The present and future of bispecific antibodies for cancer therapy

Klein, Christian; Brinkmann, Ulrich; Reichert, Janice M.; Kontermann, Roland E.

doi:10.1038/s41573-024-00896-6

Cited by 75 publications

(12 citation statements)

References 286 publications

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“…For the treatment of cancer, the pre-dominant MOA is T cell engagement, with the largest number of bsAbs approved and in clinical trials being TCEs. 5 Figure 2a shows an overview of the evolution of approved TCE bsAb formats. This class of molecules includes TCEs for the treatment of relapsed/refractory hematological cancers: 1) CD19/CD3ε blinatumomab for the treatment of ALL, 7–9 2) the CD20/CD3ε TCEs mosunetuzumab for the treatment of R/R non-Hodgkin’s lymphoma (NHL), 51 and glofitamab 53 and epcoritamab 44 for the treatment of R/R DLBCL, and 3) the BCMA/CD3ε TCEs teclistamab 43 and elranatamab, 47 and GPRC5D/CD3ε talquetamab, 45 for the treatment of R/R multiple myeloma.…”

Section: Moas For Approved Bsabsmentioning

confidence: 99%

“…Finally, given the versatility of bsAbs and the potential to mediate completely novel MOAs, the field of bsAbs is poised to see novel emerging approaches and candidates enter the clinic, hopefully providing pivotal data in the years to come, both in oncology and in non-oncology indications, including applications in infection/virology, autoimmunity, metabolism, neurology and ophthalmology. These novel concepts include different approaches as described recently, 5 including the development of: 1) effector cell engagers different from TCEs, engaging, e.g., myeloid, NK or γδ-T cells, 96–98 2) in situ assembly concepts to specifically activate bsAbs on dual target-expressing cells 99 , 100 or in the tumor microenvironment, 101 3) PROTAC-like approaches resulting in internalization and degradation of membrane proteins, 102 4) antibody-based cytokine mimetics to trigger cytokine receptors, 103 , 104 and 5) unique solutions for delivery of bsAbs beyond barriers such as the blood-brain-barrier, 105 which may have applications for the treatment of neurodegenerative and other diseases. 106 …”

Section: Outlook For the Futurementioning

confidence: 99%

“… 1–5 Of these, over 100 bsAbs have reached clinical trials. 1 , 3 , 5 Based on this major effort in developing novel bsAb formats, novel target combinations and bispecific lead molecules, the landscape has substantially changed recently and bsAb approvals are becoming frequent since 2021. In the past three years alone (2021–2023), 11 novel bsAbs were approved by health authorities in the US, Europe, Japan and/or China for use in patients ( Figure 1 , Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

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A pivotal decade for bispecific antibodies?

Surowka,

Klein

2024

mAbs

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Bispecific antibodies (bsAbs) are a class of antibodies that can mediate novel mechanisms of action compared to monospecific monoclonal antibodies (mAbs). Since the discovery of mAbs and their adoption as therapeutic agents in the 1980s and 1990s, the development of bsAbs has held substantial appeal. Nevertheless, only three bsAbs (catumaxomab, blinatumomab, emicizumab) were approved through the end of 2020. However, since then, 11 bsAbs received regulatory agency approvals, of which nine (amivantamab, tebentafusp, mosunetuzumab, cadonilimab, teclistamab, glofitamab, epcoritamab, talquetamab, elranatamab) were approved for the treatment of cancer and two (faricimab, ozoralizumab) in non-oncology indications. Notably, of the 13 currently approved bsAbs, two, emicizumab and faricimab, have achieved blockbuster status, showing the promise of this novel class of therapeutics. In the 2020s, the approval of additional bsAbs can be expected in hematological malignancies, solid tumors and non-oncology indications, establishing bsAbs as essential part of the therapeutic armamentarium.

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Section: Moas For Approved Bsabsmentioning

confidence: 99%

Section: Outlook For the Futurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A pivotal decade for bispecific antibodies?

Surowka,

Klein

2024

mAbs

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“… 44 Its human counterpart, BiTP 45 or Y101D, is been evaluated in patients with advanced-stage solid tumors (NCT05028556). 28 …”

Section: Discussionmentioning

confidence: 99%

“…However, there is no TCE approved for the treatment of solid tumors yet, 27 with the exception of the non-canonical fusion protein tebentafusp, highlighting the challenges posed by the paucity of TAA not expressed in essential normal tissues and the immunosuppressive TME. 28 If approved this year for the treatment of small cell lung cancer, the half-life extended BiTE® tarlatamab (DLL3×CD3) may be first TCE bsAb for solid tumors. 29 Similarly, CAR-T cell therapies have achieved unprecedented success in the treatment of B cell acute lymphoblastic leukemia, non-Hodgkin lymphoma and multiple myeloma, but no CAR-T cell has reached the market for the treatment of non-hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses

Tapia-Galisteo,

Sánchez-Rodríguez,

Narbona

et al. 2024

OncoImmunology

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T cell-based immunotherapies for solid tumors have not achieved the clinical success observed in hematological malignancies, partially due to the immunosuppressive effect promoted by the tumor microenvironment, where PD-L1 and TGF-β play a pivotal role. However, durable responses to immune checkpoint inhibitors remain limited to a minority of patients, while TGF-β inhibitors have not reached the market yet. Here, we describe a bispecific antibody for dual blockade of PD-L1 and TFG-β, termed AxF (scFv) 2 , under the premise that combination with T cell redirecting strategies would improve clinical benefit. The AxF (scFv) 2 antibody was well expressed in mammalian and yeast cells, bound both targets and inhibited dose-dependently the corresponding signaling pathways in luminescence-based cellular reporter systems. Moreover, combined treatment with trispecific T-cell engagers (TriTE) or CAR-T cells significantly boosted T cell activation status and cytotoxic response in breast, lung and colorectal (CRC) cancer models. Importantly, the combination of an EpCAMxCD3×EGFR TriTE with the AxF (scFv) 2 delayed CRC tumor growth in vivo and significantly enhanced survival compared to monotherapy with the trispecific antibody. In summary, we demonstrated the feasibility of concomitant blockade of PD-L1 and TGF-β by a single molecule, as well as its therapeutic potential in combination with different T cell redirecting agents to overcome tumor microenvironment-mediated immunosuppression.

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Donor Substitution Engineering of Hemicyanine Nanoparticles to Reprogram the Tumor Microenvironment and Enhance Fn14‐Targeted BiTE for Glioblastoma Photoimmunotherapy

Li,

Jiang,

Zhang

et al. 2024

Adv Funct Materials

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Glioblastoma (GBM) is a highly malignant intracranial tumor with limited treatment options. Bispecific T‐cell engagers (BiTEs) are being explored for GBM treatment, but their success is hindered by inadequate T cell infiltration and activation due to the acidic and immunosuppressive microenvironment. Photothermal immunotherapy lyses tumors and activates immune responses, complementing BiTEs. This study innovatively employs a donor engineering strategy to develop hemicyanine dyes (Hcys) that emit from near‐infrared (NIR) I to NIR II. The Hcy with excellent properties is encapsulated in an amphiphilic micelle, forming a nano assembly with lactate oxidase (PLH1100). PLH1100 exhibits spectral absorption at 980 nm, a photothermal conversion efficiency of 58.7%, and capability for NIR‐II tumor imaging. Besides photothermal tumor ablation, PLH1100 regulates lactic acid metabolism and activates immunogenic cell death, improving the tumor microenvironment and promoting T cell infiltration and activation. Further studies demonstrate PLH1100 effectively kills human and murine GBM cells, inhibits orthotopic U87 tumor growth in BALB/c‐nu mice, and enhances the efficacy of Fn14‐targeted BiTE in orthotopic GL261 tumors in C57BL/6 mice, achieving a synergistic “1+1>2” therapeutic effect. Collectively, this work opens a new pathway for using Hcy‐based molecules combined with BiTE drugs for GBM therapy, with significant clinical potential.

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The present and future of bispecific antibodies for cancer therapy

Cited by 75 publications

References 286 publications

A pivotal decade for bispecific antibodies?

A pivotal decade for bispecific antibodies?

Combination of T cell-redirecting strategies with a bispecific antibody blocking TGF-β and PD-L1 enhances antitumor responses

Donor Substitution Engineering of Hemicyanine Nanoparticles to Reprogram the Tumor Microenvironment and Enhance Fn14‐Targeted BiTE for Glioblastoma Photoimmunotherapy

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