On April 17, 2023 Antengene Corporation Limited ("Antengene" SEHK: 6996.HK), a leading innovative, global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer, reported the presentation of five posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 Meetings (AACR 2023), taking place from April 14th to 19th at the Orange County Convention Center in Orlando, Florida, the United States (Press release, Antengene, APR 17, 2023, View Source [SID1234630195]).
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"The five posters we present at AACR (Free AACR Whitepaper) 2023 provides Antengene with an opportunity to share a range of encouraging results including the expanded Phase II data of ATG-008 for the second-line treatment of patients with HBV+ HCC, as well as the preclinical results of ATG-017, ATG-037, ATG-031, and ATG-034,"said Dr. Bo Shan, Antengene’s Chief Scientific Officer. "A highlight of the results is the promising tumor response and overall survival data from the study in patients with advanced disease as they suggest that ATG-008 monotherapy represent a promising therapeutic option for patients who have received prior systemic therapy, including PD-1/PD-L1 inhibitors. Maintaining our focus on addressing patients’ unmet clinical needs, we will continue to actively explore and evaluate combinations between our existing programs and other targets and agents, with the hope of gathering sufficient rationale to support the future clinical development of these regimens."
Details of the Poster Presentations:
ATG-008 (mTORC1/2 inhibitor)
Title: Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib(ATG-008) in HBV+ advanced hepatocellular carcinoma(HCC) subjects who have received at least one prior line of systemic therapy(TORCH)
Abstract: CT150
Date: April 17, 2023
Time: 1:30 PM – 5:00 PM (Eastern Time)
1:30 AM – 5:00 AM, April 18, 2023 (Beijing Time)
This Phase II study was designed to evaluate the pharmacokinetics, safety and efficacy of ATG-008 in patients with advanced hepatitis B virus (HBV) positive hepatocellular carcinoma (HCC). 73 patients with HBV+, unresectable and refractory HCC were enrolled to receive ATG-008 at one of the four dose levels.
Data from this study showed that 3 subjects achieved a partial response (PR), all in the 45 mg QD monotherapy cohort. A total of 18 patients were enrolled in this cohort that achieved an objective response rate (ORR) of 16.7%. Among them, 11 patients (61.1%) had received at least 2 prior lines of therapy and 15 patients had been exposed to an anti-PD-1/PD-L1 checkpoint inhibitor (CPI) (83.3%). The median progression-free survival (mPFS) was 3 months in the intend-to-treat (ITT) population and 5.3 months in the 45mg QD cohort.
These data suggest that ATG-008 has single-agent efficacy in HBV+ HCC patients who have failed at least one prior systemic therapy, notably in the 45 mg QD dosing level, in which most patients had been previously exposed to an anti-PD-1/PD-L1 therapy. Further, the results indicate that ATG-008 has the potential in HBV+ HCC patients who have failed prior CPI therapy and support further study, particularly in patients who have failed prior anti-VEGF and anti-PD-l/PD-L1 therapy. ATG-008 is being evaluated in the Phase II TORCH-2 study in patients with cervical cancer and other solid tumors.
ATG-017 (ERK1/2 inhibitor)
Title: Synergistic effects of the combination of ERK1/2 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibition for cancer treatment
Abstract: 5499
Date: April 18, 2023
Time: 1:30 PM – 5:00 PM (Eastern Time)
1:30 AM – 5:00 AM, April 19, 2023 (Beijing Time)
This preclinical study was designed to test the in vivo anti-tumor effects induced by the combination of ATG-017, with EGFR inhibitor (osimertinib), KRASG12C inhibitor (ATG-012), CDK4/6 inhibitor (abemaciclib) or PD-L1 inhibitor (atezolizumab), in preclinical tumor models including three models of non-small cell lung cancer (NSCLC) (with EGF-R and KRAS mutations), and one model of T-cell lymphoma (resistant to anti-PD-L1) for assessing the tumor growth inhibition (TGI) and the presence of tumor infiltrating lymphocytes (TILs).
According to the results, ATG-017 demonstrated significant TGI (>60%) in the NSCLC models. In the T-cell lymphoma model, the combination of ATG-017 and the PD-L1 inhibitor, atezolizumab, showed significant tumor growth inhibition. Furthermore, that combination induced increased the infiltration of anti-tumor TILs, suggesting a potential role for ATG-017 in changing "cold" tumors to "hot".
These data suggest that the combination of ATG-017 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibitors have strong synergism and significantly improved TGI, thus represent promising therapeutic strategies for cancer patients. Antengene is evaluating ATG-017 in the Phase I ERASER study, as monotherapy and in combination with nivolumab, in patients with advanced solid tumors and hematological malignancies in Australia and the U.S.
ATG-037 (CD73 inhibitor)
Title: Targeting CD73-Adenosine Axis for the treatment of multiple myeloma
Abstract: 496
Date: April 16, 2023
Time: 1:30 PM – 5:00 PM (Eastern Time)
1:30 AM – 5:00 AM, April 17, 2023 (Beijing Time)
This preclinical study was designed to evaluate the potential of ATG-037 in treating multiple myeloma (MM). CD73 is a cell surface enzyme which is highly expressed in the tumor microenvironment and enables the conversion of ATP to adenosine, promoting the progression of cancer by inhibiting T-cells, natural killer (NK) cells, and dendritic cells (DCs), and inducing and enhancing the function of immunosuppressive cell types. ATG-037’s ability to inhibit the activity of CD73 was evaluated in enzyme inhibition and T cell proliferation and activation assays. In vivo efficacy was assessed in syngeneic myeloma models.
Results showed complete inhibition of CD73 with ATG-037, without a "hook effect" compared to another industry benchmark antibody program. In addition, ATG-037 completely restored the function of activated T-cells and CAR-T cells from AMP-mediated T-cell suppression, suggesting a potential application in CAR-T cell therapy. In addition, the treatment with ATG-037 resulted in significant TGI compared to vehicle controls.
These data suggest that ATG-037 has single agent anti-myeloma efficacy, thus making this abstract the first report of in vivo efficacy study of a CD73 inhibitors in myeloma animal models. Antengene is currently evaluating ATG-037 in Australia and mainland of China in the Phase I STAMINA study, as a monotherapy and in combination with pembrolizumab, in patients with locally advanced or metastatic solid tumors.
ATG-031 (anti-CD24 monoclonal antibody)
Title: ATG-031, a first-in-class humanized anti-CD24 antibody, demonstrates potent in vivo efficacy and repolarizes tumor-associated macrophages in the TME
Abstract: 6641
Date: April 19, 2023
Time: 9:00 AM – 12:30 PM (Eastern Time)
9:00 PM April 19 – 12:30 AM April 20, 2023 (Beijing Time)
This preclinical study was designed to evaluate the in vivo efficacy of ATG-031 and explored its pharmacodynamic effects.
Data showed that ATG-031 monotherapy produced robust, 60-100% TGI, with increased, synergistic tumor regression from the combination of ATG-031 with oxaliplatin (chemotherapy) or atezolizumab (CPI), evaluated in one of the murine models. Flow cytometry analysis shows that ATG-031 increases T cell (CD4/CD8) tumor infiltration and significantly lower population of Treg cells in the tumor microenvironment.
These results suggest that the first-in-class antibody, ATG-031, specifically binds to CD24 with nM affinity and blocks the interaction of CD24 and Siglec-10. ATG-031 induces efficient phagocytosis with a picomolar EC50, stimulating pro-inflammatory cytokines production by macrophages.
ATG-034 (LILRB4 antagonist antibody)
Title: ATG-034, an LILRB4 antagonist antibody, reinvigorates dendritic cells and prevents tumor progression
Abstract: 6384
Date: April 19, 2023
Time: 9:00 AM – 12:30 PM (Eastern Time)
9:00 PM April 19 – 12:30 AM April 20, 2023 (Beijing Time)
This preclinical study was designed to evaluate ATG-034, an antibody targeting LILRB4, as a potential immunotherapy. The antibody was tested using SPR, ELISA and FACS analysis to assess its ability to bind to LILRB4, block its interaction with its ligand, fibronectin, and reinvigorate DCs to an "immunogenic" state.
According to the data, ATG-034 demonstrated single-digit nanomolar affinity and blocked the interaction of LILRB4 with its target ligand, fibronectin and completely reversed fibronectin-mediated suppression of tolerized DC activation (TolDC), evidenced by increased TNF-a production. In addition, the antibody reprogrammed DCs to become immunogenic, as measured by the up regulation of several key co-stimulatory molecules (CD86, HLA-DR and HLA-ABC) and down-regulation of an M2 biomarker (CD206).
These results suggest that ATG-034 successfully reprogrammed tolerized DCs to an "immunogenic" state, thereby enhancing anti-tumor immunity and demonstrating potent in vivo anti-tumor efficacy compared to a benchmarking compound.