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Sanyou Bio Congratulates KangaBio on their IND Approval for Next-Generation IL-12 Prodrug Cancer Immunotherapy

On November 4, 2023 KangaBio reported that the U.S. FDA has granted official approval for their independent R&D clinical trial application (IND) for KGX101 (Press release, KangaBio, NOV 4, 2023, View Source [SID1234636978]). KGX101 is a recombinant IL-12 Fc fusion protein designed for intravenous injection. The KGX101 clinical trials will be carried out simultaneously in both United States and Australia. These trials will primarily focus on late-stage solid tumors and the effectiveness will either be evaluated as a standalone therapy or in combination with anti-PD-L1 antibodies. Several research centers in Australia have already commenced patient screening for participation in these clinical trials.

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Sanyou Bio congratulates our partner, KangaBio on reaching this significant milestone. This achievement strengthens our 2022 strategic partnership, which is dedicated to advancing the development and innovation of antibody-based drugs. Sanyou Bio is pleased to have played a role in KangaBio’s preclinical efficacy evaluations for KGX101, revealing promising in vivo anti-tumor efficacy and safety outcomes. We are looking forward to gaining more insights into its performance during the clinical stage.

KGX101 is a prodrug of Interleukin-12 (IL-12) created using KangaBio’s proprotein technology platform. KGX101 has a prolonged half-life due to the use of the antibody Fc region. KGX101 becomes active specifically in tumors by fusing the protease-cleavable linker that targets tumors. This minimizes systemic cytokine toxicity when the linker is cleaved by tumor-specific matrix metalloproteinases in the tumor microenvironment, KGX101, similar to IL-12, activates immune cells within the tumor, reshaping the tumor microenvironment for therapeutic benefits.

Candel Therapeutics Presents Preclinical Data from its enLIGHTEN™ Discovery Platform at SITC

On November 4, 2023 Candel Therapeutics, Inc. (the Company or Candel) (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing viral immunotherapies to help patients fight cancer, reported that it will present two posters during the 2023 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in San Diego focused on the enLIGHTEN Discovery Platform (Press release, Candel Therapeutics, NOV 4, 2023, View Source [SID1234636975]).

"We aim to leverage artificial intelligence and machine learning to expedite various aspects of drug discovery and development," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel. "Combined with our strong focus on human biology for drug discovery and our deep experience with herpes simplex virus as therapeutic vectors, Candel is poised to expand its portfolio of promising viral immunotherapy candidates and create value through discovery partnerships."

The first poster titled ‘Development of enLIGHTEN Alpha-201 herpes simplex viral vectors encoding payloads targeting the tumor microenvironment’ reports preclinical characterization of the enLIGHTEN viral chassis Alpha-201. Profiling of biological responses to Alpha-201 unveiled its potential to orchestrate changes in the tumor microenvironment, supportive of effective anti-tumor immune responses to immune checkpoint inhibitor (ICI) treatment. In preclinical models, Alpha-201 displayed enhanced peripheral blood mononuclear cell-mediated cancer cell killing and immune activation when armed with certain immunostimulatory payload combinations which was predicted in silico using the enLIGHTEN Advanced Analytics suite. These data validate Candel’s novel approach for in silico prediction of payload combinations and selection of indication-specific payloads with anti-tumoral activity using human datasets as a tool to accelerate, improve and de-risk certain aspects of the development of transformative viral immunotherapies.

"Tumor resistance to immunotherapy is driven by multiple mechanisms, which are heterogeneous in nature," said Francesca Barone, MD, PhD, Chief Scientific Officer at Candel. "By interrogating human datasets and generating predictions on tumor-specific mechanisms of progression, enLIGHTEN provides a unique opportunity to predict optimal gene payload combinations to arm viral vectors, enabling the design of multimodal therapeutics with greater potential to overcome tumor resistance."

The second poster titled ‘A novel viral immunotherapeutic targeting the CD47/SIRPα axis demonstrates potent anti-tumor effects’ describes the design of the first experimental agent based on the enLIGHTEN Discovery Platform, Alpha-201-macro1. This investigational agent is comprised of an immunostimulatory and oncolytic engineered viral chassis armed with a novel gene payload that is designed to interfere with the CD47/SIRPα pathway.

"Therapies targeting the CD47/SIRPα pathway have shown promising clinical results in solid and hematological malignancies; however, efficacy is often hindered by systemic toxicity," said Anne Diers, PhD, Senior Director of Research at Candel Therapeutics. "The Alpha-201-macro1 preclinical data presented today support the utility of local delivery of an immunologically active, multimodal agent as a potential alternative to systemic therapy. We are excited to leverage the enLIGHTEN Discovery Platform to optimize the immunostimulatory payload of this agent for activation of innate immune surveillance with the goal of maximizing its therapeutic potential."

Further details from the posters are available on the Candel website at: www.candeltx.com/media

About the enLIGHTEN Discovery Platform

Candel’s enLIGHTEN Discovery Platform is a systematic, iterative HSV-based discovery platform leveraging human biology and advanced analytics to create new viral immunotherapies for solid tumors. In October 2022, the Company announced a discovery collaboration with the University of Pennsylvania Center for Cellular Immunotherapies to identify how viral immunotherapy could enhance the efficacy of CAR-T cell therapy in solid tumors. The enLIGHTEN Discovery Platform is designed to deconvolute the complexity of the tumor microenvironment to identify druggable properties that correlate with clinical outcomes. These discoveries are translated into optimized multi-gene payloads of tumor modulators that are tailored for specific indications, disease stage, and rationally designed therapeutic combinations.

Medigene presents new data for MDG2011 demonstrating capability to generate TCR-T therapies against mKRAS

On November 4, 2023 Medigene AG (Medigene, the "Company", FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported novel preclinical data of their MDG2011 program lead candidates which are optimal affinity Kirsten rat sarcoma viral oncogene homologue mutation (mKRAS)-specific T cell receptors (TCRs) targeting human leukocyte antigens (HLA) A*11, in combination with a PD1-41BB costimulatory switch protein (CSP) at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2023 November 1-5, 2023, in San Diego, USA (Press release, MediGene, NOV 4, 2023, View Source [SID1234636974]).

The poster with the title "A novel library of optimal affinity KRAS mutation-specific T cell receptors associated with multiple HLAs, in combination with a PD1-41BB armoring and enhancement costimulatory switch receptor" is available on Medigene’s website: View Source

"The unique approach of our End-to-End (E2E) Platform has enabled us to generate three strong lead candidates for our MDG2011 program, of which we have prioritized one, targeting mKRAS G12V-HLA-A*11, confirming our ability to identify optimal affinity TCRs not only for cancer-testis antigens but also for neoantigens, both validated targets for the treatment of solid tumor patients. Our preclinical work revealed fifteen potential TCR candidates specific to mKRAS G12V, from which these three unique TCRs fulfilled and exceeded our criteria of excellent specificity, high sensitivity and safety" said Dr. Selwyn Ho, Chief Executive Officer at Medigene. "Further armoring and enhancing these TCR-T cells with technologies like the PD1-41BB CSP showed that this has clear potential to overcome the immunosuppressive solid tumor microenvironment, leading to improved and sustained outcomes of TCR-T therapies in difficult-to-treat solid tumors."

Neoantigens (also known as oncogenic driver mutations) are related to mutations that alone are sufficient to initiate and maintain cancer, with the KRAS gene being one of the most frequently altered mutations in solid cancers. To date, 21 so-called missense mutations (in which single amino acids are exchanged) have been identified in the KRAS gene, with G12D, G12V and G12C being the most common. Given the high prevalence of various mutations within the KRAS gene and the limitations of current therapeutic approaches, there is an unmet need to further improve targeted therapies.

The presented data demonstrate, utilizing a high-throughput approach, the generation of optimal affinity TCRs targeting the mKRAS G12V neoantigen presented by multiple HLA-A*11 subtypes through use of the Company’s unique E2E Platform and shows further in vitro characterization with regards to specificity, sensitivity, and safety (3S), of the multiple TCR candidates in combination with the PD1-41BB-CSP.

Robust co-expression of the recombinant TCRs (rTCRs) and the PD1-41BB CSP was demonstrated for the three TCR candidates. The TCRs showed excellent specificity for the mKRAS G12V target, verified by release of interferon-gamma (IFNγ) only detected after stimulation with mKRAS G12V targets but not after stimulation with naturally occurring wild-type KRAS. Each of the three TCR candidates exhibited a unique peptide-specific recognition pattern of G12V peptide presented by different HLA-A*11 subtypes, underpinning the fine specificity of the selected TCR candidates.

All three TCR candidates displayed high sensitivity, responding to very low levels of the mKRAS-G12V peptide presented by antigen-presenting cells pulsed with varying amounts of the mKRAS G12V peptide.

Furthermore, elevated IFNγ release was seen after stimulation of TCR-expressing T cells with tumor cell lines expressing only low levels of mKRAS antigen and cancer cell survival was limited in mKRAS G12V-positive tumor cell lines of different origin following exposure to the T cells co-expressing any of the three rTCR mKRAS G12V-HLA-A*11 with PD1-41BB CSP. These effects were limited to mKRAS G12V-expressing cells, as cancer cells harboring wild-type KRAS were not affected. In addition, increased and sustained killing ability of 3D tumor spheroids was detected with the selected TCR candidates, demonstrating the potent cytotoxic activity directed towards cancer cells with mKRAS G12V.

Finally, the three TCR candidates each showed a favorable safety profile. None of the TCRs recognized HLA allotypes other than HLA-A11 in a panel of cell lines expressing globally common HLA allotypes. Most importantly, healthy cells representing major tissues or organs did not trigger IFNγ release upon exposure to the TCR candidates, approving that cytotoxicity is restricted to cancer cells with no signs of toxicity to healthy tissue.

Sairopa Presents Early Clinical Data on ADU-1604 Compound at SITC 38th Annual Meeting

On November 4, 2023 sairopa.com – a clinical-stage company that develops novel treatments for cancer by modulating the patient’s immune system, reported early clinical data on ADU-1604, its proprietary anti-CTLA4 antibody at the SITC (Free SITC Whitepaper) 38th Annual Meeting (Press release, Sairopa, NOV 4, 2023, View Source [SID1234636973]). Data obtained from the ongoing Phase 1 dose-escalation stage in PD1 relapse/refractory melanoma patients (N=17) were presented. ADU-1604 is well tolerated at the dosages tested (25, 75, 225 and 450 mg Q3W). No dose-limiting toxicities or treatment-related severe adverse events have been reported up to now. Pre-clinical data was presented that potentially explains the suggested improved safety profile of ADU-1604 vs. other anti-CTLA4 antibodies. ADU-1604 was shown to dose-dependently increase pharmacodynamic biomarkers, which correlates with early signs of clinical activity. Finally, early clinical efficacy data was reported showing one unusually long stable disease and two ongoing tumor regressions.

Promontory Therapeutics Presents Data on Molecular Mechanisms of PT-112’s Immunogenic Effects

On November 4, 2023 Promontory Therapeutics Inc., a Phase 2 stage biotech company advancing immunogenic small molecule approaches in oncology, reported data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells (Press release, Promontory Therapeutics, NOV 4, 2023, View Source [SID1234636971]). Data suggest that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism. The presentation was made at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting, taking place November 1-5, 2023 in San Diego.

The work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York, in order to elucidate the sequence of events – beginning with inhibition of ribosomal biogenesis and culminating in selective ICD – underlying PT-112’s immune effects. Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to determine the impact of PT-112 on ER and mitochondrial stress, as well as immunogenic signaling.

"Our continued studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling."

Study findings include:

PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD.

PT-112 effects on mitochondria included increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1.

PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR).

There is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses.

PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors, and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD.

For more information about Promontory Therapeutics and PT-112, visit www.PromontoryTx.com.

About PT-112
PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112’s mechanism of action governs intracellular events that cause the release of damage associated molecular patterns, known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response. PT-112’s potential best-in-class ICD effects may create the conditions for effective and durable responses to treatment. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The company’s Phase 2 study of PT-112 in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. An active Phase 2 trial is also on-going with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors, a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation. An additional Phase 2a study has been successfully completed for non-small cell lung cancer in combination with PD-L1 inhibition.