The eIg technology to generate Ig-like bispecific antibodies

Kühl, Lennart; Beha, Nadine; Kontermann, Roland E.; Seifert, Oliver

doi:10.1080/19420862.2022.2063043

Cited by 6 publications

(11 citation statements)

References 38 publications

(43 reference statements)

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“…Based on the eIg technology, 26 Fc-comprising, bispecific antibodies for T-cell retargeting were designed with different valencies and geometries. The TAA EGFR is targeted by a humanized variant of cetuximab (hu225) 27 and CD3 on T cells by a humanized variant of UCHT1 (huU3).…”

Section: Resultsmentioning

confidence: 99%

“… 31 , 32 The ability to discriminate cancer cells from healthy cells, i.e., a low or absent activity against cells expressing moderate to low levels of EGFR, is critical for efficient and safe therapy with TCEs. In this study, the eIg technology 26 was successfully applied to generate a panel of bispecific antibodies for T-cell retargeting to EGFR-expressing cells, varying in valency for EGFR, the position of the CD3 binding arm, and the presence or absence of an Fc region, with the aim to identify molecules with favorable activity profiles.…”

Section: Discussionmentioning

confidence: 99%

“…Binding of bispecific antibodies to EGFR-ECD-moFc (extracellular domain of EGFR: aa 25–645 with C-terminal fusion to a murine IgG2a-Fc part) was analyzed by ELISA as described previously. 26 …”

Section: Methodsmentioning

confidence: 99%

“…We recently established our eIg technology as a versatile platform to generate bispecific antibodies of different geometry and valency. 26 Here, we applied this eIg technology to generate TCEs targeting EGFR and CD3, modifying valency, geometry, and size of the molecules. These molecules comprise a Fab-like anti-CD3 buildings block (eFab), substituting the C H 1 and C L domains by heterodimerizing EHD2 (hetEHD2) domains derived from human IgE heavy-chain domain 2, combined with an EGFR-targeting Fab into bi- or trivalent molecules with or without a silenced Fc region.…”

Section: Introductionmentioning

confidence: 99%

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eIg-based bispecific T-cell engagers targeting EGFR: Format matters

Kühl

Schäfer

Kraft

et al. 2023

mAbs

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Bispecific antibodies are molecules with versatile modes of action and applications for therapy. They are commonly developed as T-cell engagers (TCE), which simultaneously target an antigen expressed by tumor cells and CD3 expressed by T-cells, thereby inducing T-cell-mediated target cell killing. There is growing evidence that the molecular composition and valency for the target antigen influence the activity of TCEs. Here, the eIg platform technology was used to generate a set of bispecific TCEs targeting epidermal growth factor receptors (EGFR) and CD3. These molecules either included or lacked an Fc region and exhibited one binding site for CD3 and either one or two binding sites for EGFR (1 + 1 or 2 + 1 formats) utilizing different molecular arrangements of the binding sites. In total, 11 different TCE formats were analyzed for binding to target cells and T cells, T cell-mediated killing of tumor cells, and for the activation of T cells (release of cytokines and proliferation of T-cells). Bivalent binding to EGFR strongly increased binding and T cell-mediated killing. However, the molecular composition and position of the CD3-binding arm also affected target cell killing, cytokine release, and T-cell proliferation. Our findings support that screening of a panel of formats is beneficial to identify the most potent bispecific TCE, and that format matters.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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eIg-based bispecific T-cell engagers targeting EGFR: Format matters

Kühl

Schäfer

Kraft

et al. 2023

mAbs

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“…Most bsAbs are produced via protein engineering of the native mAb framework. − However, the evolution of bio-orthogonal (click) chemistry has facilitated the generation of novel synthetic antibody conjugates, such as ADCs. , At the moment, strain-promoted azide alkyne cycloaddition (SPAAC) and the inverse electron-demand Diels–Alder (IEDDA) reactions between strained unsaturated carbon–carbon systems and tetrazine , or ortho -quinone have been successfully applied for antibody modification …”

mentioning

confidence: 99%

Rapid Access to Potent Bispecific T Cell Engagers Using Biogenic Tyrosine Click Chemistry

Shajan,

Rochet,

Tracey

et al. 2023

Bioconjugate Chem.

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Bispecific antibodies as T cell engagers designed to display binding capabilities to both tumor-associated antigens and antigens on T cells are considered promising agents in the fight against cancer. Even though chemical strategies to develop such constructs have emerged, a method that readily converts a therapeutically applied antibody into a bispecific construct by a fully non-genetic process is not yet available. Herein, we report the application of a biogenic, tyrosine-based click reaction utilizing chemoenzymatic modifications of native IgG1 antibodies to generate a synthetic bispecific antibody construct that exhibits tumor-killing capability at picomolar concentrations. Control experiments revealed that a covalent linkage of the different components is required for the observed biological activities. In view of the highly potent nature of the constructs and the modular approach that relies on convenient synthetic methods utilizing therapeutically approved biomolecules, our method expedites the production of potent bispecific antibody constructs with tunable cell killing efficacy with significant impact on therapeutic properties.

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Antibody–drug conjugates in cancer therapy: mechanisms and clinical studies

He,

Zeng,

Wang

et al. 2024

MedComm

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Antibody–drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies’ targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.

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The eIg technology to generate Ig-like bispecific antibodies

Cited by 6 publications

References 38 publications

eIg-based bispecific T-cell engagers targeting EGFR: Format matters

eIg-based bispecific T-cell engagers targeting EGFR: Format matters

Rapid Access to Potent Bispecific T Cell Engagers Using Biogenic Tyrosine Click Chemistry

Antibody–drug conjugates in cancer therapy: mechanisms and clinical studies

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