M-3258 / EMD Serono - LARVOL DELTA

Targeting immunoproteasome-dependent β-catenin degradation as a therapeutic strategy in Relapsed/Refractory acute lymphoblastic leukemia (ASH 2025) - "Interestingly, treatment with M3258 (a selective PSMB8 inhibitor) did not interfere with β-cateninprotein degradation, suggesting that combined inhibition of both PSMB8 and PSMB9 is required forefficient inhibition...Likewise, genetic deletion of LEF1 rescued cellviability and caused resistance to Zetomipzomib and ONX-0914, highlighting the importance ofrepressive LEF1/β-catenin complexes in B- and T-ALL cells to suppress MYC. Our findings uncovered a previously unrecognized dependency of B- and T-ALL cells onimmunoproteasome-mediated β-catenin degradation to sustain MYC expression and survival... Our findings uncovered a previously unrecognized dependency of B- and T-ALL cells onimmunoproteasome-mediated β-catenin degradation to sustain MYC expression and survival. Targetingthe immunoproteasome, rather than the generic proteasome, offers a more selective strategy forlymphoid malignancies, with the potential for reduced off-target toxicity compared to..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Solid Tumor • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • CTNNB1 • MYC • PSMB10 • PSMB5 • PSMB8 • PSMB9 • TCF7

LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory Breast Cancer. (PubMed, Cancers (Basel)) - "Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC."

Biomarker • Journal • Breast Cancer • Hematological Malignancies • Immunology • Inflammatory Breast Cancer • Multiple Myeloma • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • PSMB8

Highly specific Immunoproteasome inhibitor M3258 induces proteotoxic stress and apoptosis in KMT2A::AFF1 driven acute lymphoblastic leukemia. (PubMed, Sci Rep) - "Proteasome inhibitors (PIs) bortezomib, carfilzomib and ixazomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have clinical activity in acute lymphoblastic leukemia (ALL). Treatment of KMT2A::AFF1 ALL cells with M3258, ONX-0914, and bortezomib induced proteotoxic stress that was prevented by the protein synthesis inhibitor cycloheximide, which dramatically desensitized cells to PI-induced apoptosis. Thus, similar to multiple myeloma, ALL cells are sensitive to PIs and IPIs due to increased proteotoxic stress caused by elevated rates of protein synthesis."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Targeted Protein Degradation • AFF1 • KMT2A

The role of the immunoproteasome in cardiovascular disease. (PubMed, Pharmacol Res) - "Furthermore, the immunoproteasome also serves nonimmune functions, such as maintaining protein homeostasis and regulating signalling pathways, and is involved in the pathophysiological processes of various cardiovascular diseases (CVDs). This review aims to provide a comprehensive summary of the current research on the involvement of the immunoproteasome in cardiovascular diseases, with the ultimate goal of identifying novel strategies for the treatment of these conditions."

Journal • Review • Cardiovascular • Targeted Protein Degradation

Immunoproteasome inhibitors for the treatment of t(4;11)-driven ALL (AACR 2023) - "Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • T Acute Lymphoblastic Leukemia

Translational PK/PD modeling of tumor growth inhibition and target inhibition to support dose range selection of the LMP7 inhibitor M3258 in relapsed/refractory multiple myeloma. (PubMed, J Pharmacol Exp Ther) - P1 | "The human PK and human efficacious dose range of M3258 were predicted using in vitro - in vivo extrapolation and allometric scaling methods together with a fit-for-purpose PK/PD and efficacy model based on data from several species. A comparison with data from the Phase Ia clinical study showed that the human PK was accurately predicted, whilst the extent and duration of PD response were more pronounced than estimated."

Journal • PK/PD data • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • PSMB8

LMP7-specific inhibitor M3258 modulates the tumor microenvironment of aggressive breast cancer (SABCS 2021) - "Using the exquisitely selective LMP7 inhibitor M3258, we were able to demonstrate for the first time that LMP7 plays an important role in the inflammatory microenvironment, proliferation and invasiveness of TNBC and IBC cells, in particular by modulating the pathogenic role of M2 macrophages. These data warrant future in vivo studies into the antitumor efficacy of M3258 when used with immunotherapy agents."

Biomarker • IO biomarker • Tumor microenvironment • Breast Cancer • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD4 • CD8 • IFNA1 • IFNG • PSMB8 • TNFA

Improved nonclinical safety profile of a novel, highly selective inhibitor of the immunoproteasome subunit LMP7 (M3258). (PubMed, Toxicol Appl Pharmacol) - "Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients."

Clinical • Journal • Cardiovascular • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i). (PubMed, J Med Chem) - "The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

M3258 is a selective inhibitor of the immunoproteasome subunit LMP7 (β5i) delivering efficacy in multiple myeloma models. (PubMed, Mol Cancer Ther) - P1 | "Furthermore, M3258 showed superior antitumor efficacy in selected MM and mantle cell lymphoma xenograft models compared to the approved non-selective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in MM patients (NCT04075721)."

Clinical • Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Oncology • Targeted Protein Degradation

Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein. (PubMed, Sci Rep) - "Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Oncology • Pediatrics

First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone (clinicaltrials.gov) - P1; N=10; Terminated; Sponsor: EMD Serono Research & Development Institute, Inc.; N=48 ➔ 10; Recruiting ➔ Terminated; The study was discontinued given the changed therapeutic landscape, lack of recruitment and totality of the data collected so far.

Clinical • Combination therapy • Enrollment change • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

First in Human Dose Escalation and Expansion Study With M3258 in Combination With Dexamethasone (clinicaltrials.gov) - P1; N=60; Recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open

Pharmacological Perturbation of the Immunoproteasome in Hematologic Neoplasias: Therapeutic Implications (ASH 2019) - "Established proteasome inhibitors used in clinical practice (e.g. bortezomib, carfilzomib, ixazomib) target both the canonical 20S proteasome and the immunoproteasome. These results highlight that in vivo administration of M3258 exhibits anti-tumor activity against clinically-relevant models of MM lesions, even from cell lines that have modest in vitro responsiveness to this immunoproteasome inhibitor. Furthermore, our studies with a large panel of “DNA-barcoded” cell lines indicates that the anti-tumor effects of M3258 may extend beyond MM and into other classes of hematologic malignancies, including subsets of leukemias and lymphomas, identifying previously underappreciated therapeutic implications for the class of selective immunoproteasome inhibitors."

First in Human Dose Escalation and Expansion Study With M3258 in Combination With Dexamethasone (clinicaltrials.gov) - P1; N=60; Not yet recruiting; Sponsor: EMD Serono Research & Development Institute, Inc.

Clinical • Combination therapy • New P1 trial