FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma

Abstract

Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma.

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

“…81 A new anti-CD38 mAb, FTL004, has also exhibited enhanced proapoptotic activity and displayed stronger ADCC against CD38 + malignant cells but has not been evaluated in clinical trials as yet. 10 In ADCP, binding with Fc gamma receptors (FcγRs), present on monocytes and macrophages, induces phagocytosis of antibody-opsonized tumor cells. 42 Phagocytosis contributes to the antitumor activity of the CD38 antibodies isatuximab and daratumumab.…”

“…4 The characterization of the CD38 protein and its overexpression on myeloma cells has resulted in the development of monoclonal antibodies (mAbs) targeting CD38, of which two antibodies-daratumumab and isatuximab-have been approved for clinical use. 2,[5][6][7][8][9][10] Daratumumab is approved for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) in combinations that include proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). [11][12][13][14] 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][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.…”

“…Research has also shown that CD38 is also expressed on human platelet membranes, with nicotinamide adenine dinucleotide (NAD) glycohydrolase, and adenosine diphosphate (ADP) ribose cyclase, and therefore could possibly be involved in the signal transduction pathways that lead to platelet activation 4 . The characterization of the CD38 protein and its overexpression on myeloma cells has resulted in the development of monoclonal antibodies (mAbs) targeting CD38, of which two antibodies—daratumumab and isatuximab—have been approved for clinical use 2,5–10 …”

“…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 …”