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DRUG:

SAR442257

i
Other names: SAR442257, anti-CD38xCD28xCD3 trispecific monoclonal antibody
Company:
Sanofi
Drug class:
CD3 agonist, CD38 inhibitor, CD28 agonist
Related drugs:
4ms
First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov)
P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Aug 2024 --> Mar 2025
Trial completion date
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BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
SAR442257
6ms
Pre-Clinical Assessment of SAR442257, a CD38/CD3xCD28 Trispecific T Cell Engager in Treatment of Relapsed/Refractory Multiple Myeloma. (PubMed, Cells)
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.
Preclinical • Journal • IO biomarker • Trispecific
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CD28 (CD28 Molecule) • TGFB1 (Transforming Growth Factor Beta 1)
|
SAR442257
7ms
First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov)
P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Apr 2024 --> Aug 2024
Trial completion date
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
BCL6 rearrangement • BCL2 rearrangement
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SAR442257
9ms
First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov)
P1, N=47, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Apr 2024
Enrollment closed • Trial completion date
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BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
BCL6 rearrangement • BCL2 rearrangement
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SAR442257
1year
The CD38/CD3xCD28 Trispecific Antibody (SAR442257) Potentially Represents a Novel Therapeutic Strategy for Peripheral T-Cell Lymphomas (ASH 2023)
SAR442257 also induced CD25 and CD69 expression on normal T-cells suggesting efficient T-cell activation, (data not shown). Conclusion Altogether, this study shows that 1) most PTCL cells express at least CD28 or CD38, and 2) SAR442257 can efficiently kill malignant PTCL cells, while ensuring effective T-cell activation; In view of these results, clinical investigation of SAR442257 in PTCL is warranted.
IO biomarker • Trispecific
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TNFRSF8 (TNF Receptor Superfamily Member 8) • CCR4 (C-C Motif Chemokine Receptor 4) • IL2RA (Interleukin 2 receptor, alpha) • CD69 (CD69 Molecule) • CD28 (CD28 Molecule)
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CD38 expression • IL2RA expression
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SAR442257
1year
A CD38/CD28xCD3 Trispecific T-Cell Engager (TCE) As a Potentially Active Agent for the Treatment of Older Patients with Acute Myeloid Leukemia (AML) (ASH 2023)
Aims: To evaluate CD38 as a potential therapeutic target in AML, and to determine the mode of action and preclinical efficacy of isatuximab (an IgG1 anti-CD38 mAb) and SAR442257, which is a new CD38/CD28xCD3 trispecific TCE. CD38 is widely present in blasts from older AML patients but nearly half show heterogeneous expression. While isatuximab-driven ADCC in AML cell lines and primary samples is dependent on CD38 density in tumor cells, the CD38/CD28xCD3 TCE exerted its anti-tumor efficacy regardless of CD38 density. Thus, AML patients expressing both high and low/heterogenous levels of CD38 could benefit from T cell based immunotherapeutic strategies targeting CD38.
Clinical • IO biomarker • Trispecific
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CD69 (CD69 Molecule)
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CD38 expression
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Sarclisa (isatuximab-irfc) • SAR442257
1year
A CD38/CD28xCD3 Trispecific T-Cell Engager (TCE) As a Potentially Active Agent in Multiple Myeloma Patients Relapsed and/or Refractory (RRMM) to Anti-CD38 Monoclonal Antibodies (mAbs) (ASH 2023)
Aim: Evaluate a CD38/CD28xCD3 trispecific TCE (SAR442257) as a potential therapeutic agent in the RRMM setting...First, we observed that, contrary to isatuximab and daratumumab, CD38/CD28xCD3 TCE did not reduce surface CD38 levels in the MOLP 8, RPMI 8226 and KMS 12 BM cell lines... We observed a reduction in CD38 levels in MMPC and an impaired cytotoxic activity of NK cells in RRMM patients previously exposed to anti-CD38 mAbs. We propose a second targeting of CD38 using T-cell-based immunotherapeutic agents whose efficacy depends less on CD38 antigen density, especially after longer washout periods, as a potential therapeutic strategy in the RRMM setting.
Clinical • IO biomarker • Trispecific
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CD4 (CD4 Molecule) • CD28 (CD28 Molecule) • B3GAT1 (Beta-1,3-Glucuronyltransferase 1)
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CD38 expression
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Darzalex (daratumumab) • Sarclisa (isatuximab-irfc) • SAR442257
1year
Pre-clinical characterization of SAR442257, a CD38xCD28xCD3 trispecific T-cell engager in relapsed/refractory multiple myeloma (IMW 2023)
SAR442257 has increased binding capacity for RRMM due to CD38 and CD28 targets and demonstrated activity on RRMM cells as reasonable alternative for future RRMM therapy approach.
Preclinical • IO biomarker • Trispecific
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CD28 (CD28 Molecule) • SDC1 (Syndecan 1)
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CD38 expression
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Darzalex (daratumumab) • SAR442257
over1year
First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov)
P1, N=57, Recruiting, Sanofi | Trial completion date: Jun 2025 --> Apr 2026
Trial completion date
|
BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
|
BCL6 rearrangement • BCL2 rearrangement
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SAR442257
over1year
SAR442257, A CD38/CD28/CD3 TRISPECIFIC ANTIBODY, POTENTIATES CAR T-CELL ACTIVITY AGAINST LARGE B-CELL LYMPHOMA (EHA 2023)
CD19 CAR T-cells were constructed from PBMCs of rrLBCL patients obtained at the time of apheresis using a construct like axicabtagene ciloleucel (axi-cel). The tumor microenvironment of CAR T refractory rrLBCL is enriched in clonally expanded and terminally exhausted CD8 T-cells expressing CD38. The CD38/CD28xCD3 trispecific antibody SAR442257 boosted CAR T-cell activity through recognition of CD38 on the tumor, costimulation of CAR T-cells, and induced fratricide of CD38+ T-cells; resulting in superior tumor cell killing. In addition, SAR442257 allowed CD19 CAR T-cells to kill CD19- /CD38+ LBCL cells.
CAR T-Cell Therapy • IO biomarker • Trispecific
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CD8 (cluster of differentiation 8) • LAG3 (Lymphocyte Activating 3) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2)
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CD38 expression • CD8 expression • LAG3 expression • HAVCR2 expression
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Yescarta (axicabtagene ciloleucel) • SAR442257
over4years
[VIRTUAL] CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager (AACR-II 2020)
We further show that when other anti-CD38 antibodies are bound to CD38, binding of SAR442257 to tumor cells and T-cell mediated cytotoxicity are rescued by CD28 as evidenced by loss of binding and cytotoxic activity in CD28KO cells. Overall, these data show that SAR442257 is active on both CD38 high and low MM models and that CD28 expressed on MM tumor cells can be directly targeted by SAR442257, enhancing its cytotoxicity and allowing it to bind MM cells when CD38 is occupied by other anti-CD38 antibodies
IO biomarker
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CD38 (CD38 Molecule)
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CD38 expression
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SAR442257