Delving into the Latest Updates on SAR-442257 with Synapse

Overview

Basic Info

Drug Type

Trispecific T-cell engager (TriTE)

Synonyms

Target

Mechanism

CD28 agonists(T-cell-specific surface glycoprotein CD28 agonists), CD3 modulators(T cell surface glycoprotein CD3 modulators), CD38 modulators(Lymphocyte differentiation antigen CD38 modulators)

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [2]

Active Indication-

Inactive Indication

Non-Hodgkin's lymphoma refractoryRelapse multiple myeloma

Originator Organization

Sanofi

Active Organization-

Inactive Organization

Sanofi

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Primary Objective:
To determine the maximum tolerated dose (MTD) of SAR442257 administered as a single agent in patients with relapsed and refractory multiple myeloma (RRMM) and relapsed and refractory non-Hodgkin lymphoma (RR-NHL), and determine the recommended Phase 2 dose (RP2D)
Secondary Objectives:
* To characterize the safety profile of SAR442257
* To characterize the pharmacokinetics (PK) profile of SAR442257
* To assess preliminary evidence of antitumor activity

Start Date24 Jul 2020

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with SAR-442257

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100 Translational Medicine associated with SAR-442257

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100 Patents (Medical) associated with SAR-442257

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3

Literatures (Medical) associated with SAR-442257

22 Sep 2024·British journal of haematology

A CD38/CD3xCD28 trispecific T-cell engager as a potentially active agent in multiple myeloma patients relapsed and/or refractory to anti-CD38 monoclonal antibodies.

Article

Author: Zabaleta, Aintzane ; Blanco, Laura ; San-Miguel, Jesús ; Wang, Hongfang ; Van de Velde, Helgi ; Rodriguez-Otero, Paula ; Bisht, Kamlesh ; Paiva, Bruno ; Kim, Peter S ; Tamariz-Amador, Luis-Esteban ; Lasa, Marta ; Martín-Sánchez, Esperanza

There is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257.

12 Mar 2024·Cancer Research Communications

Ex Vivo Efficacy of SAR442257 Anti-CD38 Trispecific T-cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA-targeted Therapies

Article

Author: Reiman, Lauren T. ; Sherbenou, Daniel W. ; Forsberg, Peter A. ; Keller, Alana L. ; Kim, Peter S. ; Wang, Hongfang ; Parzych, Sarah E. ; Bisht, Kamlesh ; Perez de Acha, Olivia ; van de Velde, Helgi

AbstractT cell–engaging antibodies (TCEs) are showing promising efficacy in relapsed/refractory multiple myeloma, even in patients that relapsed after B-cell maturation antigen (BCMA)-targeted therapy. Patients with multiple myeloma may have compromised T-cell health unaccounted for by preclinical models. Here, we use Myeloma Drug Sensitivity Testing (My-DST) for ex vivo measurement of anti-multiple myeloma cytotoxicity for the trispecific CD38/CD28xCD3 TCE SAR442257 through activation of the patients’ own endogenous T cells to inform clinical development of the compound in multiple myeloma. My-DST incubates primary mononuclear cells in humanized media for 48 hours followed by flow cytometry for multiple myeloma cell viability with or without drug treatment. SAR442257 was tested on 34 samples from patients with multiple myeloma across disease settings. Potential biomarkers, T-cell dependence, and degranulation were assessed. SAR442257 was effective at low dose in My-DST cultures. High ex vivo response rates were observed in primary aspirates taken from patients with multiple myeloma at diagnosis, with modestly reduced response in multiple myeloma recently treated with anti-CD38 mAbs. SAR442257 was highly effective in patients relapsing after BCMA therapy. The CD38/CD28xCD3 trispecific format was substantially more effective than a conventional bispecific CD38/CD3 antibody format and CD38 mAbs. Anti-multiple myeloma cell cytotoxicity was dependent on the presence of endogenous T cells. Surface CD38 expression was the strongest biomarker of TCE response. My-DST is capable of measuring T cell–dependent killing using the multiple myeloma patient's own bone marrow–derived T cells. SAR442257 shows promise for multiple myeloma and may be best suited for patients declared resistant to both CD38 mAbs and BCMA-targeted therapy.Significance:This study introduces the use of My-DST to measure and characterize sensitivity to anti-CD38 T-cell engager SAR442257 in primary samples using matched endogenous T cells. Preclinical testing in samples from patients with diverse treatment history supports further testing in post-chimeric antigen receptor T-cell multiple myeloma.

Cells

Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma

Article

Author: Van de Velde, Helgi ; Grab, Anna Luise ; John, Lukas ; Shome, Debarati ; Raab, Marc S. ; Gryzik, Stefanie ; Manta, Calin ; Wang, Hongfang ; Reijmers, Rogier M. ; Sarkar, Irene ; Kim, Peter S. ; Reichert, Philipp ; Bisht, Kamlesh ; Baumann, Anja ; Weinhold, Niels

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson’s r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-β (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-β inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.

1

News (Medical) associated with SAR-442257

07 Nov 2024

·firstwordpharma.com

Aditum Bio taps Chinese biotech for tri-specific autoimmune asset

Biotech investment firm Aditum Bio and China-based Leads Biolabs on Thursday announced the formation of a new company dedicated to advancing a first-in-class tri-specific T-cell engager antibody for autoimmune disorders.Oblenio Bio has secured an exclusive option to license LBL-051, a CD19xBCMAxCD3 engager designed to deplete a broader range of pathological B-cell populations across a wide spectrum of antibody-mediated autoimmune diseases, according to Leads.Immune resetEx-Novartis CEO Joe Jimenez, who co-founded and is managing director at Aditum, said that "by targeting both CD19 and BCMA in autoimmune disorders, LBL-051 has the potential to achieve a complete immune reset and superior efficacy and durability, compared to single targeting of either CD19 or BCMA alone."The tri-specific modality has emerged as a promising approach, with the companies pointing to recent clinical data from CD19 and BCMA targeted therapies showing "compelling efficacy" in hard-to-treat autoimmune diseasesDespite initial enthusiasm, bispecific T-cell engagers do not always reach sufficient efficiency since they target only one receptor on the surface of T cells. However, treatments targeting two T-cell receptors via tri-, or even tetraspecific, T-cell engagers could provide the needed costimulatory boost for T cells to work effectively.Companies such as Sanofi and Harpoon Therapeutics, which was bought earlier this year by Merck & Co. for roughly $680 million, are also working on tri-specific engagers. Harpoon's HPN217 and HPN328 are both in clinical development for myeloma and small-cell lung cancer, respectively. Sanofi's CD38/CD3xCD28 tri-specific SAR442257 is in the clinic for multiple myeloma and non-Hodgkin lymphoma.Deal up to $614MThe agreement grants Oblenio Bio exclusive worldwide rights to develop, manufacture and commercialise LBL-051. Leads is eligible for up to $35 million in upfront and near-term payments, $579 million in milestones, plus royalties on sales.Xiaoqiang Kang, chief executive at Leads, noted that LBL-051 could eventually turn out to be "a pipeline in a product."The Chinese biotech also has a previous collaboration with BeiGene. Under that deal, signed in 2021, BeiGene obtained exclusive commercialisation rights outside China for the LAG-3 targeting asset LBL-007, while providing Leads with $30 million upfront and up to $742 million in potential milestone payments.

License out/inImmunotherapy

100 Deals associated with SAR-442257

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Hodgkin's lymphoma refractory	Phase 1	ES	Sanofi	24 Jul 2020
Non-Hodgkin's lymphoma refractory	Phase 1	NO	Sanofi	24 Jul 2020
Non-Hodgkin's lymphoma refractory	Phase 1	CZ	Sanofi	24 Jul 2020
Non-Hodgkin's lymphoma refractory	Phase 1	US	Sanofi	24 Jul 2020
Non-Hodgkin's lymphoma refractory	Phase 1	KR	Sanofi	24 Jul 2020
Relapse multiple myeloma	Phase 1	NO	Sanofi	24 Jul 2020
Relapse multiple myeloma	Phase 1	US	Sanofi	24 Jul 2020
Relapse multiple myeloma	Phase 1	ES	Sanofi	24 Jul 2020
Relapse multiple myeloma	Phase 1	KR	Sanofi	24 Jul 2020
Relapse multiple myeloma	Phase 1	CZ	Sanofi	24 Jul 2020