Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab

Abstract

Purpose: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action.Experimental design: We evaluated the anti-MM activity of the fully human BCMAÂCD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor-and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated.Results: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/ PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-na€ ve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect.Conclusions: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.

T-cell redirecting bispecific antibodies targeting BCMA for the treatment of multiple myeloma

“…Because of the high single agent activity and good tolerability profile of the BCMA-targeting bispecific antibodies, these agents are ideal components of a highly effective combination therapy. We showed that the direct combination of teclistamab with the CD38-targeting antibody daratumumab enhanced MM cell lysis in an additive fashion [14]. In addition, the activity of teclistamab was significantly enhanced in bone marrow samples obtained from patients with prior daratumumab treatment.…”

“…Furthermore, teclistamab-mediated tumor cell lysis was superior when T-cells obtained from patients treated with daratumumab were used, compared to T-cells from daratumumab naïve MM patients [14]. This positive effect of daratumumab on the ability of teclistamab to kill MM cells, is probably related to the immune stimulating effects of daratumumab, which include the elimination of immune suppressor cells, induction of T-cell expansion, and increase in T-cell killing capacity [14,[21][22][23]. These data form the rationale for the ongoing phase 1 TRIMM study, which evaluates the efficacy of teclistamab plus daratumumab.…”

“…Importantly, T-cell redirecting therapies, such as chimeric antigen receptor (CAR) T-cells and bispecific antibodies ( Figure 1), have significant clinical activity in these heavily pretreated patients. teclistamab (JNJ-7957) [14]. Teclistamab activates T-cells by connecting the CD3 antigen, present on T-cells, with BCMA, which is highly and selectively expressed on the surface of normal and clonal plasma cells.…”

BCMA-Targeting Therapy: Driving a New Era of Immunotherapy in Multiple Myeloma

“…Currently, many bispecific Abs target BCMA on MM cells and CD3 on T cells or CD16 on NK effector cells. EM801 [ 30 ], BCMA-TCB2/EM901 (CC-93269) [ 30 , 89 ], JNJ-7957 [ 101 ] and TNB-383B [ 60 , 102 , 103 ] all target CD3 on T cells and BCMA on MM cells. AFM26, a tetravalent bispecific Ab targeting BCMA on MM cells and CD16A on NK cells, showed potent NK-cell-medicated ADCC [ 104 ].…”

Targeted Therapy With Immunoconjugates for Multiple Myeloma

“…Target antigen expression is an important factor for target recognition and effector function by mAbs (213). There is considerable heterogeneity in expression of target antigens between MM patients (16,(213)(214)(215)(216)(217)(218). Patients with low levels of target antigen on the tumor cell surface are at increased risk of treatment failure (213).…”