更新于：2024-11-01

CD89 x EGFR

更新于：2024-11-01

基本信息

关联

项与 CD89 x EGFR 相关的药物

MDX-214

靶点

CD89 x EGFR

作用机制

CD89抑制剂 [+1]

在研机构-

原研机构

Medarex, Inc.

在研适应症-

非在研适应症

肿瘤

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CD89 x EGFR 相关的临床结果

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100 项与 CD89 x EGFR 相关的转化医学

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0 项与 CD89 x EGFR 相关的专利（医药）

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项与 CD89 x EGFR 相关的文献（医药）

2024-07-15·The Journal of Immunology

Engineering Dimeric EGFR-directed IgA Antibodies Reveals a Central Role of CD147 during Neutrophil-mediated Tumor Cell Killing of Head and Neck Squamous Cancer Cells

Article

作者: Zwick, Anabel ; Braun, Felix Leon ; Linder, Manuel ; Linxweiler, Maximilian ; Weber, Lennert Jochen ; Lohse, Stefan

AbstractHuman IgA Abs engage neutrophils for cancer immunotherapy more effectively than IgG Abs. Previous studies demonstrated that engineering approaches improved biochemical and functional properties. In this study, we report a novel, to our knowledge, IgA2 Ab against the epidermal growth factor receptor generated by protein engineering and polymerization. The resulting molecule demonstrated a covalent linkage of L and H chains and an effective polymerization by the joining chain. The engineered dimer outperformed its monomeric variant in functional experiments on Fab-mediated modes of action and binding to the Fc receptor. The capacity to engage neutrophils for Ab-dependent cell-mediated cytotoxicity (ADCC) of adherent growing target cancer cells was cell line dependent. Although the engineered dimer displayed a long-term efficacy against the vulva carcinoma cell line A431, there was a notable in-efficacy against human papillomavirus (HPV)− head and neck squamous cell carcinoma (HNSCC) cell lines. However, the highly engineered IgA Abs triggered a neutrophil-mediated cytotoxicity against HPV+ HNSCC cell lines. Short-term ADCC efficacy correlated with the target cells’ epidermal growth factor receptor expression and the ability of cancer cell–conditioned media to enhance the CD147 surface level on neutrophils. Notably, the HPV+ HNSCC cell lines demonstrated a significant increment in releasing soluble CD147 and a reduced induction of membranous CD147 on neutrophils compared with HPV− cells. Although membranous CD147 on neutrophils may impair proper IgA–Fc receptor binding, soluble CD147 enhanced the IgA–neutrophil-mediated ADCC in a dose-dependent manner. Thus, engineering IgA Abs and impedance-based ADCC assays provided valuable information regarding the target–effector cell interaction and identified CD147 as a putative critical parameter for neutrophil-mediated cytotoxicity.

2024-04-01·Cancer Research

Human Tumor–Associated Macrophages and Neutrophils Regulate Antitumor Antibody Efficacy through Lethal and Sublethal Trogocytosis

Article

作者: Guo, Emily ; Albelda, Steven M ; Bruns, Kyle ; Singhal, Sunil ; Bermudez, Andres ; Moon, Edmund K ; Rao, Abhishek S ; Honig-Frand, Adam ; Valerius, Thomas ; Stadanlick, Jason ; Eruslanov, Evgeniy B ; Georgiou, George ; Krouse, Ryan ; Arambepola, Sachinthani ; Sullivan, Neil T

AbstractThe clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)–expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells “nibbled off” tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy.Significance:The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.

2011-03-01·Proteins: Structure, Function, and Bioinformatics3区 · 生物学

Prediction of protein binding regions

3区 · 生物学

Article

作者: Bernhard Helk ; Naresh Chennamsetty ; Vladimir Voynov ; Bernhardt L. Trout ; Veysel Kayser

AbstractIdentifying protein binding sites provides important clues to the function of a protein. Experimental methods to identify the binding sites such as determining the crystal structures of protein complexes are extremely laborious and expensive. Here, we present a computational technique called spatial aggregation propensity (SAP) based on molecular simulations to predict protein binding sites. We apply this technique to two model proteins, an IgG1 antibody and epidermal growth factor receptor (EGFR) and demonstrate that SAP predicts protein binding regions with very good accuracy. In the case of the IgG1 antibody, SAP accurately predicts binding regions with the Fc‐receptor, protein‐A, and protein‐G. For EGFR, SAP accurately predicts binding regions with EGF, TGFα, and with another EGFR. The resolution of SAP is varied to obtain a detailed picture of these binding sites. We also show that some of these binding sites overlap with protein self‐aggregation prone regions. We demonstrate how SAP analysis can be used to engineer the protein to remove unfavorable aggregation prone regions without disturbing protein binding regions. The SAP technique could be also used to predict the yet unknown binding sites of numerous proteins, thereby providing clues to their function. Proteins 2011. © 2010 Wiley‐Liss, Inc.