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- || ONX 0914 / Protalex, Amgen, M-3258 / EMD Serono
Review, Journal: The role of the immunoproteasome in cardiovascular disease. (Pubmed Central) - May 15, 2024
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.
- M-3258 / EMD Serono
Immunoproteasome inhibitors for the treatment of t(4;11)-driven ALL (Section 15; Poster Board #15) - Mar 14, 2023 - Abstract #AACR2023AACR_7338;
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.
- || M-3258 / EMD Serono
PK/PD data, Journal: 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 Central) - Oct 25, 2022
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.
- || M-3258 / EMD Serono
Clinical, Journal: M3258 is a selective inhibitor of the immunoproteasome subunit LMP7 (β5i) delivering efficacy in multiple myeloma models. (Pubmed Central) - Feb 19, 2022
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).
- || M-3258 / EMD Serono
Clinical, Journal: Improved nonclinical safety profile of a novel, highly selective inhibitor of the immunoproteasome subunit LMP7 (M3258). (Pubmed Central) - Jan 4, 2022
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.
- | ONX 0914 / Protalex
Journal: Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein. (Pubmed Central) - Nov 5, 2021
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.
- M-3258 / EMD Serono
LMP7-specific inhibitor M3258 modulates the tumor microenvironment of aggressive breast cancer (Hall 1) - Oct 26, 2021 - Abstract #SABCS2021SABCS_1313;
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.
- | M-3258 / EMD Serono
Journal: Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i). (Pubmed Central) - Oct 8, 2021
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.
- M-3258 / EMD Serono
Enrollment change, Trial termination, Combination therapy: MS201814_0010: First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone (clinicaltrials.gov) - May 12, 2021
P1, N=10, Terminated, Sponsor: EMD Serono Research & Development Institute, Inc.
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. N=48 --> 10 | Recruiting --> Terminated; The study was early discontinued due to lack of participant enrollment.
- ||| M-3258 / EMD Serono
Enrollment open, Combination therapy: MS201814_0010: First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone (clinicaltrials.gov) - Jan 29, 2020
P1, N=60, Recruiting, Sponsor: EMD Serono Research & Development Institute, Inc.
N=48 --> 10 | Recruiting --> Terminated; The study was early discontinued due to lack of participant enrollment. Not yet recruiting --> Recruiting
- Pharmacological Perturbation of the Immunoproteasome in Hematologic Neoplasias: Therapeutic Implications (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2111;
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.
- | M-3258 / EMD Serono
New P1 trial, Combination therapy: MS201814_0010: First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone (clinicaltrials.gov) - Sep 3, 2019
P1, N=60, Not yet recruiting, Sponsor: EMD Serono Research & Development Institute, Inc.