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

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

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

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

Palmitoylation of ULK1 by ZDHHC13 plays a crucial role in autophagy. (PubMed, Nat Commun) - "Genetic hierarchical analyses show that the ULK1 complex comprised of ULK1-FIP200-ATG13-ATG101 translocating from the cytosol to autophagosome formation sites as a most upstream ATG factor; this translocation is critical in autophagy initiation...Moreover, the ULK1 palmitoylated enhances the phosphorylation of ATG14L, which is required for activating PI3-Kinase and producing phosphatidylinositol 3-phosphate, one of the autophagosome membrane's lipids. Our results reveal how the most upstream ULK1 complex translocates to the autophagosome formation sites during autophagy."

Journal • ULK1

In vitro study of the expression of autophagy genes ATG101, mTOR and AMPK in breast cancer with treatment of lactoferrin and in silico study of their communication networks and protein interactions. (PubMed, Prog Biophys Mol Biol) - "Virtualization of the interaction of Lf protein with ATG101, mTOR and AMPK proteins by Pymol software showed that the N lobe region of Lf interacted with the HORMA domain of ATG101 protein, the fat domain of mTOR protein, and the CTD domain of AMPK protein. Although Lf was not able to increase the expression of autophagy-inducing genes, it may be able to induce autophagy through protein interaction by activating or inhibiting proteins related to autophagy regulation."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • AMPK • mTOR

Analysis of transcriptome differences between subcutaneous and intramuscular adipose tissue of Ningxiang pigs. (PubMed, Yi Chuan) - "Genes related to lipid metabolism, such as TCAP, NR4A1, ACACA, LPL, ELOVL6, DGAT1, PRKAA1, ATG101, TP53INP2, FDFT1, ACOX1 and SCD were identified by bioinformatic analyses and verified by qRT-PCR. Our results indicated that these genes may play important roles in the regulation of fat deposition and metabolism in the SAF and IMF tissue, providing the further mechanistic investigation of fat deposition in Ningxiang pigs."

Journal • Metabolic Disorders • ACACA • ACOX1 • AMPK • ELOVL6 • FDFT1 • NR4A1 • TP53INP2

Striking the Balance with a PD-L1×4-1BB Bispecific Antibody. (PubMed, Cancer Res) - "In this issue of Cancer Research, Yuwen and colleagues introduce ATG-101, a tetravalent PD-L1×4-1BB bispecific antibody with high programmed death ligand 1 (PD-L1) affinity and low 4-1BB affinity, aiming to mitigate hepatotoxicity...This study highlights the potential of tetravalent bispecific antibodies in cancer immunotherapy, with implications for various antibody-based treatment modalities across different fields. See related article by Yuwen et al., p. 1680."

Journal • Hepatology • Oncology

Radiolabelling and preclinical characterisation of [89Zr]Zr-Df-ATG-101 bispecific to PD-L1/4-1BB. (PubMed, Eur J Nucl Med Mol Imaging) - "[89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101."

IO biomarker • Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • PD-L1

Dietary sodium acetate and sodium butyrate improve high-carbohydrate diet utilization by regulating gut microbiota, liver lipid metabolism, oxidative stress, and inflammation in largemouth bass (Micropterus salmoides). (PubMed, J Anim Sci Biotechnol) - "In conclusion, dietary SA and SB can reduce hepatic lipid deposition; and alleviate oxidative stress and inflammation in largemouth bass fed on HC diet. These beneficial effects may be due to the altered composition of the gut microbiota caused by SA and SB. The improvement effects of SB were stronger than those associated with SA."

Journal • Inflammation • Metabolic Disorders • IL1B • PPARG • TFEB

Antengene Announces Full Year 2023 Financial Results, Highlights Clinical Progress Across First-in-Class, Best-in-Class Pipeline (PRNewswire) - "Next ATG-022 Milestone: Clinical data readout of Phase I 'CLINCH trial', including preliminary efficacy and safety in H2 2024....Next ATG-037 Milestone: Completion of Phase I dose escalation and proceed to dose expansion in H1 2024....Next ATG-101 Milestone: Completion of Phase I dose escalation and proceed to dose expansion in H1 2025."

P1 data • Trial status • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Antengene Publishes Preclinical Paper on PD-L1/4-1BB Bispecific Antibody ATG-101 in Renowned Oncology Journal Cancer Research (PRNewswire) - "Antengene Corporation Limited...announced that results of its preclinical studies on ATG-101 (PD-L1/4-1BB bispecific antibody) were published in Cancer Research in a paper titled ATG-101 is a tetravalent PD-L1×4-1BB bispecific antibody that stimulates anti-tumor immunity through PD-L1 blockade and PD-L1-directed 4-1BB activation....'ATG-101 activates 4-1BB+ T cells in a PD-L1-crosslinking dependent manner, which minimizes the hepatotoxicity associated with existing 4-1BB agonists and suppresses the growth of ICI-resistant tumors'....'The Phase I study of ATG-101 is currently in the sixth dose escalation cohort and the drug is approaching its biologically active dose with good tolerability'."

Preclinical • Trial status • Non-Hodgkin’s Lymphoma • Solid Tumor

ATG-101 is a tetravalent PD-L1×4-1BB bispecific antibody that stimulates anti-tumor immunity through PD-L1 blockade and PD-L1-directed 4-1BB activation. (PubMed, Cancer Res) - "According to computational semi-mechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 crosslinking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors."

Journal • Hepatology • Oncology

Subversion of selective autophagy for the biogenesis of tombusvirus replication organelles inhibits autophagy. (PubMed, PLoS Pathog) - "In addition, we observed that several core autophagy proteins, such as ATG1a, ATG4, ATG5, ATG101 and the plant-specific SH3P2 autophagy adaptor proteins were also re-localized to TBSV VROs, suggesting that TBSV hijacks the autophagy machinery in plant cells...We propose that the VRO-associated condensates trap those autophagy proteins, taking them away from the autophagy pathway. Overall, tombusviruses hijack selective autophagy to provide phospholipid-rich membranes for replication and to regulate the antiviral autophagic flux."

Journal • ATG5

Tegument protein UL3 of bovine herpesvirus 1 suppresses antiviral IFN-I signaling by targeting STING for autophagic degradation. (PubMed, Vet Microbiol) - "Further study showed that UL3 enhances the interaction between ATG101 and STING, and then the degradation of STING was reversed following ATG101 silencing in UL3-overexpressing cells during BoHV-1 infection. Our research results demonstrate a novel function of UL3 in regulating host's antiviral response and provide a potential mechanism for BoHV-1 immune evasion."

Journal • Infectious Disease • STING

PROBE: A Study ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Antengene Biologics Limited | N=482 ➔ 40

Enrollment change • Metastases • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

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."

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

Antengene Presents Encouraging Clinical Data from Four Pipeline Programs at the 2023 R&D Day (PRNewswire) - P1 | N=482 | PROBE (NCT04986865) | Sponsor: Antengene Biologics Limited | "Antengene Corporation Limited...is presenting encouraging clinical data of the Company's four key drugs in clinical development...at its 2023 R&D Day taking place today.....ATG-101 (PD-L1/4-1BB bispecific antibody): Early data from the Phase I PROBE trial have shown a partial response (PR) in a patient with metastatic colon adenocarcinoma (microsatellite stability biomarker [MSS], liver metastasis, and three prior lines of therapy) which is ongoing. Additionally, two patients have been on ATG-101 for 18 cycles and 17 cycles (Q3W), respectively, demonstrating durable stable disease (SD) with a good safety profile with no liver toxicities. This distinguishes ATG-101 as a safer drug compared to many molecules currently under development targeting 4-1BB."

P1 data • Colon Cancer

Antengene to Host 2023 R&D Day and Discuss Key Data with KOLs (PRNewswire) - "Antengene Corporation Limited...announced that it will host its 2023 R&D Day on November 17, 2023, to update the medical and investor communities on the company's progress with its R&D programs. The session will feature three KOL sessions, and discussions about the data of Antengene's key drugs in clinical development, including ATG-031 (anti-CD24 monoclonal antibody), ATG-101 (PD-L1/4-1BB bispecific antibody), ATG-022 (Claudin 18.2 antibody-drug conjugate), ATG-037 (CD73 inhibitor), and ATG-008 (dual mTORC1/2 inhibitor); and updates on its proprietary R&D pipeline and upcoming development for 2024."

Clinical data • Oncology

Single-cell RNA sequencing reveals the positive feedback activation loop between T and dendritic cells induced by PD-L1x4–1BB bispecific antibody (SITC 2023) - "Conclusions Transcriptional profiling of the TME revealed that ATG-101 reversed T cell exhaustion, increased T cell cytotoxicity and reduced tolerogenic DCs. Notably, due to the increased gene expression of PD-L1 in DCs and 4–1BB in T cells following ATG-101 treatment, it is anticipated that ATG-101 will promote greater T cell-Dendritic cell crosslinking over time, further activating 4–1BB signaling, strengthening T cell-DC interaction, and generating a positive feedback loop."

IO biomarker • Oncology • APOE • CCL8 • CD8 • CD80 • CDK1 • GZMB • ICAM1 • PTPRC • TNFRSF9

Antengene Presents Results from Five Investigational Programs at 2023 SITC Annual Meeting (PRNewswire) - "Antengene Corporation Limited...announced that it has presented results from five programs by poster presentation...at the 2023 Society of Immunology in Cancer Annual Meeting (SITC 2023)....Transcriptional profiling of the tumor microenvironment (TME) revealed that ATG-101 reversed T cell exhaustion, increased T cell cytotoxicity, and reduced tolerogenic dendritic cells (DCs). Due to the increased gene expression of PD-L1 in DCs and 4-1BB in T cells following ATG-101 treatment, it is anticipated that ATG-101 will promote greater T cell-dentritic cell crosslinking over time, further activating 4-1BB signalling, strengthening T cell-DC interaction, and generating a positive feedback loop."

Preclinical • Oncology

Antengene To Present Results From Five Studies at 2023 SITC Annual Meeting (PRNewswire) - "Antengene Corporation Limited...announced that it will present five programs at the 2023 Society of Immunology in Cancer Annual Meeting (SITC 2023) to be held in San Diego from November 1-5, 2023....The presentations feature five Antengene's clinical and preclinical programs, including two clinical programs, the anti-CD24 monoclonal antibody ATG-031 and the PD-L1/4-1BB bispecific antibody ATG-101; two preclinical programs, the LILRB4 antagonist antibody ATG-034 and the GPRC5D/CD3 T-cell engager ATG-021; as well as the proprietary novel AnTenGager™ platform."

Clinical data • Preclinical

PROBE: A Study of Evaluating the Safety and Efficacy of ATG-101 in Patients With Metastatic/Advanced Solid Tumors and Mature B-cell Non-Hodgkin Lymphomas (clinicaltrials.gov) - P1; N=482; Not yet recruiting; Sponsor: Antengene Biologics Limited

New P1 trial • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor