SOUTH SAN FRANCISCO, Calif., August 19, 2020 -- Surrozen Inc., a biotechnology company pioneering a new class of targeted regenerative antibodies, today announced a peer-reviewed publication describing its novel platform for the generation of potent and selective R-spondin mimetics. The article, “Tissue-targeted R-spondin mimetics for liver regeneration” was published online in Scientific Reports, a Nature Research journal.
The article describes Surrozen’s R-spondin-mimetic program, culminating in a hepatocyte-targeted bispecific antibody that potently and selectively enhances the Wnt signaling pathway in the liver. The publication describes a novel approach to the regeneration of hepatocytes, and highlights the potential for the approach in treating a range of severe liver diseases.
“This publication underscores Surrozen’s mission of developing targeted therapeutics for safe and effective tissue regeneration via the Wnt pathway. Conceived and engineered in house, Surrozen’s R-spondin mimetic platform provides an entirely new approach to targeted regeneration for various diseases. I am proud of all the scientists who contributed to this body of work.” said Wen-Chen Yeh MD, PhD, chief scientific officer of Surrozen and a co-author on the paper. “This approach, which complements our Wnt-mimetic platform, is the second proprietary platform for selectively activating the Wnt pathway that Surrozen has described in a peer-reviewed publication.”
Notable results in the publication include the discovery that hepatocyte-specific Wnt agonism can be directed through replacing LGR binding with a liver specific receptor, ASGR1. Through mutating R-spondin to replace LGR binding with ASGR1 while maintaining ZNRF3/RNF43 signaling, Surrozen has shown the ability to effectively and robustly enhance Wnt stimulation within the liver, leading to the proliferation and maturation of hepatocytes. The molecule described in the paper, αASGR1-RSPO2-RA, upregulated Wnt target genes in hepatocytes and stimulated cell proliferation specifically in the liver. Other Wnt-sensitive tissues were not responsive to administration of the R-spondin mutant. Significantly,αASGR1-RSPO2-RA showed the ability to improve liver function in diseased mice within three days.
“These results suggest that a targeted R-spondin-mimetic can stimulate functional regeneration in a cell-specific manner.” said Yang Li, PhD, vice president of Biology at Surrozen and a co-author on the paper. “The novel Wnt pathway engineering method described in the article can be tailored to diseased tissues with high levels of endogenous Wnt ligand and specific cell surface receptors, highlighting the potential of the technology to impact multiple disease areas. This publication describes the constructs and experiments that have led to SZN-043, our preclinical candidate for severe liver diseases.”
Wnt signaling plays key roles in the control of development, homeostasis,and regeneration of many essential organs and tissues, including liver,intestine, lung, kidney, central nervous system, cochlea, bone, and others.Modulation of Wnt signaling pathways has potential for treatment of degenerative diseases and tissue injuries. There are 19 Wnt ligands (Wnts) in mammals, and they signal through Frizzled receptors 1-10 and co-receptors LRP5 or 6, two families of receptors. Endogenous Wnts bind to multiple Frizzled receptors and are heavily modified post-translationally, making them difficult to manufacture consistently. R-spondin stabilizes Frizzled receptors, enhancing the body’s response to endogenous Wnts.
Since its founding in 2016, Surrozen has developed two proprietary platforms to selectively modulate the Wnt pathway for the potential treatment of injury and disease. Surrozen Wnt-mimetics, also referred to as SWAP(Surrozen Wnt signal activating proteins), are bi-specificfull-length human (IgG) antibodies that directly activate the canonical Wnt signaling pathway in target tissue. Surrozen R-spondin-mimetics, also referred to as SWEETS (Surrozen Wnt signal enhancers engineered for tissue specificity), are antibody-based molecules that enhance Wnt signaling by stabilizing Frizzled receptors on targeted cells.
SZN-043 is the first development candidate designed using Surrozen’s SWEETS platform. In preclinical animal models of liver injury and fibrosis, SZN-043 has been shown to selectively activate Wnt signaling in the liver, stimulate hepatocyte proliferation, improve synthetic function, and reduce fibrosis. The Company’s goal is to clinically evaluate the candidate in settings of drastic hepatocyte loss, such as severe acute alcoholic hepatitis (AAH), where SZN-043 may have a rapid impact on hepatocyte regeneration, as well as settings of advanced chronic disease conditions of cirrhosis. Liver cirrhosis is characterized by adecline in liver synthetic function and an increase in liver fibrosis,culminating in various complications such as portal hypertension, ascites, varices,and hepatic encephalopathy.
Surrozen is a biotechnology company pioneering a new class of targeted regenerative antibodies to repair a broad range of tissues and organs damaged by serious disease. Surrozen is designing tissue-specific antibodies that engage the body’s own biological repair mechanisms resulting in a broad pipeline of disease-specific therapies to help patients across multiple disease areas, including severe liver diseases, inflammatory bowel disease, retinopathies, hearing loss, lung and airway diseases, and certain neurological disorders. For more information, please visit surrozen.com.
VP, Corporate Development and Strategy