SAR442257 / Sanofi - LARVOL DELTA

First-in-human Single Agent Study of SAR442257 in RRMM and RR-NHL (clinicaltrials.gov) - P1 | N=47 | Terminated | Sponsor: Sanofi | Completed ➔ Terminated; Sponsor decision based on limited clinical benefit observed in both Multiple Myeloma and Non-Hodgkin Lymphoma cohorts

First-in-human • Trial termination • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6

Multiple Myeloma Cells Resistant to T-cell Therapies Exhibits a CD45+ Immune Evasive Phenotype. (PubMed, Cancer Immunol Res) - "Bone marrow samples were treated ex vivo with BCMA CAR T cells, TCEs (elranatamab, SAR442257), or activated T cells, and analyzed by flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy), and by using in an in vivo mouse model of disseminated MM...Mechanistic studies implicated secreted HSP70, while bulk RNA-sequencing revealed increased LAG-3, IFN-γ signaling, and PD-L1 expression. These findings suggest T cell-redirecting therapy (TCRT) drives an immuno-evasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory MM."

IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • IFNG • LAG3 • PD-L1 • PTPRC

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

First-in-human • Trial completion • B Cell Lymphoma • 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 Malignancies • Leukemia • Multiple Myeloma • Oncology • CD69

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

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

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

A novel B7-H4/CD3/CD28 trispecific antibody with the SpyTag-SpyCatcher technology suppresses the growth of colorectal cancer. (PubMed, Int Immunopharmacol) - "Furthermore, SpyCatcher-SpyTag technology was introduced to combine the intact B7-H4 antibody with the anti-CD3/CD28 antibody, which are elements of the CD38 × CD28 × CD3 (SAR442257) TsAb, to create a new TsAb named TsAb-B7-H4...Moreover, TsAb-B7-H4 did not induce the infammatory cytokines which produced by human PBMCs. Consequently, we successfully engineered TsAb-B7-H4 which showed antitumor efficacy in CRC."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • VTCN1

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

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

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