Welcome to the Recombinant Antibody Network

@article{pmid41818370,

title = {Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer},

author = {Corleone S Delaveris and Rita P Loudermilk and Apurva Pandey and Soumya G Remesh and Trenton M Peters-Clarke and Snehal D Ganjave and William J N Dougherty and Henry M Delavan and Chunyue Wang and Jesse Ling and Juan Antonio Camara Serrano and Fernando Salangsang and Chien-Kuang Cornelia Ding and Nancy Greenland and Carissa E Chu and Sima Porten and Veronica Steri and Jonathan Chou and Michael J Evans and Kevin K Leung and James A Wells},

doi = {10.1126/science.aec1778},

issn = {1095-9203},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {Science},

volume = {391},

number = {6790},

pages = {eaec1778},

abstract = {Overexpression of the proto-oncogene Src is common to a wide variety of cancers. In this work, we found that Src is noncanonically translocated and inverted onto the cell surface in cancer, both in vitro and in vivo. We identified autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines. Src represents the prototypical example of a family of membrane-anchored proteins that are transported by this process. Furthermore, this extracellular membrane-associated Src (eSrc) was found in primary tumors, and anti-Src antibody-based therapies mediated tumor cell killing in cell culture systems and in mouse xenograft models. Thus, intracellular -myristoylated proteins, prototypically Src, can be topologically inverted onto the cell surface in cancer and targeted with antibody therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41807832,

title = {Structures of ALG3/9/12 reveal the assembly logic of the N-glycan oligomannose core},

author = {J Andrew N Alexander and Shu-Yu Chen and Somnath Mukherjee and Mario de Capitani and Rossitza N Irobalieva and Lorenzo Rossi and Parth Agrawal and Julia Kowal and Matheus A Meirelles and Markus Aebi and Jean-Louis Reymond and Anthony A Kossiakoff and Sereina Riniker and Kaspar P Locher},

doi = {10.1038/s41589-026-02164-7},

issn = {1552-4469},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {Nat Chem Biol},

abstract = {Asparagine-linked glycans are essential for the maturation and function of most eukaryotic secretory proteins. The biosynthesis and transfer of dolichylpyrophosphate-anchored GlcNAcManGlc glycan is a highly conserved process occurring in the endoplasmic reticulum (ER) membrane and involving over a dozen membrane proteins whose dysfunction is linked to congenital disorders of glycosylation (CDGs). Three membrane-integral mannosyltransferases, ALG3, ALG9 and ALG12, mediate four consecutive mannosylation reactions that convert GlcNAcMan to GlcNAcMan. Here, using chemoenzymatically synthesized lipid-linked glycan donor and acceptor analogs, we recapitulated this biosynthetic pathway in vitro. High-resolution cryo-electron microscopy structures of pseudo-Michaelis complexes of each step revealed how the branched glycan is accurately synthesized and unwanted side products are averted. Molecular dynamics simulations and mutagenesis studies uncovered a subtle but precise mechanism selecting the dolichylphosphomannose donor substrate over dolichylphosphoglucose, which is also present in the ER membrane. Our results also provide mechanistic explanations for enzyme dysfunction in CDGs and offer opportunities for N-glycan engineering.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41756920,

title = {Targeted shedding of extracellular membrane proteins by induced protease recruitment},

author = {Zi Yao and Fangzhu Zhao and Kun Miao and Trenton M Peters-Clarke and Yun Zhang and Snehal D Ganjave and Angel L Vázquez-Maldonado and Yan Wu and Kaan Kumru and Hammam Jumaa and Kevin K Leung and James A Wells},

doi = {10.64898/2026.02.17.706468},

issn = {2692-8205},

year  = {2026},

date = {2026-02-01},

urldate = {2026-02-01},

journal = {bioRxiv},

abstract = {Extracellular targeted protein degradation has emerged as a promising therapeutic modality to eliminate proteins of interest (POIs) at the cell surface, by using bifunctional molecules to recruit natural recycling receptors or membrane-bound E3 ligases that redirect POIs to the lysosome. Another natural mechanism involves extracellular proteases that cleave and shed extracellular domains. Here, we exploit this endogenous mechanism by engineering bispecific antibody  , that recruit a classic sheddase ADAM10 to POIs, inducing selective ectodomain shedding. We first targeted the immune checkpoint receptor LAG-3 and observed robust depletion of surface LAG-3 accompanied by accumulation of soluble LAG-3 fragments in both engineered cell lines and primary human T cells. Using biochemical and imaging assays, we confirmed that this antibody-induced shedding is restricted to extracellular protease activity and occurs independently of lysosomal trafficking. Notably, induced shedding of LAG-3 on activated primary T cells partially alleviated inhibitory signaling and reinvigorated IFN  secretion. We extended the scope of induced shedding by developing  that recognize synthetic epitope-tags that enabling rapid assessment of substrate compatibility across diverse targets. Using this platform, we identified multiple immune modulatory cell-surface receptors, including IL6Rα, CD62L and MIC-A that can be targeted for shedding. In summary, this work establishes a new paradigm for targeted extracellular proteolysis and expands the toolkit for studying extracellular proteolysis with potential therapeutic benefit.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}