A novel antibody-drug conjugate, HcHAb18-DM1, has potent anti-tumor activity against human non-small cell lung cancer

Huhe, Muren; Lou, Jiaxin; Zhu, Yumeng; Zhao, Yu; Shi, Ying; Wang, Bo; Sun, Xiuxuan; Zhang, Xiaoqin; Zhang, Yang; Chen, Zhi‐Nan

doi:10.1016/j.bbrc.2019.04.046

Cited by 9 publications

(6 citation statements)

References 18 publications

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“…In recent years, targeted therapy has emerged as a promising means to treat NSCLC 21 . Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat NSCLC to inhibit EGFR pathway 22 .…”

Section: Resultsmentioning

confidence: 99%

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

Liu

et al. 2021

J Cellular Molecular Medi

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Lung adenocarcinoma (LUAD) is one of the important components of non‐small‐cell lung cancer (NSCLC) and leads to many deaths every year. During the initiation and progression of the LUAD, the Hh‐GLI2 pathway plays critical roles. Several components of this pathway have been shown to be amplified or overexpressed in LUAD, providing this pathway as an attractive target for therapeutics. However, a gap in our understanding of the Hh‐GLI2 pathway is the identity of transcriptional targets of GLI2 that drive LUAD tumorigenesis. Here, we show that the oncogene CRKL is a direct target of GLI2. GLI2 turns on CRKL transcription through binding its second intron. Furthermore, CRKL is an essential mediator for GLI2‐driven proliferation and migration of LUAD cells. Depletion of CRKL blunts Hh‐GLI2 pathway‐mediated cell proliferation and invasion. Lastly, we find that CRKL knockout cells are more sensitive to EGFR‐TKI and chemotherapeutics. Taken together, our work here identifies a specific target for Hh‐related malignancies and provides CRKL as a promising therapeutic target for LUAD.

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Section: Resultsmentioning

confidence: 99%

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

Liu

et al. 2021

J Cellular Molecular Medi

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“…than HcHAb18 alone and no activity with DM1 alone either, and there was equal weight gain in both treatment and control animal study groups (112).…”

Section: Enhancing Efficacy and Safety With Cd147-targeted Therapies ...mentioning

confidence: 88%

“…ADC designed using maytansinoid-based cytotoxic agent emtansine (DM1) linked by the non-cleavable chemical linker SMCC to CD147 antibody HcHAb18 (HcHAb18-DM1) in NSCLC cells both in vitro and in vivo, was shown to be specifically internalized by CD147 + tumor cells, successfully delivering the payload (DM1) and releasing the active metabolites through lysosomal cleavage, leading to cell cycle arrest at G2/M (112,113). This activity is dependent on CD147 expression and high proliferative cells, features significantly in malignant cells than in normal tissue cells; HcHAb18-DM1 was six times more effective…”

Section: Enhancing Efficacy and Safety With Cd147-targeted Therapies ...mentioning

confidence: 99%

CD147: an integral and potential molecule to abrogate hallmarks of cancer

Nyalali,

Leonard,

et al. 2023

Front. Oncol.

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CD147 also known as EMMPRIN, basigin, and HAb18G, is a single-chain type I transmembrane protein shown to be overexpressed in aggressive human cancers of CNS, head and neck, breasts, lungs, gastrointestinal, genitourinary, skin, hematological, and musculoskeletal. In these malignancies, the molecule is integral to the diverse but complimentary hallmarks of cancer: it is pivotal in cancerous proliferative signaling, growth propagation, cellular survival, replicative immortality, angiogenesis, metabolic reprogramming, immune evasion, invasion, and metastasis. CD147 also has regulatory functions in cancer-enabling characteristics such as DNA damage response (DDR) and immune evasion. These neoplastic functions of CD147 are executed through numerous and sometimes overlapping molecular pathways: it transduces signals from upstream molecules or ligands such as cyclophilin A (CyPA), CD98, and S100A9; activates a repertoire of downstream molecules and pathways including matrix metalloproteinases (MMPs)-2,3,9, hypoxia-inducible factors (HIF)-1/2α, PI3K/Akt/mTOR/HIF-1α, and ATM/ATR/p53; and also functions as an indispensable chaperone or regulator to monocarboxylate, fatty acid, and amino acid transporters. Interestingly, induced loss of functions to CD147 prevents and reverses the acquired hallmarks of cancer in neoplastic diseases. Silencing of Cd147 also alleviates known resistance to chemoradiotherapy exhibited by malignant tumors like carcinomas of the breast, lung, pancreas, liver, gastric, colon, ovary, cervix, prostate, urinary bladder, glioblastoma, and melanoma. Targeting CD147 antigen in chimeric and induced-chimeric antigen T cell or antibody therapies is also shown to be safer and more effective. Moreover, incorporating anti-CD147 monoclonal antibodies in chemoradiotherapy, oncolytic viral therapy, and oncolytic virus-based-gene therapies increases effectiveness and reduces on and off-target toxicity. This study advocates the expedition and expansion by further exploiting the evidence acquired from the experimental studies that modulate CD147 functions in hallmarks of cancer and cancer-enabling features and strive to translate them into clinical practice to alleviate the emergency and propagation of cancer, as well as the associated clinical and social consequences.

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“…Different forms of the anti-CD147 HAb18 were developed, a chimeric antibody, cHAb18, containing variable heavy and light chains of the HAb18 antibody and constant regions of human IgG1γ1, modulated cytoskeleton rearrangement via FAK-PI3K-AKT signaling pathway and inhibited invasion and metastasis in hepatocellular carcinoma [74]. HcHAb18 antibody conjugates with a cytotoxic drug that is a maytansinoid derivative (DM1) to promote antitumor activity in lung cancer [107].…”

Section: Cd147 Therapeutic Targeting Strategiesmentioning

confidence: 99%

CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker

Landras

Moura

Jouenne

et al. 2019

Cancers

106

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Microenvironment plays a crucial role in tumor development and progression. Cancer cells modulate the tumor microenvironment, which also contribute to resistance to therapy. Identifying biomarkers involved in tumorigenesis and cancer progression represents a great challenge for cancer diagnosis and therapeutic strategy development. CD147 is a glycoprotein involved in the regulation of the tumor microenvironment and cancer progression by several mechanisms—in particular, by the control of glycolysis and also by its well-known ability to induce proteinases leading to matrix degradation, tumor cell invasion, metastasis and angiogenesis. Accumulating evidence has demonstrated the role of CD147 expression in tumor progression and prognosis, suggesting it as a relevant tumor biomarker for cancer diagnosis and prognosis, as well as validating its potential as a promising therapeutic target in cancers.

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A novel antibody-drug conjugate, HcHAb18-DM1, has potent anti-tumor activity against human non-small cell lung cancer

Cited by 9 publications

References 18 publications

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

CD147: an integral and potential molecule to abrogate hallmarks of cancer

CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker

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