A new anti-HER2 antibody that enhances the anti-tumor efficacy of trastuzumab and pertuzumab with a distinct mechanism of action

Zhang, Xuesai; Chen, Jianhe; Weng, Zhibing; Li, Qingrou; Zhao, Le; Yu, Ning; Deng, Lan; Xu, Wei; Yang, Yan; Zhu, Zhenping; Huang, Haomin

doi:10.1016/j.molimm.2020.01.009

Cited by 38 publications

(30 citation statements)

References 43 publications

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“…Advanced epitope mapping of B100 proved a docking to receptor domain III with a binding efficiency that is-when bound to SK-BR-3 cells-higher than that of trastuzumab and pertuzumab. This feature is possibly due to the different epitope binding and is most likely one parameter that contributes to the high treatment efficiency in vitro [29]. A synergistic treatment effect of two anti-HER2 antibodies binding to different epitopes has not only been demonstrated for trastuzumab and pertuzumab in BC but also for other antibody combinations used for the treatment of additional malignancies [30].…”

Section: Discussionmentioning

confidence: 99%

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)

et al. 2020

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Background: Antibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. Trastuzumab that targets the human epidermal growth factor related receptor 2 (HER2) is one of the greatest success stories in this field. For decades, trastuzumab based treatment regimens are significantly improving the prognosis of HER2-positive breast cancer patients both in the metastatic and the (neo-) adjuvant setting. Nevertheless, ≥ 50% of trastuzumab treated patients experience de-novo or acquired resistance. Therefore, an enhanced anti-HER2 targeting with improved treatment efficiency is still aspired. Methods: Here, we determined cellular and molecular mechanisms involved in the treatment of HER2-positive BC cells with a new rabbit derived HER2 specific chimeric monoclonal antibody called "B100″. We evaluated the B100 treatment efficiency of HER2-positive BC cells with different sensitivity to trastuzumab both in vitro and in the presence of a human immune system in humanized tumor mice. Results: B100 not only efficiently blocks cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed equivalent HER2 internalization and recycling capacity, similar Fc receptor signaling, but different HER2 epitope recognition with high binding and treatment efficiency. In trastuzumab resistant SK-BR-3 based humanized tumor mice the B100 treatment eliminated the primary tumor but even more importantly eradicated metastasized tumor cells in lung, liver, brain, and bone marrow. Conclusion: Overall, B100 demonstrated an enhanced anti-tumor activity both in vitro and in an enhanced preclinical HTM in vivo model compared to trastuzumab or pertuzumab. Thus, the use of B100 is a promising option to complement and to enhance established treatment regimens for HER2-positive (breast) cancer and to overcome trastuzumab resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted.

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Section: Discussionmentioning

confidence: 99%

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)

et al. 2020

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“…However, the molecular pathways that are behind these positive results are not completely known and remain an active research area [31]. Among them, three main mechanisms have been proposed to be responsible for Tmab antitumor activity: (I) cell cycle arrest triggered by the inhibition of the MAPK and PI3K signaling cascades; (II) antibody-dependent cellular cytotoxicity (ADCC); and (III) the increased production of anti-angiogenic factors ( Figure 2) [31,32]. The aberrant activation of the PI3K/AKT/mTOR and MEK/ERK pathways has been linked to an induction of cellular proliferation and survival rate, while the in vivo inhibition of such pathways has shown to reduce tumor growth [33].…”

Section: Trastuzumab: More Than a Guide For Nanomedicinesmentioning

confidence: 99%

“…Finally, it has also been demonstrated that, through the mentioned inhibition of the PI3K/AKT/mTOR pathway, Tmab decreases the expression of some proangiogenic factors like the vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) ( Figure 2c) [36]. However, the molecular pathways that are behind these positive results are not completely known and remain an active research area [31]. Among them, three main mechanisms have been proposed to be responsible for Tmab antitumor activity: (I) cell cycle arrest triggered by the inhibition of the MAPK and PI3K signaling cascades; (II) antibody-dependent cellular cytotoxicity (ADCC); and (III) the increased production of anti-angiogenic factors ( Figure 2) [31,32].…”

Section: Trastuzumab: More Than a Guide For Nanomedicinesmentioning

confidence: 99%

“…Physical adsorption NPs (PLGA-TPGS) Docetaxel Breast Liu et al [39] NPs (PEI/PLGA) Paclitaxel Breast Yu et al [40] NPs (PEI/PLGA) Docetaxel Breast Zhang et al [41] NPs (PLGA/MTT) Paclitaxel Breast Sun et al [42] Physical and ionic adsorption and carbodiimide chem. NPs (PLGA) Docetaxel Breast Choi et al [43] Carbodiimide chemistry NPs (PLGA-Phis-PEG) Doxorubicin Breast Zhou et al [47] NPs (TPGS-g-chitosan) Docetaxel Breast Mehata et al [6] NPs (Alginate-piperazine) Paclitaxel Breast, ovarian Nieto et al [31] NPs (PLGA) Cisplatin Ovarian Domínguez-Ríos et al [49] NPs (Chitosan) Gemcitabine Pancreatic Arya et al [50] NPs (Magnetic) -Breast Almaki et al [53] Maleimide alkynes and azides (SPAAC) enabled copper-free click-chemistry and started to be preferred to CuAAC to functionalize DDS to prevent copper bioaccumulation [68]. In the end, the inversedemand Diels-Alder reaction with 1,2,4,5-tetrazine (Tz) and trans-cyclooctene (TCO) (iEDDA) provided an ungraded reaction rate and also began to be applied in biomedicine ( Figure 5) [68,71].…”

Section: Type Of Dds Payload Targeted Type Of Her2+ Cancer Referencementioning

confidence: 99%

“…Manifold mechanisms of primary and treatment-emergent resistance to this antibody have been purposed, including compensatory signaling from either HER family members or other receptor types (such as epidermal growth factor or vascular endothelial growth factor receptors (EGFR and VEGFR)) [92]. For this reason, other antibodies and peptides that are able to block HER2 dimerization with other HER family members or that inhibit simultaneously other receptors have been developed [31]. Among them, two antibodies have been already approved by the FDA to treat HER2+ advanced breast cancer: pertuzumab (Perjeta ® ) and lapatinib (Tykerb TM ) [31,90].…”

Section: Current and Future Situation Of Trastuzumab-based Nanomedicinementioning

confidence: 99%

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Trastuzumab: More than a Guide in HER2-Positive Cancer Nanomedicine

2020

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HER2 overexpression, which occurs in a fifth of diagnosed breast cancers as well as in other types of solid tumors, has been traditionally linked to greater aggressiveness. Nevertheless, the clinical introduction of trastuzumab has helped to improve HER2-positive patients’ outcomes. As a consequence, nanotechnology has taken advantage of the beneficial effects of the administration of this antibody and has employed it to develop HER2-targeting nanomedicines with promising therapeutic activity and limited toxicity. In this review, the molecular pathways that could be responsible for trastuzumab antitumor activity will be briefly summarized. In addition, since the conjugation strategies that are followed to develop targeting nanomedicines are essential to maintaining their efficacy and tolerability, the ones most employed to decorate drug-loaded nanoparticles and liposomes with trastuzumab will be discussed here. Thus, the advantages and disadvantages of performing this trastuzumab conjugation through adsorption or covalent bindings (through carbodiimide, maleimide, and click-chemistry) will be described, and several examples of targeting nanovehicles developed following these strategies will be commented on. Moreover, conjugation methods employed to synthesized trastuzumab-based antibody drug conjugates (ADCs), among which T-DM1 is well known, will be also examined. Finally, although trastuzumab-decorated nanoparticles and liposomes and trastuzumab-based ADCs have proven to have better selectivity and efficacy than loaded drugs, trastuzumab administration is sometimes related to side toxicities and the apparition of resistances. For this reason also, this review focuses at last on the important role that newer antibodies and peptides are acquiring these days in the development of HER2-targeting nanomedicines.

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Inetetamab in combination with rapamycin and chemotherapy for trastuzumab‐treated metastatic human epidermal growth factor receptor 2‐positive breast cancer with abnormal activation of PI3K/Akt/mTOR pathway

Wang

Jiang

et al. 2023

Cancer Reports

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BackgroundHuman epidermal growth factor receptor 2 (HER2) overexpression is an independent prognostic factor of poor prognosis and a predictor of efficacy of anti‐HER2 therapy. A limited number of patients can receive standard second‐line therapy (DS‐8201 or T‐DM1) for metastatic HER2‐positive in some parts of the world, including China, due to many factors, such as cost–benefit ratios.CaseA 51‐year‐old premenopausal woman was diagnosed with HER2‐positive breast cancer. The pathological stage was ypT3N2M0 and stage IIIA. Trastuzumab targeted therapy combined with goserelin depot was started along with letrozole endocrine therapy. After eight courses of treatment, magnetic resonance imaging (MRI) examination revealed new multiple metastases in the liver, and progression disease (PD) was evaluated. Due to abnormal activation of the phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the patient, treatment was changed to the mammalian target of rapamycin (mTOR) inhibitor combined with the anti‐HER‐2 agents inetetamab and paclitaxel, while partial response (PR) was evaluated after 6 cycles of treatment. As the patient was hormone receptor (HR) positive, treatment was changed to the inetetamab + rapamycin + exemestane regimen. The lesion continued to shrink and PR was evaluated for 8 cycles. The original regimen was continued, PR was evaluated after 12 courses of treatment. The abdominal MRI performed showed an increase in the volume of intrahepatic multiple metastatic tumor lesion. Efficacy was used to assess for PD and the progression‐free survival (PFS) was 317 days.ConclusionA phosphatidylinositol‐4, 5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) mutation in trastuzumab‐treated metastatic HER2‐positive breast cancer female had a long PFS by treating with the mammalian target of rapamycin inhibitor in combination with the anti‐HER‐2 agent inetetamab.

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A new anti-HER2 antibody that enhances the anti-tumor efficacy of trastuzumab and pertuzumab with a distinct mechanism of action

Cited by 38 publications

References 43 publications

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)

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)

Trastuzumab: More than a Guide in HER2-Positive Cancer Nanomedicine

Inetetamab in combination with rapamycin and chemotherapy for trastuzumab‐treated metastatic human epidermal growth factor receptor 2‐positive breast cancer with abnormal activation of PI3K/Akt/mTOR pathway

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