SAR442257 / Sanofi - LARVOL DELTA

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Mar 2025 ➔ Mar 2026

Trial completion date • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • BCL2 • BCL6

Multiple Myeloma Persister Cells Surviving Bispecific Antibodies and CAR-T Cells Exhibit New CD45+ Expression (ASH 2024) - "Myeloma Drug Sensitivity Testing (My-DST) was performed as previously described using 1nM anti-BCMA bsAbs elranatamab and teclistamab, anti-GPRC5D talquetamab, and anti-CD38 SAR442257 (Walker et al, Blood Adv. Conclusion : These data support that (1) CD45 expression increases at the RNA and protein level on MM persisting after TCRT, (2) this is caused by a soluble factor secreted by stimulated T cells, and (3) LAG-3 may be a potential target for post-TCRT MM. The CD45+LAG-3+ phenotype aligns with previous reports of an immunosuppressive response cancer cells may use to provide protection from T cell attack."

CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CTCs • IL6 • LAG3 • PTPRC • SDC1

First-in-Human Phase 1 Study of SAR442257 in Patients with Relapsed/Refractory Multiple Myeloma and Non-Hodgkin Lymphoma (ASH 2024) - P1 | "Conclusion : This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation."

Clinical • IO biomarker • P1 data • Cytomegalovirus Infection • Epstein-Barr Virus Infections • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Hepatology • Infectious Disease • Lymphoma • Multiple Myeloma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • CD4 • CD8 • CRP • CXCL8 • IL6

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. (PubMed, Br J Haematol) - "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."

IO biomarker • Journal • Trispecific • Hematological Malignancies • Multiple Myeloma • Oncology

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Aug 2024 ➔ Mar 2025

Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • BCL2 • BCL6

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."

IO biomarker • Journal • Preclinical • Trispecific • Hematological Malignancies • Multiple Myeloma • Oncology • CD28 • TGFB1

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Apr 2024 ➔ Aug 2024

Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • BCL2 • BCL6

Ex Vivo Efficacy of SAR442257 anti-CD38 Trispecific T Cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA Targeted Therapies. (PubMed, Cancer Res Commun) - "My-DST is capable of measuring T cell-dependent killing using the MM patient's own bone-marrow derived T cells. SAR442257 shows promise for MM and may be best suited for patients declared resistant to both CD38 mAbs and BCMA targeted therapy."

IO biomarker • Journal • Preclinical • Trispecific • Hematological Malignancies • Multiple Myeloma • Oncology

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=47 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting | Trial completion date: Apr 2026 ➔ Apr 2024

Enrollment closed • Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • BCL2 • BCL6

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 • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CCR4 • CD28 • CD69 • IL2RA • TNFRSF8

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 • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • CD69

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 • Hematological Malignancies • Multiple Myeloma • Oncology • B3GAT1 • CD28 • CD4

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."

IO biomarker • Preclinical • Trispecific • Hematological Malignancies • Multiple Myeloma • Oncology • CD28 • SDC1

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=57 | Recruiting | Sponsor: Sanofi | Trial completion date: Jun 2025 ➔ Apr 2026

Trial completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • BCL2 • BCL6

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 • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immune Modulation • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • HAVCR2 • LAG3

SAR442257, a CD38/CD28/CD3 trispecific antibody, potentiates CAR T-cell activity against large B-cell lymphoma (ICML 2023) - "CD19 CAR T were constructed from PBMCs of rrLBCL patients obtained at time of apheresis using a construct like axicabtagene ciloleucel. In addition, SAR442257 allowed CD19 CART-cells to kill CD19-/CD38+ LBCL cells. Encore Abstract - previously submitted to EHA 2023"

CAR T-Cell Therapy • IO biomarker • Trispecific • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • HAVCR2 • LAG3

SAR442257: Primary completion of P1 trial (NCT04401020) in patients with r/r multiple myeloma and r/r NHL in Jan 2024 (Sanofi) - Q4 & FY2022 Results: Completion of P1 trial in patients with r/r multiple myeloma and r/r NHL on Jun 5, 2025

Trial completion date • Trial primary completion date • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=57 | Recruiting | Sponsor: Sanofi | Trial completion date: Apr 2024 ➔ Apr 2025

Trial completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome

"After CD28 stimulation was official quasi taboo for years as a result of the TeGenero disaster, more and more companies are now pursuing this approach, e.g. $SNY -> SAR442257 (CD38/CD28XCD3), $XNCR -> B7-H3xCD28, PD-L1xCD28 etc." (@GermanBiotech)

CD38

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1; N=57; Recruiting; Sponsor: Sanofi; Initiation date: Dec 2020 ➔ Jul 2020

Clinical • Trial initiation date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • CD38

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1; N=57; Recruiting; Sponsor: Sanofi; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Sanofi's emerging oncology pipeline highlighted at the AACR Virtual Annual Meeting II (PRNewswire) - "Preclinical data show anti-tumor activity in Sanofi's investigational compounds, including an oral selective estrogen receptor degrader (SERD) and an anti-CEACAM5 antibody-drug conjugate. Data reinforce Sanofi's commitment to multiple myeloma; include new preclinical findings for Sarclisa® (isatuximab-irfc), and anti-CD38 antibody and CD38/CD28xCD3 trispecific T-cell engager. More than 20 presentations from Sanofi Oncology Research supporting additional investigation of priority compounds in breast, lung and blood cancers….Preclinical data for Sanofi's investigational compounds in breast, lung, multiple myeloma and other cancers will be featured at the American Academy of Cancer Research (AACR) Virtual Annual Meeting II on June 22-24."

Preclinical • Acute Lymphocytic Leukemia • Breast Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology

[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 • Hematological Malignancies • Multiple Myeloma • Oncology • CD38

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1; N=57; Not yet recruiting; Sponsor: Sanofi; Trial primary completion date: May 2022 ➔ Jan 2024

Clinical • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1; N=57; Not yet recruiting; Sponsor: Sanofi

Clinical • New P1 trial • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology