HLX22, an anti-HER-2 monoclonal antibody, in patients with advanced solid tumors overexpressing human epidermal growth factor receptor 2: an open-label, dose-escalation, phase 1 trial

Zhu, Xiaodong; Ding, Yanhua; Wang, Qian; Yang, Guiyu; Zhou, Liang; Wang, Qingyu

doi:10.1007/s10637-023-01338-7

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…In clinical development, HLX22 was well tolerated at 3, 10, and 25 mg/kg once every 3 weeks in the phase I dose-escalation study aiming to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of HLX22 in patients with advanced solid tumors who had failed or were intolerant to standard therapies. No dose-limiting toxicity occurred during the study, and no serious adverse events occurred during the treatment period [ 14 ]. And further phase II trials to evaluate the clinical efficacy and safety of HLX22 in combination with HLX02 and chemotherapy in the HER2-positive locally advanced or metastatic gastric cancer as the first-line therapy are warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Both in vitro and in vivo studies demonstrated that HLX22 in combination with HLX02 exhibited synergistic tumor growth inhibitory effect in gastric cancer cell lines, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, suggesting that gastric cancer patients may benefit from the HLX22 and HLX02 combination treatment. In addition, the phase I trial showed that HLX22 was well tolerated with favorable pharmacokinetic properties in patients with advanced HER2 overexpressing solid tumors, and no dose-limiting toxicity occurred during the study [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

Wei,

Zhang,

Yang

et al. 2024

J Transl Med

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Background Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer. Methods We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Results HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-β-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo. Conclusions These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

Wei,

Zhang,

Yang

et al. 2024

J Transl Med

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“…HLX22 is a novel monoclonal antibody against domain IV of HER2. The targeted epitope is different compared to trastuzumab, enabling the simultaneous binding of both antibodies [83]. In a phase I study, HLX22 was tolerable and showed moderate anti-tumor activity after the failure of standard therapy lines in HER2-positive advanced solid cancer [83].…”

Section: Monoclonal and Bispecific Antibodiesmentioning

confidence: 99%

HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments

Scheck,

Hofheinz,

Lorenzen

2024

Cancers

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Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.

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Targeting HER2 in solid tumors: Unveiling the structure and novel epitopes

Liu,

Song,

Cheng

et al. 2024

Cancer Treatment Reviews

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HLX22, an anti-HER-2 monoclonal antibody, in patients with advanced solid tumors overexpressing human epidermal growth factor receptor 2: an open-label, dose-escalation, phase 1 trial

Cited by 4 publications

References 26 publications

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments

Targeting HER2 in solid tumors: Unveiling the structure and novel epitopes

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