CD14

Data provide support for planned expanded clinical development of best-in-class RGT-61159 in MYB-dependent hematologic cancers, including AML Potent anti-tumor activity observed, providing further evidence for the promising mechanism of RGT-61159 as the company advances the drug candidate in its ongoing Phase 1a/b clinical trial in patients with relapsed or refractory ACC or CRC WOBURN, Mass., Dec. 9, 2024 /PRNewswire/ -- Rgenta Therapeutics, a clinical-stage biotechnology company pioneering the development of a new class of oral small molecules targeting RNA for oncology and neurological disorders, announced today the presentation of preclinical data demonstrating anti-tumor activity of RGT-61159, a potent, selective oral small molecule inhibitor of MYB, a master oncogene in human malignancies. The data, which are being presented at the 66th American Society of Hematology Annual Meeting and Exposition being held December 7-10, 2024, in San Diego, CA, support the development of RGT-61159 as a potential treatment for acute myeloid leukemia (AML). "As demonstrated by the data being presented at ASH, RGT-61159 leads to the elimination of MYB RNA and protein in cancer cells and results in significant anti-tumor activity," said Simon Xi, Ph.D., co-founder and chief executive officer of Rgenta. "Importantly, RGT-61159 is active in a range of AML models harboring the most prevalent genetic alterations found in patients that often lead to resistance to current treatments. These data support our plans to extend our clinical development of RGT-61159 beyond our existing programs in solid tumors, adenoid cystic carcinoma (ACC) and colorectal cancer (CRC), and into hematologic malignancies such as AML." RGT-61159 is a potent, selective oral small molecule inhibitor of the MYB oncogene that functions by inducing the inclusion of a cryptic exon into MYB RNA transcripts, resulting in the activation of the nonsense mediated decay pathway and promoting MYB mRNA depletion and thus, MYB protein degradation. The data presented at ASH demonstrate that RGT-61159 potently eliminates MYB RNA and protein in a dose-dependent manner in AML cancer cell lines. As a single agent, RGT-61159 showed significant anti-tumor activity in several AML cell line-derived xenograft (CDX) models that harbor the most prevalent genetic alterations found in patients. In addition, RGT-61159 driven MYB inhibition led to a robust, dose-dependent increase in the differentiation markers CD11b and CD14 on the surface of THP-1 AML cells and the reduction of master oncogenes such as MYC and BCL2 across a broad panel of AML cell lines, providing a strong rationale for its development as a treatment for patients with AML. "Genomic analyses of different AML cell lines treated with RGT-61159 shed further light on key oncogenes including BCL2 and MYC that are significantly regulated by MYB inhibition and further demonstrate RGT-61159's anti-tumor activity of leukemic cells is driven by inhibition of MYB signaling," said Travis Wager, Ph.D., co-founder, president and chief scientific officer. "These data also confirm the role of MYB as a convergent dependency across AML tumors and highlight the potential of RGT-61159, a best-in-class MYB inhibitor, as a novel therapeutic approach to address this malignancy." About RGT-61159 RGT-61159 is an orally available small molecule designed to specifically modulate splicing of the transcription factor MYB resulting in the inhibition of the oncogenic MYB protein production, which has the potential to induce cell death of the cancer cells overexpressing MYB protein. MYB acts as a master regulator of cell proliferation, self-renewal, and differentiation processes and its aberrant expression has been demonstrated in multiple forms of human cancer including adenoid cystic carcinoma (ACC), acute myeloid leukemias (AML), T-cell acute lymphoblastic leukemias (T-ALL), colorectal cancer (CRC), small cell lung cancer (SCLC) and breast cancer. Rgenta is evaluating RGT-61159 in an ongoing multi-center, open-label Phase 1a/b clinical trial in patients with advanced relapsed or refractory ACC or CRC. The Phase 1a/b study is designed to evaluate safety, tolerability, pharmacokinetics and target engagement and clinical efficacy of RGT-61159 in patients with ACC or CRC. Additional information about the Phase 1a/b clinical trial can be accessed at ClinicalTrials.gov (NCT06462183). About Acute Myeloid Leukemia (AML) AML is a blood cancer that starts in the bone marrow, begins to make large numbers of abnormal cells, is characteristically fast growing, and moves quickly into the blood. AML is the most common type of acute leukemia in adults, and it accounts for about 10% of all new blood cancers each year. In the United States, there are about 20,000 new cases of AML per year. The average age of people diagnosed with AML is 68 years old, and while it is uncommon in people under 45, it can occur in adolescents and children. While complete remission can be achieved in up to 70% of patients with newly diagnosed AML, prognosis remains poor with only approximately 32% of patients that remain alive 5 years after diagnosis. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative strategy for most patients. Up to 40% of patients relapse after allogeneic HCT, and 5-year overall survival (OS) rates for these patients are low, approximately 30–40%. About Rgenta Therapeutics Rgenta Therapeutics is a clinical stage biotechnology company developing a pipeline of oral RNA-targeting small molecule medicines with an initial focus on oncology and neurological disorders. Our proprietary platform mines the massive genomics data to identify targetable RNA processing events and design small-molecule glues to modulate the interactions among the spliceosome, regulatory proteins, and RNAs. Our lead programs and unique approach are unlocking the therapeutic potential of historically undruggable targets in human diseases. Learn more at: . Contacts Investors: Sylvia Wheeler Wheelhouse Life Science Advisors [email protected] Elizabeth Wolffe, Ph.D. Wheelhouse Life Science Advisors [email protected] Media Aljanae Reynolds Wheelhouse Life Science Advisors [email protected] SOURCE Rgenta Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Strengthens Lyell’s clinical pipeline with the addition of IMPT-314, a dual-targeting CD19/CD20 CAR T-cell product candidate Data from ImmPACT’s multi-center Phase 1-2 clinical trial of IMPT-314 in patients with large B-cell lymphoma treated in the 3rd line CAR-naïve setting to be presented at a major medical conference later this year; initiation of a pivotal trial for IMPT-314 expected in 2025 Lyell has prioritized its pipeline to focus on next-generation CAR T-cell therapies, including IMPT-314 and LYL119, and is discontinuing development of LYL797, LYL845 and earlier-stage TIL programs Cash runway following the close of the transaction is expected to fund operations into 2027, through important clinical milestones for each pipeline program Lyell will host an investor webcast at 4:30 PM ET today Oct. 24, 2024 -- Lyell Immunopharma, Inc. (Nasdaq: LYEL) announced today that it has entered into a definitive agreement to acquire ImmPACT Bio USA Inc. (“ImmPACT”), a privately-owned clinical-stage biotechnology company. ImmPACT’s lead program, IMPT-314, is a CD19/20-targeting chimeric antigen receptor (CAR) T-cell product candidate that Lyell will continue to develop for hematologic malignancies, including large B-cell lymphoma. IMPT-314 was designed to outperform the efficacy of approved CD19 CAR T-cell therapies via a dual-targeting CAR T-cell design and to improve CAR T-cell persistence by enriching for naïve and central memory T cells during manufacturing. The acquisition of ImmPACT is expected to significantly strengthen Lyell’s clinical-stage pipeline of next- generation CAR T-cell therapies and complement its suite of proprietary technologies designed to generate longer-lasting, functional T cells to achieve more durable outcomes for patients with solid tumors and hematologic malignancies. “Lyell’s vision is to bring meaningful and durable clinical benefit to patients suffering from cancer with our next-generation cell therapies,” stated Lynn Seely, M.D., Lyell’s President and Chief Executive Officer. “The emerging data from ImmPACT’s ongoing Phase 1-2 trial and the Phase 1 clinical data from a published UCLA-sponsored trial suggest the potential of IMPT-314 to have improved complete response rates and duration of response compared to the approved CD19 CAR T-cell therapies in CAR-naïve patients with aggressive B-cell lymphoma. Since licensing this product candidate from UCLA, the team at ImmPACT has made impressive progress in the multi-center IMPT-314 Phase 1-2 clinical program. We look forward to presenting initial data from this program at a major medical conference later this year and initiating a pivotal trial for IMPT-314 in 2025.” “I am incredibly proud of the ImmPACT team and all of their accomplishments in developing next-generation CAR T-cell therapies,” stated Sumant Ramachandra, M.D., Ph.D., Chief Executive Officer of ImmPACT. “This transaction validates our novel science and enhances the potential for this therapy to make a meaningful impact on patients' lives. I am confident that in Lyell, we have found a team that shares our passion for advancing novel science to benefit patients.” ImmPACT licensed its dual-targeting CD19/CD20 CAR T-cell product candidate from the University of California, Los Angeles (UCLA). Phase 1 data in 13 patients with relapsed/refractory (R/R) aggressive non-Hodgkin lymphoma treated in a UCLA-sponsored clinical trial were presented at the 2024 AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy. CAR T-cell naïve patients with R/R diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma after at least two lines of therapy or mantle cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma after at least three lines of therapy were evaluated. Autologous T cells were obtained and enriched for CD14-/CD25-/CD62L+ naïve or memory T cells. Twelve out of 13 patients achieved a complete or partial response (92% objective response rate), with ten achieving a confirmed complete response (CR) (77% CR rate). The median progression-free survival was 50.1 months, and median overall survival was not reached with a median follow up of 32 months (range: 5.7 – not estimable). A favorable safety profile was observed. The ongoing Phase 1-2 clinical trial initiated by ImmPACT is a multi-center, open-label clinical trial designed to evaluate the tolerability and clinical benefit of IMPT-314 in patients with R/R aggressive B-cell lymphoma and determine a recommended Phase 2 dose. Initial Phase 1-2 clinical data evaluating IMPT-314 primarily in patients who have received at least two prior lines of therapy for large B-cell lymphoma will be presented at a major medical conference this year. IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of R/R aggressive B-cell lymphoma. Lyell expects to initiate a pivotal trial in 2025 for IMPT-314 in patients in the 3rd line setting who have not yet been exposed to CAR T-cell therapy. In connection with the acquisition, Lyell has prioritized its pipeline to focus resources on its most differentiated CAR T-cell clinical programs, including IMPT-314 following the close of the acquisition and LYL119. The enhanced anti-exhaustion technology incorporated into LYL119, including c-Jun overexpression, NR4A3 knockout, Epi-R and Stim R, has the potential to achieve improved efficacy at lower cell doses with an acceptable safety profile. In a validated in vivo preclinical model of non-small cell lung cancer, LYL119 achieved tumor control at a 10-fold lower cell dose than LYL797 with more gradual cell expansion to peak, and a substantial increase in the duration of cell killing demonstrated by a repetitive tumor cell killing assay in vitro. Lyell is discontinuing development of LYL797, its ROR1-targeted CAR T-cell product candidate to focus on the Phase 1 clinical trial of its next-generation ROR1-targeted CAR T-cell product candidate LYL119, which is expected to initiate enrollment of patients with platinum-resistant ovarian cancer or relapsed/refractory endometrial cancer this year or early next year. The LYL845 tumor-infiltrating lymphocyte (TIL) program is also being discontinued as the clinical data in patients with advanced melanoma did not meet our rigorous pre-determined criteria for continued development. Its next-generation TIL and rejuvenation programs that are in preclinical development will also be discontinued. Following the close of the transaction, Lyell expects its cash balance will fund operations into 2027, through important clinical milestones for each pipeline program, including initiation of a pivotal trial for IMPT-314, which is expected to start in 2025. Upon closing, Lyell will acquire worldwide rights to ImmPACT’s pipeline, including the next- generation bispecific CD19/CD20 autologous CAR T-cell therapy, currently in clinical development for B-cell lymphoma and autoimmune diseases, and an activating TGF-beta Claudin 18.2 CAR T-cell candidate, which is in preclinical development. Lyell will prioritize the development of IMPT-314 for patients with B-cell lymphoma. Deal terms include upfront consideration payable upon closing the potential transaction of $30 million in cash, subject to certain adjustments, and 37.5 million shares of Lyell common stock. ImmPACT shareholders will also be eligible to receive contingent consideration consisting of 12.5 million shares of Lyell common stock that may be earned upon the achievement of a value-enhancing clinical milestone and a low single-digit royalty on future net sales of the dual-targeting CD19/20 CAR T-cell product in the United States. The proposed transaction, which has been unanimously approved by the Boards of Directors of both companies, is expected to close in the fourth quarter of 2024. The closing of the proposed transaction is subject to expiration of the Hart-Scott-Rodino antitrust waiting period and the satisfaction of other customary closing conditions. Goldman Sachs & Co LLC is acting as sole financial advisor to Lyell in this transaction and Skadden, Arps, Slate, Meagher & Flom LLP is acting as its legal advisor. Cooley LLP is acting as ImmPACT’s legal advisor. Lyell’s management will host an investor conference call and Webcast beginning at 4:30 pm ET today. The Webcast can be accessed here. A replay of the event and presentation materials will be archived on the Investor page of the Lyell Website following the end of the event. Lyell is a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with solid tumors or hematologic malignancies. Lyell’s product candidates are enhanced with novel technology designed to generate T cells that resist exhaustion and have qualities of durable stemness in order to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical response. Lyell is based in South San Francisco, California with facilities in Seattle and Bothell, Washington. To learn more, please visit www.lyell.com. The content above comes from the network. if any infringement, please contact us to modify.

In December 2023, the Genentech team published a research paper entitled "Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8" in the journal Nature Communications, which reported the structural mechanisms by which the CCR8 receptor is activated by the natural chemokine CCL1 and inhibited by antagonistic antibodies. The C-C chemokine receptor 8 (CCR8) is a Class A G protein-coupled receptor that is highly enriched and selectively expressed in the regulatory T cells (Treg cells) within tumors. These Treg cells play a role in suppressing anti-tumor effector T cell responses. Numerous studies indicate that patients with higher levels of Treg cells in their bodies have poorer clinical outcomes and prognoses in a variety of cancers. Therefore, it is speculated that by selectively depleting Treg cells within tumors, it might be possible to reactivate anti-tumor immune responses and enhance the efficacy of cancer immunotherapies. Researchers have developed an antagonistic monoclonal antibody, mAb1, that specifically binds to the extracellular region of human CCR8. Initially, New Zealand White rabbits were immunized with recombinant human CCR8, rabbi cell lines expressing human CCR8, exosomes containing CCR8, and sulfated and non-sulfated peptides from the N-terminal region of human CCR8. Single B cells were isolated using the method previously published by the Genentech team in the journal PLoS One in 2020. Subsequently, the B cell culture supernatant was subjected to fluorescence-activated cell sorting (FACS) to isolate IgG-positive B cells, which were distributed into individual wells. These cells were then combined with CHO cells expressing human and monkey CCR8, as well as control CHO cells, for detection and identification. Ultimately, from over 480 types of anti-CCR8 antibodies capable of binding to CHO cells expressing human or monkey CCR8, antibodies were selected based on their relative mean fluorescence intensity (MFI) on the human and monkey CCR8-expressing CHO cell lines and their sequence diversity. The selected antibodies showed less than a five-fold difference in relative MFI between human and monkey CCR8 on CHO cells, identifying five unique antibody clusters (labeled Ab1-Ab5). Researchers then constructed humanized versions of these monoclonal antibodies, designated Abx.H1L1, and expressed and purified antibodies and Fabs in the Expi293 expression system. To assess the binding capability of these monoclonal antibodies to Treg cells, researchers evaluated their ability to bind to Treg cell subsets in human peripheral blood mononuclear cells (PBMCs) or dissociated tumor cells (DTCs). The experiments utilized a variety of labeled antibodies including CD45, CD3, CD8, CD4, and CD14, as well as FOXP3, to define the Treg cell population (CD45+CD14-CD3+CD8-CD4+FOXP3+). In addition, OX40 was used as a positive control, with Herceptin and anti-hIgG serving as negative controls. An example with PBMCs is shown in the figure below: The results showed that three out of five CCR8 mAb clones could specifically stain Treg cells without staining conventional CD4 or CD8 T cells. The CCR8 relative mean fluorescence intensity was ranked as follows: hu.Ab4.H1L1 > hu.Ab5.H1L1 > hu.Ab3.H1L1. Subsequently, researchers conducted further studies on the antibody-dependent cellular cytotoxicity (ADCC) of hu.Ab3.H1L1, hu.Ab4.H1L1, and hu.Ab5.H1L1, using hIgG1 as a negative control. Afterward, researchers evaluated the activity of hu.Ab3.H1L1, hu.Ab4.H1L1, and hu.Ab5.H1L1 in activating or antagonizing CCR8 (using CCL1 as an agonist), with hIgG1 serving as the negative control. Downstream Ca2+ signaling changes were assessed using the FLIPR method. The results indicated that none of the three antibodies were capable of activating the downstream Ca2+ signal of CCR8, but only hu.Ab4.H1L1 was able to block the action of CCL1 on the receptor. In the meantime, the author also conducted a parallel comparison of three reported antibodies against CCR8, including Yoshida (a humanized anti-human CCR8 antibody), 433H (a mouse anti-human CCR8 mAb from BD Biosciences), and L263G8 (a mouse anti-human CCR8 mAb from BioLegend). All three control antibodies were capable of antagonizing the effects of CCL1. To confirm the selectivity of multiple antibodies for CCR8, the researchers used flow cytometry to identify the specific binding of hu.Ab3.HILI, hu.Ab4.HILI, and hu.Ab5.HILI, as well as Yoshida, L263G8, and 433H, to various chemokine receptors. The results showed that only the antibodies hu.Ab4.HILI and hu.Ab5.HILI stained cells expressing human CCR8, confirming their specificity for human CCR8. In contrast, the antibody hu.Ab3.HILI exhibited staining for several other GPCRs, indicating a lack of specificity. The antibody-related data mentioned above are derived from the Genentech company's patent US20230049152A1. Researchers utilized chimeras of CCR8 and CCR5 to study the epitope characteristics for antibody recognition of various extracellular regions of the receptors, including N-term, ECL1, ECL2, and ECL3. The results indicate that ECL1 and ECL2 are involved in the formation of the interactive epitopes between the antibody and the receptor. In subsequent studies, researchers employed cryo-electron microscopy to resolve the structures of the antibody mAb1 in complex with the inactive state of CCR8, as well as the structure of the active state complex of CCL1 with CCR8 and the downstream Gi subtype protein. Cryo-EM structural analysis confirms that the primary interaction regions between the antibody fragment Fab1 and the receptor are ECL1 and ECL2. Here, Fab1 forms an extensive interaction interface with CCR8's ECL1 and ECL2, primarily driven by electrostatic interactions, which is predominantly mediated by its CDRH3, with contributions from CDRH1, CDRH2, CDRL1, and CDRL3. References:  1.Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8 2.https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-43601-8