On July 16, 2024 Mabwell (688062.SH), an innovation-driven biopharmaceutical company with entire industry chain, reported that its self-developed novel B7-H3-targeting ADC (R&D code: 7MW3711) has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA), for the treatment of small cell lung cancer (Press release, Mabwell Biotech, JUL 16, 2024, View Source [SID1234644897]).

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The FDA grants Orphan Drug Designation to treatments for rare diseases in the United States that affect fewer than 200,000 patients. Orphan Drug Designation offers policy benefits to drug developers, including as aid with medication development, tax credits for a part of clinical trial expenditures, and seven years of market exclusivity upon approval.

7MW3711 is a novel B7-H3-targeting ADC developed by Mabwell’s IDDC platform. It is composed of innovative antibody molecule, novel linker, and novel payload Mtoxin (TOP1i). When 7MW3711 enters human body, it specifically binds to antigens on the tumor cell membrane surface, be internalized and trafficked to the lysosome, release cytotoxic drug, and induce the apoptosis of tumor cells.

7MW3711 is pharmaceutical characterized as stable structure, homogeneous composition, high purity, and it is suitable for industrial scale-up. Compared with ADCs in the same class at home and abroad, 7MW3711 has shown better tumor killing effects in multiple animal tumor models. In the safety evaluation model of animals including cynomolgus monkeys, the on-target and off-target toxicities of 7MW3711 are effectively controlled, showing its good safety profile and pharmacokinetic properties. The above research results indicate that 7MW3711 has clinical differentiation characteristics and a promising future of clinical development.

About the next generation ADC platform – IDDC

IDDC is a next generation ADC site-specific conjugation technology platform independently developed by Mabwell, consisting of multiple systematic core patented technologies including the site-specific conjugation process DARfinity, the site-specific linker IDconnect, the novel payload Mtoxin, and the conditional release structure LysOnly. The next generation ADCs developed based on the above systematic patented technologies have better structural uniformity, quality stability, efficacy, and tolerability. The novel payload Mtoxin (MF6) demonstrates good pharmacodynamics, bystander killing efficacy, and anti-multidrug resistance.

The IDDC platform has been validated in multiple drug candidates under development. Mabwell currently has several ADCs in clinical development stages. Among them, the novel Nectin-4-targeting ADC, 9MW2821, is in Phase III clinical trial for the indication of urothelial carcinoma. The novel B7-H3-targeting ADC, 7MW3711, and Trop-2-targeting ADC, 9MW2921, are both in clinical trial stages.

On July 15, 2024 GRAIL, Inc. (NASDAQ: GRAL), a healthcare company whose mission is to detect cancer early when it can be cured, reported an update on the PATHFINDER 2 and NHS-Galleri registrational clinical trials evaluating the Galleri multi-cancer early detection (MCED) test (Press release, Grail, JUL 15, 2024, View Source [SID1234644877]). GRAIL has completed the PATHFINDER 2 study’s planned enrollment of more than 35,000 participants who are eligible for guideline-recommended cancer screening at more than 30 healthcare institutions in North America. In addition, GRAIL has completed the third and final round of study visits for the NHS-Galleri trial, which enrolled more than 140,000 participants.

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"The PATHFINDER 2 and NHS-Galleri studies will significantly expand our existing clinical validation and performance evidence for the Galleri test. By supplementing our robust clinical evidence program with more than 35,000 participants in the U.S. for PATHFINDER 2 and over 140,000 participants in England for NHS-Galleri, we will continue our generation of additional performance, safety, and clinical utility data," said Bob Ragusa, Chief Executive Officer at GRAIL. "Both studies were designed to enroll a diverse participant population, representative of socio-economic, ethnicity, gender and age differences, and we are proud of the diversity of the study populations. The data from these studies, as well as supplemental data from our other clinical studies, will support our premarket approval application submission for Galleri to the FDA, which is currently in process with a modular submission under a Breakthrough Device Designation from the FDA. We look forward to seeing results from the first 25,000 individuals enrolled in the PATHFINDER 2 study in the second half of 2025 and final results from the NHS-Galleri trial in 2026."

About the PATHFINDER 2 Study (NCT05155605)
PATHFINDER 2 is a prospective, multi-center, interventional study evaluating the safety and performance of Galleri in a population of individuals aged 50 years and older who are eligible for guideline-recommended cancer screening in the United States. PATHFINDER 2 is being conducted pursuant to an FDA-approved investigational device exemption (IDE) application and began enrolling in December 2021. The primary objectives of the study are 1) to evaluate the safety and effectiveness of GRAIL’s MCED test based on the number and type of diagnostic evaluations performed in participants who receive a cancer signal detected test result, and 2) to evaluate the performance of GRAIL’s MCED test across various measures, including positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, and cancer signal origin (CSO) prediction accuracy. Participants who receive a cancer signal detected result undergo additional diagnostic testing based on the predicted CSO to determine if a cancer is present. Secondary objectives include utilization of guideline-recommended cancer screening procedures after use of the MCED test, and participant reported outcomes (PRO) over several time points, including an assessment of participants’ anxiety and satisfaction with the MCED test. Timepoints for collection will include baseline measurement prior to testing, post-results, and post-diagnostic resolution for positive test results.

The PATHFINDER 2 study is being conducted with leading healthcare institutions across the United States, including Cleveland Clinic, Duke University Health System, Flushing Hospital Medical Center, Henry Ford Health System, Hoag, Inova, Jamaica Hospital Medical Center, Kelsey-Seybold Clinic, Mayo Clinic, Morehouse School of Medicine, Ochsner Health, Oregon Health & Science University, Sarah Cannon, Sutter Health, University of Oklahoma, University of Pittsburgh, Virginia Commonwealth University, Weill Cornell Medicine, and others.

About the NHS-Galleri Trial (NCT05611632)
In 2020, NHS England selected GRAIL to assist with the United Kingdom’s ambitions for early cancer detection and to assess Galleri for potential population screening on a national scale. In 2021, we initiated the NHS-Galleri trial, a fully enrolled prospective randomized controlled clinical utility trial of over 140,000 participants between the ages of 50 and 77 at the time of enrollment, to evaluate the implementation of Galleri alongside the existing NHS standard of care screenings. The primary objective of the trial is to assess whether implementation of Galleri can reduce the incidence of late-stage cancers through early cancer detection. The trial aimed to enroll a representative population sample to promote health equity and was fully enrolled in just over 10 months.

The trial is designed for participants to provide three blood draws over a two-year period, with the first draw taken at enrollment. As a randomized controlled trial, half of the trial participants have received the Galleri test, and half have had their blood sample stored for future analysis. Any participant in the interventional arm with a cancer signal detected result has been referred for further diagnostic workup within the NHS. All other participants and their physicians remain blinded as to which arm of the study they are in. The NHS-Galleri trial design was published in Cancers in 2022.

Collaborators include Queen Mary University of London, King’s College London Cancer Prevention Trials Unit, and NHS England.

On July 15, 2024 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported that data published in the journal Cell demonstrate that neoadjuvant monotherapy with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib results in a high response rate and reshapes the tumor microenvironment (TME), providing new targets for immunotherapy and combination regimens in patients with homologous recombination deficiency (HRD) positive ovarian cancer (Press release, Zai Laboratory, JUL 15, 2024, View Source [SID1234644879]). The study revealed niraparib preferentially suppresses certain immune cells that support the growth of HRD-positive ovarian tumors.

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This Zai Lab-supported study also showed that targeted clearance of infiltrating regulatory T cells (eTregs) using Zai Lab’s investigational CCR8 antibody, ZL-1218, significantly sensitized niraparib against HRD tumors, resulting in decreased tumor burden in pre-clinical models.

"Given the prevalence of HRD in cancer and its role in rendering tumors vulnerable to PARP inhibition, this study fills the knowledge gap regarding the impact of HRD and related therapies on the tumor microenvironment," said Professor Qinglei Gao, Chief of Gynecologic Oncology Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. "By decoding the tumor-reactive T cells in the HRD-positive TME that are regulated by eTregs, these findings have profound implications for future oncology research and therapeutic development for HRD-positive ovarian cancer and other HRD-related cancers."

To investigate the effects of HRD, neoadjuvant therapies, and their interactions on the TME, investigators utilized tumor tissues from a clinical study (NCT04507841) evaluating niraparib for the neoadjuvant treatment of unresectable ovarian cancer. In parallel, tissue samples from patients receiving neoadjuvant chemotherapy (NACT) were also collected.

Profiling of these samples yielded valuable data delineating the divergence in TME between HRD-positive vs. homologous recombination-proficient (HRP) tumors, as well as their respective phenotypic evolution following the introduction of neoadjuvant therapies.

Key findings of the study included:

Patients receiving neoadjuvant monotherapy with niraparib achieved 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively.
Overall, the safety profile of NANT was manageable, and no new safety signal was observed, with hematologic toxicities as the most common treatment-related adverse events.
The results indicate that NANT is an effective neoadjuvant treatment option for controlling disease progression in patients with HRD-positive high-grade serous ovarian cancer (HGSOC).
eTregs were identified as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells.
The addition of the CCR8 antibody, ZL-1218, to niraparib showed a significantly pronounced inhibitory effect on eTregs in pre-clinical models, suppressing tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
"Zai Lab is pleased to support this important translational research which breaks new ground in our understanding of the tumor microenvironment in HRD-positive ovarian cancer," said Rafael G. Amado, M.D., President, Head of Global Research and Development, Zai Lab. "By identifying new immunotherapeutic targets in the TME, these findings could bolster efforts to improve outcomes for patients with HRD+ tumors."

On July 15, 2024 GC Cell (KRX: 144510.KS) and Checkpoint Therapeutics ("Checkpoint") (Nasdaq: CKPT) reported a collaboration to explore the combined therapeutic potential of cosibelimab, Checkpoint’s anti-PD-L1 antibody with dual mechanism of action, with GC Cell’s Immuncell-LC, an innovative autologous Cytokine Induced Killer ("CIK") T cell therapy composed of cytotoxic T lymphocytes and natural killer T cells (Press release, Checkpoint Therapeutics, JUL 15, 2024, View Source [SID1234644860]).

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This collaboration will initially focus on conducting in vitro combination studies to evaluate the synergistic effects of these two therapies on cancer cell destruction. Positive preliminary data from these studies could potentially pave the way for future in vivo research and clinical studies.

The anticipated synergy between cosibelimab’s antibody-dependent cellular cytotoxicity ("ADCC") mechanism of action and Immuncell-LC’s robust autologous CIK T cell response is supported by extensive research. This combination is expected to leverage immune system components more effectively in targeting and eliminating cancer cells.

James Park, CEO of GC Cell, highlighted the agreement’s potential: "This collaboration is a pivotal step towards significant technological collaborations. The integration of cosibelimab’s clinical efficacy and safety profile with our Immuncell-LC could set new therapeutic standards in immuno-oncology. We are optimistic that this partnership will lead to effective commercial licensing or joint development in the future."

James F. Oliviero, CEO of Checkpoint Therapeutics, concurred: "Both cosibelimab, with its dual mechanism of action, and Immuncell-LC show great promise as potential immuno-oncologic therapies. We are pleased to work in collaboration with GC Cell to determine if using the two therapies in combination may offer even greater potential benefits than being used singly."

About Immuncell-LC
Immuncell-LC stands as the sole commercially approved adoptive T cell therapy for hepatocellular carcinoma adjuvant treatment. Comprising autologous, significantly expanded CIK (Cytokine Induced Killer) T lymphocytes, it has demonstrated proven efficacy in a large-scale Phase 3 clinical trial—reducing the risk of recurrence by 37% and decreasing mortality by 79% compared to the active surveillance group. Administered to over 10,000 patients in South Korea, Immuncell-LC has shown an excellent safety profile without treatment-related serious adverse events.

About Cosibelimab
Cosibelimab is a potential differentiated, high affinity, fully-human monoclonal antibody of IgG1 subtype that directly binds to programmed death ligand-1 ("PD-L1") and blocks the PD-L1 interaction with the programmed death receptor-1 ("PD-1") and B7.1 receptors. Cosibelimab’s primary mechanism of action is based on the inhibition of the interaction between PD-L1 and its receptors PD-1 and B7.1, which removes the suppressive effects of PD-L1 on anti-tumor CD8+ T-cells to restore the cytotoxic T cell response. Cosibelimab is potentially differentiated from the currently marketed PD-1 and PD-L1 antibodies through sustained high tumor target occupancy of PD-L1 to reactivate an antitumor immune response and the additional potential benefit of a functional Fc domain capable of inducing ADCC for potential enhanced efficacy.

On July 15, 2024 Integrated DNA Technologies (IDT), a global leader in CRISPR genome editing solutions, reported a licensing agreement with SeQure Dx, a company focused on off-target analysis for preclinical and clinical gene modification customers, bolstering IDT’s complete CRISPR portfolio comprised of world-class RUO to CGMP solutions from design to analysis (Press release, INTEGRATED DNA TECHNOLOGIES, JUL 15, 2024, View Source [SID1234644880]). The licensing agreement enables IDT to support cell and gene therapy developers through all phases of their CRISPR-based therapeutic programs by providing comprehensive off-target analysis services, powered by SeQure Dx’s GUIDE-seq technology, alongside IDT’s award-winning rhAmpSeq CRISPR Analysis System.

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"Off-target effects continue to be a primary concern in genome editing and are still not fully understood," said Sandy Ottensmann, VP/General Manager, Gene Writing & Editing Business Unit at IDT. "With an increasing pipeline of CRISPR-based therapeutics that are entering and progressing in trials, the delivery of safer and more efficient genome editing platforms to the clinic becomes paramount. IDT’s expanded off-target analysis capabilities demonstrate a transformational shift we are making to support cell and gene therapy developers in their transition to the clinic, in a drive to make life-changing therapies as safe as possible."

Dr. Keith Joung, Scientific Founder of SeQure Dx, added, "SeQure’s best-in-class off-target nomination and confirmation platforms will seamlessly complement IDT’s CRISPR-based portfolio of products and services. By combining SeQure’s & IDT’s innovative technologies, this will enhance precision and safety in gene editing, bringing transformative solutions to researchers and patients worldwide."

The licensing agreement with SeQure Dx expands IDT’s comprehensive off-target analysis capabilities by providing the company access to SeQure Dx’s next generation sequencing-based gene editing off-target analysis technology, GUIDE-seq. Originally developed by Keith Joung’s group at Massachusetts General Hospital, GUIDE-seq is a widely used off-target nomination assay, making it an excellent starting point for developing and evaluating CRISPR-focused therapeutics. Broadly used by academic researchers, biotechs, large pharma and biopharma companies to help characterize potential off-target events in their genome editing results, GUIDE-seq provides genome-wide, unbiased identification of double-stranded breaks by sequencing. It has contributed in part to the successful development and release of multiple therapeutics.

IDT’s CRISPR Innovation Journey

Last year, to help address development and manufacturing challenges in a capacity-constrained market for CGMP/Q7 services, IDT opened a therapeutic oligonucleotide manufacturing facility in the U.S. to support the increased demand for high-quality cell and gene therapy components. These critical reagents are foundational to delivering on the promise of therapies to patients and are key to accelerating the path to clinic for developers.

With IDT’s proprietary rhAmpSeq CRISPR Analysis System, regulatory expertise, RUO to CGMP manufacturing capabilities, and dedicated support team, customers can expect differentiated off-target analysis services from a single provider for their CRISPR therapeutic development. Launched in 2021, IDT’s rhAmpSeq CRISPR Analysis System is an end-to-end solution for characterizing and quantifying the full array of on- and off-target genome editing events in CRISPR research products. The novel tool, endorsed by renowned scientists, continues to grow in popularity as an assay for off-target confirmation, and enables the robust analysis of resulting next generation sequencing data. For more information about IDT’s comprehensive off-target analysis services and capabilities, visit https://go.idtdna.com/OTE-analysis-request-consult.