Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial

Bannerji, Rajat; Arnason, Jon; Advani, Ranjana H.; Brown, Jennifer R.; Allan, John N.; Ansell, Stephen M.; Barnes, Jeffrey A.; O’Brien, Susan; Chávez, Julio C.; Duell, Johannes; Rosenwald, Andreas; Crombie, Jennifer; Ufkin, Melanie; Li, Jingjin; Zhu, Min; Ambati, Srikanth R.; Chaudhry, Aafia; Lowy, Israel; Topp, Max S.

doi:10.1016/s2352-3026(22)00072-2

Cited by 157 publications

(99 citation statements)

References 24 publications

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“…Whereas most patients in the phase I studies of glofitamab were heavily pretreated and most were refractory to the previous treatment line (90.6%), only a very small proportion of these patients was previously treated with CAR T cells (2.9%) [ 11 , 22 ]. Bannerji et al reported a CR rate of 27% in 30 patients with DLBCL treated with odronextamab after CAR T failure [ 10 ]. Schuster et al reported on the use of mosunetuzumab, another CD20/CD3 bispecific antibody, in patients with poor-prognosis B cell lymphomas [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Bispecific T cell engaging antibodies are antibody constructs with two or more antigen binding domains, one recognizing a tumor antigen, such as the B cell maturation antigen (BCMA), CD19 or CD20, and the other recognizing CD3 on T cells, which is essential for T cell receptor-mediated T cell activation [ 8 ]. Several antibody constructs targeting CD20 and the CD3ε subunit, such as mosunetuzumab [ 9 ], odronextamab [ 10 ] or glofitamab [ 11 , 12 ], have shown promising activity in relapsed or refractory (R/R) lymphomas.…”

Section: Introductionmentioning

confidence: 99%

“…Among all 145 heavily pretreated patients, ORR was 51% with a substantially higher response rate in patients with follicular lymphoma (91%). In another study, of 30 patients with diffuse large B cell lymphoma (DLBCL), who had been previously treated with CAR T therapy, the ORR was 33% and the complete response (CR) rate was 27% [ 10 ]. In another phase I dose-escalation study, mosunetuzumab was studied in 236 patients with R/R B cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

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Experiences with Glofitamab Administration following CAR T Therapy in Patients with Relapsed Mantle Cell Lymphoma

Heini

Bacher

Porret

et al. 2022

Cells

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Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and autologous stem cell transplantation, Rituximab maintenance, Bruton’s tyrosine kinase (BTK) inhibitors and CAR T therapy has substantially improved survival. Still, options for patients relapsing after CAR T therapy are limited and recommendations for the treatment of these patients are lacking. We report two cases of patients with mantle cell lymphoma who relapsed after CAR T therapy and were treated with the bispecific CD20/CD3 T cell engaging antibody glofitamab. Both patients showed marked increases of circulating CAR T cells and objective responses after glofitamab administration. Therapy was tolerated without relevant side effects in both patients. One patient completed all 12 planned cycles of glofitamab therapy and was alive and without clinical progression at the last follow-up. The second patient declined further treatment after the first cycle and succumbed to disease progression. We review the literature and investigate possible mechanisms involved in the observed responses after administration of glofitamab, such as proliferation of CAR T cells, anti-tumor effects of the bispecific antibody and the role of other possibly contributing factors. Therapy with bispecific antibodies might offer an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR T therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Experiences with Glofitamab Administration following CAR T Therapy in Patients with Relapsed Mantle Cell Lymphoma

Heini

Bacher

Porret

et al. 2022

Cells

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“…Finally, immunogenicity observed in non-clinical species is not predictive of human responses; this is especially true in hyper-immunized animals used to raise positive control antibodies which typically generate a robust immunogenic response. Importantly, the incidence of treatment-emergent ADA to odronextamab in humans is low (15).…”

Section: Discussionmentioning

confidence: 99%

Interference in a Neutralizing Antibody Assay for Odronextamab, a CD20xCD3 Bispecific mAb, from Prior Rituximab Therapy and Possible Mitigation Strategy

Irvin

D’Orvilliers

Bloch

et al. 2022

AAPS J

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A cell-based assay was developed to detect neutralizing anti-drug antibodies (NAbs) against odronextamab, a CD20xCD3 bispecific monoclonal antibody (mAb) under investigation for treatment of CD20+ B cell malignancies. In this assay, odronextamab bridges between two cell types, CD20-expressing HEK293 cells and CD3-expressing Jurkat T cells that generate a luciferase signal upon CD3 clustering. Patient samples containing NAbs directed to either arm of the bispecific drug block the odronextamab bridge formation between the cell lines thus preventing the generation of the luciferase signal. We determined that other anti-CD20 therapeutics also block bridge formation, resulting in false-positive results. In patient samples from odronextamab clinical trials, approximately 30% of baseline samples had a strong false-positive NAb signal that correlated with the presence of prior rituximab (anti-CD20) therapy. We determined that rituximab interference can be minimized by the addition of anti-rituximab antibodies in the NAb assay. Understanding and mitigating the impact of prior biologic exposure is increasingly important for implementing a successful bioanalytical strategy to support clinical drug development, especially in the immuno-oncology field. Graphical Abstract Odronextamab neutralizing antibody assay, interference, and mitigation. A Design of the odronextamab neutralizing antibody (NAb) assay where anti-CD20xCD3 drug bridges between CD20-expressing HEK293 cells and Jurkat T cells expressing an NFAT response element and luciferase reporter. True NAb prevents odronextamab from bridging between target and effector cells, thus preventing the expression of luciferase. B Interference with odronextamab from other anti-CD20 therapeutic antibodies (e.g., rituximab) from prior disease treatment generates a false-positive NAb result. Assay interference can be mitigated with an anti-idiotypic antibody against the interfering therapy.

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“…The CRS rate was 28% in all 145 patients, and symptoms were mostly mild to moderate. No neurotoxicity or tumor lysis syndrome was observed [ 65 ]. A phase 2 trial (ELM-2, NCT03888105) is actively enrolled.…”

Section: Bites Bikes Checkpoint Inhibitory T-cell–engaging Antibodies...mentioning

confidence: 99%

Therapeutic Advances in Immunotherapies for Hematological Malignancies

Nogami

Sasaki

2022

IJMS

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Following the success of immunotherapies such as chimeric antigen receptor transgenic T-cell (CAR-T) therapy, bispecific T-cell engager therapy, and immune checkpoint inhibitors in the treatment of hematologic malignancies, further studies are underway to improve the efficacy of these immunotherapies and to reduce the complications associated with their use in combination with other immune checkpoint inhibitors and conventional chemotherapy. Studies of novel therapeutic strategies such as bispecific (tandem or dual) CAR-T, bispecific killer cell engager, trispecific killer cell engager, and dual affinity retargeting therapies are also underway. Because of these studies and the discovery of novel immunotherapeutic target molecules, the use of immunotherapy for diseases initially thought to be less promising to treat with this treatment method, such as acute myeloid leukemia and T-cell hematologic tumors, has become a reality. Thus, in this coming era of new transplantation- and chemotherapy-free treatment strategies, it is imperative for both scientists and clinicians to understand the molecular immunity of hematologic malignancies. In this review, we focus on the remarkable development of immunotherapies that could change the prognosis of hematologic diseases. We also review the molecular mechanisms, development processes, clinical efficacies, and problems of new agents.

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Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial

Cited by 157 publications

References 24 publications

Experiences with Glofitamab Administration following CAR T Therapy in Patients with Relapsed Mantle Cell Lymphoma

Experiences with Glofitamab Administration following CAR T Therapy in Patients with Relapsed Mantle Cell Lymphoma

Interference in a Neutralizing Antibody Assay for Odronextamab, a CD20xCD3 Bispecific mAb, from Prior Rituximab Therapy and Possible Mitigation Strategy

Therapeutic Advances in Immunotherapies for Hematological Malignancies

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