clinician might miss that someone is vulnerable to a genetic disease if that person’s particular gene variation hasn’t been documented as a risk because the data used to build the reference were too narrow.  Take the complex gene for lipoprotein(a), a type of low-density cholesterol. Clinical studies have shown that higher levels of lipoprotein(a) correspond with a greater risk of having a heart attack. Mutations in the gene for lipoprotein(a) are associated with the biggest genetic risk for coronary heart disease in African Americans—but because the gene hasn’t been completely sequenced, there are many cases that lacked a clear cause. “Now that we can actually sequence that gene in its entirety, and we can understand the variation in that gene, we can start to go back to unexplained cases of patients with coronary heart disease and risk and associate it with variation that now comes out of the pangenome,” Eichler explained. Another example is complement factor 4A and 4B, or C4A and C4B, which is involved in the immune response. Structural variations in the genes for C4A and C4B that result from a process called gene conversion have been closely linked to schizophrenia. The pangenomic reference gives insight into those variations, so clinicians and scientists can develop more accurate associations in patients, Eichler said. “We know the signal is there for these few examples, but there’s a lot more left to be discovered,” he added. “We now have the framework to actually do that discovery.” DNA sequencing technology has progressed significantly in the 20 years since the Human Genome Project published the original human genome map. One major improvement making the new reference possible is long-read DNA sequencing, which interprets long stretches of DNA at a time. Others include advanced computational techniques that enable researchers to align single sequences from many different individuals and assemble them together to create the guide. “[These tools] are allowing us to create genomes that are essentially complete, and when you have the complete sequence, you have the complete genetic variation,” Eichler said.