Abstract
Cell surface receptor-targeted protein degraders hold promise for drug discovery. However, their application is restricted because of the complexity of creating bifunctional degraders and the reliance on specific lysosome-shuttling receptors or E3 ubiquitin ligases. To address these limitations, we developed an autophagy-based plasma membrane protein degradation platform, which we term AUTABs (autophagy-inducing antibodies). Through covalent conjugation with polyethylenimine (PEI), the engineered antibodies acquire the capacity to degrade target receptors through autophagy. The degradation activities of AUTABs are self-sufficient, without necessitating the participation of lysosome-shuttling receptors or E3 ubiquitin ligases. The broad applicability of this platform was then illustrated by targeting various clinically important receptors. Notably, combining specific primary antibodies with a PEI-tagged secondary nanobody also demonstrated effective degradation of target receptors. Thus, our study outlines a strategy for directing plasma membrane proteins for autophagic degradation, which possesses desirable attributes such as ease of generation, independence from cell type and broad applicability.
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Data availability
The data supporting the findings of this study are available within the paper and its Supplementary Information and in the ScienceDB repository (https://doi.org/10.57760/sciencedb.11745). The RNA-seq data generated in this study are available from the Gene Expression Omnibus database under accession code GSE279343. The proteomic raw data were deposited to the ProteomeXchange Consortium through the iProX repository with the dataset identifier PXD056766. The tandem mass spectra obtained from quantitative proteomic analysis were searched against the full UniProt human database. Source data are provided with this paper.
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Acknowledgements
We thank Z. Li for her help in plasmid preparation. This work was supported by grant 2023YFA0915400 (to L.C. and H.L.) from the National Key R&D Program of China, grants 32371450 (to X.S.), 82304546 (to M.L.) and 21977111 (to L.F.) from the National Natural Science Foundation of China, grants 202381515040008 (to L.M. and H.L.), 2023A1515011765 (to L.F.) and 2021A1515012114 (to X.S.) from the Natural Science Foundation of Guangdong Province, grant 2020B1111540001 (to L.C.) from the Guangdong Provincial Key Area R&D Program, grants JCYJ20200109114608075 (to X.S.), JCYJ20210324120200001 (to H.L.) and JCYJ20210324101805014 (to K.L.) from the Shenzhen Science and Technology Program, grant D2301003 (to L.F.) from Shenzhen Medical Research Funds, grants JCYJ20220818100412028 (to L.F.) and JCYJ20220818101404010 (to L.F.) from the Shenzhen Fundamental Research Program and a grant from the SIAT Innovation Program for Excellent Young Researchers (to H.L.).
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H.L., L.F., X.S. and L.C. conceptualized the project and supervised the study. B.C., M.L. J.L. and X.S. performed most of the cell biological, biochemical and animal experiments. J.Z., H.T. and L.F. synthesized and characterized the AUTAB conjugates. Y.L., Z.Z., L.D., W.S., W.Z. and K.L. participated in cell culture, immunofluorescence staining and flow cytometric analysis. R.L., J.R., H.H. and L.M. provided special technical support and discussed the data. B.C., M.L., X.S., L.F. and H.L. wrote the manuscript.
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Extended data
Extended Data Fig. 1 Autophagy activation upon PEI treatment.
a, The corresponding quantifications of confocal images in Fig. 1c–h and Fig. 1j (Fig. 1c, n = 10 cells; Fig. 1d, n = 12 cells; Fig. 1e, n = 15 cells; Fig. 1f, n = 15 cells; Fig. 1g, n = 12 cells; Fig. 1h, n = 10 cells; Fig. 1j, n = 15 cells, means ± s.d.; Quantification is unnecessary for the untreated group due to the absence of PEI signal in cell.). b,c, Representative images and relative quantifications of mCherry-LC3B (b) or mCherry-LC3C (c) stably expressing HeLa cells upon treatment with 1 μM of L25K PEI for indicated period of times. The quantifications are shown on the right (n = 15 cells per group, means ± s.d.). DNA in b and c was counterstained with DAPI. Scale bars, 10 μm.
Extended Data Fig. 2 AUTAB induces LC3C-mediated autophagy in a target receptor-dependent manner.
a, The corresponding quantifications of confocal images in Fig. 2d–f (Fig. 2d, n = 10 cells per group; Fig. 2e, n = 15 cells per group; Fig. 2f, Atz group, n = 14 cells, Atz-AUTAB group, n = 15 cells, means ± s.d.). b, HA-PD-L1 and mCherry-LC3C expressing HeLa cells transfected with scramble or PD-L1 siRNA were incubated with 100 nM Atz-AUTAB for 1 h. Cells were then fixed, and stained with antibodies against Atz. Enlarged images of the white box are presented on the right, with arrowheads indicating the colocalization of mCherry-LC3C and Atz-AUTAB. The quantification is shown on the right of the panel (n = 15 cells per group, means ± s.d.). DNA in b was counterstained with DAPI. Scale bars, 10 μm. Statistical significance was calculated via unpaired two-tailed Student’s t-test (a, b).
Extended Data Fig. 3 Atz-AUTAB accelerates PD-L1 endocytosis.
a, Schematic representation of Atz-AUTAB uptake assay (see Methods section for details). b, Confirmation by western blotting of PD-L1 knockdown in stable expressing HA-PD-L1 HeLa cells. c, HA-PD-L1 expressing HeLa cells with scramble or PD-L1 siRNA were incubated with 1 nM Atz or Atz-AUTAB for 1 h. After fixation, the surface-remaining and internalized Atz/Atz-AUTAB were sequentially stained before or after cell permeabilization. The fluorescence intensities of internalized Atz-AUTAB were quantified, and the data are expressed as each normalized value relative to the scramble group (scramble group, n = 16 cells; siPD-L1 group, n = 14, means ± s.d.). d, HA-PD-L1 expressing HeLa cells were incubated with 1 nM Atz or Atz-AUTAB for 1 h. After fixation, the surface-remaining and internalized Atz/Atz-AUTAB were sequentially stained before or after cell permeabilization. The quantification of the internalized Atz or Atz-AUTAB is shown on the right (Atz group, n = 28 cells; Atz-AUTAB group, n = 22; means ± s.d.). e, HeLa cells stably expressing HA-PD-L1 were subjected to antibody feeding-based internalization assay. Representative examples of internalized PD-L1 and surface-remaining PD-L1 are shown. The quantification of the internalized PD-L1 is shown below as indicated (untreated group, n = 15 cells for 1 h internalization, n = 16 for 2 h; L25K PEI group, n = 14 for 1 h, n = 17 for 2 h; Atz group, n = 27 for 1 h, n = 26 for 2 h; Atz-AUTAB group, n = 18 for 1 h, n = 16 for 2 h; means ± s.d.). DNA in c and d was counterstained with DAPI. Scale bars, 10 μm. Statistical significance was calculated via unpaired two-tailed Student’s t-test (c-e).
Extended Data Fig. 4 Atz-AUTAB treatment damages endosome membrane and triggers LC3C-mediated autophagy.
a,b, HeLa cells stably expressing HA-PD-L1 were treated with 100 nM Atz or Atz-AUTAB for 1 h. Cells were then fixed, co-stained using antibodies against galectin-3, Atz, and Rab5 (a) or Rab7 (b), and imaged by confocal microscopy. Enlarged views of the white boxed regions are shown below. The arrowheads indicate the triple colocalization of galectin-3, Atz-AUTAB, and Rab5 or Rab7. The relative quantification is shown on the right (n = 15 cells per group, means ± s.d.). c,d, HeLa cells concurrently expressing HA-PD-L1 and mCherry-LC3C were treated with 100 nM Atz or Atz-AUTAB for 20 min. After fixation, cells were co-stained with antibodies against Atz and Rab5 (c) or Rab7 (d), followed by confocal microscopy imaging. The white boxed regions are magnified below. The arrowheads indicate the colocalization of mCherry-LC3C and Atz-AUTAB on either early (Rab5-positive) or late (Rab7-positive) endosomes. The quantification is shown on the right (n = 15 cells per group, means ± s.d.). Scale bars, 10 μm. Statistical significance was calculated via unpaired two-tailed Student’s t-test (a-d).
Extended Data Fig. 5 AUTAB induces membrane damage at cell surface.
a, Over-expressing HA-PD-L1 and mCherry-LC3C HeLa cells were treated with 100 nM Atz or Atz-AUTAB for 1 h, then fixed and co-stained with antibodies against ATG9A and Atz. Images were taken by confocal microscopy. The white boxed regions in the images are enlarged below and the arrowheads point to the colocalization between ATG9A, mCherry-LC3C and Atz-AUTAB. The corresponding colocalization quantization is on the right (n = 15 cells per group, means ± s.d.). b, Plasma membrane permeabilization was evaluated with PI uptake assay in stably expressing HA-PD-L1 HeLa cells treated with 250 nM L25K PEI, 100 nM Atz, 25 nM and 100 nM Atz-AUTAB for 1 h. Percentage of cells with PI-positive was quantified (n = 3 biological replicates, means ± s.d.). DNA in b was counterstained with Hoechst 33258. Scale bars, 10 μm (a) or 100 μm (b). Statistical significance was calculated via unpaired two-tailed Student’s t-test (a, b).
Extended Data Fig. 6 Mechanical characterization of Atz-AUTAB-mediated PD-L1 degradation.
a-c, Degradation of exogenously expressed PD-L1 assessed by western blotting in HA-PD-L1 stably expressing HeLa cells following treatment as in Fig. 3a–c. d, Western blot of PD-L1 in MDA-MB-231 cells treated with 6.25 nM Atz-AUTAB for 24 h in the presence or absence of 200 μM chloroquine. e, Western blot analysis of PD-L1 and LC3B in MDA-MB-231 cells treated with indicated concentrations of Atz, L25K PEI, and Atz-AUTAB for 12 h and followed by release for 12 h. f, MDA-MB-231 cells with or without siRNA mediated knockdown of LC3B were subjected to treatment with 6.25 nM Atz-AUTAB for 12 h. The PD-L1 levels were detected by immunoblotting. g, Western blot analysis of GABARAP, GABARAPL1, GABARAPL2 in LC3C knockout MDA-MB-231 cells treated with or without 6.25 nM Atz-AUTAB for 12 h. h, Western blot of PD-L1 in MDA-MB-231 cells treated with 6.25 nM Atz-AUTAB for 12 h under siRNA-mediated knockdown of GABARAP, GABARAPL1, and GABARAPL2 respectively. i, HA-PD-L1 stable expressing HeLa cells transfected with scramble or LC3C, GABARAP, GABARAPL1, and GABARAPL2 siRNA were incubated with 100 nM Atz-AUTAB for 1 h. Cells were then fixed and co-stained with antibodies against galectin-3, Lamp1 and Atz. The enlarged images of the white box are presented below, with arrowheads indicating the colocalization of galectin-3, Lamp1 and Atz-AUTAB. The quantification is shown on the right (n = 15 cells per group, means ± s.d.). j, Western blot of PD-L1 in MDA-MB-231 cells treated with 6.25 nM Atz-AUTAB for the indicated time (0, 12, 16, 20 h) under siRNA-mediated knockdown of ATG4B. Scale bars, 10 μm. Statistical significance was calculated via unpaired two-tailed Student’s t-test (i).
Extended Data Fig. 7 EGFR degradation driven by Ctx-AUTAB.
a, SDS-PAGE analysis of the Ctx-AUTAB with Coomassie blue staining. b, Representative surface EGFR immunostaining images of HeLa cells treated with 10 nM L25K PEI, 5 nM Ctx or 5 nM Ctx-AUTAB for 4 h. c, Flow cytometry analysis of surface EGFR levels in live HeLa cells upon treatment with 10 nM L25K PEI, 5 nM Ctx or 5 nM Ctx-AUTAB for 4 h. Mean fluorescence intensity of surface EGFR relative to the untreated group was quantified (n = 3 biological replicates, means ± s.d.). d, Quantification of triple colocalization between mCherry-LC3C, EGFR and Ctx-AUTAB or Ctx in Fig. 4a (n = 15 cells per group, means ± s.d.). e,f, Representative confocal images (e) and quantification (f) showing the colocalization of EGFR and RFP-Lamp1 in HeLa cells following 1 h of treatment with 10 nM L25K PEI, 5 nM Ctx or 5 nM Ctx-AUTAB (n = 10 cells per group, means ± s.d.). g, Western blot analysis of EGFR in HeLa cells treated with increasing concentrations of Ctx-AUTAB for 24 h. h, Western blot of EGFR in HeLa cells following treatment with 25 nM of Ctx-AUTAB for the indicated time periods. DNA in b and e was counterstained with DAPI. Scale bars, 10 μm. Statistical significance was calculated via unpaired two-tailed Student’s t-test (c, d, f).
Extended Data Fig. 8 Ole-AUTAB accelerates CD73 degradation.
a, SDS-PAGE analysis of the Ole-AUTAB with Coomassie blue staining. b, Quantification of colocalization between mCherry-CD73 and LysoTracker in Fig. 4h (n = 15 cells per group, means ± s.d.). c, Live-cell flow cytometry analysis of surface CD73 levels in mCherry-CD73 stably expressing HeLa cells upon treatment with 200 nM L25K PEI, 100 nM Ole or 100 nM Ole-AUTAB for 12 h. Mean fluorescence intensity of surface CD73 relative to the untreated group was quantified (n = 3 biological replicates, means ± s.d.). d,e, Western blot analysis of CD73 in U87-MG cells upon treatment with increasing concentrations of Ole-AUTAB for 24 h (d), or upon treatment with 100 nM of Ole-AUTAB for different times (e). f, Western blotting to detect the CD73 degradation in Ole-AUTAB treated U87-MG cells in the presence or absence of bafilomycin A1 or chloroquine for 24 h. Statistical significance was calculated via unpaired two-tailed Student’s t-test (b, c).
Extended Data Fig. 9 Gel electrophoresis validation and functional examination of various types of established AUTABs.
a,b, SDS-PAGE analysis of distinct Atz-AUTABs covalently tagged with various types of PEIs, including L2.5 K PEI, B800 PEI, B2K PEI and B25 K PEI (a), and Ctx-AUTAB and Ole-AUTAB that were both conjugated with L2.5K PEI (b). c, Western blot analysis of EGFR in HeLa cells or CD73 in U87-MG cells that were respectively treated with Ctx-AUTABs or Ole-AUTABs for 24 h at the indicated concentrations. d, SDS-PAGE analysis of Atz-AUTABs respectively prepared using acetylated L2.5 K PEI. e, Quantification of colocalization between Atz-AUTAB (L2.5 K), mCherry-LC3C and HA-PD-L1 in Fig. 5f (n = 15 cells per group, means ± s.d.). f, SDS-PAGE analysis of Atz-AUTABs respectively prepared using poly-L-Lys with varying sizes (4–15 K, and 15–30 K). g, Quantification of colocalization between PolyLys-Atz-AUTABs, mCherry-LC3C and HA-PD-L1 in Fig. 5h (n = 15 cells per group, means ± s.d.). Statistical significance was calculated via unpaired two-tailed Student’s t-test (e, g).
Extended Data Fig. 10 Therapeutic potential of AUTAB in vivo.
a, Schematic illustration of the general treatment procedure for anti-tumor study. C57BL/6 J mice with MC38 subcutaneous xenografts were administered doses of 5 mg/kg mouse PD-L1 antibody (mPD-L1-Ab) or mPD-L1-Ab-AUTAB by intravenous injection every 2 ~ 3 days for 5 times. b, SDS-PAGE analysis of the mPD-L1-Ab-AUTAB with Coomassie blue staining. c,g, Body weights (c) and MC38 tumor volumes (d) of mice were monitored during administration with mPD-L1-Ab or mPD-L1-Ab-AUTAB (n = 8 mice per group, means ± s.d.). e,f, Photographs of excised tumors are shown (e) and the weight of tumors was quantified (f) at the end of the treatments (n = 8 mice per group, means ± s.d.). g, Western blot of PD-L1 in MC38 xenografts in e (n = 4 mice per group). h, Tumor tissues in e were sectioned, stained for CD8, and imaged. The mean number of CD8-positive cells per field was quantified and is shown on the right (n = 4 mice, means ± s.d.). DNA in h was counterstained with DAPI. Scale bars, 50 μm. Statistical significance was calculated via unpaired two-tailed Student’s t-test (d, f, h).
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Cheng, B., Li, M., Zheng, J. et al. Chemically engineered antibodies for autophagy-based receptor degradation. Nat Chem Biol 21, 855–866 (2025). https://doi.org/10.1038/s41589-024-01803-1
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DOI: https://doi.org/10.1038/s41589-024-01803-1
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