xirestomig (ATG-101) / Antengene, Oricell - LARVOL DELTA

Exceptional Response to BTK Inhibitors in Aggressive Lymphomas Linked to Chronic Selective Autophagy (ASH 2023) - "Unexpectedly, we identified multiple autophagy-related genes involved autophagosome formation (ATG9A, ATG101, ATG13, RB1CC1 and ATG14) and autophagosome membrane expansion (ATG2A, WIPI2, WDR45) that strongly counteracted the toxicity of BTKi (≥3 SD)...Collectively, we identified a non-canonical form of selective autophagy that chronically degrades MYD88L265P, is counter-selected in MCD tumors, and is promoted by BTK inhibitors. Our findings help to elucidate the exceptional benefit of BTK-targeted therapies in the MCD DLBCL subtype and offer a rationally designed combination therapy regimen to specifically degrade this mutant allele of MYD88."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BRD4 • CD79B • IRF4 • MYD88 • RB1CC1 • SYK • TLR9

ULK1/2 Inhibitors that Degrade ATG13 Effectively Target KRAS-Mutant Cancers. (PubMed, bioRxiv) - "Previously, we developed small molecule ULK1 inhibitors that not only inhibit ULK kinase activity but also induced the degradation of other core members of the ULK complex including ATG101 and ATG13...Finally, immunohistochemical staining of orthotopic pancreatic tumors reveals a significant increase in CD4⁺ and CD8⁺ T cell infiltration upon treatment, suggesting that SBP-1750 enhances anti-tumor immunity. These findings support further development of SBP-1750 as a novel ATG-targeting cancer therapy."

Journal • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • KRAS

Reconstitution of multistep recruitment of ULK1 to membranes in autophagy. (PubMed, bioRxiv) - "Human ULK1C consists of ULK1 itself, FIP200, and the HORMA domain heterodimer ATG13:ATG101...Biochemical reconstitution and cell-based assays show that the PVP motif is essential for in vitro ULK1 phosphorylation of ATG16L1 and important for BNIP3/NIX-dependent mitophagy. These data establish a stepwise pathway for recruitment of the ULK1 KD to the vicinity of the membrane surface downstream of PI3KC3-C1."

Journal • ATG16L1 • ULK1

RAN Promotes Autophagy and Malignant Progression of Lung Adenocarcinoma through ATG101. (PubMed, Adv Biol (Weinh)) - "Suppression of ATG101 effectively counteracts the enhanced proliferation induced by RAN overexpression, highlighting ATG101 as a key mediator of RAN's effects. This study underscores the critical molecular dynamics of LUAD driven by RAN, suggesting that the RAN-ATG101 axis can serve as a novel therapeutic target."

Journal • Lung Adenocarcinoma • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Antengene Hosts 2025 R&D Day Showcasing Encouraging Clinical Data and Solid Progress with Investigational Programs (The Malaysian Reserve) - "...it will present the latest data and future plans for three mid/late-stage clinical programs, including ATG-022 (CLDN18.2 antibody-drug conjugate [ADC]), ATG-037 (oral CD73 small molecule inhibitor), and ATG-101 (PD-L1/4-1BB bispecific antibody). The company will also share the latest progress on ATG-125 (B7H3 x PD-L1 bispecific ADC): A B7H3 x PD-L1 targeted therapy featuring “'O + ADC' dual-effect molecules for the treatment of solid tumors and its AnTenGager™ T-cell engager (TCE) technology platform which incorporates steric hindrance masking, along with updates on several key preclinical programs."

Clinical data • Colorectal Cancer • Hematological Malignancies • Melanoma • Neuroendocrine Carcinoma • Non Small Cell Lung Cancer • Ovarian Cancer

High Tumor Mutational Burden Associates with Increased CD8 T-Cell Presence, Decreased Tumor Heterogeneity, and Increased AICDA Expression in an HIV-Inclusive Cohort of Diffuse Large B-Cell Lymphoma (ASH 2024) - "TMB-high tumors had increased expression of tumor-promoting autophagy-related genes (ATG101, ATG3), and purine and pyrimidine metabolism genes (POLR1C, CDA, NME1)...This study highlights the interplay between genomic complexity, intrinsic tumor features and immune response in DLBCL. Our findings may lead to new therapeutic avenues for DLBCL patients regardless of HIV status, though further work must be done to elucidate the role of AICDA and systemic immunity on tumorigenesis and anti-tumor response."

Heterogeneity • Tumor mutational burden • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Human Immunodeficiency Virus • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • AICDA • ATG3 • CD8 • DDB2 • IFNGR1 • IRF1 • LIG1 • LRIG1 • POLH • POLR1D • STAT1 • TMB

Lnc-HZ14 promotes LLPS-mediated SPHK1 aggrephagy degradation to suppress trophoblast cell proliferation in unexplained recurrent miscarriage. (PubMed, Autophagy) - "Meanwhile, lnc-HZ14 also promotes autophagy by activating ETV4-mediated transcription of ATG101 and PPP1R15A/GADD34...As for miscarriage treatment, therapeutic upregulation of SPHK1 by treatment with phorbol 12-myristate 13-acetate (PMA), an SPHK1 agonist recovers mouse placental proliferation and alleviates mouse miscarriage. Collectively, this study shows for the first time the regulatory roles of lnc-HZ14, LLPS, and aggrephagy degradation of SPHK1 in unexplained recurrent miscarriage, uncovering novel pathogenesis and biological mechanisms of unexplained RM and also providing potential targets for treatment against miscarriage."

Journal • Targeted Protein Degradation • ETV4 • PPP1R15A • SPHK1 • SQSTM1

Revisiting the evolution of the yeast Atg1 complex. (PubMed, Autophagy Rep) - "In contrast, the fission yeast Schizosaccharomyces pombe Atg1 complex incorporates Atg101 instead of Atg29 and Atg31 and features a rod-shaped Atg17 scaffold. Collectively, our findings delineate the potential evolutionary trajectories of the Atg1 complex in yeast. Abbreviations: ATG, autophagy-related; BLAST, basic local alignment search tool; C-Mad2, closed Mad2; EAT, Early Autophagy Targeting/Tethering; EM, electron microscopy; His-MBP, histidine-maltose binding protein; HORMA, Hop1, Rev7, and Mad2; IDR, intrinsically disordered region; O-Mad2, open Mad2; iTOL, Interactive Tree of Life; PAS, phagophore assembly site; PI3K, phosphatidylinositol 3-kinase; PMSF, phenylmethylsulfonyl fluoride; pTM, predicted template modeling; RMSD, root mean square deviation; TOR, target of rapamycin; TORC1, TOR complex 1."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Evolutionary diversification of the autophagy initiation complex: reduced Atg101 dependency and changes in Atg9 binding to Atg13. (PubMed, Autophagy) - "Furthermore, both KpAtg101 and KpAtg31 are involved in Atg1 complex assembly in K. phaffii. These findings suggest that the reduced importance of Atg101 in the Atg13-Atg9 interaction and Atg1 complex assembly enabled the eventual loss of ATG101 in some Holomycota species, including S. cerevisiae."

Journal • RB1CC1 • ULK1

A Trial of ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=33 | Terminated | Sponsor: Antengene (Hangzhou) Biologics Co., Ltd. | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2025 ➔ Mar 2025 | N=62 ➔ 33 | Trial completion date: Dec 2025 ➔ Mar 2025; The sponsor has decided to adjust the development strategy of the investigational drug in this study.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

The neuroprotective role of chlorogenic acid and Fisetin in differentiated neuronal cell line-SHSY5Y against amyloid-β-induced neurotoxicity. (PubMed, Toxicol In Vitro) - "Autophagy-related pathways were significantly modulated which was evidenced by increased PRKAA1 (AMPK) and decreased MTOR mRNA levels, alongside elevated expression of ATG101, ATG13, ULK1, SQSTM1 (p62) and reduced ATG5 levels. Furthermore, our docking studies also revealed good Fisetin and CGA binding affinity within AMPK and mTOR's binding pocket (FKBP12-FRB). Although the neuroprotective effects of CGA and Fisetin are underscored by transcriptional and docking studies, further translational and biophysical validation is required to demonstrate their therapeutic efficacy against AD-related neurodegeneration."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Pain • AMPK • ATG5 • DLG4 • MFN2 • mTOR • PINK1 • SQSTM1 • SYP

Caloric restriction mimetics chlorogenic acid and fisetin as potential autophagy inducers targeting ATG101. (PubMed, Biochem Biophys Rep) - "Therefore, these CRMs can be responsible for their potential as autophagy inducers. These findings offer significant insights into the molecular processes through which CRMs may improve neurodegenerative diseases by triggering autophagy."

Journal • Alzheimer's Disease • CNS Disorders • ULK1

The triad interaction of ULK1, ATG13, and FIP200 is required for ULK complex formation and autophagy. (PubMed, Elife) - "In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101...We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1-ATG13-FIP200 triadic interaction is crucial for autophagosome formation and provides a structural basis and insights into the regulation mechanism of autophagy initiation in mammals."

Journal • ULK1

PROBE: A Study ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=31 | Terminated | Sponsor: Antengene Biologics Limited | Trial completion date: Jan 2026 ➔ Jan 2025 | Recruiting ➔ Terminated | Trial primary completion date: Oct 2025 ➔ Jan 2025; It is due to the recent changes in the competitor landscape and strategic consideration

Trial completion date • Trial primary completion date • Trial termination • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Innovative discovery and mechanistic validation of HyT-PD ligands for selective CDK9-targeted protein degradation. (PubMed, Acta Pharm Sin B) - No abstract available

Journal • Targeted Protein Degradation • CDK9

First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy-lysosome pathway. (PubMed, Acta Pharm Sin B) - "Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins."

Journal • Oncology • Targeted Protein Degradation • CDK9

A Trial of ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=62 | Active, not recruiting | Sponsor: Antengene (Hangzhou) Biologics Co., Ltd. | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Aug 2024 ➔ Aug 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

FIP200 governs plasma B cell differentiation by regulating mitochondrial homeostasis and heme biosynthesis (IMMUNOLOGY 2025) - "We found that B cells deficient in FIP200, a mammalian autophagy sensor which complexes with ULK1/ATG13/ATG101 to initiate autophagy in response to a range of stimuli, failed to undergo normal immune cell reorganization in response to fasting...Moreover, single-cell RNAseq suggested that heme biosynthesis was affected in FIP200-deficient B cells; notably, the administration of heme was sufficient to rescue plasma cell differentiation of FIP200-deficient B cells. Thus, FIP200 determines B cell fates by controlling mitophagy and metabolic reprogramming.Keywords: Animals Rodent; Cells B Cells; Molecules Antibodies; Processes Cell Differentiation; Techniques/Approaches Molecular Biology"

Late-breaking abstract • Metabolic Disorders • NLRP3 • ULK1

TRIM22 functions as a scaffold protein for autophagy initiation. (PubMed, Anim Cells Syst (Seoul)) - "Domain mapping revealed that the SPRY domain mediates interactions with ATG13 and FIP200, while the N-terminal region interacts with ULK1 and ATG101...These findings demonstrate that TRIM22 acts as a scaffold protein to promote autophagy initiation, in addition to its previously described role in autophagosome-lysosome fusion. Our study provides new insights into the molecular mechanisms by which TRIM proteins regulate multiple stages of the autophagy process."

Journal • Alzheimer's Disease • CNS Disorders • BECN1 • TRIM22 • ULK1

Transcriptomic analysis of suspended Vero cells and reduction of cellular autophagy by epidermal growth factor (PubMed, Sheng Wu Gong Cheng Xue Bao) - "In addition, the Vero-XF group showed significantly up-regulated expression of ATG101, ATG2A, and STX17 and insignificant change in the expression of NBR1, compared with the Vero-AD group...Finally, the exogenous supplementation of EGF at 10, 20, and 30 μg/L in the culture system reduced the autophagy level of Vero-XF by 22.35%, 48.15%, and 71.29%, increased the specific growth rate by 15.48%, 33.33%, and 57.14%, and decreased the apoptosis rate by 2.84%, 15.46%, and 16.23%, respectively. The results of this study preliminarily reveal that the activation of autophagy is one of the reasons for the slow growth of Vero-XF, which provides reference for the subsequent culture of suspended Vero cells."

Journal • ATG9B • EGF • LAMP2 • RAB7A

Targeting the ATG101 And ULK1 complex in pancreatic ductal adenocarcinoma: computational approach (AACR 2025) - "Results suggested that the interaction of ATG101-ULK1 was strong, and hydroxychloroquine reduced this interaction. Site-directed mutagenesis is essential to understanding the molecular interaction (ATG101-ULK2) and the role of residues in PDAC."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ULK1

RNA-Seq analysis reveals the different mechanisms triggered by bovine and equine after infection with FMDV. (PubMed, Vet Med Sci) - "Both water buffaloes and Mongolian horses express integrin receptors that allow FMDV entry into cells. Therefore, the resistance of Mongolian horses to FMDV may result from more changes in intracellular mechanisms, including processes such as autophagy and apoptosis. Significant differences were observed between water buffaloes and Mongolian horses in these processes, suggesting that these processes influence FMDV replication and synthesis."

Journal • Infectious Disease • ATG12 • ATG16L1 • ATG3 • ATG4B • BCL2A1 • BECN1 • CASP3

A phase I trial of ATG-101, an investigational PD-L1×4-1BB bispecific antibody, in patients with advanced solid tumors and mature B cell non-Hodgkin lymphomas: PROBE-CN (ESMO 2024) - "The patients receive a dose intravenously once every 28 days (1 cycle), and the DLTs will be evaluated during the first cycle. As of 5 January 2024, four clinical sites in China are open to recruitment and 22 patients across eight dose levels have been enrolled."

Clinical • Metastases • P1 data • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pancreatic Cancer • Solid Tumor

The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization. (PubMed, Cell Rep) - "To gain insights into functions of the holo-complex, we generated a deep interactome by combining affinity purification- and proximity labeling-mass spectrometry of all four complex members: ULK1, ATG13, ATG101, and RB1CC1/FIP200...In growth conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, which supports the recruitment of AMBRA1 to the ER membrane, positively affecting autophagy."

Journal • AMBRA1 • RB1CC1 • ULK1

Antengene Announces 2024 Interim Financial Results, Highlights Progress in R&D and Commercialization (PRNewswire) - P1 | N=40 | PROBE (NCT04986865) | Sponsor: Antengene Biologics Limited | "ATG-101 is currently undergoing dose-escalation studies in the US, the Mainland of China, and Australia. The treatment has demonstrated excellent tolerability, with no significant liver toxicity observed to date. Encouragingly, durable stable disease has been observed even at low dose levels, as along with a partial response in a patient with microsatellite stable (MSS) colorectal cancer. The Phase I dose escalation phase is on track for completion by the first half of 2025."

P1 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor