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PRECLINICAL EVALUATION OF THE NEW BCMAXCD3 BISPECIFIC ANTIBODY JNJ-957 FOR THE TREATMENT OF MULTIPLE MYELOMA
Author(s): ,
Kristine Frerichs
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
,
Marloes Broekmans
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
,
Jhon Marin Soto
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
,
Berris van Kessel
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
,
Amy Axel
Affiliations:
Research & Development,Janssen,Spring House PA ,United States
,
Christopher Chiu
Affiliations:
Research & Development,Janssen,Spring House PA ,United States
,
Homer Adams III
Affiliations:
Research & Development,Janssen,Spring House PA ,United States
,
Sonja Zweegman
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
,
Tuna Mutis
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
Niels van de Donk
Affiliations:
Hematology,VU University Medical Center,Amsterdam,Netherlands
(Abstract release date: 05/17/18) EHA Library. Frerichs K. 06/17/18; 214621; S1579
Ms. Kristine Frerichs
Ms. Kristine Frerichs
Contributions
Abstract

Abstract: S1579

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 09:00 - 09:15

Location: Room A7

Background
Multiple myeloma (MM) patients with disease refractory to all available treatments have a very poor outcome. B-cell maturation antigen (BCMA) is a tumor necrosis factor (TNF) family surface protein involved in differentiation of B-cells to plasma cells. The selective expression of BCMA on plasma cells renders it an attractive target for novel MM treatment strategies.

Aims
We evaluated the preclinical activity of a new BCMAxCD3 bispecific antibody (JNJ-957) for the treatment of MM. We also analyzed the biomarkers and T-cell subsets associated with the in vitro JNJ-957 response. 

Methods
MM cell lysis by JNJ-957 was analyzed in MM cell lines and whole bone marrow (BM) samples from MM patients. In MM cell lines, peripheral blood mononuclear cells (PB MNC) from healthy donors or MM patients were used as effector cells. Serial dilutions of JNJ-957 (0.0064-4µg/ml) were incubated with the samples for 48 hours. The lysis of CD138high/CD38+ MM cells was assessed by flow cytometry. At baseline, the MNC were characterized for the composition of different T-cell subsets. JNJ-957 induced T-cell activation and degranulation were measured by the expression of CD25 and CD107a, respectively.

Results
JNJ-957 effectively killed BCMA+ MM cell lines (NCI-H929 and RPMI8226) in a dose-dependent manner by healthy donor or MM patient derived PB MNCs . In newly diagnosed (ND)MM patient samples (n=8), the mean lysis of MM cells by JNJ-957 4.0µg/mL was 79% (range: 66-92%; figure 1A). Similar MM lysis, but with a larger variation, was achieved in lenalidomide (LEN) refractory patient samples (n=15; mean lysis at 4.0µg/mL: 69%; range: 24-98%; fig 1B), who were also bortezomib (73%), pomalidomide (82%) and carfilzomib (9%) refractory. JNJ-957 was also effective in samples from MM patients who were daratumumab (DARA) refractory (n=11; mean lysis at 4.0µg/mL: 83%; range: 52-99%; fig 1C). NK- and T-cell frequencies were not affected. JNJ-957-mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T-cells.The heterogeneity in MM cell lysis by JNJ-957 could not be explained by BCMA or PD-L1 expression levels on MM cells, the presence of standard or high-risk cytogenetic abnormalities, or composition of T-cell subsets. Only at suboptimal JNJ-957 doses, the MM cell lysis was affected by high frequency of regulatory T-cells (Treg) and low frequency of effector memory (Tem) and terminally differentiated effector (TEMRA) T-cells.

Since improvement in tumor reduction could be aided by the recently discovered immune stimulatory effects of DARA, we also analyzed sequential BM aspirates from MM patients before and after DARA treatment (n=5). Here we observed comparable BCMA expression, yet improved MM cell lysis by JNJ-957 in samples obtained after disease progression during DARA compared to samples before DARA initiation (mean lysis at 4.0µg/mL: 93 vs 74%; fig 1D).  

Conclusion
The BCMAxCD3 bispecific antibody, JNJ-957, effectively lysed primary MM cells both in samples derived from heavily pre-treated DARA-refractory patients and those with low BCMA surface expression. Optimal JNJ-957 dosing overcame the negative influence of  high Treg and low Tem/TEMRA frequencies on the extent of MM cell killing. Our data also suggest that in vivo pretreatment with DARA improves the response to JNJ-957. Altogether, this strengthens the preclinical rationale for an ongoing phase 1 study with JNJ-957 in relapsed/refractory MM.

Session topic: 13. Myeloma and other monoclonal gammopathies – Biology & Translational Research

Keyword(s): Antibody targeting, Ex vivo, Multiple Myeloma

Abstract: S1579

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 09:00 - 09:15

Location: Room A7

Background
Multiple myeloma (MM) patients with disease refractory to all available treatments have a very poor outcome. B-cell maturation antigen (BCMA) is a tumor necrosis factor (TNF) family surface protein involved in differentiation of B-cells to plasma cells. The selective expression of BCMA on plasma cells renders it an attractive target for novel MM treatment strategies.

Aims
We evaluated the preclinical activity of a new BCMAxCD3 bispecific antibody (JNJ-957) for the treatment of MM. We also analyzed the biomarkers and T-cell subsets associated with the in vitro JNJ-957 response. 

Methods
MM cell lysis by JNJ-957 was analyzed in MM cell lines and whole bone marrow (BM) samples from MM patients. In MM cell lines, peripheral blood mononuclear cells (PB MNC) from healthy donors or MM patients were used as effector cells. Serial dilutions of JNJ-957 (0.0064-4µg/ml) were incubated with the samples for 48 hours. The lysis of CD138high/CD38+ MM cells was assessed by flow cytometry. At baseline, the MNC were characterized for the composition of different T-cell subsets. JNJ-957 induced T-cell activation and degranulation were measured by the expression of CD25 and CD107a, respectively.

Results
JNJ-957 effectively killed BCMA+ MM cell lines (NCI-H929 and RPMI8226) in a dose-dependent manner by healthy donor or MM patient derived PB MNCs . In newly diagnosed (ND)MM patient samples (n=8), the mean lysis of MM cells by JNJ-957 4.0µg/mL was 79% (range: 66-92%; figure 1A). Similar MM lysis, but with a larger variation, was achieved in lenalidomide (LEN) refractory patient samples (n=15; mean lysis at 4.0µg/mL: 69%; range: 24-98%; fig 1B), who were also bortezomib (73%), pomalidomide (82%) and carfilzomib (9%) refractory. JNJ-957 was also effective in samples from MM patients who were daratumumab (DARA) refractory (n=11; mean lysis at 4.0µg/mL: 83%; range: 52-99%; fig 1C). NK- and T-cell frequencies were not affected. JNJ-957-mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T-cells.The heterogeneity in MM cell lysis by JNJ-957 could not be explained by BCMA or PD-L1 expression levels on MM cells, the presence of standard or high-risk cytogenetic abnormalities, or composition of T-cell subsets. Only at suboptimal JNJ-957 doses, the MM cell lysis was affected by high frequency of regulatory T-cells (Treg) and low frequency of effector memory (Tem) and terminally differentiated effector (TEMRA) T-cells.

Since improvement in tumor reduction could be aided by the recently discovered immune stimulatory effects of DARA, we also analyzed sequential BM aspirates from MM patients before and after DARA treatment (n=5). Here we observed comparable BCMA expression, yet improved MM cell lysis by JNJ-957 in samples obtained after disease progression during DARA compared to samples before DARA initiation (mean lysis at 4.0µg/mL: 93 vs 74%; fig 1D).  

Conclusion
The BCMAxCD3 bispecific antibody, JNJ-957, effectively lysed primary MM cells both in samples derived from heavily pre-treated DARA-refractory patients and those with low BCMA surface expression. Optimal JNJ-957 dosing overcame the negative influence of  high Treg and low Tem/TEMRA frequencies on the extent of MM cell killing. Our data also suggest that in vivo pretreatment with DARA improves the response to JNJ-957. Altogether, this strengthens the preclinical rationale for an ongoing phase 1 study with JNJ-957 in relapsed/refractory MM.

Session topic: 13. Myeloma and other monoclonal gammopathies – Biology & Translational Research

Keyword(s): Antibody targeting, Ex vivo, Multiple Myeloma

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