On April 9, 2024 Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered cytokine therapies designed to address areas of unmet need for patients with a variety of cancers, reported poster presentations with pre-clinical data from its Interleukin-18 (IL-18) and IL-12 programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting taking place April 5-10 in San Diego, California (Press release, Mural Oncology, APR 9, 2024, View Source [SID1234641937]). This is the first time Mural has shared findings from either program. The details for the presentations are as follows, and both posters are available at View Source

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Interleukin-18 engineered for resistance to IL-18 binding protein (IL-18BP) and half-life extension to enhance its therapeutic potential (Abstract #4076):

IL-18 is a potent immune-stimulating cytokine, but it is limited by IL-18 binding protein (IL-18BP) – a secreted high affinity decoy receptor that binds with, and neutralizes, IL-18, thus limiting its efficacy over time.
Mural’s protein engineering approach is twofold: first, it introduces mutations to IL-18 that are designed to minimally impact the structure while eliminating binding to IL-18BP. Secondly, it fuses IL-18 to protein scaffolds to extend the half-life and increase the cytokine’s exposure.
The company believes the half-life enhancement may lead to a more durable immunological effect, as demonstrated by the interferon gamma and Th1 response, proinflammatory reactions necessary for the body’s immune response.
Notably, the duration of Th1 response observed was significantly longer (approximately 7-9 days) than a "naked" approach without this half-life extension, which is generally cleared in 2-3 days.
The optimal balance of potency and pharmacokinetic enhancement is still being determined to nominate a lead IL-18 development candidate.
"Resistance to IL-18BP is the foundation of our approach. The mutations we introduced prevented the binding protein from neutralizing the cytokine’s efficacy. We show that resistance to IL-18BP combined with the drug’s extended half-life leads to a durable immunological effect in preclinical models. Our observation of increases in Th1 cytokines, which have been shown elsewhere to correlate with response to checkpoint inhibitors, are encouraging indications that our engineered IL-18 may provide a therapeutic complement to checkpoint inhibitor immunotherapy1,2," said Mark Whitmore, Ph.D., Principal Scientist of Cancer Biology, and the poster’s lead author.

Generation of tumor targeted self-assembling split IL-12 subunits for the treatment of cancer (Abstract #4066):

IL-12p70 is a potent stimulator of the immune system with profound anti-tumor activity but very poor tolerability.
Mural’s protein engineering approach aims to mitigate IL-12’s hallmark toxicity by splitting the heterodimer into two inactive monomers: IL-12p35 and IL-12p40. These individual subunits are separately fused to two non-competitive antibody fragments.
The goal of this is to assemble active IL-12p70 preferentially in the tumor microenvironment. The sequential administration of these targeted subunits concentrates the IL-12p70 activity primarily at the tumor site, thereby limiting systemic formation and associated toxicities.
In vivo analysis demonstrated that targeting both subunits resulted in the greatest accumulation and retention of IL-12p70 complex in the tumor.
"We believe that by self-assembling the split IL-12 subunits within the tumor microenvironments, we can circumvent native IL-12’s severe toxicities without compromising its efficacy. The data presented today provide strong rationale for our strategy of non-competitively targeting each subunit to a unique epitope on the same molecule," said Joshua Heiber, Ph.D., Director of Research & Development, Cancer Biology, and the poster’s lead author.

On April 9, 2024 Manhattan BioSolutions, Inc. ("Manhattan Bio"), an emerging biotechnology company developing new classes of precision biologics for the treatment of advanced cancers, reported a collaborative poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego, California (Press release, Manhattan BioSolutions, APR 9, 2024, View Source [SID1234641936]). The poster, titled "A potent FGFR4-targeted antibody-drug conjugate therapy for patients with rhabdomyosarcoma and other cancers expressing FGFR4," highlights the promising preclinical efficacy of this innovative therapeutic approach. The research is a result of a collaboration between Manhattan Bio, the National Cancer Institute (NCI), part of the US National Institutes of Health (NIH), and Binghamton University.

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The lead investigator is Javed Khan, MD, Senior Investigator and Deputy Chief of the Genetics Branch at the NCI Center for Cancer Research. The study utilized a highly specific monoclonal antibody that targets FGFR4, a receptor overexpressed in various cancers, including rhabdomyosarcoma (RMS). The antibody was conjugated to the cytotoxic MMAE payload through a protease-cleavable valine-citrulline linker, generating a potent FGFR4-targeted ADC. This work builds on an earlier collaboration agreement between Manhattan Bio, the NCI, and Binghamton University announced in 2023.

"We are thrilled to share the compelling preclinical data generated through our ongoing collaboration with the NCI and Binghamton University," said Dr. Borys Shor, CEO of Manhattan Bio. "While this proof-of-concept study utilized a standard linker-payload system, we are excited to continue our work with cutting-edge topoisomerase 1 inhibitor warheads currently being developed at Manhattan Bio. We believe that by combining the highly selective FGFR4 antibody with our proprietary linker-payload technologies, we can further enhance the therapeutic potential of this ADC for pediatric patients with RMS and for patients with other types of tumors."

On April 9, 2024 IN8bio, Inc. (Nasdaq: INAB) a clinical-stage biopharmaceutical company developing innovative gamma-delta T cell therapies, reported new preclinical data from its non-signaling gamma-delta T cell based Chimeric Antigen Receptor-T cell (nsCAR) platform, known as INB-300, that demonstrated improved selectivity to target leukemia cells while preserving healthy ones (Press release, In8bio, APR 9, 2024, View Source [SID1234641935]). The data support the potential for nsCAR to have a wider therapeutic window and to be used to prevent on-target off-tumor killing of healthy tissue that may express the CAR-T target. The data was presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 on April 9, 2024.

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IN8bio’s nsCAR platform is based on the natural ability of gamma-delta T cells to distinguish between healthy and malignant tissue. By using a Chimeric Antigen Receptor (CAR) that lacks a signaling domain, IN8bio believes it has created a technology that enables these cells to differentiate between tumor and healthy tissue, even when both express the CAR-targeted antigen.

Approved CAR-T therapies have shown remarkable efficacy against B cell malignancies, offering hope to patients with limited treatment options. However, extending this therapy to myeloid malignancies and solid tumors has proven challenging since the antigens they target are also often found on the surface of healthy blood cells and tissues. This unintended targeting of healthy cells and tissues has led to many of the toxicities, including patient deaths, observed in prior CAR-T therapies and has limited their utility. Unlike traditional CAR-T therapy, IN8Bio’s nsCAR is designed to direct the gamma delta T cell to its target while maintaining their unique gamma-delta T cell receptors, allowing them to identify and specifically eliminate heterogeneous tumor cells through recognition of tumor-associated stress antigens.

The new data presented at AACR (Free AACR Whitepaper) included results from proprietary constructs targeting CD33 and/or CD123 for in vitro evaluation against various types of leukemia, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The study results demonstrated notable differences between cells expressing traditional signaling CARs and those expressing the nsCAR constructs, which include a reduction in activation-induced cell death with nsCAR constructs.

The nsIL3-33mb15 CAR (CD123+CD33+IL-15) enhancement of the gamma delta T cells against leukemia cells demonstrated an average 1.8x increase in tumor killing capability across three AML cell lines (HL-60, KG-1a and MOLM-13), compared to unmodified gamma-delta T cells as measured by a 24-hour cytotoxicity assay. Importantly, the nsCAR cells did not lead to significant killing of healthy cells expressing the CD33 or CD123 target, demonstrating the selectivity of the nsCAR platform. Results were run in triplicate and on average the selectivity was increased by 5.5x. Across all runs, killing by the nsIL3-33mb15 construct against healthy CD34+ HPCs was below that of un-transduced control gamma-delta T cells.

"INB-300 can selectively target leukemia cells while preserving healthy tissue. We are now conducting further optimization to improve the integration of membrane-bound IL-15 co-expression to potentially enhance both the efficacy and safety of next-generation adoptive cell therapies against a wider spectrum of cancers," said Lawrence Lamb, Ph.D., co-founder and Chief Scientific Officer of IN8bio. "These results can potentially improve INB-300, as we advance towards IND enabling studies of our next-generation gamma-delta T cell therapies to treat cancers."

About INB-300

INB-300 is an nsCAR gamma-delta T cell platform with several preclinical product candidates, including the INB-330 program against AML targets, that combine our expertise in gamma-delta T cells and genetic engineering. These nsCAR constructs lack signaling domains in order to take advantage of the unique properties of gamma-delta T cells to differentiate between healthy and tumor tissues. IN8bio is advancing new nsCAR constructs against multiple targets to treat both solid and liquid tumors.

On April 9, 2024 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, reported that its research collaborators presented positive preclinical data for Reqorsa Immunogene Therapy (quaratusugene ozeplasmid) and NPRL2 gene therapy, which both utilize the Company’s non-viral Oncoprex Delivery System for the treatment of lung cancer (Press release, Genprex, APR 9, 2024, View Source [SID1234641934]). These studies were presented at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is being held April 5-10, 2024 in San Diego, California.

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"We continue to expand our growing body of preclinical evidence supporting REQORSA’s therapeutic potential to treat a variety of cancers, as well as the therapeutic potential of our non-viral delivery system to deliver tumor suppressor genes for the treatment of cancer," said Rodney Varner, Chairman, President and Chief Executive Officer at Genprex. "We are especially delighted to have three preclinical studies presented at one of the largest professional cancer research meetings among the world’s top oncologists and the cancer research community."

Featured Genprex-supported posters presented at AACR (Free AACR Whitepaper) 2024 include:

Title: "Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing Non-Small Cell Lung Carcinoma can induce cellular apoptosis"

Session Category: Molecular/Cellular Biology and Genetics

Session Title: Apoptosis and Ferroptosis

Session Date and Time: Sunday, April 7 from 1:30 p.m. – 5:00 p.m. PT

Location: Poster Section 15

Poster Board Number: 7

Abstract Presentation Number: 351

Title: "Mechanism of NPRL2 gene therapy induced anti-tumor immunity in KRAS/STK11mt aPD1 resistant metastatic NSCLC"

Session Category: Immunology

Session Title: Inflammation, Host Factors, and Epigenetic Influences on Cancer Development and Treatment

Session Date and Time: Monday, April 8 from 9:00 a.m. – 12:30 p.m. PT

Location: Poster Section 5

Poster Board Number: 18

Abstract Presentation Number: 1420

Title: "Tumor Suppressor Gene TUSC2 suppresses energy metabolism in lung cancer cells with opposite effects in normal bronchial epithelial cells"

Session Category: Experimental and Molecular Therapeutics

Session Title: Cancer Biology and Metastasis

Session Date and Time: Monday, April 8 from 1:30 p.m. – 5:00 p.m. PT

Location: Poster Section 22

Poster Board Number: 6

Abstract Presentation Number: 3158

In the first poster, entitled "Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing Non-Small Cell Lung Carcinoma can induce cellular apoptosis," researchers reported that REQORSA induced apoptosis in alectinib resistant EML4-ALK positive non-small cell lung cancer (NSCLC) cell lines. Alectinib is an ALK-inhibitor commonly used to treat patients with ALK rearrangements such as EML4-ALK positive NSCLCs. This research suggests that REQORSA may be an effective treatment in patients progressing on alectinib.

The second poster, entitled, "Mechanism of NPRL2 gene therapy induced anti-tumor immunity in KRAS/STK11mt aPD1 resistant metastatic NSCLC" detailed a humanized mouse model study in which the researchers investigated the anti-tumor immune responses to NPRL2 gene therapy in pembrolizumab resistant KRAS/STK11mt NSCLC. In the study, lung metastases in humanized mice were treated through I.V. injection of NPRL2 nanoparticles, made with the ONCOPREX Delivery System, with or without pembrolizumab. The study found that the NPRL2 treatment by itself led to a marked decrease in the size of lung metastases but pembrolizumab had no effect. Additionally, a greater anti-tumor effect was seen in humanized compared to non-humanized mice, demonstrating that immune cells play a role in the effects of the NPRL2 nanoparticle therapy. Study findings suggest that NPRL2 gene therapy induces anti-tumor activity against KRAS/STK11mt tumors through dendritic cell-mediated antigen presentation and cytotoxic immune cell activation. The Company believes this data could support the potential for a new drug candidate in its pipeline, and it also provides further evidence for the Company’s belief that the ONCOPREX Delivery System has the ability to be successful using genes other than the TUSC2 gene the Company is already using in clinical trials with REQORSA.

In the third poster, entitled, "Tumor Suppressor Gene TUSC2 suppresses energy metabolism in lung cancer cells with opposite effects in normal bronchial epithelial cells" researchers reported that TUSC2-deficient cancer cells consistently exhibited decreased glycolytic rates and mitochondrial ATP production, leaving these cells without enough energy to support their vital functions. By comparison, when Beas2B, a normal human bronchial epithelial cell line with normal levels of TUSC2, was transfected with a TUSC2 containing plasmid, the glycolytic rate and mitochondrial metabolism was increased. This suggests the mechanism by which REQORSA treatment affects immune and other non-cancerous cells that leads to increased immune response against tumors. The study further suggested that REQORSA may play an important role as a cancer treatment to target and disrupt the metabolism of cancer cells, leading to a decrease in the rate of glycolysis.

These AACR (Free AACR Whitepaper) posters have been made available on Genprex’s website at www.genprex.com.

Quaratusugene ozeplasmid mediated TUSC2 upregulation in EML4-ALK bearing Non-Small Cell Lung Carcinoma can induce cellular apoptosis Mechanism of NPRL2 gene therapy induced anti-tumor immunity in KRAS/STK11mt aPD1 resistant metastatic NSCLC Tumor Suppressor Gene TUSC2 suppresses energy metabolism in lung cancer cells with opposite effects in normal bronchial epithelial cells
About Reqorsa Therapy
REQORSA (quaratusugene ozeplasmid) for NSCLC and small cell lung cancer (SCLC) consists of the TUSC2 gene expressing plasmid encapsulated in non-viral nanoparticles made from lipid molecules (Genprex’s ONCOPREX Delivery System) with a positive electrical charge. REQORSA is injected intravenously and specifically targets cancer cells, which generally have a negative electrical charge. REQORSA is designed to deliver the functioning TUSC2 gene to cancer cells while minimizing their uptake by normal tissue. REQORSA has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer cells, re-establishes pathways for programmed cell death, or apoptosis, in cancer cells, and modulates the immune response against cancer cells.

Genprex’s strategy is to develop REQORSA in combination with currently approved therapies and believes that REQORSA’s unique attributes position it to provide treatments that improve on these current therapies for patients with NSCLC, SCLC, and possibly other cancers.

About The Oncoprex Delivery System

Genprex’s ONCOPREX Delivery System is a novel non-viral approach that utilizes lipid-based nanoparticles in a lipoplex form to deliver tumor suppressor genes deleted during the course of cancer development. The platform allows for the intravenous delivery of various tumor suppressor genes, and potentially other genes, to achieve a therapeutic affect without the risk of toxicity often associated with viral delivery systems. Genprex believes this system allows for delivery of a number of cancer-fighting genes, alone or in combination with other cancer therapies, to combat multiple types of cancer.

On April 9, 2024 Gennao Bio, a privately held genetic medicines company developing first-in-class, targeted nucleic acid therapeutics, reported new preclinical results on the application of its non-viral, cell penetrating gene monoclonal antibody (GMAB) platform technology as an antibody-drug conjugate (ADC) for the treatment of solid tumors (Press release, Gennao, APR 9, 2024, View Source [SID1234641933]). The data were presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024.

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Exploratory research evaluating GMAB’s ability to deliver conjugated cytotoxic payloads was conducted through Gennao’s ongoing collaboration with the laboratory of Peter M. Glazer, M.D., Ph.D., Chair of the Department of Therapeutic Radiology, Professor of Genetics and Robert E. Hunter Professor of Therapeutic Radiology at the Yale School of Medicine and co-founder of Gennao. In preclinical studies, our GMAB technology demonstrated selective delivery of payloads into tumors by targeting ENT2, a nucleoside transporter that is highly overexpressed in many tumors. ENT2 overexpression on both the plasma and nuclear membranes allows GMAB targeted therapies to internalize directly into the cytoplasm of tumor cells avoiding the endocytic pathway and traffic directly into the nucleus. In vitro studies of the GMAB ADC conjugated to exatecan, a potent topoisomerase I inhibitor, exhibited nuclear localization and activation of the DNA damage response pathway leading to tumor cell death.

"The safe targeted delivery of cytotoxic drugs continues to be a challenge for the development of new ADCs. Leveraging GMAB as an ADC represents a highly differentiated approach to the delivery of drugs exclusively to tumors while avoiding harmful impact to healthy tissue. In preclinical studies, chronic treatment of the GMAB ADC demonstrated significant tumor regression and was well tolerated, providing support for the continued investigation of this novel delivery platform as an ADC," said Dr. Glazer.

In a preclinical study utilizing the DLD1 BRCA2 gene knockout xenograft mouse model of colorectal cancer, two aggressive systemic dosing regimens of the GMAB ADC were compared to exatecan alone and control. The GMAB ADC demonstrated durable tumor regression and a significant survival benefit compared to control and exatecan alone. Safety analyses showed no change in body weight throughout treatment and no change in blood chemistry markers indicative of no kidney or liver toxicity. Further, since ENT2 is also expressed in skeletal muscle, serum chemistry and analysis of muscle tissue sections demonstrated no indication of tissue damage to muscle.

"These preclinical results reinforce the versatility of the GMAB platform and its ability to deliver therapeutic payloads beyond genetic medicine to targeted tissue," Chris Duke, chief executive officer of Gennao. "Additional in vivo studies are planned through our collaboration with Yale to further optimize the GMAB ADC approach. The ability to leverage a novel antigen target, combined with GMAB’s unique biology, offers the potential to create promising novel, first-in-class treatment options for individuals living with cancer."