On April 20, 2023 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported that CT041, an autologous CAR T-cell product candidate against the protein Claudin18.2 (CLDN18.2), has achieved IND clearance from the National Medical Products Administration (NMPA) for the postoperative adjuvant therapy of CLDN18.2 positive pancreatic cancer (PC) (Press release, Carsgen Therapeutics, APR 20, 2023, View Source [SID1234630367]).

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Dr Raffaele Baffa, Chief Medical Officer of CARsgen, commented that "We are glad to receive the IND clearance from NMPA for the adjuvant treatment of CLDN18.2 positive pancreatic cancer using CT041. Pancreatic cancer remains a deadly disease with a dismal prognosis and lack of effective therapies. As indicated in previous clinical trials, CT041 has shown promising efficacies in treating pancreatic cancer. With this IND clearance, we look forward to exploring the use of CT041 for the adjuvant treatment and its potential to create deeper responses for pancreatic cancer patients. Driven by the vision of ‘Making Cancer Curable’, we will continue to explore the use of our CAR T-cells in the earlier line treatment of various cancer types."

About CT041

CT041 is an autologous CAR T-cell product candidate against the protein CLDN18.2 that has the potential to be the first-in-class globally. CT041 targets the treatment of CLDN18.2 positive solid tumors with a primary focus on gastric cancer/gastroesophageal junction cancer (GC/GEJ) and PC.

Active trials in CARsgen include investigator-initiated trials, a Phase Ib clinical trial for advanced GC/GEJ and PC and a confirmatory Phase II clinical trial for advanced GC/GEJ in China (CT041-ST-01, NCT04581473), and a Phase 1b/2 clinical trial for advanced gastric or pancreatic adenocarcinoma in North America (CT041-ST-02, NCT04404595). In January 2022, CT041 was granted Regenerative Medicine Advanced Therapy (RMAT) Designation by U.S. FDA for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma with CLDN18.2 positive tumors. In November 2021, CT041 was granted PRIME Eligibility by the EMA for the treatment of advanced gastric cancer. In 2020 and 2021, CT041 received Orphan Drug designation from the U.S. FDA for the treatment of GC/GEJ and Orphan Medicinal Product designation from the EMA for the treatment of advanced gastric cancer. A Phase 2 clinical trial of CT041 in the U.S. is planned to initiate in the first half of 2023.

On April 20, 2023 OSE Immunotherapeutics SA (ISIN: FR0012127173; Mnemo: OSE) reported two additional posters preenting the latest research updates on CLEC-1 (new myeloid immune checkpoint), from its Myeloid platform, at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in Orlando (Florida) on April 14-19 (Press release, OSE Immunotherapeutics, APR 20, 2023, View Source [SID1234630377]).

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CLEC-1, novel myeloid immune checkpoint target

The academic collaboration conducted with Dr Elise Chiffoleau’s team at the Center for Translational Research in Transplantation and Immunology (1) has led to identify CLEC-1 as a checkpoint, a receptor expressed by myeloid cells inhibiting key pro-phagocytic and T-cell cross-priming functions and hence limiting anti-tumor immune responses.

Dr Aurore Morello, Head of Research of OSE Immunotherapeutics, comments: "Altogether, the data presented at the AACR (Free AACR Whitepaper) meeting demonstrate that CLEC-1 acts as a new immune checkpoint in myeloid cells and highlight the CLEC-1/new ligand TRIM21 axis as a new target for cancer immunotherapy. These latest data generated from our teams’ collaboration provide evidence to further support the preclinical evaluation of monoclonal antagonist antibodies targeting CLEC-1. Importantly, this opens the way for further upcoming translational clinical studies aiming at developing a new myeloid immune checkpoint therapy releasing the breaks on macrophages and dendritic cells."

"CLEC-1 inhibitory myeloid checkpoint blockade enhances antitumor responses and tumor phagocytosis by macrophages".

CLEC-1 blockade with proprietary monoclonal antibodies increases tumor rejection in monotherapy and synergizes with chemotherapy. Anti-CLEC-1 monoclonal antibodies profoundly impacted the tumor environment: frequencies of invigorated dendritic cells and macrophages, activated cells and memory T-cells were increased, while frequencies of immunosuppressive myeloid cells and PD1-expressing T-cells were largely decreased.

The findings presented also revealed a previously unrecognized function for CLEC-1 in myeloid cells as a specific sensor of non-homeostatic cell death. The data showed that the absence of CLEC-1 suppresses tumor growth and hinders immunosuppressive tumor microenvironment.

"TRIM21 is a novel endogenous partner of the inhibitory myeloid checkpoint CLEC-1 involved in tumor antigen cross-presentation".

TRIM21, an intra-cellular Fc receptor and E3 ubiquitin ligase, is identified as a novel interaction partner for CLEC-1 (a discovery published in ‘Sciences Advances’ last November: Drouin et al., 2022). The research demonstrated the functional relevance of CLEC-1 interaction with its ligand. High TRIM21 expression is predictive of worse overall survival in patients with hepatocellular carcinoma, pancreatic cancer, or glioma. Mechanistically, CLEC-1 inhibition enhances the capacity of dendritic cells to cross-present tumor antigens to T lymphocytes, a process known to be regulated by TRIM21 through its E3 ubiquitin ligase activity. Antagonist anti-CLEC-1 or anti-TRIM21 antibodies are therefore being evaluated to further confirm the involvement of the newly identified CLEC-1 interaction with TRIM21 in the regulation of CLEC-1’s function as an inhibitory myeloid checkpoint.

(1) Collaborative academic program between OSE Immunotherapeutics and Dr Elise Chiffoleau’s research teams (Center for Research in Transplantation and Translational Immunology (CR2TI), UMR1064, INSERM, Nantes University at Nantes University Hospital, View Source).

Poster presentation details:

Poster CLEC#1

Title: "CLEC-1 inhibitory myeloid checkpoint blockade enhances antitumor responses and tumor phagocytosis by macrophages""
Session Category: Immunology
Session Title: Immune Checkpoints
Session Date and Time: April 19, 2023 – 9:00 AM – 12:30 PM
Location: Section 23
Poster Board Number: 2

Poster CLEC#2

Title: "TRIM21 is a novel endogenous partner of the inhibitory myeloid checkpoint CLEC-1 involved in tumor antigen cross-presentation"
Session Category: Immunology
Session Title: Immune Checkpoints
Session Date and Time: April 19, 2023 – 9:00 AM – 12:30 PM
Location: Poster Section 23
Poster Board Number: 9

On April 20, 2023 Abdera Therapeutics Inc., a biopharmaceutical company leveraging its advanced antibody engineering ROVEr platform to design and develop tunable, precision radiopharmaceuticals for cancer, reported that it has raised $142 million in combined Series A and B financing (Press release, Abdera Therapeutics, APR 20, 2023, View Source [SID1234630376]). Versant Ventures and Amplitude Ventures led the Series A round, with participation from Northview Ventures as well as founding partners of Abdera, adMare BioInnovations and AbCellera. The Series B round was led by venBio Partners with participation from existing investors as well as new investors including Viking Global Investors, Qiming Venture Partners USA and RTW Investments.

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"Radiopharmaceuticals hold the potential to transform the treatment of cancer, but the ability to finely tune radioisotope delivery to the tumor, while sparing healthy tissue, remains a major challenge for this class of drugs," said Lori Lyons-Williams, president and chief executive officer. "Abdera’s ROVEr platform enables the design of antibody-based radiopharmaceuticals that are ideally suited to specific cancer targets with optimized PK properties to pair with a radioisotope of choice and maximize therapeutic impact. Our goal is to leverage the power and flexibility of our platform to pursue a variety of oncology targets, advance potential best-in-class new cancer medicines and build Abdera into a leading radiopharmaceutical company."

Engineering the Future of Precision Radiopharmaceuticals

Current radiopharmaceutical targeting approaches leverage either small ligands or large proteins. While small ligands may lead to rapid tumor penetration and elimination, they are often associated with low total tumor accumulation, high renal uptake, and kidney toxicity. Large formats, often using existing antibodies not designed specifically for radiopharmaceutical therapy, may avoid renal uptake, but their large size and long half-life in circulation may limit tumor penetration and cause systemic irradiation potentially leading to bone marrow toxicities. The therapeutic index is not ideal with either approach.

Abdera’s Radio Optimized Vector Engineering (ROVEr) platform allows the company to design novel antibody-based radiopharmaceuticals with high affinity antigen binding domains to cancer targets and an engineered Fc domain that fine tunes the antibodies’ PK to best suit the delivery of therapeutic isotopes. Abdera aims to optimize the therapeutic index of potent radioisotopes emitting alpha or beta particles to selectively destroy tumor cells while sparing healthy cells, providing patients with potentially transformative new cancer treatments.

"We design our targeting molecules as heavy-chain-only antibodies, which we believe are the optimal size to achieve an ideal balance of target specificity, tumor penetration and accumulation of the radioisotope while avoiding high renal uptake," said Adam Judge, Ph.D., co-founder and senior vice president, research. "Our modular format offers the ability to fuse novel antigen binding domains designed for any cancer target of interest to an engineered Fc domain, rapidly creating antibodies with appropriate PK for radiopharmaceutical development. Abdera has generated promising proof-of-concept data in a variety of tumor models, leveraging a platform that provides an excellent foundation upon which to build a differentiated pipeline of potential best-in-class programs."

"Versant has been an early mover in the emerging radiopharmaceutical field, and we believe that Abdera’s approach represents a new wave of innovation in this space to address important cancer targets that may be intractable to other approaches," said Joel Drewry, Ph.D., principal at Versant Ventures. "We’re excited to be working with an exceptional management team and investor syndicate to advance the company’s cutting-edge technology."

Lead Program Targeting DLL3 Advancing Toward Clinic

Abdera’s lead program targets delta-like ligand 3 (DLL3), a protein in the Notch pathway that is upregulated and specifically expressed in small cell lung cancer (SCLC) and other solid tumors, with very rare expression on nonmalignant cells. The company’s DLL3 program is advancing through preclinical development, and Abdera expects to submit an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) in 2024. In addition, Abdera is advancing a robust pipeline for other undisclosed cancer targets.

"DLL3 is a well-validated target for SCLC, a cancer with few treatment options," said Yvonne Yamanaka, Ph.D., principal, venBio Partners. "Radiopharmaceuticals from Abdera’s ROVEr platform have the potential to address DLL3 and other tumor antigens that have been challenging to optimally target with conventional modalities due to low levels of expression. We look forward to working with Abdera to advance the company’s DLL3 program into the clinic and develop new radiopharmaceuticals for other cancers with high unmet need."

Purpose-Built Team

Abdera is led by an exceptional team of scientists and company builders with demonstrated track records in drug development spanning oncology, radiopharmaceuticals and biologics.

"Abdera is curating an ideal team to build a leading radiopharmaceutical company, spanning members with deep expertise in biologics and radiochemistry and experience developing one of the most commercially successful radiopharmaceuticals to launch in recent years," said Nancy Harrison, venture partner at Amplitude Ventures. "We are pleased to have worked with the company’s talented co-founders to grow Abdera and we look forward to what this team can achieve.

Abdera’s executive team includes:

Lori Lyons-Williams, president and chief executive officer
Adam Judge, Ph.D., co-founder and senior vice president, research
Lana Janes, Ph.D., co-founder and senior vice president, operations and innovation
Michael Abrams, Ph.D., co-founder and senior advisor
Kawa Chiu, chief technical officer
Jennifer McNealey, chief financial officer
Alison Armour, M.D., FRCR, FRCP, interim chief medical officer
Kelly Parker, senior vice president, human resources
Abdera’s board of directors includes:

Garry Nicholson, independent director and chairman of the board
Joel Drewry, Ph.D., principal, Versant Ventures
Nancy Harrison, venture partner, Amplitude Ventures
Maria Koehler, M.D., Ph.D., chief medical officer, Repare Therapeutics
Colin Walsh, Ph.D., partner, Qiming Venture Partners USA
Yvonne Yamanaka, Ph.D., principal, venBio Partners
Lori Lyons-Williams, president and chief executive officer

On April 20, 2023 MAIA Biotechnology, Inc. (NYSE American: MAIA) reported preliminary survival data in the Part A safety lead-in of its ongoing phase 2 trial, THIO-101 evaluating THIO in patients with advanced Non-Small Cell Lung Cancer (NSCLC) (Press release, MAIA Biotechnology, APR 20, 2023, View Source [SID1234630375]).

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The first 2 patients enrolled in Part A of the study continue to be alive, approximately 10 and 9 months respectively, from treatment initiation. Both patients have advanced Stage IV metastatic disease and are heavily pretreated, receiving third and fourth line of therapy respectively after previously failing treatment with an immune checkpoint inhibitor.

As previously reported, the first 6 evaluable patients in Part A of THIO-101 cleared the THIO high dose (THIO 360 mg per cycle (120 mg on Days 1-3 Q3W) followed by the standard 350 mg dose of cemiplimab on Day 5) with no dose limiting toxicities. Treatment has been generally well tolerated and enrollment is underway in Part B. As of now, the first 2 patients continue to be progression free following their last dose, 7 and 6 months respectively, with no new treatment.

"The current treatment options in patients with advanced relapsed or refractory NSCLC who failed two or more therapy regimens are limited and show minimal benefit. Furthermore, discontinuation of treatment is rapidly followed by physical decline and death, therefore seeing patients with such survival and no disease progression in this clinical setting, is noteworthy," says MAIA’s Chief Medical Officer Mihail Obrocea.

"This observation may correlate well with the evidence of induction of innate and adaptive immune responses seen in the preclinical models of lung cancer, where only three doses of THIO followed by an immune checkpoint inhibitor resulted in long-lasting complete tumor regression with no recurrence," says MAIA’s Chief Scientific Officer, Sergei Gryaznov.

"In real-world clinical practice, observed survival in such heavily pretreated patients is 3-4 months. These preliminary survival results are very encouraging for patients with lung cancer," added Vlad Vitoc, MAIA’s Chief Executive Officer.

About THIO-101, a Phase 2 Clinical Trial

THIO-101 is a multicenter, open-label, dosing finding Phase 2 clinical trial. It is the first trial designed to evaluate THIO’s potential immune system activation effects in NSCLC patients by administering THIO in advance of administration of an immune checkpoint inhibitor allowing for immune activation and PD-1 sensitivity to take effect. The trial will test the hypothesis that low doses of THIO administered prior to a checkpoint inhibitor will enhance and prolong immune response in patients with advanced NSCLC who previously did not respond or developed resistance and progressed after first-line treatment regimen containing another checkpoint inhibitor. The trial design has two primary objectives: (1) to evaluate the safety and tolerability of THIO administered as an anticancer agent and a priming immune system agent (2) to assess the clinical efficacy of THIO using Overall Response Rate (ORR) as the primary clinical endpoint. For more information on this Phase II trial, please visit ClinicalTrials.gov using the identifier NCT05208944.

About THIO

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a telomere-targeting agent currently in clinical development to evaluate its activity in non-small cell lung cancer (NSCLC), in sequential administration with Regeneron’s anti-PD1 therapy, Libtayo (cemiplimab). Telomeres play a fundamental role in the survival of cancer cells and their resistance to current therapies. THIO is being developed as a second or later line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.

On April 20, 2023 Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, reported a collaboration with Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura., "Astellas"), by which Astellas will license a suite of Twist’s VHH antibody libraries to be used by Astellas for drug discovery and development (Press release, Twist Bioscience, APR 20, 2023, View Source [SID1234630374]).

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"We are pleased to extend our collaboration with Astellas to three agreements across two groups within the company, showcasing our ability to meet the varying needs of our customers and support their success," said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. "This latest collaboration with Astellas demonstrates how Twist can enable our customers to grow their pipelines both externally with our antibody discovery services and by supporting their internal discovery with our highly specific and potent antibody libraries."

Under the terms of the agreement, Astellas will license a suite of Twist’s VHH libraries for a period of five years and will use the libraries to conduct research and development activities. Twist will receive an upfront payment and will be eligible to receive annual maintenance fees and fees per product through payments associated with specific clinical and commercial milestones. Twist will also be eligible to receive royalty payments on product sales.

Twist VHH Antibody Libraries

Antibodies contain two variable domains, the heavy and the light chains. A VHH antibody, also known as a single domain antibody, is the antigen binding domain of the heavy chain, with three complementary determining regions (CDRs), or areas where antigens bind to the antibody. Twist’s VHH libraries use novel methods that combine synthetic and natural approaches to maximize diversity up to 10 billion for each library, creating high quality VHH libraries for use against any protein target. The small size of the VHH antibodies allow them to access targets that traditional antibodies cannot, with tight binding affinity. The modular nature of VHH antibodies supports creation of bi- or multi-specific antibodies ideal for developing next generation therapies specific to oncology, autoimmune disease and virology. During the pandemic, Twist published on the use of these libraries to neutralize SARS-CoV-2 (MAbs. 2022; 14(1): 2002236).