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@article{pmid41556618,

title = {Tetravalent antibodies are more potent and efficacious erythropoiesis-stimulating agents than erythropoietin in vivo},

author = {Jarrett J Adams and Levi L Blazer and Jacky Chung and Minoo Karimi and Taylor Davidson and Bailey Blair and Carlos Waddle and Craig A Hokanson and Heather A Bruce and Alexander U Singer and Eva-Maria Tombak and Kiira Gildemann and Nele Tamberg and Kaja Kiiver and Mart Ustav and Yue Ma and Luigi Colombo and Lily Jun-Shen Huang and Stephen W Michnick and Orson W Moe and Sachdev S Sidhu},

doi = {10.1002/pro.70462},

issn = {1469-896X},

year  = {2026},

date = {2026-02-01},

urldate = {2026-02-01},

journal = {Protein Sci},

volume = {35},

number = {2},

pages = {e70462},

abstract = {Recent studies have shown that tetravalent antibodies are potent and efficacious agonists of the erythropoietin (EPO) receptor (EPOR) both in vitro and in vivo. To identify antibody-based erythropoiesis-stimulating agents (ESAs) with therapeutic potential, we evaluated various tetravalent antibody formats for EPOR agonism and key biophysical properties necessary for biologic drug development. We identified two distinct tetravalent antibody formats that strongly stimulated the growth of UT7/Epo cells, which rely on EPOR signaling for proliferation. Moreover, one of these formats exhibited ideal biophysical characteristics for drug development. This format consisted of a diabody (Db) and two antigen-binding fragment (Fab) arms fused to the N- and C-termini of an Fc domain, respectively, to form a tetravalent Db-Fc-Fab (EPRA-0322). In a mouse model expressing the human EPOR, EPRA-0322 induced erythropoiesis with greater potency, efficacy, and duration than darbepoetin, a hyperglycosylated EPO currently used in clinical practice. These findings highlight tetravalent antibodies, and the Db-Fc-Fab format in particular, as promising next-generation ESAs suitable for large-scale production and clinical use.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41254216,

title = {Temporal photoproximity labeling of ligand-activated EGFR neighborhoods using MultiMap},

author = {Zhi Lin and Wayne Ngo and Yu-Ting Chou and Harry Wu and Katherine J Susa and Young-Wook Jun and Trever G Bivona and Jennifer A Doudna and James A Wells},

doi = {10.1038/s41589-025-02076-y},

issn = {1552-4469},

year  = {2026},

date = {2026-02-01},

urldate = {2025-11-01},

journal = {Nat Chem Biol},

volume = {22},

number = {2},

pages = {192--204},

abstract = {Photoproximity labeling proteomics (PLP) methods have recently shown that cell surface receptors can form lateral interactome networks. Here, we present a paired set of PLP workflows that dynamically track neighborhood changes for oncogenic epidermal growth factor receptor (EGFR) over time, both outside and inside of cells. We achieved this by augmenting the multiscale PLP workflow we call MultiMap, where three photoprobes with different labeling ranges were photoactivated by one photocatalyst, eosin Y, anchored extracellularly and intracellularly on EGFR. We identified hundreds of neighboring proteins that changed within minutes to over 1 h after the addition of EGF. These neighborhoods reveal dynamic interactomes during early, middle and late signaling that drive phosphorylation, internalization, degradation and transcriptional regulation. This rapid 'molecular photographic' labeling approach provides snapshots of signaling neighborhoods, revealing their dynamic nature and potential for drug targeting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41564137,

title = {A cytokine receptor-targeting chimera 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 = {10.1073/pnas.2524129123},

issn = {1091-6490},

year  = {2026},

date = {2026-01-01},

urldate = {2026-01-01},

journal = {Proc Natl Acad Sci U S A},

volume = {123},

number = {4},

pages = {e2524129123},

abstract = {Extracellular targeted protein degradation (eTPD) is an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver, limiting specific degradation in other tissues. 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 (K. Pance ,  , 273-281 (2023)]. Here, we dramatically expand the kineTAC toolbox by constructing 81 different 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 against specific targets. 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}

}