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.

On April 17, 2023 Presage Biosciences, a pioneer in translational oncology whose mission is understanding the complexity of drug response in the tumor microenvironment (TME), reported that it will present at the Immunology, TME Minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting (Press release, Presage Biosciences, APR 17, 2023, View Source;core-civo-technology-reveals-unexpected-effects-of-an-investigational-ubiquitination-inhibitor-on-checkpoint-blockade-301798045.html [SID1234630194]). In an independent study, Presage’s innovative multiplexed trackable microdosing platform (CIVO) was used to introduce an investigational ubiquitin inhibitor (TAK-243) alone and in combination with anti-PD1. The resulting data demonstrated that TAK-243 has potential to increase anti-tumor immunogenicity and prime tumors for response to immune checkpoint inhibition.

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The Session (MS.IM01.03 – Immune Checkpoints at Tumor Beds, #3476) is titled "TAK-243 increases tumor immunogenicity enhancing systemic anti-tumor immune response and tumor regression in combination with immune checkpoint inhibition in a syngeneic model of lymphoma" and will be presented live on April 17, 2023 from 3:52pm-4:07pm EST.

"We are excited to showcase these novel findings on the TME and how we have paired CIVO with sophisticated spatial profiling to translate preclinical findings to human disease" said Richard Klinghoffer, Presage’s Chief Executive Officer. "We continue our work with fellow innovators in oncology to deliver key translational data early in the clinical development process."

After AACR (Free AACR Whitepaper) 2023, Presage Biosciences’ CIVO technology will be further showcased at two events:

The 4th Annual International Phase-0/Microdosing Stakeholder Meeting in Boston, MA on April 24th. Presage is featured speaker, panel moderator and sponsor at this year’s event;
Life Science Innovation Northwest (LSINW) in Seattle, WA on April 25. LSINW is the Pacific Northwest’s largest annual life science conference.
About CIVO

Comparative In Vivo Oncology (CIVO) is Presage’s patented platform that enables multiplexed intratumoral microdosing and generation of deep spatial biology insights. Presage’s CIVO technology and analysis capabilities are unparalleled at providing insight into drug-exposed areas of the intact tumor microenvironment. Presage is pairing the use of CIVO with molecular profiling technologies in both preclinical and Phase 0 trials in order to inform and de-risk oncology drug development.

On April 17, 2023 Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) ("Corbus" or the "Company"), a precision oncology company, reported details of new pre-clinical data on CRB-601, its avβ8 blocking antibody, presented as a poster at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, held April 14-19, 2023 in Orlando, FL (Press release, Corbus Pharmaceuticals, APR 17, 2023, View Source [SID1234630193]).

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The poster titled "CRB-601, an avβ8 blocking antibody, prevents activation of TGFβ and exhibits anti-tumor activity associated with immune cell remodeling of the tumor microenvironment" explores the relationship between CRB-601 antitumor activity, PK and its binding to the αvβ8 receptor in the tumor. In addition, the impact on TGFβ pathway signaling and tumor immune cell population are also presented. Tumor growth was evaluated in mice bearing orthotopically implanted murine breast cancer EMT6 or colon cancer MC38 and treated with CRB-601.

CRB-601 exhibited dose dependent tumor growth inhibition (TGI) in the EMT6 tumor model which was significantly augmented in combination with anti-PD1 therapy. These effects were associated with changes in tumor micro-environment (TME) immune cell populations with marked increases in infiltrating T cells, NK cells and M1 polarized macrophages. Efficacy correlated with cell surface αvβ8 occupancy by CRB-601. CRB-601 treatment downregulated phosphorylation of SMAD proteins pSMAD2 and pSMAD3, consistent with blockade of the canonical TGFβ signaling pathway.

Rachael Brake, PhD, Chief Scientific Officer of Corbus stated: "We are building on our early efficacy. We can now demonstrate that CRB-601 has robust anti-tumor activity alone and as a combination partner with anti-PD-1 and that these effects are associated with documented receptor engagement, a reduction of TGFb1 levels in the tumor micro-environment (TME), and inhibition of downstream canonical TGFb signaling. Together this data reinforces the potential of this new approach in blocking activation of TGFb locally in the TME."

On April 17, 2023 Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory disease, reported data presentations on two first-in-class programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting held in Orlando, Florida, on April 14–19, 2023 (Press release, BioTheryX, APR 17, 2023, View Source [SID1234630192]). The presentations highlight preclinical data for bifunctional degraders of cyclin-dependent kinase (CDK) 4/6 for the treatment of solid tumors, and bifunctional degraders of son of sevenless homolog 1 (SOS1) for the treatment of KRAS mutant cancers. Additionally, the Company has nominated BTX-9341 as a development candidate for the CDK4/6 degrader program and has commenced IND-enabling studies.

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"Biotheryx is advancing first-in-class bifunctional degraders developed through our PRODEGY platform to overcome common resistance mechanisms to existing inhibitors and provide differentiated treatment possibilities for people facing cancer," said Philippe Drouet, President and Chief Executive Officer of Biotheryx. "At AACR (Free AACR Whitepaper), we are proud to share encouraging preclinical data that highlights the potential of these exciting programs. BTX-9341, our oral CDK4/6 development candidate, has demonstrated superior efficacy in preclinical models of ER+/HER2- breast cancer when compared to CDK4/6 inhibitors, superior blood-brain-barrier penetration while importantly also showing the ability to be effective in models resistant to existing CDK4/6 inhibitors. Similarly, in preclinical KRAS mutant cancer models, our SOS1 degraders resulted in greater than 90% degradation of SOS1 in tumors and led to significant tumor growth inhibition."

AACR 2023 Presentation Details:

Title: Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer and triple negative breast cancer
Presenter: Hannah Majeski, Ph.D., Principal Scientist – Biology
Abstract #: 1553
Session: Cell Cycle/Cell Proliferation Inhibitors for Cancer Therapy
Session Date and Time: Monday, April 17, 2023, at 9:00 a.m. ET

Highlights:

CDK4/6 inhibitors are used to treat estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer, but some patients have exhibited innate resistance, and many are shown to develop acquired resistance after three years on therapy.
Biotheryx’s CDK4/6 bifunctional degraders demonstrated in vitro CDK4 and CDK6 degradation in multiple breast cancer cell lines and potent inhibition of cell proliferation. This potency was shown to be superior to CDK4/6 inhibitors and due to Cereblon-mediated target degradation.
CDK4/6 bifunctional degraders were active in a CDK4/6 inhibitor resistant cell line and in multiple PDX CDK4/6 inhibitor resistant organoid models.
CDK4/6 bifunctional degraders exhibited good tumor exposure when dosed orally, and induced a dose-dependent reduction in CDK4, CDK6, and pRB levels in MCF7 xenograft tumors. This resulted in dose dependent tumor growth inhibition and superior efficacy compared to CDK4/6 inhibitors.
These degraders have also shown blood brain barrier penetration and superior inhibition of tumor growth in an MCF7 intracranial mouse model compared to a CDK4/6 inhibitor.
The combination of the enhanced efficacy, activity in resistant cell lines and blood brain barrier penetration demonstrate the potential for CDK4/6 degraders in a range of potential cancer indications.
Title: Development of bifunctional CRBN-SOS1 degraders for treatment of mutant KRAS cancers
Presenter: Kyle Begovich, Ph.D., Senior Scientist – Biology
Abstract #: 1578
Session: New Therapeutic Targeted Agents
Session Date and Time: Monday, April 17, 2023, at 9:00 a.m. ET

Highlights:

KRAS is the most frequently mutated cancer-causing oncogene and is mutated in over 20% of all human cancers, including an estimated 90% of pancreatic tumors and 45% of colorectal tumors. Combinational therapeutic approaches are needed to avoid drug resistance in the treatment of KRAS mutant cancers, such as coupling KRAS inhibition with a blockade of its guanine exchange factor (GEF), SOS1, to keep KRAS in its inactive state as well as prevent upstream pathway reactivation.
Biotheryx SOS1 degraders demonstrated antiproliferative effects across a range of KRAS-mutated cell lines. Consistent with this notion, treatment with SOS1 degraders in KRAS-mutant xenograft models resulted in greater than 90% degradation of SOS1 in tumors and subsequently led to significant tumor growth inhibition as a single agent.

SOS1 degraders also exhibited synergistic effects with other RAS/MAPK inhibitors in in vitro studies as well as KRAS-mutant xenograft models.

These data support the potential of SOS1 degradation as a valuable treatment option for a range of KRAS mutant cancers.

Following the presentations at the meeting, PDF copies of the presentations and posters will be available in the "Publications and Presentations" section of Biotheryx’s website.

On April 17, 2023 Convergent Therapeutics Inc., a clinical-stage biotechnology company, reported the details of a plenary presentation of a dose-escalation study evaluating the efficacy and safety of its lead asset, CONV01-α (225Ac−J591), a prostate-specific membrane antigen (PSMA)-targeted monoclonal antibody linked to actinium-225 (225Ac) (Press release, Convergent Therapeutics, APR 17, 2023, View Source [SID1234630191]). The plenary talk will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando on Monday, April 17 by Jones T. Nauseef (M.D., Ph.D.), an Assistant Professor of Medicine in the Division of Hematology & Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and a genitourinary medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. The title of the presentation is "Phase I dose-escalation study of fractionated dose 225Ac-J591 for metastatic castration resistant prostate cancer."

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This presentation will focus on safety and efficacy data from a Weill Cornell Medicine-sponsored phase I/II dose-escalation study (NCT04506567) in patients with metastatic castration resistant prostate cancer. Across the 23 patients evaluable for response via prostate specific antigen (PSA), a fractionated dose-intense regimen of CONV01-α (225Ac−J591) demonstrated safety and notable activity. 96% of patients showed a decline in PSA levels, 70% of patients had a best PSA decline of ≥50%, and 26% of patients had a best PSA decline of ≥90%. The most common hematologic adverse events were thrombocytopenia, neutropenia, and anemia. The most common non-hematologic adverse events observed were low grade (Gr 1-2) fatigue, pain flare, xerostomia, and elevated AST.

"We are pleased by the results of this cohort of our study of fractionated dose 225Ac-J591 that demonstrated few high-grade attributable adverse events," said Dr. Nauseef. "Reductions in PSA as well as CTC responses demonstrate promising preliminary evidence of efficacy. We are excited by the potential of 225Ac-J591 for treatment of patients with metastatic castration resistant prostate cancer."

"These critical results are an important confirmation of the major activity and safety profile of CONV01-α (225Ac−J591)," said Dr. Philip Kantoff, CEO of Convergent Therapeutics. "We are continuing to advance CONV01-α (225Ac−J591) as an impactful therapeutic to fill an unmet need in prostate cancer."