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

Verkleij, Christie P.M.; Frerichs, Kristine A.; Broekmans, Marloes E.C.; Absalah, Saida; Maas-Bosman, Patricia W.C.; Kruyswijk, Sandy; Nijhof, Inger S.; Mutis, Tuna; Zweegman, Sonja; Donk, Niels W.C.J. van de

doi:10.18632/oncotarget.27792

Cited by 26 publications

(17 citation statements)

References 33 publications

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“…BiTE connects the CD3 antibody ScFv and the tumor-associated antigen (TAA) or tumor-specific antigen ScFv with G4S linker to redirect T cells to cancer cells and perform targeted killing ( 70 , 71 ). In addition to blinatumomab, other BsAbs use the BiTE platform; these include CD3 × BCMA (B-cell maturation antigen) (AMG420) ( 72 , 73 ), CD3 × CD33 (AMG330) ( 74 , 75 ), CD3 × PSMA (prostate-specific membrane antigen) (AMG212) ( 76 ), and CD3 × EGFRvIII (epithelial growth factor receptor variant III) (AMG596) ( 77 , 78 ). BsAbs on the BiTE platform are small and have a short half-life of only about 2 h which means necessitates administration with continuous intravenous infusion is needed ( 79 , 80 ).…”

Section: Bsab Molecular Platformsmentioning

confidence: 99%

Bispecific Antibodies: From Research to Clinical Application

Tang³

et al. 2021

Front. Immunol.

168

131

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Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical therapeutic effects of BsAbs are superior to those of monoclonal antibodies (MoAbs), with broad applications for tumor immunotherapy as well as for the treatment of other diseases. Recently, with progress in antibody or protein engineering and recombinant DNA technology, various platforms for generating different types of BsAbs based on novel strategies, for various uses, have been established. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. The detailed mechanisms of clinical/therapeutic action have been demonstrated with these different types of BsAbs. Three kinds of BsAbs have received market approval, and more than 110 types of BsAbs are at various stages of clinical trials. In this paper, we elaborate on the classic platforms, mechanisms, and applications of BsAbs. We hope that this review can stimulate new ideas for the development of BsAbs and improve current clinical strategies.

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Section: Bsab Molecular Platformsmentioning

confidence: 99%

Bispecific Antibodies: From Research to Clinical Application

Tang³

et al. 2021

Front. Immunol.

168

131

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“…Thus, treatment with a bispecific antibody targeting another antigen may be more effective. In addition, a combination of bispecific antibodies, simultaneously targeting different antigens, may mitigate tumor antigen escape [163]. BCMA/CD3 BiTE AMG420 is the first-in-class bsMAb in MM.…”

Section: Bispecific Monoclonal Antibodiesmentioning

confidence: 99%

Harnessing the Immune System to Fight Multiple Myeloma

Krejcik

Barnkob

Nyvold

et al. 2021

Cancers

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Multiple myeloma (MM) is a heterogeneous plasma cell malignancy differing substantially in clinical behavior, prognosis, and response to treatment. With the advent of novel therapies, many patients achieve long-lasting remissions, but some experience aggressive and treatment refractory relapses. So far, MM is considered incurable. Myeloma pathogenesis can broadly be explained by two interacting mechanisms, intraclonal evolution of cancer cells and development of an immunosuppressive tumor microenvironment. Failures in isotype class switching and somatic hypermutations result in the neoplastic transformation typical of MM and other B cell malignancies. Interestingly, although genetic alterations occur and evolve over time, they are also present in premalignant stages, which never progress to MM, suggesting that genetic mutations are necessary but not sufficient for myeloma transformation. Changes in composition and function of the immune cells are associated with loss of effective immune surveillance, which might represent another mechanism driving malignant transformation. During the last decade, the traditional view on myeloma treatment has changed dramatically. It is increasingly evident that treatment strategies solely based on targeting intrinsic properties of myeloma cells are insufficient. Lately, approaches that redirect the cells of the otherwise suppressed immune system to take control over myeloma have emerged. Evidence of utility of this principle was initially established by the observation of the graft-versus-myeloma effect in allogeneic stem cell-transplanted patients. A variety of new strategies to harness both innate and antigen-specific immunity against MM have recently been developed and intensively tested in clinical trials. This review aims to give readers a basic understanding of how the immune system can be engaged to treat MM, to summarize the main immunotherapeutic modalities, their current role in clinical care, and future prospects.

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“…Because formation of the cytolytic synapse is independent of standard antigen recognition and co-stimulation, immune escape mechanisms of tumor cells are evaded [ 8 ]. T cell activation finally leads to tumor cell lysis through the release of perforins and granzymes which induce apoptosis [ 40 , 41 ].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

The Agony of Choice—Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond

Straßl¹,

Schreder²,

Steiner

et al. 2021

Cancers

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Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody–drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.

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

Cited by 26 publications

References 33 publications

Bispecific Antibodies: From Research to Clinical Application

Bispecific Antibodies: From Research to Clinical Application

Harnessing the Immune System to Fight Multiple Myeloma

The Agony of Choice—Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond

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