Bispecific Antibody to ErbB2 Overcomes Trastuzumab Resistance through Comprehensive Blockade of ErbB2 Heterodimerization

Li, Bohua; Meng, Yanchun; Zheng, Lei; Zhang, Xunming; Tong, Qing; Tan, Wenlong; Hu, Shi; Li, Hui; Chen, Yang; Song, Jinjing; Zhang, Ge; Lei, Z. H.; Zhang, David; Hou, Sheng; Qian, Weizhu; Guo, Yajun

doi:10.1158/0008-5472.can-13-0657

Cited by 51 publications

(53 citation statements)

References 44 publications

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“…A variety of compensatory mechanisms may underlie acquired resistance to EGFR-or HER2-targeted agents, including switching dimerization partners (7), upregulation of ligands for HER3 or EGFR (24,26,41), or overexpression of particular receptors, especially HER3, which are identified as an evolved response to current anti-HER/ErbB agents needing early and direct blockade (42). In a previous study, a bispecific antibody generated from trastuzumab and pertuzumab also supported this hypothesis, overcoming acquired resistance to trastuzumab by effectively blocking HER2/HER3 heterodimerization (19). Moreover, receptor crosstalk of MET plays a critical role in the development of resistance to EGFR family inhibitors.…”

Section: Discussionmentioning

confidence: 91%

“…Indeed, in 2009, catumaxomab (Removab, Neovii Biotech) was approved as the first bispecific antibody drug for the treatment of malignant ascites (18). For anti-HER-targeted therapy, previous studies have shown that bispecific antibodies engineered from anti-EGFR or -HER2 may give promising results (19,20). Moreover, two-in-one antibodies, which created a surface that specifically binds two target antigens with high affinity using a single antibody binding site (21,22), have aroused abundant interest in the field.…”

Section: Introductionmentioning

confidence: 99%

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Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

et al. 2015

Cancer Research

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The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody. Cancer Res; 75(1); 159-70. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

et al. 2015

Cancer Research

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“…The in vitro and in vivo tumor proliferation inhibition studies demonstrated that MBS301’s efficacy was obviously superior to that of T-mab or P-mab used alone. We found that the in vitro growth of trastuzumab-resistant HCC1419 cells was not affected by the addition of T-mab or P-mab alone; 20 however, growth was inhibited by the treatment with MBS301 or the combination of T-mab and P-mab. In MDA-MB-175VII, a HER2 low expression (HER2 oncoprotein 1+) breast cancer cell line, 21 the inhibition rate by MBS301 was 82.8%, slightly higher than others.…”

Section: Discussionmentioning

confidence: 83%

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Huang

Liu

et al. 2018

mAbs

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MBS301, a glyco-engineered bispecific anti-human epidermal growth factor receptor 2 (HER2) antibody with a typical IgG1 monoclonal antibody structure, was developed through dual-cell expression and in vitro assembling process. MBS301 consists of two half antibodies engineered from trastuzumab and pertuzumab, respectively. Integrity and purity profiles of MB301 indicated that the heterodimerization of the two half antibodies was successful. The high and similar melting temperatures (Tm1,72.0°C and Tm2, 84.8°C) of MBS301 compared with those of its parental monoclonal antibodies trastuzumab and pertuzumab (in-house made T-mab and P-mab, respectively) revealed its structural compactness. With computer-modeling experiments and Biacore binding and competition kinetics studies, the binding stoichiometry between MBS301 and HER2-ECD was determined to be 1:1 and the two arms of MBS301 were shown to bind to domains II and IV of HER2-ECD antigen simultaneously. MBS301 displayed synergistic bioactivities as the combination of T-mab and P-mab in vitro in multiple cancer cell lines and in vivo in xenograft mouse model studies, and showed more effective activity than T-mab or P-mab used individually. Moreover, fucose-knockout dramatically increased MBS301’s binding affinity to low affinity FcγRIIIa allotype 158F (KD = 2.35 × 10−7M) to near the high affinity level of allotype V158 (KD = 1.17 × 10−7M). This resulted in far more effective ADCC activity of MBS301 than the combination of T-mab and P-mab in killing HER2-positive cancer cells. Hence, a novel fully afucosylated anti-HER2 bispecific antibody with improved antitumor activities was generated and shown to have the potential to be used for treating HER2-positive but trastuzumab-resistant solid tumors.

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“…Because it was first identified as a family of possible oncogenes, the EGFR receptor family has been an attractive therapeutic target as these receptors are frequently upregulated in many cancers. Development of new HER2-targeted therapies, including antibody-delivered cytotoxins and chimeric antigenbased immune cell repertoires, has shown promise in both research and clinical settings (14,15,(30)(31)(32). However, while clinical targeting of EGFR function through small molecule inhibitors or antibody inhibition of EGFR signaling has shown some promise, successful long-term outcomes are rare because of compensatory kinase domain mutations or alternate receptor signaling and problems with toxicity to normal tissue (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

Simon

Antignani

Sarnovsky

et al. 2016

JNCI J Natl Cancer Inst

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Background: Triple-negative breast cancers (TNBCs) are typically more aggressive and result in poorer outcomes than other breast cancers because treatment options are limited due to lack of hormone receptors or amplified human epidermal growth factor receptor 2 (HER2). Many TNBCs overexpress the epidermal growth factor receptor (EGFR) or manifest amplification of the EGFR gene, supporting EGFR as a therapeutic target. While EGFR-directed small molecule inhibitors have shown limited effectiveness in clinical settings, use of EGFR as a mechanism of delivering enzymatic cytotoxins to TNBC has not been demonstrated. Methods: Using the single-chain variable fragment (scFv) of the 806 antibody that binds only cells with overexpressed, misfolded, or mutant variants of the EGFR, a recombinant immunotoxin was engineered through gene fusion with Pseudomonas aeruginosa Exotoxin A (806-PE38). The potency of 806-PE38 on reducing TNBC cell growth in vitro and in xenograft models (n 6) was examined for six TNBC cell lines. All statistical tests were two-sided. Results: 806-PE38 statistically significantly reduced the viability of all tested TNBC lines, with IC 50 values below 10 ng/mL for three of six cell lines, while not affecting cells with wild-type EGFR (IC 50 >300 ng/mL). Systemic treatments with 806-PE38 vs vehicle resulted in statistically significantly reduced tumor burdens (806-PE38 mean ¼ 128 mm 3 [SD ¼ 46 mm 3 ] vs vehicle mean ¼ 749 mm 3 [SD ¼ 395 mm 3 ], P ¼ .001) and increased median survival (806-PE38 median ¼ 82 days vs vehicle median ¼ 50 days, P ¼ .01) in a MDA-MB-468 TNBC mouse xenograft. Deletion of the catalytic residue eliminated both cytotoxic activity in vitro and the reduction in tumor burden and survival (P ¼ .52). Conclusions: These data support the further development of the 806-PE38 immunotoxin as a therapeutic agent for the treatment of patients with EGFR-positive TNBC. Follow-up experiments with combination therapies will be attempted to achieve full remissions.

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Bispecific Antibody to ErbB2 Overcomes Trastuzumab Resistance through Comprehensive Blockade of ErbB2 Heterodimerization

Cited by 51 publications

References 44 publications

Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

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