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@article{pmid40949987,

title = {A cytokine receptor-targeting chimera (kineTAC) toolbox for expanding extracellular targeted protein degradation},

author = {Kaan Kumru and Zi Yao and Brandon B Holmes and Fangzhu Zhao and Yun Zhang and Emilio Ferrara and Trenton M Peters-Clarke and Kevin K Leung and James A Wells},

doi = {10.1101/2025.09.02.673832},

issn = {2692-8205},

year  = {2025},

date = {2025-10-06},

urldate = {2025-09-01},

journal = {bioRxiv},

abstract = {Extracellular targeted protein degradation (eTPD) is as an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver. Cytokine receptor targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (Pance K, Gramespacher JA., Byrnes, JR, Salangsang F., Serrano JAC, Cotton AD, Steri V, and Wells JA,  , 41, 273-281). Here, we dramatically expand the kineTAC toolbox by constructing 81 new kineTACs based on an unbiased list of cytokines, chemokines and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues and some were more potent than the original CXCL12-based kineTAC. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type-selective eTPD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Adams2025,

title = {An asymmetric tetrabody is a potent and efficacious agonist of the erythropoietin receptor in vitro and in vivo},

author = {Jarrett J. Adams and Levi L. Blazer and Jacky Chung and Minoo Karimi and Taylor Davidson and Heather A. Bruce and Alexander U. Singer and Ning Yang and Lia Cardarelli and Isabelle Pot and Luigi Colombo and Lily Jun‐shen Huang and Yue Ma and Stephen W. Michnick and Orson W. Moe and Sachdev S. Sidhu},

doi = {10.1002/pro.70292},

issn = {1469-896X},

year  = {2025},

date = {2025-09-17},

urldate = {2025-10-00},

journal = {Protein Science},

volume = {34},

number = {10},

publisher = {Wiley},

abstract = {Abstract: Erythropoietin (EPO) initiates EPO receptor (EPOR) signaling in hematopoietic cells by binding to an asymmetric EPOR dimer through two different sites. We engineered dimeric diabody‐Fc (Db‐Fc) fusion proteins that appeared to act as potent agonists of human EPOR in cell proliferation assays. However, detailed analysis of their oligomeric forms revealed that the predominant Db‐Fc species bound EPOR with high affinity but failed to induce cell proliferation. Instead, a minor oligomeric form, identified as a putative tetrabody (Tb) fused to two Fc domains (Tb‐Fc), proved to be the minimal active form. The existence of a tetrameric agonist was further supported by crystallography, which revealed an asymmetric Tb structure. Additionally, the structure of an antigen‐binding fragment (Fab) bound to EPOR revealed an epitope distinct from the EPO binding sites, and structural modeling showed that engagement of two of the four binding sites on the Tb could form an asymmetric EPOR dimer nearly identical to the active conformation recruited by EPO. In a knock‐in mouse model, where mouse EPOR was replaced by human EPOR, purified Tb‐Fc stimulated erythropoiesis with greater potency, efficacy, and duration than darbepoetin, a recombinant EPO that is the leading therapeutic erythropoiesis‐stimulating agent (ESA). Collectively, these findings demonstrate that asymmetric tetravalent antibodies such as Tb‐Fc represent promising next‐generation ESAs that provide enhanced potency, efficacy, and durability. Moreover, they may reduce the oncogenic and cardiovascular risks associated with the pleiotropy of EPO.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40897170,

title = {Characterization of the OMP biogenesis machinery in Fusobacterium nucleatum},

author = {Claire Overly Cottom and Eva Heinz and Satchal Erramilli and Anthony Kossiakoff and Daniel J Slade and Nicholas Noinaj},

doi = {10.1016/j.str.2025.08.008},

issn = {1878-4186},

year  = {2025},

date = {2025-08-01},

urldate = {2025-08-01},

journal = {Structure},

abstract = {F. nucleatum is a Gram-negative bacteria that causes oral infections and is linked to colorectal cancer. Pathogenicity relies on a type of β-barrel outer membrane protein (OMP) called an autotransporter. The biogenesis of OMPs is typically mediated by the barrel assembly machinery (BAM) complex. In this study, we investigate the evolution, composition, and structure of the OMP biogenesis machinery in F. nucleatum. Our bioinformatics and proteomics analyses indicate that OMP biogenesis in F. nucleatum is mediated solely by the core component BamA. The structure of FnBamA highlights distinct features, including four POTRA domains and a C-terminal 16-stranded β-barrel domain observed as an inverted dimer. FnBamA represents the original composition of the assembly machinery, and a duplication event that resulted in BamA and TamA occurred after the split of other lineages, including the Proteobacteria, from the Fusobacteria. FnBamA, therefore, likely serves a singular role in the biogenesis of all OMPs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}