SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma

Abstract

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

“…96 Inhibition of CD38 ectoenzymatic activity is a unique feature of isatuximab, whereas daratumumab has nearly no direct inhibition of CD38 enzymatic activity. 2,18,97 This might be due to the unique binding mode of isatuximab as, although significant conformational changes occur in CD38 upon isatuximab binding, the catalytic site remains. As previously mentioned, isatuximab and daratumumab bind to different, nonoverlapping epitopes of CD38.…”

“…[15][16][17] Other CD38 antibodies currently under preclinical and clinical development for the treatment of MM include MOR202, TAK-079, SAR442085, CID-103, and FTL004. 6,7,9,10,18 CD38 is also expressed in other hematologic malignancies, such as chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia, Waldenström's macroglobulinemia, and NK/T-cell lymphoma. 19,20 The role of CD38 antibodies in treating these malignancies is being actively investigated.…”

“…Isatuximab is approved for the treatment of adult patients with RRMM in combination with pomalidomide and dexamethasone (Pd), and in combination with carfilzomib and dexamethasone (Kd), in patients who have received at least two prior therapies, including lenalidomide and a PI, or who have received one–three prior lines of therapy, respectively 15–17 . Other CD38 antibodies currently under preclinical and clinical development for the treatment of MM include MOR202, TAK‐079, SAR442085, CID‐103, and FTL004 6,7,9,10,18 …”

Targeting CD38 in Neoplasms and Non-Cancer Diseases

“…Efficacy of the therapy based on usage of each of the four mAbs suggests that ADCC is the main process responsible for defeating MM cells [ 70 ]. Interestingly, novel studies in improving the efficacy of isatuximab led to the discovery of SAR442085, a novel anti-CD38 antibody with enhanced ADCC antitumor activity against multiple myeloma [ 71 ]. SAR442085 has greater binding affinity than daratumumab and isatuximab for FcγRIIa and FcγRIIIa, which results in NK cells activation against primary plasma cells.…”

Mature B‐ and plasma‐cell flow cytometric analysis: A review of the impact of targeted therapy

“…Daratumumab (IgG1κ) and isatuximab (IgG1κ mAb; Sanofi; Frampton, 2021) both targeting CD38 are approved by FDA. Additional anti‐CD38 drugs including SAR442085 (IgG1 backbone with enhanced FcγR binding; Snofi; Kassem et al, 2022), MOR202 (IgG1λ; Morphosys; van de Donk et al, 2018), and TAK 079 (higher affinity to myeloma cells than red cells and platelets; Takeda; Krishnan et al, 2020) are currently in human trials (van de Donk & Usmani, 2018). Additionally, several pre‐clinical phase anti‐CD38 antibodies are under development, including Ab79 (Takeda), Ab19 (Takeda), and CD3/CD38 bispecific antibodies (Xencor; van de Donk et al, 2016).…”