T-cell–engaging Therapy for Solid Tumors

Miguel, Maria J. de; Umaña, Pablo; Morais, Ana Luiza Gomes de; Moreno, Víctor; Calvo, Emiliano

doi:10.1158/1078-0432.ccr-20-2448

Cited by 23 publications

(14 citation statements)

References 86 publications

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“…Figure 3a shows the EC 50 estimates with the corresponding %RSE values represented as horizontal error bars. Since the mathematical model effectively captures the pharmacodynamic effects (10) over time of all four scenarios and model-misspecification was excluded, we regard the estimated EC 50 value as a good approximation of the "reference" potency, which can be used as a benchmark for the static and time-independent analysis. The estimated parameters and %RSE values are summarized in supplemental table S1.…”

Section: Accuracy Of Auce-based Methods To Estimate Ec 50mentioning

confidence: 99%

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A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis

Vyver

Eigenmann

Ovacik

et al. 2021

AAPS J

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CD3-bispecific antibodies are a new class of immunotherapeutic drugs against cancer. The pharmacological activity of CD3-bispecifics is typically assessed through in vitro assays of cancer cell lines co-cultured with human peripheral blood mononuclear cells (PBMCs). Assay results depend on experimental conditions such as incubation time and the effector-to-target cell ratio, which can hinder robust quantification of pharmacological activity. In order to overcome these limitations, we developed a new, holistic approach for quantification of the in vitro dose–response relationship. Our experimental design integrates a time-independent analysis of the dose–response across different time points as an alternative to the static, “snap-shot” analysis based on a single time point commonly used in dose–response assays. We show that the potency values derived from static in vitro experiments depend on the incubation time, which leads to inconsistent results across multiple assays and compounds. We compared the potency values from the time-independent analysis with a model-based approach. We find comparably accurate potency estimates from the model-based and time-independent analyses and that the time-independent analysis provides a robust quantification of pharmacological activity. This approach may allow for an improved head-to-head comparison of different compounds and test systems and may prove useful for supporting first-in-human dose selection.

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Section: Accuracy Of Auce-based Methods To Estimate Ec 50mentioning

confidence: 99%

“…More than 200 CD3-bispecifics are currently in development as novel cancer immunotherapies (1,4). CD3-bispecifics activate an anti-cancer immune response by redirecting T-cells to the tumor (5), with promising anticancer activity (6)(7)(8) in both hematological (9) and solid (10) tumors.…”

Section: Introductionmentioning

confidence: 99%

A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis

Vyver

Eigenmann

Ovacik

et al. 2021

AAPS J

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“…Many of bispecific antibodies currently being developed are bispecific T-cell engagers. 22 , 127–131 One of the first IgG-based, and Roche’s first, T-cell bispecific antibody (TCB) to enter clinical trials was the heterodimeric and trivalent CEA/CD3ε 2 + 1 TCB cibisatamab (RG7802). It is a heterodimeric CEA/CD3ε bispecific antibody in the 1 + 1 CrossMab CH 1 −CL format to which a single additional Fab targeting CEA is fused to the N-terminus of the knob-containing heavy chain ( Figure 2d ).…”

Section: Applications In Cancer Immunotherapy: Dual Checkpoint Inhibitors T and Innate Cell Engaging Bispecifics And Tumor-targeted Co-stmentioning

confidence: 99%

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

Surowka

Schaefer

Klein

2021

mAbs

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Bispecific antibodies have recently attracted intense interest. CrossMab technology was described in 2011 as novel approach enabling correct antibody light-chain association with their respective heavy chain in bispecific antibodies, together with methods enabling correct heavy-chain association using existing pairs of antibodies. Since the original description, CrossMab technology has evolved in the past decade into one of the most mature, versatile, and broadly applied technologies in the field, and nearly 20 bispecific antibodies based on CrossMab technology developed by Roche and others have entered clinical trials. The most advanced of these are the Ang-2/VEGF bispecific antibody faricimab, currently undergoing regulatory review, and the CD20/CD3 T cell bispecific antibody glofitamab, currently in pivotal Phase 3 trials. In this review, we introduce the principles of CrossMab technology, including its application for the generation of bi-/multispecific antibodies with different geometries and mechanisms of action, and provide an overview of CrossMab-based therapeutics in clinical trials.

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“…Bispecific antibodies binding a surface tumor antigen and CD3ε induce tumor redirected T cell killing 1 . A bispecific T-cell engager BiTE redirecting killing to CD19 on B cells termed blinatumomab 2 has been approved for the treatment of acute lymphoblastic leukemia (ALL).…”

Section: Introductionmentioning

confidence: 99%

“…The concept of T-cell redirection is being pursued for other malignant hematological diseases such as multiple myeloma targeting BCMA 3 , 4 . In essence, the agents bind to the tumor cells and only when attached to a plasma membrane, the monovalent anti CD3ε component triggers T-cell activation through the T-cell receptor leading to tumor cell killing 1 .…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers

Teijeira¹,

Miguéliz²,

Garasa³

et al. 2022

Theranostics

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Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.

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T-cell–engaging Therapy for Solid Tumors

Cited by 23 publications

References 86 publications

A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis

A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers

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