SAR442257

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.

P1, N=47, Completed, Sanofi | Active, not recruiting --> Completed

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.

P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Mar 2025 --> Mar 2026

P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Aug 2024 --> Mar 2025

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.

P1, N=47, Active, not recruiting, Sanofi | Trial completion date: Apr 2024 --> Aug 2024

P1, N=47, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Apr 2024

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.

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.

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.

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.