Immune Effector Functions of Human IgG2 Antibodies against EGFR

Rösner, Thies; Kahle, Steffen; Montenegro, Francesca; Matlung, Hanke L.; Jansen, J.H. Marco; Evers, Mitchell; Beurskens, Frank J.; Leusen, Jeanette H.W.; Berg, Timo K. van den; Valerius, Thomas

doi:10.1158/1535-7163.mct-18-0341

Cited by 26 publications

(26 citation statements)

References 68 publications

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“…Unlike IgG2 type antibodies, the specific response functions of IgG1 mainly include ADCC and CDC ( 41 ). Panitumumab is a human IgG2 isotype, which is often considered to have limited immune effector functions ( 42 ). Most of these antibodies are humanized or chimeric antibodies with reduced immunogenicity and antigen affinity.…”

Section: Anti-tumor Mechanisms and Effects Of Egfr Mabsmentioning

confidence: 99%

The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells

et al. 2020

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Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor involved in homeostatic regulation of normal cells and carcinogenesis of epithelial malignancies. With rapid development of the precision medicine era, a series of new therapies targeting EGFR are underway. Four EGFR monoclonal antibody drugs (cetuximab, panitumumab, nimotuzumab, and necitumumab) are already on the market, and a dozen other EGFR monoclonal antibodies are in clinical trials. Here, we comprehensively review the newly identified biological properties and anti-tumor mechanisms of EGFR monoclonal antibodies. We summarize recently completed and ongoing clinical trials of the classic and new EGFR monoclonal antibodies. More importantly, according to our new standard, we re-classify the complex evolving tumor cell resistance mechanisms, including those involving exosomes, non-coding RNA and the tumor microenvironment, against EGFR monoclonal antibodies. Finally, we analyzed the limitations of EGFR monoclonal antibody therapy, and discussed the current strategies overcoming EGFR related drug resistance. This review will help us better understand the latest battles between EGFR monoclonal antibodies and resistant tumor cells, and the future directions to develop anti-tumor EGFR monoclonal antibodies with durable effects.

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Section: Anti-tumor Mechanisms and Effects Of Egfr Mabsmentioning

confidence: 99%

The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells

et al. 2020

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“…54 Recently, it has been demonstrated that EGFR-specific IgG2 can induce CDC and ADCC. 55 This underlines the necessity of using Fc mutations to reduce FcγR interaction also for this supposedly less Fccompetent IgG subclass. In this study, IgG2 displayed a clearly inferior cellular clustering capacity, which is likely caused by reduced flexibility.…”

Section: Discussionmentioning

confidence: 97%

Influence of the bispecific antibody IgG subclass on T cell redirection

Kapelski

Cleiren

Attar

et al. 2019

mAbs

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T cell redirection mediated by bispecific antibodies (BsAbs) is a promising cancer therapy. Dual antigen binding is necessary for potent T cell redirection and is influenced by the structural characteristics of a BsAb, which are dependent on its IgG subclass. In this study, model BsAbs targeting CD19xCD3 were generated in variants of IgG1, IgG2, and IgG4 carrying Fc mutations that reduce FcγR interaction, and two chimeric IgG subclasses termed IgG1:2 and IgG4:2, in which the IgG1-or IgG4-F(ab) 2 are grafted on an IgG2 Fc. Molecules containing an IgG2 or IgG4-F(ab) 2 domain were confirmed to be the most structurally compact molecules. All BsAbs were shown to bind both of their target proteins (and corresponding cells) equally well. However, CD19xCD3 IgG2 did not bind both antigens simultaneously as measured by the absence of cellular clustering of T cells with target cells. This translated to a reduced potency of IgG2 BsAbs in T-cell redirection assays. The activity of IgG2 BsAbs was fully restored in the chimeric subclasses IgG4:2 and IgG1:2. This confirmed the major contribution of the F(ab) 2 region to the BsAb's functional activity and demonstrated that function of BsAbs can be modulated by engineering molecules combining different Fc and F(ab) 2 domains.

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“…M1 macrophages can inhibit tumor development by releasing tumor-suppressing molecules, including TNF-a (45). M1 macrophages also induce tumor cell apoptosis through phagocytosis (46), ADCC (47), and release of TNF and nitric oxide (NO) (48). Studies have shown that M1-type macrophages can promote tumor immunity by recruiting cytotoxic T cells (49).…”

Section: Antitumor Effects Of Macrophagesmentioning

confidence: 99%

Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment

Zhang

Zhao

et al. 2021

Front. Immunol.

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The tumor immune microenvironment plays a vital role in the metastasis of colorectal cancer. As one of the most important immune cells, macrophages act as phagocytes, patrol the surroundings of tissues, and remove invading pathogens and cell debris to maintain tissue homeostasis. Significantly, macrophages have a characteristic of high plasticity and can be classified into different subtypes according to the different functions, which can undergo reciprocal phenotypic switching induced by different types of molecules and signaling pathways. Macrophages regulate the development and metastatic potential of colorectal cancer by changing the tumor immune microenvironment. In tumor tissues, the tumor-associated macrophages usually play a tumor-promoting role in the tumor immune microenvironment, and they are also associated with poor prognosis. This paper reviews the mechanisms and stimulating factors of macrophages in the process of colorectal cancer metastasis and intends to indicate that targeting macrophages may be a promising strategy in colorectal cancer treatment.

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Immune Effector Functions of Human IgG2 Antibodies against EGFR

Cited by 26 publications

References 68 publications

The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells

The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells

Influence of the bispecific antibody IgG subclass on T cell redirection

Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment

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