On March 9, 2022 GT Biopharma, Inc. (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary tri-specific natural killer (NK) cell engager, TriKE protein biologic technology platform, reported that preclinical data demonstrating its novel TriKE driving NK cell immunotherapy against non-small cell lung cancer (NSCLC) in the hypoxic solid tumor microenvironment at ESMO (Free ESMO Whitepaper)’s Targeted Anticancer Therapies Congress (TAT) (Press release, GT Biopharma, MAR 9, 2022, View Source [SID1234609830]).

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Gregory Berk, M.D., the Company’s President of R&D and Chief Medical Officer noted, "This pre-clinical evidence suggests, despite the difference in circulating immune cells of Stage IVB NSCLC patients, a mesothelin-targeted TriKE can work alongside current standard of care and provide benefit even in the hypoxic environment of a solid tumor, meriting further investigation of this novel, targeted TriKE."

Driving NK cell immunotherapy against NSCLC, in the context of hypoxia, using Tri-specific Killer Engager (TriKE)

Background – Currently, Tri-specific killer engagers (TriKE) are being tested in the clinic to treat leukemia and lymphoma. These TriKE’s cross-link CD16/FcγRIII and the tumor antigen on NK cells which drives cytotoxicity while IL15 provides survival and proliferation signals to NK cells. Mesothelin (MSLN), is currently a tumor antigen being targeted in various cancers including NSCLC. The current study conducted by Dr. Jeff Miller’s laboratory, University of Minnesota, evaluated whether a MSLN-targeted TriKE could drive cytotoxicity towards NSCLC cells at all stages of disease in the presence of hypoxia, a challenge in the NSCLC tumor microenvironment.

Study design and analysis – Using peripheral blood mononuclear cells (PBMC) collected from NSCLC patients, (1) before patients started standard treatment, (2) after initial treatment and (3) at disease progression where applicable. The study challenged patient PBMC with a NSCLC cell line (NCI-H460) for 5 hours in the presence of monensin and brefeldin A, measuring degranulation (CD107a) and cytokine production (IFNγ) by flow cytometry (live, single CD56+/CD3- cells). Compared to NK cells alone (NT); NK cells alone with drug (‘TriKE’); or NK cells with tumor alone.

Results
NSLC have altered NK cells – Differential abundance analysis of immune subsets in early stage or late stage patient groups were performed using Astrolabe Diagnostics software. The TriKE was able to induce significant (p<0.0001) activity against H460 cells for both groups. The analysis revealed a greater abundance of CD56+/CD16+ NK cells and fewer CD33+/CD14- myeloid cells in early stage patients compared to late stage patients before treatment onset. The lack of CD16, which drives cytotoxicity, and the abundance of myeloid cells, that can suppress NK cell function, suggested late stage NSCLC patients may respond differently to biologics targeting NK cell cytotoxicity.

Mesothelin-targeted TriKE drives NK cell function regardless of disease stage and at all stages of treatment: While hypoxia impairs NK cell cytotoxicity, the study’s MSLN-targeted TriKE enhanced NK cell cytotoxicity of lung cancer cells (H460) after exposure to hypoxia for 7 days, during exposure to hypoxia and in the assay itself. The data demonstrated that TriKE induced degranulation and cytokine production in patient NK cells when in the presence of tumor cells (H460) at all stages of treatment (before treatment, after initial treatment and at progression).

Conclusion – This pre-clinical evidence suggests, despite the difference in circulating immune cells of Stage IVB NSCLC patients, mesothelin-targeted TriKE can work alongside current standard of care and provide benefit even in the hypoxic environment of a solid tumor.

The ESMO (Free ESMO Whitepaper) poster presentation details are as follows:

ESMO Targeted Anticancer Therapies Congress (TAT)
Title: Driving NK cell immunotherapy against NSCLC, in the context of hypoxia, using Tri-specific Killer Engager (TriKE)
Abstract Number: 250
Session: Immunotherapy
Presenter: Jeff Miller, M.D., Consulting Chief Scientific Officer, University of Minnesota
Presentation Type: Poster
Session Date and Time: March 7, 9:20 AM (CET) (On-demand e-poster display)
Location: Virtual
Poster Board Number: 17P

The presentation was published on the ESMO (Free ESMO Whitepaper) website. It is also available on the GT Biopharma website: View Source

Non-small cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small cell lung cancer (SCLC). Non-small cell lung cancer (NSCLC) is a disease class including squamous cell carcinoma (25% of lung cancers), adenocarcinoma (40% of lung cancers), and large cell carcinoma (10% of lung cancers) in which malignant cancer cells form in the tissues of the lung. For more information about NSCLC please click here.

On March 9, 2022 DURECT Corporation (Nasdaq: DRRX) reported that Dr. James E. Brown, President and CEO, Dr. WeiQi Lin, Executive Vice President of R&D and Dr. Norman Sussman, Chief Medical Officer, will be participating in a fireside chat hosted by Francois Brisebois, Managing Director, Senior Biotechnology Research Analyst at Oppenheimer & Co. Inc. at the Oppenheimer 32nd Annual Healthcare Conference on Tuesday, March 15, 2022 (Press release, DURECT, MAR 9, 2022, https://www.prnewswire.com/news-releases/durect-corporation-fireside-chat-at-the-oppenheimer-32nd-annual-healthcare-conference-301499423.html [SID1234609829]).

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Presentation details are as follows:

Oppenheimer 32nd Annual Healthcare Conference

Date:

March 15, 2022

Time:

1:20pm – 1:50pm Eastern Daylight Time

Format:

Fireside chat hosted by Francois Brisebois

Webcast:

View Source

The webcast link of the presentation will also be available by accessing DURECT’s homepage at www.durect.com and clicking on "Event Calendar" under the "Investors" section.

On March 9, 2022 Bridge Biotherapeutics (KQ288330), a South Korean clinical-stage biotechnology company focused on developing novel drugs for cancer, fibrosis and inflammation, reported that a poster featuring preclinical candidate BBT-207 will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2022 annual meeting taking place on April 8-13 in New Orleans, Louisiana (Press release, Bridge Biotherapeutics, MAR 9, 2022, View Source [SID1234609828]).

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The following abstract is now available on AACR (Free AACR Whitepaper)’s website.

Presentation Title: BBT-207, a Novel, 4th Generation, Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) With Broad-Spectrum Activity to Both Treatment-Emergent and Drug-Naive Mutants for the Treatment of NSCLC

Session Category: Experimental and Molecular Therapeutics

Session Title: Tyrosine Kinase and Phosphatase Inhibitors (PO.ET06.01)

Session Date & Time: Tuesday, April 12, 2022, 1:30 pm — 5:00 pm

Abstract Number: 3346

BBT-207, which is currently under IND-enabling preclinical development, is an internally discovered fourth generation EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) with potent preclinical activity against a broad range of EGFR mutations in non-small cell lung cancer (NSCLC). Preclinical activity profile of BBT-207 allows it to be positioned in earlier line settings for the first, second and third generation EGFR TKI resistant patients.

BBT-207 was developed with the goal of providing treatment options in earlier line settings such as for patients who harbor C797S double mutations that arise from the progression on the third generation EGFR TKIs in NSCLC.

"We are excited to showcase the preclinical data which suggests that BBT-207 may have the potential to be positioned as a frontline treatment as targeting C797S mutations in NSCLC, especially C797S double mutations," and "we will continue to make advancements of BBT-207 and anticipate submitting the US IND by the end of this year," said Jimmy Jin M.D., Ph.D., the Head of Discovery Biology of Bridge Biotherapeutics.

BBT-207 is planned to enter a Phase I study in metastatic NSCLC in 1H 2023.

On March 9, 2022 Transcenta Holding Limited ("Transcenta") (HKEX: 06628), a clinical stage biopharmaceutical company with fully-integrated capabilities in discovery, research, development and manufacturing of antibody-based therapeutics, reported that Transcenta has presented the safety/tolerability and preliminary anti-tumor activity data in gastric and pancreatic cancers of TST001 China phase I clinical trial as a poster presentation at the 2022 International Gastric Cancer Congress (IGCC) (Press release, Transcenta, MAR 9, 2022, View Source;tolerability-and-preliminary-anti-tumor-activity-data-in-gastric-and-pancreatic-cancers-of-tst001-monotherapy-from-china-phase-i-clinical-trial-at-the-2022-international-gastric-cancer-congress-301499080.html [SID1234609827]).

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The primary objectives of this phase I study (NCT04495296) are to evaluate the safety and tolerability, to identify MTD and recommended phase 2 dose (RP2D) in patients with advanced or metastatic solid tumors who progressed on or after standard treatments. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-tumor activity.

In the dose escalation phase, patients without preselection of tumor Claudin18.2 expression were given increasing doses of TST001 intravenously every 3 weeks (Q3W) using a 3+3 design. As of November 23rd, 2021, 11 patients had been treated at the dose levels of 3, 6, and 10 mg/kg Q3W. 9 patients were DLT evaluable with no DLT reported and MTD has not been reached. TST001 demonstrated a roughly linear PK profile as both Cmax and AUC increased proportionally across the dose range following the first dose. No drug accumulation was observed in Q3W cohort. 10 mg/kg Q3W was designated as RP2D for further expansion study and additional patients with Claudin18.2 overexpression were enrolled into the expansion phase at the 10 mg/kg Q3W dose. The most common AEs (>20%) included nausea, vomiting, anemia, hypoalbuminemia, abdominal distension, constipation. In terms of efficacy, one patient in the 6 mg/kg Q3W dose-escalation cohort who progressed on multiple lines of chemotherapies, anti-PD1 and anti-VEGF therapies achieved a confirmed partial response at week 12. Post the data cut-off date, additional confirmed PRs were observed at recommended phase 2 dose in the newly enrolled monotherapy expansion cohorts including gastric cancer and pancreatic cancer patients with Claudin18.2 expression. One pancreatic cancer patient with medium-low Claudin 18.2 expression achieved 82% tumor reduction at 12 weeks post-treatment. Enrollment of patients for the monotherapy expansion cohorts is ongoing and full data will be updated and reported in future medical conference.

In this Phase 1 clinical study, TST001 demonstrated a manageable & tolerable safety profile in patients with advanced solid tumors and preliminary anti-tumor activity in a heavily pretreated gastric and pancreatic cancer patient expressing Claudin18.2.

"Claudin18.2 is an ideal target with great anti-tumor potential for cancer treatment. TST001, a high affinity Claudin18.2 humanized antibody, is safe and displayed promising anti-tumor activity in Claudin18.2 over-expressing gastric and pancreatic cancer patients." said Dr. Michael Shi, EVP, Head of Global R&D and CMO of Transcenta, "We will continue to characterize the safety and anti-tumor activities of the monotherapy in various Claudin18.2 expressing solid tumors as well as combination therapy with standard of care for first line gastric cancer. We believe TST001 could offer new and more effective treatment options for gastric cancer patients."

"Gastric cancer is one of the highly prevalent malignant tumor types in China. In recent years, Claudin18.2 has emerged as a promising cancer treatment target for gastric cancer beyond HER2 and PD-L1. TST001 is the second most advanced global program targeting Claudin 18.2 and has shown promising signals of anti-tumor activities with manageable safety profile. I look forward to the start of the global phase III registration-enabling trial for testing TST001 as the treatment for first line gastric cancer," said Professor Lin Shen from Beijing Cancer Hospital.

About TST001

TST001 is a high affinity humanized anti-Claudin18.2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities and potent anti-tumor activities in tumor xenograft models. TST001 is the second Claudin18.2 targeting antibody therapeutic candidate being developed globally. TST001 is generated using Transcenta’s Immune Tolerance Breaking Technology (IMTB) platform. TST001 kills Claudin18.2 expressing tumor cells by mechanisms of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Leveraging advanced bioprocessing technology, the fucose content of TST001 was significantly reduced during the production, which further enhanced NK cells mediated ADCC activity of TST001. Clinical trials for TST001 are ongoing in China and US (NCT04396821, NCT04495296/CTR20201281). TST001 was granted Orphan Drug Designation in the US by FDA for the treatment of patients with gastric cancer or gastroesophageal junction (GC/GEJ).

On March 9, 2022 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative commercial stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class therapeutics in hematology and oncology, reported that China National Medical Products Administration (NMPA) has approved the Phase I study of ATG-101 (the PROBE-CN study) for the treatment of advanced/ metastatic solid tumors and B-cell non-Hodgkin lymphoma (B-NHL) (Press release, Antengene, MAR 9, 2022, View Source [SID1234609826]).

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ATG-101 is a novel bispecific antibody that was designed to block the binding of immunosuppressive PD-1/PD-L1 and conditionally induce 4-1BB stimulation, thus activating anti-tumor immune effectors, while delivering enhanced anti-tumor activity, with an improved safety profile. In preclinical studies, ATG-101 demonstrated significant anti-tumor activity in animal models of resistant tumors as well as those that progressed on anti-PD-1/L1 treatment. Furthermore, ATG-101 has also showed an excellent safety profile in GLP toxicology studies.

Shanghai East Hospital of Tongji University is the lead site for the study, which will be conducted at four centers across China. This open-label, multicenter Phase I study is designed to assess the safety and tolerability of intravenously administered ATG-101 monotherapy in patients with advanced/metastatic solid tumors and B-NHL. The study will be conducted in two parts (dose-escalation and a dose-expansion).

Professor Ye Guo, Deputy Director of Medical Oncology at Shanghai East Hospital of Tongji University, Director of the hospital’s center for Phase I trials, and principal investigator of the study, commented: "Disease that is resistant or refractory to standard of care therapies (chemotherapy, targeted therapy, and immunotherapy, etc.) is a common challenge in the treatment of many malignancies. Patients with those tumor types have urgent unmet medical needs. Mounting evidence supports the potential benefits of bispecific antibodies as a promising modality for the treatment of malignant tumors. ATG-101 is a novel PD-L1/4-1BB bispecific antibody. It was designed to incorporate high affinity for PD-L1 and conditional activation of 4-1BB, intended to reduce the risk of 4-1BB related hepatoxicity. It is my great pleasure to lead the PROBE-CN trial, the first clinical study of ATG-101 in China. My team will work seamlessly with other investigators and Antengene’s research team. We hope that ATG-101 will offer an effective and safe treatment option for patients with advanced tumors."

Dr. Jay Mei, Founder, Chairman and CEO of Antengene, said: "In a very short span of time, ATG-101 has progressed from pre-clinical stage through a series of exciting milestones, including the IND clearances in Australia and the U.S., and the most recent approval by the NMPA in China for the study of ATG-101 in patients with advanced/metastatic solid tumors and B-NHL. We are very pleased with the program’s achievements and we hope this important study will help progress an effective novel treatment for patients with solid tumors and NHL who have relapsed or become refractory to anti-PD-1/L1 therapies."

About ATG-101

ATG-101 is a novel PD-L1/4-1BB bi-specific antibody being developed for the treatment of advanced/metastatic solid tumors and B-cell non-Hodgkin lymphoma (B-NHL). ATG-101 was designed to activate anti-tumor immune effectors, by forming a cell-antibody-cell trimer to simultaneously block the binding of PD-L1/PD-1 and induce 4-1BB stimulation. In PD-L1 over-expressing cancer cells, ATG-101 has shown potent PD-L1 crosslinking-dependent 4-1BB agonist activity, with the potential for delivery of enhanced therapeutic efficacy, whilst mitigating risk of hepatoxicity. To date, ATG-101 has received regulatory clearances in China, the U.S., and Australia to enter a Phase I study for the treatment of advanced/metastatic solid tumors and NHL, and the PROBE study has already been initiated in Australia and in the process of initiation in the U.S.