A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM)

Wege, Anja K.; Kirchhammer, Nicole; Kazandjian, Linda Veronique; Prassl, Sandra; Brandt, Michael R.; Piendl, Gerhard; Ortmann, O.; Fischer, Stephan; Brockhoff, Gero

doi:10.1186/s12967-020-02484-9

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…The assay can be used to evaluate the effects of antibody glycosylation on their ADCC activity in early drug development (Chung et al, 2014). In addition, it has the performance characteristics (precision, accuracy, and linearity) required for a potency assay for lot release and stability study (Parekh et al, 2012;Prior et al, 2017;Wege et al, 2020).…”

Section: Adcc Reporter Bioassay Using Engineered Adcc Bioassay Effect...mentioning

confidence: 99%

Determining ADCC Activity of Antibody‐Based Therapeutic Molecules using Two Bioluminescent Reporter‐Based Bioassays

et al. 2021

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Antibody Fc effector function is one of the main mechanisms of action (MoA) for therapeutic monoclonal antibodies. Measurement of antibody‐dependent cellular cytotoxicity (ADCC) is critical for understanding the Fc effector function during monoclonal antibody development. This article covers two cell‐based ADCC bioassays which can quantitatively measure the antibody potency in ADCC. Basic Protocol 1 describes the ADCC reporter bioassay using engineered ADCC effector cells which measures the FcγRIIIa‐mediated luciferase reporter activation upon the binding of antibody‐coated target cells. Basic Protocol 2 describes the PBMC ADCC bioassay using primary peripheral blood mononuclear cells (PBMC) as effector cells and engineered HiBiT target cells in an assay that measures the release of HiBiT from target cells upon antibody‐mediated target lysis. Optimization of several key assay parameters including cell handling, effector:target (E:T) ratios, assay plate, and plate reader requirement, and how these parameters impact assay performance are discussed. © 2021 Promega Corporation. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: ADCC reporter bioassay using engineered ADCC bioassay effector cells Basic Protocol 2: PBMC ADCC bioassay using primary PBMC and engineered HiBiT target cells

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Section: Adcc Reporter Bioassay Using Engineered Adcc Bioassay Effect...mentioning

confidence: 99%

Determining ADCC Activity of Antibody‐Based Therapeutic Molecules using Two Bioluminescent Reporter‐Based Bioassays

et al. 2021

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“…Here, we quantitatively analyzed the expression and the secretion of different checkpoint molecules in humanized tumor mice (HTM) models specific for HER2 + , hormone receptor positive, and TNBC. HTM develop a human immune system and human tumor growth [16], and they have already enabled the identification of novel therapeutic antibodies [17], prognostic and potentially predictive markers [18], and probably side effects during immunomodulatory cytokine stimulation [19]. The expression of different checkpoint molecules has already been described in patient-derived (humanized) tumor mice (PDX) mice using multi-color-flow cytometry [20].…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion

Bruß¹,

Kellner²,

Albert³

et al. 2023

Cancers

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Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the soluble forms thereof (e.g., PD-1, TIM-3, LAG-3, PD-L1, PD-L2 and others) in humanized tumor mice (HTM) simultaneously harboring cell line-derived (JIMT-1, MDA-MB-231, MCF-7) or patient-derived breast cancer and a functional human immune system. We identified tumor-infiltrating T cells with a triple-positive PD-1, LAG-3 and TIM-3 phenotype. While PD-1 expression was increased in both the CD4 and CD8 T cells, TIM-3 was found to be upregulated particularly in the cytotoxic T cells in the MDA-MB-231-based HTM model. High levels of soluble TIM-3 and galectin-9 (a TIM-3 ligand) were detected in the serum. Surprisingly, soluble PD-L2, but only low levels of sPD-L1, were found in mice harboring PD-L1-positive tumors. Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2+ and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape.

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“…HER2 plays an important role in regulation of complex intracellular pathways in response to biochemical stimuli such as epidermal growth factor (EGF) and transforming growth factor (TGF- β ) for critical decision of cell fate within cancer cells [ 3 – 6 ]. Trastuzumab (TZB), the first humanized mono-clone antibody, selectively targets HER2 on cancer cells and provides successful survival benefits in HER2 + metastatic breast cancers [ 7 , 8 ]. It has been shown that TZB initiates the apoptosis signaling in cancer cells by suppressing the anti-apoptotic family, Bcl-2 members [ 9 ], which subsequently induces up-regulation of BAX, apoptosis inducer.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies

Lee

Kim

2021

PLoS Comput Biol

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Acute administration of trastuzumab (TZB) may induce various forms of cognitive impairment. These cancer-related cognitive changes (CRCC) are regulated by an adverse biological process involving cancer stem cells (CSCs) and IL-6. Recent studies have reported that atorvastatin (ATV) may change the dynamic of cognitive impairment in a combination (TZB+ATV) therapy. In this study, we investigate the mutual interactions between cancer stem cells and the tumor cells that facilitate cognitive impairment during long term TZB therapy by developing a mathematical model that involves IL-6 and the key apoptotic regulation. These include the densities of tumor cells and CSCs, and the concentrations of intracellular signaling molecules (NFκB, Bcl-2, BAX). We apply the mathematical model to a single or combination (ATV+TZB) therapy used in the experiments to demonstrate that the CSCs can enhance CRCC by secreting IL-6 and ATV may interfere the whole regulation. We show that the model can both reproduce the major experimental observation on onset and prevention of CRCC, and suggest several important predictions to guide future experiments with the goal of the development of new anti-tumor and anti-CRCC strategies. Moreover, using this model, we investigate the fundamental mechanism of onset of cognitive impairment in TZB-treated patients and the impact of alternating therapies on the anti-tumor efficacy and intracellular response to different treatment schedules.

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A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM)

Cited by 5 publications

References 38 publications

Determining ADCC Activity of Antibody‐Based Therapeutic Molecules using Two Bioluminescent Reporter‐Based Bioassays

Determining ADCC Activity of Antibody‐Based Therapeutic Molecules using Two Bioluminescent Reporter‐Based Bioassays

Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion

Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies

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