Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma.

Buelow, Ben; Choudry, Priya; Clarke, Starlynn; Dang, Kevin; Davison, Laura; Aldred, Shelley Force; Harris, Katherine E.; Pratap, Payal; Pham, Duy; Rangaswamy, Udaya S.; Schellenberger, Ute; Shah, Nina; Trinklein, Nathan D.; Ugamraj, Harshad; Wiita, Arun P.; Schooten, Wim van

doi:10.1200/jco.2018.36.15_suppl.8034

Cited by 16 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, TNB‐383B induced dose‐dependent CTL degranulation with no T cell expansion, a mild increase (<100‐fold) of CRS‐associated cytokines (IL‐2, TNF‐α) and no increased IL‐6 production in BM aspirate culture supernatants. These findings are consistent with previous in vitro work using PBMCs with this T‐BsAb showing that its αCD3 moiety preferentially engages effector over regulatory T cells and have low T‐activating activity [6,7]. Critically, E max parametric modeling in our ex vivo assay showed that maximum PC lysis by TNB‐383B was reached at 0.01 μg while maximum CTL degranulation required up to 0.1 μg dose, confirming that full T cell activation is not required to achieve killing of target cells.…”

Section: Discussionsupporting

confidence: 92%

Ex vivo efficacy of BCMA‐bispecific antibody TNB‐383B in relapsed/refractory multiple myeloma

Foureau

Bhutani

Robinson

et al. 2020

eJHaem

Self Cite

View full text Add to dashboard Cite

TNB‐383B is a fully human BCMA‐targeting T‐cell engaging bispecific monoclonal antibody (T‐BsAb). We assessed ex vivo efficacy of this drug to mediate killing of bone marrow mononuclear cells (BMMCs) freshly isolated from 10 patients with relapsed multiple myeloma (MM). BMMC were treated ex vivo with TNB‐383B at doses ranging from 0.001‐1 μg. Plasma cell (PC) lysis, viability, BCMA expression, CTL distribution, and degranulation were assessed by flow cytometry. Cytokine response to TNB‐383B was quantified by multiplex protein assay. Dose‐dependent PC lysis was triggered in all cases by TNB‐383B at doses as low as 0.001 μg (P = .0102). Primary MM cells varied in BCMA expression. High BCMA+ PC count correlated with increased PC lysis (P = .005) and significant CTL degranulation specific to TNB‐383B treatment (P = .0153 at 1 μg). High E:T ratio in bone marrow specimens led to lower viable and higher apoptotic PC compared with low E:T ratio (P < .001). Three cytokines were significantly modulated by TNB‐383B: IL‐2/TNFα increased by ∼4 ± 3.5‐fold average (P < .005 at 1 μg) and IP10 increased by ∼50 ± 15‐fold (P < .001 at 1 μg). We conclude that TNB‐383B triggers primary PC lysis and CTL degranulation in a dose‐dependent fashion ex vivo with no T cell expansion and mild increase of CRS‐associated cytokines.

show abstract

Section: Discussionsupporting

confidence: 92%

Ex vivo efficacy of BCMA‐bispecific antibody TNB‐383B in relapsed/refractory multiple myeloma

Foureau

Bhutani

Robinson

et al. 2020

eJHaem

Self Cite

View full text Add to dashboard Cite

show abstract

“…One limitation of AMG 420, and similar bispecific antibody constructs, is that its relatively short half-life necessitates prolonged intravenous infusion using a central venous access device, though this short half-life may help manage treatment-emergent AEs, such as CRS [41,45]. To address this limitation, several groups are developing bispecific antibody constructs with longer halflives that are being investigated in ongoing clinical trials, including AMG 701 (NCT03287908) [52], CC-93269 (NCT03486067) [57], JNJ-64007957 (NCT03145181) [54], REGN5458 (NCT03761108) [55], and TNB-383B (NCT03933735) ( Table 4) [56]. Unlike CAR T-cell therapies, bispecific antibody constructs themselves do not proliferate but rather act by inducing expansion of antigenexperienced T cells.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

“…Other BCMA-targeted bispecific antibody constructs in clinical development that have demonstrated preclinical efficacy include JNJ-957 (a humanized BCMA × CD3 bispecific antibody construct with DuoBody® technology) [54], REGN5458 (a humanized BCMA × CD3 bispecific antibody construct) [55], TNB-383B (a fully human BCMA × CD3 bispecific antibody construct with a lowactivating αCD3 arm that preferentially activates effector T cells over regulatory T cells) [56], and CC-93269 (previously known as BCMA-TCB2/EM901, a dual-arm, human IgG1-based bispecific antibody construct with one CD3 and two BCMA-binding sites) [57,58]. Currently, one anti-BCMA ADC (GSK2857916) has demonstrated antimyeloma activity in a phase 1 trial ( Table 2; described further below), and others have been investigated in preclinical species.…”

Section: Other Bispecific Antibody Constructs In Clinical Developmentmentioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

Self Cite

View full text Add to dashboard Cite

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

show abstract

“…TNB-383B and TNB-384B have been developed by Tenebio based on in silico analysis of heavy chain only/fixed light chain antibody sequences ( 202 ). TNB-383B is a BCMA x CD3 bispecific T-cell redirecting antibody incorporating an activating a unique anti-CD3 moiety (selective in the -383B platform, pan-T-cell activator in the -384B platform), two heavy-chain-only anti-BCMA moieties for a 2:1 tumor associated antigen to CD3 stoichiometry, and a silenced human IgG4 Fc tail ( 203 ).…”

Section: The Baff-april-bcma Systemmentioning

confidence: 99%

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma

et al. 2021

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) directed against antigen-specific of multiple myeloma (MM) cells have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), but the choice of the antigen is crucial for the development of effective immuno-therapy in MM. Recently new immunotherapeutic options in MM patients have been developed against different myeloma-related antigens as drug conjugate-antibody, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR)-T cells. In this review, we will highlight the mechanism of action of immuno-therapy currently available in clinical practice to target CD38, SLAMF7, and BCMA, focusing on the biological role of the targets and on mechanisms of actions of the different immunotherapeutic approaches underlying their advantages and disadvantages with critical review of the literature data.

show abstract

Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma.

Cited by 16 publications

References 0 publications

Ex vivo efficacy of BCMA‐bispecific antibody TNB‐383B in relapsed/refractory multiple myeloma

Ex vivo efficacy of BCMA‐bispecific antibody TNB‐383B in relapsed/refractory multiple myeloma

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma

Contact Info

Product

Resources

About