FZD1

Pioneering AI technology successfully designs antibodies de novo for six therapeutic targets, including one without an experimentally resolved structure SEOUL, South Korea, March 17, 2025 /PRNewswire/ -- Galux Inc., a South Korean startup specializing in AI-driven protein therapeutics design, has published a study showcasing the capabilities of its AI platform, GaluxDesign, in de novo antibody design. This research marks an important milestone in AI-driven antibody discovery, demonstrating the successful design of antibodies against six distinct therapeutic targets, including a target without an experimentally resolved structure. Continue Reading A graphical representation verifying the binding strength between the antibodies designed by GaluxDesign and each therapeutic target. "De novo antibody design has been one of the major challenges in AI-based drug discovery, requiring atomic-level precision to ensure specific binding to target epitopes," said Chaok Seok, CEO of Galux. "A few previously reported cases of de novo antibody design have shown only limited success, particularly in terms of target diversity and binding affinity. Our findings prove that AI can reliably generate novel antibodies with high precision, specificity, and sensitivity across diverse therapeutic targets." A graphical representation verifying the binding strength between the antibodies designed by GaluxDesign and each therapeutic target. The study presents an AI-driven approach to de novo antibody design. The team identified binders from a yeast display single-chain variable fragment (scFv) library comprising approximately one million designed antibody sequences, followed by screening binders against a target protein. Binders with varying binding strengths were identified for six targets, including PD-L1, HER2, EGFR(S468R), ACVR2A/B, FZD7, and ALK7. Notably, the team successfully designed antibodies targeting ALK7, a protein without an experimentally resolved structure, as well as antibodies targeting a novel epitope of FZD7 discriminating subtypes FZD1 and FZD5. This highlights the platform's broad applicability for novel antibody discovery. The designed PD-L1 targeting antibody showed outstanding binding affinity (KD=9.0pM) and developability comparable to the commercial therapeutic antibody Atezolizumab. Additionally, antibodies designed for EGFR(S468R) displayed exceptional specificity, precisely distinguishing the mutant from wild-type EGFR based on a single amino acid difference, which is an essential feature for minimizing off-target effects in early-stage drug development. "This study underscores the potential of AI-driven antibody design and its broad applicability in antibody discovery," added Seok. "By continuously advancing our AI platform with a deep understanding of atomic-level protein interactions, we aim to transform therapeutic drug discovery, improving both efficiency and success rates." The full research paper is available here: About Galux With over 25 years of expertise in the field, Galux is pioneering AI-powered protein design with its proprietary platform, GaluxDesign, which enables precise de novo protein design and engineering. GaluxDesign has been developed to deeply understand the physical principles that govern protein folding and interactions. This approach enables the platform to tackle various protein design challenges including epitope-specific antibody design. Since its incorporation in 2020, the company has raised USD 18 million from reputable investors, including InterVest, Pathway Partners, DAYLI Partners, LG Corp., and KDB Capital. SOURCE Galux WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Bispecific antibodies (bsAbs) possess unique advantages due to their ability to simultaneously target two distinct antigens, which helps to enhance the immune system's recognition and killing of tumor cells. As of the end of 2023, 14 bsAbs have been approved: 11 of them for cancer treatment and 3 for non-oncological indications. BsAbs come in various structural formats, target different antigens, and mediate antitumor functions through different molecular mechanisms. The development of antibodies targeting G protein-coupled receptor (GPCR) targets is relatively more challenging compared to traditional drugs such as small molecules, peptides, recombinant hormones, etc., with slower progress in comparison. In contrast, the development of Antibody-Drug Conjugates (ADCs) targeting members of the GPCR family has seen a gradual increase in research momentum over the past decade. Dual-specificity antibodies related to GPCRAccording to statistics from the Synapse database, there are currently 23 bispecific antibody therapeutics worldwide targeting GPCR (G protein-coupled receptor) class targets, including targets such as CXCR4 (+PD-L1) , GPRC5D (+CD3) , GPRC5D (+BCMA+CD30) , SSTR2 (+CD3) , ETA (+CD3) , ETA (+TGF-B) , CCR8 (+TIGIT) , CCR8 (+CTLA4) , CCR2 (+M-CSF) , FZD5 (+LRP6) , FZD4 (+LRP5), GIPR+GLP-1R, FSHR (+albumin) , LGR5 (+EGFR). Johnson & Johnson's Talquetamab became the world's first approved bispecific antibody targeting a GPCR class target to be marketed. Bispecific antibodies that target both GPRC5D and CD3 include Nanjing Leads Biolabs' LBL-034, which is in Phase 1/2 clinical trials, and Roche's Forimtamig, which is in Phase 1 clinical development. Additionally, the GPRC5D+CD3+BCMA trispecific antibody MBS314, co-developed by Kyinno Biotechnology and Beijing Mabworks Biotech, is in Phase 1/2 clinical trials, and the GPRC5D+CD3+BCMA trispecific antibody SIM-0500, co-developed by Simcere Pharmaceutical Group Limited and Shanghai Xianxiang Pharmaceutical Technology, is in the clinical application stage. Translate the following text into English with professional accuracy: The Dutch biotechnology company Merus has developed a bispecific product, Petosemtamab (MCLA-158), currently in Phase 1/2 clinical trials. This is a bispecific Biclonics® fucose-low full human IgG1 antibody that simultaneously targets the epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). Petosemtamab is designed with three independent mechanisms of action: Inhibition of the EGFR-dependent signaling pathway: By binding with EGFR on the surface of tumor cells, it blocks normal signal transmission, thereby inhibiting processes such as tumor cell proliferation, migration, and angiogenesis.  LGR5-mediated EGFR internalization and degradation: Petosemtamab can bind to LGR5, leading to the internalization and degradation of EGFR within cancer cells, further diminishing EGFR’s pro-carcinogenic activity.  Enhancement of antibody-dependent cellular cytotoxicity and phagocytosis (ADCC/ADCP): With its bispecific structure, Petosemtamab can recruit and activate the immune system's natural killer (NK) cells and macrophages, enhancing their ability to recognize and eliminate cancer cells expressing EGFR and LGR5, thus achieving indirect antitumor effects. At the 2023 Annual Meeting of the American Association for Cancer Research (AACR), Merus presented the results of a Phase 1/2 clinical trial cohort expansion, showing that Petosemtamab demonstrated a manageable safety profile and significant therapeutic effects in patients with advanced head and neck squamous cell carcinoma (HNSCC). Among the 43 patients with advanced HNSCC treated with Petosemtamab, the overall response rate (ORR) reached 37.2%, with tumor reductions observed in 16 patients. The data specifics included: 1 patient achieved a complete response (CR), and 15 patients had partial responses (PR). In addition, 15 patients achieved a stable disease (SD) condition. As a result, the disease control rate (DCR) was 72.1% (n=31/43; 95% CI, 56.3%-84.7%), which means that over seventy percent of the patients experienced no tumor progression or saw reductions in tumor size following treatment. The bi-specific product SZN-1326, originally developed by the American biotechnology company Surrozen, is in Phase 1 clinical research. The product is designed based on Surrozen's proprietary SWAP™ technology, with the goal of modulating the Wnt signaling pathway in intestinal epithelium. The Wnt/β-catenin signaling pathway plays a crucial role in the renewal of intestinal stem cells, the maintenance of intestinal epithelial homeostasis, and the regeneration process. Studies have confirmed that this pathway is dysregulated in inflammatory bowel disease (IBD). Fzd5 is a Wnt receptor with high expression in intestinal epithelial tissues. SZN-1326 is a bi-specific, effectorless IgG1 antibody that targets both FZD5 and 8, as well as the LRP6 receptor. Preclinical research has indicated that SZN-1326 can effectively activate the Wnt signaling pathway. Furthermore, in organoid cultures of the intestine, it can stimulate the growth of the organoids; it increases the expression levels of the Wnt target gene Axin2 in colonic tissue; and in a mouse model, SZN-1326 can also ameliorate colitis symptoms induced by Dextran Sulfate Sodium (DSS). At present, bispecific antibodies targeting GPCR class targets are primarily indicated for cancer-related clinical applications, with popular therapeutic directions including multiple myeloma, plasma cell myeloma, solid tumors, and more. However, there is also a diversity of clinical indications, such as bispecific antibodies targeting GIPR and GLP-1R for the treatment of obesity and diabetes, bispecific antibodies targeting ETA for the treatment of pulmonary fibrosis and pulmonary arterial hypertension, bispecific antibodies targeting FSHR for the treatment of male/female infertility, and bispecific antibodies targeting FZD4 for the treatment of diabetic retinopathy and wet age-related macular degeneration.

Morphogens are the secreted molecules that pattern embryonic tissues. These molecules are important not only for the embryo during development, but also for the adult during tissue repair. However, the way these morphogens are distributed to ensure patterning occurs is still not fully understood. Using a combination of experiments and mathematical modeling, researchers learned more about the role morphogens play in tissue patterning. Their results are relevant to medical applications, such as drug design. Morphogens are molecules that travel from biological cell to cell to pattern tissues in the embryo. These molecules are important not only for the embryo during development, but also for the adult during tissue repair. However, the way these morphogens are distributed to ensure patterning occurs is still not fully understood. Using a combination of experiments and mathematical modeling, a research team from the University of Tokyo and their international collaborators has learned more about the role morphogens play in tissue patterning. The results are relevant to medical applications, such as drug design. The team's findings are published in the journal eLife. The Wnt morphogen has emerged as a key regulator of heart development in vertebrates. These Wnt proteins are molecules that play an important role in cell development. However, it is still generally unclear to scientists exactly how Wnt regulates heart development. There are differences among the vertebrate classes, as well as redundancy in some species. However, scientists can study how Wnt regulates heart development in the Xenopus, an aquatic frog that is native to sub-Saharan Africa. The Xenopus, with its lungs and three-chamber heart, is cost-effective and useful to scientists in their study of human diseases. In Xenopus heart development, scientists have already established that the Wnt6 morphogen is sent out by the epidermis, those outer layers of cells that make up the skin, to pattern the cardiogenic mesoderm, which is the group of cells in the embryo that will form the heart. From this patterning, a relatively thin pericardium (the membrane around the heart) and a broad myocardium (the heart's muscular tissue) develop. Scientists are still working to better understand how the Wnt6 morphogen distribution is regulated to ensure reproducible positioning of the pericardium and myocardium in the cardiogenic mesoderm. "It is still unclear how reproducible patterning can be achieved with diffusing molecules, especially when that patterning concerns differentiation of thin tissues." said Takayoshi Yamamoto, an assistant professor at the University of Tokyo and the first author and corresponding on the paper. Scientists do know that in early embryo development, the range of Wnt8 morphogen signaling is precisely regulated heparan sulfate and secreted Wnt binding proteins, including Frzb (which is also known as sFRP3). Heparan sulfate is a carbohydrate that is important is embryo development. Wnt signaling is one of the main processes by which tissue takes shape during the development of the embryo. The research team wondered whether mechanisms similar to those that operate in early embryos also regulate distribution of Wnt6 morphogen in the cardiogenic mesoderm. The Wnt receptor, Frizzled7, is essential for heart development. The expression of Frizzled7 is increased by Wnt signaling in the development of the nervous system in the Xenopus and in the development of human embryonic carcinoma cells, but there are no such reports in heart development. So the research team focused their study to analyze the way Wnt signaling occurs in the development of the heart, focusing on the extracellular components -- the Frizzled7 cell-surface receptor, sFRP1 (an inhibitor of Wnt6 that can also travel from cell to cell) and heparan sulfate. "With a combination of experiments and mathematical modeling, this receptor-feedback appears essential to shape a steep gradient of Wnt signaling. In addition, computer simulation revealed that this feedback imparts robustness against variations of Wnt ligand production and allows the system to reach a steady state quickly," said Yamamoto. Wnt6 and sFRP1 molecules not only regulate normal heart development in the embryo, but also regulate repair and regeneration after heart muscle injury, such as in the case of a myocardial infarction, or heart attack. "Our findings will be relevant to medical applications, for example, for drug design, since cell-surface molecules such as Frizzled or a specific modification of heparan sulfate or even the secreted molecule sFRP1, generally provide better drug targets than molecules inside cells. To reveal the precise regulation of morphogens and to consider medical applications, regulatory mechanisms of these components must be investigated further," said Yamamoto. The research was conducted in collaboration with researchers at the University of Aberdeen in the U.K.