A Novel Anti-HER2 Bispecific Antibody With Potent Tumor Inhibitory Effects In Vitro and In Vivo

Mohammadi, Mehdi; Jeddi‐Tehrani, Mahmood; Golsaz‐Shirazi, Forough; Arjmand, Mohammad; Bahadori, Tannaz; Judaki, Mohammad Ali; Shiravi, Fariba; Zare, Hengameh Ahmadi; Haghighat, Farzaneh Notash; Mobini, Maryam; Amiri, Mohammad Mehdi; Shokri, Fazel

doi:10.3389/fimmu.2020.600883

Cited by 15 publications

(21 citation statements)

References 57 publications

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“…The wild type of anti-HER2 BsAb, WBiHT, was developed and characterized in our previous work 10. Briefly, WBiHT was developed using variable domains of trastuzumab and hersintuzumab in DVD-Ig format, in which, the variable domains of hersintuzumab and trastuzumab were in the outer and inner layers, respectively, in both heavy and light chains of the DVD-Ig.…”

Section: Resultsmentioning

confidence: 99%

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A Novel Fc-Engineered Anti-HER2 Bispecific Antibody With Enhanced Antitumor Activity

Mohammadi

Jeddi‐Tehrani

Golsaz‐Shirazi

et al. 2023

Journal of Immunotherapy

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Human epidermal growth factor receptor 2 (HER2) overexpression has been demonstrated in a variety of cancers. Targeted therapy with anti-HER2 monoclonal antibodies (mAbs) has been approved as a therapeutic modality. Despite the efficacy of mAbs in tumor treatment, many patients do not benefit from this therapeutic platform. Fragment crystallizable (Fc) engineering is a common approach to improve the efficacy of therapeutic mAbs. Five Fc-engineered mAbs have so far been approved by FDA. We have recently developed an anti-HER2 bispecific mAb, BiHT, constructed from variable domains of trastuzumab, and our novel humanized anti-HER2 mAb, hersintuzumab. BiHT displayed promising antitumor activity as potently as the combination of the parental mAbs. Here, we aimed to modify the Fc of BiHT to improve its therapeutic efficacy. The Fc-engineered BiHT (MBiHT) bound to recombinant HER2 and its subdomains with an affinity similar to BiHT. It also recognized native HER2 on different cell lines, inhibited their proliferation, downregulated HER2 expression, and suppressed downstream signaling pathways similar to BiHT. Compared with BiHT, MBiHT displayed enhanced antibody-dependent cellular cytotoxicity activity against various tumor cell lines. It also inhibited the growth of ovarian xenograft tumors in nude mice more potently than BiHT. Our findings suggest that MBiHT could be a potent therapeutic candidate for the treatment of HER2-overexpressing cancer types.

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Section: Resultsmentioning

confidence: 99%

“…In our previous study, we developed and characterized a potent anti-HER2 BsAb (BiHT) using variable domains of trastuzumab and hersintuzumab in dual variable domain immunoglobulin (DVD-Ig) platform, designated trasintuzumab 10. The antitumor activity of trasintuzumab was as efficient as the combination of the parental mAbs both in vitro and in vivo 10…”

mentioning

confidence: 99%

A Novel Fc-Engineered Anti-HER2 Bispecific Antibody With Enhanced Antitumor Activity

Mohammadi

Jeddi‐Tehrani

Golsaz‐Shirazi

et al. 2023

Journal of Immunotherapy

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“…97,272 Although the HER-2-targeting TKI lapatinib has achieved a good effect in BC, it has not been effective against GC. 273 Bispecific antibodies with dual-targeting functions have also shown encouraging results, 274 but further research is still needed. In short, these HER-2-targeted therapies may obviate the resistance to first-line drugs, reduce metastasis or prevent recurrence, and may also be used in combination with chemoradiotherapy and monoclonal antibodies to further improve first-line therapy in patients with GC.…”

Section: Discussionmentioning

confidence: 99%

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

Sun¹,

Li²,

Chen³

et al. 2022

JIR

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Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.

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“…MM-111 was discontinued in a trial of patients with advanced HER2-positive GEA due to worse PFS and OS, and all further clinical trials have now been withdrawn [63]. In addition, several drugs are currently being tested in preclinical studies [64] [65] (Tables 1, 2; Fig. 1B).…”

Section: Bispecific Antibodies (Bsabs)mentioning

confidence: 99%

HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives

Zhang

et al. 2022

Biomark Res

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Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein–Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.

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A Novel Anti-HER2 Bispecific Antibody With Potent Tumor Inhibitory Effects In Vitro and In Vivo

Cited by 15 publications

References 57 publications

A Novel Fc-Engineered Anti-HER2 Bispecific Antibody With Enhanced Antitumor Activity

A Novel Fc-Engineered Anti-HER2 Bispecific Antibody With Enhanced Antitumor Activity

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives

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